Clinical trial NCT06172348
Conditions: Healthy Volunteers
Keywords: Pharmacokinetics Adults
Sponsor: Pfizer
Start date: 2024-02-01; Completion date: 2024-03-28
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare if three forms of study medicine (called ritlecitinib) get processed differently in healthy adults.

This study is seeking healthy participants who have:

* Aged 18 years or older;
* male or female who are healthy as determined by medical assessment;
* BMI of 16-32 kg/m2, and a total body weight \>45 kg (99 lb).

All participants in this study will receive a ritlecitinib oral dose in three different forms (solution, capsule 1 and capsule 2).

The study will take up to 2.5 months, including the screening period and follow-up phone call. Participants will have to stay at the study clinic for at least 13 days. There will be 4 periods in total for this study. On day 1 of each period, participants will take one form of Riltecitinib without food for the first three periods and with food for the last period. Participants will have blood samples taken both before and after taking ritlecitinib. A follow-up phone call will be made at 28 to 35 days after the last study period.

Detailed description:
Ritlecitinib is a covalent and irreversible inhibitor of JAK3 with high selectivity over the other JAK isoforms (JAK1, JAK2, and TYK2). Ritlecitinib also inhibits irreversibly the TEC family kinases with selectivity over the broader human kinome. Treatment with ritlecitinib is expected to inhibit the inflammatory pathways mediated by IL 7, IL 15 and IL 21, all implicated in UC, CD, AA, RA, and vitiligo and therefore under development in these indications. Moreover, due to lack of activity against the other JAK isoforms, ritlecitinib is expected to spare immunoregulatory cytokines such as IL 10, IL 27 and IL 35, which are critical to the maintenance of immunosuppressive functions and immune homeostasis.

This study aims to investigate the pharmacokinetics (PK) and relative bioavailability of 2 new modified release (MR) capsule formulations of ritlecitinib, MR1 (release duration: 6-8 hours) and MR2 (release duration:13 15 hours) as single doses in fasted and fed conditions.

This is a single dose, open-label, randomized, 4-period, 6-sequence crossover study in a single cohort of approximately 12 healthy participants randomized to one of the sequences (containing 1 solution and 2 modified release \[MR1 and MR2\] capsule formulations of ritlecitinib) described in the table below. The first 3 periods are under fasted condition and the fourth period is under fed condition to investigate the effect of food on the PK of MR1 and MR2.

For a given participant, the total study duration from screening to follow-up phone call will be between approximately 8 to 11 weeks.

Screening will occur within 28 days prior to the first dose of the study intervention. Each participant will go through Periods 1 through 4 and dosing in each treatment period will be separated by at least 3 days to minimize any carryover effect.

Venous PK blood samples for PK analysis will be collected pre-dose and post-dose in each period.

Arms: arm 1: Ritlecitinib 100 mg solution (fasted, Period 1), followed by ritlecitinib 100 mg MR capsule 1 (fasted, Period 2), followed by ritlecitinib 100 mg MR capsule 2 (fasted, Period 3), and followed by ritlecitinib 100 mg MR capsule 1 (fed, Period 4) arm 2: Ritlecitinib 100 mg MR capsule 1 (fasted, Period 1), followed by ritlecitinib 100 mg MR capsule 2 (fasted, Period 2), followed by ritlecitinib 100 mg solution (fasted, Period 3), and followed by ritlecitinib 100 mg MR capsule 1 (fed, Period 4) arm 3: Ritlecitinib 100 mg MR capsule 2 (fasted, Period 1), followed by ritlecitinib 100 mg solution (fasted, Period 2), followed by ritlecitinib 100 mg MR capsule 1 (fasted, Period 3), and followed by ritlecitinib 100 mg MR capsule 1 (fed, Period 4) arm 4: Ritlecitinib 100 mg solution (fasted, Period 1), followed by ritlecitinib 100 mg MR capsule 1 (fasted, Period 2), followed by ritlecitinib 100 mg MR capsule 2 (fasted, Period 3), and followed by ritlecitinib 100 mg MR capsule 2 (fed, Period 4) arm 5: Ritlecitinib 100 mg MR capsule 1 (fasted, Period 1), followed by ritlecitinib 100 mg MR capsule 2 (fasted, Period 2), followed by ritlecitinib 100 mg solution (fasted, Period 3), and followed by ritlecitinib 100 mg MR capsule 2 (fed, Period 4) arm 6: Ritlecitinib 100 mg MR capsule 2 (fasted, Period 1), followed by ritlecitinib 100 mg solution (fasted, Period 2), followed by ritlecitinib 100 mg MR capsule 1 (fasted, Period 3), and followed by ritlecitinib 100 mg MR capsule 2 (fed, Period 4)
Interventions: intervention 1: Ritlecitinib
Intervention descriptions: intervention 1: Ritlecitinib 100 milligrams (mg) will be provided as either solution or capsule formulation (2 capsules of 50 mg)

Protocol documents:
Prot_000.pdf: 
PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 1
A PHASE 1, OPEN-LABEL STUDY IN HEALTHY PARTICIPANTS TO 
INVESTIGATE THE PHARMACOKINETICS OF RITLECITINIB FOLLOWING 
SINGLE ORAL ADMINISTRATION OF MODIFIED RELEASE FORMULATIONS 
UNDER FED AND FASTED CONDITIONS
Study Intervention Number:
PF-06651600
Study Intervention Name:
Ritlecitinib
US IND Number:
130983
EuCT Number:
2023-505603-23-00
ClinicalTrials.gov ID:
N/A
Pediatric Investigational Plan Number:
N/A
Protocol Number:
B7981086
Phase:
1
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Study to Learn How Different Manufactured Products of the Study 
Medicine Called Ritlecitinib are Taken up Into the Blood in Healthy Adults When Taken 
on an Empty Stomach or When Taken With a Meal in Healthy Adults
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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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 2
Document History
Document
Version Date
Amendment 1
07 Nov 2023
Original protocol
19 Jun 2023
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s). 
Protocol Amendment Summary of Changes Table
Amendment 1 (07 November 2023)
Overall Rationale for the Amendment: 
Description of Change
Brief Rationale
Section # and Name
Non-substantial Modification(s)
IP manual term is 
changed to EDR and 
protocol and PCRU’s 
local/site procedure.
IP manual will not be used in the 
study.
Sections 6.1.1 and 6.2.
Tasso device validation 
has been deleted.
Tasso device will not be used in 
this study because of the AEs of the 
Tasso device reported in a recent 
clinical study. 
Sections 1.1, 1.3, 2.3.1, 
3, 4.1, 4.2, 8.5, and 
9.3.2.1.
Estimated total blood 
sampling volume for 
individual participants is 
updated from 155 mL to 
150 mL.
Tasso device has been deleted and 
therefore, total blood sampling
volume was updated accordingly. 
Section 8.1.
Additional physical exam 
is added at the end of 
each period.
The physical exam will be more 
frequently conducted, including at 
Day 3 of each period or at early 
termination.
Section 1.3.
Additional description to 
Table 2 was added such 
as the treatment names 
A; B & C are 
representative. 
It will clarify the discrepancy 
between protocol and 
randomization code.
Sections 1.1 and 4.1.
Editorial and formatting changes and clarifications were made throughout the document.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................14
1.3. Schedule of Activities .............................................................................................15
2. INTRODUCTION ...............................................................................................................23
2.1. Study Rationale .......................................................................................................23
2.2. Background .............................................................................................................23
2.2.1. Nonclinical Pharmacology..........................................................................23
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................23
2.2.3. Nonclinical Safety ......................................................................................23
2.2.4. Clinical Overview of Ritlecitinib................................................................23
2.2.4.1. Pharmacokinetic Overview of Ritlecitinib................................24
2.2.4.2. Safety Overview of Ritlecitinib.................................................24
2.3. Benefit/Risk Assessment.........................................................................................29
2.3.1. Risk Assessment.........................................................................................30
2.3.2. Benefit Assessment.....................................................................................31
2.3.3. Overall Benefit/Risk Conclusion................................................................31
3. OBJECTIVES AND ENDPOINTS.....................................................................................31
4. STUDY DESIGN.................................................................................................................31
4.1. Overall Design.........................................................................................................31
4.2. Scientific Rationale for Study Design.....................................................................32
4.2.1. Choice of Contraception/Barrier Requirements .........................................32
4.2.2. Collection of Retained Research Samples..................................................33
4.3. Justification for Dose ..............................................................................................33
4.4. End of Study Definition ..........................................................................................33
5. STUDY POPULATION......................................................................................................33
5.1. Inclusion Criteria.....................................................................................................34
5.2. Exclusion Criteria....................................................................................................34
5.3. Lifestyle Considerations..........................................................................................38
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 4
5.3.1. Contraception..............................................................................................38
5.3.2. Meals and Dietary Restrictions...................................................................38
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................40
5.3.4. Activity .......................................................................................................40
5.3.5. Vaccination.................................................................................................40
5.4. Screen Failures ........................................................................................................41
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................41
6.1. Study Intervention(s) Administered........................................................................41
6.1.1. Administration............................................................................................42
6.2. Preparation, Handling, Storage, and Accountability...............................................42
6.2.1. Preparation and Dispensing........................................................................43
6.3. Assignment to study intervention............................................................................44
6.4. Blinding...................................................................................................................44
6.4.1. Blinding of Participants..............................................................................44
6.4.2. Blinding of Site Personnel..........................................................................44
6.4.3. Blinding of the Sponsor..............................................................................44
6.5. Study Intervention Compliance...............................................................................44
6.6. Dose Modification...................................................................................................44
6.7. Continued Access to Study Intervention After the End of the Study......................45
6.8. Treatment of Overdose............................................................................................45
6.9. Prior and Concomitant Therapy..............................................................................45
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................46
7.1. Discontinuation of Study Intervention ....................................................................46
7.1.1. Potential Cases of Acute Kidney Injury .....................................................46
7.1.2. Liver Injury.................................................................................................48
7.2. Participant Discontinuation/Withdrawal From the Study.......................................48
7.2.1. Withdrawal of Consent...............................................................................48
7.3. Lost to Follow-Up ...................................................................................................49
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................49
8.1. Administrative Procedures ......................................................................................49
8.2. Efficacy Assessments..............................................................................................50
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 5
8.3. Safety Assessments .................................................................................................50
8.3.1. Physical Examinations................................................................................51
8.3.2. Vital Signs ..................................................................................................51
8.3.2.1. Blood Pressure and Pulse Rate..................................................51
8.3.2.2. Temperature ..............................................................................52
8.3.3. Electrocardiograms.....................................................................................52
8.3.4. Clinical Safety Laboratory Assessments ....................................................52
8.3.5. COVID-19 Specific Assessments...............................................................53
8.3.6. Pregnancy Testing ......................................................................................53
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................53
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......54
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................55
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................55
8.4.2. Method of Detecting AEs and SAEs ..........................................................55
8.4.3. Follow-Up of AEs and SAEs......................................................................55
8.4.4. Regulatory Reporting Requirements for SAEs...........................................56
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................56
8.4.5.1. Exposure During Pregnancy......................................................56
8.4.5.2. Exposure During Breastfeeding ................................................58
8.4.5.3. Occupational Exposure .............................................................58
8.4.6. Cardiovascular and Death Events...............................................................58
8.4.7. Disease Related- Events and/or Disease -Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................59
8.4.8. Adverse Events of Special Interest.............................................................59
8.4.8.1. Lack of Efficacy........................................................................59
8.4.9. Medical Device Deficiencies......................................................................59
8.4.10. Medication Errors.....................................................................................59
8.5. Pharmacokinetics ....................................................................................................60
8.5.1. Feces collection and analysis......................................................................61
8.6. Genetics...................................................................................................................61
8.6.1. Specified Genetics ......................................................................................61
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 6
8.7. Biomarkers ..............................................................................................................61
8.8. Immunogenicity Assessments.................................................................................61
8.9. Health Economics ...................................................................................................61
9. STATISTICAL CONSIDERATIONS ................................................................................61
9.1. Statistical Hypotheses .............................................................................................62
9.2. Analysis Sets ...........................................................................................................62
9.3. Statistical Analyses .................................................................................................62
9.3.1. General Considerations...............................................................................63
9.3.2. Pharmacokinetic analysis............................................................................63
9.3.3. Other Safety Analyses ................................................................................64
9.3.3.1. Electrocardiogram Analyses......................................................65
9.3.4. Other Analyses............................................................................................65
9.4. Interim Analyses .....................................................................................................65
9.5. Sample Size Determination.....................................................................................65
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................69
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............69
10.1.1. Regulatory and Ethical Considerations ....................................................69
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................69
10.1.2. Financial Disclosure .................................................................................70
10.1.3. Informed Consent Process ........................................................................70
10.1.4. Data Protection .........................................................................................71
10.1.5. Committees Structure ...............................................................................72
10.1.5.1. Data Monitoring Committee ...................................................72
10.1.6. Dissemination of Clinical Study Data ......................................................72
10.1.7. Data Quality Assurance ............................................................................73
10.1.8. Source Documents....................................................................................74
10.1.9. Use of Medical Records............................................................................74
10.1.10. Study and Site Start and Closure ............................................................75
10.1.11. Publication Policy...................................................................................76
10.1.12. Sponsor’s Medically Qualified Individual..............................................77
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 7
10.2. Appendix 2: Clinical Laboratory Tests .................................................................78
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................80
10.3.1. Definition of AE .......................................................................................80
10.3.2. Definition of an SAE ................................................................................81
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................83
10.3.4. Reporting of SAEs....................................................................................86
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................88
10.4.1. Male Participant Reproductive Inclusion Criteria....................................88
10.4.2. Female Participant Reproductive Inclusion Criteria.................................88
10.4.3. Woman of Childbearing Potential ............................................................88
10.4.4. Contraception Methods.............................................................................89
10.5. Appendix 5: Genetics............................................................................................91
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........92
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................94
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................94
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............94
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................94
10.7.3. Kidney Function Calculation Tools..........................................................95
10.7.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................95
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................97
10.9. Appendix 9: Abbreviations ...................................................................................99
11. REFERENCES ................................................................................................................103
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 8
LIST OF TABLES
Table 1.
Pharmacokinetic Sampling Schema for Each Period ...............................22
Table 2.
Study Design and Treatments...................................................................32
Table 3.
Study Interventions...................................................................................41
Table 4.
Definitions of PK Parameters...................................................................64
Table 5.
Expected Widths of the 90% Confidence Intervals (With 80% 
Tolerance Probability) for Different Possible Estimated Effects of 
ritlecitinib MR1 and MR2 Formulations in Fasted and Fed 
Conditions on PK Parameters...................................................................67
Table 6.
Protocol Required Safety Laboratory Assessments..................................78
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 9
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Open-Label Study in Healthy Participants to Investigate the 
Pharmacokinetics of Ritlecitinib Following Single Oral Administration of Modified Release 
Formulations Under Fed and Fasted Conditions
Brief Title: 
A Study to Learn How Different Manufactured Products of the Study Medicine Called 
Ritlecitinib are Taken up Into the Blood in Healthy Adults When Taken on an Empty 
Stomach or When Taken With a Meal in Healthy Adults.
Regulatory Agency Identification Number(s):
US IND Number:
130983
[EudraCT/EU CT] Number:
2023-505603-23-00.
ClinicalTrials.gov ID:
N/A
Pediatric Investigational Plan Number:
N/A
Protocol Number:
B7981086
Phase:
Phase 1
Rationale:
Ritlecitinib is a covalent and irreversible inhibitor of JAK3 with high selectivity over the 
other JAK isoforms (JAK1, JAK2, and TYK2). Ritlecitinib also inhibits irreversibly the TEC
family kinases with selectivity over the broader human kinome. Treatment with ritlecitinib is 
expected to inhibit the inflammatory pathways mediated by IL-7, IL-15 and IL-21, all 
implicated in UC, CD, AA, RA, and vitiligo and therefore under development in these 
indications. Moreover, due to lack of activity against the other JAK isoforms, ritlecitinib is 
expected to spare immunoregulatory cytokines such as IL-10, IL-27 and IL-35, which are 
critical to the maintenance of immunosuppressive functions and immune homeostasis.
This study aims to investigate the PK and relative bioavailability of 2 new MR capsule 
formulations of ritlecitinib, MR1 (release duration: 6-8 hours) and MR2 (release 
duration:13-15 hours) as single doses in fasted and fed conditions.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 10
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

To determine the PK profile and relative 
bioavailability of ritlecitinib as 2 MR capsule 
formulations, MR1 and MR2, relative to
solution formulation under fasted conditions in 
healthy adult participants.

