Clinical trial NCT05128058
Conditions: Healthy
Sponsor: Pfizer
Start date: 2021-10-22; Completion date: 2022-01-14
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 1, open label, two-arm study to assess target occupancy and functional inhibition of JAK3 and TEC kinases by Ritlecitinib in healthy adult participants

Detailed description:

Arms: arm 1: Subjects will be dosed with 50 mg Ritlecitinib on Day 1 and followed up till Day 3 arm 2: Subjects will be dosed with 200 mg Ritlecitinib on Day 1 and followed up till Day 3
Interventions: intervention 1: Ritlecitinib 50 mg intervention 2: Ritlecitinib 200 mg
Intervention descriptions: intervention 1: 50 mg single dose intervention 2: 200 mg single dose

Protocol documents:
Prot_000.pdf: 
PF-06651600
Protocol B7981045
Final Protocol Amendment 2, 10 November 2021 
PFIZER CONFIDENTIAL
Page 1
AN OPEN LABEL, PHASE 1, TWO-ARM STUDY TO ASSESS TARGET 
OCCUPANCY AND FUNCTIONAL INHIBITION OF JAK3 AND TEC KINASES BY 
SINGLE DOSES OF RITLECITINIB IN HEALTHY ADULT PARTICIPANTS
Study Intervention Number:
PF-06651600
Study Intervention Name:
Ritlecitinib
US IND Number:
EudraCT Number:
N/A
ClinicalTrials.gov ID:  
N/A
Protocol Number:
B7981045
Phase:
1
Brief Title: A Phase 1 target occupancy study with ritlecitinib.
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Document History
Document
Version Date
Amendment 2
10 November 2021
Amendment 1
01 October 2021
Original protocol
12 August 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 2 (10-November-2021)
Overall Rationale for the Amendment: This amendment is to clarify acceptable forms of 
contraception for women of child bearing potential.
Section # and 
Name
Description of Change
Brief Rationale
10.4.2. Female 
Participant 
Reproductive 
Inclusion Criteria
1. Removal of “with low user 
dependency”.
To maintain consistency 
with Section 10.4.4.
10.4.4 
Contraception 
Methods
1. Removal of bullet points 6 and 7:
“Combined (estrogen and 
progestogen containing) hormonal 
contraception associated with 
inhibition of ovulation.
a.
Oral;
b. Intravaginal;
c.
Transdermal.
Progestogen only hormone 
contraception associated with 
inhibition of ovulation.
a.
Oral;
b. Injectable”.
To provide appropriate 
contraception guidance 
for study participants


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Section # and 
Name
Description of Change
Brief Rationale
2. Removal of “One of the following 
effective barrier methods must be 
used in addition to the highly 
effective methods listed above that 
are user dependent:
a.
Male or female condom 
with or without spermicide;
b. Cervical cap, diaphragm, or 
sponge with spermicide;
c.
A combination of male 
condom with either cervical 
cap, diaphragm, or sponge 
with spermicide 
(double-barrier methods)”.


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................11
1.3. Schedule of Activities .............................................................................................12
2. INTRODUCTION ...............................................................................................................15
2.1. Study Rationale .......................................................................................................15
2.2. Background .............................................................................................................16
2.2.1. Nonclinical Pharmacology..........................................................................16
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................16
2.2.3. Nonclinical Safety ......................................................................................16
2.2.4. Clinical Overview.......................................................................................17
2.3. Benefit/Risk Assessment.........................................................................................20
2.3.1. Risk Assessment.........................................................................................22
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. Choice of Contraception/Barrier Requirements .........................................24
4.2.3. Collection of Retained Research Samples..................................................24
4.3. Justification for Dose ..............................................................................................25
4.4. End of Study Definition ..........................................................................................25
5. STUDY POPULATION......................................................................................................26
5.1. Inclusion Criteria.....................................................................................................26
5.2. Exclusion Criteria....................................................................................................27
5.3. Lifestyle Considerations..........................................................................................30
5.3.1. Meals and Dietary Restrictions...................................................................30


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5.3.2. Caffeine, Alcohol, and Tobacco .................................................................31
5.3.3. Activity .......................................................................................................31
5.3.4. Contraception..............................................................................................32
5.4. Screen Failures ........................................................................................................32
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................32
6.1. Study Intervention(s) Administered........................................................................32
6.1.1. Administration............................................................................................32
6.1.2. Medical Devices .........................................................................................33
6.2. Preparation, Handling, Storage, and Accountability...............................................33
6.2.1. Preparation and Dispensing........................................................................34
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................34
6.3.1. Allocation to Study Intervention ................................................................34
6.3.2. Breaking the Blind......................................................................................34
6.4. Study Intervention Compliance...............................................................................34
6.5. Dose Modification...................................................................................................34
6.6. Continued Access to Study Intervention After the End of the Study......................34
6.7. Treatment of Overdose............................................................................................35
6.8. Concomitant Therapy..............................................................................................35
6.8.1. Rescue Medicine.........................................................................................35
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................36
7.1. Discontinuation of Study Intervention ....................................................................36
7.2. Participant Discontinuation/Withdrawal from the Study........................................36
7.2.1. Withdrawal of Consent...............................................................................37
7.3. Lost to Follow up ....................................................................................................37
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................37
8.1. Efficacy Assessments..............................................................................................39
8.2. Safety Assessments .................................................................................................39
8.2.1. Physical Examinations................................................................................39
8.2.2. Vital Signs ..................................................................................................39
8.2.2.1. Respiratory Rate........................................................................40
8.2.2.2. Temperature ..............................................................................40


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8.2.3. Electrocardiograms.....................................................................................40
8.2.3.1. Continuous Cardiac Monitoring by Telemetry .........................41
8.2.4. Clinical Safety Laboratory Assessments ....................................................41
8.2.5. COVID-19 Specific Assessments...............................................................41
8.2.6. Pregnancy Testing ......................................................................................41
8.2.7. Suicidal Ideation and Behavior Risk Monitoring.......................................42
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................42
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......42
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................43
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................43
8.3.2. Method of Detecting AEs and SAEs ..........................................................43
8.3.3. Follow-up of AEs and SAEs.......................................................................43
8.3.4. Regulatory Reporting Requirements for SAEs...........................................44
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................44
8.3.5.1. Exposure During Pregnancy......................................................44
8.3.5.2. Exposure During Breastfeeding ................................................46
8.3.5.3. Occupational Exposure .............................................................46
8.3.6. Cardiovascular and Death Events...............................................................47
8.3.7. Disease Related Events and/or -Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................47
8.3.8. Adverse Events of Special Interest.............................................................47
8.3.8.1. Lack of Efficacy........................................................................47
8.3.9. Medical Device Deficiencies......................................................................47
8.3.10. Medication Errors.....................................................................................47
8.4. Pharmacokinetics and Pharmacodynamics .............................................................48
8.4.1. Pharmacokinetics........................................................................................48
8.4.2. Pharmacodynamics.....................................................................................49
8.4.2.1. Target Occupancy: ....................................................................49
8.5. Genetics...................................................................................................................49
8.5.1. Specified Genetics ......................................................................................49
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8.5.2. Retained Research Samples for Genetics ...................................................49
8.6. Biomarkers ..............................................................................................................50
8.6.1. Retained Research Samples for Biomarkers...............................................50
8.7. Immunogenicity Assessments.................................................................................50
8.8. Health Economics ...................................................................................................50
9. STATISTICAL CONSIDERATIONS ................................................................................50
9.1. Statistical Hypotheses .............................................................................................50
9.2. Analysis Sets ...........................................................................................................50
9.3. Statistical Analyses .................................................................................................51
9.3.1. Primary Endpoints ......................................................................................51
9.3.2. Secondary Endpoints ..................................................................................51
9.3.3. Tertiary Endpoints ......................................................................................52
9.3.4. Safety Analyses ..........................................................................................52
9.3.4.1. Electrocardiogram Analyses......................................................53
9.3.5. Other Analyses............................................................................................53
9.4. Interim Analyses .....................................................................................................53
9.5. Sample Size Determination.....................................................................................53
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................54
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............54
10.1.1. Regulatory and Ethical Considerations ....................................................54
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................54
10.1.2. Financial Disclosure .................................................................................55
10.1.3. Informed Consent Process ........................................................................55
10.1.4. Data Protection .........................................................................................56
10.1.5. Committees Structure ...............................................................................56
10.1.5.1. Data Monitoring Committee ...................................................56
10.1.6. Dissemination of Clinical Study Data ......................................................56
10.1.7. Data Quality Assurance ............................................................................58
10.1.8. Source Documents....................................................................................59
10.1.9. Study and Site Start and Closure ..............................................................59


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10.1.10. Publication Policy...................................................................................60
10.1.11. Sponsor’s Qualified Medical Personnel .................................................61
10.2. Appendix 2: Clinical Laboratory Tests .................................................................62
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................64
10.3.1. Definition of AE .......................................................................................64
10.3.2. Definition of an SAE ................................................................................65
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs During 
the Active Collection Period............................................................................66
10.3.4. Reporting of SAEs....................................................................................70
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................71
10.4.1. Male Participant Reproductive Inclusion Criteria....................................71
10.4.2. Female Participant Reproductive Inclusion Criteria.................................71
10.4.3. Woman of Childbearing Potential ............................................................72
10.4.4. Contraception Methods.............................................................................73
10.5. Appendix 5: Genetics............................................................................................74
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........75
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................77
10.8. Appendix 8: Protocol Amendment History...........................................................79
10.9. Appendix 9: Abbreviations ...................................................................................82
11. REFERENCES ..................................................................................................................87
LIST OF TABLES
Table 1.
Schedule of Activities for Study...............................................................12
Table 2.
Table of Blood Sampling for Study Drug, Functional Assay and 
Target Occupancy.....................................................................................14
Table 3.
Geometric mean C48, Cmax and Cavg for Healthy Participants and 
Patient Populations Under Evaluation......................................................25
Table 4.
Protocol Required Safety Laboratory Assessments..................................62
LIST OF FIGURES
Figure 1.
Study Schema ...........................................................................................11


