Clinical trial NCT05097716
Conditions: Healthy Volunteers
Keywords: pharmacokinetics (PK)
Sponsor: Pfizer
Start date: 2021-11-02; Completion date: 2022-01-10
Enrollment: 12 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1, 2-period, multiple-dose, open-label, single fixed sequence study of the effect of ritlecitinib on tolbutamide pharmacokinetics in healthy participants.

Detailed description:
A total of approximately 12 healthy male and/or female participants will be enrolled in the study to obtain at least 10 evaluable participants who complete the study. This is an open-label study not requiring an assessment of efficacy or pharmacodynamics markers, but it will include pharmacokinetic estimation drug-drug interactions.

Arms: arm 1: In Period 1, participants will be dosed with a single administration of tolbutamide 500 mg tablet on Day 1. Period 1 will be immediately followed by Period 2 with no washout. In Period 2, participants will be dosed with oral 200 mg ritlecitinib QD for 10 days followed by administration of a single dose of 500 mg tolbutamide oral tablet within approximately 5 minutes after administration of a 200 mg dose of ritlecitinib on the morning of Day 10.
Interventions: intervention 1: Ritlecitinib intervention 2: Tolbutamide
Intervention descriptions: intervention 1: Ritlecitinib 200 mg provided as four 50 mg oral capsules intervention 2: Tolbutamide 500 mg provided as one 500 mg oral tablet

Protocol documents:
Prot_000.pdf: 
Ritlecitinib (PF-06651600)
Protocol B7981069
Final Protocol Amendment 1, 17 September 2021
PFIZER CONFIDENTIAL
Page 1
PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, 2-PERIOD STUDY TO ESTIMATE 
THE EFFECT OF MULTIPLE-DOSE RITLECITINIB (PF-06651600) ON THE
PHARMACOKINETICS OF SINGLE-DOSE TOLBUTAMIDE IN HEALTHY 
PARTICIPANTS
Study Intervention Number:
PF-06651600
Study Intervention Name:
Ritlecitinib
US IND Number:
131,503
EudraCT Number:
2021-003611-25
ClinicalTrials.gov ID:
Not Applicable
Protocol Number:
B7981069
Phase:
1
Short Title: Open-Label, Fixed-Sequence, 2-Period Study to Evaluate the Effect of 
Multiple-Dose Ritlecitinib on the PK of Tolbutamide
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.


Ritlecitinib (PF-06651600)
Protocol B7981069
Final Protocol Amendment 1, 17 September 2021
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Amendment 1
17 September 2021
Original protocol
14 July 2021
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any global protocol administrative 
clarification letter.
Protocol Amendment Summary of Changes Table
Amendment 1 (17-September-2021)
Section # and 
Name
Description of Change
Brief Rationale
Section 5.2
Exclusion 
Criteria #17
Update Exclusion Criteria #17 to 
“Known participation in a 
clinical trial of ritlecitinib and 
the participant experienced a 
ritlecitinib-related AE that led to 
discontinuation or had a 
ritlecitinib-related SAE.”
The portion of the exclusion criterion
that prohibited participation in a 
ritlecitinib study during the 60 days 
prior to the first dose of investigational 
product in B7981069 has been removed. 
The study team determined that the 
expected follow-up periods included in 
prior ritlecitinib studies that participants 
may be involved in, together with the 
screening period into this study, would 
be sufficient to allow for washout of 
ritlecitinib from previous studies and for 
a return of any impacted drug 
metabolizing enzymes from previous 
studies to their baseline activity.


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Protocol B7981069
Final Protocol Amendment 1, 17 September 2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema (Not Applicable)........................................................................................11
1.3. Schedule of Activities .............................................................................................12
2. INTRODUCTION ...............................................................................................................16
2.1. Study Rationale .......................................................................................................16
2.2. Background .............................................................................................................16
2.2.1. Nonclinical Pharmacology..........................................................................17
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................17
2.2.3. Nonclinical Safety ......................................................................................17
2.2.4. Clinical Overview.......................................................................................17
2.2.4.1. Clinical Overview of Ritlecitinib..............................................17
2.2.4.2. PK Overview of Ritlecitinib......................................................18
2.3. Benefit/Risk Assessment.........................................................................................20
2.3.1. Risk Assessment.........................................................................................21
2.3.2. Benefit Assessment.....................................................................................23
2.3.3. Overall Benefit/Risk Conclusion................................................................23
3. OBJECTIVES AND ENDPOINTS.....................................................................................23
4. STUDY DESIGN.................................................................................................................23
4.1. Overall Design.........................................................................................................23
4.2. Scientific Rationale for Study Design.....................................................................24
4.2.1. Diversity of Study Population ....................................................................24
4.2.2. Collection of Retained Research Samples..................................................24
4.3. Justification for Dose ..............................................................................................25
4.3.1. Justification of Ritlecitinib Dose ................................................................25
4.3.2. Justification of Tolbutamide Dose..............................................................25
4.4. End of Study Definition ..........................................................................................25
5. STUDY POPULATION......................................................................................................25
5.1. Inclusion Criteria.....................................................................................................26


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5.2. Exclusion Criteria....................................................................................................26
5.3. Lifestyle Considerations..........................................................................................31
5.3.1. Meals and Dietary Restrictions...................................................................31
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................31
5.3.3. Activity .......................................................................................................32
5.3.4. Contraception..............................................................................................32
5.3.5. Vaccination.................................................................................................32
5.4. Screen Failures ........................................................................................................33
6. STUDY INTERVENTION..................................................................................................33
6.1. Study Intervention(s) Administered........................................................................33
6.1.1. Administration............................................................................................33
6.2. Preparation/Handling/Storage/Accountability ........................................................34
6.2.1. Preparation and Dispensing........................................................................35
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................35
6.3.1. Allocation to Study Intervention ................................................................35
6.4. Study Intervention Compliance...............................................................................35
6.5. Dose Modification...................................................................................................35
6.6. Continued Access to Study Intervention After the End of the Study......................36
6.7. Treatment of Overdose............................................................................................36
6.8. Concomitant Therapy..............................................................................................36
6.8.1. Rescue Medicine.........................................................................................37
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................37
7.1. Discontinuation of Study Intervention ....................................................................37
7.2. Participant Discontinuation/Withdrawal From the Study.......................................37
7.2.1. Withdrawal of Consent...............................................................................38
7.3. Lost to Follow-up....................................................................................................38
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................39
8.1. Efficacy Assessments..............................................................................................40
8.2. Safety Assessments .................................................................................................40
8.2.1. Physical Examinations................................................................................40
8.2.2. Vital Signs ..................................................................................................41


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8.2.2.1. Temperature ..............................................................................41
8.2.3. Electrocardiograms.....................................................................................41
8.2.4. Clinical Safety Laboratory Assessments ....................................................42
8.2.5. COVID-19 specific assessments.................................................................43
8.2.6. Estimated Glomerular Filtration Rate.........................................................43
8.2.7. Pregnancy Testing ......................................................................................43
8.3. Adverse Events and Serious Adverse Events, and Other Safety Reporting............44
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......44
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................45
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................45
8.3.2. Method of Detecting AEs and SAEs ..........................................................45
8.3.3. Follow-up of AEs and SAEs.......................................................................45
8.3.4. Regulatory Reporting Requirements for SAEs...........................................45
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................46
8.3.5.1. Exposure During Pregnancy......................................................46
8.3.5.2. Exposure During Breastfeeding ................................................48
8.3.5.3. Occupational Exposure .............................................................48
8.3.6. Cardiovascular and Death Events (Not applicable)....................................48
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs (Not applicable) ..................................................48
8.3.8. Adverse Events of Special Interest (Not applicable)..................................48
8.3.8.1. Lack of Efficacy (Not applicable).............................................48
8.3.9. Medical Device Deficiencies (Not applicable)...........................................49
8.3.10. Medication Errors.....................................................................................49
8.4. Pharmacokinetics ....................................................................................................49
8.5. Genetics...................................................................................................................50
8.5.1. Specified Genetics ......................................................................................50
8.5.2. Retained Research Samples for Genetics ...................................................51
8.6. Biomarkers ..............................................................................................................51
8.6.1. Retained Research Samples for Biomarkers...............................................51
8.7. Immunogenicity Assessments.................................................................................51


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8.8. Health Economics ...................................................................................................52
9. STATISTICAL CONSIDERATIONS ................................................................................52
9.1. Statistical Hypotheses .............................................................................................52
9.2. Analysis Sets ...........................................................................................................52
9.3. Statistical Analyses .................................................................................................52
9.3.1. General Considerations...............................................................................53
9.3.2. Primary Endpoints ......................................................................................53
9.3.3. Other Endpoints..........................................................................................54
9.3.4. Other Safety Analyses ................................................................................54
9.3.5. Other Analyses............................................................................................54
9.4. Interim Analyses .....................................................................................................54
9.5. Sample Size Determination.....................................................................................54
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................56
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............56
10.1.1. Regulatory and Ethical Considerations ....................................................56
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................56
10.1.2. Informed Consent Process ........................................................................57
10.1.3. Data Protection .........................................................................................57
10.1.4. Committees Structure ...............................................................................58
10.1.4.1. Data Monitoring Committee ...................................................58
10.1.5. Dissemination of Clinical Study Data ......................................................58
10.1.6. Data Quality Assurance ............................................................................59
10.1.7. Source Documents....................................................................................60
10.1.8. Study and Site Start and Closure ..............................................................61
10.1.9. Publication Policy.....................................................................................62
10.1.10. Sponsor’s Qualified Medical Personnel .................................................62
10.2. Appendix 2: Clinical Laboratory Tests .................................................................64
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................66
10.3.1. Definition of AE .......................................................................................66


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10.3.2. Definition of SAE.....................................................................................67
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs During 
the Active Collection Period............................................................................68
10.3.4. Reporting of SAEs....................................................................................72
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................73
10.4.1. Male Participant Reproductive Inclusion Criteria....................................73
10.4.2. Female Participant Reproductive Inclusion Criteria.................................73
10.4.3. Woman of Childbearing Potential ............................................................73
10.4.4. Contraception Methods.............................................................................74
10.5. Appendix 5: Genetics............................................................................................76
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........77
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................79
10.8. Appendix 8: Guidelines for Participant Safety Monitoring and 
Discontinuation..........................................................................................................81
10.8.1. Participant Safety Monitoring...................................................................81
10.8.2. Participant Discontinuation Criteria .........................................................82
10.9. Appendix 9: Abbreviations ...................................................................................84
11. REFERENCES ..................................................................................................................88


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Final Protocol Amendment 1, 17 September 2021
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LIST OF TABLES
Table 1.
Schedule of Activities...............................................................................12
Table 2.
Pharmacokinetic Sampling Schema .........................................................15
Table 3.
Treatment Flow Diagram..........................................................................24
Table 4.
Plasma Pharmacokinetic Parameter Definitions.......................................52
Table 5.
Estimated 90% CIs for Different Underlaying Effects.............................55
Table 6.
Protocol-Required Safety Laboratory Assessments .................................64


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Final Protocol Amendment 1, 17 September 2021
PFIZER CONFIDENTIAL
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: Open-Label, Fixed-sequence, 2-Period Study to Evaluate the Effect of 
Multiple-Dose Ritlecitinib on the PK of Tolbutamide
Rationale
This is a Phase 1, 2-period, multiple-dose, open-label, single fixed sequence study of the 
effect of ritlecitinib on tolbutamide pharmacokinetics in healthy participants. A total of 
approximately 12 healthy male and/or female participants will be enrolled in the study to 
obtain at least 10 evaluable participants who complete the study. The study is designed as a 
fixed sequence study to avoid the long washout period needed in a crossover design due to 
long half-lives of CYP enzymes to revert back to their baseline values. The fixed-sequence 
design has a low risk of period effect. This is an open-label study not requiring an assessment 
of efficacy or pharmacodynamics markers, but it will include PK estimation DDIs.
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

To evaluate the effect of multiple-dose ritlecitinib 
(PF-06651600) on the PK of a single, oral dose of 
tolbutamide in healthy participants.