PK parameters of ritlecitinib (fasted): Cmax, 
AUCinf (if data permit), otherwise AUClast
Secondary: 
Secondary: 

To evaluate the effect of food on ritlecitinib 
exposure following administration as 2 MR 
capsule formulations, MR1 and MR2 in 
healthy adult participants.

PK parameters of ritlecitinib (fed): Cmax, AUCinf
(if data permit), otherwise AUClast.

To evaluate safety and tolerability of 
ritlecitinib following single oral administration 
as MR1 and MR2 capsule formulations in 
healthy adult participants.

Assessment of AEs, clinical laboratory tests, 
vital signs and 12-lead ECG.
Overall Design
This is a single dose, open-label, randomized, 4-period, 6-sequence crossover study in a 
single cohort of approximately 12 healthy participants randomized to one of the sequences 
(containing 1 solution and 2 modified release [MR1 and MR2] capsule formulations of 
ritlecitinib) described in the table below where the treatment names A; B & C are 
representative. The first 3 periods are under fasted condition and the fourth period is under 
fed condition to investigate the effect of food on the PK of MR1 and MR2. 
Study design and treatments
Sequence
Period 1
Period 2
Period 3
Period 4
1 (n=2)
A
B
C
B, fed
2 (n=2)
B
C
A
B, fed
3 (n=2)
C
A
B
B, fed
4 (n=2)
A
B
C
C, fed
5 (n=2)
B
C
A
C, fed
6 (n=2)
C
A
B
C, fed
Treatment A: ritlecitinib 100 mg PO solution
Treatment B: ritlecitinib 100 mg (2 × 50 mg) MR1 capsules
Treatment C: ritlecitinib 100 mg (2 × 50 mg) MR2 capsules
090177e19f28ce19\Approved\Approved On: 15-Nov-2023 04:36 (GMT)


PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 11
Number of Participants
A total of approximately 12 healthy male and/or female adult participants will be randomly 
assigned to study interventions in the study. 
Study Population: 
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:

Participants aged 18 or older (or the minimal age of consent in accordance with 
location regulations) at screening. 

Male and female participants who are healthy as determined by medical evaluation 
including a detailed medical history, full physical examination (which includes BP 
and pulse rate measurement), clinical laboratory tests, and 12-lead ECG.

BMI of 16 to 32 kg/m2, and a total body weight >45 kg (99 lb). 

Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.

Capable of giving signed informed consent.
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:

Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease.

Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). 

Known immunodeficiency disorder, including positive serology for HIV, or a first 
degree relative with a hereditary immunodeficiency.

Infection with hepatitis B or hepatitis C viruses according to protocol specific testing 
algorithm history.

Participants with any of the specified acute or chronic infections or infection history.

History of febrile illness within 5 days prior to the first dose of study intervention.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 12

History of any lymphoproliferative disorder such as EBV related lymphoproliferative 
disorder, history of lymphoma, history of leukemia, or signs or symptoms suggestive 
of current lymphatic or lymphoid disease.

Known present or a history of malignancy other than a successfully treated or excised 
nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in 
situ.
Evidence of untreated or inadequately treated active or latent Mycobacterium TB infection.
Study Arms and Duration:
Study Interventions
Intervention Name
ritlecitinib (100 mg) solution
ritlecitinib (100 mg) MR1
ritlecitinib (100 mg) MR2
Use
Experimental
Dose Formulation
PO solution
Capsule
Capsule
Unit Dose Strength
100 mg in 100 mL provided 
in dosing bottle
50 mg/capsule
50 mg/capsule
Route of 
Administration
Oral
IMP or NIMP/AxMP
IMP
Study Interventions
Study 
Interventions
Period 1
Period 2
Period 3
Period 4
Study 
Interventions
Description
Participants will receive a single dose of IP on Day 1 of each period. 
For a given participant, the total study duration from screening to follow-up phone call will 
be between approximately 8 to 11 weeks.
Screening will occur within 28 days prior to the first dose of the study intervention. Each 
participant will go through Periods 1 through 4 and dosing in each treatment period will be 
separated by at least 3 days to minimize any carryover effect. 
Venous PK blood samples for PK analysis will be collected pre-dose and at times specified 
in the SoA. 
Participants may be discharged between periods at the discretion of PI. Following final 
discharge, participants will receive a follow-up phone call 28 to 35 days following the last 
dose of study intervention. 
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
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Participants who discontinue prior to completion of the study for reasons unrelated to safety 
may be replaced at the discretion of the PI and the sponsor. Participants withdrawn for safety 
reasons will not be replaced.
Statistical Methods
This study will include relative bioavailability and food effect evaluations. In the relative 
bioavailability evaluation, natural log transformed AUCinf (if data permit), AUClast, and Cmax 
of ritlecitinib will be analyzed using a mixed effect model with treatment, sequence, and 
period as fixed effects and participant within sequence as a random effect. In the food effect 
evaluation, dose-normalized natural log transformed AUClast and Cmax of ritlecitinib will be 
analyzed using a mixed effect model with treatment and sequence as fixed effects and 
participant within sequence as a random effect. For both the relative bioavailability and food 
effect evaluation, estimates of the adjusted mean differences (Test/Reference) and 
corresponding 90% confidence intervals will be obtained from the model. The adjusted mean 
differences and 90% confidence intervals for the differences will be exponentiated to provide 
estimates of the ratio of adjusted geometric means (Test/Reference) and 90% confidence 
intervals for the ratios.
The plasma concentrations of ritlecitinib will be listed and descriptively summarized by 
nominal PK sampling time, formulation and food condition. Ritlecitinib PK parameters will 
also be summarized by formulation and food condition. AEs, ECGs, BP, pulse rate and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of participants. Any clinical laboratory, ECG, BP, and pulse rate
abnormalities of potential clinical concern will be described. Safety data will be presented in 
tabular and/or graphical format and summarized descriptively, where appropriate.
Ethical Considerations:
The results of previous studies of ritlecitinib support the investigation of ritlecitinib for AA, 
RA, vitiligo, UC and CD. Taking into account the measures to minimize risk to participants, 
the potential risks associated with ritlecitinib are justified by the anticipated benefits of 
informing safety and pharmacokinetics of MR formulations of ritlecitinib for future clinical 
development of therapies localized to the gut.
This is a short-term PK study and therefore no benefit to the participants is expected.
Based on the current clinical and nonclinical experience with ritlecitinib and information 
from other JAK inhibitors and TEC family kinase inhibitors (eg, tofacitinib, ruxolitinib, 
baricitinib, upadacitinib, abrocitinib, ibrutinib and acalabrutinib), the important potential 
risks for ritlecitinib are: serious infections, opportunistic infections and viral reactivation, 
malignancy, and thromboembolism. Identified risks that could have adverse outcomes 
include: dermatologic effects (ie. rash, urticaria), decreased lymphocyte counts, and 
decreased platelet counts. 
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
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Participants will be expected to commit time and may experience some discomfort while 
undergoing study assessments. In addition, participants of childbearing potential must agree 
to use appropriate contraception methods. Participants should avoid vaccination with live 
attenuated replication-competent vaccines. It is recommended that participants keep their diet 
habits constant throughout the study.
1.2. Schema
Not applicable.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 9: Abbreviations.
Screening
Treatment Period
Notes
Period 1 
Period 2
Period 3
Period 4
Follow-up Contact
Early 
Termination/
Discontinuation

Follow-up contact 
will occur by 
telephone and must 
occur 28 to 35 days 
after the last 
administration of 
ritlecitinib.
Days Relative to Day 1
Day -28 to 
Day -2
Day -
1
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day
1
Day 
2
Day 
3
28-35 Days after 
last dose in Period 
4
Study Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Informed consent
X
CRU confinement
X











X

Period 4: final 
discharge from CRU.
Participants may be 
discharged between 
periods at the 
discretion of PI. 
Inclusion/exclusion criteria
X
X

Inclusion/exclusion 
criteria should be
updated on Day -1
since screening.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
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TMF Doc ID: 164.01
Page 16
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 9: Abbreviations.
Screening
Treatment Period
Notes
Period 1 
Period 2
Period 3
Period 4
Follow-up Contact
Early 
Termination/
Discontinuation

Follow-up contact 
will occur by 
telephone and must 
occur 28 to 35 days 
after the last 
administration of 
ritlecitinib.
Days Relative to Day 1
Day -28 to 
Day -2
Day -
1
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day
1
Day 
2
Day 
3
28-35 Days after 
last dose in Period 
4
Study Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Medical/medication history 
(update) 
X
X

Period 1 only.

Include history of 
alcohol abuse, 
tobacco/nicotine 
containing products, 
licit and illicit drug 
use or dependence 
within 6 months of 
Screening. For Day -
1, records should be 
reviewed or updated 
only.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 9: Abbreviations.
Screening
Treatment Period
Notes
Period 1 
Period 2
Period 3
Period 4
Follow-up Contact
Early 
Termination/
Discontinuation

Follow-up contact 
will occur by 
telephone and must 
occur 28 to 35 days 
after the last 
administration of 
ritlecitinib.
Days Relative to Day 1
Day -28 to 
Day -2
Day -
1
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day
1
Day 
2
Day 
3
28-35 Days after 
last dose in Period 
4
Study Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Physical examination
X
X
X
X
X
X
X

Complete (full) 
physical examination 
must either be 
conducted at 
Screening or upon 
Admission on Day -1
of Period 1 only; brief
physical examination 
will be performed on 
Day 3 of each period 
or at early 
termination/discontin
uation, and as needed 
per investigator 
discretion if there are 
findings during the 
previous examination, 
new/open adverse 
events.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
TMF Doc ID: 164.01
Page 18
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 9: Abbreviations.
Screening
Treatment Period
Notes
Period 1 
Period 2
Period 3
Period 4
Follow-up Contact
Early 
Termination/
Discontinuation

Follow-up contact 
will occur by 
telephone and must 
occur 28 to 35 days 
after the last 
administration of 
ritlecitinib.
Days Relative to Day 1
Day -28 to 
Day -2
Day -
1
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day
1
Day 
2
Day 
3
28-35 Days after 
last dose in Period 
4
Study Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Safety laboratory
X
X
X
X
X
X
X

Participants should 
fast for at least 4 
hours prior to any 
safety blood 
collection. Additional 
laboratory 
assessments may be 
performed if deemed 
necessary by the 
investigator. Refer to 
Table 5 in 
Section 10.2. Day 3 
safety labs of every 
period to be done 
after PK blood 
sampling.
Demography, height and 
weight
X
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 9: Abbreviations.
Screening
Treatment Period
Notes
Period 1 
Period 2
Period 3
Period 4
Follow-up Contact
Early 
Termination/
Discontinuation

Follow-up contact 
will occur by 
telephone and must 
occur 28 to 35 days 
after the last 
administration of 
ritlecitinib.
Days Relative to Day 1
Day -28 to 
Day -2
Day -
1
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day
1
Day 
2
Day 
3
28-35 Days after 
last dose in Period 
4
Study Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Pregnancy test (WOCBP 
only)
X
X

Given that the 
participant will be 
confined in CRU for 
the entire study, if 
tested negative on 
admission, no further 
test is needed.
Contraception check 
X
X
X
X

The contraception 
check is to confirm 
that contraception, if 
applicable, is used 
consistently and 
correctly.
Review prior or concomitant 
treatments and medications
X
X












X
X
FSH (WONCBP only)
X

Serum FSH for 
confirmation of 
postmenopausal status 
only
Urine drug testing
X
X
Supine 12-lead single ECG 
X
X
X
X
X
X
X

Day 1 ECG to be done 
pre-dose. 
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
PFIZER CONFIDENTIAL
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TMF Doc ID: 164.01
Page 20
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 9: Abbreviations.
Screening
Treatment Period
Notes
Period 1 
Period 2
Period 3
Period 4
Follow-up Contact
Early 
Termination/
Discontinuation

Follow-up contact 
will occur by 
telephone and must 
occur 28 to 35 days 
after the last 
administration of 
ritlecitinib.
Days Relative to Day 1
Day -28 to 
Day -2
Day -
1
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day
1
Day 
2
Day 
3
28-35 Days after 
last dose in Period 
4
Study Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Supine blood pressure, pulse 
rate and temperature
X
X
X
X
X
X
X

Day 1 vital signs are 
collected prior to pre-
dose (baseline) blood 
drawn.
HIV, HBsAg, HBcAb, 
HCVAb
X

If HBsAg is negative 
and HBcAb is 
positive, HBsAb 
should be evaluated.
QuantiFERON®TB Gold test 
or equivalent
X
Study intervention 
administration
X
X
X
X

Please refer to Section 
5.3.2 for details 
regarding dosing 
under fed and fasted 
state.
Pharmacokinetic blood 
sampling 
X
X
X
X
X
X
X
X
X
X
X
X
X

PK sample collection 
will be done pre-dose 
and at times post-
dose as shown in 
Table 1 below.
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PF-06651600 (Ritlecitinib)
Protocol B7981086
Final Protocol Amendment 1, 07 Nov 2023
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 9: Abbreviations.
Screening
Treatment Period
Notes
Period 1 
Period 2
Period 3
Period 4
Follow-up Contact
Early 
Termination/
Discontinuation

Follow-up contact 
will occur by 
telephone and must 
occur 28 to 35 days 
after the last 
administration of 
ritlecitinib.
Days Relative to Day 1
Day -28 to 
Day -2
Day -
1
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day 
1
Day 
2
Day 
3
Day
1
Day 
2
Day 
3
28-35 Days after 
last dose in Period 
4
Study Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Feces collection for MR2 
(treatment C) arm only
X
X
X
X
X
X
X
X

Each bowel 
movement to be 
collected only for the 
MR2 arm up to a 
period of 72 hours. 
Samples may be 
analyzed based on 
sponsor discretion.
Serious and nonserious 
adverse event monitoring
X













X
X
COVID-19 related procedures














Performed per local 
procedures
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PF-06651600 (Ritlecitinib)
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Table 1.
Pharmacokinetic Sampling Schema for Each Period
Visit Identifier 
Notes
Study Day
1
2
3
Hours After Dose
0
0.5
1
2
3
4
6
10
12
16
24
36
48

Hour 0 = predose PK 
samples collection. 
Any time prior to 
dosing ritlecitinib on 
the day of dosing.
Study intervention administration
X
PK blood sampling for IR arm
X
X
X
X
X
X
X
X
X
X