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
An open label, Phase 1, two-arm study to assess target occupancy and functional inhibition of 
JAK3 and TEC kinases by single doses of ritlecitinib in healthy adult participants
Brief Title:
A Phase 1 target occupancy study with ritlecitinib.
Rationale
This study aims to assess the target coverage/TO by ritlecitinib of two distinct families of 
kinases that are irreversibly bound (JAK3 and TEC kinases). In addition to TO, the study will 
include an assessment of the effect of ritlecitinib on pathways that functionally depend on 
either JAK3 or TEC kinases. Together these results will enable a more complete assessment 
of the relative degree of pathway coverage over a broad range of exposures and over a length 
of time that allows for recycling/production of new target (ie JAK3 and TEC family kinases). 
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
•
To characterize the TO of JAK3 and TEC kinases 
in peripheral blood mononuclear cells (PBMCs) 
after single oral dose of ritlecitinib
•
Percent TO for JAK3 and TEC kinases (BTK, 
ITK, RLK, TEC and BMX)
Secondary: 
Secondary: 
•
To evaluate the plasma exposure of ritlecitinib 
over 48 hours after single oral dose administration 
•
Ritlecitinib plasma PK parameters
•
Cmax,Tmax, Clast,  Cav, AUClast and, AUC24
•
To evaluate the safety and tolerability of an oral 
dose of ritlecitinib when administered alone and 
in healthy adult participants
•
Assessment of TEAEs, clinical laboratory 
tests, and vital signs
Tertiary:
Tertiary:
•
To characterize the relationship between TO in 
PBMCs and plasma ritlecitinib exposure over 
48 hours after single oral dose
•
Maximal inhibition (occupancy) by ritlecitinib 
(TOmax)
•
Ritlecitinib plasma concentrations at 
50% TOmax (IC50) 
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Overall Design
Brief Summary
This is a Phase 1, open label, parallel group, two-arm study to assess target occupancy and 
functional inhibition of JAK3 and TEC kinases by single doses of ritlecitinib in healthy adult 
participants.
Ritlecitinib is not expected to provide any clinical benefit to healthy participants. This study 
is designed to evaluate JAK3 and TEC kinase inhibition data for further clinical 
development.
Number of Participants
Approximately 16 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
Single doses of 50 mg and 200 mg are being used in the study which are expected to 
encompass concentrations observed in patient populations at clinically relevant doses.
Participants will be enrolled to receive either 50 mg or 200 mg single dose of ritlecitinib on 
Day 1. Blood samples to assess ritlecitinib PK, target occupancy and functional assays will 
be collected over 48 hours. Participants will remain in the CRU until Day 3 when they will 
be discharged after completion of study activities.
No dose changes/adjustments including flexible dosing; dose reductions, interruptions, or 
tapering is allowed as per study protocol.


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Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
Percent TO
 
will be assessed 
graphically and summarized by nominal timepoints using descriptive statistics. In addition, 
relationship between TO and plasma exposure of ritlecitinib will be assessed graphically and 
suitable exposure-response population models will be explored to quantify the relationship.
1.2. Schema
Figure 1.
Study Schema
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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 for Study
Visit Identifier
Screening
ET
Follow-upl
Days Relative to Day 1a
D -28 to D -2
D -1
D 1
D 2
D 3
Informed consent
X
CRU confinement
X


X
Inclusion/exclusion criteria
X
X
Medical/medication history
X
X
Physical examinationb
X
X
Safety laboratory
X
X
X
X
Demography (including height & weight)
X
Contraception check
X
X
X
X
X
Pregnancy test (WOCBP only)
X
X
X
X
Serum FSH (postmenopausal women only)c
X
Urine drug testing
X
X
Vital signs (supine BP and pulse rate)
X
Xd
X
X
12 Lead ECG (single)
X
Xd
X
X
HIV, HBsAg, HBcAb, HCVAb screene
X
QFT-G
X
COVID-19 questionnairef
X
X
COVID-19 testingg
X
X
COVID-19 check temperatureh
X



X
Retained Research Samples for Genetics (Prep 
D1)i
X
Ritlecitinib dosingj
X
Ritlecitinib PK blood samplek
X
X
X
X
Functional assay blood samplingk
X
X
X


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Table 1.
Schedule of Activities for Study
Visit Identifier
Screening
ET
Follow-upl
Days Relative to Day 1a
D -28 to D -2
D -1
D 1
D 2
D 3
Target occupancy blood samplingk
X
X
X
CRU discharge 
X
Prior/Concomitant medication assessment
X




X
X
Serious and nonserious AE monitoring
X




X
X
a.
Day relative to start of study treatment (Day 1).
b.
Complete physical exam could be done at screening or admission on Day -1. Brief physical exam to be done only in case of finding at previous exam or new/open AE if 
applicable, at the discretion of the investigator.
c.
Any female who has been amenorrheic for at least 12 consecutive months.
d.
Collect before drug administration.
e.
All participants will undergo screening for Hepatitis B, Hepatitis C and HIV for eligibility. Please refer to Section 5.2 for testing algorithm, reflex testing, and full eligibility 
criteria.
f.
Check exposure to positive participant, residence or travel in area of high incidence and COVID-19 related signs and symptoms. 
g.
The testing for COVID-19 pathogen by PCR will be performed at each visit. For participants admitted for residence, a subsequent COVID-19 test will be performed after 
4 days (ie, upon completion of 4 × 24 hours in-house), or if they develop COVID-19 like symptom(s).
h.
To be done twice daily during residence.
i.
Prep D1 Retained Research Samples for Genetics: 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.
j.
Participants will be dosed with ritlecitinib following an overnight fast of at least 10 hours at approximately 08:00±2 hours.
k.
Refer to Table 2 for details of ritlecitinib dosing, ritlecitinib PK sampling, functional assay blood sampling and target occupancy assay blood sampling.
l.
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(s). At the discretion 
of the investigator, telephone contact may be substituted with an on-site visit in case of additional follow-up of open AEs or clinically significant laboratory findings.


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Table 2.
Table of Blood Sampling for Study Drug, Functional Assay and Target Occupancy
Study Day
1
2
3
Hours Before/After Dose
-1a
0a
1
2
4
8
24
48
Ritlecitinib dosing
X
Ritlecitinib PK blood sampling
X
X
X
X
X
X
X
Target occupancy blood sampling
X
X
X
X
X
X
X
X
a.
Predose samples.
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2. INTRODUCTION
Ritlecitinib (previously known as PF-06651600) is a potent, covalent, and irreversible 
inhibitor of JAK3 with high selectivity over the other three JAK isoforms (JAK1, JAK2, and 
TYK2. Ritlecitinib also inhibits irreversibly the TEC family kinases BTK, BMX, ITK, RLK, 
and TEC) with selectivity over the broader human kinome. Ritlecitinib is being developed for 
the treatment of UC, CD, AA, RA, and vitiligo.
2.1. Study Rationale 
Inhibition of JAK3 by ritlecitinib is expected to modulate γ-common chain cytokine 
pathways, such as IL-7, IL-9, IL-15, and IL-21, but expected to spare inhibition of other 
JAK-dependent pathways that do not utilize JAK3, including IL-6 signaling and key 
immuno-suppressive cytokines, such as IL-10, IL-27 and IL-35.1 Selective JAK3 targeting 
may reduce adverse effects from other JAK pathways, including cytopenia's
(JAK2-dependent), cardiovascular events, malignancies, and severe infections. Inhibition of 
TEC kinases by ritlecitinib is expected to modulate T cell and B cell development and 
function (TEC kinases are activated downstream of the TCR and BCR). These effects by 
ritlecitinib on TCR signaling have been shown to inhibit the cytotoxic function of 
CD8+T cells and NK cells.2 There is limited information on the degree of target occupancy
by Ritlecitinib on JAK3 and TEC kinases (ie, irreversible kinase binding) in humans, and 
how TO and target turnover of both JAK3 and TEC kinases a) is regulated by drug half-life, 
and b) how TO translates into functional effects on specific cell types and pathways.3
TO of JAK3 and the five TEC kinases by ritlecitinib has been demonstrated in vivo in 
NOD-scid IL2r-null mice engrafted with human PBMCs which expresses JAK3 and TEC 
kinases.2 Despite the large variation in occupancy measurements likely due to differing levels 
of human PBMC engraftment and the small number of mice (n=3) per time point, 
approximately 100% occupancy of JAK3 and most of the TEC kinases, except RLK, was 
observed in the spleen samples from early time points (0.25 to 5 h). A slower recovery of 
unbound BTK was seen compared to JAK3 and ITK due to relatively longer half-life of BTK 
(12-24 hours vs. 2-3 hours for JAK3/ITK). Since the PK profile of ritlecitinib is characterized 
by rapid absorption and rapid elimination half-life, it is important to study the relationship 
between TO of JAK3 and the TEC kinase family and the functional consequences of their 
inhibition over time by ritlecitinib in healthy participants to provide insights in assessing the 
impact in patients with inflammatory and autoimmune diseases. Based on the predicted PK
for ritlecitinib, along with the need to assess target occupancy (and functional inhibition) in a 
predefined specimen collection window, at least 2 doses would be required to capture 
expected concentrations in patients at clinically relevant doses and also to better understand 
the expected hysteresis in exposure and response.


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2.2. Background 
2.2.1. Nonclinical Pharmacology
Ritlecitinib is a potent, covalent, and irreversible inhibitor of JAK3 with high selectivity over 
the other 3 JAK isoforms (JAK1, JAK2, and TYK2). Ritlecitinib also inhibits irreversibly the 
TEC kinase family (BTK, BMX, ITK, TEC and RLK/TXK), with high selectivity over the 
broader kinome. In hWB, ritlecitinib potently inhibits signaling of the common- γ chain 
receptors for IL-2, IL-4, IL-7, IL-15, and IL-21 but does not inhibit signaling of cytokines 
that are JAK3 independent such as IL-10, IFNα, IL-6, IL-27, IL-12 and IL-23 or EPO 
signaling in CD 34+ progenitor cells. In addition, ritlecitinib also inhibits the cytotoxic 
function of CD8+T cells and NK cells.
Further information is available in the current version of the ritlecitinib IB.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
In vitro and in vivo metabolite profiling indicated that glutathione related conjugation is the 
primary clearance mechanism for ritlecitinib with minor CYP450-mediated oxidation. 
Regarding enzymatic DDI, ritlecitinib showed a low risk of in vitro interaction due to 
reversible inhibition of the major CYP450, UGT, GST, and SULT enzymes at a maximum 
clinical daily dose of 200 mg (unbound Cmax 4.8 μM). However, ritlecitinib showed in vitro 
evidence of DDI of CYP3A and CYP1A2, and there was in vitro induction of CYP3A4 and 
CYP2B6 mRNA levels at 50 to 100 µM, while no CYP1A2 induction was noted. Clinically, 
ritlecitinib showed a moderate impact on midazolam (Cmax ratio 1.81; AUCinf ratio 2.69) and 
no impact on effavirez (CYP2B6) exposure. Therefore, the predominant ritlecitinib effect on 
CYP3A4 is inhibition, with no evidence of induction for either CYP3A4 or CYP2B6.
Regarding transporter DDI, ritlecitinib is not a substrate for OATP1B1 or OATP1B3. 
However, ritlecitinib showed an in vitro risk of DDI with BCRP, OATP1B1, OCT2, OAT1, 
OAT3, OCT1, MATE1, and MATE2K. In a clinical DDI study, a minor decrease in the 
Cmax ratio (0.74) of rosuvastatin (BCRP) but no effect on its AUCinf (OATP1B1) or renal 
clearance (OAT3) were observed with co-administration of ritlectinib. In addition, there were 
no significant changes in creatinine clearance (OCT2/MATE1/2K) from baseline with 
multiple doses up to 800 mg of ritlecitinib. These results suggest that there was no clinically 
significant inhibition of these transporters in vivo.
Further information is available in the current version of the ritlecitinib IB.
2.2.3. Nonclinical Safety
Ritlecitinib was administered QD for up to 6 months in rats and 9 months in dogs (two 
9-month dog studies were conducted). The NOAEL in the 6-month rat and second 9-month 
dog studies were 200 and 10 mg/kg/day (unbound AUC values of 53,700 and 
7940 ng•h/mL), respectively. Based on the results of the nonclinical studies, target organs 
identified following ritlecitinib administration include CNS/PNS in dogs, the immune and 
hematolymphopoietic systems (thymus, spleen, lymph nodes, bone marrow, circulating 