Cmax and AUCinf (if data permit, otherwise AUClast) of 
tolbutamide.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of ritlecitinib 
when coadministered with a single dose of 
tolbutamide.

Incidence of treatment-emergent adverse events
Other/Exploratory: 
Other/Exploratory: 

To characterize the PK of a single oral dose of 
tolbutamide in healthy participants.

Plasma tolbutamide PK parameters:Tmax, AUClast, 
CL/F, Vz/F and t½, as data permit.
Overall Design
Brief Summary
This is a Phase 1, 2-period, multiple-dose, open-label, single fixed sequence study of the 
effect of ritlecitinib on tolbutamide pharmacokinetics in healthy participants. A total of 
approximately 12 healthy male and/or female participants will be enrolled in the study to 
obtain at least 10 evaluable participants who complete the study. Participants who withdraw 
from the study or are considered non-evaluable may be replaced at the discretion of the 
sponsor.


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Participants will be screened within 28 days of the first dose of study medication. 
Participants will report to the CRU the day prior to Day 1 dosing (Day -1) in Period 1 for 
both treatment sequences. Participants will remain in the CRU for a total of 16 days and 
15 nights. This includes 4 days and 4 nights (starting the night of admission to the CRU) in 
Period 1 and 12 days and 11 nights in Period 2. There will be no washout period between 2 
treatment periods.
In Period 1, participants will be dosed with a single administration of tolbutamide 500 mg 
tablet on Day 1. Tolbutamide PK will be assessed for 36 hours following dosing. Period 1 
will be immediately followed by Period 2 with no washout. In Period 2, participants will be 
dosed with oral 200 mg ritlecitinib QD for 10 days followed by administration of a single 
dose of 500 mg tolbutamide oral tablet within approximately 5 minutes after administration 
of a 200 mg dose of ritlecitinib on the morning of Day 10. Tolbutamide PK in Period 2 will
again be assessed at pre-dose and over 36 hours after tolbutamide dosing. Dosing with oral 
200 mg ritlecitinib QD will continue through Day 10.
Participants will have a telephone contact between 28 calendar days and 35 calendar days 
after the last administration of the investigational product.
Number of Participants
Approximately 12 participants will be enrolled to study intervention.
Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. A participant will be considered enrolled if the informed consent is 
not withdrawn prior to participating in any study activity after screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
Intervention Groups and Duration
In Period 1, participants will be dosed with a single administration of tolbutamide 500 mg 
tablet on Day 1. Period 1 will be immediately followed by Period 2 with no washout. In 
Period 2, participants will be dosed with oral 200 mg ritlecitinib QD for 10 days followed by 
administration of a single dose of 500 mg tolbutamide oral tablet within approximately
5 minutes after administration of a 200 mg dose of ritlecitinib on the morning of Day 10. 
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately up to 11 weeks.


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Protocol B7981069
Final Protocol Amendment 1, 17 September 2021
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Data Monitoring Committee or Other Independent Oversight Committee: No.
Statistical Methods
There is no formal research hypothesis to be statistically tested for this study. The purpose of 
this study is to estimate the PK effect, as well as safety and tolerability of multiple-dose 
ritlecitinib with a single, oral dose of tolbutamide in healthy participants.
Natural log transformed AUCinf, AUClast, and Cmax of tolbutamide will be analyzed using a 
mixed effect model with treatment as a fixed effect and participant as a random effect. 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will 
be obtained from the model. The adjusted mean differences and 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios. Tolbutamide alone will be the Reference 
treatment, while the tolbutamide co‑administered with ritlecitinib will be the Test treatment.
1.2. Schema (Not Applicable)


Ritlecitinib (PF-06651600)
Protocol B7981069
Final Protocol Amendment 1, 17 September 2021
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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.
Table 1.
Schedule of Activities 
Screening
Period 1
Period 2
FU Phone 
Call
ET
Visit Identifiera
Abbreviations used in 
this table may be found 
in Section 10.9
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 1
Day 2
Day 3
to Day 
8
Day 9
Day 10
Day 11
Day 12
28-35 Days 
after Last 
Dosen
Informed consent
X
Inclusion/Exclusion 
Criteria
X
CRU confinement
X









X
Medical, drug, tobacco 
and alcohol history
X
X
Demography
X
Complete/limited
physical examinationb
X
X
Xo
Xo
Safety laboratoryc
X
X
X
X
X
X
TB screeningd
X
Serum FSH 
(postmenopausal women 
only)
X
Pregnancy test (for 
WOCBP only)e
X
X
X
X
Serology: HBsAg, 
HBcAb, HCV Ab, and 
HIVf
X


Ritlecitinib (PF-06651600)
Protocol B7981069
Final Protocol Amendment 1, 17 September 2021
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Table 1.
Schedule of Activities 
Screening
Period 1
Period 2
FU Phone 
Call
ET
Visit Identifiera
Abbreviations used in 
this table may be found 
in Section 10.9
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 1
Day 2
Day 3
to Day 
8
Day 9
Day 10
Day 11
Day 12
28-35 Days 
after Last 
Dosen
Collection of baseline
sample for potential viral 
screensg
X
Retained Research 
Sample for Genetics 
(Prep D1)h
X
Retained Research 
Sample for Biomarkers 
(Prep B2)h
X
Genotyping for 
CYP2C9h
X
Urine drug screen
X
X
COVID-19 testing
X
X
X
X
COVID-19 temperature
check
X
X
X
X
X
X
X
X
X
X
X
X
X
COVID-19 check 
questionnaire
X
X
X
Single 12-Lead ECGi
X
X
X
X
Vital signs (supine BP, 
pulse rate and oral 
temperature)i
X
X
X
X
Contraception check
X
X
X
X
X
Tolbutamide dosing
Xj
Xk
Ritlecitinib QD dosing
X
X
X
X
Xk
Tolbutamide PK blood 
samplesl
X
X
X
X
Serious and non-serious 
AE monitoringm
X










X
X
X
Prior/concomitant 
treatment assessment
X










X
X
CRU discharge 
X


Ritlecitinib (PF-06651600)
Protocol B7981069
Final Protocol Amendment 1, 17 September 2021
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Table 1.
Schedule of Activities 
Screening
Period 1
Period 2
FU Phone 
Call
ET
Visit Identifiera
Abbreviations used in 
this table may be found 
in Section 10.9
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 1
Day 2
Day 3
to Day 
8
Day 9
Day 10
Day 11
Day 12
28-35 Days 
after Last 
Dosen
a.
Day relative to start of study treatment (Day 1).
b.
Complete physical examination can be performed either at Screening or Day -1 of Period 1. See Section 8.2.1.
c.
Safety laboratory samples will be collected following an overnight fast of at least 12 hours.
d.
TB screening will utilize IGRA. Details of eligibility are described in Appendix 2.
e.
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.
f.
All participants will undergo screening for Hepatitis B and Hepatitis C for eligibility. Please refer to Appendix 2 for testing algorithm, reflex testing, and full eligibility 
criteria.
g.
A serum sample will be collected at baseline and submitted to the central lab. The sample will be stored and analyzed at a later date only at the sponsor’s request. For 
example, in certain cases of suspected viral infection (eg, disseminated herpes zoster or varicella), the sponsor may request to analyze the sample to determine if the subject 
had exposure to that virus.
h.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a participant visit.
i.
ECG and vital signs will be collected before dosing on Day 1 of Period 1 and on Day 12 of Period 2.
j.
Participants will be dosed with tolbutamide within approximately 10 minutes of completion of a standard breakfast.
k.
On the day of co administration of tolbutamide and ritlecitinib, within approximately 10 minutes of completion of a standard breakfast, the dosing will be administered at 
approximately 08:00 ±2 hours. Ritlecitinib will be administered first. After swallowing the ritlecitinib dose, tolbutamide should be administered within approximately 5 
minutes.
l.
PK blood samples are to be collected at pre-dose, at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, and 36 hours post-dose in Periods 1 and 2.
m.
All potential treatment related events of rash will be followed up until resolution or agreement with Pfizer. See Section 10.8.1.
n.
Participants will have a telephone contact between 28 calendar days and 35 calendar days after the last administration of the investigational product.
o.
Limited physical exam as deemed appropriate by the investigator.


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Table 2.
Pharmacokinetic Sampling Schema
Study Day for Period 1 
1
2
Study Day for Period 2 
10
11
Hours After Dose
0
0.5
1
2
3
4
5
6
8
12
16
24
36
Tolbutamide administration
X
Tolbutamide PK blood sampling 
Xa
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: PK = pharmacokinetic.
a.
Pre-dose sample.


