A LOW-INTERVENTIONAL, PROSPECTIVE, MULTI-CENTER STUDY TO EVALUATE REAL-WORLD CLINICAL, BIOCHEMICAL AND PATIENT-REPORTED RESPONSES TO TOFACITINIB INDUCTION THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS IN SWITZERLAND
Conditions: Ulcerative Colitis
Sponsor: Pfizer

Tofacitinib
Protocol A3921395
Final Protocol Amendment 2, 22 March 2022
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STUDY PROTOCOL
KIC-START: A LOW-INTERVENTIONAL, PROSPECTIVE, MULTI-CENTER 
STUDY TO EVALUATE REAL-WORLD CLINICAL, BIOCHEMICAL AND 
PATIENT-REPORTED RESPONSES TO TOFACITINIB INDUCTION 
THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE 
ULCERATIVE COLITIS IN SWITZERLAND
Compound Number:
CP-690550
Compound Name:
Tofacitinib (Xeljanz®)
US IND Number:
NA
EudraCT Number:
NA
Protocol Number:
A3921395
BASEC Number:
2021-01788
Phase:
4
Short Title: A Low-Interventional Study To Evaluate Clinical, Biochemical, And 
Patient-Reported Responses To Tofacitinib Induction Therapy For Ulcerative 
Colitis
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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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
23 July 2021
NA
Protocol 
Amendment 1
substantial
29 September 2021
Summary and Section 9.3: Added, “The 
Clinical Trial Unit of Inselspital is 
responsible for study data management 
activities (implementation and 
maintenance of the study database)”.
Section 1.3 – Table 1
Clarification that informed consent is 
only required once during screening 
visit. 
Section 1.3 – Table 1; Section 3.1 –
Table 4 and Section 8.1.1.3
To comply with the request of ethic 
committee instead of date of birth, only 
month and year of birth will be 
collected. 
Section 4.2.1; Section 5.2 and section 
7.1
To address ethics committee comments 
and stay in line with drug label 
pregnancy was eliminated as a reason 
for study exclusion and discontinuation.
Section 5.1
Clarification in inclusion criteria 
section that decision to prescribe 
tofacitinib is independent of study 
participation. 
Appendix 5
Clarification of study and patient data 
location. 
Harmonization of PRO names 
throughout the document. 
Minor administrative 
changes/clarifications and corrections
throughout the document.
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Protocol 
Amendment 2
administrative
22 March 2022
Cover page
Removed SNCTP Number as not 
applicable.
Sections 8.3.10 and 8.4
To align with the safety language in the 
new Pfizer LIS2 protocol template 
(CT45-GSOP-RF15B 2.0), as well as 
comply with the nature and design of 
the study, the language about 
medication errors and overdose was
updated. Specifically, removed 
superfluous text in section 8.3.10, 
removed information on what should be 
done in the event of an overdose was 
and replaced it with a reference to 
section 8.3.10. Medication Errors. 
Definitions for medication error and 
overdose were added to Appendix 2
(sections 10.2.3 and 10.2.4).
Appendix 1
Added contact details for medical 
monitor to Responsible Parties list
(Section 10.1.2) and updated Pfizer 
Team details to reflect any changes in 
positions.
Section 8.3 and Appendix 1 section 
10.2.2
Removed the contact details for the 
Pfizer clinician and medical monitor
from the footnotes, as these are 
provided in the Responsible Parties list 
(Section 10.1.2).
Table 7 removed from protocol and put 
in a separate sites and investigators log, 
so that protocol does not need to be 
amended every time a site and/or 
investigator is added or removed from 
the study.
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TABLE OF CONTENTS
TABLE OF CONTENTS.......................................................................................................... 4
LIST OF TABLES.................................................................................................................... 7
1. PROTOCOL SUMMARY.................................................................................................... 8
1.1. Synopsis.................................................................................................................... 8
1.2. Schema ................................................................................................................... 13
1.3. Schedule of Activities ............................................................................................ 13
2. INTRODUCTION .............................................................................................................. 17
2.1. Study Rationale ...................................................................................................... 17
2.2. Background ............................................................................................................ 17
2.2.1. Clinical Overview...................................................................................... 19
2.3. Benefit/Risk Assessment........................................................................................ 20
3. RESEARCH QUESTIONS, OBJECTIVES AND ENDPOINTS...................................... 21
3.1. Variables................................................................................................................. 23
4. STUDY DESIGN................................................................................................................ 24
4.1. Overall Design........................................................................................................ 24
4.2. Scientific Rationale for Study Design.................................................................... 25
4.2.1. Rationale for Contraception/Pregnancy Testing........................................ 25
4.2.2. Strengths and Limitations of the Research Methods ................................. 26
4.3. Justification for Dose.............................................................................................. 27
4.4. End of Study Definition ......................................................................................... 27
5. STUDY POPULATION..................................................................................................... 27
5.1. Inclusion Criteria.................................................................................................... 27
5.2. Exclusion Criteria................................................................................................... 28
5.3. Lifestyle Considerations......................................................................................... 28
5.3.1. Contraception............................................................................................. 29
5.4. Screen Failures ....................................................................................................... 29
6. STUDY INTERVENTIONS .............................................................................................. 29
6.1. Study Intervention(s).............................................................................................. 30
6.1.1. Diagnostic or Monitoring Study Interventions.......................................... 30
6.2. Preparation/Handling/Storage/Accountability ....................................................... 31
6.2.1. Central Supply: Preparation and Dispensing............................................. 32
7. PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY..................... 33
7.1. Participant Discontinuation/Withdrawal from the Study....................................... 33
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7.1.1. Withdrawal of Consent.............................................................................. 34
7.2. Lost to Follow-up ................................................................................................... 34
8. STUDY ASSESSMENTS AND PROCEDURES.............................................................. 34
8.1. Efficacy Assessments............................................................................................. 35
8.1.1. Protocol-required Assessments.................................................................. 35
8.1.2. SOC Assessments ...................................................................................... 41
8.2. Safety Assessments ................................................................................................ 42
8.2.1. Protocol-Required Clinical Safety Laboratory Assessments..................... 42
8.2.2. Pregnancy Testing ..................................................................................... 42
8.3. Adverse Events and Serious Adverse Events......................................................... 43
8.3.1. Time Period and Frequency for Collecting AE and SAE 
Information (“Active Collection Period”) ...................................................... 44
8.3.2. Method of Detecting AEs and SAEs ......................................................... 45
8.3.3. Follow-up of AEs and SAEs...................................................................... 45
8.3.4. Regulatory Reporting Requirements for SAEs.......................................... 45
8.3.5. Exposure During Pregnancy or Breastfeeding, and Environmental 
Exposure ......................................................................................................... 45
8.3.6. Cardiovascular and Death Events.............................................................. 48
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs............................................................................. 48
8.3.8. Adverse Events of Special Interest............................................................ 48
8.3.9. Medical Device Deficiencies..................................................................... 48
8.3.10. Medication Errors .................................................................................... 48
8.4. Treatment of Overdose........................................................................................... 49
8.5. Pharmacokinetics.................................................................................................... 49
8.6. Pharmacodynamics................................................................................................. 50
8.7. Genetics.................................................................................................................. 50
8.8. Biomarkers ............................................................................................................. 50
8.9. Immunogenicity Assessments................................................................................ 50
8.10. Health Economics................................................................................................. 50
9. STATISTICAL CONSIDERATIONS................................................................................ 50
9.1. Statistical Hypotheses............................................................................................. 50
9.2. Sample Size Determination.................................................................................... 51
9.3. Data Management................................................................................................... 51
9.4. Case Report Forms/Data Collection Tools/Electronic Data Record...................... 52
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9.5. Data Analysis ......................................................................................................... 53
9.5.1. Datasets to be Analyzed, Analysis Population .......................................... 53
9.5.2. Primary Analysis ....................................................................................... 53
9.5.3. Secondary Analysis ................................................................................... 54
9.6. Interim Analyses..................................................................................................... 55
9.7. Data Monitoring Committee or Other Independent Oversight Committee............ 55
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ......................................................................................................... 56
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............. 56
10.1.1. Regulatory and Ethical Considerations ................................................... 56
10.1.2. Responsible Parties.................................................................................. 57
10.1.3. Financial Disclosure ................................................................................ 58
10.1.4. Informed Consent Process ....................................................................... 58
10.1.5. Data Protection ........................................................................................ 59
10.1.6. Dissemination of Clinical Study Data ..................................................... 59
10.1.7. Data Quality Assurance ........................................................................... 61
10.1.8. Source Documents................................................................................... 62
10.1.9. Study and Site Start and Closure ............................................................. 62
10.1.10. Publication Policy.................................................................................. 63
10.2. Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..................................................................... 64
10.2.1. Definition of AE ...................................................................................... 64
10.2.2. Definition of SAE.................................................................................... 65
10.2.3. Definition of Medication Error................................................................ 67
10.2.4. Definition of Overdose ............................................................................ 68
10.2.5. Recording/Reporting and Follow-up of AEs and/or SAEs during 
the Active Collection Period........................................................................... 68
10.2.6. Reporting of SAEs................................................................................... 72
10.3. Appendix 3: Liver Safety: Suggested Actions and Follow up 
Assessments -Potential Cases of Drug Induced Liver Injury................................... 73
10.4. Appendix 4: Country Specific Requirements....................................................... 75
10.4.1. Switzerland .............................................................................................. 75
10.5. Appendix 5: Protocol Specific Appendices.......................................................... 78
10.6. Appendix 6: Abbreviations .................................................................................. 79
11. REFERENCES ................................................................................................................. 83
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LIST OF TABLES
Table 1.
SoA .......................................................................................................... 14
Table 2.
Schedule of Procedures Between Study Visits........................................ 16
Table 3.
Study Objectives and Endpoints.............................................................. 21
Table 4.
Study Variables........................................................................................ 23
Table 5.
PROs and Related Instrument for Collection .......................................... 38
Table 6.
Reporting of Medication Errors............................................................... 49
Table 7.
Reporting of Safety Events...................................................................... 69
Table 8.
Abbreviations........................................................................................... 79
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title
A low-interventional study to evaluate clinical, biochemical, and patient-reported responses 
to tofacitinib induction therapy for ulcerative colitis
Rationale
A number of studies have been published demonstrating the RWE of tofacitinib in patients
with UC.1-8 While it is known that tofacitinib therapy is associated with a rapid onset of 
symptom relief in terms of the PMS components (stool frequency and rectal bleeding), the 
response of other important PROs, such as fatigue, urgency and abdominal pain, are less well 
characterized.9,10 Measuring these PROs will provide a broader understanding of how 
patients experience response to tofacitinib treatment. Moreover, response of fCAL during 
tofacitinib induction therapy is currently not fully understood.11 Regular measurements of
fCAL levels, a widely used biomarker in UC, will provide a measure of the response of 
intestinal inflammation to tofacitinib induction therapy. Early measurements will assess the 
validity of fCAL as an early biochemical predictor of treatment response.
This study aims to generate granular RWD on and provide the opportunity to explore the 
relationships between tofacitinib induction therapy and changes in PMS, PROs and intestinal 
inflammation during tofacitinib induction therapy in UC.
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Objectives and Endpoints
Primary Objective:
Primary Endpoint:
Evaluate the RW effectiveness of tofacitinib 
induction therapy in patients with UC.
Proportion of participants achieving clinical
responsea at W8.
Secondary Objectives:
Secondary Endpoints:
Evaluate RW response to tofacitinib treatment based 
on PMS.