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lymphocytes, and red blood cells) and adrenal gland in rats and dogs, kidney in rats, and the 
GI system in dogs. Functional effects on the cardiovascular system (heart rate and BP) were 
also observed in dogs. Effects on bone marrow and the immune and hematolymphopoietic 
systems were consistent with the known pharmacological activity of JAK3 and/or TEC 
kinase inhibition.
In a second GLP compliant 9 month toxicity study in dogs, adverse effects following 
administration of ritlecitinib consisted of decreased lymphoid cellularity in animals 
administered ≥20 mg/kg/day leading to over-immunosuppression based on evidence of skin 
infection (Demodex spp, papillomavirus, and interdigital cysts); axonal dystrophy in the CNS 
and PNS in animals administered ≥20 mg/kg/day and in the autonomic nerves of the adrenal 
gland in animals administered 20 (20 QD) mg/kg/day; and auditory threshold and waveform 
deficits in the BAEP associated with the axonal dystrophy at 40 mg/kg/day.
Ritlecitinib was not genotoxic in the microbial reverse mutation assay or the in vivo rat 
micronucleus assay but was positive in an in vitro micronucleus assay in human 
lymphoblastoid TK6 cells. Based on a follow-up chromosome aberration test that was 
negative and a flow cytometric aneuploidy assessment that demonstrated an increase in 
hypodiploidy, hyperdiploidy, and polyploidy, an aneugenic mechanism of action was 
determined. Ritlecitinib did not induce micronuclei in polychromatic reticulocytes when 
administered to rats for 4 days as part of the 8-week pivotal study. Nonpivotal dose 
range-finding and pivotal EFD studies in rats and rabbits were conducted. In the pivotal EFD 
study in rats, fetal skeletal malformations and variations, and decreased fetal weights were 
observed; in the pivotal EFD study in rabbits, fetal skeletal and visceral malformations, 
skeletal variations, and decreased fetal weights were observed. Ritlecitinib did not produce a 
positive response in the mouse allergy model, suggesting low likelihood of hypersensitivity 
reactions. There was no evidence of cutaneous or ocular phototoxicity after oral 
administration of ritlecitinib to rats for 3 days at doses up to 200 mg/kg/day.
Further information is available in the current version of the ritlecitinib IB.
2.2.4. Clinical Overview
Ritlecitinib has been evaluated in healthy participants in a FIH B7981001 study, in a 
bioavailability (BA) B7981003 study which compared the relative BA of solution versus 
tablet, and a PK study in healthy Japanese participants (B7981008). Ritlecitinib has also been 
evaluated in participants in a PK DDI study to evaluate the potential steady state DDI in 
healthy adult participants between IRAK4 (PF-06650833) and ritlecitinib (B7981028). It has 
also been evaluated in participants with moderate to severe RA in B7981006 and in patients 
with moderate to severe alopecia areata (B7931005). There are ongoing studies in 
participants with moderate to severe alopecia areata (B7981015), active non-segmental 
vitiligo (B7981019), moderate to severe active ulcerative colitis (B7981005), and moderate 
to severe active Crohn’s disease (B7981007). 


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Studies in healthy participants
The FIH study (B7981001) was a Phase 1, randomized, double-blind, third-party open, 
placebo controlled, single and multiple dose escalation, parallel group study in healthy adult 
participants. During the single dose period, participants received doses of 5, 20, 50, 100, 200, 
400, or 800 mg of ritlecitinib in a dose escalation format. Participants returned for the 
multiple dose period to receive doses of 50, 200, or 400 mg QD or 100 or 200 mg BID for 
14 days.
B7981008 was a Phase 1, randomized, double blind, third-party open, placebo-controlled
study to evaluate the safety, tolerability, PK and PD after multiple oral doses of ritlecitinib in 
healthy Japanese adult participants. Six participants were randomized, with 2 participants 
receiving placebo and 4 participants receiving ritlecitinib 200 mg QD, respectively.
B7981003 was a Phase 1, open label, single-dose 3-way crossover study to evaluate the 
relative bioavailability of a solid dose formulation of ritlecitinib under fasting conditions and 
the effect of a high fat meal on the bioavailability of the solid dosage formulation of 
PF-06651600 in healthy participants. A total of 14 participants were randomized to study 
treatment.
In all the above studies, ritlecitinib was found to be well tolerated and to have an acceptable 
safety profile.
Summary of Clinical PK
The PK profile of ritlecitinib is characterized by rapid absorption median (Tmax ranging from 
≤0.75 – 1.5 hour), rapid elimination (t½ of ~2 hours) and are approximately dose 
proportional. 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 (predose) ritlecitinib beyond 
Day 6. Ritlecitinib has been evaluated at single oral doses ranging from 5 mg to 800 mg and 
multiple oral doses ranging from 50 mg to 400 mg QD and at 100 mg and 200 mg BID for 
14 days. The clearance mechanisms for ritlecitinib in humans appear to be primarily by 
metabolism. Less than 10% of ritlecitinib is excreted unchanged in the urine.
In vitro and in vivo metabolite profiling suggested that the primary clearance mechanisms for 
ritlecitinib were both CYP450 mediated oxidation and glutathione related conjugation. 
Biliary excretion of ritlecitinib was limited in the rat and renal elimination was limited in 
humans. Reaction phenotyping in recombinant enzyme systems identified CYP3A4 as the 
predominant CYP450 isoform responsible for the metabolism of ritlecitinib, with minor 
contributions from CYP2C19 and CYP3A5.
CCI


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Further information is available in the current version of the ritlecitinib IB.
Phase 2a Study in RA
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
on background of methotrexate. 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. Most 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, electrocardiogram 
(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 [CFB]), lymphocyte counts (21% CFB), neutrophil counts (17% CFB), and 
hemoglobin (3% CFB). 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.
Phase 2a Study in Alopecia Areata
Study B7931005 was a Phase 2a, double-blind, placebo-controlled, multi-center study to 
evaluate the efficacy and safety profile of ritlecitinib and PF-06700841 (a TYK2/JAK1 
inhibitor) in participants with moderate to severe alopecia areata. The study consists of the 
initial 24-week double-blind treatment period (completed), and an ongoing up to 12 months 
single-blind extension period that includes 6 months of active treatment, that is followed by a 
6 months 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 in the initial 6 month double-blind treatment period.
The initial 24-week double-blind treatment period has been completed. During this treatment 
period, participants in the ritlecitinib group were treated with 200 mg of 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 B7981005, there were no deaths and no participant in the ritlecitinib
treatment group experienced a SAE. The proportion of participants who experienced TEAEs 
in the placebo treatment group (74.5%) was comparable with the ritlecitinib treatment group 
(66.7%). The TEAEs reported in more than 5% (1 in 20) participants with alopecia areata 
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.


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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 CFB, 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. 
Two participants in the ritlecitinib group discontinued due to TEAEs. For 1 of the 
2 participants assigned to ritlecitinib who discontinued from study treatment due to an AE, 
the investigator rated the causality as related (angioedema).
Further information regarding clinical experience with ritlecitinib is available in the current 
version of the IB.
2.3. Benefit/Risk Assessment
Ritlecitinib is not expected to provide any clinical benefit to healthy participants. This study 
is designed primarily to determine the relationship between TO of JAK3 and the TEC kinase 
family and the functional consequences of their inhibition overtime by ritlecitinib in healthy 
participants. These results are expected to provide insights on the mechanism of action for 
ritlecitinib, and in assessing the impact of ritlecitinib in patients with inflammatory diseases.
In multiple clinical studies, the safety/tolerability profile of ritlecitinib has been extensively 
characterized and has been shown to have an acceptable safety and tolerability profile.
Ritlecitinib is an immune modulator and, as such, can be associated with the potential risk of 
infections (including serious infections), opportunistic infections, and viral reactivation. The 
risk of infection from this single dose study is low, but nonetheless participants will be 
closely monitored in this study.
In the MAD period of the Phase 1 Study of ritlecitinib, the most frequently reported TEAEs 
across all treatment groups were diarrhea and headache, which were experienced by 8 and 
7 participants, respectively. In Phase 2 Study of ritlecitinib in RA patients (B7981006), the 
most common TEAEs by SOC were Infections and Infestations (6 participants in total, 
8.6%). The majority of the all-causality TEAEs were mild in severity. In Phase 2a Study of 
ritlecitinib and brepocitnib in AA patients (B7931005), the most commonly reported 
treatment related- TEAEs for ritlecitinib by preferred term were upper respiratory tract 
infection (6.3%), and acne, nausea,and headache (each at 4.2%). 
The expected exposures of ritlecitinib in this study are lower than the highest exposures 
observed in the SAD/MAD FIH study (see Justification for Dose in Section 4.3). Therefore, 
the risk to the participants in this study is expected to be minimal. In addition, any risks are 
minimized by appropriate safety measures including safety laboratory measurements, ECGs, 
vital signs, and counseling for appropriate use of contraception for study participants.


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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ritlecitinib may be found in the IB, which is the SRSD for this study.


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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention: Ritlecitinib
1.
Potential risks associated with study 
intervention include the following:
a.
transient decrease in leukocyte and 
platelet counts.
1.
The potential risks are based on prior studies 
for ritlecitinib in healthy participants and 
RA, AA and vitiligo patients. Details are 
presented in the IB. 
1.
Eligibility criteria and study assessments 
have been selected to ensure that only 
appropriate participants are included in the 
study (see Section 5).
Other 
The COVID-19 pandemic may pose risks to study 
participation. 
Participants may have increased risk of 
SARS-CoV-2 infection by undergoing a study 
procedure at a study facility.
Inclusion of COVID-19 specific assessments 
according to the Schedule of Activities and CRU 
confinement for the entire duration of study.