Ritlecitinib PK blood 
samples (2 mL blood 
to yield minimum of 
0.5 mL plasma) are to 
be collected.
PK blood sampling for MR1 arm (fed and fasted)
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sampling for MR2 arm (fed and fasted)
X
X
X
X
X
X
X
X
X
X
X
X
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PF-06651600 (Ritlecitinib)
Protocol B7981086
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2. INTRODUCTION
Ritlecitinib is a selective covalent inhibitor of JAK3 and the TEC family kinases and is 
currently under development for the treatment of AA, RA, vitiligo, UC, and CD.
2.1. Study Rationale 
The purpose of the study is to evaluate the PK, safety, and tolerability of ritlecitinib
following single oral doses as IR and MR formulations in healthy, adult participants under 
fasted and fed conditions. The objective is to evaluate the relative bioavailability and food 
effect of 2 new MR capsule formulations, MR1 and MR2. Overall, results from this study
will facilitate further development of an MR formulation for future clinical studies.
2.2. Background 
Ritlecitinib is a covalent and irreversible inhibitor of JAK3 with high selectivity over the 
other JAK isoforms (JAK1, JAK2, and TYK2). Ritlecitinib also inhibits irreversibly the 
tyrosine kinase expressed in TEC family kinases with selectivity over the broader human 
kinome. Treatment with ritlecitinib is expected to inhibit the inflammatory pathways 
mediated by IL-7, IL-15 and IL-21, all implicated in UC, CD, AA, RA, and vitiligo.
Moreover, due to lack of activity against the other JAK isoforms, ritlecitinib is expected to 
spare immunoregulatory cytokines such as IL-10, IL-27 and IL-35, which are critical to the 
maintenance of immunosuppressive functions and immune homeostasis.
2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of ritlecitinib can be found in the current IB.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Details of the nonclinical PK and metabolism of ritlecitinib can be found in the current IB.
2.2.3. Nonclinical Safety
The NOAELs in the 6-month rat and second 9-month dog toxicity studies were 200 and 
10 mg/kg/day, respectively. These exposures represent 50-fold exposure multiple in the rat 
study and a 7.4-fold exposure multiple in the dog study relative to the clinical dose of 50 mg. 
In the second 9-month dog toxicity study, the NOAEL of 10 mg/kg/day was based on 
adverse overimmunosuppression and axonal dystrophy (not axonal degeneration) in the CNS 
and the PNS at ≥20 mg/kg/day, accompanied by functional auditory deficits (BAEP) at the 
highest dose of 40 mg/kg/day (a 33-fold exposure multiple relative to the clinical dose of 
50 mg).
Further information is available in the current version of the ritlecitinib IB. 
2.2.4. Clinical Overview of Ritlecitinib
As of 30 May 2022, 26 clinical studies with ritlecitinib have been completed (22 Phase 1 
studies in healthy participants or special populations and 6 Phase 2 or Phase 3 studies in 
participants with RA, AA, UC or vitiligo). A total of 464 participants were exposed to 
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PF-06651600 (Ritlecitinib)
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ritlecitinib in the Phase 1 healthy participant and special population studies. In completed and 
ongoing interventional Phase 2 and Phase 3 studies in AA and vitiligo, 1628 participants 
have received ritlecitinib. 
2.2.4.1. Pharmacokinetic Overview of Ritlecitinib
The PK profile of ritlecitinib is characterized by rapid absorption (following single doses of 
5 to 200 mg, with median Tmax values 0.75 hours; and more slowly at the higher doses, with 
a median Tmax of 1.00 and 1.50 hours for the 400- and 800-mg doses, respectively), rapid 
elimination (t½ ranging from 1.1 to 2.5 hours) and are approximately dose proportional. 
Following multiple oral doses, steady-state was reached approximately by Day 4 due to 
non-stationary PK. Ritlecitinib has been evaluated at single oral doses ranging from 5 mg to 
800 mg and multiple oral doses ranging from 50 mg to 400 mg QD and at 100 mg and 
200 mg BID for 14 days. The clearance mechanisms for ritlecitinib in humans are primarily 
by metabolism, with approximately 4% of the dose excreted as unchanged drug in urine. 
2.2.4.1.1. Effect of Food on PK of Ritlecitinib 
Overall, food does not have a clinically significant impact on the systemic exposures of 
ritlecitinib and the product may be administered regardless of food intake. 
In Study B7981003 (Module 5.3.1.1 B7981003 CSR), the co-administration of a single 
50 mg tablet with a high-fat breakfast reduced Cmax by ~39%, with no meaningful change in 
AUCinf and a slight increase in Tmax.
In Study B7981029 (Module 5.3.1.2 B7981029 CSR), the co-administration of a single 
100 mg capsule with a high-fat breakfast reduced Cmax by ~32% with no meaningful change 
in AUCinf and a slight increase in Tmax. 
On the basis of the consistency of the PK results from B7981003 and B7981029 and dosing 
without regard to food in B7981015 Phase 2b/3 trial, ritlecitinib may be administered with or 
without food. 
2.2.4.2. Safety Overview of Ritlecitinib
2.2.4.2.1. Studies in Healthy Participants
In 22 healthy participant studies, ritlecitinib was found to be well tolerated and to have an 
acceptable safety profile.
Additional single dose 2- or 3-way crossover studies were performed to examine drug 
interactions (B7981017, B7981018, B7981023), food effect and relative bioavailability 
(B7981003) of ritlecitinib. Each study included 12 to 14 healthy participants.
In all the above studies, ritlecitinib was found to be well tolerated and to have an acceptable 
safety profile.
The current IB should be referred to for more detailed information.
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2.2.4.2.2. Phase 2a Study in Rheumatoid Arthritis
The completed Phase 2a study B7981006 was an 8-week randomized, double-blind, 
placebo-controlled, parallel-group, multicenter study in participants with moderate-to-severe
active RA with an inadequate response to methotrexate. A total of 70 participants were 
randomized to study treatment; 28 participants received placebo and 42 participants received 
ritlecitinib 200 mg QD. Participants remained on stable background arthritis therapy, which 
had to include methotrexate (supplemented with folic/folinic acid per the local treatment 
guidelines).
Ritlecitinib was determined to be generally safe and well tolerated in this study. There were 
no deaths or SAEs. TEAEs were numerically higher in participants receiving ritlecitinib 
compared to those receiving placebo. The majority of the AEs were mild in severity. Overall, 
the most frequently reported treatment-related TEAE was Lymphopenia 
(2 [2.9%] participants in total: 2 [4.8%] participants in the ritlecitinib group and 
0 participants in the placebo group). A total of 3 participants (7.1%) in the ritlecitinib group 
and 0 participants in the placebo group permanently discontinued due to TEAEs. One 
participant discontinued due to suicidal ideation, 1 participant discontinued due to 
lymphopenia, and the third participant discontinued due to hepatotoxicity. There were no 
SAEs nor deaths among participants who participated in Study B7981006. 
2.2.4.2.3. Phase 2a Study in Crohn’s disease
Study B7981007 is an ongoing Phase 2a, randomized, double-blind, placebo-controlled, 
parallel group, multicenter study to examine the efficacy of ritlecitinib (200 mg QD for 
8 weeks followed by 50 mg QD for 4 weeks or placebo) and PF-06700841 in participants 
with moderate to severe active CD.
As of 30 May 2022, a total of 241 patients were evaluable for AEs, of whom 188 have 
reported 735 AEs. The most frequently reported (≥5%) all causality AEs were Crohn’s
disease (14.9%), SARS-CoV-2 test positive (10.8%), abdominal pain (9.1%), headache 
(7.1%), arthralgia (6.6% each), acne, fatigue, lymphopenia, and urinary tract infection (5.0% 
each).
As of 30 May 2022, a total of 69 SAEs in 54 participants have been reported. Eleven SAEs 
were reported pre-randomization in 11 participants.
During the open-label extension period, as of 30 May 2022, 13 SAEs were reported in 
14 participants of which 3 SAEs were assessed as treatment-related by the investigator. The 
following SAEs were considered unrelated to ritlecitinib by the investigator: tonsillitis, 
Crohn’s disease (5 events; exacerbation/flare of CD), female genital tract fistula, abdominal 
abscess, diarrhea hemorrhagic, clostridium difficile infection, vomiting, ileus, diarrhea, 
abdominal pain (2 events), anaemia, small intestinal obstruction, and lymphopenia. Except 
for 1 event of female genital tract fistula, all other events recovered/resolved. 
Three SAEs were considered related to ritlecitinib by the investigator, which included 
Clostridium difficile infection, diarrhoea haemorrhagic, and lymphopenia.
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2.2.4.2.4. Phase 2b Study in vitiligo
Study B7981019 is a completed Phase 2b, randomized, double-blind, parallel group, 
multicenter, placebo-controlled, dose ranging study to investigate different doses of 
ritlecitinib with a partial blinded extension period to evaluate the efficacy and safety of 
ritlecitinib in active non-segmental vitiligo. 
In the 24-week double-blind DR Treatment Period, participants were randomized to 1 of 5 
treatment groups (2 groups with a ritlecitinib induction dose of 200 mg QD or 100 mg QD 
for 4 weeks followed by maintenance dosing of 50 mg QD for 20 weeks, and 3 groups with 
50 mg QD, 30 mg QD, and 10 mg QD ritlecitinib dosing for 24 weeks) or matching placebo. 
There were 6 groups with QD dosing in the Extension Period of 24 weeks: ritlecitinib 
induction dosing of 200 mg for 4 weeks followed by maintenance dosing of 50 mg for 
20 weeks (open-label); 3 groups with induction dosing of 200 mg for 4 weeks followed by 
maintenance dosing of 50 mg for 20 weeks, 50 mg for 24 weeks, and 30 mg for 24 weeks 
(blinded); brepocitinib only (induction dosing of 60 mg for 4 weeks followed by maintenance 
dosing of 30 mg for 16 weeks [open-label]); observation-only (no treatment) group (open-
label).
In the DR treatment period, of the 364 treated participants (298 treated with ritlecitinib), 
66 (18.1%) discontinued from study intervention, of whom 11 received placebo treatment.
Across treatment groups, the proportion of participants who discontinued study intervention 
ranged from 13.4% (100/50 mg) to 28.0% (30 mg). The primary reason for discontinuation 
from study intervention was withdrawal by participant (29 [8.0%]). There were 19 (5.2%) 
participants who discontinued study intervention due to AEs: 2 (3.1%) in 200/50 mg, 
4 (6.0%) in 100/50 mg, 5 (7.5%) in 50 mg, 2 (4.0%) in 30 mg, 3 (6.1%) in 10 mg and 3 
(4.5%) in placebo. In the Extension Period, there were 7 ritlecitinib treated participants who 
discontinued study intervention due to AEs.
The majority of all-causality TEAEs in participants across treatment groups in both treatment 
periods were mild or moderate in severity. There were 277 (76.1%) participants with 756 all 
causality TEAEs in the DR Period. The most frequently reported all-causality TEAEs were 
nasopharyngitis (15.9%), URTI (11.5%), and headache (8.8%). There were 126 
(34.6%) participants with 195 treatment-related AEs. The most frequently reported 
treatment-related TEAEs were nasopharyngitis (4.1%), diarrhea (1.9%), and headache 
(1.9%). The majority of treatment-related TEAEs across treatment groups were mild or 
moderate in severity, and the number of severe events was not dose-dependent.
In the DR period, SAEs were reported in 4 participants (migraine in 50 mg, esophageal 
spasm in 30 mg, migraine in 10 mg, neurogenic bladder in placebo). All events were assessed 
as unrelated to the study intervention and the participants recovered. No SAEs were reported 
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in the 200/50 mg or 100/50 mg groups. One SAE (uterine leiomyoma, assessed as unrelated) 
was reported in the Extension Period.
There were no clinically meaningful trends for hematology, lipids, or chemistry lab 
parameters in participants treated with ritlecitinib. 
2.2.4.2.5. Phase 2b/3 Study in Alopecia Areata 
B7981015 was a Phase 2b/3, randomized, double-blind, placebo-controlled-, dose
ranging- study to investigate ritlecitinib in participants with ≥50% scalp hair loss due to AA. 
The study had a maximum duration of approximately 57 weeks. This included an up to 
5-week Screening period, a 48-week treatment period, and a 4-week follow-up period (for 
participants who did not roll over into the open-label, long-term Study B7981032). The 
treatment period was comprised of a placebo-controlled period that included a 4-week 
loading phase and a 20-week maintenance phase, followed by a 24-week extension phase. 
The study completed enrollment with a total of 718 participants. Eligible participants were 
randomized to blinded 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, and placebo-50 mg, 
respectively) manner for a total of 7 treatment sequences. 
A total of 1097 participants were screened and 718 participants were randomized to 
treatment. Of these, 715 (99.6%) received treatment (3 participants were not treated) and 
101 (14.1%) discontinued treatment and 614 (85.5%) participants completed the study. The 
proportion of participants who experienced all-causality TEAEs was similar across treatment 
groups up to Week 24 (placebo-controlled period) and up to Week 48 (overall). Up to 
Week 24, the most frequently reported TEAEs in any group included nasopharyngitis, 
headache, and upper respiratory tract infection. The incidence of nasopharyngitis, folliculitis, 
urticaria, dizziness and urinary tract infection was higher in participants treated with 
ritlecitinib (particularly 200/50 mg and 200/30 mg) than placebo. Most TEAEs were mild to 
moderate in severity. Fourteen participants experienced 16 SAEs up to Week 48: 

200/50 mg (4 participants): appendicitis; empyema and sepsis; invasive lobular breast 
carcinoma, spontaneous abortion. 

200/30 mg (2 participants): appendicitis; chemical poisoning and suicidal behavior. 

50 mg (2 participants): breast cancer; pulmonary embolism.

30 mg (1 participant): diverticulitis. 

10 mg (2 participants): suicidal behavior; eczema.

Placebo-200/50 mg: no SAEs. 

Placebo-50 mg (3 participants): spontaneous abortion; conversion disorder; heavy 
menstrual bleeding. These treatment-emergent SAEs were all reported during the Placebo
Controlled Period. 
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Of the 16 SAEs, 12 were considered by the investigator as unrelated to study intervention. 
The 4 SAEs that were considered related to study intervention in the opinion of the 
investigator were sepsis and empyema (both in 1 participant); breast cancer; and eczema. 
There were no deaths in the study.
Treatment with ritlecitinib was associated with changes in hematological parameters, some of 
which were dose dependent. In the first weeks of the study, there were slight, transient 
decreases in hemoglobin and small, variable changes in neutrophil and leukocyte levels. 
Small, early decreases in platelets were observed with ritlecitinib treatment; these levels 
remained stable up to Week 48. Dose-dependent early decreases in absolute lymphocyte 
levels, T lymphocytes (CD3) and T lymphocyte subsets (CD4 and CD8) were observed. 
There was a dose-dependent early decrease in CD16/56 (NK cells), particularly in groups 
who had received a 200 mg loading dose of Ritlecitinib for 4 weeks. Overall, there were no 
clinically meaningful effects of ritlecitinib on ALT, AST, bilirubin, or alkaline phosphatase. 
The incidence of elevation in hepatic enzymes was low and not dose dependent. Up to Week 
48, there were no potential Hy’s law cases. 
2.2.4.2.6. Phase 3 Study in Alopecia Areata
Study B7981032 is an ongoing 5-year Phase 3 open-label, multicenter study to evaluate the
safety and efficacy of ritlecitinib in adult and adolescent participants ≥12 years of age with 
AA. The study has 2 treatment periods and an observation period with a maximum duration 
of approximately 38 months in the TP1. This phase includes up to a 5-week screening period, 
a 36-month open-label treatment period, and a 4-week follow-up period when not 
participating in the TP2. The TP2 is available for participants in countries where ritlecitinib 
is not commercially available at the time of their Month 36 visit. This includes up to 
24 months of study intervention (or until availability of commercial product in their country, 
or until the sponsor terminates the study in that country, whichever occurs first) and a 4-week 
follow-up period after completion or discontinuation of the study intervention. 
Study B7981032 includes eligible participants enrolling from the index Studies B7931005 
and B7981015, as well as de novo participants (ie, those who have not previously received 
study intervention in Study B7931005 or B7981015).
As of 30 May 2022, a total of 1050 participants were evaluable for AEs, of whom 832 had
reported 3369 TEAEs. The most frequently (≥5% of participants) reported TEAEs were 
SARS-CoV-2 test positive (17.8%), headache (14.3%), cough (7.9%), pyrexia (7.9%), and 
acne (7.7%). As of 30 May 2022, 56 (5.3%) participants were permanently discontinued 
from study intervention and/or the study due to a TEAE.
As of 30 May 2022, 45 participants had experienced 53 SAEs. There were 2 deaths reported 
in Study B7981032: a participant with breast cancer, and another with both acute respiratory 
failure and cardiorespiratory arrest.
The current IB should be referred to for more detailed information.
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2.3. Benefit/Risk Assessment
Ritlecitinib is not expected to provide any clinical benefit to healthy participants of this 
study. Study B7981086 is designed to evaluate the performance of MR capsule formulations 
MR1 and MR2 of ritlecitinib under fasted and fed conditions. This study is designed 
primarily to generate safety, tolerability, and PK data for further clinical development of MR 
formulations of ritlecitinib. In this study, ritlecitinib will be administered at single doses of 
100 mg.
Ritlecitinib was determined to be well tolerated and to have an acceptable safety profile in 
the clinical studies.
Based on clinical data (single oral doses of ritlecitinib up to 800 mg and multiple oral doses 
up to 400 mg), both 400 mg QD and 200 mg BID have demonstrated their safety and 
tolerability in healthy participants. The dose of 200 mg QD has demonstrated safety and 
tolerability of up to 8 weeks in RA patients (B7981006). In those studies, no clinically 
significant changes in vital signs, electrocardiogram or laboratory data were observed. No 
dose limiting AEs were reported and no participants met the protocol specified individual 
stopping rules. Hence, ritlecitinib is predicted to be well tolerated at a single dose of 100 mg 
in this study. In addition, participant safety is ensured by inpatient monitoring during the 
dosing period and throughout 48 hours postdose.
Ritlecitinib is an immunomodulator and, as such, can be associated with the potential risk of 
infections (including serious infections), opportunistic infections, and viral reactivation. The 
risk of infection will be monitored in this study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ritlecitinib may be found in the IB, which is SRSD for this study.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention ritlecitinib 