Proportion of participants achieving clinical 
remissionb at W8.

Proportion of participants achieving clinical 
responsea at W16.

Proportion of participants achieving clinical 
remissionb at W16.
Evaluate the RW response to tofacitinib treatment 
on quality of life based on IBDQ score.

Proportion of participants achieving IBDQ 
remissionc at W8.

Proportion of participants achieving IBDQ 
remissionc at W16.

Proportion of participants achieving IBDQ 
responsed at W8.

Proportion of participants achieving IBDQ 
responsed at W16.
Evaluate RW response to tofacitinib treatment based 
on fCAL concentrations.

Proportion of participants achieving biochemical 
remissione at W8.

Proportion of participants achieving biochemical 
remissione at W16.
Elucidate fCAL and PRO responses to tofacitinib 
induction therapy for UC.
Median changes from baseline in PROs and fCAL 
over time (ie, map response curves).
Assess whether PRO responses occur prior to, with 
or lag behind clinical responses.
Correlations between changes in amplitude and
timing of PMS, PROs, IBDQ score and fCAL 
concentrations.
Verify the validity of fCAL as a convenient
surrogate biomarker to assess early response to
tofacitinib treatment.

Median fCAL concentrations over time stratified 
by W8 and W16 clinical remission status.b

Median fCAL concentrations over time stratified 
by W8 and W16 clinical response status.a

Median fCAL concentrations at W8 by W8 
clinical response status.a
Exploratory Objectives:
Exploratory Endpoints:
Assess effect of prior exposure to biologics, 
concomitant medications and tofacitinib induction 
dose, on treatment outcomes.
Stratification of PMS outcomes, PROs and fCAL 
levels based on: i) prior exposure to TNFi, 
vedolizumab and ustekinumab; ii) concomitant 
medication with corticosteroids or aminosalicylic 
acids; iii) predominant tofacitinib dose.
Assess effect of baseline patient demographics and 
disease characteristics on the likelihood of achieving 
clinical, fCAL or PROs response.
Regression analyses on baseline patient and disease 
characteristics with respect to PMS, fCAL or PROs
measures.
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a.
Clinical response: reduction in PMS from baseline of ≥2 points or achieving clinical remission.12
b.
Clinical remission: PMS of ≤2 with no subscore >1.12
c.
IBDQ remission: IBDQ score ≥170.12
d.
IBDQ response: IBDQ score ≥16 points higher than IBDQ baseline score.
e.
Biochemical remission: fCAL concentration ≤250 mg/g.11 Optimal fCAL cut-off values for the detection of active 
disease vary from 50 μg/g to 250 μg/g [2, 38, 47] depending on the test used, location of the disease and 
intra-individual patient variability. In this study, biochemical remission is defined as a fCAL concentration ≤250 μg/g.
f.
FMS response: decrease from baseline total Mayo score of ≥3 points and ≥30%, with an accompanying decrease in the 
rectal bleeding subscore of ≥1 or absolute rectal bleeding subscore ≤1.12
g.
Remission: a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0.12
h.
Mucosal healing: a Mayo endoscopic subscore of ≤1.12
i.
According to treating physician’s assessment of bowel wall thickness, normalization and extension; bowel wall 
vascularity, loss of stratification, loss of colonic haustration, structure formation and hyperechogenic reaction adjacent 
to the bowel wall.
j.
According to treating physician’s observations and assessments.
Evaluate RW response to tofacitinib treatment based
on FMS and IUS outcomes.

Proportion of participants achieving FMS 
responsef at W8.

Proportion of participants achieving remissiong at 
W8.

Proportion of participants achieving FMS 
responsef at W16.

Proportion of participants achieving remissiong at 
W16.

Proportion of participants achieving mucosal 
healingh at W8.

Proportion of participants achieving mucosal 
healingh at W16.

Proportion of participants achieving response
according to IUS assessmenti at W8.

Proportion of participants achieving remission
according to IUS assessmenti at W8.

Proportion of participants achieving response 
according to IUS assessmenti at W16.

Proportion of participants achieving remission 
according to IUS assessmenti at W16.
Evaluate impact of tofacitinib treatment on activity 
of individual EIMs and categories of EIMs 
(mucocutaneous, musculoskeletal, ocular,
hepatobiliary).

Proportion of participants with improvement in 
EIMj (individual or categorical) at W8.

Proportion of participants with improvement in 
EIMj (individual or categorical) at W16.
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Overall Design
This study is an open-label, prospective, low-interventional, multi-center study conducted in 
Switzerland in a real-world setting uncontrolled by any comparison groups. Patients will be 
included if they are 18 years of age or older, provide written, informed consent and are 
prescribed tofacitinib for moderate to severe UC as per the Swiss label and as per physician’s 
clinical judgement, independently of this study.13 Importantly, no additional endoscopy will 
be performed and data will only be used from endoscopies and intestinal ultrasound
assessments performed as SOC and at physician’s discretion.
A research version of the Sidekick Health IBD companion App, designed for the study, will 
be used to conveniently collect PROs at predefined timepoints according to the study 
protocol. Via their personal mobile phone, participants will be provided with brief PRO 
questionnaires that encompass important elements of the subjective experience of UC. PROs 
will be collected daily until Week 2 and thereafter twice weekly until Week 8. To fully 
capture the 16-week induction period and account for delayed responders, PROs will be 
recorded in all participants at Week 16. Patients not owning a mobile phone compatible with 
the Sidekick Health IBD App or not willing to have it installed will not be included in the 
study.
For regular and convenient fCAL measurements, participants will use the CALEX® Cap 
system (BÜHLMANN Laboratories AG), to collect stool samples at home. Samples will be 
analyzed with the Quantum Blue® (BÜHLMANN Laboratories AG) device at POC to 
quantitatively assess fCAL concentration. To allow valuable insights into the sensitivity and 
timing of early fCAL responses with respect to disease activity and symptom changes during 
induction therapy, fCAL concentrations will be measured more often during the first week of 
induction therapy (4 times), followed by measurements on a weekly basis during the 
following weeks and up to Week 8. An additional measurement is planned at Week 16. 
Number of Participants
Approximately 60 participants will be enrolled. A participant is considered enrolled if 
protocol-required procedures at baseline visit are performed. An enrolled participant who 
discontinues the study before Week 8 study (ie, Week 8 visit is not performed), will be 
replaced by enrolling a new participant. Participants who are screened for the purpose of 
determining eligibility for the study, but do not meet the eligibility criteria, or who do not 
perform the baseline visit, are not considered enrolled to the study and are declared screen 
failures. Screen failures will not be rescreened.
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Treatment Cohorts and Duration of Study Participation
Patients who are prescribed tofacitinib (Xeljanz®) for the treatment of moderately to severely 
active UC will be included in the study. This protocol does not recommend or promote the 
prescription and use of tofacitinib, and tofacitinib will not be provided as part of this study. 
The clinical decision for the prescription of tofacitinib should be clearly separated from the 
decision to propose enrollment in this study to the patient. It is expected that a large 
proportion of enrolled participants will have prior exposure to TNF-antagonists, as tofacitinib 
is commonly prescribed in this population in Switzerland.
Doses of tofacitinib treatment should be based on the Swiss label recommendations,13 as well 
as clinical and individual needs, and are determined by the treating physician. The standard 
tofacitinib induction dosing is 10 mg twice daily for an 8-week induction period, after which 
the dosage is reduced to the recommended maintenance dose of 5 mg twice daily, although 
prolongation of the 10 mg twice daily dose up to 16 weeks is permitted if clinically indicated. 
If off-label doses are used, inclusion in the study is permitted.
The active study period starts at patient signature of ICD, obtained not later than the first day 
of tofacitinib treatment initiation and continues for the entire 8-week induction period, and 
additionally at Week 16. Data collected up to 42 days prior to the first day of tofacitinib 
initiation (ie, baseline visit) can be used for study purposes and analyses. The safety reporting 
period will extend for an additional 4 weeks (28 days) after the Week 16 visit, or after the 
discontinuation/withdrawal date, if the participant has discontinued the study prematurely. 
A participant is considered to have completed the study if he/she has completed all study 
procedures, including the Week 16 study visit and the 28 days of safety monitoring following 
this visit.
Data Monitoring Committee or Other Independent Oversight Committee: 
Not used in this study.
Statistical Methods
This study seeks to test the following hypotheses:

Tofacitinib induction therapy is associated with a rapid improvement in the PMS, 
intestinal inflammation (ie, reduced fCAL concentrations), QoL and symptoms 
(PROs).

Changes in different types of treatment outcomes (ie, PMS, PROs and fCAL 
concentrations) are correlated. 