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2.3.2. Benefit Assessment
There is no benefit expected to the participants.
2.3.3. Overall Benefit/Risk Conclusion
Ritlecitinib is not expected to provide any clinical benefit to healthy participants. This study 
is justified by taking into account measures taken to minimize the potential risks to study 
participants identified in association with ritlecitinib risk.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
•
To characterize the TO of JAK3 and TEC kinases 
in PBMCs after single oral dose of ritlecitinib
•
Percent TO for JAK3 and TEC kinases (BTK, 
ITK, RLK, TEC and BMX)
Secondary:
Secondary: 
•
To evaluate the plasma exposure of ritlecitinib 
over 48 hours after single oral dose administration 
•
Ritlecitinib plasma PK parameters
•
Cmax, Tmax, Clast, Cav, AUClast, and AUC24
•
To evaluate the safety and tolerability of an oral 
dose of ritlecitinib when administered alone and 
in healthy adult participants
•
Assessment of TEAEs, clinical laboratory 
tests, and vital signs
Tertiary:
Tertiary:
•
To characterize the relationship between TO in 
PBMCs and plasma ritlecitinib exposure over 
48 hours after single oral dose
•
Maximal inhibiton (occupancy) by ritlecitinib
(TOmax)
•
Ritlecitinib plasma concentrations at 
50% TOmax (IC50) 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, single dose, open label, two-arm study to assess TO of JAK3 and TEC 
kinases by ritlecitinib in healthy adult participants. A total of approximately 16 healthy male 
and/or female participants, 8 in each cohort, will be enrolled and dosed to achieve at least 
6 participants completing each dose level. Participants who discontinue from the study for 
non-safety reasons may be replaced at the sponsor’s discretion.
Participants will be screened within 28 days of the first dose of study medication. 
Participants will report to the CRU 1 day prior to Day 1 dosing (Day -1).
CCI


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Participants will be enrolled to receive either 50 mg or 200 mg single dose of ritlecitinib on 
Day 1. Blood samples to assess ritlecitinib PK, target occupancy and functional assays will 
be collected over 48 hours. Participants will remain in the CRU until Day 3 when they will 
be discharged after completion of study related activities as indicated in the SoA.
Participants will have a telephone contact at least 28 calendar days, and up to 35 calendar 
days after administration of the investigational product(s). At the discretion of the 
investigator, telephone contact may be substituted with an on-site visit in case of additional 
follow-up of open AEs or clinically significant laboratory findings. A brief overview of the 
study is provided in Figure 1.
4.2. Scientific Rationale for Study Design
This study aims to assess the target coverage/TO by ritlecitinib of two distinct families of 
kinases that are irreversibly bound (JAK3 and TEC kinases). In addition to TO, the study will 
include an assessment of the effect of ritlecitinib on pathways that functionally depend on 
either JAK3 or TEC kinases. Together these results enable a more complete assessment of 
the relative degree of pathway coverage over a broad range of exposures and over a length of 
time that allows for recycling/production of new target (ie, JAK3 and TEC family kinases).
A parallel design is preferred over a crossover design in this case due to uncertainty around 
the crossover period washout period due to the unknown duration of downstream effects 
which are being measuring for the first time in humans.
A single dose study is designed with 2 arms of 50 mg and 200 mg dose of ritlecitinib. The 
two doses are expected to provide concentrations encompassing those seen at clinically 
relevant doses in patients with RA, UC, AA and vitiligo. As the PK of ritlecitinib is linear in 
the clinical dosing range, and steady state/multiple dose exposure-response can be predicted
from single doses exposures. Although there is no food-effect, the doses are to be taken 
under fasted conditions to standardize PK. There is no need for blinding of this single-dose
study since the endpoints described above are objective/quantitative and there are no safety 
concerns that need to be addressed by blinding.
4.2.1. Diversity of Study Population 
Not applicable.
4.2.2. Choice of Contraception/Barrier Requirements
Nonclinical studies suggest risk for severe manifestations of developmental toxicity at 
relevant clinical exposures for ritlecitinib. Therefore, the use of a highly effective method of 
contraception is required (see Appendix 4).
4.2.3. 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
Single doses of 50 mg and 200 mg are being used in the study. A dose-ranging simulation 
using a pop-PK model for ritlecitinib4 showed that the proposed doses in healthy participants 
would provide, over the 48-hour collection interval, geometric mean C48, Cmax and Cavg
concentration that encompasses those from clinical doses in patients with RA, UC, CD, AA 
or vitiligo (Table 3).
Table 3.
Geometric mean C48, Cmax and Cavg for Healthy Participants and Patient
Populations Under Evaluation
Population
Dose (mg)
C48 (ng/mL)
Cmax (ng/mL)
Cavg(ng/mL)
Healthy
50
BQL
247.44
11.19
Healthy
200
BQL
1085.10
60.57
RA
100
BQL
482.60
51.21
UC
100
BQL
460.24
49.88
AA
50
BQL
256.59
17.07
Vitiligo
50
BQL
263.56
15.12
Based on prior Phase 1 data, 50 mg and 200 mg QD doses of ritlecitinib are expected to be 
safe and well tolerated in this study. A dose level of 200 mg QD ritlecitinib has demonstrated 
acceptable safety and tolerability for up to 14 days in healthy participants (B7981001), up to 
4 weeks in participants with alopecia areata (B7931005) and up to 8 weeks in RA and UC 
participants (B7981006 and B7981005). The projected AUC48 and Cmax of 2907 ng•h/mL and 
1085 ng/mL at 200 mg single dose provides exposure margin of 3.2- and 2-fold, respectively 
from NOAEL observed in dogs in second 9-month toxicity study (Highest dose in dogs, 
10 mg/kg/day; Cmax (free) = 1910 ng/mL; AUC24,ss (free) = 7940 ng•h/mL; fu,dog = 0.82, 
fu,human=0.86).
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure (phone contact) shown in the SoA and any 
requested unplanned visit(s).
The end of the study (LPLV) is defined as the date the investigator reviews the last 
participant’s final safety data and determines that no further evaluation is required for the 
participant to complete the trial.


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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age and Sex:
1. Male and female participants must be 18 to 60 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 female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination including BP and pulse 
rate measurement, 12-lead ECG, or clinical and laboratory tests.
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.


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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, 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. Infection with HIV, hepatitis B or hepatitis C viruses according to protocol-specific 
testing algorithm. For HIV, hepatitis B and hepatitis C, all participants will undergo 
testing for HIV, HBsAg, HBcAb and HCVAb during Screening. Please refer to 
Appendix 2 for testing algorithm, reflex testing, and full eligibility criteria.
4. Have evidence of untreated or inadequately treated active or latent Mycobacterium 
TB infection as evidenced by the following:

A positive QFT-G test performed within the 12 weeks prior to screening. IF the 
laboratory reports the test 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 test only with approval from the Pfizer Medical Monitor on a 
case-by-case basis.

History of either untreated or inadequately treated latent or active TB infection.

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 
multidrug resistant TB infections are <5% or an acceptable alternative 
regimen) or active (acceptable multi-drug regimen) TB infection, neither a 
QFT-G test nor a PPD test need to be obtained. Details of previous course of 
therapy (eg, medication(s) used, dose, duration of therapy) should be 
documented in the source documentation.

A participant who is currently being treated for active or latent TB infection 
must be excluded from the study.
5. Participants with any of the following acute or chronic infections or infection history:

Any infection requiring treatment within 2 weeks prior to the screening visit.

Any infection requiring hospitalization, parenteral antimicrobial therapy within 
60 days of the first dose of investigational product.


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
Any infection judged to be an opportunistic infection or clinically significant by 
the investigator, within the past 6 months of the first dose of the investigational 
product.

Known active or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections.

History of a recurrent (more than one episode of) localized, dermatomal herpes 
zoster, or history of disseminated (one 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 and symptoms 
suggestive of current lymphatic or lymphoid disease.
8. Participants have a known present 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. Vaccination with live virus, attenuated live virus, or any live viral components 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 
vaccine components should be avoided during treatment and for 6 weeks following 
completion of treatment. Following vaccination with live component vaccines, the 
virus may be shed in bodily fluids, including stool, and there is a potential risk that 
the virus may be transmitted. 
Such vaccines include but are not limited to: FluMist® (intranasal influenza vaccine), 
attenuated rotavirus vaccine, varicella (chickenpox) vaccine, attenuated typhoid 
fever vaccine, oral polio vaccine, MMR vaccine, vaccinia (smallpox) vaccine, and 
Zostavax® (zoster vaccine live).
10. Have received only one of the 2 required doses of COVID-19 vaccine.
11. Other medical or psychiatric conditions including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality, or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with 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 
the study.


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Prior/Concomitant Therapy:
12. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.8 Concomitant Therapy for additional details).
Prior/Concurrent Clinical Study Experience:
13. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention
used in this study (whichever is longer). 
14. Known participation in a clinical trial of ritlecitinib within 30 days prior to the first 
dose of study medications.
15. Known participation in a clinical trial of ritlecitinib and participant experienced 
treatment-related adverse events that led to discontinuation or an SAE (≥CTCAE 
Grade 3).
Diagnostic Assessments:
16. A positive urine drug test.
17. Screening supine 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 be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
18. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities that
may affect participant safety or interpretation of study results (eg, baseline QTcF
interval >450 msec, complete LBBB, signs of an acute or -indeterminate age
myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, 
second- or third degree- AV block, or serious bradyarrhythmias or tachyarrhythmias). 
If the baseline uncorrected QT interval is >450 msec, this interval should be -rate 
corrected using the Fridericia method and the resulting QTcF should be used for 
decision making and reporting. If QTcF exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or 
QRS values should be used to determine the participant’s eligibility.
Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding a participant.
19. 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;


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
Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is≤ULN.

Hemoglobin level ≤135 g/L (13.5 g/dL) for males and ≤120 g/L (12.0 g/dL) for 
females.

Platelet count ≤100×109/L (100,000 cells/mm3) or ≥1000×109/L (1,000,000 
cells/mm3).

WBC count ≤3.0 × 109/L (3000 cells/mm3) or ANC <1500 cells/mm3 or ALC 
<800 cells/mm3.

eGFR ≤60 mL/min/1.73m2 based on CKD-EPI equation.
Other Exclusions:
20. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
22. History of sensitivity to heparin or heparin-induced thrombocytopenia.
23. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
24. 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.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample.