viral reactivation

serious infections and opportunistic 
infections

malignancy and lymphoproliferative 
disorders

thromboembolism

dermatologic effects (eg, rash, acne, 
folliculitis, urticaria)

reduction in platelet count and 
lymphocyte count
Clinical experience with other JAK inhibitors 
Ritlecitinib clinical studies (B7931005, 
B7981015, B7981019, B7981032, and 
B7981037) and pre-clinical studies
Exclusion of participants at risk. Short duration of 
treatment. Safety labs at screening and baseline and when 
deemed necessary by the investigator throughout the study. AE 
monitoring throughout the study.
Study Procedures blood collection for PK
Extravasation, bruising, local discomfort
Collection of up to 12 PK plasma samples per 
period per sequence
Use of highly qualified nurses, with venipuncture 
experience. 
Use of alternating arms for adjacent time points can 
provide more resting and healing time for each arm 
between samplings.
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2.3.2. Benefit Assessment
There are no benefits to the participants in the study.
2.3.3. Overall Benefit/Risk Conclusion
Ritlecitinib will be administered for the first time as single dose of MR formulations MR1 
and MR2 in healthy participants who would be contributing to the process of developing new 
and effective formulations to maximize the therapeutic index of therapies in any 
gastrointestinal indication. Medical evaluations/assessments associated with study procedures 
(eg, physical examination, ECG and labs) will be done for all participants in the study. There 
are no benefits to the participants and the risk to the participants is considered minimal.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To determine the PK profile and relative 
bioavailability of ritlecitinib as 2 MR capsule 
formulations, MR1 and MR2, relative to 
solution formulation under fasted conditions in 
healthy adult participants.

PK parameters of ritlecitinib (fasted): Cmax,
AUCinf (if data permit), otherwise AUClast
Secondary: 
Secondary: 

To evaluate the effect of food on ritlecitinib 
exposure following administration as 2 MR 
capsule formulations, MR1 and MR2 in 
healthy adult participants.

PK parameters of ritlecitinib (fed): Cmax, AUCinf 
(if data permit), otherwise AUClast.

To evaluate safety and tolerability of 
ritlecitinib following single oral administration 
as MR1 and MR2 capsule formulations in 
healthy adult participants.

Assessment of AEs, clinical laboratory tests, 
vital signs and 12-lead ECG.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To estimate additional PK parameters of 
ritlecitinib following single oral administration 
as MR1 and MR2 capsule formulations in 
healthy adult participants.

Tmax, and if data permit, Tlag , CL/F ,Vz/F , and t½
4. STUDY DESIGN
4.1. Overall Design
This is a single dose, open-label randomized, 4-period, 6-sequence crossover study in a 
single cohort of approximately 12 healthy male and/or female participants randomized to one 
of the sequences (containing 1 solution and 2 MR [MR1 and MR2] capsule formulations of 
ritlecitinib) displayed in Table 2 where the treatment names A; B & C are representative. The 
first 3 periods are under fasted condition and the fourth period is under fed condition to 
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investigate food effect on the PK of modified release formulations MR1 and MR2. Dosing in 
each treatment period will be separated by at least 3 days to minimize any carryover effect. 
The study includes standard inpatient monitoring of study participants following single oral 
doses. Standard safety laboratory tests and urinalysis both before and after dosing will assess 
participant safety, while intensive blood draws following ritlecitinib administration will 
provide PK exposure data to characterize the relative bioavailability and absorption rate from 
different formulations. Normal venous PK blood samples for PK analysis will be collected 
pre-dose and at times specified in the SoA. For a given participant, the total study duration 
from screening to follow-up phone call will be between approximately 8 and 11 weeks.
Participants may be discharged between periods at the discretion of PI.
Participants who discontinue prior to completion of the study for reasons unrelated to safety 
may be replaced at the discretion of the PI and the sponsor. Participants withdrawn for safety 
reasons will not be replaced.
Table 2.
Study Design and Treatments
Sequence
Period 1
Period 2
Period 3
Period 4
1 (n=2)
A
B
C
B, fed
2 (n=2)
B
C
A
B, fed
3 (n=2)
C
A
B
B, fed
4 (n=2)
A
B
C
C, fed
5 (n=2)
B
C
A
C, fed
6 (n=2)
C
A
B
C, fed
Treatment A: ritlecitinib 100 mg PO solution
Treatment B: ritlecitinib 100 mg (2 × 50 mg) MR1 capsules
Treatment C: ritlecitinib 100 mg (2 × 50 mg) MR2 capsules
4.2. Scientific Rationale for Study Design
The current study aims to characterize PK and bioavailability of ritlecitinib as MR1 and MR2 
formulations relative to solution formulation and to assess the food effect on the PK of MR1 
and MR2 formulations in healthy participants. 
The formulation of ritlecitinib that is currently being used in Phase 2 studies is a commercial 
IR capsule. In order to achieve more consistent delivery to the gut, 2 new MR capsule 
formulations (MR1, MR2) designed to deliver drug in a manner that is independent of the 
variability of GI transit times in fed and fasted conditions will be evaluated in this study. 
In this study, MR1 and MR2, with in vitro release durations of 6-8 hours and 13-15 hours 
respectively, will be evaluated at a dose strength of 100 mg. Based on preliminary SimCYP 
simulations for these formulations, the sample collection up to 48 hours is deemed sufficient 
to characterize the concentration-time profile. In addition, a 3-day washout is expected to 
provide concentration <5% of Cmax in the subsequent period for this study.
4.2.1. Choice of Contraception/Barrier Requirements 
In animals, ritlecitinib was associated with fetal changes in bones and some internal organs, 
and lower fetal body weights. It is not known whether ritlecitinib is secreted into human 
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milk. Because of that and because of the investigational nature of ritlecitinib, it should not be 
administered to pregnant women, breastfeeding women, or fertile WOCBP who are 
unwilling or unable to use contraception as defined in the study protocol. Men in the study 
are not required to use birth control, because ritlecitinib is not likely to transfer to a partner 
through semen at pharmacologically relevant blood levels (see Appendix 4).
4.2.2. Collection of Retained Research Samples
Retained Research Samples will not be collected in this study.
4.3. Justification for Dose
A single dose of 100 mg is selected for MR capsules, MR1 and MR2. This dose, assuming 
50% relative bioavailability, will result in systemic exposure equal to 50 mg IR which is a 
clinically relevant dose. A 100 mg PO solution will be used to establish relative 
bioavailability with this formulation and to support deconvolution to estimate regional 
absorption. The 100 mg dose has been used in other bioavailability studies for ritlecitinib 
(B7981022, B7981029).
Based on clinical data (single oral doses of ritlecitinib up to 800 mg and multiple oral doses 
up to 400 mg), both 400 mg QD and 200 mg BID have demonstrated their safety and 
tolerability in healthy participants. The dose of 200 mg QD has demonstrated safety and 
tolerability of up to 8 weeks in RA patients (B7981006). In those studies, no clinically 
significant changes in vital signs, electrocardiogram or laboratory data were observed. No 
dose limiting AEs were reported and no participants met the protocol specified individual 
stopping rules. Hence, ritlecitinib is predicted to be well tolerated at a single dose of 100 mg 
in this study. This dose is 8-fold lower than the highest single oral dose and 4-fold lower than 
the highest repeated oral dosing regimen evaluated in previous studies.
4.4. End of Study Definition
The end of the study is defined as the date of last scheduled procedure shown in the SoA for 
the last participant in the study.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last scheduled procedure shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and female participants aged 18 years or older (or the minimum age of consent 
in accordance with local regulations) at screening who are overtly healthy as 
determined by medical evaluation including medical history, physical examination,
and laboratory tests. 
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Other Inclusion Criteria:
2.
BMI of 16-32 kg/m2, and a total body weight >45 kg (99 lb).
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
4. Capable of giving signed informed consent as described in Appendix 1 (Section 
10.1.3), which includes compliance with the requirements and restrictions listed in the 
ICD and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
5. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 

Known immunodeficiency disorder, including positive serology for HIV, or a first 
degree relative with a hereditary immunodeficiency.

Infection with hepatitis B or hepatitis C viruses according to protocol specific 
testing algorithm.
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a. For hepatitis B, all participants will undergo testing for HBsAg and HBcAb.

If HBsAg is positive, the participant must be excluded from participation in 
the study.

If HBsAg and HBcAb are both negative, the participant is eligible for study 
inclusion.

If HBsAg is negative and HBcAb is positive, HBsAb should be evaluated:
i. If HBsAb is negative, the participant must be excluded from participation in 
the study;
ii. If HBsAb is positive, the participant is eligible for study inclusion.
b. For hepatitis C, all participants will undergo testing for HCVAb. Participants 
who are HCVAb positive should be reflex-tested for HCV RNA and allowed to 
enroll only if negative.
6. Participants with any of the following acute or chronic infections or infection history:

Any infection requiring treatment within 2 weeks prior to dosing.

Any infection requiring hospitalization or parenteral antimicrobial therapy 
within 60 days of the first dose of study intervention.

Any infection judged to be an opportunistic infection or clinically significant 
by the investigator, within the past 6 months of the first dose of study 
intervention.

Known active or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections.

History of recurrent (more than one episode of) localized dermatomal herpes 
zoster, or history of disseminated (single episode) herpes simplex or 
disseminated herpes zoster.
7. History of febrile illness within 5 days prior to the first dose of study intervention.
8. History of any lymphoproliferative disorder such as EBV related lymphoproliferative 
disorder, history of lymphoma, history of leukemia, or signs or symptoms suggestive 
of current lymphatic or lymphoid disease.
9. Known present or a history of malignancy other than a successfully treated or excised 
nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in 
situ.
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10. History of active or latent Mycobacterium TBA: participant who is currently being 
treated for active or latent Mycobacterium TB infection or has a history of 
Mycobacterium TB must be excluded from the study.
11. Any medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality or other conditions that may 
increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study.
Prior/Concomitant Therapy:
12. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention with the exception of moderate/strong CYP3A inducers or inhibitors 
which are prohibited within 14 days plus 5 half-lives prior to the first dose of study 
intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details).
13. Vaccination with live attenuated replication-competent vaccine within the 6 weeks 
prior to the first dose of study intervention. (Refer to Section 5.3.5 for additional 
details).
Prior/Concurrent Clinical Study Experience:
14. Previous administration of an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). Participation in 
studies of other investigational products (drug or vaccine) at any time during their 
participation in this study.
Diagnostic Assessments:
15. A positive urine drug test. A single repeat for positive drug screen may be allowed.
16. A positive serum pregnancy test.
17. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic) for 
participants <60 years; and ≥150/90 mm/Hg for participants ≥60 years old, following 
at least 5 minutes of supine rest. If systolic BP is ≥140 or 150 mm Hg (based on age) 
or diastolic ≥90 mm Hg, the BP should be repeated 2 more times and the average of 
the 3 BP values should be used to determine the participant’s eligibility. 
18. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, 
complete LBBB, signs of an acute or indeterminate- age myocardial infarction, ST-T 
interval changes suggestive of myocardial ischemia, second- or third- degree AV 
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block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 450 ms, or 
QRS exceeds 120 ms, the ECG should be repeated twice, and the average of the 
3 QTcF or QRS values should be used to determine the participant’s eligibility. 
Computer interpreted- ECGs should be overread by a physician experienced in 
reading ECGs before excluding a participant.
19. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening or Day -1, as assessed by the study-specific- laboratory and confirmed by a 
single repeat test, if deemed necessary: 

AST or ALT level > 1.5 × ULN;

Total bilirubin level >1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN;

Hemoglobin level <120 g/L (12.0 g/dL);

Platelet count <150 × 109/L (150,000 cells/mm3);

ANC <1.2 × 109/L (1200 cells/mm3);

ALC <0.8 × 109/L (800 cells/mm3);

eGFR <60 mL/minute/1.73 m2 based on the CKD-EPI equation
In the opinion of the investigator or Pfizer (or designee), have any clinically
significant laboratory abnormality that could affect interpretation of study data or the 
participant's participation in the study.
Other Exclusion Criteria:
20. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).
21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
22. Use of tobacco/nicotine containing products in excess of 5 cigarettes/day.
23. History of severe allergic or anaphylactic reactions.
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24. WOCBP who are unwilling or unable to use an acceptable method of contraception as 
outlined in Section 10.4 during the intervention period and for at least 28 days after 
the last dose of study intervention.
25. Females on HRT and whose menopausal status is in doubt.
26. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
Investigator site staff directly involved in the conduct of the study and their family members, 
site staff otherwise supervised by the investigator, and sponsor and sponsor delegate 
employees directly involved in the conduct of the study and their family members.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. The investigator or designee will advise the participant to seek advice about the 
donation and cryopreservation of germ cells prior to the start of study intervention, if 
applicable.
At time points indicated in SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions

Administration of investigational product will be done in fasted state in Periods 1-3 of 
this study, and under high-fat meal condition in Period 4.

Under any meal condition, participants will refrain from consuming grapefruit, or 
grapefruit related- citrus fruits (eg, Seville oranges, pomelos) from 7 days prior to the 
first dose of study intervention until collection of the final PK blood sample.
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
Except when the investigational product is dosed under high-fat meal condition, the 
total daily nutritional composition should be approximately 55% carbohydrate, 
30% fat, and 15% protein and the daily caloric intake per participant should not 
exceed approximately 3200 kcal while confined.

The investigational product should be administered with approximately 240 mL of 
ambient temperature water.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.
Dosing under fasted condition:

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample.

Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices—see above) may be 
consumed with meals and the evening snack.
Dosing under fed condition:

Following an overnight fast of at least 10 hours (and collection of required laboratory 
and PK samples), participants should start a high fat (approximately 50% of total 
caloric content of the meal should be from fat; 30% from carbohydrates and 20% 
from protein – exceptions to this should be recorded), high calorie (approximately 
800 to 1000 calories) breakfast approximately 30 minutes prior to administration of 
the investigational product. The breakfast will be consumed over approximately 
20 minutes with investigational product administered within approximately 
10 minutes after completion of the meal. Participants will be encouraged to eat the 
full meal on Day 1 and are required to eat a minimum of approximately 80% of the 
meal. 

The breakfast will be a high calorie/high fat test meal. The following breakfast as a 
representative example of a high fat, high calorie meal: 2 eggs fried in butter, 2 strips 
of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes, 8 fluid 
ounces (240 mL) of whole milk.

Water can be allowed as desired except for 1 hour after investigational product 
administration. There are no water restrictions prior to dosing for participants dosed 
under fed conditions. 
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5.3.3. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period.

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol during confinement in the CRU. Participants may 
undergo an alcohol breath test or blood alcohol test at the discretion of the 
investigator.

Participants will abstain from the use of tobacco- or nicotine- containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.4. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted.