Improvements in PROs and fCAL concentrations can predict treatment outcomes 
(ie, clinical outcome measures) at end of induction therapy. 
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Based on PMS data from the OCTAVE Induction and RW studies, feedback from Swiss 
gastroenterologists on drop-out rates during the first 8 weeks of tofacitinib therapy and 
assuming that most participants will have prior exposure to TNF-antagonists, we estimated 
that a sample size of 60 participants should be sufficient to detect a significant reduction
from baseline in PMS at Week 8.
Data analysis will include both ITT and PP analyses. Detailed methodology for summary and 
statistical analyses of data collected in this study will be documented in a SAP.
For data management, the EDC system SecuTrial will be used. All data entered in the EDC 
system will be transferred to the database using TLS encryption and will be stored on a Linux 
server in a dedicated Oracle database at the Inselspital Bern, Switzerland. The Clinical Trial 
Unit of Inselspital is responsible for study data management activities (implementation and 
maintenance of the study database). Participants’ study-related data will be collected in a 
coded manner. No interim analyses are planned. At final analysis, data files will be extracted 
from the database into statistical packages to be analyzed.
1.2. Schema
Not applicable.
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to STUDY 
ASSESSMENTS AND PROCEDURES (Section 8) of the protocol for detailed information 
on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unscheduled visits) in addition to those listed in the 
SoA table, to conduct evaluations or assessments required to protect the well-being of the 
participant. Such visits should be documented in the study specific form “Unscheduled visit”, 
detailing the reason for the unscheduled visit, clinical and other procedures performed and 
outcomes, where applicable.
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Table 1.
SoA
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 6.
Screeninga
Day -35 to -7
Baselineb
Day 0
Visit 
Week 8
Day 56
Visit 
Week 16
Day 112
Follow-upc
Week 20
Day 140
Early 
Termination/
Discontinuationd
Visit Window
±7 days
±14 days ±14 days
+7 days
Protocol-required assessments
Eligibility criteria assessment
X
Informed consent
X
Patient demographics: month and 
year of birth, gender, BMI, smoking 
status
X
UC disease characteristics
PMS
X
X
X
X
Advanced treatment history
X
Co-morbidities, including EIMs
X
X
X
Study Registration
X
Introduction to Sidekick Health IBD 
App and stool home-collection kit
X
Tofacitinib exposure (dose)
X
X
X
X
Concomitant treatment(s)
X
→
→
→
X
Serious and nonserious AE 
monitoring
X
→
→
→
→
→
SOC assessments
UC disease characteristics
Date of UC diagnosis
X
UC extent (location)e
X
X
X
X
CRP level
X
X
X
X
Mayo Endoscopic subscoref
X
X
X
X
IUSg
X
X
X
X
Abbreviations: →= ongoing/continuous procedure.
a.
Performing screening and baseline visit on the same day is permitted. Participant should however be given sufficient 
and reasonable time to consider participation in the study (ICD can be provided prior to screening visit).
b.
Baseline is defined as day of tofacitinib first dose intake. In case the participant starts tofacitinib later than day of 
baseline visit, PROs and stool collection should begin with tofacitinib first dose intake.
c.
A follow-up contact with participant must be scheduled at the end of the AE/SAE active collection period as defined in 
Section 8.3.1. Safety monitoring will generally continue for an additional 4 weeks (28 days) after Week 16 visit, or 
after the discontinuation/withdrawal date for participants who discontinue the study prematurely. 
d.
Study-specific discontinuation form will be used to collect reason for study or drug discontinuation, clinical and other 
undertaken procedures at discontinuation, as well as outcome, where applicable.
e.
Extent of disease is defined based on endoscopic findings. Endoscopy is not mandatory. Disease extent will only be 
assessed if endoscopy is performed as part of SOC. Endoscopy is expected at either screening/baseline visit and again 
at either Week 8 or Week 16 visits.
f.
Mayo Endoscopic subscore is based on endoscopic findings. Mayo Endoscopic subscore and PMS will be used to 
calculate FMS. FMS will only be calculated if endoscopy is performed as part of SOC and according to physician’s 
assessment. Endoscopy is expected at either screening/baseline visit and again at either Week 8 or Week 16 visits.
g.
Data from IUS will be collected and analyzed in an exploratory fashion, only if available and performed as part of 
SOC.
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Other procedures between study visits:
PROs and fCAL levels will be regularly assessed between scheduled study visits. Table 2
summarizes the frequency of these assessments during the study period. Refer to STUDY 
ASSESSMENTS AND PROCEDURES section (Section 8) of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol.
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Table 2.
Schedule of Procedures Between Study Visits
…
Days from baseline
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
Stool frequency
Rectal bleeding
Urgency of defecation
Abdominal pain
Quality of sleep
Daily fatigue
Weekly fatigue
Disease-specific quality of life
* Stool samples can be collected at +/- 3 days starting from week 2.
week 1
week 2
week 3
week 4
week 5
week 7
week 8
week 16
112
week 6
Stool sample collection* for fCAL analysis
PROs collection
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2. INTRODUCTION
This low-interventional study will evaluate the effectiveness of tofacitinib (Xeljanz®) in 
treating patients with moderately to severely active UC, by collecting prospective
longitudinal data on PMS, PROs and fCAL levels in a real-world setting in Switzerland. 
Tofacitinib is an oral JAKi that is approved for the treatment of moderately to severely active 
UC and will be studied in participants with UC. Tofacitinib will be prescribed according to 
the approved Swiss product label13 and treatment will be guided by clinical judgement of 
study investigators, independently of this study. This protocol does not recommend or 
promote the prescription and use of tofacitinib, and tofacitinib will not be provided as part of 
this study. The clinical decision for the prescription of tofacitinib should be clearly separated 
from the decision to propose enrollment in the study to the patient.
This study is expected to contribute to the growing body of RWE of tofacitinib’s safety and 
efficacy profile in UC. Conventional clinical outcomes will give a better understanding of 
response and remission rates in a representative, post-marketing population. These 
conventional measures will be supplemented by an array of PROs to give a broader 
understanding of how patients experience response to treatment. Regular measurement of 
fCAL levels, a widely used biomarker in UC utilized to guide treatment decisions, which 
shows potential as an early biochemical predictor of treatment response, will provide a 
measure of the response of intestinal inflammation to tofacitinib induction therapy.
2.1. Study Rationale 
A number of studies have now been published demonstrating the RWE of tofacitinib in 
patients with UC, however these studies did not assess PROs beyond the rectal bleeding and 
stool frequency components of the Mayo score.1-8 Moreover, while it is known that 
tofacitinib therapy is associated with a rapid onset of symptom relief in terms of the PMS 
components (stool frequency and rectal bleeding), the response of other important PROs, 
such as fatigue, urgency and abdominal pain, are less well characterized.9,10 Measuring these 
PROs will provide a broader understanding of how patients experience response to tofacitinib 
treatment.
To address this gap and to supplement data from clinical trials, this study aims to generate 
granular RWD on and provide the opportunity to explore the relationships between 
tofacitinib induction therapy and changes in PMS, PROs and intestinal inflammation during 
tofacitinib induction therapy. Furthermore, it will allow us to gain insight into time to 
symptom relief in a real-world setting, which has hitherto not been studied. 
2.2. Background 
Ulcerative colitis is a chronic inflammatory disease that causes inflammation and ulceration
of the colon and rectum and is characterized by a remitting and relapsing clinical course.
Together with CD, it is a major component of the term IBD. Symptoms are often unspecific 
and may vary with disease activity and can include debilitating episodes of rectal bleeding, 
urgency, diarrhea and abdominal pain, potentially causing a life-long burden and reduction of 
quality of life for patients.14-16 Endoscopy is the fundamental diagnostic tool used for initial 
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diagnosis of UC, to distinguish between CD and UC, monitor disease and assess and treat 
complications. Although endoscopy has long been used, technologic advances have allowed 
additional tools to assist in the management of IBD. In Switzerland, IUS is commonly used 
in daily practice and represents a non-invasive, well-tolerated and cost-effective modality to 
assess disease activity and to guide therapy decisions in patients with UC.17
Data from the Swiss IBD cohort study suggests that the overall incidence and prevalence of 
IBD in Switzerland is increasing. IBD has recently been recognized as a global chronic
condition, with a prevalence of approximately 5 million people diagnosed with IBD 
worldwide. The last decade has brought significant progress in our understanding of the 
pathophysiology of IBD, with several effective treatments targeting the autoinflammatory 
pathways that mediate the disease.18
The efficacy and safety of tofacitinib for the treatment of moderately to severely active UC 
has been well characterized in pivotal clinical trials.12 Tofacitinib is taken as a 10 mg twice 
daily dose for an 8-week induction period, after which the dosage is reduced to the 
recommended maintenance dose of 5 mg twice daily, although prolongation of the 10 mg 
twice daily induction dose up to 16 weeks is permitted if clinically indicated.13 If adequate 
therapeutic benefit is not achieved after 16 weeks of 10 mg twice daily dosing, tofacitinib
must be discontinued.
Understanding the effect of therapies on different PROs is increasingly recognized as a 
crucial aspect in the successful management of IBD patients.9,10,19 While the widely used and 
validated Mayo score in UC includes patient-reported stool frequency and rectal bleeding, 
the response of other important PROs, such as fatigue, mood, appetite and pain, are less well
-characterized. Measuring these holistic PROs can provide insight into aspects of the disease 
and the benefits of a given therapy that are not fully captured by the clinical endpoints used 
in research and clinical practice. The importance of capturing PROs is further evidenced by 
the emergence of guidance from regulatory authorities,20-29 which can rapidly be turned into 
insights that enable physicians to optimize disease management and deliver tailored care to 
their patients. In addition, embedding digital patient solutions in clinical care may be 
valuable in IBD management and this study will assess the use of a research version of the 
IBD companion App, developed by Sidekick Health (Sidekick Health IBD App) specifically 
for the study, for the collection of early and holistic PROs. The native (non-research) 
Sidekick Health IBD App is already available to IBD patients in Switzerland through the 
Swiss IBD patient association (Crohn Colitis Schweiz). At their own discretion, study 
participants will have the opportunity to use functionalities of the native Sidekick Health IBD 
App (eg, disease-specific and lifestyle management modules, activity tracking, food diary), 
in addition to completing the research program.
Increased understanding of IBD pathophysiology has led to the development of disease 
biomarkers to gauge response to treatment, of which fCAL is among the most 
well-established.30-32 fCAL is a small anti-microbial protein detected in stool that constitutes 
approximately 60% of neutrophil cytoplasm. As migration of neutrophils into the intestinal 
mucosa is a hallmark of active intestinal inflammation, fCAL serves as a sensitive 
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noninvasive marker to differentiate IBD from IBS, measure response to therapy and to 
monitor and predict disease flares.33-36 In addition, fCAL is extremely resistant to bacterial
degradation, being stable in stool for up to one week at room temperature, which contributes 
to its suitability as a laboratory marker. To date, the gold standard test to assess fCAL levels 
in IBD patients is ELISA. This method has been used for over 20 years, but it requires 
specialized expertise and laboratory equipment, is time-consuming and is costly. The 
BÜHLMANN Quantum Blue® point-of-care device used in this study, offers an alternative 
method to the standard ELISA technique, which is easy to use, affordable and provides 
accurate results within 15 minutes. 
In Switzerland, monitoring fCAL levels has been incorporated into best-practice
recommendations for monitoring IBD disease activity,37,38 and reimbursement of fCAL
analyses by the compulsory Swiss health care insurance is stipulated by the Swiss FOPH.
2.2.1. Clinical Overview
Three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in 
adults with UC were conducted to evaluate the efficacy of tofacitinib as induction (OCTAVE 
Induction 1 and 2) and maintenance therapy (OCTAVE Sustain trial).12 In the OCTAVE 
Induction 1 and 2 trials, participants were randomized to receive therapy with 10 mg twice 
daily tofacitinib therapy or placebo for 8 weeks. The primary end point was remission at 
8 weeks, defined as a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding 
subscore of 0. In the OCTAVE Sustain trial, participants who had a clinical response to 
induction therapy were randomly assigned to receive maintenance therapy with tofacitinib 
(either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was 
remission at 52 weeks.
A post-hoc analysis of data from the 2 phase 3 OCTAVE Induction 1 and 2 clinical trials
demonstrated significant and rapid-onset (within 3 days) of improvement in symptoms, in 
terms of components of the Mayo score (stool frequency, rectal bleeding) among participants
given tofacitinib compared to placebo. Daily Mayo stool frequency and rectal bleeding 
subscores were calculated using diary data from the first 15 days of therapy.39 Little is known 
however about how quickly physicians and patients should expect to see other relevant 
symptoms, such as fatigue and urgency, decrease following commencement of tofacitinib 
therapy. It is specifically unclear whether these PRO responses occur prior to, with or lag 
behind clinical responses.
In both OCTAVE induction trials, the proportion of participants with an IBDQ score 
indicative of remission (a score of ≥170) and the proportion of participants with an IBDQ 
score indicative of a treatment response (a score ≥16 points higher than the baseline score) 
were significantly larger with tofacitinib than with placebo at weeks 4 and 8.
In terms of safety, in the OCTAVE Induction 1 and 2 trials, the rates of overall infection and 
serious infection were higher with tofacitinib than with placebo. 
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Despite fCAL being one of the few reliable and widely employed biomarkers for disease 
activity and treatment response in IBD, the response of fCAL during tofacitinib induction 
therapy for UC is currently not fully understood. In a double-blind, placebo-controlled, phase 
2 trial, correlations between clinical and endoscopic outcomes with fCAL concentrations 
were assessed at Week 8. Only limited data are available, but a moderate correlation of fCAL 
with tofacitinib-induced clinical improvement was observed.11
2.3. Benefit/Risk Assessment
In this study, measures are taken to minimize risks to participants and are justified by the 
anticipated benefits that may be afforded to participants. 
Participants are given the opportunity to report symptoms regularly and are provided
throughout the study with interactive IBD-specific educational and lifestyle modules through 
the Sidekick Health IBD App. Regularly reporting and learning about symptoms can provide 
stimulus for the participant to build necessary confidence to handle symptoms and self-
management of their disease. On the other hand, repeatedly focusing on disease symptoms 
may promote a disease-centered attitude and negatively impact the participant’s perception of 
the efficacy of their treatment.
Short and simple validated questionnaires have been chosen to assess PROs that are regularly 
collected, such as to reduce participant questionnaire burden but still maintain the validity
and utility of the assessments.27
Stool sample collection for fCAL measurements is designed in this study such as to minimize 
burden to participants. The method used for sample collection is noninvasive, rapid, easy to 
use and will be carried out at the participant’s residence. Eleven samples will be collected 
over an 8-week period (56 days), and once again at Week 16. As fCAL is a widely used 
biomarker in gastroenterologists’ clinical practice in Switzerland, UC patients are used to 
performing stool sample collection. Thus, we presume that the stool sample collections will 
not impose excessive burden, nor discomfort, on the study participants.
Lastly, this study is categorized as Category A research project according to the Swiss 
Human Research Ordinance as the planned measures for sampling biological material (stool 
collection) and collection of personal data and PROs through questionnaires entail only 
minimal risks and burdens in terms of intensity and potential risk on participant’s health. 
Treating physicians and site staff will be blinded to their patient’s fCAL measurements and 
PRO responses, thus these additional measurements will not be used to inform treatment 
decisions. Moreover, tofacitinib will be prescribed in accordance with the approved Swiss 
product label for the approved indication and population. 
Full information about the known and expected benefits and risks and reasonably expected 
AEs of tofacitinib (Xeljanz®) may be found in the approved Swiss product label, which is the 
SRSD for this study. The SRSD should be used by the investigator for prescribing purposes 
and guidance.
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3. RESEARCH QUESTIONS, OBJECTIVES AND ENDPOINTS
Table 3.
Study Objectives and Endpoints
Primary Objective:
Primary Endpoint:
Evaluate the RW effectiveness of tofacitinib 
induction therapy in patients with UC.
Proportion of participants achieving clinical 
responsea at W8.
Secondary Objectives:
Secondary Endpoints:
Evaluate RW response to tofacitinib treatment based 
on PMS.