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
Water is permitted until 1 hour prior to study intervention administration.  Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices—see below) may be 
consumed with meals and the evening snack. 

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample. 

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample. Participants may undergo an alcohol breath test or blood 
alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing.


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5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use highly effective
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
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 by the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study 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, study intervention refers to Ritlecitinib.
6.1. Study Intervention(s) Administered
For this study, the investigational product is ritlecitinib. 
The 50 mg dose will be administered as a single 50 mg capsule and the 200 mg dose as four 
50 mg capsules which will be supplied to the CRU in bulk along with individual dosing 
containers for unit dosing. Investigational product will be presented to the participants in 
individual dosing containers.
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive study intervention
at approximately 0800 hours (plus or minus 2 hours) on Day 1. Investigator site personnel 
will administer study intervention with ambient temperature water to a total volume of 
approximately 240 mL. Participants will swallow the study intervention whole and will not 
manipulate or chew the study intervention prior to swallowing.


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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.
6.1.2. Medical Devices 
Not applicable.
6.2. Preparation, Handling, Storage, and 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 PCRU local/site procedures.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
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.


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7. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s local/site procedures. All destruction must 
be adequately documented. If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual.
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.
Capsules 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 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.
6.3.2. Breaking the Blind
Not applicable. 
6.4. Study Intervention Compliance
Investigational product will be administered under the supervision of investigator site 
personnel. The oral cavity of each participant will be examined following dosing to ensure 
the investigational product was taken.
6.5. Dose Modification
No dose changes/adjustments including flexible dosing; dose reductions, interruptions, or 
tapering is allowed as per study protocol.
6.6. Continued Access to Study Intervention After the End of the Study
Not applicable.


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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.
There is no specific treatment for an overdose with ritlecitinib.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study intervention
(whichever is longer).
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 7 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case
basis).
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 
≤1 g/day.
Hormonal contraceptives that meet the requirements of this study (Appendix 4) are allowed 
to be used in participants who are WOCBP.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
6.8.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with Ritlecitinib; standard medical 
supportive care must be provided to manage the AEs. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since this is a single dose study, this section is not applicable.
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 study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor;

At the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, 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.


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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.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, 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.


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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 cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, banked biospecimens, may 
be used without repeat collection, as appropriate.
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 
380 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 56 consecutive 
days.


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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, and participant reported symptoms.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source 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.


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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. Respiratory Rate 
Not applicable.
8.2.2.2. Temperature
Not applicable.
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) 
should not be used 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 5 minutes in a supine position. 
To ensure the safety of the participants, a qualified individual at the investigator site will 
make comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
post dose 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 post dose 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 QTcF intervals do not return to less than the criteria listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 


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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.
8.2.3.1. Continuous Cardiac Monitoring by Telemetry
Not applicable.
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 to 35 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.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.5. COVID-19 Specific Assessments 
Participants will be tested for SARS-CoV-2 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. 
Additional testing may be required by local regulations or by the Principal Investigator.
8.2.6. 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 to the participant’s receiving the study intervention. Pregnancy tests will also be done 


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whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded if the serum pregnancy result is positive.
8.2.7. Suicidal Ideation and Behavior Risk Monitoring 
Not applicable.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
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 
Ritlecitinib (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative)
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, except as indicated below, 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.


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If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study because of an AE 
or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the CT 
SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and he/she 
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.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
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 or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).


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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 toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators, as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. 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 is 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 male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.


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
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 ingestion.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes his female partner prior to or around the 
time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until a minimum 
of 28 calendar days after 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 liveborn 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;


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
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.
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 ingestion. 
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 any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 
whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.


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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
This section is not applicable because efficacy is not expected in the study population.
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.


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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 and Pharmacodynamics
8.4.1. Pharmacokinetics
For the measurement of ritlecitinib concentrations, blood samples of 2 mL to provide 
approximately 0.5 mL of plasma will be collected into appropriately labeled tubes containing 
K2EDTA (dipotassium ethylenediaminetetraacetic acid) at times specified in the SoA. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose 
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.
Samples will be used to evaluate the PK of ritlecitinib. Samples collected for analyses of 
ritlecitinib concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study, for metabolite identification and/or evaluation of 
the bioanalytical method, or for other internal exploratory purposes.
Genetic analyses will not be performed on these plasma samples (unless consent for this was 
included in the informed consent). Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of ritlecitinib 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.


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8.4.2. Pharmacodynamics
The following samples for pharmacodynamics are required and will be collected from all 
participants in this study as specified in the SoA:
•
Target occupancy blood sample.
8.4.2.1. Target Occupancy:
Whole blood samples (approximately 30 mL) will be collected according to the timepoints 
specified in the SoA in sodium heparin tubes. PBMCs will be lysed and protein will be 
isolated. An ATP-competitive probe will be used to pull-down kinases that are not covalently 
bound to PF-06651600. Protein isolate will be digested with trypsin and unique peptides 
within JAK3, BMX, BTK, ITK, TEC and TXK have been identified and will be used to 
quantitate the amount of each kinase that is not occupied by ritlecitinib.
8.5. Genetics
8.5.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
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. 
CCI
CCI
CCI


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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
Biomarkers evaluated in this study are detailed in Section 8.4.2.
8.6.1. Retained Research Samples for Biomarkers
Retained Research Samples for biomarker analysis will not be collected in this study.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
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 formal inferential statistics will be applied to the safety or PK data.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:


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Population
Description
Enrolled
All participants who sign the ICD.
Randomly assigned to 
investigational product 
All participants who sign the ICD and meet all eligibility 
criteria.
Evaluable
The PK concentration population is defined as all participants 
enrolled and treated who have at least 1 concentration of 
ritlecitinib.
The PD population is defined as all enrolled and treated who 
have at least 1 TO measurement.
Safety Analysis Set
All participants who take at least 1 dose of investigational 
product. 
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary, secondary 
 
endpoints.
9.3.1. Primary Endpoints
The primary endpoint in human PBMCs is TO of JAK3, BTK, ITK, RLK, TEC and BMX 
after a single dose of ritlecitinib. Target occupancy for each kinase at time t will be evaluated 
as follows:
% ܶܽݎ݃݁ݐܱܿܿݑ݌ܽ݊ܿݕ௧ൌ100 % െ% ܨݎ݁݁ܶܽݎ݃݁ݐ௧
with ܱܶ଴as the baseline variable of target occupancy, which is the mean of the two pre-dose 
measurements at Hour -1 and Hour 0 on Day 1. If only one of the two pre-dose 
measurements is available, ܱܶ଴is the available pre-dose measurement.
TO profiles will be assessed graphically and summarized by nominal timepoints using 
descriptive statistics.
9.3.2. Secondary Endpoints
The secondary endpoints are pharmacokinetic parameters of ritlecitinib after single oral dose. 
PK parameters will be derived, given available data, following single dose administration 
from the concentration-time profiles for ritlecitinib as follows:
CCI


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Parameter
Definition
Method of Determination
AUC24
Area under the plasma concentration-time 
curve from time 0 to 24 hours
Linear/Log trapezoidal method
AUClast
Area under the plasma concentration-time 
curve from time 0 to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
Cav
Average plasma concentration from time 0 to 
the time of the last quantifiable concentration 
AUC24/24
Cmax
Maximum plasma observed concentration
Observed directly from data
Clast
Plasma concentration at 48 hours post-dose
Observed directly from data
Tmax
Time to reach Cmax
Observed directly from data as time of first 
occurrence
Concentrations will be assessed graphically. Concentrations (by nominal timepoints) and PK 
parameters will be summarized using descriptive statistics.
9.3.3. Tertiary Endpoints
The relationship between TO and plasma exposure of ritlecitinib will be assessed graphically. 
If a trend in the relationship between drug plasma concentration and TO is observed, a 
suitable exposure-response population model (eg, Turnover models) may be utilized to 
further quantify the relationship.5,6
9.3.4. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, 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 
CCI
CCI


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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.
9.3.4.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment:
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
9.3.5. Other Analyses
Pharmacogenomic data from Retained Research Samples may be collected during 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, facilitating PK/PD modeling, and/or supporting clinical 
development.
9.5. Sample Size Determination
A sufficient number of participants will be screened to achieve 8 participants enrolled to 
study intervention for an estimated total of at least 6 evaluable participants per dose level. 
The sample size of this study (2 arms, approximately 8 participants per arm, up to 
approximately 16 completers) was selected based on clinical consideration to adequately 
characterize the TO of JAK3 and TEC kinases, and PK/PD considerations and on the need to 
minimize exposure to healthy participants at each dose level. No formal inferential statistics 
would be applied to the TO, PK/PD and safety data.
Dropouts may be replaced at the discretion of the sponsor and investigator, unless the reason 
for drop-out is a clinically relevant drug-related safety or tolerability event.


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (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. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Not applicable.
10.1.3. 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 on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.


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Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, 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 ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use a DMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, 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.


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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.
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 data from these trials available 
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 by 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.


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10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source 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 


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provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in Source Document 
Locator, which is maintained by the sponsor’s designee (PCRU).
Description of the use of the computerized system is documented in the Source Document 
Locator, which is maintained by the sponsor’s designee (PCRU).
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.
10.1.9. 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 sponsor or 
designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.


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Reasons for the early closure of a study-site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
10.1.10. 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.


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10.1.11. 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 CTMS. To facilitate access to 
appropriately qualified medical personnel for study related medical questions or problems, 
participants are provided with an ECC at the time of informed consent. The ECC contains, at 
a minimum, (a) protocol and study intervention identifiers, (b) participant’s study 
identification number, (c) site emergency phone number active 24 hours/day, 7 days per 
week.
The ECC is intended to augment, not replace, the established communication pathways 
between the 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 4) will be performed at times defined in the SoA
section of this protocol. Additional laboratory results may be reported on these samples as a 
result of the method of analysis or the type of analyzer used by the clinical laboratory, or as 
derived from calculated values. These additional tests would not require additional collection 
of blood. Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues.
At screening, HbsAg and HbcAb will be tested:
a.
If both tests are negative, the participant is eligible for study inclusion;
b. If HbsAg is positive, the participant must be excluded from participation in the study;
c.
If HbsAg is negative and HbcAb is positive, HbsAb reflex testing is required:
i.
If HbsAb is negative, the participant must be excluded from participation in the 
study;
ii. If HbsAb is positive, the participant is eligible for study inclusion.
See Section 7.1 for more information on participant safety monitoring and discontinuation
regarding clinical lab tests.
Table 4.
Protocol Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
TBili
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya

Urine drug screeningb

Pregnancy test (-hCG)c

eGFR (CKD-EPI)
At screening only:

Serum FSHd

HBsAg/HBcAb

HCVAbe

HIV

QFT-G (IGRA)
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
c.
Local serum testing will be standard for the protocol. Serum or urine -hCG for female participants of 
childbearing potential.
d.
For confirmation of postmenopausal status only.
e.
All participants will undergo testing for HCVAb during Screening.