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing.
5.3.5. Vaccination
Vaccination with live virus, attenuated live virus, or any live viral components is prohibited 
within the 6 weeks prior to the first dose of investigational product, during the study, and for 
6 weeks after the last dose of the investigational product. Similarly, current routine 
household contact with individuals who have been vaccinated with live vaccine components 
should be avoided during treatment and for 6 weeks following completion of treatment. 
Following vaccination with live component vaccines, the virus may be shed in bodily fluids, 
including stool, and there is a potential risk that the virus may be transmitted.
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, vaccinia (smallpox) 
vaccine, and Zostavax® (zoster vaccine live).
Recombinant subunit vaccines (eg, HepBV, HPV) are permitted and it is preferable that the 
last dose is administered at least 4 weeks prior to Day 1. Live attenuated vaccines that are 
known not to be replication-competent in humans are permitted. Such vaccines include but 
are not limited to the Modified Vaccinia Ankara Bavarian Nordic (Jynneos®, Imvamune®, 
Imvanex®) smallpox and monkeypox vaccine. By contrast, the ACAM2000 smallpox and 
monkeypox vaccine is prohibited because it is live and replicates in humans.
Vaccines (including COVID-19 vaccines) that are not live attenuated are permitted.
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Individuals receiving immunosuppressive therapy may have a diminished response to 
vaccination.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention/enrolled in the study. Screen 
failure data are collected and remain as source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and medical devices, and other 
interventions (eg, surgical and behavioral) intended to be administered to the study 
participants during the study conduct.
For the purposes of this protocol, study intervention refers to ritlecitinib 100 mg dose.
6.1. Study Intervention(s) Administered
For this study, the study intervention is ritlecitinib, which will be administered as solution
and MR1 and MR2 capsules. 
Ritlecitinib as modified release formulations, MR1 and MR2, will be extemporaneously 
prepared by the CRU using bulk supply provided by Pfizer. Ritlecitinib PO solution dosages 
will similarly be extemporanously prepared by the CRU using materials provided by Pfizer.
Study intervention will be presented to the participants in individual dosing containers.
Table 3.
Study Interventions 
Intervention Name
ritlecitinib (100 mg)
solution
ritlecitinib (100 mg) MR1
ritlecitinib (100 mg) MR2
Type 
Small molecule
Use
Experimental
Dose Formulation
PO solution
Capsule
Capsule
Unit Dose Strength
100 mg in 100 mL 
provided in dosing bottle
50 mg/capsule
50 mg/capsule
Dosage Level
100 mg single dose
100 mg single dose
100 mg single dose
Route of 
Administration
Oral
IMP or NIMP/AxMP
IMP
Sourcing
Provided centrally by the sponsor.
Packaging and 
Labeling
Extemporaneous 
preparation by the CRU
Extemporaneous 
preparation by the CRU 
Extemporaneous 
preparation by the CRU 
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Study Interventions
Study 
Interventions
Period 1
Period 2
Period 3
Period 4
Experimental
Experimental
Experimental
Experimental
Participants will receive a single dose of IP on Day 1 of each period. 
6.1.1. Administration
Investigational products will be administered orally and according to the conditions 
described in the Schedule of Activities and Meals and Dietary Restrictions of this protocol.
Following an overnight fast of at least 10 hours, participants will receive study intervention
at approximately 0800 hours (plus or minus 2 hours). For fed period (Period 4), following an 
overnight fast of at least 10 hours, participants should start breakfast approximately 
30 minutes prior to administration of the drug product. Investigator site personnel will 
administer study intervention during each period according to the EDR and Protocol with 
ambient temperature water to a total volume of approximately 240 mL. Participants will 
swallow the study intervention whole and will not manipulate or chew the study intervention
prior to swallowing.
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing.
Administration of study intervention(s) at the site will be performed by an appropriately 
qualified and trained member of the study staff as allowed by local, state, and institutional 
guidance. 
Following administration of study intervention(s) at the site, participants will be observed for 
48 hours by an appropriately qualified and trained member of the study staff. Appropriate 
medication and other supportive measures for management of a medical emergency will be 
available in accordance with local guidelines and institutional guidelines.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, temperature) 
have been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention.
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a minimum, 
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daily minimum and maximum temperatures for all site storage locations must be 
documented and available upon request. Data for nonworking days must indicate the 
minimum and maximum temperatures since previously documented upon return to 
business.
4. Any excursions from the study intervention label storage conditions should be reported to 
Pfizer upon discovery along with actions taken. The site should actively pursue options 
for returning the study intervention to the labeled storage conditions, as soon as possible. 
Once an excursion is identified, the study intervention must be quarantined and not used 
until Pfizer provides permission to use the study intervention. Specific details regarding 
the excursion definition and information to report for each excursion will be provided to 
the site in the PCRU’s local/site procedures.
5. Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the label.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records), such as 
the IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions 
are provided in the PCRU’s local/site procedures. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the PCRU’s local/site procedures.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
Ritlecitinib MR1 and MR2 powder-in-capsules and Ritlecitinib oral solution will be prepared 
in the CRU by 2 operators, one of whom is a pharmacist. Details of dose preparation will be
given in a separate EDR. Prepared doses will be provided in unit dose containers and labeled 
in accordance with Pfizer regulations and the investigator site’s labeling requirements.
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6.3. Assignment to study intervention
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
6.4. Blinding
This is an open-label study.
6.4.1. Blinding of Participants
Participants will be unblinded to their assigned study intervention.
6.4.2. Blinding of Site Personnel
Investigators and other site staff will be unblinded to participants’ assigned study 
intervention. 
PCRU pharmacy staff responsible for preparing all study interventions will be unblinded. 
PCRU site staff providing technical system support to pharmacy staff and supporting blinded 
laboratory data processes will be unblinded. These site staff providing system support will 
not be involved in any data collection or clinic floor activities.
6.4.3. Blinding of the Sponsor
As this is an open label study, the sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of safety assessment, facilitating dose escalation
decisions, facilitating PK/PD modeling, and/or supporting clinical development.
6.5. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.6. Dose Modification
Dose modification is not permitted during the study.
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6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation.
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician. 
6.8. Treatment of Overdose
For this study, any dose of ritlecitinib greater than 800 mg within a 24-hour time period will 
be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and follow up until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).
at least until the next scheduled follow-up.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 4 days from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.
6.9. Prior and Concomitant Therapy
Participants will abstain from all concomitant treatments, except for the treatment of adverse 
events. 
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention with the exception of moderate/strong CYP3A inducers or inhibitors which are 
prohibited within 14 days plus 5 half-lives- prior to the first dose of study intervention.
Limited use of nonprescription medications that are not believed to affect participant safety 
or the overall results of the study may be permitted on a case -by -case basis following 
approval by the sponsor. Acetaminophen/paracetamol may be used at doses of ≤1 g/day.
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Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention
will be documented as concomitant treatments.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: treatment-related 
SAEs, serious infections, and other events as described in Section 5.2. 
Discontinuation of study intervention does not represent withdrawal from the study. If study 
intervention is permanently discontinued, the participant should remain in the study to be 
evaluated for safety. See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.1.1. Potential Cases of Acute Kidney Injury
Participants exposed to IMP demonstrating transient or sustained increase in Screat (with 
decrease in Screat-based eGFR or eCrCl) require expedited evaluation to differentiate AKI 
from DICI. DICI is defined as transporter-mediated effect related to altered renal tubular 
creatinine handling without histological injury.
AKI may be due to one or more types of injury, including DIKI. Differentiation of DIKI 
from other causes of AKI and from DICI may require clinical, radiographic, histopathologic, 
and laboratory assessments, as well as nephrology consultation.
Follow-up Assessments
The participant should return to the site for evaluation as soon as possible, preferably within 
48 hours of awareness of the abnormal results. 
Evaluation should include physical examination, laboratory tests, detailed medical and 
surgical history, review of all medications (including recreational drugs and supplements 
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[herbal]), family history, sexual history, travel history, blood transfusion, and potential 
occupational exposure to chemicals. 
Laboratory assessments should include simultaneous serum cystatin C (Scys) and serum 
creatinine (Screat) tests. Estimates of eGFR, eCrCl and Screat-based eGFR and combined 
Screat-Scys-based eGFR should also be derived using the appropriate equation described in 
Appendix 7: Kidney Safety: Monitoring Guidelines.
Assessments of urine albumin-to-creatinine ratio or urine volume may also be performed as 
appropriate.
Differentiating Acute Kidney Injury from DICI
A confirmed Screat increase is defined as:
(i) ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours OR 
(ii) confirmed Screat increase ≥1.5 times baseline (known or suspected to have occurred 
within the prior 7 days). 
Based on the assessments performed, suspected AKI (including DIKI) may be differentiated 
from DICI as follows.
Adult participants
AKI (including DIKI)
Any one of the below
DICI
Scys & Screat
Simultaneous, confirmed serum cystatin 
C (Scys) increase and confirmed Screat 
increase 
Confirmed Screat increase without 
confirmed increase in reflex Scys 
AND 
Confirmed Screat-based eGFR 
decrease without confirmed combined 
Screat-Scys-based eGFR decrease.
eGFR
Decrease in Screat-based eGFR and 
combined Screat-Scys-based eGFR (when 
available)
Albuminuria or 
proteinuria
Confirmed albuminuria increase (see 
Appendix 7 for Grades A1 to A3 
quantitation)
Urine volume
Urine volume <0.5 mL/kg/h for 6 
consecutive hours
Regardless of the presence or absence of increase in Screat, DIKI and other causes of AKI 
may be suspected if either there is (i) new-onset or worsening albuminuria or proteinuria are 
detected or (ii) urine volume (if measured) is <0.5 mL/kg/h for 6 consecutive hours).
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All confirmed cases of clinically relevant decrease in kidney function should be considered 
potential cases of DIKI if no other reason for the kidney function abnormalities has been 
found.
7.1.2. Liver Injury 
A participant who meets the criteria as described in Appendix 6 will be withdrawn from 
study intervention.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;