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2. INTRODUCTION
Ritlecitinib (PF-06651600) is a selective covalent inhibitor of JAK3 and the tyrosine kinase 
expressed in 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 estimate the inductive effect of multiple-dose ritlecitinib on 
single dose PK of tolbutamide. In vitro studies indicated mild induction potential of 
ritlecitinib for CYP3A4 (R 0.08), CYP2B6 (R 0.23), CYP1A2 (R 0.07), CYP2C8 (R 0.06), 
CYP2C9 (R 0.29), and CYP2C19 (R 0.32) enzymes, where R represents the predicted ratio 
of intrinsic clearance values of a probe substrate for an enzymatic pathway in the absence
and presence of an inducer. The effect of ritlecitinib on CYP3A4 and CYP2B6 was evaluated 
in a drug interaction study with coadministration of both sensitive CYP3A substrate, 
midazolam, and sensitive CYP2B6 substrate, efavirenz (B7981017), and the results indicated 
that ritlecitinib is a moderate CYP3A inhibitor and does not affect CYP2B6 enzymes. The 
CYP2C enzymes are regulated by pregnane X receptor (PXR) pathway, which regulates 
CYP3A enzymes as well.1 Study B7981017 results implied the net effect of ritlecitinib on 
CYP3A from both enzyme induction and inhibition, and enzyme induction risk of ritlecitinib
through PXR pathway cannot be completely ruled out. Therefore, a DDI study assessing the 
ritlecitinib effect on the in vivo pharmacokinetics of a sensitive CYP2C substrate needs to be 
conducted to rule out an inducive effect on the aforementioned isoenzymes.
Tolbutamide is a first generation sulphonylurea developed for treatment of diabetes mellitus. 
When administered orally, tolbutamide is readily absorbed from the gastrointestinal tract. 
Absorption and pharmacodynamic effects of tolbutamide are not impacted by food. 
Detectable levels of tolbutamide are present in the plasma within 20 minutes after oral 
ingestion of a 500 mg tolbutamide tablet, with peak levels occurring at 3 to 4 hours and 
minimal amounts detectable at 24 hours. The half-life of tolbutamide is 4.5 to 6.5 hours. 
Tolbutamide is mainly metabolized by CYP2C9 and acts as a sensitive substrate for this
isoenzyme.2,3 Tolbutamide metabolites are eliminated renally. The current study is designed 
to estimate any inductive effect of PF-06651600 on the pharmacokinetics of tolbutamide.
2.2. Background 
Ritlecitinib is a covalent and irreversible inhibitor of JAK3 with high selectivity over the 
other 3 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, AA, RA, CD and vitiligo. 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.


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2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of ritlecitinib can be found in the current IB for 
ritlecitinib.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Details of the nonclinical PK and metabolism of ritlecitinib can be found in the current 
ritlecitinib IB.  
2.2.3. Nonclinical Safety
Based on the absence of adverse effects at the highest dose tested, the NOAEL in the 8-week 
dog study was 45 mg/kg/day. In the first 9-month dog study, the NOAEL was 5 mg/kg/day, 
the lowest dose tested, based on the adverse finding of axonal dystrophy in the brainstem and 
associated waveform defects in males and females administered ≥20 mg/kg/day, the next 
highest dose used in that study. In the second 9-month dog toxicity study, the NOAEL was 
10 mg/kg/day, based on adverse over-immunosuppression and axonal dystrophy in the CNS 
and PNS at ≥20 mg/kg/day, accompanied by functional auditory deficits (BAEP) at the 
highest dose of 40 mg/kg/day. The 10 mg/kg/day dose corresponded to a mean AUC24 of 
7940 ng•h/mL and exposure margins were 6.5x and 1.5x the AUC24 at the 50 mg and 200 mg 
clinical doses, respectively.
Further information is available in the current version of the ritlecitinib IB.
2.2.4. Clinical Overview
2.2.4.1. Clinical Overview of Ritlecitinib
Ritlecitinib has been explored in healthy participants in 14 Phase 1 trials including an FIH 
Study B7981001 study, a relative BA study of oral solution formulation of ritlecitinib relative 
to tablets (B7981003), a PK study in Japanese participants (B7981008), an ADME study 
(B7981011), a drug interaction study with midazolam and efavirenz (B7981017), a drug 
interaction study with oral hormonal contraceptive for ritlecitinib 200 mg QD (B7981018)
and 50 mg ritlecitinib 50 mg QD (B7981035), a palatability study which investigated the 
palatability of oral formulations of ritlecitinib for pediatric use (B7981021), a relative 
bioavailability study of candidate capsule formulations of ritlecitinib relative to tablets
(B7981022), a drug interaction study with itraconazole (B7981023), a drug interaction study 
with rosuvastatin (B7981024), a drug interaction study with sumatriptan (B7981025), a drug 
interaction study with rifampin (B7981026), and a PK study in Chinese participants 
(B7981036). Ritlecitinib was also investigated in specific populations of hepatic impairment 
(B7981016) and renal impairment (B7981020). Ritlecitinib has been investigated in 
2 Phase 2 trials in participants with RA (B7981006) and AA (B7981005). There are ongoing 
studies in participants with AA (B7981015 and B7981032), Vitiligo (B7981019), UC 
(B7981005) and CD (B7981007).


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2.2.4.2. PK Overview of Ritlecitinib
The PK profile of ritlecitinib is characterized by rapid absorption (Tmax of ~1 hour), rapid 
elimination (t½ of ~2 hours) and is approximately dose proportional. 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. Even though 
ritlecitinib has a short t½ (~2 hours), steady state generally appears to be reached by Day 4 for 
the QD regimens and Day 6 for the BID regimens based on similar median trough (pre-dose) 
ritlecitinib beyond Day 6. The accumulation ratio for 50 and 200 mg QD was also 1.4 and 
1.8 respectively, suggesting nonlinear characteristics of ritlecitinib PK. Ritlecitinib is 
primarily cleared by metabolism. Less than 8% of ritlecitinib is excreted unchanged in the 
urine.
2.2.4.2.1. Studies in Healthy Participants
In all 14 Phase 1 studies in healthy participants, ritlecitinib was found to be well tolerated 
and to have an acceptable safety profile.
Further information is available in the current version of the ritlecitinib IB.
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, multi-center 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 TEAEs reported in more than 5% (1 in 20) 
participants with RA receiving ritlecitinib were influenza and lymphopenia. The majority of 
the AEs were mild in severity. There was 1 mild case of herpes simplex in the ritlecitinib
group that was considered to be treatment-related with no cases in the placebo group. There 
were no clinically relevant changes in vital signs, ECG, or audiometric assessments. By the 
Week 8 time point (as early as 2 weeks), in the ritlecitinib group, there were decreases in the 
median platelet counts (25% change from baseline), lymphocyte counts (21% change from 
baseline), neutrophil counts (24% change from baseline), and hemoglobin (3% change from 
baseline). None of these were deemed to be clinically relevant by the investigator and values 
returned to near baseline by the 12-week follow-up visit.
2.2.4.2.3. Phase 2a Study in Alopecia Areata
Study B7931005 is a Phase 2a, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety profile of ritlecitinib and PF-06700841 (a TYK2/JAK1 
inhibitor) in participants with moderate to severe AA. The study consists of the initial 


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24-week double-blind treatment period, an up to 12-month single-blind extension period, and 
a 6-month crossover open-label extension period. A total of 142 participants were 
randomized to study treatment; 47 participants received placebo, 48 participants received 
ritlecitinib, and 47 participants received PF-06700841.
During the initial 24-week double-blind treatment period, participants in the ritlecitinib group 
were treated with 200 mg of ritlecitinib QD during a 4-week induction phase, followed by 
dosing with 50 mg QD in a maintenance phase. At Week 24, an interim analysis provided 
data on both efficacy and safety and indicated clinical improvement for participants treated 
with ritlecitinib.
During the initial 24-week treatment period of Study B7931005, there were no deaths and no 
participants in the ritlecitinib treatment group experienced an SAE. The proportion of 
participants who experienced TEAEs in the placebo treatment group (74.5%) was 
comparable with the ritlecitinib treatment group (62.5%). The TEAEs reported in more than 
5% (1 in 20) participants with AA receiving ritlecitinib were headache, infections of upper 
respiratory tract, acne, diarrhea, nausea, and skin infections. The majority of events were 
mild. No serious infections, malignancies, cases of herpes zoster, or cases of herpes simplex 
were reported in the ritlecitinib group. Hematological changes were observed in both active 
groups during the induction and maintenance periods, but were not associated with clinically 
relevant TEAEs. During the induction period, when participants received ritlecitinib 200 mg 
QD for 4 weeks, decreases in mean platelet and lymphocyte counts (-18% and -24% mean 
change from baseline, respectively) were observed in the ritlecitinib group. During the 
maintenance period, when participants received 50 mg QD for 20 weeks, there was 
improvement in the platelet and lymphocyte counts in the ritlecitinib group. Neutrophil 
counts were increased at Week 4 (12% change from baseline) and Week 24 (10% change 
from baseline) in the ritlecitinib treatment group. Two participants in the ritlecitinib group 
discontinued due to TEAEs. 
In addition to the initial 24-week period, the trial included 2 extensions. Extension 1 was a 
Single-Blind Extension Period in which the participants had treatment withdrawn and were 
then re-treated for up to 24 weeks with the initially assigned IP after the participants reached 
a pre-specified retreatment criterion (ie, 30% hair loss from the regrown hair at Week 24). 
The second extension was a Cross-Over Open Label Extension Period in which the Week 24 
non-responders were assigned the opposite active treatment than the one received in the 
initial (Week 0-24) treatment period. There were no SUSARS, serious infections, adverse 
events of QTcF prolongation, malignancies and/or no case of herpes zoster during the 
extension periods.
More detailed information about ritlecitinib can be found in the current version of the 
ritlecitinib IB, which is the SRSD for this study.


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2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ritlecitinib may be found in the current IB, which is the SRSD for 
this study.
The SRSD for tolbutamide is the USPI for Tolbutamide4. The main potential side effect of 
tolbutamide is hypoglycemia. Treatment of subjects with 6-phosphate dehydrogenase 
(G6PD) deficiency can result in hemolytic anemia. Mild adverse reactions include gastro-
intestinal effects (nausea, epigastric fullness, heartburn). AEs due to dermatologic, 
hematologic, metabolic and endocrine reactions can occur as described in the USPI.