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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.
IGRA
QFT-G will be performed during screening. Blood sampling may include 3 mL up to 10 mL 
of blood. Test should be performed in accordance with the product specific processing and 
analyzing instructions.


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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), symptoms, 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 condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug- interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “-life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.


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d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic, 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 significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
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) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 


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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with 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 or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.


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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: 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 or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.


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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 or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or 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 a 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) 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
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study intervention:

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom may 
break or leak when having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), 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. The investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.


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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.
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. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.


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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. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone -releasing system.
4. Bilateral tubal occlusion (eg, bilateral tubal ligation).
5. Vasectomized partner.

A 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 
6. 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 multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements.  

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses.  

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede 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 Hy’s law 
cases, 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 co-formulated
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, 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 AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New onset- atrial flutter or fibrillation, with controlled ventricular response rate: ie,
rate <120 bpm.

New onset type I second degree (Wenckebach) AV block of >30 seconds’ duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New onset left bundle branch block (QRS >120 msec).

New onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 

In awake, symptom free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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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 
torsade's 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: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC).  The protocol amendment summary of changes 
tables for past amendment(s) can be found below:
Amendment 1 (01-October-2021)
Overall Rationale for the Amendment: This amendment is to enunciate details of 
clarifications 
 
 and statistical analysis. 
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis: 
Objectives and 
Endpoints 
and
1. Removal of “%” from primary 
endpoint
 
 
 
 
 
 
 
 
1. Typographic error, 
removed to avoid 
repetition
 
 
 
 
  
 
 
 
   
1.1 Synopsis: 
Statistical Methods
1. Replace “Baseline corrected TO” 
with “Percent TO” 
 
 
1. Clarification of 
primary 
 
endpoint statistical 
methods 
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CCI
CCI
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Section # and Name
Description of Change
Brief Rationale
2.2.1 Nonclinical 
Pharmacology
Addition of “RLK”
Clarification of TEC 
enzymes
5.2 Exclusion 
Criteria
1. Exclusion Criteria # 3, addition of 
“HIV”
2. Exclusion Criteria # 14, replace “90 
days” with “30 days”    
1. Clarification of HIV 
screening as shown in 
SoA and Table 6
2. To facilitate subject 
recruitment for those 
with known 
participation in a 
clinical trial of 
ritlecitinib
8. Study 
Assessments and 
Procedures
Replace “350 mL” with “380 mL”
Update on blood volume 
required to accommodate 
JAK3 inhibition assay
8.4.2 
Pharmacodynamcics
1. Addition of section 8.4.2.1. for 
Target Occupancy assay
 
 
 
 
 
 
 
For clarification of 
various 
pharmacodynamic  assays 
 
9.3.1 Primary 
Endpoints
1. Addition of “for each kinase”
2. Addition of “with ܱܶ଴as the 
baseline variable of target 
occupancy, which is the mean of 
the two pre-dose measurements at 
Hour -1 and Hour 0 on Day 1. If 
only one of the two pre-dose 
measurements is available, ܱܶ଴is 
Clarification of statistical 
methods for primary 
endpoint
CCI
CCI


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Section # and Name
Description of Change
Brief Rationale
the available pre-dose 
measurement.”
3. Deleted “Baseline corrected”
10.1.11. Sponsor’s 
Qualified Medical 
Personnel
1. Delete “and (d) Pfizer Call Center 
number”
2. Delete “The Pfizer Call Center 
number should only be used when 
the investigator and site staff 
cannot be reached. The Pfizer Call 
Center number is not intended for 
use by the participant directly; if a 
participant calls that number 
directly, he or she will be directed 
back to the investigator site”
Template modification
10.2. Appendix 2: 
Clinical Laboratory 
Tests
1. Replaced “QuantiFERON TB Test” 
with QFT-G
2. Replaced Interferon Gamma 
Release Assay with “IGRA”
To maintain consistency 
in the protocol
CCI


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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
activities of daily living
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
AUC
area under the curve
AUC24
area under the plasma concentration time profile from time 0 to 24 hours
AUC24,ss
area under the plasma concentration time profile from time 0 to 24 hours
at steady state
AUC48
area under the plasma concentration time profile from time 0 to 48 hours
AUCinf
area under the plasma concentration time profile from time 0 extrapolated 
to infinity
AUClast
area under the plasma concentration time profile from time 0 to the time of 
the last quantifiable concentration
AUCtau
area under the plasma concentration-time profile from time 0 to time tau, 
the dosing interval
AV
atrioventricular
BA
bioavailability
BAEP
brainstem auditory evoked potential
BBS
Biospecimen Banking System
BCR
B cell receptor
BCRP
breast cancer resistance protein
BESP
bile salt export pump
-hCG
beta human chorionic gonadotropin
BID
twice a day
BMI
body mass index
BMX
bone marrow tyrosine kinase gene in chromosome X
BP
blood pressure
BPM
beats per minute
BSEP
bile salt export pump
BTK
Bruton’s tyrosine kinase
BUN
blood urea nitrogen
Cav
Average plasma concentration from time 0 to the time of the last 
quantifiable concentration


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Abbreviation
Term
CD
cluster of differentiation
CFB
change from baseline
CFR
Code of Federal Regulations
CI
confidence interval
CIA
collagen induced arthritis
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Clast
Plasma concentration at 48 hours post-dose
CL/F
apparent clearance
Cmax
maximum observed concentration
Cmin
minimum observed concentration
CMV
Cytomegalovirus
CNS
central nervous systems
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
clinical study report
CT
clinical trial
CTCAE
common terminology criteria for adverse events
CTMS
clinical trial management system
CYP
cytochrome P450
D
day
DDI
drug-drug interaction 
DILI
drug induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EBV
Epstein barr virus
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
EFD
embryo-fetal developmental
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EPO
erythropoietin
ET
early termination


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Abbreviation
Term
EU
European Union
EudraCT
European Clinical Trials Database
F
absolute oral bioavailability
Fa
fraction absorbed
FACS
fluorescence activated cell sorting
FIH
first in human
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GI
gastrointestinal
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
HS
hidradenitis suppurativa
HSV
herpes simplex virus
hWB
human whole blood
IB
investigator’s brochure
IC50
50% inhibitory concentration
ICD
informed consent document
ICH
International Council for Harmonisation
IgD
Immunoglobulin D
IGRA
Interferon Gamma Release Assays
IL
interleukin
IMP
investigational medicinal product
IND
investigational new drug 
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IQMP
Integrated Quality Management Plan
IR
immediate release
IRAK4
interleukin 1 receptor associated kinase 4
IRB
institutional review board
ITK
IL 2 inducible T-cell kinase
IUD
intrauterine device
IV
intravenous


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Abbreviation
Term
JAK
Janus kinase 
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LBBB
left bundle branch block
LFT
liver function test
LPLV
last participant last visit
MAD
multiple ascending dose
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MMR
measles, mumps, and rubella combination vaccine
MR
modified-release
mRNA
messenger RNA
msec
milli-second
NADPH
nicotinamide adenine dinucleotide phosphate
N/A
not applicable
NK
natural killer
NOAEL
No-observed-adverse-effect level
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PBMC
Peripheral blood mononuclear cells
PCR
polymerase chain reaction
PCRU
Pfizer clinical research unit
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
pH
potential of hydrogen
PK
pharmacokinetic(s)
PNS
peripheral nervous systems
PPD
purified protein derivative
PR
PR interval
PT
prothrombin time
PTR
peak-to-trough ratio
PVC
premature ventricular contraction/complex
QD
once daily
QFT-G
QuantiFERON Gold-TB test
QID
4 times a day
QRS
QRS interval
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
CCI


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Abbreviation
Term
qual
qualitative
RA
rheumatoid arthritis
RLK
resting lymphocyte kinase
RBC
red blood cell
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
SoA
schedule of activities
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
SULT
sulfotransferases
SUSAR
suspected unexpected serious adverse reaction
t½
half-life
TB
tuberculosis
TBili
total bilirubin
TBNK
T cell, B cell, natural killer cell
TCR
T cell receptor
TEAE
treatment emergent adverse event
TEC
tyrosine kinase expressed carcinoma
THC
tetrahydrocannabinol
TK6
thymidine kinase-6
TLR
toll--like receptor
Tmax
time for Cmax
TO
target occupancy
TOmax
maxmum target occupancy
TXK
tyrosine kinase expressed in T cells
TYK
tyrosine kinase
UC
Ulcerative colitis
UDP
glucuronosyltransferase
UGT
glucuronosyltransferase
ULN
upper limit of normal
US
United States
VZV
Varicella zoster virus
WBC
white blood cell
WOCBP
woman/women of childbearing potential
CCI


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11. REFERENCES
1.
Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, et al. Discovery of a 
JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over 
pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016;11(12):3442-51.
2.
Xu H, Jesson MI, Seneviratne UI, Lin TH, Sharif MN, Xue L, et al. PF-06651600, a 
Dual JAK3/TEC Family Kinase Inhibitor. ACS Chem Biol. 2019;14(6):1235-42.
3.
Barf T, Covey T, Izumi R, van de Kar B, Gulrajani M, van Lith B, et al. Acalabrutinib 
(ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated 
Selectivity and In Vivo Potency Profile. J Pharmacol Exp Ther. 2017;363(2):240-52.
4.
Wojciechowski J. PMAR - Population Pharmacokinetic Modeling of Ritlecitinib in 
Healthy Volunteers, and Patients with Moderate-to-Severe Rheumatoid Arthritis, 
Moderate-to-Severe Alopecia Areata, Moderate-to-Severe Ulcerative Colitis, or Active 
Non-Segmental Vitiligo. 2021.
5.
Abelo A, Eriksson UG, Karlsson MO, Larsson H, Gabrielsson J. A turnover model of 
irreversible inhibition of gastric acid secretion by omeprazole in the dog. J Pharmacol 
Exp Ther. 2000;295(2):662-9.
6.
Daryaee F, Tonge PJ. Pharmacokinetic-pharmacodynamic models that incorporate 
drug-target binding kinetics. Curr Opin Chem Biol. 2019;50:120-7.