Participant meeting protocol specified criteria for discontinuation.
At the time of discontinuation from the study, if possible, an early discontinuation visit 
should be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol- specified follow- up procedures. The only 
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exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 
the participant is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law.
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
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record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days because of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may not need to be repeated, as appropriate.
Every effort should be made to ensure that protocol- required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol- required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
150 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.2. Efficacy Assessments
Efficacy parameters are not evaluated in this study. 
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
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8.3.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant- reported symptoms.
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source record 
and will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
8.3.2.1. Blood Pressure and Pulse Rate
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
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8.3.2.2. Temperature
Body temperature will be measured. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
8.3.3. Electrocardiograms
Standard 12-lead ECGs will be collected at times specified in the SoA section of this
protocol using an ECG system that automatically calculates the HR and measures PR, QT, 
QTcF, and QRS intervals. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 5 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements, defined as pre-dose ECG of the current period.
Additional ECG monitoring will occur if a) a postdose QTc interval is increased by ≥60 msec
from the baseline and is >450 msec; or b) an absolute QTc value is ≥500 msec for any 
scheduled ECG. If either of these conditions occurs, then 2 additional ECGs will be collected 
approximately 2 to 4 minutes apart to confirm the original measurement. If the QTc values 
from these repeated ECGs remain above the threshold value, then a single ECG must be 
repeated at least hourly until QTc values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 8.
8.3.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
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Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 calendar days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
Participants may undergo random urine drug testing at the discretion of the investigator.
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments
Participants will be tested for COVID-19 prior to being admitted to the clinic for 
confinement), or if they develop COVID-19-like symptoms as required by local regulations 
or by the PI.
8.3.6. Pregnancy Testing
A urine or serum pregnancy test is required at screening. Following screening, pregnancy 
tests may be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. 
Pregnancy tests will be performed in WOCBP at the times listed in the SoA. Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced,
and a second negative pregnancy test result will be required at the baseline visit prior to 
starting the study intervention. Pregnancy tests will also be done whenever 1 menstrual cycle 
is missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study. Pregnancy tests may also be repeated if requested by 
IRBs/ECs or if required by local regulations. If a urine test cannot be confirmed as negative 
(eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded if the serum pregnancy result is positive.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
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authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has concluded study participation, and they 
consider the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
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8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious 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.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
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Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.
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
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then inseminates his female partner prior to or around 
the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until at least 28 days after last dose 
of study intervention.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed report is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial report. 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 reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
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Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
inhalation, or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so the 
information is not recorded on a CRF. However, a copy of the completed report is 
maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure 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 about the occupational exposure does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completedreport is maintained in the investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
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8.4.7. Disease Related- Events and/or Disease -Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
GI disorders that include constipation, feces discoloration, diarrhea, dyspepsia, flatulence, 
nausea, vomiting, abdominal pain and occult blood will be reported as AEs of special interest 
to assess local tolerability of the MR formulations. 
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes. Should an aggregate analysis indicate that 
these prespecified events occur more frequently than expected, eg, based on epidemiological 
data, literature, or other data, then this will be submitted and reported in accordance with 
Pfizer’s safety reporting requirements. Aggregate analyses of safety data will be performed 
on a regular basis per internal SOP. 
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.4.1 through Section 8.4.4. An AESI is to be recorded as an AE or SAE on the CRF. 
In addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
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Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, such medication errors occurring to a study participant are recorded on the 
medication error page of the CRF, which is a specific version of the AE page and, if 
applicable, any associated serious and nonserious AE(s), are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
Blood samples of approximately 2 mL, to provide a minimum of 0.5 mL of plasma, will be 
collected for measurement of plasma concentrations of ritlecitinib as specified in the SoA. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples will be used to evaluate the PK of study intervention. Samples collected for analyses 
of study intervention (plasma) concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study, for metabolite identification 
and/or evaluation of the bioanalytical method, or for other internal exploratory purposes. The 
exploratory results may not be reported in the CSR.
Genetic analyses will not be performed on these PK plasma samples. Participant 
confidentiality will be maintained.
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Samples collected for measurement of plasma concentrations of study intervention will be 
analyzed using a validated analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case -by -case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.5.1. Feces collection and analysis
Feces will be collected for following oral administration of ritlecitinib (Treatment C only) up 
to 72 hours.
Details of the collection of aliquots, volume, processing, storage and shipping of the urine
and feces samples will be provided in the lab manual and supporting documentation. The
actual date and time (24-hour clock time) of each sample will be recorded. Samples may be 
analyzed at the discretion of the sponsor based on PK data from the study.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
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modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No formal inferential statistics will be applied to the safety or PK data.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled 
“Enrolled” means a participant’s, or their legally 
authorized representative’s, agreement to participate in a 
clinical study following completion of the informed 
consent process and randomization. 
Full analysis set 
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention. 
Participants will be analyzed according to the product 
they actually received.
Safety analysis set
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention.
Participants will be analyzed according to the product 
they actually received.
Defined Analysis Set
Description
PK Concentration
The PK concentration population is defined as all participants 
randomized and treated who have at least 1 concentration in 
at least 1 treatment period.
PK Parameter
The PK parameter analysis population is defined as all 
participants randomized and treated who have at least 1 of the 
PK parameters of primary interest in at least 1 treatment 
period.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
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9.3.1. General Considerations
Details of the analyses will be provided in the Statistical Analysis Plan. Briefly, ritlecitinib 
concentrations will be listed by participant and treatment, and summarized by treatment and 
food condition. Individual participant mean and median profiles of the plasma concentration-
time data will be plotted by treatment and food condition using actual and nominal times, 
respectively. Mean and median profiles will be presented on both linear and log scales. Data 
permitting the PK parameters AUClast, AUCinf, Cmax, Tmax, and t½ will be summarized by 
treatment and food condition as per Pfizer data standards. 
For relative bioavailability analysis, the single dose of ritlecitinib MR1 and MR2 
administered in fasted state are the Test treatments. Single dose of ritlecitinib solution under 
fasted condition is the Reference treatment. For food effect assessment, PF-06651600 MR1 
and MR2 in fasted state are the Reference treatments while ritlecitinib MR1 and MR2
administered in fed state are Test treatments.
For the relative bioavailability evaluation, natural log transformed AUCinf (if data permit), 
AUClast and Cmax will be analyzed using a mixed effect model with treatment, sequence, and 
period as fixed effects and participant within sequence as a random effect. For the food effect 
evaluation, natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed 
using a mixed effect model with sequence and treatment as fixed effects and participant 
within sequence as a random effect. In both analyses, estimates of the adjusted mean 
differences (Test-Reference) and corresponding 90% confidence intervals will be obtained 
from the model. The adjusted mean differences and 90% confidence intervals for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% confidence intervals for the ratios.
9.3.2. Pharmacokinetic analysis
Pharmacokinetic parameters following a single dose administration will be derived from the 
concentration-time profiles (actual PK sampling times will be used in the derivation of PK 
parameters) as follows in Table 4.
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Table 4.
Definitions of PK Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentrationtime profile from time 
0 to the time of the last quantifiable 
concentration (Clast) 
Linear/Log trapezoidal method
AUCinfa
Area under the plasma 
concentration-time profile from time 
0 extrapolated to infinite time
AUClast + (Clast/kel),
where Clasta is the predicted plasma concentration 
at the last quantifiable time point estimated from 
the log-linear regression analysis 
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t½a
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the log-linear 
concentration-time curve. Only those data points 
judged to describe the terminal log-linear decline 
will be used in the regression
CL/Fa
Apparent Clearance 
Dose/AUCinf
Vz/Fa
Apparent volume of distribution 
after oral dose
Dose/(AUCinf*kel) after oral dose
Tlaga
Lag time
Time prior to the time corresponding to the first 
quantifiable concentration
a if data permits
9.3.3. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
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collection period will be captured as AEs, if those findings meet the definition of an AE.
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
9.3.3.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Degree of 
Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
9.3.4. Other Analyses 
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned to 
be included in the CSR.
9.4. Interim Analyses
No interim analysis will be conducted for this study.
9.5. Sample Size Determination
A sufficient number of participants will be screened to achieve 12 participants randomly 
assigned to study interventions such that exactly 2 participants will be enrolled to each of the 
6 sequences. The sample size is empirically selected and is not based on statistical power 
calculation. 
Analyses of data from studies B7981022, B7981029, and B7981030 suggest a 
within-participant standard deviation of 0.117 for log (AUC inf) and within-participant 
standard deviation of 0.226 for log (Cmax). The sample size of approximately 12 participants 
has been chosen.
The following table (Table 5) presents the reference boundaries and width of the confidence 
intervals for a range of estimates of the means ratio for pairs of treatments (Test vs 
Reference). The calculation assumes the selection of the default value (80%) of the tolerance 
parameter in the conventional calculation1. The values of within- participant standard 
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deviations (standard deviation of 0.117 for log (AUCinf) and standard deviation of 0.226 for 
log (Cmax)) and corresponding widths of the confidence intervals were used. The width of the 
confidence intervals for fed versus fasted comparison is larger because only half of the 
participants contribute observations for this comparison.
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Table 5.
Expected Widths of the 90% Confidence Intervals (With 80% Tolerance Probability) for Different Possible 
Estimated Effects of ritlecitinib MR1 and MR2 Formulations in Fasted and Fed Conditions on PK Parameters
Estimated 
ratio of 
means
n=6
n=12
n=18
AUCinf
Cmax
AUCinf
Cmax
AUCinf
Cmax
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
MR/solution
0.1
(0.08,0.12)
0.03
(0.07,0.14)
0.06
(0.09,0.11)
0.02
(0.08,0.12)
0.04
(0.09,0.11)
0.02
(0.09,0.12)
0.03
0.2
(0.17,0.24)
0.07
(0.15,0.27)
0.13
(0.18,0.22)
0.04
(0.17,0.24)
0.08
(0.19,0.22)
0.03
(0.17,0.23)
0.06
0.3
(0.25,0.35)
0.10
(0.22,0.41)
0.19
(0.27,0.33)
0.06
(0.25,0.36)
0.12
(0.28,0.32)
0.05
(0.26,0.35)
0.09
0.4
(0.34,0.47)
0.13
(0.29,0.55)
0.26
(0.36,0.44)
0.08
(0.33,0.48)
0.15
(0.37,0.43)
0.06
(0.35,0.46)
0.12
0.5
(0.42,0.59)
0.17
(0.36,0.69)
0.32
(0.45,0.55)
0.10
(0.41,0.61)
0.19
(0.46,0.54)
0.08
(0.43,0.58)
0.15
0.6
(0.51,0.71)
0.20
(0.44,0.82)
0.39
(0.54,0.66)
0.12
(0.50,0.73)
0.23
(0.56,0.65)
0.09
(0.52,0.70)
0.18
0.7
(0.59,0.83)
0.23
(0.51,0.96)
0.45
(0.63,0.77)
0.14
(0.58,0.85)
0.27
(0.65,0.76)
0.11
(0.60,0.81)
0.21
0.8
(0.68,0.94)
0.26
(0.58,1.10)
0.52
(0.72,0.88)
0.16
(0.66,0.97)
0.31
(0.74,0.86)
0.12
(0.69,0.93)
0.24
0.9
(0.76,1.06)
0.30
(0.66,1.24)
0.58
(0.82,0.99)
0.18
(0.74,1.09)
0.35
(0.83,0.97)
0.14
(0.78,1.04)
0.27
1
(0.85,1.18)
0.33
(0.73,1.37)
0.65
(0.91,1.10)
0.20
(0.83,1.21)
0.38
(0.93,1.08)
0.15
(0.86,1.16)
0.30
1.1
(0.93,1.30)
0.36
(0.80,1.51)
0.71
(1.00,1.21)
0.22
(0.91,1.33)
0.42
(1.02,1.19)
0.17
(0.95,1.28)
0.33
1.2
(1.02,1.41)
0.40
(0.87,1.65)
0.77
(1.09,1.32)
0.24
(0.99,1.45)
0.46
(1.11,1.30)
0.18
(1.04,1.39)
0.36
MR fed/fasted
0.1
(0.07,0.14)
0.07
(0.05,0.20)
0.15
(0.08,0.12)
0.03
(0.07,0.14)
0.06
(0.09,0.11)
0.02
(0.08,0.13)
0.05
0.2
(0.14,0.28)
0.14
(0.10,0.40)
0.30
(0.17,0.24)
0.07
(0.15,0.27)
0.13
(0.18,0.23)
0.05
(0.16,0.25)
0.09
0.3
(0.21,0.43)
0.22
(0.15,0.59)
0.44
(0.25,0.35)
0.10
(0.22,0.41)
0.19
(0.27,0.34)
0.07
(0.24,0.38)
0.14
0.4
(0.28,0.57)
0.29
(0.20,0.79)
0.59
(0.34,0.47)
0.13
(0.29,0.55)
0.26
(0.35,0.45)
0.10
(0.32,0.50)
0.19
0.5
(0.35,0.71)
0.36
(0.25,0.99)
0.74
(0.42,0.59)
0.17
(0.36,0.69)
0.32
(0.44,0.56)
0.12
(0.40,0.63)
0.23
0.6
(0.42,0.85)
0.43
(0.30,1.19)
0.89
(0.51,0.71)
0.20
(0.44,0.82)
0.39
(0.53,0.68)
0.14
(0.48,0.76)
0.28
0.7
(0.49,1.00)
0.51
(0.35,1.39)
1.03
(0.59,0.83)
0.23
(0.51,0.96)
0.45
(0.62,0.79)
0.17
(0.55,0.88)
0.33
0.8
(0.56,1.14)
0.58
(0.40,1.58)
1.18
(0.68,0.94)
0.26
(0.58,1.1)
0.52
(0.71,0.90)
0.19
(0.63,1.01)
0.38
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Table 5.
Expected Widths of the 90% Confidence Intervals (With 80% Tolerance Probability) for Different Possible 
Estimated Effects of ritlecitinib MR1 and MR2 Formulations in Fasted and Fed Conditions on PK Parameters
Estimated 
ratio of 
means
n=6
n=12
n=18
AUCinf
Cmax
AUCinf
Cmax
AUCinf
Cmax
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
90% CI 
CI width
0.9
(0.63,1.28)
0.65
(0.45,1.78)
1.33
(0.76,1.06)
0.30
(0.66,1.24)
0.58
(0.80,1.02)
0.22
(0.71,1.14)
0.42
1
(0.70,1.42)
0.72
(0.50,1.98)
1.48
(0.85,1.18)
0.33
(0.73,1.37)
0.65
(0.89,1.13)
0.24
(0.79,1.26)
0.47
1.1
(0.77,1.57)
0.79
(0.56,2.18)
1.62
(0.93,1.30)
0.36
(0.80,1.51)
0.71
(0.98,1.24)
0.27
(0.87,1.39)
0.52
1.2
(0.84,1.71)
0.87
(0.61,2.38)
1.77
(1.02,1.41)
0.40
(0.87,1.65)
0.77
(1.06,1.35)
0.29
(0.95,1.51)
0.56
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or the investigator's representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their 
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
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Participants must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations.
A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples. The investigator or 
authorized designee will explain to each participant the objectives of the additional research.
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period. A separate signature will be 
required to document a participant’s agreement to allow specimens to be used for additional 
research. Participants who decline to participate in this optional additional research will not 
provide this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participan-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
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10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
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the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents.
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
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When participant’s data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes a source document and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor’s designee (Pfizer CRU).
The investigator must maintain accurate documentation (source record) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Use of Medical Records
There may be instances when copies of medical records for certain cases are requested by 
Pfizer Safety, where ethically and scientifically justified and permitted by local regulations, 
to ensure participant safety.
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Due to the potential for a participant to be re-identified from their medical records, the 
following actions must be taken when medical records are sent to the sponsor or sponsor 
designee:

The investigator or site staff must redact personal information from the medical 
record. The personal information includes, but is not limited to, the following:
participant names or initials, participant dates (eg, birth date, date of hospital 
admission/discharge, date of death), participant identification numbers (eg, Social 
Security number, health insurance number, medical record number, 
hospital/institution identifier), participant location information (eg, street address, 
city, country, postal code, IP address), participant contact information (eg, 
telephone/fax number, email address).

Each medical record must be transmitted to the sponsor or sponsor designee using 
systems with technical and organizational security measures to ensure the protection 
of personal data (eg, Florence is the preferred system if available). 
There may be unplanned situations where the sponsor may request medical records (eg, 
sharing medical records so that the sponsor can provide study-related advice to the 
investigator). The medical records should be submitted according to the procedure described 
above.
10.1.10. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study site 
closure visit has been performed.
The investigator may initiate study site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;
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
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.11. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. 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 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study intervention or Pfizer related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
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10.1.12. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the SToD team Roster.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’s study identification number, (c) site 
emergency phone number active 24 hours/day, 7 days per week.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. 
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests (Table 6) will be performed at times defined in the SoA
section of this protocol. Additional laboratory results may be reported on these samples as a 
result of the method of analysis or the type of analyzer used by the clinical laboratory, or as 
derived from calculated values.  These additional tests would not require additional 
collection of blood. Unscheduled clinical laboratory measurements may be obtained at any 
time during the study to assess any perceived safety issues.
Table 6.
Protocol Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Direct bilirubinh
Indirect bilirubin
Cystatin C
Local dipstick:
pHa
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Spot urine
Laboratory:
Microscopyb

Urine drug screeningc

Pregnancy test (-hCG)d

eGFR-CKD-EPI 2021
At screening only:

Serum FSHe

Hepatitis B surface 
antigenf

Hepatitis B core antibodyf

Hepatitis C virus (HCV) 
RNA

Hepatitis C antibodyf

Human immunodeficiency 
virus

QuantiFERON® TB Gold 
or equivalentg
a. Can be performed on dipstick or pH-meter device.
b. Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
c. At Screening and Admission. The minimum requirement for drug screening includes cocaine, THC, 
opiates/opioids, benzodiazepines, and amphetamines (others are site and study specific).
d. Serum β-hCG for female participants of childbearing potential.
e. At Screening for confirmation of postmenopausal status only.
f. If HBsAg is negative and HBcAb is positive, HBsAb should be evaluated.
g. Complete at screening. Previous testing for QuantiFERON® TB Gold Test will be accepted if completed 
within 12 weeks prior to screening. Otherwise, the testing should be completed at screening and results 
available prior to Day 1.
h. Only if total bilirubin is elevated.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
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purpose will be shipped to either a Pfizer approved- BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal test results that meet any of the conditions below must be recorded as 
an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
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d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations, such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious. The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are 
considered synonymous. These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel. Such cases are also 
considered for reporting as product defects, if appropriate.
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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs using the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure 
to the product under 
study to a 
nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
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*
EDP (with or without an associated SAE): is reported to Pfizer Safety using the CT SAE Report 
Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form.

When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. Refer to Section 10.1.9 for actions 
that must be taken when medical records are sent to the sponsor or sponsor 
designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
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An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the
sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
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Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eg, eSAE or PSSA).

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
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SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is one of the methods to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are not required to use contraception in this study, because ritlecitinib is 
not likely to transfer to a partner through semen at pharmacologically relevant blood levels.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and agrees to use an acceptable contraceptive method during the 
intervention period (for a minimum of 28 days after the last dose of study 
intervention). The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea or oligomenorrhea) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
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For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
3. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
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been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation used in combination with a barrier method:

Oral + barrier*;

Intravaginal + barrier*;

Transdermal + barrier*.
7. Progestogen only hormone contraception associated with inhibition of ovulation used 
in combination with a barrier method:

Oral + barrier*;

Injectable + barrier*.
Sexual Abstinence
8. 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.
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following

Male or female condom, with or without spermicide.

Cervical cap, diaphragm, or sponge with spermicide.
Male condom and female condoms should not be used together (due to risk of failure with 
friction).
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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses.

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili 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 T bili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For participants with baseline AST OR ALT OR T bili 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 T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
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Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, eosinophils (%), and alkaline phosphatase. Consideration should also be 
given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology. A detailed history, including relevant information, 
such as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or 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, total bile acids, liver imaging (eg, biliary tract), and 
collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline Screat 
measurement to estimate kidney function [Screat-based eGFR] or creatinine clearance 
[eCrCl]). Obtaining Screening or Baseline Scys and postbaseline reflex Scys (if confirmed 
Screat increase ≥0.3 mg/dL) makes it feasible to distinguish AKI from DICI. If Screat 
increase is confirmed after baseline, then reflex measurement of Scys is indicated:
ADULTS: Currently, 2021 CKD-EPI eGFR equations (Screat only-based and combined 
Screat plus Scys-based) are valid for use in adults only. At baseline Screat and Scys values 
are needed to calculate 2021 CKD-EPI eGFR by Screat only-based equation (see 
Section 10.7.2.1) and by combined Screat plus Scys-based equation. When post-baseline 
Screat increase ≥0.3 mg/dL is confirmed, then reflex Scys measurement is needed to enable 
post-baseline comparison of eGFR changes (Screat only-based eGFR and combined Screat 
plus Scys eGFR). 
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
eGFR (mL/min/1.73m²)2
2021 CKD-
EPI      Screat
Only
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
NA
eGFR = 143 × (Screat/0.7)-0.241 × (0.9938)Age
Female
if > 0.7
NA
eGFR = 143 × (Screat/0.7)-1.200 × (0.9938)Age
Male
if ≤ 0.9
NA
eGFR = 142 × (Screat/0.9)-0.302 × (0.9938)Age
Male
if > 0.9
NA
eGFR = 142 × (Screat/0.9)-1.200 × (0.9938)Age
2021 CKD-
EPI     
Screat-Scys 
Combined
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if ≤ 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age
Female
if > 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if ≤ 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if ≤ 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if > 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
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10.7.3. Kidney Function Calculation Tools
The sponsor has provided the following resources to investigational sites when required to 
calculate age-specific kidney function at Screening, Baseline, and post-Baseline visits. Site 
calculations of kidney function can be performed manually, using the age appropriate 
formulae (see Section 10.7.2) and can use recommended online kidney function calculators 
to reduce the likelihood of a calculation error. 
The United States National Kidney Foundation Online Calculators. 