Proportion of participants achieving clinical 
remissionb at W8.

Proportion of participants achieving clinical 
responsea at W16.

Proportion of participants achieving clinical 
remissionb at W16.
Evaluate the RW response to tofacitinib treatment 
on quality of life based on IBDQ score.

Proportion of participants achieving IBDQ 
remissionc at W8. 

Proportion of participants achieving IBDQ 
remissionc at W16.

Proportion of participants achieving IBDQ 
responsed at W8.

Proportion of participants achieving IBDQ 
responsed at W16.
Evaluate RW response to tofacitinib treatment based 
on fCAL concentrations.

Proportion of participants achieving biochemical 
remissione at W8. 

Proportion of participants achieving biochemical
remissione at W16.
Elucidate fCAL and PRO responses to tofacitinib 
induction therapy for UC.
Median changes from baseline in PROs and fCAL 
over time (ie, map response curves).
Assess whether PRO responses occur prior to, with 
or lag behind clinical responses.
Correlations between changes in amplitude and 
timing of PMS, PROs, IBDQ score and fCAL 
concentrations.
Verify the validity of fCAL as a convenient 
surrogate biomarker to assess early response to 
tofacitinib treatment.

Median fCAL concentrations over time stratified 
by W8 and W16 clinical remission status.b

Median fCAL concentrations over time stratified 
by W8 and W16 clinical response status.a

Median fCAL concentrations at W8 by W8 
clinical response status.a
Exploratory Objectives:
Exploratory Endpoints:
Assess effect of prior exposure to biologics, 
concomitant medications and tofacitinib induction 
dose, on treatment outcomes.
Stratification of PMS outcomes, PROs and fCAL 
levels based on: i) prior exposure to TNFi, 
vedolizumab and ustekinumab; ii) concomitant 
medication with corticosteroids or aminosalicylic 
acids; iii) predominant tofacitinib dose.
Assess effect of baseline patient demographics and 
disease characteristics on the likelihood of achieving 
Regression analyses on baseline patient and disease 
characteristics with respect to PMS, fCAL or PROs 
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a.
Clinical response: reduction in PMS from baseline of ≥2 points or achieving clinical remission.12
b.
Clinical remission: PMS of ≤2 with no subscore >1.12
c.
IBDQ remission: IBDQ score ≥170.12
d.
IBDQ response: IBDQ score ≥16 points higher than IBDQ baseline score.
e.
Biochemical remission: fCAL concentration ≤250 mg/g.11 Optimal fCAL cut-off values for the detection of active 
disease vary from 50 μg/g to 250 μg/g [2, 38, 47] depending on the test used, location of the disease and intra-
individual patient variability. In this study, biochemical remission is defined as a fCAL concentration ≤250 μg/g.
f.
FMS response: decrease from baseline total Mayo score of ≥3 points and ≥30%, with an accompanying decrease in the 
rectal bleeding subscore of ≥1 or absolute rectal bleeding subscore ≤1.12
g.
Remission: a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0.12
h.
Mucosal healing: a Mayo endoscopic subscore of ≤1.12
i.
According to treating physician’s assessment of bowel wall thickness, normalization and extension; bowel wall 
vascularity, loss of stratification, loss of colonic haustration, structure formation and hyperechogenic reaction adjacent 
to the bowel wall.
j.
According to treating physician’s observations and assessments.
clinical, fCAL or PROs response.
measures.
Evaluate RW response to tofacitinib treatment based 
on FMS and IUS outcomes.

Proportion of participants achieving FMS 
responsef at W8.

Proportion of participants achieving remissiong at 
W8.

Proportion of participants achieving FMS 
responsef at W16.

Proportion of participants achieving remissiong at 
W16.

Proportion of participants achieving mucosal 
healingh at W8.

Proportion of participants achieving mucosal 
healingh at W16.

Proportion of participants achieving response 
according to IUS assessmenti at W8.

Proportion of participants achieving remission 
according to IUS assessmenti at W8.

Proportion of participants achieving response 
according to IUS assessmenti at W16.

Proportion of participants achieving remission 
according to IUS assessmenti at W16.
Evaluate impact of tofacitinib treatment on activity 
of individual EIMs and categories of EIMs 
(mucocutaneous, musculoskeletal, ocular, 
hepatobiliary).

Proportion of participants with improvement in 
EIMj (individual or categorical) at W8.