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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
Reductions in platelet counts and 
lymphocyte counts.
In B7931005 study, reductions in platelet counts and lymphocyte counts 
were observed during treatment with 200 mg QD but were not 
considered clinically meaningful and improved after switching to 50 mg 
QD.
Eligibility criteria and study 
assessments have been selected to 
ensure that only appropriate 
participants are included in the study.
Potential risk of infections.
Ritlecitinib is an immunomodulator and, as such, can be associated with 
the potential risk of infections (including serious infections), 
opportunistic infections, and viral reactivation.
Participants with significant infection 
history will be excluded (See 
Section 5.2) and the occurrence of 
infections will be monitored in the
study.
Potential fetal risk.
In animals, ritlecitinib was associated with fetal changes in bones and 
some internal organs, and lower fetal body weights.  
WOCBP who are unwilling or unable 
to use contraception as defined in the 
study protocol will be excluded (See 
Section 5.3.4. and Appendix 4).
Potential risk of secreting into human
milk.
It is not known whether ritlecitinib is secreted into human milk.
Ritlecitinib should not be administered 
to breastfeeding women and exposure 
during breastfeeding should be 
reported to Pfizer Safety (See 
Section 8.3.5.2).
Study Intervention: Tolbutamide
Phototoxicity
Porphyria cutanea tarda and photosensitivity reactions have been 
reported with sulfonylureas.5
The risk of phototoxicity with a single 
dose of tolbutamide (500 mg) is 
considered to be low. Additionally, 
participants will remain at the clinic 
during study participation and will be 
monitored.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hypoglycemia
Tolbutamide is an oral blood glucose lowering drug of the sulfonylurea 
category. As with all sulfonylurea medications, there is a potential risk 
of hypoglycemia in patients with renal/hepatic/adrenal/pituitary 
insufficiency. Elderly, debilitated, malnourished patients or those taking 
beta-adrenergic blocking drugs may be at increased risk of 
hypoglycemic episodes. Severe/prolonged exercise and alcohol use may 
also increase the risk of hypoglycemia.
The risk of clinically significant 
hypoglycemia with a single dose of 
tolbutamide (500 mg) is considered to 
be low. In addition, the study will 
enroll healthy volunteers and exclude 
subjects with metabolic conditions that 
would increase their risk of 
participation. Subjects will remain at
the clinic during study participation; 
physical activity, nutrition, and 
laboratory results will be monitored.
Gastrointestinal, dermatological, 
hematological, metabolic, and 
endocrine reactions.
Potential adverse reactions associated with tolbutamide or sulfonylurea 
treatment.5
A single dose of tolbutamide (500 mg) 
will be administered as part of the 
B7981069 and the risk of associated 
adverse reactions or laboratory 
abnormalities is low. Laboratory 
results and signs/symptoms will be 
monitored.


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2.3.2. Benefit Assessment
Neither ritlecitinib nor tolbutamide is expected to provide any clinical benefit to healthy 
participants. This study is designed primarily to generate PK, safety, and tolerability data for 
further clinical development of ritlecitinib.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with ritlecitinib and tolbutamide are justified by the anticipated 
benefits that may be afforded to patients with AA, vitiligo, RA, UC and CD treated with 
ritlecitinib.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To evaluate the effect of multiple-dose ritlecitinib 
(PF-06651600) on the PK of a single, oral dose of 
tolbutamide in healthy participants.

Cmax and AUCinf (if data permit, otherwise AUClast) of 
tolbutamide.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of ritlecitinib 
when coadministered with a single dose of 
tolbutamide.

Incidence of treatment-emergent adverse events
Other/Exploratory: 
Other/Exploratory: 

To characterize the PK of a single oral dose of 
tolbutamide in healthy participants.

Plasma tolbutamide PK parameters:Tmax, AUClast,
CL/F, Vz/F and t½, as data permit.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, 2-period, multiple-dose, open-label, single fixed sequence study of the 
effect of ritlecitinib on tolbutamide pharmacokinetics in healthy participants. A total of 
approximately 12 healthy male and/or female participants will be enrolled in the study to 
obtain at least 10 evaluable participants who complete the study. Participants who withdraw 
from the study may be replaced at the discretion of the sponsor.
Participants will be screened within 28 days of the first dose of study medication. 
Participants will report to the CRU the day prior to Day 1 dosing (Day -1) in Period 1 for 
both treatment sequences. Participants will remain in the CRU for a total of 16 days and 
15 nights. This includes 4 days and 4 nights (starting the night of admission to the CRU) in 
Period 1 and 12 days and 11 nights in Period 2. There will be no washout period between
2 treatment periods.


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In Period 1, participants will be dosed with a single administration of tolbutamide 500 mg 
tablet on Day 1. Tolbutamide PK will be assessed for 36 hours following dosing. Period 1 
will be immediately followed by Period 2 with no washout. In Period 2, participants will be 
dosed with oral 200 mg ritlecitinib QD for 10 days followed by administration of a single 
dose of 500 mg tolbutamide oral tablet within approximately 5 minutes after administration 
of a 200-mg dose of ritlecitinib on the morning of Day 10. Tolbutamide PK in Period 2 will
again be assessed at pre-dose and over 36 hours after tolbutamide dosing. (Table 3)
Table 3.
Treatment Flow Diagram
Period
Day*
Treatment
1
1
Tolbutamide 500 mg (single dose)
2
1-9
Ritlecitinib 200 mg QD
10
Ritlecitinib 200 mg QD + tolbutamide 500 mg (single dose)
11
No treatment given 
12
No treatment given (discharge)
Follow-up
28-35 after last dose of 
investigational product
Follow-up phone contact 
*Note: Day is relative to the first day of study intervention dosing (including tolbutamide and ritlecitinib) in 
each period.
Participants will have a telephone contact at least 28 calendar days, and up to 35 calendar 
days after the last administration of the investigational product.
4.2. Scientific Rationale for Study Design
The study is being designed as a fixed-sequence study to avoid the long washout period
needed in a crossover design due to long half-lives of CYP enzymes to revert back to their 
baseline values. The fixed-sequence design has a low risk of period effect given the short 
time between the 2 periods. This is an open-label study not requiring an assessment of 
efficacy or pharmacodynamics markers, but it will include PK estimation for DDIs.
Since tolbutamide has a t½ of 4.5 – 6.5 hours, plasma PK samples for tolbutamide will be 
collected up to 36 hours post-dosing to ensure that the majority of tolbutamide is recovered.
There will be no separate washout between 2 periods, because 9 days of ritlecitinib dosing in 
Period 2 is considered adequate to cover the washout of tolbutamide from Period 1 based on 
ritlecitinib t½.
4.2.1. Diversity of Study Population
Reasonable attempts will be made to enroll participants with other races than White and at 
least 1 female participant.
4.2.2. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.


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4.3. Justification for Dose
4.3.1. Justification of Ritlecitinib Dose
The study will use the ritlecitinib dose of 200 mg given QD for 10 days. The choice of this 
dose is based on the highest ritlecitinib dose currently being evaluated in Phase 3 study for 
AA program. The dose level of 200 mg QD has demonstrated its safety and tolerability for 
up to 14 days in healthy participants (B7981001), up to 4 weeks in participants with AA
(B7931005) and up to 8 weeks in RA participants (B7981006) (Refer to Section 2.2.4).
Enzyme induction can take several days for effects to manifest and alter enzyme activity. 
Multiple dose administration of the investigational drug for a minimum of 10 days is 
generally considered adequate. Therefore, ritlecitinib will be administered for 10 days in this 
study.
4.3.2. Justification of Tolbutamide Dose
The study will use the single dose of tolbutamide 500 mg. Tolbutamide is mainly metablized 
by CYP2C9 and acts as a sensitive substrate for this isoenzyme.2,3 The therapeutic dose of 
tolbutamide is from 250 mg up to 3 g and most DDI studies involving tolbutamide as a 
substrate have been conducted at the 500 mg dose level.2,6,7 In a drug interaction study with 
rifampin, a potent enzyme inducer for CP3A4, CYP2C19, CYP2C9, and CYP2B6, the total 
clearance of tolbutamide 500 mg SD was increased by about 1.92-fold.7
Tolbutamide is not known to induce or inhibit any metabolizing enzymes and therefore it is 
not expected to affect the exposures of ritlecitinib. Ritlecitinib is not expected to increase 
tolbutamide exposure. Thus, the combination of 200 mg ritlecitinib and 500 mg tolbutamide
is expected to be generally safe and well tolerated by healthy participants.
4.4. End of Study Definition
The end of the study is defined as the date of the last scheduled procedure shown in the SoA
for the last participant in the trial.
A participant is considered to have completed the study if he/she has 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. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and female participants must be 18 to 65 years of age, inclusive, at the time of 
signing the ICD.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Male and/or female participants who are healthy as determined by medical evaluation 
including medical history, full physical examination (including BP and pulse rate 
measurements), clinical laboratory tests, and 12-lead ECG.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
4. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, 
dermatological or allergic disease (including drug allergies, but excluding untreated, 
asymptomatic, seasonal allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
3. Known immunodeficiency disorder, including positive serology for HIV at screening, 
or a first degree relative with a hereditary immunodeficiency.


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4. Infection with hepatitis B or hepatitis C viruses according to protocol specific testing 
algorithm.
a.
For hepatitis B, all participants will undergo testing for HBsAg and HBcAb. Only 
participants who are both HBsAg negative and HBcAb negative are eligible
(regardless of the HBsAb result, if the latter is also reported due to local standard 
of care).
b. For hepatitis C, all participants will undergo testing for HCVAb. Only 
participants who are HCVAb negative are eligible.
5. Participants with any of the following acute or chronic infections or infection history:

Any infection requiring treatment within 2 weeks prior to the dosing visit.

Any infection requiring hospitalization or parenteral antimicrobial therapy within 
60 days of the first dose of investigational product.

Any infection judged to be an opportunistic infection or clinically significant by 
the investigator within the past 6 months of the first dose of investigational 
product.

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.
6. History of febrile illness within 5 days prior to the first dose of investigational 
product.
7. 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.
8. Known presence or a history of malignancy other than a successfully treated or 
excised non-metastatic basal cell or squamous cell cancer of the skin or cervical 
carcinoma in situ.
9. Participants who, according to the product label for tolbutamide, would be at 
increased safety risk if dosed with tolbutamide.
10. History of hypersensitivity to tolbutamide or any of its excipients.


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11. Other medical or psychiatric condition (including recent [within the past year] or 
active suicidal ideation/behavior, laboratory abnormality, or other conditions or 
situations related to COVID-19 pandemic [eg, contact with a positive case, residence, 
or travel to an area with high incidence]) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
entry into this study.
12. Known glucose 6-phosphate dehydrogenase (G6PD) deficiency.
Prior/Concomitant Therapy:
13. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 
5 half-lives (whichever is longer) prior to Day 1. Limited use of nonprescription 
medications that are not thought 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.
Herbal supplements, hormonal contraceptives and HRT must be discontinued at least 
28 days prior to the first dose of investigational product; Depo-Proveraand 
SAYANAPRESS must be discontinued at least 6 months prior to dosing of 
investigational product.
14. Systemic therapy with any of the medications that are moderate or strong CYP2C9 
inhibitors within 28 days or 5 half-lives (whichever is longer) or moderate or strong 
CYP2C9 inducers within 28 days or 5 half-lives (whichever is longer) prior to the 
first dose of investigational product (Section 6.8).
15. Vaccination with a live attenuated vaccine within 6 weeks prior to the first dose of 
study intervention (refer to Section 5.3.5 for additional details). 
Prior/Concurrent Clinical Study Experience:
16. Previous administration of investigational products (eg, drugs or vaccines) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of investigational product used in this study (whichever is longer).
17. Known participation in a clinical trial of ritlecitinib and the participant experienced a 
ritlecitinib-related AE that led to discontinuation or had a ritlecitinib-related SAE.
Diagnostic Assessments:
18. A positive urine drug test.
19. A positive pregnancy test.
20. BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at least 5 minutes of 
supine rest. If BP is 140 mm Hg (systolic) or 90 mm Hg (diastolic), the BP should 


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be repeated 2 more times and the average of the 3 BP values should be used to 
determine the participant’s eligibility.
21. Any of the following conditions:

Screening 12-lead ECG that demonstrates:

Clinically significant abnormalities requiring treatment (eg, acute myocardial 
infarction, serious tachy- or brady-arrhythmias) or indicating serious 
underlying heart disease (eg, cardiomyopathy, Wolff Parkinson–White 
syndrome);

Confirmed QTcF (time from the start of the Q wave to the end of the T wave 
on ECG corrected using Fridericia’s correction factor) prolongation 
(>450 milliseconds).