Adults (18 years and above) - 2021 CKD-EPI Creatinine Online Calculator (eGFR): 
https://www.kidney.org/professionals/KDOQI/gfr_calculator
Investigational sites are responsible to ensure that the accurate age-specific equation is 
selected and that the correct units are used for serum creatinine (mg/dL only), serum cystatin 
C (mg/L only), total body weight (kg only), and age (years). Investigators are expected to (i) 
review and confirm correctness of the kidney function calculation results and (ii) evaluate the 
calculated value within the context of historical information available to them in the 
participant’s medical record. Investigators are responsible for the clinical oversight of the 
participant eligibility process, kidney function calculation, and dose selection and 
adjustments per study protocol. Investigators are encouraged to direct questions or 
uncertainties regarding kidney function and dosing to the Pfizer Clinical Team and Medical 
Monitor, if needed.
10.7.4. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to Kidney 
Disease: Improving Global Outcomes (KDIGO) criteria for both pediatric and adult 
participants.
KDIGO criteria 
grade (G)
Study 
Population
G1
G2
G3
G4
G5
Decreased Kidney 
Function due to 
either Acute or 
Chronic Kidney 
Injury 
Adult 
participants
eGFR 
(mL/min/1.73m²)
≥90 
≥60 to 89
30 to 59 
15 to 29
<15
KDIGO albuminuria (A) 
criteria
A1
A2
A3
Albumin-to-creatinine 
ratio (ACR)
<30 mg/g
OR  
<3 mg/mmol 
30 to 300 mg/g
OR 
3 to 30 mg/mmol
>300 mg/g 
OR 
>30 mg/mmol
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CTCAE 
Term (2017)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
AKI
NA
NA
Hospitalization 
indicated
Life-
threatening 
consequences; 
dialysis 
indicated
Death
AKI: A disorder characterized by acute loss of kidney function (within 2 weeks) and is traditionally classified as 
pre-renal (low blood flow into kidneys), renal (kidney damage), or post-renal causes (ureteral or bladder outflow 
obstruction.
Creatinine 
increased
>ULN to 1.5 ×
ULN
>1.5 to 3.0 ×
baseline OR
>1.5 to 3.0 ×
ULN
>3.0 to 6.0 ×
baseline OR 
>3.0 to 6.0 ×
ULN
>6.0 × ULN
NA
CKD
eGFR ≥60 to 89 
mL/min/1.73m² 
OR        eCrCl 
≥60 to 80 
mL/min 
eGFR 30 to 59 
mL/min/1.73m² 
OR         eCrCl 
30 to 59 
mL/min
eGFR 15 to 29 
mL/min/1.73m² 
OR        eCrCl 
15 to 29 
mL/min
eGFR <15 
mL/min/1.73m² 
OR       eCrCl 
<15 mL/min      
OR      dialysis 
indicated
Death
Proteinuria
ADULTS: 
Proteinuria 1+ 
OR        
Proteinuria >0.5 
to <1.0 g/24 h
ADULTS: 
Proteinuria 2+ 
or 3+       OR      
Proteinuria 1.0 
to <3.5 g/24 h
ADULTS: 
Proteinuria 4+     
OR        
Proteinuria 
≥3.5 g/24 h
NA
NA
CKD: A disorder characterized by gradual and usually permanent loss of kidney function resulting in kidney 
failure.
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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute).

New prolongation of QTcF by >60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30-second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

Absolute value of QTcF > 450 ms AND QTcF change from baseline >60 ms.

New ST-T changes suggestive of myocardial ischemia.

New onset- LBBB (QRS complex>120 ms).

New onset- right bundle branch block (QRS complex>120 ms).

Symptomatic bradycardia.

Asystole

In awake, symptom-free- participants in sinus rhythm, with documented 
asystolic pauses ≥3 seconds or any escape rate <40 bpm, or with an escape 
rhythm that is below the AV node;

In awake, symptom-free- participants with atrial fibrillation and bradycardia 
with 1 or more asystolic pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.
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
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as
torsades de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30-seconds duration).

Second- or third degree- AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The major events of potential clinical concern listed above are recommended as “alerts” or notifications 
from the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all-
inclusive of what is to be reported as AEs/SAEs.
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10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AA
alopecia areata
Abs
absolute
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under the plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time 0 to 
the time of the last quantifiable concentration
AV
atrioventricular
AxMP
auxiliary medicinal product
BAEP
brainstem auditory evoked potential
-hCG
-human chorionic gonadotropin
BID
twice a day
BMI
body mass index
BP
blood pressure
Bpm
beats per minute
BUN
blood urea nitrogen
CD
Crohn’s Disease
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology
CL/F
Apparent clearance after oral dose
Cmax
maximum observed concentration
CNS
central nervous system
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
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Abbreviation
Term
CSR
Clinical Study Report
CT
clinical trial
CTIS
Clinical Trial Information System
DCT
data collection tool
DICI
drug-induced creatinine increase
DIKI
drug-induced kidney injury
DILI
drug-induced liver injury
DR
dose ranging
EBV
Epstein Barr Virus
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal 
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IL
interleukin
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Abbreviation
Term
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IP
investigational product
IPAL
Investigational Product Accountability Log
IR
immediate release
IRB
Institutional Review Board
JAK
Janus kinase
KDIGO
Kidney Disease Improving Global Outcomes
kel
first-order elimination rate constant
t½
terminal phase half-life
LBBB
left bundle branch block
LFT
liver function test
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MMR
measles, mumps, rubella
MQI
medically qualified individual
MR
modified release
NA (N/A)
not applicable; not available
NIMP
non-investigational medicinal product
NOAEL
no-observed-adverse-effect level
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
PI
principle investigator
PK
pharmacokinetic(s)
PNS
peripheral nervous system
PO
orally
PSSA
Pfizer’s Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
Once a day
QFT-G
QuantiFERON®-TB Gold In-Tube
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
RA
rheumatoid arthritis
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
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Abbreviation
Term
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Scys
serum cystatin C
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
tuberculosis 
T bili
total bilirubin
TEAE
treatment-emergent adverse events
TEC
tyrosine kinase expressed in hepatocellular carcinoma
THC
tetrahydrocannabinol
Tlag
time before the first concentration above the limit of 
quantification or above the first concentration in the interval
Tmax
time for maximum plasma concentration
TP
treatment period
TYK
tyrosine kinase
ULN
upper limit of normal
UC
ulcerative colitis
URTI
upper respiratory tract
US
United States
Vz/F
apparent volume of distribution
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of non childbearing potential
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11. REFERENCES
1.
. Sample size calculation: cross-over trials to demonstrate 
bioequivalence or estimate bioavailability. Clinical biostatistics technical report #5.1 
(Version Date: April 24, 2002)
2.
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49.
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SAP_001.pdf: 
Protocol B7981086 (PF-06651600 Ritlecitinib) Statistical Analysis Plan
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022
PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
Page 1 of 22
Protocol B7981086
A PHASE 1, OPEN-LABEL STUDY IN HEALTHY PARTICIPANTS TO 
INVESTIGATE THE PHARMACOKINETICS OF RITLECITINIB FOLLOWING 
SINGLE ORAL ADMINISTRATION OF MODIFIED RELEASE FORMULATIONS 
UNDER FED AND FASTED CONDITIONS
Statistical Analysis Plan 
(SAP)
Version:
2.0  
Date:
25 Mar 2024
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Protocol B7981086 (PF-06651600 Ritlecitinib) Statistical Analysis Plan
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................5
2.1. Modifications to the Analysis Plan Described in the Protocol..................................5
2.2. Study Objectives, Endpoints, and Estimands............................................................5
2.3. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint(s) ..................................................................................................7
3.2. Secondary Endpoint(s) ..............................................................................................7
3.3. Tertiary/Exploratory Endpoint(s)..............................................................................8
3.4. Baseline Variables.....................................................................................................8
3.5. Safety Endpoints .......................................................................................................8
3.5.1. Adverse Events.............................................................................................9
3.5.2. Laboratory Data............................................................................................9
3.5.3. Vital Signs ....................................................................................................9
3.5.4. ECG ..............................................................................................................9
3.5.5. Other Safety Data .........................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................10
4.1. Treatment Misallocations........................................................................................10
4.2. Protocol Deviations.................................................................................................10
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................11
5.1. Hypotheses and Decision Rules ..............................................................................11
5.2. General Methods .....................................................................................................11
5.3. Methods to Manage Missing Data ..........................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoint(s) ................................................................................................12
6.2. Secondary Endpoint(s) ............................................................................................13
6.3. Tertiary/Exploratory Endpoint(s)............................................................................14
6.4. Descriptive and Graphical Summaries of PK Parameters.......................................14
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6.5. Baseline and Other Summaries and Analyses.........................................................15
6.5.1. Study Conduct and Participant Disposition................................................15
6.5.2. Study Treatment Exposure .........................................................................16
6.5.3. Concomitant Medications and Nondrug Treatments..................................16
6.6. Safety Summaries and Analyses .............................................................................16
6.6.1. Adverse Events...........................................................................................16
6.6.2. Laboratory Data..........................................................................................16
6.6.3. Vital Signs ..................................................................................................16
6.6.4. Electrocardiograms.....................................................................................16
7. INTERIM ANALYSES.......................................................................................................16
7.1. Introduction .............................................................................................................16
7.2. Interim Analyses and Summaries............................................................................17
APPENDICES .........................................................................................................................18
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Study Design and Treatments.....................................................................6
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....18
Appendix 2. Example SAS Code for Analyses .......................................................................19
Appendix 3. List of Abbreviations...........................................................................................21
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
15 Aug 2023
Original 
19 Jun 2023
N/A
N/A
2
25 Mar 2024
Protocol 
Amendment 1
07 Nov 2023
To remove 
analysis related 
to PK collection
via Tasso to be 
consistent with 
Protocol 
Amendment 1, 
and modify 
safety analysis
for ECG and 
VS.
Section 2.2 removed tertiary objective and 
endpoints related to Tasso micro-sampling 
device
Section 3.1, 3.2 updated notation for Kel
Section 3.3 removed analysis of the
endpoints related to Tasso micro-sampling 
device
Section 3.4 modified baseline definitions 
for ECG and VS
Section 3.5.3 modified language on post-
baseline for calculation of change from 
baseline in vital signs; removed calculation 
for maximum decrease/increase
Section 3.5.4 modified language on post-
baseline for calculation of change from 
baseline in ECG; removed calculation for 
maximum decrease/increase
Section 4,  removed section reference 
related to PK analysis of Tasso micro-
sampling device
Section 6.4 removed PK concentration 
presentation for Tasso micro-sampling 
device
Section 6.5 modified language for 
demographic summary to be by gender and 
overall
Section 6.6.3 modified language for vital 
signs summary to be for Periods 1-3 and 
Period 4
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Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Section 6.6.4 modified language for ECG 
summary to be for Periods 1-3 and Period 
4; removed using average for replicate 
measurements
Appendix 1, updated categorization of 
ECG and VS to be based on change from 
baseline
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B7981086. This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition will also be reflected in a protocol amendment.
(copied from protocol)
Ritlecitinib is a covalent and irreversible inhibitor of JAK3 with high selectivity over the 
other JAK isoforms (JAK1, JAK2, and TYK2). Ritlecitinib also inhibits irreversibly the 
tyrosine kinase expressed in TEC family kinases with selectivity over the broader human 
kinome. Treatment with ritlecitinib is expected to inhibit the inflammatory pathways 
mediated by IL-7, IL-15 and IL-21, all implicated in UC, CD, AA, RA, and vitiligo. 
Moreover, due to lack of activity against the other JAK isoforms, ritlecitinib is expected to 
spare immunoregulatory cytokines such as IL-10, IL-27 and IL-35, which are critical to the 
maintenance of immunosuppressive functions and immune homeostasis.
The purpose of the study is to evaluate the PK, safety, and tolerability of ritlecitinib
following single oral doses as solution and MR formulations in healthy, adult participants 
under fasted and fed conditions. The objective is to evaluate the relative bioavailability and 
food effect of 2 new MR capsule formulations, MR1 and MR2. Overall, results from this 
study will facilitate further development of an MR formulation for future clinical studies.
2.1. Modifications to the Analysis Plan Described in the Protocol
Not applicable.
2.2. Study Objectives, Endpoints, and Estimands
As this is an inpatient, healthy volunteer study, estimands are not applicable. The table below 
is copied directly from the protocol.
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Protocol B7981086 (PF-06651600 Ritlecitinib) Statistical Analysis Plan
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Objectives
Endpoints
Primary: 
Primary: 

To determine the PK profile and relative 
bioavailability of ritlecitinib as 2 MR capsule 
formulations, MR1 and MR2, relative to 
solution formulation under fasted conditions in 
healthy adult participants.

PK parameters of ritlecitinib (fasted): Cmax,
AUCinf (if data permit), otherwise AUClast
Secondary: 
Secondary: 

To evaluate the effect of food on ritlecitinib
exposure following administration as 2 MR 
capsule formulations, MR1 and MR2 in 
healthy adult participants.

PK parameters of ritlecitinib (fed): Cmax, AUCinf 
(if data permit), otherwise AUClast.

To evaluate safety and tolerability of 
ritlecitinib following single oral administration 
as MR1 and MR2 capsule formulations in 
healthy adult participants.

Assessment of AEs, clinical laboratory tests, 
vital signs and 12-lead ECG.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To estimate additional PK parameters of 
ritlecitinib following single oral administration 
as MR1 and MR2 capsule formulations in 
healthy adult participants.

Tmax, and if data permit, Tlag , CL/F ,Vz/F , and t½
2.3. Study Design
This is a single dose, open-label randomized, 4-period, 6-sequence crossover study in a 
single cohort of approximately 12 healthy male and/or female participants randomized to one 
of the sequences (containing 1 solution and 2 MR [MR1 and MR2] capsule formulations of 
ritlecitinib) displayed in Table 2. The first 3 periods are under fasted condition and the fourth 
period is under fed condition to investigate food effect on the PK of modified release 
formulations MR1 and MR2. 
Table 2.
Study Design and Treatments
Sequence
Period 1
Period 2
Period 3
Period 4
1 (n=2)
A
B
C
B, fed
2 (n=2)
B
C
A
B, fed
3 (n=2)
C
A
B
B, fed
4 (n=2)
A
B
C
C, fed
5 (n=2)
B
C
A
C, fed
6 (n=2)
C
A
B
C, fed
A: ritlecitinib 100 mg PO solution
B: ritlecitinib 100 mg (2 x 50 mg) MR1 capsules
C: ritlecitinib 100 mg (2 x 50 mg) MR2 capsules
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The PK profile and relative bioavailability of ritlectinib as 2 MR capsule formulations, MR1 
and MR2, relative to solution formulation under fasted conditions will be derived from the 
concentration-time profiles as shown in the table below, if data permit.
Parameter
Definition
Method of Determination
Cmax
Maximum plasma concentration
Observe directly from the data
AUClast
Area under the plasma 
concentration versus time curve 
from time zero to the time of last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinfa
Area under the plasma 
concentration versus time curve
AUClast + (Clast/kel), where Clast is the predicted 
plasma concentration at the last quantifiable 
time point estimated from the log-linear 
regression analysis; kel is the terminal phase rate 
constant calculated by a linear regression of the 
log-linear concentration-time curve
a If data permit.
3.2. Secondary Endpoint(s)
To evaluate the effect of food on ritlecitinib exposure following administration as 2 MR 
formulations, MR1 and MR2, the following secondary endpoints for the PK of ritlecitinib 
will be derived from the concentration-time profiles as shown in the table below.
Parameter
Definition
Method of Determination
Cmax
Maximum plasma concentration
Observe directly from the data
AUClast
Area under the plasma 
concentration versus time curve 
from time zero to the time of last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinfa
Area under the plasma 
concentration versus time curve
AUClast + (Clast/kel), where Clast is the predicted 
plasma concentration at the last quantifiable 
time point estimated from the log-linear 
regression analysis; kel is the terminal phase rate 
constant calculated by a linear regression of the 
log-linear concentration-time curve
a If data permit.
Another secondary endpoint is evaluating the safety and tolerability of ritlecitinib following 
single oral administration as MR1 and MR2 capsule formulations through the assessment of 
AEs, clinical laboratory tests, vital signs, and 12-lead electrocardiogram (ECG).
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3.3. Tertiary/Exploratory Endpoint(s)
To estimate additional PK parameters of ritlecitinib following single oral administration as 
MR1 and MR2 capsule formulations in healthy adult participants, the following 
tertiary/exploratory endpoints for the PK of ritlecitinib will be derived from the 
concentration-time profiles as shown in the table below.
Parameter
Definition
Method of Determination
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t½a
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the log-linear 
concentration-time curve. Only those data points 
judged to describe the terminal log-linear decline 
will be used in the regression
CL/Fa
Apparent Clearance 
Dose/AUCinf
Vz/Fa
Apparent volume of distribution 
after oral dose
Dose/(AUCinf*kel) after oral dose
Tlaga
Lag time
Time prior to the time corresponding to the first 
quantifiable concentration
a if data permits.
3.4. Baseline Variables
Start and end dates of study treatment: The date of first dose (start date) of study 
treatment is the earliest date of non-zero dosing of the study drug.  The date of last dose of 
study treatment is the latest date of non-zero dosing of the study drug. 
Definition of baseline: For vital signs and ECG, the baseline measurement of Periods 1-3 is 
the last pre-dose measurement taken on Day 1 of Period 1, and the baseline measurement of 
Period 4 is the last pre-dose measurement taken on Day 1 of Period 4. For safety labs,  the 
baseline measurement is the pre-dose measurement on Day -1.  
3.5. Safety Endpoints
The following data are considered in standard safety summaries (see protocol for collection 
days, baseline assessment, and list of parameters):

adverse events;

laboratory data;

vital signs data;