Proportion of participants with improvement in 
EIMj (individual or categorical) at W16.
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3.1. Variables
Table 4.
Study Variables
Variable
Role
Data source(s)
Operational definition
Tofacitinib 
Tofacitinib intake
Exposure
Participant medical 
records/ CRF
Documentation by treating physician of 
tofacitinib prescription including doses.
Tofacitinib doses
Exposure, 
Effect-modifier, 
Sub-group 
identifier
PMS
Stool frequency
Baseline 
characteristics &
Outcome
Participant medical 
records/ CRF
Documentation by treating physician of 
PMS score at baseline and at Week 8 and 
16 visits. 
Rectal bleeding
Physician’s global 
assessment
PROs
Stool frequency
Outcome
Answers reported by 
participant and 
captured in Sidekick 
Health IBD App
Participants receive notifications to their 
mobile phone to answer study 
questionnaires at predefined timepoints 
according to protocol schedule.
Rectal bleeding
Urgency of defecation
Abdominal Pain
Quality of sleep
Daily Fatigue
Weekly fatigue
Disease-specific
quality of life
fCAL analysis
fCAL measurements at 
POC 
Outcome
Quantitative result
(in µg/g) given after 
analysis with 
Quantum Blue®
(BÜHLMANN 
Laboratories AG) 
device and cassette.
Participants will collect stool samples at 
home using pre-filled CALEX® Cap 
Extraction Devices (BÜHLMANN 
Laboratories AG) and will send their 
samples to POC for analysis. 
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Variable
Role
Data source(s)
Operational definition
Patient demographics and medical history
Year and month of 
birth
Baseline 
characteristics
Participant medical 
records/ CRF
Documentation by treating physician of 
participant demographics and medical 
history.
Gender
Baseline 
characteristics
BMI
Baseline 
characteristics
Smoking status
Baseline 
characteristics
Co-morbidities, 
including EIMs
Effect modifier, 
Sub-group 
identifier, 
Potential 
confounder
Concomitant 
medication
Effect modifier, 
Sub-group 
identifier, 
Potential 
confounder
Disease characteristics
Advanced therapy 
history
Baseline 
characteristics, 
Effect modifier, 
Sub-group 
identifier 
Participant medical 
records/ CRF
Documentation by treating physician of 
all treatments received since UC 
diagnosis, including dosages, duration 
and reason for discontinuation. 
Safety and Pharmacovigilance
Incidence of (S)AEs 
related to drug or to 
study interventions
Outcome
Study (S)AEs forms
and logs, medical 
records and 
Pharmacovigilance 
database 
Treating physician will report (S)AEs as 
per study and usual pharmacovigilance 
requirements and document events in 
study (S)AEs forms and logs and medical 
records. 
4. STUDY DESIGN
4.1. Overall Design
This study is an open-label, prospective, low-interventional, multi-center study conducted in 
Switzerland in a real-world setting uncontrolled by any comparison groups. Approximately 
60 adults who are prescribed tofacitinib for moderately to severely active UC will be enrolled 
in the study. It is expected that a large proportion of enrolled participants will have prior 
exposure to TNF-antagonists, as tofacitinib is commonly prescribed in this population in 
Switzerland. 
Importantly, no additional endoscopy will be performed and data will only be used from 
endoscopies and intestinal ultrasound assessments performed as SOC and at physician’s 
discretion.
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Although the main focus will be on the first 8 weeks of induction therapy, participants will 
be additionally followed-up at Week 16 to allow inclusion of data from participants with an 
insufficient response at 8 weeks. The active study period starts at participant signature of 
ICD, obtained not later than the first day of tofacitinib treatment initiation and continues for 
the entire 8-week induction period, and additionally at Week 16. Data collected up to 42 days 
prior to first day of tofacitinib initiation (ie, baseline visit) can be used for study purposes and 
analyses. The safety reporting period will extend for an additional 4 weeks (28 days) after the 
Week 16 visit, or after the discontinuation/withdrawal date for participants who discontinue
the study prematurely. Safety reporting is further described in Section 8.3. Participants will 
continue to receive standard medical care from their treating physician beyond Week 16, 
independently of end of study period or study outcomes.
This study has 2 minimal risk and burden protocol-required interventions: home stool 
collection for fCAL concentration measurements and digital collection of PROs through the
research version of the Sidekick Health IBD App installed on study participants’ personal 
mobile phone (refer to Section 6 for further details). 
4.2. Scientific Rationale for Study Design
This study is designed to enable a characterization of the relationship between changes in 
PMS, PROs and intestinal inflammation during tofacitinib induction therapy. To fully 
capture the 16-week induction period and account for delayed responders, PROs will be 
recorded in all participants at Week 16. Due to the likelihood that some participants will stop 
therapy or change doses of tofacitinib during the second 8-week period, data during this 
period will be analyzed in an exploratory fashion. A study-specific research version of the 
Sidekick Health IBD App is designed to conveniently collect PROs at predefined timepoints 
according to the study protocol.
To allow valuable insights into the sensitivity and timing of early fCAL responses with 
respect to disease activity and symptom changes during induction therapy, regular and 
convenient measurements of fCAL concentrations are designed in this study. To evaluate 
fCAL responses as predictors of induction therapy outcome, fCAL concentrations will be
measured more often during the first week of induction therapy (4 times), followed by 
measurements on a weekly basis during the following weeks and up to Week 8. An 
additional measurement is planned at Week 16.
4.2.1. Rationale for Contraception/Pregnancy Testing
To date, no adequate and well-controlled clinical studies have been performed with the use of 
tofacitinib during pregnancy and there are no data on the transplacental passage of 
tofacitinib. However, tofacitinib was shown to be teratogenic in rats and rabbits and caused 
effects on the fertility of female rats, on the parturition and peri- and postnatal development 
of young rats. 
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The current approved Swiss label for Xeljanz®13 (tofacitinib) does not recommend Xeljanz®
be administered during pregnancy unless clearly necessary and recommends the use of an 
effective contraception method for WOCBP while under treatment with Xeljanz® and for at 
least 4 weeks following treatment termination. 
This protocol, however, does not require pregnancy testing prior to inclusion and during the 
study, nor does it require the use of an adequate method of contraception during the study 
period. WOCBP who are not using an adequate method of contraception under routine care, 
or who are not willing to use effective contraception during the study period will not be 
excluded from the study. Investigators are however advised to monitor WOCBP as per their 
standard routine clinical practice.  
4.2.2. Strengths and Limitations of the Research Methods
Potential limitations exist in collecting regular individual PROs as these are highly variable
and subjective. It is believed that participants build a cognitive representation of their 
disease, including beliefs around the cause, symptoms, consequences and duration, which 
subsequently guides their behaviors in terms of disease management. Patient disease 
perceptions may influence their symptoms experiences, with negative beliefs associated with 
worsening symptoms and burden, even in the absence of active disease. To minimize these 
potential confounding factors, PROs collected in this study are based on established and 
validated questionnaires and do not include any free-text questions. Using a digital 
technology to collect PROs may have several advantages such as convenience, real-time
tracking of patient symptoms and quality of collected data. Nevertheless, as this digital App 
may not be compatible with all mobile phones and operating systems, a risk of bias in the 
selection of study participants is introduced. Moreover, UC is common in people aged 60 and 
above, who may be less willing to use innovative technologies on mobile phones, or may 
simply not own a compatible mobile phone, and would thus be excluded from participating 
in the study. However, in today’s digital era and in a Swiss setting, exclusion rate due to the 
use of a digital technology is anticipated to be reasonably low.
This real-world study aims to enhance the external validity (ie, the generalizability) of real-
world data compared to data from randomized clinical trials, which have restrictive inclusion
criteria. The eligibility criteria of this study are designed to reduce bias and to avoid the 
exclusion of selected populations. Furthermore, participating investigators are 
gastroenterologists treating IBD patients in both private and public institutions across 
Switzerland, further increasing generalizability to the Swiss patient population in this study. 
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4.3. Justification for Dose
Doses of tofacitinib treatment should be based on the Swiss label recommendations, as well 
as clinical and individual needs, and are determined by the treating physician. The standard 
tofacitinib induction dosing is 10 mg twice daily for at least 8 weeks, after which the dosage 
is reduced to the recommended maintenance dose of 5 mg twice daily, although prolongation 
of the 10 mg twice daily dose up to 16 weeks is permitted if clinically indicated. If off-label 
doses are used, patient will still be included in the study.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all study 
procedures, including Week 16 study visit, as well as safety monitoring 28 days following 
the Week 16 visit.
The end of the study is defined as the date of last scheduled procedure shown in the SoA for 
the last participant in the study globally.
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.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants 18 years of age or older at screening visit; 
Type of Participant and Disease Characteristics:
2. Participants with confirmed diagnosis of UC and who are prescribed tofacitinib 
(Xeljanz®) for moderately to severely active UC as per the Swiss label13 and as per 
physician’s clinical judgement, independently of this study;
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, study interventions (Section 6), and other study procedures (Section 8);
Informed Consent:
4. Capable of giving personally signed informed consent as described in Appendix 1
10.1.4, 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. Presence of clinical findings suggestive of Crohn’s disease;
Prior/Concomitant Therapy:
2. Any previous exposure to tofacitinib including participation in the tofacitinib clinical 
program;
3. Co-medication with any other advanced therapies for UC (biologics*, azathioprine, 
mercaptopurine and methotrexate) or any other JAK inhibitor.
*TNF, integrin or cytokine antagonists.
Other Exclusions:
4. Any identified contra-indications for use of tofacitinib as per the Swiss label.13
5. Not owning a handheld digital device compatible with the Sidekick Health App, not 
willing to have it installed on this device or not capable of using the App;
6. 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
To account for the observational and real-world clinical setting of this study, study protocol 
does not encourage any changes to the smoking, physical activity and dietary habits of the 
participants. 
For the purposes of this protocol, BMI and smoking status will be assessed at baseline as part 
of patient demographics data and will be subject to sub-group analysis in an exploratory 
fashion.
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5.3.1. Contraception
Based on preclinical data, tofacitinib has a potential risk of teratogenicity and early fetal loss. 
Due to this risk, the current approved Swiss tofacitinib label recommends the use of an 
effective contraception method for WOCBP while under treatment with Xeljanz® and for at 
least 4 weeks following treatment termination. 
This protocol, however, does not require the use of an adequate method of contraception 
during the study period. WOCBP who are not using an adequate method of contraception 
under routine care, or who are not willing to use effective contraception during the study 
period will not be excluded from the study. Investigators are however advised to monitor 
WOCBP as per their standard routine clinical practice.
5.4. Screen Failures
Screen failures are defined as:

Participants who are eligible, consent to participate in the clinical study but are not 
subsequently enrolled in the study (baseline visit is not performed or protocol
-required procedures at baseline are missing). Screen failure data are collected and 
remain as source and are not reported to the clinical study database (ie, CRF).

Individuals for whom eligibility criteria were checked but who do not meet the 
criteria for participation in this study. Non eligible individuals may not be rescreened.
Each study site will keep a Screening log to document study Screen Failures and reason for 
failure. Screen failures will not be enrolled in the study.
6. STUDY INTERVENTIONS
In this study, there are no therapeutic study interventions, however the study does involve 
protocol-required diagnostic and monitoring procedures (interventions) that are considered to 
pose only minimal risk or burden to the study participant, specifically:
1. Home stool collection using CALEX® Cap Collection Sets for subsequent fCAL 
measurements at POC;
2. Collection of PROs using participant’s Sidekick Health IBD App research account on 
their personal mobile phone.
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6.1. Study Intervention(s) 
6.1.1. Diagnostic or Monitoring Study Interventions
Home stool collection using CALEX® Cap Collection Set for fCAL measurements at 
POC
Study participants will be introduced, at baseline visit, to the convenient and hygienic stool
specimen collection system intended for home use. Each study participant will receive at the 
beginning of the study a container containing 15 CALEX® Cap Collection Sets. These Sets
should be stored at room temperature. Each CALEX® Cap Collection Set contains:

1 CALEX® Cap Extraction device pre-filled with extraction buffer (5 mL).

2 stool collection sheets.

1 study paper card: pre-filled with participant’s study ID and an empty field for 
date and time of sample collection to be completed by the participant.

1 illustrated instruction for use leaflet in English, German and French.

1 transparent resealable bag.

1 pre-paid and pre-addressed UN3373 packaging.
Although 12 stool collections are planned according to Table 2, 3 extra CALEX® Cap 
Collection Sets will be provided to participants at the beginning of the study. This is to 
account for any collection procedure failures or other unexpected reasons requiring the use of 
additional sets. 
Between study visits, and according to Table 2 schedule, the participant will use a CALEX®
Cap extraction device to collect at home a standardized amount of stool sample in a buffered 
solution, as illustrated in the instruction for use leaflet. The participant must indicate the date 
and time of sample collection on the provided paper card, place the CALEX® Cap extraction 
device in the provided transparent resealable bag and then place the latter in the pre-paid and 
pre-addressed UN3373 packaging provided. Lastly, the participant will post the packaging by 
normal postal mail on the same day or on the next day at the latest, for fCAL concentration 
measurements at POC.
As fCAL concentrations decrease with increasing time between bowel movements, 
participants will be advised to collect stool samples for fCAL testing from the first bowel 
movement of the day. Because of the day-to-day variability in fCAL levels, participants will 
be advised to collect their stool samples at a similar time throughout the study.
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Collection of PROs using Sidekick Health IBD App on participant’s mobile phone
Upon study inclusion (ie, baseline visit), participants will have to download the Sidekick
Health App to their personal mobile phone. If a participant is already using the Sidekick 
Health App before enrollment to the study, he/she will be able to continue using the 
functionalities of the native App. However, for study purposes, each participant will be given 
a unique study login to initiate their research account for the App and will be introduced to 
the different functionalities of the App. No personal data (eg, name, surname, personal email 
or address) will be captured in the research-version of the App, the participant will be 
identified solely by his/her unique study ID and study email. Site staff will ensure the App is 
working correctly and that the participant is able to use it. Participants who are not willing to 
adhere to PRO questionnaires procedure and schedule, or not willing to download or use the 
study Sidekick Health IBD App, will not be able to participate in the study, as defined by 
study exclusion criteria. 
Between study visits, participants will be prompted to complete the PRO questionnaires 
within the Sidekick Health IBD App on their mobile phone via pop-up notifications at 
predefined timepoints (as described in Table 2) and at the same time every day. Participants 
can choose the language (German/French) in which they wish to receive the questionnaires
and use the App. It is estimated that full completion of all questionnaires will require no 
more than 10 minutes per day. Participants will be prompted to complete the questionnaires 
via pop-up notifications from the App. In the event the participant’s mobile phone is 
switched off, out of battery, or the participant forgets to fill-in the questionnaires, a reminder 
will be sent the following day and if necessary a study nurse will attempt to contact the 
participant by phone, after which the data will be treated as missing. Participants will be 
informed about the importance to respond to questionnaires whenever required. Data
captured in the App will be transferred to the study database on a regular basis.
6.2. Preparation/Handling/Storage/Accountability
The following instructions apply to the CALEX® Cap Collection Sets, referred to as study 
interventions in this section:
1. Study site investigator or designee must confirm that appropriate conditions have 
been maintained during transit from central supply for all study interventions 
received and any discrepancies are reported and resolved before use of the study 
intervention. 
2. All study interventions must be stored in an appropriate and secured environment 
with controlled access to authorized site staff only.
3. Study interventions should be kept in the original packaging as received from central 
supply. Study interventions will be labelled by site staff with participant study ID 
before they are dispensed.
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4. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply study intervention to enrolled participants. Site staff 
will instruct participants on the proper storage requirements for take-home study 
intervention.
5. Site staff must ensure appropriate records are maintained for study intervention
accountability. Accountability records will account for received study interventions 
from central supply and study interventions dispensed to enrolled participants. 
6. At the end of the study period for each participant, all unused study interventions 
must be returned to the investigator by the participant and recorded in the 
accountability records. Returned study intervention must not be re-dispensed to other 
participants. At site closure, all unused study interventions must be returned to central 
supply.
7. Applies to POC only: all received study interventions containing biospecimens must 
be stored appropriately and in a secured and controlled environment. POC staff must 
ensure appropriate records are maintained for study intervention accountability. 
Accountability records will account for received study interventions from study 
participants, analyzed study interventions and destroyed study interventions. All 
destructions must be adequately documented. Destruction is authorized to take place 
at POC and POC staff must ensure that the materials and biological samples are 
destroyed in compliance with the study Biospecimen Management Plan, applicable 
environmental regulations, institutional policy, and any special instructions provided 
by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery. 
6.2.1. Central Supply: Preparation and Dispensing
All study interventions needed for the entire study period will be ordered with BÜHLMANN 
Laboratories AG, Switzerland and sent to central supply. Herein, central supply refers to 
GALSER SA in Switzerland. Reconditioning of the original BÜHLMANN Laboratories AG 
packaging will be performed by qualified staff member of the central supply; containers
containing CALEX® Cap Collection Sets with other necessary materials. Central supply will 
ensure that:

All study interventions are stored in an appropriate and secured environment with 
controlled access to authorized staff only. 

Appropriate records are maintained for study intervention accountability. 
Accountability records will account for received study interventions from
BÜHLMANN Laboratories AG and study interventions dispensed to study sites. 

Study sites are supplied with adequate quantities of study interventions at the 
appropriate time. 
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7. PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY
7.1. Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request. The study 
investigator and/or study sponsor may decide to discontinue a participant from the study. 
Reasons for discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up (Section 7.2);

Death;

Study terminated by sponsor;

Withdrawal of consent (Section 7.1.1);

Any other justified reason.
In this study, drug under study refers to tofacitinib. Participants who stop tofacitinib 
treatment for any reason during the study, will not be discontinued/withdrawn. 
Participant will remain in the study and all protocol-required assessments until Week 16 must 
be completed. Participants who discontinue tofacitinib treatment prior to end of study will be 
included in the ITT analysis. Treatments received following tofacitinib discontinuation will 
be recorded as part of study data. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. Refer to 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 and then are 
prematurely withdrawn from the study. 
Participants who decide to withdraw from the study, should be questioned regarding their 
reason for withdrawal, but do not have to justify their decision.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved. 
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.
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If the participant withdraws from the study and also withdraws consent for disclosure of 
future information (Section 7.1.1), 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.
7.1.1. Withdrawal of Consent 
Participants should notify the investigator in writing of the decision to withdraw consent for
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 was from study 
procedures and/or study follow-up, and this information should be entered on the appropriate 
CRF page.
7.2. 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 study site for a 
protocol-required study visit and/or cannot be contacted for follow-up:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible 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 equivalent method). These contact attempts should be documented in the 
participant’s study record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Participants who discontinue the study prior to the Week 8 visit, for any of the above reasons, 
will be replaced by enrolling new participants. 
8. STUDY ASSESSMENTS AND PROCEDURES
Protocol-required study procedures and their timing are summarized in the SoA. Protocol
waivers or exemptions are not allowed. SOC assessments for which data will be collected if 
available and their timing, are also summarized in the SoA. 
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue from the 
study.
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Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. Every effort should be made to ensure that protocol-required 
tests and procedures (study interventions) are completed as described. However, it is 
anticipated that there may be circumstances outside the control of the investigator that may 
make it infeasible 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 
procedure cannot be performed, the investigator will document the reason for the missed 
procedure and any corrective and preventive actions that he or she has taken to ensure that 
required processes are adhered to as soon as possible. Such incidents will be documented in a 
Study Protocol Deviation Form or in a Note to File. The study team must be informed of 
these incidents in a timely manner. Due to COVID-19 pandemic, adapted measures are 
permitted if they are deemed necessary to ensure the rights, safety and well -being of study 
participants. Such measures should be clearly documented and communicated to study 
sponsor in a timely manner. 
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, or record reasons for screening failure, as 
applicable. The investigator (or an appropriate delegate at the investigator site) must obtain a 
signed and dated ICD before performing any study-specific (protocol-required) procedures.
Procedures conducted as part of the participant’s routine clinical management (eg, laboratory
tests, endoscopy, IUS) and recorded in the medical record prior to the participant signing of 
the ICD may be utilized for screening or baseline purposes provided the procedures were 
performed within the time frame defined in the SoA.
For samples being collected and shipped, detailed collection, processing, storage, shipment
and destruction instructions, as well as contact information are detailed in the Biospecimen 
Management Plan and will be provided to the investigator site prior to initiation of the study.
8.1. Efficacy Assessments
8.1.1. Protocol-required Assessments
8.1.1.1. PMS Assessment
The 12-point Mayo score is an instrument designed to measure UC disease activity based on 
a combination of endoscopic findings and the patient’s clinical characteristics.40 The 
non-invasive PMS excludes the endoscopic component of the full Mayo scoring system and
ranges from 0 to 9 points. The PMS consists of the following 3 subscores, each graded from 
0 to 3, with higher scores indicating more severe disease:

Stool frequency (0-3);

Rectal bleeding (0-3);

Physician global assessment (0-3).
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Stool frequency subscore assessment:

0 = Normal number of stools;

1 = 1–2 stools more than normal;

2 = 3–4 stools more than normal;

3 = 5 or more stools than normal.
Rectal bleeding subscore assessment:

0 = No blood seen;

1 = Blood streaks seen in stool less than half the time;

2 = Blood seen in stool most of the time;

3 = Blood alone passes.
Physician global assessment subscore assessment:

0= Normal;

1= Mild Colitis;

2= Moderate Colitis;

3= Severe Colitis.
Each patient serves as his or her own control to establish the degree of abnormality of the 
stool frequency. The daily rectal bleeding score represents the most severe bleeding of the 
day. The physician global assessment subscore acknowledges the 2 other subscores (stool 
frequency and rectal bleeding), patient’s recollection of abdominal discomfort, general sense 
of wellbeing, and other observations, such as physical findings and patient’s performance 
status. 
It is recommended that the same physician performs all such assessments for a particular 
study participant throughout the study. 
PMS will be assessed at the baseline, Week 8 and Week 16 visits. Failure to assess PMS at 
these study visits will constitute a protocol deviation.
Endpoints based on the Partial Mayo scores are defined as follows:

Clinical remission: total PMS of ≤2 with no subscore exceeding 1 point;12
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
Clinical response: meeting one of the following criteria: (1) reduction in PMS of
≥2 points from baseline or (2) achieving clinical remission as described above.12
The FMS will be calculated if endoscopy is performed as SOC. The Mayo Endoscopic 
subscore assessed as SOC and PMS assessed as protocol-required assessment will be used to 
calculate FMS. Endoscopy is not a protocol-required procedure, nor a mandatory assessment 
for inclusion in the study.
8.1.1.2. PROs Assessment
The Sidekick Health IBD App installed on participants’ personal mobile phones will be used 
to collect PROs during the study. PROs are collected between study visits. Via their personal 
mobile phone, participants will be provided with brief PRO questionnaires that encompass 
important elements of the subjective experience of UC. PROs will be collected daily until 
Week 2 and thereafter twice weekly until Week 8. Participants will receive training from 
qualified staff and important information related to the App and the study questionnaires in 
writing. Responses to questionnaires are time-stamped and will be reviewed for completeness 
by automated predefined processes and rules. Participants will receive notifications to input
PROs at scheduled timepoints, according to study protocol. 
It is important to note that PROs are collected and evaluated in a different manner than the 
observed AEs. Given these differences, no attempt will be made to resolve any apparent 
discrepancies between experienced AEs and PRO data collected from participants. AE 
incidence rates will not be assessed from PRO data but from information recorded on the 
study dedicated AEs forms and related CRF pages. 
Table 5 details the various study PROs and the related instrument for collection:
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Table 5.
PROs and Related Instrument for Collection
PRO
Instrument 
Description
Stool frequency
Participant will answer the question 
“How many times did you need to visit 
the toilet to have a bowel movement
today?” using the stool frequency 
subscore of Mayo scoring system.40,41
Scores range from 0 to 3 and higher scores 
indicate more severe disease activity: 

0 = Normal number of stools;

1 = 1–2 stools more than normal;

2 = 3–4 stools more than normal;

3 = 5 or more stools than normal.
Each participant serves as his or her own 
control to establish the degree of 
abnormality of stool frequency. 
Rectal bleeding
Participant will answer the question 
“How would you describe the blood in 
your stool today?” using the rectal 
bleeding subscore of Mayo scoring 
system.40,41
Scores range from 0 to 3 and higher scores 
indicate more severe disease activity: 

0 = No blood seen;

1 = Streaks of blood with stool less 
than half the time;

2 = Obvious blood with stool most 
of the time;

3 = Blood alone passes.
The daily bleeding score represents the most 
severe bleeding of the day.
Each participant serves as his or her own 
control to establish the degree of rectal 
bleeding.
Urgency of 
defecation
NRS to respond to “How severe was 
your urgency (sudden or immediate 
need) to have a bowel movement in 
the past 24 hours?”, according to 
Dubinsky et al.42
11-point horizontal NRS anchored at 0 (“No 
urgency”) and 10 (“Worst possible 
urgency”).
Participant can input a score from 0 to 10.
Abdominal pain
NRS to answer the question “How 
much abdominal pain have you felt 
today?” according to Spiegel et al.43
10-point horizontal NRS anchored at 
1 (“None”) and 10 (“Very severe”).
Participant can input a score from 1 to 10.
Quality of sleep
NRS to answer the question “How did 
you sleep last night?”, based on Rubin 
et al.’s Sleep VAS.27
11-point horizontal NRS anchored at 0 
(“Very bad”) and 10 (“Great”).
Participant can input a score from 0 to 10.
Daily fatigue
NRS to respond to “Please rate your 
fatigue (weariness, tiredness) by 
selecting the number that describes 
your worst level of fatigue during the 
past 24 hours” according to Gladman 
et al.44
11-point horizontal NRS anchored at 0 (“no
fatigue”) and 10 (“as bad as you can 
imagine”).
Participant can input a score from 0 to 10.
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PRO
Instrument 
Description
Weekly fatigue
FACIT-F for weekly measurements of 
fatigue.45
FACIT-F: 13-point questionnaire; responses 
to each question are recorded on a 5-point 
Likert scale. Scores range from 0 to 52, with 
higher scores representing greater fatigue. 
Participant responses are based on 
symptoms felt during the last 7 days.
Disease-specific 
quality of life
IBDQ46
32-item questionnaire grouped into 
4 dimensions: bowel function, emotional 
status, systemic symptoms and social 
function. The 4 domains are scored as 
follows: 