Long QT Syndrome, a family history of Long QT Syndrome, or a history of 
Torsades de Pointes;
22. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary:

AST or ALT level >1.5 × ULN;

Total bilirubin level >1.5 × ULN;

Hemoglobin level 120 g/L (12.0 g/dL);

Platelet count 150 × 109/L (150,000 cells/mm3);

WBC count of 3.0 × 109/L (3000 cells/mm3);

ANC 1500 cells/mm3;

ALC 800 cells/mm3;

eGFR 60 mL/min/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.


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23. Have evidence of untreated or inadequately treated active or latent infection with 
Mycobacterium tuberculosis (TB) as follows (see details in Appendix 2).

A positive QFT-G In-Tube test performed within the 3 months prior to screening.  
If the laboratory reports the test result as indeterminate, the test should be 
repeated. If the result of the repeat test is indeterminate, a PPD test may be 
substituted for the QFT-G In-Tube test only with approval from the Pfizer 
Medical Monitor on a case by case basis.
Note: If a participant has previously received an adequate course of therapy for 
either latent (9 months of isoniazid in a locale where rates of primary multi drug 
resistant TB infection are <5% or an acceptable alternative regimen) or active 
(acceptable multi drug regimen) TB infection, neither a QFT-G In-Tube test nor a 
PPD test need be obtained.
A participant who is being treated for latent or active TB infection is not eligible 
for this study.
Other Exclusions:
24. 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 (males) and 4 (females) 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).
25. Use of tobacco/nicotine containing products in excess of 5 cigarettes/day.
26. History of severe allergic or anaphylactic reaction to kinase inhibitors or excipients (if 
known, document the specific excipient or drug).
27. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
28. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
29. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.  


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5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 12 hours 
prior to any safety laboratory evaluations.

Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices, see
below) may be consumed with meals and the evening snack.

On PK days (Period 1 Day 1 and Period 2 Day 10), participants should begin 
breakfast approximately 30 minutes prior to tolbutamide administration. The 
breakfast will be consumed over approximately a 20-minute interval with tolbutamide
administered within approximately 10 minutes of completion of the meal. Participants 
will be encouraged to complete the entire breakfast. There are no water restrictions 
prior to and after dosing. No restriction will be placed on breakfast on other study 
days provided other restrictions are followed.

On PK days (Period 1 Day 1 and Period 2 Day 10), lunch will be provided 
approximately 4 hours after tolbutamide dosing. Food restrictions only apply on the 
days when tolbutamide is dosed.

On PK days (Period 1 Day 1 and Period 2 Day 10), dinner will be provided 
approximately 9 to 10 hours after tolbutamide dosing. Food restrictions only apply on 
the days when tolbutamide is dosed.

An evening snack is permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of investigational product until collection of the final PK blood sample.

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and 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 caffeine containing products for 24 hours prior to the 
start of dosing and during confinement in the CRU.


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
Participants will abstain from the use of tobacco or nicotine containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant from the permitted list of contraception methods (see Appendix 4 Section 10.4) 
and will confirm that the participant has been instructed in its consistent and correct use. At 
time points indicated in the SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart (participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception)
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 or if pregnancy is known or suspected in the participant
or partner.
5.3.5. Vaccination 
Vaccination with a live attenuated vaccine is prohibited within the 6 weeks prior to the first 
dose of study intervention, during the study, and for 6 weeks after the last dose of study 
intervention. Similarly, current routine household contact with individuals who have been 
vaccinated with live attenuated vaccines 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 live attenuated 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 vaccine, vaccinia (smallpox) vaccine, and Zostavax®
(zoster vaccine live).
Vaccines (including COVID-19 vaccines) that are not live attenuated are permitted.


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5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to investigational product/entered in the study. 
Screen failure data are collected and remain as source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
For this study, the investigational products are ritlecitinib (PF-06651600, 200 mg provided as 
four 50 mg capsules) and tolbutamide (500 mg provided as one 500 mg tablet).
Ritlecitinib (PF-06651600) 50 mg capsules will be supplied to the CRU in bulk along with 
individual dosing containers for unit dosing.
Tolbutamide 500 mg tablets will be supplied to the CRU. 
6.1.1. Administration
Administration of investigational product (ritlecitinib [PF-06651600] and/or tolbutamide) 
will be carried out according to the conditions described in the SoA and Section 5.3.1 of this 
protocol.
For Period 1, on Day 1, approximately 10 min after a standard breakfast, participants will 
receive tolbutamide at approximately 08:00 hours (±3 hours) with approximately 240 mL of 
ambient temperature water.
For Period 2, ritlecitinib will be administered under non-fasting conditions on Days 1 to 9.
On the morning of Day 10, approximately 10 min after a standard breakfast, ritlecitinib and 
tolbutamide doses will be administered at 08:00 hours (±2 hours), with ambient temperature 
water to a total volume of approximately 240 mL. Ritlecitinib will be administered first. 
After swallowing the ritlecitinib dose, tolbutamide should be administered within 
approximately 5 minutes. 
For coadministration day, participants may receive additional ambient temperature water up 
to 100 mL, if needed.
The time of ritlecitinib and tolbutamide administrations will be recorded.


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Participants will swallow the investigational product whole, and will not manipulate or chew 
the investigational product prior to swallowing.
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the PCRU site procedures.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label.
5. Study interventions should be stored in their original containers and in accordance 
with documentation provided to the site.
6. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record.
7. Further guidance and information for the final disposition of unused study 
interventions are provided by CRU or as per local procedures, All destruction must be 


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adequately documented. If destruction is authorized to take place at the investigator 
site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities. 
Ritlecitinib (200 mg, four 50 mg capsules) and tolbutamide (500 mg, provided as one 500 mg 
tablet) will be prepared at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist). 
The tablets and capsules will be provided in unit dose containers and labeled in accordance 
with Pfizer regulations and the clinical site’s labeling requirements. 
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
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 site and, in 
accordance with the randomization numbers, the participant will receive the study treatment 
regimen assigned to the corresponding randomization number.
6.4. Study Intervention Compliance
Participants 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. The oral cavity of each participant will be examined following dosing to 
ensure the investigational product was taken.
6.5. Dose Modification 
Dose modification is not allowed in the current study.


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6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. 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.
Any dose of tolbutamide greater than 3000 mg within a 24-hour time period will be 
considered an overdose.
There is no specific antidote or specific treatment for an overdose of ritlecitinib. For 
tolbutamide, investigators should consider the treatment of overdose as per USPI.5
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
ritlecitinib and tolbutamide can no longer be detected systemically (at least 2 days).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to 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 medical monitor (determined on a case-by-case 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
6.8. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤3 g/day. Ibuprofen may be used at doses ≤1200 mg/day.
Systemic therapy with any of the medications that are moderate or strong CYP2C9 inhibitors 
or moderate or strong CYP2C9 inducers within 28 days or 5 half-lives (whichever is longer) 
are prohibited prior to the first dose of investigational product.


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Females using hormonal contraceptives or taking HRT may be eligible to participate in this 
study if they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study. Depo-Provera
must be discontinued at least 6 months prior to the first dose of study treatment. Note that 
another approved method of contraception must then be used (Section 10.4.3).
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. Concomitant drug and non-drug treatment 
will be collected. All participants will be questioned about concomitant treatment at each 
clinic visit.
Treatments taken within 28 days before the first dose of investigational product will be 
documented as a prior treatment. Treatments taken after the first dose of investigational 
product will be documented as concomitant treatments.
6.8.1. Rescue Medicine
There is no specific rescue therapy to reverse the AEs caused by ritlecitinib or tolbutamide; 
standard medical supportive care must be provided to manage the AEs. 
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 as outlined in 
Section 10.8.2.
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.
See Appendix 8 for guidelines for safety monitoring and discontinuation guidelines.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;


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
At the discretion of the investigator for behavioral, compliance, or administrative 
reasons.  
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.  
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1 for 
disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.


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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier group may be 
used in a subsequent group without rescreening, provided laboratory results obtained prior to 
the first dose administration meet eligibility criteria for this study. In addition, other clinical 


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assessments or specimen collections, eg, banked biospecimens, may be used without repeat 
collection, 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 may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
145 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Not Applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, gastrointestinal including lymph nodes, skin and 
participant reported symptoms.


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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 data 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 8.3.1 to 8.3.3.
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and 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.
8.2.2.1. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
8.2.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) is not 
recommended given the potential risk of discrepancies with ECGs acquired using standard 
limb lead placement. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 10 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements (Period 1, Day 1 pre-dose). Additional ECG 


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monitoring will occur if a) a postdose QTcF interval is increased by ≥60 msec from the 
baseline and is >450 msec; or b) an absolute QT 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 msec from the baseline and is >450 msec, or b) 
an absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator), or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring. A cardiologist should be 
consulted if QTc intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 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 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.


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See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
Participant 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.  
8.2.5. COVID-19 specific assessments 
Participants will be tested for SARS-COVID-19 infection by PCR prior to being admitted to 
the clinic for confinement and a subsequent COVID-19 test will be performed after 4 days 
(i.e. upon completion of 4 x 24 hours in house), or if they develop COVID-19 like symptoms. 
Additional testing may be required by local regulations or by the Principal Investigator.
8.2.6. Estimated Glomerular Filtration Rate
eGFR will be calculated using the following equation developed by the CKD-EPI , which 
utilize SCr:
CKD-EPI

If female and SCr is 0.7 mg/dL:
GFR (mL/min/1.73 m2) = 144 × (SCr/0.7) – 0.329 × 0.993age (× 1.159, if black).