ECG results.
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3.5.1. Adverse Events
An adverse event (AE) is considered a Treatment-Emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment. All events that start on or after the 
first dosing day and time/start time, if collected, but before the end of the last follow-up date, 
will be flagged as TEAEs. The algorithm will not consider any events that started prior to the 
first dose date. If an AE starts on the same day as the first dose date, it will be considered 
treatment emergent unless the CRF data indicates otherwise via explicitly recording time for 
AE onset which was occurred before the first treatment dosing.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol. 
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards. The assessment will not take into 
account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter. 
The baseline measurement is the pre-dose measurement on Day -1. 
3.5.3. Vital Signs
Supine blood pressure and pulse measurements will be taken at all time points listed in the 
Schedule of Activities given in the protocol. 
For calculation of change from baseline for Periods 1 - 3, the baseline of Period 4 is used as 
post-baseline; for Period 4, the measurement on Day 3 will be used as the post-baseline 
measurement.
3.5.4. ECG
Single supine 12-lead ECG will be taken at all time points listed in the Schedule of Activities 
given in the protocol.  For calculation of change from baseline for Periods 1 - 3, the baseline 
of Period 4 is used as post-baseline; for Period 4, the measurement on Day 3 will be used as 
the post-baseline measurement.
The QT, QTc, PR, QRS and heart rate will be recorded at each assessment time. 
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula: 
QTcF = QT / (RR)1/3  
where RR = 60/HR (if not provided)
3.5.5. Other Safety Data
Additional safety data will be collected as described in the protocol and will be listed if 
collected in the sponsor’s database.
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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
Population
Description
Applicable Analysis (for 
additional information 
refer to section 6)
Enrolled
“Enrolled” means a participant’s, or their
legally authorized representative’s, 
agreement to participate in a clinical study 
following completion of the informed 
consent process and randomization.
Full analysis 
set 
All participants randomly assigned to study 
intervention and who take at least 1 dose of 
study intervention. Participants will be 
analyzed according to the product they 
actually received.
Safety analysis 
set
All participants randomly assigned to study 
intervention and who take at least 1 dose of 
study intervention. Participants will be 
analyzed according to the product they 
actually received.
Sections 6.2, 6.5, 6.6
PK 
concentration
All participants who have at least 1
measurable concentration in at least 1
treatment period.
Section 6.4
PK parameter
All participants who have at least 1 PK
parameter of interest (Section 3) quantified 
in at least 1 treatment period.
Sections 6.1, 6.2, 6.3, 6.4
4.1. Treatment Misallocations
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated.
If a participant takes a treatment that is not consistent with the treatment they are randomized 
to, then they will be reported under the treatment that they actually receive for all safety, PK 
and pharmacodynamic analyses, where applicable.
4.2. Protocol Deviations
Participants who experience events that may affect their PK profile may be excluded from 
the PK analysis. At the discretion of the pharmacokineticist, a concentration value may also 
be excluded if the deviation in sampling time is of sufficient concern or if the concentration 
is anomalous for any other reason.
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A full list of protocol deviations will be compiled and reviewed prior to database closure.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
As this is an exploratory study, no formal hypothesis testing will be performed.
5.2. General Methods
Descriptive analyses will be performed. Some measures will be summarized using graphical 
representations by treatment, where appropriate.
For continuous variables, the data will be summarized using the number of subjects, mean, 
median, standard deviation, minimum, and maximum in accordance with current Pfizer’s 
data and reporting standards. For appropriate PK parameters, geometric mean and geometric 
coefficient of variation (geocv%) will also be summarized. See Section 6.4 for details.
For categorical or ordinal variables, number of subjects, numbers and percentages of subjects 
meeting the categorical criteria will be supplied in accordance with current Pfizer’s data and 
reporting standards.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
Methods to handle missing PK data are described below. 
Concentrations Below the Limit of Quantification:
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ” where LLQ 
will be replaced with the value for the lower limit of quantification).
Deviations, Missing Concentrations and Anomalous Values: 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true: 
1. A concentration has been collected as ND (ie not done) or NS (ie no sample), 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
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Pharmacokinetic Parameters: 
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a subject’s concentration data, the parameter will be coded as NC 
(ie, not calculated).  (Note that NC values will not be generated beyond the day that a subject 
discontinues).  In summary tables, statistics will be calculated by setting NC values to 
missing; and statistics will be presented for a particular dose with ≥3 evaluable 
measurements. 
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed from 
the gastrointestinal tract), this will be footnoted in summary tables and will not be included in 
the calculation of summary statistics or statistical analyses.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)

PK parameters of ritlecitinib (fasted): Cmax, AUCinf (if data permit), otherwise 
AUClast
The outcomes of interest will be assessed for relative bioavailability analyses observations 
collected under fasted condition (in periods 1-3).  These treatments are denoted by letters A, 
B, and C.
A = ritlecitinib 100 mg PO solution
B = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules
C = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effect model with sequence, period and treatment as fixed effects and subject within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model.  The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios.
The mixed effects model will be implemented using SAS Proc Mixed, with REML 
estimation method and Kenward-Roger degrees of freedom algorithm.  The illustrative SAS 
code is presented in the Appendix 2.
For relative bioavailability analysis, the single dose of ritlecitinib MR1 and MR2 
administered in fasted state are the Test treatments.  Single dose of ritlecitinib solution under 
fasted condition is the Reference treatment.  
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report.  If there are major 
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deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
A listing of the descriptive and graphical summaries for PK parameters is presented in 
Section 6.4.
In addition, for the parameters AUCinf (if data permit), AUClast and Cmax, a listing of the 
individual subject ratios (Test/Reference) will also be provided.  Box and whisker plots for 
individual subject parameters (AUCinf, AUClast, and Cmax) will be presented by treatment and 
overlaid with geometric means.
6.2. Secondary Endpoint(s)

PK parameters of ritlecitinib (fed): Cmax, AUCinf (if data permit), otherwise 
AUClast
By the design of the trial, all of the observations made in the fed state are positioned in the 
single treatment periods and therefore the evaluation of the food effect is potentially 
confounded by the period effect.  We assume that the magnitude of the food effect is much 
larger than the magnitude of the period effect and will be able to support this assumption by 
estimating the magnitude of the period effect for periods 1-3 in the relative bioavailability 
analysis described in Section 6.1.
The analysis will be based on the subset of data observed for the following MR treatments:
B = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules under the fasted state
C = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules under the fasted state
B,fed = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules under the fed state
C,fed = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules under the fed state
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effect model with sequence and treatment as fixed effects and subject within sequence 
as a random effect.  Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% confidence intervals will be obtained from the model.  The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 
90% confidence intervals for the ratios.
Note that in this analysis the period is not included as a fixed effect.  The mixed effects 
model will be implemented using SAS Proc Mixed, with REML estimation method and 
Kenward-Roger- degrees of freedom algorithm.  The illustrative SAS code is presented in the 
Appendix 2.
For food effect assessment, ritlecitinib MR1 and MR2 in fasted state are the Reference 
treatments while ritlecitinib MR1 and MR2 administered in fed state are Test treatments.
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Similarly to the analysis in Section 6.1, the residuals from the model will be examined for 
normality and the presence of outliers via visual inspection of plots of residuals vs predicted 
values and normal probability plots of residuals but these will not be included in the clinical 
study report.  If there are major deviations from normality or outliers then the effect of these 
on the conclusions will be investigated through alternative transformations and/or analyses 
excluding outliers.  Justification for any alternative to the planned analysis will be given in 
the report of the study.
A listing of the descriptive and graphical summaries for PK parameters is presented in 
Section 6.4.
In addition, for the parameters AUCinf (if data permit), AUClast and Cmax, a listing of the 
individual subject ratios (Test/Reference) will also be provided.  Box and whisker plots for 
individual subject parameters (AUCinf, AUClast and Cmax) will be presented by treatment and 
overlaid with geometric means.

Assessment of AEs, clinical laboratory tests, vital signs and 12-lead ECG
For the secondary endpoint concerning safety, adverse events, laboratory data, vital signs, 
ECG data, and other safety data will be listed and summarized in accordance with the 
sponsor reporting standards as described in Section 3.5.
6.3. Tertiary/Exploratory Endpoint(s)

Tmax, and if data permit, Tlag , CL/F ,Vz/F , and t½
A listing of the descriptive and graphical summaries for additional PK parameters is 
presented in Section 6.4.
6.4. Descriptive and Graphical Summaries of PK Parameters
PK parameters will be collected as primary or secondary endpoints per Section 3.  Each PK 
parameter will be summarized by treatment and include the set of summary statistics as 
specified in the table below, where both mean and median profiles will be presented on both 
linear and log scales. 
Parameter
Summary Statistics
AUCinfa
AUClast
Cmax
CL/Fa
Vz/Fa
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric cv%.
Tmax, Tlaga
N, median, minimum, maximum.
t1/2a
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum.
a If data permit 
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Supporting data from the estimation of t½ and AUCinf will be listed by treatment: terminal 
phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); the 
percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of time 
points used in the estimation of kel.  These data may be included in the clinical study report.
Presentations for ritlectinib concentrations from venous blood samples will include:

A listing of all concentrations sorted by subject ID, period and nominal time 
postdose.  The concentration listing will also include the actual times.  Deviations 
from the nominal time will be given in a separate listing.

A summary of concentrations by treatment and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by treatment (all treatments on the same plot per scale, based 
on the summary of concentrations by treatment and time postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).

Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment 
per scale).

Individual concentration time plots by subject (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each subject (containing 
all treatments) per scale].
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
6.5. Baseline and Other Summaries and Analyses
Demographic data collected at screening will be reported as part of the standard baseline 
summary tables.  A breakdown of demographic data will be provided for age, race, weight, 
body mass index, and height.  Each will be summarized by gender and all participants in 
accordance with the sponsor reporting standards. 
6.5.1. Study Conduct and Participant Disposition
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
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laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by 
treatment.  Data will be reported in accordance with the sponsor reporting standards.
6.5.2. Study Treatment Exposure
Not applicable.
6.5.3. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
6.6. Safety Summaries and Analyses
A set of summary tables split by treatment will be produced to evaluate any potential risk 
associated with the safety and toleration of administering ritlectinib as PO solution, MR1, or 
MR2 formulation.
6.6.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
6.6.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards. The baseline measurement is the pre-dose measurement on Day -1.  
6.6.3. Vital Signs
For each planned time point, baseline values and change from baseline values in Periods 1-3 
and Period 4 will be summarized with descriptive statistics (using sponsor default standards)
as appropriate.
These data will be listed in accordance with the sponsor reporting standards. The thresholds 
used in the categorical summarization of vital signs data are presented in the Appendix 1.
6.6.4. Electrocardiograms
For each planned time point, baseline values and change from baseline values in Periods 1-3 
and Period 4 will be summarized with descriptive statistics (using sponsor default standards)
as appropriate.
These data will be listed in accordance with the sponsor reporting standards. The thresholds 
used in the categorical summarization of vital signs data are presented in the Appendix 1.
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study.  As this is a sponsor-
open- study, the sponsor may conduct unblinded reviews of the data during the course of the 
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study for the purpose of safety assessment, facilitating PK/PD modeling, and/or supporting 
clinical development. 
7.2. Interim Analyses and Summaries
Available safety and PK data may be reviewed.
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APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
>30-60
>60
Categories for PR and QRS
PR (ms)
≥300 
PR (ms) increase 
from baseline
Baseline >200 and  
≥25% increase
Baseline ≤200 and 
≥50% increase
QRS (ms)
≥140
QRS (ms) increase 
from baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
<90
Systolic BP (mm Hg) change 
from baseline
decrease ≥30
increase ≥30
Diastolic BP (mm Hg)
<50
Diastolic BP (mm Hg) change 
from baseline
decrease ≥20
increase ≥20
Supine pulse rate (bpm)
<40
>120
Measurements that fulfill these criteria are to be listed in the clinical study report.
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Appendix 2. Example SAS Code for Analyses
Examples of the PROC MIXED code is provided below. 
We start from the dataset ds with the following letter codes for the treatments 
A = ritlecitinib 100 mg PO solution
B = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules
C = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules
B,fed = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules under the fed state
C,fed = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules under the fed state
For analysis of bioavailability, we use a subset of data (ds1) that does not include period 4 
(ie, treatments B,fed and C,fed).
A = ritlecitinib 100 mg PO solution
B = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules
C = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules
We calculate contrasts 'A vs B' and 'A vs C'
proc mixed data=ds1;
class seq period trt subject;
model l&var=seq period trt/ ddfm=KR;
random subject(seq) ;
lsmeans trt;
estimate 'A vs B ' trt -1  1 0  /cl alpha=0.1;
            estimate 'A vs C ' trt -1  0 1   /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
For analysis of food effect, we use a subset of data (ds2) that includes relevant doses
B = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules
C = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules
B,fed = ritlecitinib 100 mg (2 × 50 mg) MR1 capsules under the fed state
C,fed = ritlecitinib 100 mg (2 × 50 mg) MR2 capsules under the fed state
We calculate contrasts of interest ('B vs B,fed ' and 'C vs C,fed ') without adjustment for 
period effect.
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proc mixed data=ds2;
class seq trt subject;
model l&var=seq trt/ ddfm=KR;
random subject(seq) ;
lsmeans trt;
estimate 'B vs B,fed ' trt   -1  0 1 0  /cl alpha=0.1;
            estimate 'C vs C,fed ' trt    0  -1 0 1   /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
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Appendix 3. List of Abbreviations
Abbreviation
Term
Abs
absolute
AE
adverse event
AUC
area under the curve
AUCinf
area under the plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time 0 to the 
time of the last quantifiable concentration
BA
bioavailability
BE
bioequivalence
BLQ
below the limit of quantitation
BOCF
baseline observation carried forward
BP
blood pressure
bpm
beats per minute
CDARS
Clinical Data Analysis and Reporting System (of US Food and Drug 
Administration)
CI
confidence interval
CL/F
Apparent clearance after oral dose
Cmax
maximum observed concentration
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
EAC
event adjudication committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
FAS
full analysis set
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMR
geometric mean ratio
GMT
geometric mean titer
ICD
informed consent document
ICH
International Council for Harmonisation
IRC
internal review committee
IST
independent statistical team
ITT
intent-to-treat
kel
first-order elimination rate constant
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOD
limit of detection
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Abbreviation
Term
LS
least-squares
LSM
least-squares mean
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed-effects model with repeated measures
MNAR
missing not at random
N/A
not applicable
NOAEL
no-observed-adverse-effect level
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per-protocol
PPAS
per-protocol analysis set
PRO
patient-reported outcome
PT
preferred term
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RCDC
reverse cumulative distribution curve
RR
relative risk
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SGS
Statistical Guidance Standards
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t½
terminal phase half-life
TA
therapeutic area
TEAE
treatment-emergent adverse event
Tlag
time before the first concentration above the limit of quantification or 
above the first concentration in the interval
Tmax
time to reach Cmax
ULN
upper limit of normal
Vz
volume of distribution for extravascular dosing
Vz/F 
apparent volume of distribution for extravascular dosing
WHO 
World Health Organization
WHODD
World Health Organization Drug Dictionary
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