SAP_001.pdf: 
Protocol B7981045 (PF-06651600) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 1
Protocol B7981045
AN OPEN LABEL, PHASE 1, TWO-ARM STUDY TO ASSESS TARGET
OCCUPANCY AND FUNCTIONAL INHIBITION OF JAK3 AND TEC KINASES BY
SINGLE DOSES OF RITLECITINIB IN HEALTHY ADULT PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
18 Oct 2021


Protocol B7981045 (PF-06651600) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................6
3.1. Primary Endpoint(s) ..................................................................................................6
3.2. Secondary Endpoint(s) ..............................................................................................6
3.2.1. PK Parameters ..............................................................................................6
3.3. Other Endpoint(s)......................................................................................................7
3.3.1. Tertiary Endpoints ........................................................................................7
3.4. Baseline Variables.....................................................................................................7
3.5. Safety Endpoints .......................................................................................................8
3.5.1. Adverse Events.............................................................................................8
3.5.2. Laboratory Data............................................................................................8
3.5.3. Vital Signs ....................................................................................................8
3.5.4. ECG ..............................................................................................................9
3.5.5. Other Safety Data .........................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Continuous Endpoints ...........................................................10
5.2.2. Analyses for Categorical Endpoints ...........................................................10
5.3. Methods to Manage Missing Data ..........................................................................10
6. ANALYSES AND SUMMARIES ......................................................................................11
6.1. Primary Endpoint(s) ................................................................................................11


Protocol B7981045 (PF-06651600) Statistical Analysis Plan
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6.2. Secondary Endpoint(s) ............................................................................................12
6.2.1. PK Parameters ............................................................................................12
6.2.2. Safety Endpoints.........................................................................................13
6.2.2.1. Adverse Events..........................................................................13
6.2.2.2. Laboratory Data.........................................................................13
6.2.2.3. Vital Signs.................................................................................13
6.2.2.4. Electrocardiograms....................................................................14
6.3. Other Endpoint(s)....................................................................................................14
6.3.1. Tertiary Endpoints ......................................................................................14
6.4. Subset Analyses.......................................................................................................14
6.5. Baseline and Other Summaries and Analyses.........................................................15
6.5.1. Treatment and Disposition of Subjects.......................................................15
6.5.2. Concomitant Medications and Nondrug Treatments..................................15
7. INTERIM ANALYSES.......................................................................................................15
7.1. Introduction .............................................................................................................15
7.2. Interim Analyses and Summaries............................................................................15
8. APPENDICES .....................................................................................................................16
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Plasma PK Parameters................................................................................7
Table 3.
PK Parameters to be Summarized Descriptively......................................12
LIST OF FIGURES
Figure 1.
Study Schema .............................................................................................6
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....16
Appendix 2. List of Abbreviations...........................................................................................17


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
18 Oct 2021
Protocol 
Amendment 1
01 Oct 2021
N/A
N/A
2. INTRODUCTION
Ritlecitinib (previously known as PF-06651600) is a potent, covalent, and irreversible 
inhibitor of JAK3 with high selectivity over the other three JAK isoforms (JAK1, JAK2, and 
TYK2. Ritlecitinib also inhibits irreversibly the TEC family kinases BTK, BMX, ITK, RLK, 
and TEC) with selectivity over the broader human kinome. Ritlecitinib is being developed for 
the treatment of UC, CD, AA, RA, and vitiligo.
Inhibition of JAK3 by ritlecitinib is expected to modulate γ-common chain cytokine pathways, 
such as IL-7, IL-9, IL-15, and IL-21, but expected to spare inhibition of other JAK-dependent 
pathways that do not utilize JAK3, including IL-6 signaling and key immuno-suppressive 
cytokines, such as IL-10, IL-27 and IL-35. Selective JAK3 targeting may reduce adverse 
effects from other JAK pathways, including cytopenia's (JAK2 dependent), cardiovascular 
events, malignancies, and severe infections. Inhibition of TEC kinases by ritlecitinib is 
expected to modulate T cell and B cell development and function (TEC kinases are activated 
downstream of the TCR and BCR). These effects by ritlecitinib on TCR signaling have been 
shown to inhibit the cytotoxic function of CD8+T cells and NK cells. There is limited 
information on the degree of target occupancy by Ritlecitinib on JAK3 and TEC kinases 
(ie, irreversible kinase binding) in humans, and how TO and target turnover of both 
JAK3 and TEC kinases a) is regulated by drug half-life, and b) how TO translates into 
functional effects on specific cell types and pathways.
TO of JAK3 and the five TEC kinases by ritlecitinib has been demonstrated in vivo in NOD 
scid IL2r-null mice engrafted with human PBMCs which expresses JAK3 and TEC kinases. 
Despite the large variation in occupancy measurements likely due to differing levels of 
human PBMC engraftment and the small number of mice (n=3) per time point, 
approximately 100% occupancy of JAK3 and most of the TEC kinases, except RLK, was 
observed in the spleen samples from early time points (0.25 to 5 h). A slower recovery of 
unbound BTK was seen compared to JAK3 and ITK due to relatively longer half-life of BTK 
(12 24 hours vs. 2-3 hours for JAK3/ITK). Since the PK profile of ritlecitinib is characterized 
by rapid absorption and rapid elimination half-life, it is important to study the relationship 
between TO of JAK3 and the TEC kinase family and the functional consequences of their 
inhibition over time by ritlecitinib in healthy participants to provide insights in assessing the 
impact in patients with inflammatory and autoimmune diseases. Based on the predicted PK 
for ritlecitinib, along with the need to assess target occupancy (and functional inhibition) in 


Protocol B7981045 (PF-06651600) Statistical Analysis Plan
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a predefined specimen collection window, at least 2 doses would be required to capture 
expected concentrations in patients at clinically relevant doses and also to better understand 
the expected hysteresis in exposure and response.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B7981045.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary: 
Primary: 
•
To characterize the TO of JAK3 and TEC kinases 
in peripheral blood mononuclear cells (PBMCs) 
after single oral dose of ritlecitinib
•
Percent TO for JAK3 and TEC kinases (BTK, 
ITK, RLK, TEC and BMX)
Secondary: 
Secondary: 
•
To evaluate the plasma exposure of ritlecitinib 
over 48 hours after single oral dose 
administration 
•
Ritlecitinib plasma PK parameters
•
Cmax,Tmax, Clast, Cav, AUClast and, AUC24 
•
To evaluate the safety and tolerability of an oral 
dose of ritlecitinib when administered alone and 
in healthy adult participants
•
Assessment of TEAEs, clinical laboratory tests, 
and vital signs
Tertiary:
Tertiary:
•
To characterize the relationship between TO in 
PBMCs and plasma ritlecitinib exposure over 
48 hours after single oral dose
•
Maximal inhibition (occupancy) by ritlecitinib 
(TOmax)
•
Ritlecitinib plasma concentrations at 
50% TOmax (IC50) 
2.2. Study Design
This is a Phase 1, single dose, open label, two-arm study to assess TO of JAK3 and TEC 
kinases by ritlecitinib in healthy adult participants. A total of approximately 16 healthy male 
and/or female participants, 8 in each cohort, will be enrolled and dosed to achieve at least 
6 participants completing each dose level. Participants who discontinue from the study for 
non safety reasons may be replaced at the sponsor’s discretion.
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Participants will be enrolled to receive either 50 mg or 200 mg single dose of ritlecitinib on 
Day 1 (See Figure 1). Blood samples to assess ritlecitinib PK, target occupancy and 
functional assays will be collected over 48 hours. Participants will remain in the CRU until 
Day 3 when they will be discharged after completion of study related activities as indicated 
in the SoA.
Figure 1.
Study Schema
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoint in human PBMCs is TO of JAK3 BTK, ITK, RLK, TEC and BMX
after a single dose of ritlecitinib. Target occupancy for each kinase at time t will be evaluated 
as follows:
% ܶܽݎ݃݁ݐ ܱܿܿݑ݌ܽ݊ܿݕ௧ൌ100 % െ% ܨݎ݁݁ ܶܽݎ݃݁ݐ௧
with ܱܶ଴as the baseline variable of target occupancy, which is the mean of the two pre-dose 
measurements at Hour -1 and Hour 0 on Day 1. If only one of the two pre-dose 
measurements is available, ܱܶ଴is the available pre-dose measurement. (see Section 3.4).
3.2. Secondary Endpoint(s)
3.2.1. PK Parameters
The secondary endpoints are pharmacokinetic parameters of ritlecitinib after single oral 
dose. PK parameters will be derived, given available data, following single dose 
administration from the concentration-time profiles for ritlecitinib as follows:


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Table 2.
Plasma PK Parameters
Parameter
Definition
Method of Determination
AUC24
Area under the plasma concentration-time 
curve from time 0 to 24 hours
Linear/Log trapezoidal method
AUClast
Area under the plasma concentration-time 
curve from time 0 to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
Cav
Average plasma concentration from time 0 to 
the time of the last quantifiable concentration 
AUC24/24
Cmax
Maximum plasma observed concentration
Observed directly from data
Clast
Plasma concentration at 48 hours post-dose
Observed directly from data
Tmax
Time to reach Cmax
Observed directly from data as time of first 
occurrence
3.3. Other Endpoint(s)
3.3.1. Tertiary Endpoints
Maximal target occupancy by ritlecitinib (TOmax) and Ritlecitinib plasma concentrations at 
50% TOmax (IC50) will be derived, if data permit.
3.4. Baseline Variables
Baseline TO, 
will be defined as the mean of the two pre-dose 
measurements at Hour -1 and Hour 0 on Day 1. If only one of the two pre-dose 
measurements is available, the baseline will be defined as the available pre-dose 
measurement.
In general, for all other analyses, baseline will be defined based on observations collected 
prior to first dose. Baseline values for demographics, medical and other history will be based 
on measures collected at Visit 1/Screening visit. Study Day 1 is defined as the day the subject 
receives first dose of study drug. For purposes of all other analyses including analyses for 
change from baseline, the baseline value will be defined as measured on Day 1 pre-dose. If a 
value is missing on Day 1, then the last available observation before Day 1 will be used.
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3.5. Safety Endpoints
The following data are considered in standard safety summaries (see protocol for collection 
days, baseline assessment, and list of parameters):

AEs;

clinical laboratory tests;

vital signs;

ECG.
3.5.1. Adverse Events
An adverse event (AE) is considered a Treatment-Emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment. All events that start on or after the 
first dosing day and time/start time, if collected, but before the last dose plus the lag time,
will be flagged as TEAEs. The lag time is defined by the Pfizer Standard of 365 days post
last dose of Ritlecitinib. The algorithm will not consider any events that started prior to the 
first dose date. If an AE starts on the same day as the first dose date, it will be considered 
treatment emergent unless the CRF data indicates otherwise via explicitly recording time for 
AE onset which was occurred before the first treatment dosing.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol. 
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards. The assessment will not take into 
account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter. 
Baseline of safety laboratory tests is defined as the pre-dose measurement on Day -1.
3.5.3. Vital Signs
Supine blood pressure and pulse measurements will be taken at all time points listed in the 
Schedule of Activities given in the protocol. 