Bowel symptoms: 10 to 70;

Systemic symptoms: 5 to 35;

Emotional function: 12 to 84;

Social function: 5 to 35.
The total IBDQ score ranges from 32 to 
224. For the total score and each domain, a 
higher score indicates better quality of life. 
Questionnaire is designed to collect data 
from the previous 2 weeks. 
Endpoints based on collected PROs are defined as follows:

IBDQ remission: total IBDQ score of ≥170;

IBDQ response: increase in IBDQ score from baseline of ≥16 points;

MCID in the FACIT-F score: minimum individual change in the FACIT-F score from 
baseline of 3.45
8.1.1.3. fCAL Concentrations Assessment
All fCAL measurements will be performed in batches at 1 central study site (central POC) by 
an appropriately trained study nurse. CALEX® Cap devices containing biospecimens will be 
stored at 2-8°C until they are analyzed, after which they will be destroyed according to local 
practices and as described in the Biospecimen Management Plan. Both investigators and 
participants will be blinded to the results of fCAL measurements throughout the study. 
Investigators may perform independent fCAL assessments, in addition to those mandated by 
the protocol, if such assessments are deemed appropriate and necessary for the participant’s 
disease management. Results from these independent fCAL measurements will not be 
recorded in the CRF nor reimbursed.
fCAL measurements will be performed using the BÜHLMANN Laboratories AG Quantum 
Blue® device and the Quantum Blue fCAL extended test cassette (LF-CALE25), which is a 
lateral flow test developed using the same monoclonal antibodies as the gold-standard 
ELISA. Once the CALEX® Cap Extraction devices arrive at POC, they are ready to be 
analyzed, and no further manipulation is required. The range of the test is 30 to 1000 µg/g. 
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To obtain fCAL measurements, 60 ul of the solution in the CALEX® Cap device is loaded 
onto a test cassette. During the mandatory 12 min incubation time, fCAL present in the 
sample binds to gold-coated monoclonal antibodies present on the test membrane. The 
solution proceeds along the membrane over 12 minutes to a test line, where antibodies 
specific to the anti-fCAL complexes are bound, darkening the test line. A second line with 
anti-fCAL antibodies serves as a reference control that the Quantum Blue® reader compares 
based on image analysis. A lot-specific standard curve on the device is used to calculate the 
result in micrograms of fCAL per gram of stool sample (µg/g) and the quantitative result is
displayed on the device screen. Measurements obtained on Quantum Blue® device will be 
entered manually to the corresponding eCRF page by central POC study nurse or an 
authorized study member, independent of patient care.
Optimal fCAL cut-off values for the detection of active disease vary from 50 μg/g to 
250 μg/g 2,38,47 depending on the test used, location of the disease and intra-individual patient 
variability. In this study, biochemical remission is defined as a fCAL concentration 
≤250 μg/g.11
In addition to the protocol-required procedures described above, the following data will be 
collected and is required for compliance with study protocol:

Patient demographics including month and year of birth, gender and BMI upon 
inclusion in the study (at baseline).

Baseline smoking status defined as: current smoker, former smoker or never smoked.

UC disease characteristics; advanced treatment history including reason for treatment 
change or discontinuation. Advanced treatment history is collected at baseline, per 
SoA.

Tofacitinib exposure dose throughout the study duration.

All concomitant medications, especially corticosteroids and 5-ASA.

All co-morbidities, including EIMs.

All serious and non-serious adverse events (refer to Section 8.3).
8.1.1.4. Other Assessments
Additional data will be collected to address further exploratory objectives:

Discontinuation incidence: study-specific discontinuation form will be used to 
collect reason for study or drug discontinuation, clinical and other undertaken 
procedures at discontinuation, as well as outcome, where applicable.
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
Unscheduled visits: in the event where the participant requires an on-site visit in 
addition to the scheduled visits listed in the SoA table, these visits will be 
documented in study-specific unscheduled visits forms. The unscheduled visits form 
will be used to collect reason of additional visits, clinical and other procedures
undertaken during such visits, as well as outcome, where applicable.
8.1.2. SOC Assessments
This study protocol intends to collect the assessments described below in an observational 
manner only. If any of the following assessment is missing, it will not constitute a protocol 
deviation.
Patient medical records will be referred to for SOC assessment reports or results. The 
participant is aware that his/her medical records will be consulted as part of this study. The 
treating physician or study site staff will grant access to these records, securely kept, and 
managed locally on site as per standard procedures. 
The following data will be collected, if available, and reported into the corresponding pages
of the CRF:

UC disease characteristics: date of diagnosis and extent. Extent will be assessed if 
colonoscopy is performed and defined as either ulcerative proctitis, proctosigmoiditis, 
left-sided colitis or pancolitis;

CRP level: concentration in mg/L and date of test.
Mayo Endoscopic subscore. Mayo Endoscopic subscore and PMS assessed as protocol-
required assessment will be used to calculate FMS. FMS will only be calculated if 
endoscopy is performed as part of SOC and according to physician’s assessment. Mayo 
Endoscopic subscore calculation:
0= Normal or inactive disease.
1= Mild disease (erythema, decrease of vascular pattern, slight friability).
2= Moderate disease (marked erythema, absent vascular pattern, friability, 
erosions)
3=Severe disease (spontaneous bleeding, ulceration)

IUS:48
o
Measurement (in mm) of colonic wall thickness at all colon parts (ascending, 
transverse, descending and sigmoid) and of rectal wall thickness; 
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
Evaluation of the extension of wall-thickening according to physician’s 
observations;

Evaluation of normalization of wall-thickening according to physician’s 
observations;
o
Evaluation (yes, no) for: loss of stratification, loss of colonic haustration, structure 
formation and hyperechogenic reaction adjacent to the bowel wall;
o
Evaluation of bowel wall vascularity according to Limberg score:53
0= no bowel wall thickening, no vascularization
1= bowel wall thickening without vascularization
2 (hypo-flow)= bowel wall thickening with short stretches of vascularity as 
spots
3 (hyper-flow)= bowel wall thickening with longer stretches of vascularity
4 (hyper-flow)= bowel wall thickening with longer stretches of vascularity 
reaching the mesentery
Endoscopy or IUS images will not be retrieved as part of study records. Only evaluations and 
physician’s reported observations will be recorded as study records.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements or other safety assessments may be obtained at any time during the 
study to assess any perceived safety issues.
Safety data are collected for the purpose of meeting routine pharmacovigilance reporting 
requirements. Safety data will not be analyzed, but simply reported on a case-by-case basis.
8.2.1. Protocol-Required Clinical Safety Laboratory Assessments
Protocol-required clinical safety laboratory assessments will not be performed in this study.
8.2.2. Pregnancy Testing
To date, no adequate and well-controlled clinical studies have been performed with the use of 
tofacitinib during pregnancy and there are no data on the transplacental passage of 
tofacitinib. However, tofacitinib was shown to be teratogenic in rats and rabbits and caused 
effects on the fertility of female rats, on the parturition and peri- and postnatal development 
of young rats. 
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The local approved label for Xeljanz® does not recommend Xeljanz® be administered during 
pregnancy unless clearly necessary. However, this study does not require pregnancy testing 
prior to inclusion.13
8.3. Adverse Events and Serious Adverse Events
In a LIS2 “product under study” refers to the drug, therapeutic medical device or the vaccine 
product (or any active comparator or placebo) that is under study in the LIS2. Herein, 
“product under study” refers to tofacitinib (Xeljanz®).
The definitions of an AE, SAE and RRI can be found in Appendix 2 (10.2). The investigator 
is required to assess whether any AE may be related to participation in the study. All AEs 
(ie, serious and non-serious, including those attributed to a protocol-required procedure 
identified as RRI) are collected in the clinical study database. Should a participant, in the 
investigator’s opinion, suffer a medically important RRI caused by their participation in the 
study, the designated Pfizer clinician or medical monitor must be notified immediately by 
telephone or email.
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 
HCPs (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (Section 7.1).
During the active safety collection period (Section 8.3.1), each participant will be questioned 
about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
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8.3.1. Time Period and Frequency for Collecting AE and SAE Information (“Active 
Collection Period”)
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 protocol-required procedure), through and including a minimum of 28 calendar days,
after the Week 16 visit, or after the discontinuation/withdrawal date.
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 and Pfizer concurs with that assessment.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues the product under study
because of an AE or SAE, prior to all scheduled doses having been administered, then 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 solicit 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 product under study, 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 2 (10.2). 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 SAEs and non-serious AEs occurring during the active collection period (Section 8.3.1)
must be recorded in the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs.
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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 2 (10.2).
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until the event has resolved, stabilizes or is otherwise explained, 
or the participant has been lost to follow-up (as defined in Section 7.2).
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 2 (10.2).
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of the 
product 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 the product 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. Exposure During Pregnancy or Breastfeeding, and Environmental Exposure
The requirements for reporting pregnancy or breastfeeding and environmental/occupational 
exposure apply throughout the entire active collection period and are outlined below; when 
such reports are required per protocol, the report must be transmitted to Pfizer Safety within 
24 hours of investigator awareness.
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8.3.5.1. Exposure During Pregnancy EDP
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing the
product under study.

A male participant who is receiving or has discontinued the product under study 
exposes a female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to the 
product under study due to environmental exposure. Below are examples of 
environmental exposure during pregnancy:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the product under study by ingestion.

A male family member or healthcare provider who has been exposed to the 
product under study 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 for the clinically-relevant time period.

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 
preprocedural test findings are conclusive for a congenital anomaly and the findings are 
reported).
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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), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator considers that the infant death may be related to exposure 
to the product under study. 
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 the product under study.