If female and SCr is >0.7 mg/dL:
GFR (mL/min/1.73 m2) = 144 × (SCr/0.7) – 1.209 × 0.993age (× 1.159, if black).

If male and SCr is 0.9 mg/dL:
GFR (mL/min/1.73 m2) = 141 × (SCr /0.9) – 0.411 × 0.993age (× 1.159, if black).

If male and SCr is >0.9 mg/dL:
GFR (mL/min/1.73 m2) = 141 × (SCr /0.9) – 1.209 × 0.993age (× 1.159, if black).
8.2.7. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention. Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may also be 
repeated if requested by IRBs/ ECs or if required by local regulations.


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8.3. Adverse Events and 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 
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 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, after the last administration of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
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 definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AE or SAE after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and he/she 


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considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, 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.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.


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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. 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 exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.
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, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP Supplemental Form, 


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regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until 28 days after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must 
report information to Pfizer Safety using the CT SAE Report Form and EDP 
Supplemental Form. Since the exposure information does not pertain to the 
participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report 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 does not pertain to a participant enrolled in the study, 
the information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events (Not applicable)
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs (Not applicable)
8.3.8. Adverse Events of Special Interest (Not applicable)
8.3.8.1. Lack of Efficacy (Not applicable)
This section is not applicable because efficacy is not expected in the study population.


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8.3.9. Medical Device Deficiencies (Not applicable)
8.3.10. 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.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Pharmacokinetics
Blood samples of approximately 3 mL, to provide approximately 1 mL plasma, will be 
collected for measurement of plasma concentrations of tolbutamide 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 


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samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time (eg, within 6 minutes of a 60-minute sample) relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and data collection tool (eg, CRF/DCT). Collection of samples more 
than 10 hours after dose administration that are obtained ≤1 hour away from the nominal 
time relative to dosing will not be captured as a protocol deviation, as long as the exact time 
of the collection is noted on the source document and data collection tool (eg, CRF/DCT). 
Samples will be used to estimate the PK of tolbutamide. Samples collected for analyses of 
tolbutamide concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study, for metabolite identification, metabolite assay for 
tolbutamide and/or ritlecitinib, and/or evaluation of the bioanalytical method, or for other 
internal exploratory purposes.
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of tolbutamide 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.
8.5. Genetics
8.5.1. Specified Genetics
A 4-mL blood pharmacogenomic sample for DNA isolation will be collected into plastic 
K2-EDTA tubes, as defined in the SoA. DNA samples will be analyzed for the purpose of 
assessing the impact of allelic variants of CYP2C9 as variation in this gene may influence the 
metabolism and PK of tolbutamide. Additionally, these samples may also be used for 
retrospective evaluation of additional genetic variants associated with variation in PK, 
biomarker response, or to explore AEs should these be observed. Samples will be retained for 
a period of up to 3 years after regulatory approval.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested
from the participant.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in sponsor-identified study-specific 
central laboratory manual. The PGx sample must be processed and shipped as indicated in 
the instructions provided to the investigator site, to maintain sample integrity. Any deviations 


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from the PGx processing steps, including any actions taken, must be documented and 
reported to the sponsor. On a case-by-case basis, the sponsor may make a determination as to 
whether sample integrity has been compromised. Any sample deemed outside of established 
stability, or of questionable integrity, will be considered a protocol deviation.
Any data outside of the CYP2C9 genotyping will be used for internal exploratory purposes 
and will not be included in the clinical study report.
8.5.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s) and 
safety biomarkers. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the banked samples.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in lab manual and other supporting 
documentation.
8.6. Biomarkers
Collection of samples for biomarker research is also part of this study. 
The following sample for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA:

A 10 mL whole blood for serum (Prep B2) sample.
8.6.1. Retained Research Samples for Biomarkers
These Retained Research Samples will be collected in this study:
A 10 mL whole blood for serum (Prep B2) sample will be collected according to the SoA, as 
local regulations and IRB/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s) and 
safety biomarkers. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the banked samples.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in lab manual and other supporting 
documentation.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.


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8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No statistical hypothesis will be tested in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
PK Parameter Evaluable
The PK Evaluable population is defined as all participants 
treated who have at least 1 of the PK parameters of primary 
interest in at least 1 treatment period.
PK Concentration
The PK Concentration population is defined as all participants 
treated who have at least 1 concentration in at least 1 treatment 
period.
Safety
All participants assigned to the study intervention and who 
take at least 1 dose of the study intervention.  Participants will 
be analyzed according to the intervention they actually 
received.
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. Table 4 shows the definition for 
the PK parameters.
Table 4.
Plasma Pharmacokinetic Parameter Definitions
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentration-time profile from time 
0 to time of the last quantifiable 
concentration (Clast)
Linear/Log trapezoidal rule


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Table 4.
Plasma Pharmacokinetic Parameter Definitions
Parameter
Definition
Method of Determination
AUCinf
Area under the plasma 
concentration-time profile from time 
0 extrapolated to infinite time
AUClast + (Clast*/kel), where Clast* is the 
predicted plasma concentration at the 
last quantifiable time point estimated 
from the log-linear regression analysis, 
and kel is the terminal phase rate 
constant calculated by a linear 
regression through at least 3 data 
points in the terminal phase of the 
log-linear concentration-time curve
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of 
first occurrence
CL/F
Apparent clearance
Dose/AUCinf
Vz/F
Apparent volume of distribution 
following oral administration
Vz/F= Dose /(AUCinf*kel)
t½
Terminal plasma elimination half-life
Loge(2)/kel, Only those data points 
judged to describe the terminal 
log-linear decline will be used in the 
regression
9.3.1. General Considerations
Methodology for summary and statistical analyses of the data collected in this study is 
outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate, however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.3.2. Primary Endpoints
Natural log-transformed parameters AUCinf (if data permit, otherwise AUClast) and Cmax of
tolbutamide will be analyzed using a mixed effect model with treatment as a fixed effect and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% CIs will be obtained from the model.  The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CI for the ratios. Tolbutamide
administered alone will be the Reference treatment and tolbutamide co-administered with 
ritlecitinib will be the Test treatment.
Actual PK sampling times will be used in the derivation of PK parameters. The tolbutamide
AUCinf, AUClast and Cmax will be listed and summarized descriptively by treatment.  


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9.3.3. Other Endpoints
The tolbutamide Tmax, AUClast, CL/F, Vz/F and t½, as data permit, will be listed and 
summarized descriptively by treatment. Plasma concentrations will be listed and summarized 
descriptively by treatment and nominal PK sampling time. Individual participant and 
summary profiles (mean and median plots) of the plasma concentration-time data will be 
plotted using actual and nominal times, respectively.
9.3.4. 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 
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.
9.3.5. Other Analyses 
Pharmacogenomic or biomarker data from Retained Research Samples 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 formal interim analysis will be conducted for this study. 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, and/or supporting clinical development. 
9.5. Sample Size Determination
The following table presents the width of 90% confidence interval for approximately n=12 
and different estimated effects of ritlecitinib on the pharmacokinetics of a single, oral dose of
tolbutamide.


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Table 5.
Estimated 90% CIs for Different Underlaying Effects 
Parameter
Estimated Effect
(100*Test/Reference)
90% CI LB
90% CI UB
90% CI Width
AUCinf
70%
59.1%
82.9%
23.8%
75%
63.3%
88.8%
25.5%
80%
67.6%
94.7%
27.2%
85%
71.8%
100.7%
28.9%
90%
76.0%
106.6%
30.6%
95%
80.2%
112.5%
32.3%
100%
84.4%
118.4%
34.0%
105%
88.7%
124.3%
35.7%
These calculations are based on the estimate of within-participant standard deviation of 0.20
for tolbutamide loge AUCinf  as obtained from published studies.8,9,10


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
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 


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of any serious breaches of this protocol or of ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study, 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 study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.
10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.


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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.4. Committees Structure
10.1.4.1. Data Monitoring Committee
This study will not use a DMC. 
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.


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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or
electronically signing the CRF.
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.


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The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, 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 IQMP
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.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the 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.


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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 source data can be found in the source document locator, 
which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the CRO if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.


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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.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications,
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Investigators Site Master File.
To facilitate access to appropriately qualified medical personnel for studyrelated medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 


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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 investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, 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 concerns.
Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry (fasting)
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs 
and %)
Eosinophils (Abs and %)
Monocytes (Abs and %)
Basophils (Abs and %)
Lymphocytes (Abs and 
%)
BUN/urea and 
creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
Uric acid
CK
Total cholesterol
HDL cholesterol
LDL cholesterol
(calculated)
Triglycerides
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya

COVID-19 testing

FSHb

Pregnancy test (β-hCG)d

HBsAge

HBcAbe

HCVAbe

HIVQuantiFERON®-TB 
Gold Teste

Urine drug screeningc

eGFR-CKD-EPIe

Viral screenf
Testing as indicated (reflex 
testing; refer to Section 10.8.1
and Section 10.8.2 for 
guidance/criteria):

FACS-TBNK

Urine myoglobin 
Section 10.8.1.
Additional 
Assessments for Hy’s 
Law:
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
GGT
PT/INR
Total bile acids


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Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry (fasting)
Urinalysis
Other
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
At Screening for confirmation of postmenopausal status only.
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 -hCG for female participants of childbearing potential according to Schedule of Activities.
e.
Complete at screening. Previous testing for QuantiFERON®-TB Gold Test will be accepted if 
completed within 12 weeks prior to baseline. Otherwise should be completed at screening and results 
available prior to Day -1.
f.
A serum sample will be collected at baseline and submitted to the central lab. The sample will be stored 
and analyzed at a later date only at the sponsor’s request. In certain cases of suspected viral infection (eg, 
disseminated herpes zoster or varicella), the sponsor may request to analyze the sample to determine if 
the subject had exposure to that virus.
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.
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing prior to dosing must be negative for participants to receive investigational 
product


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.  Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
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 which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
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 detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.


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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) which 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, is considered serious.  
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 important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs 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 on 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) 


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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, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
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 non-participant (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.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the 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/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.


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
The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.

Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self 
care ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 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.


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
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.


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
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 Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study based on the 
following considerations:

Ritlecitinib is not likely to transfer to a partner through semen at pharmacologically 
relevant blood levels.

According to the tolbutamide USPI information5, there is no requirement for male 
contraceptive use during treatment.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s). The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention.
A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period and for at least 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 in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.


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Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as 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.

For women using HRT, FSH should be measured after an appropriate washout 
of HRT (at least 14 days after the last dose of HRT). HRT must be 
discontinued at least 28 days before the first dose of ingestigational product 
and for at least 28 days after the last dose of ritlecitinib.