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The baseline measurement is the pre-dose measurement at Hour 0 taken on Day 1. The 
maximum decrease and increase from baseline over all measurements taken postdose for 
supine systolic and diastolic blood pressures will be determined. The maximum increase 
from baseline will be calculated by first subtracting the baseline value from each postdose 
measurement to give the change from baseline. The maximum of these values over the entire 
study will then be selected, except in the case where a subject does not show an increase. In 
such an instance, the minimum decrease should be taken. 
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline. In cases where a subject does not show a 
decrease, the minimum increase should be taken. 
3.5.4. ECG
Single supine 12-lead ECG will be taken at all time points listed in the Schedule of Activities 
given in the protocol. The baseline measurement is the pre-dose measurement at Hour 0 
taken on Day 1.
The QT, QTc, PR, QRS and heart rate will be recorded at each assessment time. 
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula: 
QTcF = QT/(RR)1/3  
where RR = 60/HR (if not provided)
The maximum absolute value (post-dose) and the maximum increase from baseline for 
QTcF, QT, heart rate, PR and QRS, will be determined for all measurements taken post-dose 
for QTcF, heart rate, PR and QRS.
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each postdose measurement to give the change from baseline. The maximum of 
these values over the entire study will then be selected, except in the case where a subject 
does not show an increase. In such an instance, the minimum decrease should be taken.
3.5.5. Other Safety Data
Additional safety data will be collected as described in the protocol and will be listed if 
collected in the sponsor’s database.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.


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Population
Description
Enrolled
All participants who sign the ICD.
Randomly assigned to 
investigational product 
All participants who sign the ICD and meet all eligibility 
criteria.
Evaluable
The PK concentration population is defined as all participants 
enrolled and treated who have at least 1 concentration
measurement of ritlecitinib.
The PD population is defined as all enrolled and treated who 
have at least 1 TO measurement.
Safety Analysis Set
All participants who take at least 1 dose of investigational 
product. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
No formal hypothesis testing will be performed in this study.
5.2. General Methods
Descriptive analyses will be performed. Some measures will be summarized using graphical 
representations by dose, where appropriate.
5.2.1. Analyses for Continuous Endpoints
For continuous variables, the data will be summarized using the number of subjects, mean, 
median, standard deviation, minimum, and maximum in accordance with current Pfizer’s 
data and reporting standards. For appropriate PK parameters, geometric mean and geometric 
coefficient of variation (geocv%) will also be summarized. For the summaries of TO and 
baseline corrected TO, the 90% CI for the mean will also be presented.
Summaries will be presented by dose and nomial time post-dose, if appropriate.
5.2.2. Analyses for Categorical Endpoints
For categorical or ordinal variables, number of subjects, numbers and percentages of subjects 
meeting the categorical criteria will be supplied in accordance with current Pfizer’s data and 
reporting standards.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
Methods to handle missing PK data are described below. 


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Concentrations Below the Limit of Quantification:
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ” where LLQ 
will be replaced with the value for the lower limit of quantification).
Deviations, Missing Concentrations and Anomalous Values: 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true: 
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample), 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing. 
Pharmacokinetic Parameters: 
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a subject’s concentration data, the parameter will be coded as NC 
(ie, not calculated). (Note that NC values will not be generated beyond the day that a subject 
discontinues). In summary tables, statistics will be calculated by setting NC values to 
missing; and statistics will be presented for a particular dose with ≥3 evaluable 
measurements. 
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed from 
the gastrointestinal tract), this will be footnoted in summary tables and will not be included in 
the calculation of summary statistics or statistical analyses.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
The primary analysis will be performed on the PD population (see Section 4).
The primary endpoint is TO of JAK3, BTK, ITK, RLK, TEC and BMX after a single dose of 
ritlecitinib. TO profiles, CFB and percent CFB in TO profiles of each kinase will be assessed 
graphically and summarized by dose and nominal timepoints using appropriate descriptive 
statistics as described in Section 5.2.1.


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6.2. Secondary Endpoint(s)
6.2.1. PK Parameters
The PK parameters detailed in Table 2 will be listed and summarized for participants in the 
PK concentration population (see Section 4). Missing values will be handled as detailed in 
Section 5.3. The PK parameters will be calculated using standard non-compartmental 
methods. Each PK parameter will be summarized by dose and will include the set of 
summary statistics as specified in the table below.
Table 3.
PK Parameters to be Summarized Descriptively
Parameter
Summary Statistics
AUC24, AUClast, Cav, Cmax, 
Clast
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
For the derivation of PK parameters, actual PK sampling times will be used.
To assess the relationship between the PK parameters and dose, AUC24, AUClast and Cmax
will be plotted against dose (using a logarithmic scale), and will include individual subject 
values and the geometric means for each dose. Geometric means will have a different symbol 
than the individual values. These plots will be presented for both the dose-normalized (to a 
1mg dose, by dividing the individual values and raw geometric means by dose) and non 
dose-normalized versions of these parameters.
Presentations for Ritlecitinib concentrations will include:

A listing of all concentrations sorted by subject ID, dose 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 dose 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 dose (all treatments on the same plot per scale, based on the 
summary of concentrations by dose and time postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by dose (all treatments on the same plot per scale, based on the 
summary of concentrations by dose and time postdose).


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
Individual concentration time plots by dose (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each dose per 
scale).

Individual concentration time plots by subject (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each subject (containing 
all doses) per scale].
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
Additional PK analyses may be performed if deemed appropriate.
6.2.2. Safety Endpoints
All safety analyses will be performed on the safety population (see Section 4).
The safety endpoints detailed in Section 3.5 will be listed and summarized descriptively in 
accordance with the sponsor reporting standards based on the safety, with more details 
provided below. 
A set of summary tables split by dose will be produced to evaluate any potential risk 
associated with the safety and toleration of administering Ritlecitinib.
6.2.2.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
Subject discontinuations due to adverse events will be detailed by dose. Data will be reported 
in accordance with sponsor reporting standards.
6.2.2.2. Laboratory Data
Laboratory data will be listed and summarized by dose in accordance with the sponsor 
reporting standards. The baseline measurement is the pre-dose measurement on Day -1. 
6.2.2.3. Vital Signs
The baseline measurement is the pre-dose measurement at Hour 0 taken on Day 1.
Baseline values and change from baseline values within each dose will be summarized with 
descriptive statistics (using sponsor default standards). The thresholds used in the categorical 
summarization of vital signs data are presented in the Appendix 1.


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Maximum and minimum absolute values and maximum changes from baseline for supine 
vital signs will also be summarised descriptively by dose using categories as defined in
Appendix 1. Numbers and percentages of participants meeting the categorical criteria will be
provided. All planned and unplanned post-dose time points will be counted in these 
categorical summaries.
6.2.2.4. Electrocardiograms
The baseline measurement is the pre-dose measurement at Hour 0 taken on Day 1 of each 
period.
Baseline values and change from baseline values within each dose will be summarized with 
descriptive statistics (using sponsor default standards). The thresholds used in the categorical 
summarization of ECG data are presented in the Appendix 1.
Maximum absolute values and increase from baseline for QTcF, PR and QRS will also be 
summarised descriptively by dose using categories as defined in Appendix 1. Numbers and 
percentages of participants meeting the categorical criteria will be provided. All planned and 
unplanned post-dose time points will be counted in these categorical summaries. For QT and 
heart rate, there was no related criteria regarding the maximum absolute value and maximum 
increase.
6.3. Other Endpoint(s)
6.3.1. Tertiary Endpoints
If data permit, TOmax and IC50 will be estimated using a turnover model. These PD endpoints 
are considered exploratory and will not be included in the CSR. An additional PKPD 
modelling results will be reported separately in a population modelling analyses report 
(PMAR), if necessary.
6.4. Subset Analyses
Not applicable.
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6.5. Baseline and Other Summaries and Analyses
Demographic data collected at screening will be reported as part of the standard baseline 
summary tables. A breakdown of demographic data will be provided for age, race, weight, 
body mass index, and height. Each will be summarized by dose in accordance with the 
sponsor reporting standards. 
6.5.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for safety (adverse events and laboratory data). Frequency counts will 
be supplied for subject discontinuation(s) by dose. Data will be reported in accordance with 
the sponsor reporting standards.
6.5.2. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
7. 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, facilitating PK/PD modeling, and/or supporting clinical 
development.
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Available safety and PK data may be reviewed.


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8. APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
Categories for PR and QRS
PR (ms)
max. ≥300 
PR (ms) increase 
from baseline
Baseline >200 
and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) increase 
from baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Measurements that fulfill these criteria are to be listed in the clinical study report.


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Appendix 2. List of Abbreviations
Abbreviation
Term
AA
alopecia areata
AE
adverse event
AUC
area under the curve
AUC24
area under the plasma concentration time profile from time 0 to 24 hours
AUClast
area under the plasma concentration time profile from time 0 to the time of 
the last quantifiable concentration
AV
atrioventricular
BCR
B cell receptor
BLQ
below the limit of quantification
BMX
bone marrow tyrosine kinase gene in chromosome X
BP
blood pressure
BTK
Bruton’s tyrosine kinase
Cav
Average plasma concentration from time 0 to the time of the last 
quantifiable concentration
CD
Crohn's disease
CI
confidence interval
Clast
Plasma concentration at 48 hours post-dose
Cmax
maximum observed concentration
CFB
change from baseline
COVID-19
coronavirus disease 2019
CRF
case report form
CRU
clinical research unit
CSR
clinical study report
D
day
DMC
data monitoring committee
EC
ethics committee
ECG
electrocardiogram
HR
heart rate
IC50
50% inhibitory concentration
ICD
informed consent document
IL
Interleukin
ITK
IL 2 inducible T-cell kinase
JAK
Janus kinase 
LLQ
lower limit of quantification
msec
milli-second
N/A
not applicable
NK
natural killer
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Abbreviation
Term
PBMC
Peripheral blood mononuclear cells
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PR
PR interval
QRS
QRS interval
QT
Q wave interval
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
RA
rheumatoid arthritis
RLK
resting lymphocyte kinase
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities
SOP
standard operating procedure
TBNK
T cell, B cell, natural killer cell
TCR
T cell receptor
TEAE
treatment emergent adverse event
TEC
tyrosine kinase expressed carcinoma
Tmax
time for Cmax
TO
target occupancy
TOmax
maxmum target occupancy
TYK
tyrosine kinase
UC
Ulcerative colitis