A female whose menopausal status is in doubt will be required to use one of the 
allowed nonhormonal highly effective contraception methods.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency 
1. Non-hormonal Intrauterine device (IUD).
2. Bilateral tubal occlusion or ligation.


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3. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
1. Sexual abstinence.

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to 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.  

Samples for specified genetic analysis (see Section 8.5.1) will be stored for up to  
3 years after regulatory approval or other 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 an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).


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


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


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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to
<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR 
>100 bpm (such as torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as 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 enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.8. Appendix 8: Guidelines for Participant Safety Monitoring and Discontinuation
These guidelines for participant safety monitoring and discontinuation are to be applied to all 
participants in Study B7981069. Additional individual participant monitoring is at the 
discretion of the investigator and dependent on any perceived safety concerns. Unscheduled 
clinical labs may be obtained at any time during the study to assess such concerns, and a
participant may be withdrawn at any time at the discretion of the investigator.
10.8.1. Participant Safety Monitoring
All potential treatment-related events of rash will be followed up until resolution or 
agreement with Pfizer.
In the case of a positive urine pregnancy test, the participant will have investigational product
interrupted and a serum sample collected on the same day (or as soon as possible) and 
submitted to the laboratory for pregnancy testing.
The following laboratory abnormalities require re-testing until resolution or agreement 
with Pfizer:
Laboratory 
Variable
Laboratory Value
Re-testing 
Timeframec
Hematology
Absolute Neutrophil 
Count
<1000/mm3 (<1.0 × 109/L)
24-48 hours
Hemoglobin
<10.0 g/dL (<6.21 mmol/L or <100 g/L) 
OR
Decrease of ≥2.0 g/dL from baseline
24-48 hours
Platelet count
<100,000/mm3 (<100.0 × 109/L)
24-48 hours
ALCa
<600/mm3 (<0.6 × 109/L)
24-48 hours
Serum Chemistry
CKb
>3 × ULN
24-48 hours
AST
See Appendix 6 for potential cases of drug-induced liver 
injury.
24-48 hours
ALT
See Appendix 6 for potential cases of drug-induced liver 
injury.
24-48 hours
TBili
See Appendix 6 for potential cases of drug-induced liver 
injury.
24-48 hours
a.
Participants with ALC <500/mm3 (0.5 × 109/L) will be reflex-tested for FACS-TBNK until the ALC
resolves or stabilizes at a level acceptable to the investigator and sponsor.
b.
In addition to re-testing creatinine kinase >3 × ULN, urine myoglobin will be performed as reflex 
testing for any participant with CK >10 × ULN.
c.
Timeframe is based on the awareness of the abnormal results.


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10.8.2. Participant Discontinuation Criteria
Treatment will be discontinued and the participant withdrawn from this study for:
Adverse Events:

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
parenteral antimicrobial therapy or hospitalization for treatment or meeting other 
criteria that require the infection to be classified as serious adverse event;

Treatment-related SAEs;

Other serious or severe AEs, at the discretion of the investigator or sponsor.
ECG Findings:

Confirmed QTcF >500 milliseconds;

Confirmed increase from baseline in QTcF of >60 milliseconds.
Laboratory Abnormalities:

All the following laboratory abnormalities require discontinuation if they are
confirmed by retest. Refer to the re-testing timeframes for laboratory abnormalities in 
Section 10.8.1.

ANC <750/mm3 (<0.75 × 109/L);

Hemoglobin <9.0 g/dL (<5.59 mmol/L or <90 g/L) or a decrease of >30% from 
baseline (either criterion or both);

Platelet count <75,000/mm3 (<75.0 × 109/L);

ALC <500/mm3 (<0.5 × 109/L).
NOTE: Participants with ALC <500/mm3 (0.5 × 109/L) will be reflex tested for 
FACS-TBNK until the ALC resolves or stabilizes at a level acceptable to the 
investigator and sponsor.

Creatine kinase >10 × ULN.
NOTE: In addition to re-testing creatinine kinase >3 × ULN, urine myoglobin will 
be performed as reflex testing for any participant with creatine kinase 
>10 × ULN.


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
AST or ALT that meet ANY of the following:

>3 times ULN with at least one total bilirubin value >2 times ULN;

>3 times ULN accompanied by signs or symptoms consistent with hepatic 
injury (eg, new onset elevated PT/INR);

Two sequential AST or ALT elevations >5 times ULN, regardless of total 
bilirubin or accompanying signs or symptoms.
NOTE: In each case, there is a need for additional investigations, such as review of ethanol, 
recreational drug and dietary supplement consumption; testing for acute hepatitis A, B or C 
infection and biliary tract imaging should be promptly discussed with the sponsor or 
designee.


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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 of daily living
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC24
area under the plasma concentration-time profile from time 0 to time
24 hours.
AUClast
area under the plasma concentration-time profile from time 0 to time 
of the last quantifiable concentration
AUCinf
area under the plasma concentration-time profile from time 
0 extrapolated to infinite time
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
bpm
beats per minute
BA
bioavailability
BAEP
Brainstem auditory evoked potentials
BID
twice a day
BMI
body mass index
BP
blood pressure
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 Collaboration
Clast
last quantifiable concentration
CL/F
apparent clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
CO2
carbon dioxide (bicarbonate)
COVID-19
Coronavirus disease
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale


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Abbreviation
Term
CYP
cytochrome
CSR
Clinical Study Report
CT
clinical trial
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
EBV
Epstein Barr Virus
EC
ethics committee
ECC
Emergency Contact Card
ECG
electrocardiogram
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FACS-TBNK
fluorescence-activated cell sorting- T-,B- and NK-cells
FIH
first in human
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
HCVAb
hepatitis C antibody
HDL
high-density lipoprotein
HepBcAb
hepatitis B core antibody
HepBsAb
hepatitis B surface antibody
HepBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
IGRA
Interferon Gamma Release Assay
IL
interleukin
INR
international normalized ratio
IQMP
Integrated Quality Management Plan
IRB
Institutional Review Board


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Abbreviation
Term
IUD
intrauterine device
IV
intravenous
LB
lower bound
LDL
low-density lipoprotein
LFT
liver function test
JAK
Janus kinase 
kel
first-order elimination rate constant
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MMR
measles, mumps, and rubella
NK
Natural Killer
NOAEL
no-observed-adverse-effect level
PCRU
Pfizer Clinical Research Unit
PGx
pharmacogenomics
PI
principal investigator
PPD
purified protein derivative
PK
pharmacokinetic(s)
PNS
peripheral nervous system
PR
the period that extends from the beginning of the P wave until the 
beginning of the QRS complex
PT
prothrombin time
PVCs
premature ventricular contractions
PXR
pregnane X receptor
QD
once daily
QT
time from the beginning of the QRS complex to the end of the T 
wave
QTc
corrected QT interval
QTcF
corrected QTc using (Fridericia method)
QTF-G
QuantiFERON-TB Gold
qual
qualitative
RA
rheumatoid arthritis
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCr
serum creatinine
SD
single dose
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
t½:
terminal half-life


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Abbreviation
Term
TB
tuberculosis
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TEC
TEC gene
THC
tetrahydrocannabinol
Tmax
time to reach Cmax
TYK
tyrosine kinase
UB
upper bound
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
Vz/F
apparent volume of distribution following oral administration
WBC
white blood cell
WOCBP
woman of childbearing potential


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11. REFERENCES
1
Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator 
of xenobiotic metabolism. Endocr Rev 2002;23:687 –702.
2
Back D J, Tjia J, Mönig H, et al. Selective inhibition of drug oxidation after 
simultaneous administration of two probe drugs, antipyrine and tolbutamide. Eur J Clin 
Pharmacol 1988;34(2):157-63.
3
Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis Mar-Apr 
1990;12 Suppl 3:S327-33.
4
Viatris Inc. Tolbutamide Product Detail website. Available from: 
https://www.viatris.com/en-us/lm/countryhome/us-
products/productcatalog/productdetails?id=34d22324-71e0-45c7-bc72-6d30d2fd4ef2. 
Accessed: 15 Jun 2021.
5
DailyMed. Tolbutamide Tablet Drug Label Information website. Available from: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3995eed8-39ec-ce5e-8cc2-
062f93445c8d. Accessed: 15 Jun 2021.
6
Veronese M E, Miners J O, Randles D, et al. Validation of the tolbutamide metabolic 
ratio for population screening with use of sulfaphenazole to produce model phenotypic 
poor metabolizers. Clin Pharmacol Ther 1990 Mar;47(3):403-11.
7
Vormfelde SV, Brockmöller J, Bauer S, et al. Relative impact of genotype and enzyme 
induction on the metabolic capacity of CYP2C9 in healthy volunteers. Clin Pharmacol 
Ther 2009 Jul;86(1):54-61.
8
Gillen M, Yang C, Wilson D, et al. Evaluation of pharmacokinetic interactions between 
lesinurad, a new selective urate reabsorption inhibitor, and CYP enzyme substrates 
sildenafil, amlodipine, tolbutamide, and repaglinide. Clin Pharmacol Drug Dev 2017 
Jul;6(4):363-76.
9
Perkins, E, Posada, M, Kellie Turner, P, et al. Physiologically Based pharmacokinetic 
modelling of cytochrome P450 2C9-related tolbutamide drug interactions with 
sulfaphenazole and tasisulam. Eur J Drug Metab Pharmacokinet 2018; 43(3): 355–67.
10
Gross AS, Bridge S, GM. Pharmacokinetics of tolbutamide in ethnic Chinese. Shenfield 
Br J Clin Pharmacol 1999;47(2):151-6
                                                

SAP_001.pdf: 
Protocol B7981069 (PF-06651600) Statistical Analysis Plan
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PFIZER CONFIDENTIAL
Protocol B7981069
PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, 2-PERIOD 
STUDY TO ESTIMATE THE EFFECT OF MULTIPLE-DOSE 
RITLECITINIB (PF-06651600) ON THE PHARMACOKINETICS 
OF SINGLE-DOSE TOLBUTAMIDE IN HEALTHY 
PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
 
 Statistician 
 
Date:
16-SEP-2021
PPD
PPD
P
P
PPD


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PFIZER CONFIDENTIAL
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
September 16, 2021
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD


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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
2.2.1. Primary Objective.........................................................................................6
2.2.2. Secondary Objective.....................................................................................6
2.2.3. Exploratory Objective...................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES AND DECISION RULES...........................................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
5. ANALYSIS SETS .................................................................................................................6
5.1. Enrolled participants .................................................................................................6
5.2. Pharmacokinetic (PK) Analysis Set ..........................................................................7
5.2.1. PK Concentration..........................................................................................7
5.2.2. PK Parameter Evaluable...............................................................................7
5.3. Pharmacodynamic Analysis Set................................................................................7
5.4. Safety Analysis Set....................................................................................................7
5.5. Other Analysis Sets ...................................................................................................7
5.6. Treatment Misallocations..........................................................................................7
5.7. Protocol Deviations...................................................................................................7
5.7.1. Deviations Assessed Prior to Randomization...............................................7
5.7.2. Deviations Assessed Post-Randomization....................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Efficacy Endpoint(s) .................................................................................................8
6.2. Safety Endpoints .......................................................................................................8
6.3. PK Endpoints.............................................................................................................8
6.3.1. PD Endpoints................................................................................................8


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6.4. Covariates..................................................................................................................8
7. HANDLING OF MISSING VALUES ..................................................................................8
7.1. Concentrations Below the Limit of Quantification...................................................9
7.2. Deviations, Missing Concentrations and Anomalous Values ...................................9
7.3. Pharmacokinetic Parameters .....................................................................................9
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ............................9
8.1. Statistical Methods ....................................................................................................9
8.2. Statistical Analyses .................................................................................................10
8.3. Safety Analysis........................................................................................................11
8.3.1. Treatment and Disposition of Participants .................................................11
8.3.2. Demographic and Clinical Examination Data............................................12
8.3.3. Discontinuation(s).......................................................................................12
8.3.4. Adverse Events...........................................................................................12
8.3.5. Laboratory Data..........................................................................................12
8.3.6. Vital Signs Data..........................................................................................12
8.3.7. ECG Data....................................................................................................12
8.3.8. COVID-19 Assessment ..............................................................................12
8.3.9. Concomitant Treatments.............................................................................12
8.3.10. Pharmacogenomics and Biomarker Data..................................................12
8.3.11. Screening and Other Special Purpose Data ..............................................13
9. APPENDICES .....................................................................................................................14
LIST OF TABLES
Table 1.
Treatment Flow Diagram............................................................................5
Table 2.
PK Parameters to be Summarized Descriptively by Treatment ...............10
LIST OF FIGURES
None.
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................14


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PFIZER CONFIDENTIAL
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
Ritlecitinib (PF-06651600) is a selective covalent inhibitor of JAK3 and the tyrosine kinase 
expressed in TEC family kinases and is currently under development for the treatment of 
alopecia areata, rheumatoid arthritis, vitiligo, ulcerative colitis, and Crohn’s disease.
Tolbutamide is a first generation sulphonylurea developed for treatment of diabetes mellitus.
The purpose of the study is to estimate the inductive effect of multiple-dose ritlecitinib on 
single dose PK of tolbutamide.
2.1. Study Design
This is a Phase 1, 2-period, multiple-dose, open-label, single fixed sequence study of the 
effect of ritlecitinib on tolbutamide pharmacokinetics in healthy participants. A total of 
approximately 12 healthy male and/or female participants will be enrolled in the study to 
obtain at least 10 evaluable participants who complete the study. Participants who withdraw
from the study may be replaced at the discretion of the sponsor.
In Period 1, participants will be dosed with a single administration of tolbutamide 500 mg 
tablet on Day 1. Tolbutamide PK will be assessed for 36 hours following dosing. Period 1 
will be immediately followed by Period 2 with no washout. In Period 2, participants will be 
dosed with oral 200 mg ritlecitinib QD for 10 days followed by administration of a single 
dose of 500 mg tolbutamide oral tablet within approximately 5 minutes after administration 
of a 200-mg dose of ritlecitinib on the morning of Day 10. Tolbutamide PK in Period 2 will 
again be assessed at pre-dose and over 36 hours after tolbutamide dosing.
Table 1.
Treatment Flow Diagram
Period
Day*
Treatment
1
1
Tolbutamide 500 mg (single dose)
2
1-9
Ritlecitinib 200 mg QD 
10
Ritlecitinib 200 mg QD + tolbutamide 500 mg 
(single dose)
11
No treatment given
12
No treatment given (discharge)
Follow-up
28-35 after last dose of 
investigational product
Follow-up phone contact
*Note: Day is relative to the first day of study intervention dosing (including tolbutamide and 
ritlecitinib) in each period.


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PFIZER CONFIDENTIAL
Participants will have a telephone contact at least 28 calendar days, and up to 35 calendar 
days after the last administration of the investigational product.
2.2. Study Objectives
2.2.1. Primary Objective

To evaluate the effect of multiple-dose ritlecitinib (PF-06651600) on the PK of a 
single, oral dose of tolbutamide in healthy participants.
2.2.2. Secondary Objective

To evaluate the safety and tolerability of ritlecitinib when coadministered with a 
single dose of tolbutamide.
2.2.3. Exploratory Objective

To characterize the PK of a single oral dose of tolbutamide in healthy participants.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. 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, and/or supporting clinical development.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No statistical hypothesis will be tested in this study.
4.2. Statistical Decision Rules
There are no statistical decision rules.
5. ANALYSIS SETS
5.1. Enrolled participants
"Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. A participant will be considered enrolled if the informed consent is 
not withdrawn prior to participating in any study activity after screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.


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5.2. Pharmacokinetic (PK) Analysis Set
5.2.1. PK Concentration 
The PK Concentration population is defined as all participants treated who have at least 
1 concentration in at least 1 treatment period.
5.2.2. PK Parameter Evaluable
The PK Evaluable population is defined as all participants treated who have at least 1 of the 
PK parameters of primary interest in at least 1 treatment period.
5.3. Pharmacodynamic Analysis Set
None.
5.4. Safety Analysis Set
All participants assigned to the study intervention and who take at least 1 dose of the study 
intervention. Participants will be analyzed according to the intervention they actually 
received.
5.5. Other Analysis Sets
None.
5.6. 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, for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, and PK analyses, 
where applicable.
5.7. Protocol Deviations
Participants who experience events that may affect their PK profile (eg lack of compliance 
with dosing) may be excluded from the PK analysis. At the discretion of the 
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.7.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 5.1 and 5.2 of the protocol.


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5.7.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure. Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Vital Signs and ECG data will be databased and available upon request. Laboratory data and 
adverse events will be reported as per sponsor reporting standards.
6.3. PK Endpoints
Blood samples for PK analysis of tolbutamide will be taken according to the Schedule of 
Activities given in the protocol.
The following PK parameters will be calculated for tolbutamide (if possible) from the 
concentration-time data using standard non-compartmental methods:
PK Parameter
Analysis Scale
Tolbutamide
AUClast
ln
A, D
AUCinf*
ln
A, D
Cmax
ln
A, D
Tmax
R
D
CL/F*
ln
D
Vz/F*
ln
D
t1/2*
R
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits
6.3.1. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.


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7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’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 participant discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment with ≥3 evaluable measurements.  For statistical 
analyses (ie, analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed in 
the body), this will be footnoted in summary tables and will not be included in the calculation 
of summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The interactive effect on PK parameters will be determined by constructing 90% confidence 
intervals around the estimated difference between the Test and Reference treatments using a 
mixed effects model based on natural log transformed data. The mixed effects model will be 
implemented using SAS Proc Mixed, with REML estimation method and Kenward-Roger 
degrees of freedom algorithm.


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8.2. Statistical Analyses
Natural log-transformed parameters AUCinf (if data permit, otherwise AUClast) and Cmax of
tolbutamide will be analyzed using a mixed effect model with treatment as a fixed effect and
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference)
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of
adjusted geometric means (Test/Reference) and 90% CI for the ratios. Tolbutamide
administered alone will be the Reference treatment and tolbutamide co-administered with
ritlecitinib will be the Test treatment.
The tolbutamide AUCinf, AUClast and Cmax will be listed and summarized descriptively by
treatment.
The tolbutamide Tmax, CL/F, Vz/F and t½, as data permit, will be listed and summarized 
descriptively by treatment. Plasma concentrations will be listed and summarized 
descriptively by treatment and nominal PK sampling time. Individual participant and 
summary profiles (mean and median plots) of the plasma concentration-time data will be 
plotted using actual and nominal times, respectively.
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report. If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers. 
Justification for any alternative to the planned analysis will be given in the report of the 
study.
Table 2.
PK Parameters to be Summarized Descriptively by Treatment
Parameter
Summary Statistics
AUCinf, AUClast, 
Cmax, CL/F, Vz/F
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum.
Box and whisker plots for individual participant parameters (AUCinf, AUClast and Cmax) will 
be presented by treatment and overlaid with geometric means.
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. This data may be included in the clinical study report.
Presentations for tolbutamide concentrations will include:


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
A listing of all concentrations sorted by participant ID, treatment 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 participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant
(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 participant plots by time, the actual PK sampling time will 
be used.
8.3. Safety Analysis
All safety analyses will be performed on the safety population. A set of summary tables split 
by treatment will be produced to evaluate any potential risk associated with the safety and 
toleration of administering tolbutamide with or without ritlecitinib. Additionally, AEs will be 
reported for 3 phases: tolbutamide alone, ritlecitinib alone, and tolbutamide with ritlecitinib.
8.3.1. Treatment and Disposition of Participants
Participant evaluation groups will show end of study participant disposition and will show 
which participants were analyzed for pharmacokinetics, as well as for safety (adverse events 
and laboratory data). Frequency counts will be supplied for participant discontinuation(s) by 
treatment.
Data will be reported in accordance with the sponsor reporting standards.


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8.3.2. Demographic and Clinical Examination Data
A break down of demographic data will be provided for age, race, weight, body mass index, 
and height. Each will be summarized by sex at birth and ‘All Participants’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Participant discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
treatment.
8.3.5. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards. The baseline measurement is the last predose measurement of Period 1.
8.3.6. Vital Signs Data
Vital Signs data will be databased and available upon request.
8.3.7. ECG Data
ECG data will be databased and available upon request.
8.3.8. COVID-19 Assessment
Participants will be tested for SARS-COVID-19 infection by PCR prior to being admitted to 
the clinic for confinement and a subsequent COVID-19 test will be performed after 4 days 
(ie, upon completion of 4 x 24 hours in house), or if they develop COVID-19 like symptoms.
If a participant develops COVID-19 during the study, it would be reported as an AE and 
summarized along with other AE data.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. Pharmacogenomics and Biomarker Data
Pharmacogenomic or biomarker data from Retained Research Samples 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.


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8.3.11. Screening and Other Special Purpose Data
Screening data will available upon request.


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9. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC MIXED code is provided below:
proc mixed data=tab.pk;
class trt participant;
model l&var=trt/ ddfm=KR;
random participant /participant=participant;
lsmeans trt;
estimate 'Test vs Reference' trt  1  -1  /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows;
A = Tolbutamide co-administered with Ritlecitinib (Test) ;
B = Tolbutamide administered alone (Reference)  */;