A female is found to be breastfeeding while being exposed or having been exposed to 
the product under study (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 product under study 
by inhalation or skin contact.
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a product 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.
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8.3.5.3. Environmental Exposure
An environmental exposure, including an occupational exposure, occurs when a person not 
enrolled in the study as a participant receives unplanned direct contact with, or exposure to, 
the product under study. 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. 
The investigator must report any instance of environmental exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form. This form must be 
used to report the exposure even if no SAE is associated with the exposure.
Since the information about the exposure does not pertain to a participant enrolled in the 
study, the information is not recorded on the CRF; however, a copy of the completed CT 
SAE Report Form must be maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is the failure of expected pharmacologic action or therapeutic benefit of the
product under study.
Lack of efficacy is collected in the CRF but is reportable to Pfizer Safety only if associated 
with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the product under 
study by the wrong participant, or at the wrong time, or at the wrong dosage strength.
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Table 6.
Reporting of 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 product under study;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Other examples include, but are not limited to:

The administration of expired drug;

The administration of an incorrect drug;

The administration of an incorrect dosage;

The administration of the product under study that has undergone temperature 
excursion from the specified storage range, unless it is determined by the sponsor that 
the product in question is acceptable for use.
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.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
Sponsor does not recommend specific treatment for an overdose; a specific antidote does not 
exist. A symptomatic treatment is recommended according to the Swiss approved label. 
Refer to Section 8.3.10 Medication Errors for reporting requirements for an overdose.
8.5. Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
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8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Not applicable.
8.8. Biomarkers
The following samples for biomarker research are protocol-required and will be collected 
from all participants during the study as specified in the SoA:

Participant stool sample collection for fCAL concentration measurements.
Stool samples for fCAL concentration measurements will be collected to evaluate response to 
tofacitinib induction therapy and to verify the validity of fCAL concentrations as a 
convenient surrogate biomarker to assess early response to tofacitinib therapy (secondary 
endpoints). Stool samples will be collected with BÜHLMANN’s stool extraction device, the
CALEX® Cap Collection Set. Samples will be analyzed centrally at the POC using 
BÜHLMANN’s 3rd generation Quantum Blue® Reader, a monoclonal antibodies lateral flow
test. Samples will be destroyed immediately after analysis according to local practices and 
the Biospecimen Management Plan. No further sample storage or use is planned. 
8.9. Immunogenicity Assessments
Immunogenicity assessments will not be performed in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
9.1. Statistical Hypotheses
The study hypotheses that will be subject to statistical testing are that:

Tofacitinib induction therapy is associated with a rapid improvement in the PMS, 
intestinal inflammation (ie, reduced fCAL concentrations), QoL and symptoms
(PROs).

Changes in different types of treatment outcomes (ie, PMS, PROs and fCAL 
concentrations) are correlated. 

Improvements in PROs and fCAL concentrations can predict treatment outcomes 
(clinical outcome measures) at end of induction therapy. 
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9.2. Sample Size Determination
Based on PMS data from the OCTAVE Induction and RW studies, feedback from Swiss 
gastroenterologists on drop-out rates during the first 8 weeks of tofacitinib therapy and 
assuming that most participants will have prior exposure to TNF-antagonists, we estimated 
that a sample size of 60 participants should be sufficient to detect a significant reduction 
from baseline in PMS at Week 8.
Thus, a total of approximately 60 study participants will be enrolled into the study. A 
participant is considered enrolled if protocol-required procedures at baseline visit are 
performed. An enrolled participant who discontinues the study before Week 8 study 
(ie, Week 8 visit is not performed), will be replaced by enrolling a new participant. The main 
aim of the study is to describe the frequency of participants achieving a clinical response 
after 8 weeks of treatment with a given precision. There will be no formal hypothesis testing; 
frequencies will be estimated with 95% Wilson confidence intervals. 
We expect that 60% of participants will achieve a clinical response at Week 8 (ie, effect size 
based on data from a RW study with a comparable study population).7 A sample of 
60 participants will result in a 2-sided 95% Wilson confidence interval55 around a frequency 
of 60% from 47.4 to 71.4%.
In the OCTAVE Induction studies, the mean change in PMS from baseline at Week 8 was 
approximately -3.1 and the standard deviation in PMS at baseline was approximately 1.3.12
Thus, if we assume a standard deviation in PMS of 1.3 at baseline and at Week 8, the 
worst-case scenario would be that the standard deviation for mean change in PMS between 
baseline and Week 8 amounts to 2.6. Thus, a sample size of 60 participants and a standard 
deviation in change in PMS from baseline of 2.6, would yield a 95% confidence interval with 
a width of ±0.66 points (ie, power >95% to detect a -3.1 change from baseline), able to detect
a difference as low as -1.2, with 90% power.
9.3. Data Management
The Data Management system used in this study is a dedicated EDC system, SecuTrial. The 
EDC system is activated for the study only once a formal test procedure has been passed 
successfully. All data entered in the EDC system are stored on a Linux server in a dedicated 
Oracle database at Inselspital Bern, Switzerland. The Clinical Trial Unit of Inselspital is 
responsible for study data management activities (implementation and maintenance of the 
study database).
Study-related data of the participant will be collected in a coded manner. The names of the 
participants will not be disclosed. A code (unique, consecutive numbered per site) will be 
attributed to each participant registered in the eCRF. A codebook will be created describing 
the datasets and all variables to be collected and the associated coding.
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The server hosting the EDC system and the database is kept in a locked server-room. Only 
the system administrators have direct access to the server. A role concept with personal 
passwords (site investigator, statistician, monitor, administrator etc.) regulates permission of 
each user for system and database use.
All data entered into the eCRFs are transferred to the database using TLS encryption. Each 
data point has attributes attached to it identifying the user who entered it with the exact time 
and date. Retrospective alterations of data in the database are recorded in an audit table. A 
multi-level back-up system is implemented. 
At final analysis, data files will be extracted from the database into statistical packages to be 
analyzed. After database lock, the status of the database is recorded in special archive tables.
9.4. Case Report Forms/Data Collection Tools/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer collectively to both
pCRF and eCRF.
A CRF is required and should be completed for each included participant. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and paper form and will be 
password protected and secured in a locked room to prevent access by unauthorized third 
parties.
The investigator has the ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the pCRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. eCRFs have an audit trail functionality to track all modifications. 
In this study, some source documents are the hospital or the physician's chart. Data collected
on the CRFs must match those charts. Study source documents are further described in
Appendix 1 (10.1.8). 
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9.5. Data Analysis
9.5.1. Datasets to be Analyzed, Analysis Population
Study protocol adherence will be assessed based on adherence to fCAL measurements and 
PROs questionnaires completion. Adherence to tofacitinib will not be assessed.
a.
ITT analysis will include participants who were included in the study 
(ie, performed baseline visit and received a study identification number). This 
analysis will therefore include all study participants, regardless of their adherence 
to study protocol procedures.
b. PP analysis will include all study participants who, at the end of the study, met the 
following criteria:
o
fCAL measurements: At least 6 stool samples out of 12 are collected and 
provided (ie, 50% of fCAL measurements), including a baseline stool sample 
(ie, baseline fCAL concentration is available)
o
For each PRO, the participant has completed at least 50% of the scheduled 
questionnaires, as well as the baseline questionnaire. A PRO questionnaire is 
deemed completed if all items of the questionnaire have been answered.
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a SAP, which will be dated, filed and maintained by the sponsor. The SAP 
may modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment.
9.5.2. Primary Analysis
Proportions of participants achieving clinical, IBDQ and biochemical response* and 
remission† at Week 8 and Week 16 will be calculated and reported with the associated 
95% Wilson confidence interval.
The course of continuous secondary outcomes (PROs and fCAL) over time will be depicted 
by box plots showing medians, quartiles, and outlying values.
                                                
* Clinical response: (1) Reduction in PMS from baseline of >2 points or (2) achieving clinical remission.12
IBDQ response: IBDQ score ≥16 points higher than IBDQ baseline score.
† Clinical remission: PMS of ≤2 with no subscore >1.12
   IBDQ remission: IBDQ score ≥170.12
Biochemical remission: fCAL concentration ≤250 mg/g.11
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T ofaciti ni b
Pr ot o c ol A 3 9 2 1 3 9 5
Fi nal Pr ot oc ol A me n d me nt 2 , 2 2 M arc h 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 4 5 -G S O P -R F 1 5 B 1. 0 L o w -I nter ve nti o nal St u d y 2 ( LI S 2) Pr ot oc ol Te m plate 0 1 -Dec -2 0 2 0
Pa ge 5 4 of 8 7
C orrelati o n bet wee n P M S, P R Os, I B D Q sc ore a n d f C A L c o nce ntrati o ns will be assesse d b y 
t he S pear ma n c orrelati o n c oefficie nt.
T he c o urse of f C A L o ver ti me will be s h o w n se parately f or partici pa nts wit h a n d wit h o ut 
cli nical res p o nse, as well as f or partici pa nts wit h a n d wit h o ut re missi o n at W ee k 8 a n d 
W ee k 1 6.
T hese a nal y ses will als o be c o n d ucte d o n t he s u bset of partici pa nts t hat c o m plete 8 wee ks of 
t ofaciti ni b t hera py .
9. 5. 3. Sec o n d ar y A n al ysis
T he f oll o wi n g bas eli ne c haracteristi cs were i de ntifie d t o p ote ntiall y m o dif y t he treat me nt 
effect: 
1.
P ri or e xp os ure t o T N Fi, ve d oliz u ma b a n d uste ki n u ma b;
2.
C o nc o mita nt me dicati o n wit h c ortic oster oi ds a n d/ or a mi n osalic y lic aci ds; 
3.
P re d o mi na nt t ofaciti ni b d ose.
T hese c haracteri stics will be use d for stratifie d a nal y ses. 
T he effect of parti ci pa nts’ baseli ne c haracter istics o n c ha n ge i n P M S, P R Os a n d f C A L val ues 
will be i n vesti gate d usi n g ge neralize d mi xe d m o dels f o r re peate d meas ure me nts. 
M ore o ver, pr o p orti o ns o f: 
-
P artici pa nts ac hie vi n g F M S res p o nse ‡ at W 8;
-
P artici pa nts ac hie vi n g re missi o n § at W 8;
-
P artici pa nts ac hi e vi n g F M S res p o nse at W 1 6 ;
-
P artici pa nts ac hie vi n g re missi o n at W 1 6 ;
-
P artici pa nts ac hie vi n g m uc osal h eali n g * * at W 8;
-
P artici pa nts ac hie vi n g m uc osal heali n g at W 1 6;
-
P artici pa nts ac hie vi n g res p o nse acc or di n g t o I U S assess me nt† † at W 8;
-
P artici pa nts ac hie vi n g re m issi o n acc or di n g t o I U S assess me nt at W 8;
-
P artici pa nts ac hie vi n g res p o nse acc or di n g t o I U S assess me n t at W 1 6;
                                                
‡ F M S res p o nse: Decrease fr o m baseli ne t otal Ma y o sc ore of ≥3 p oi nts a n d ≥3 0 %, wit h a n acc o m pa n yi n g decrease i n t he 
rectal blee di n g s u bsc ore of ≥1 or a bs ol ute rectal blee d i n g s ubsc ore of ≤1 .1 2
§ Re miss i o n: a t otal Ma y o sc ore of ≤2, wit h n o s u bsc ore > 1 a n d a rectal blee di n g s u bsc ore of 0 .1 2
* * M uc osal heali n g: a Ma y o e n d osc o pic s u bsc ore of ≤1 .1 2
† † Acc or di n g t o treati n g p h ysicia n’s assess me nt of b o wel wall t hic k ness, n or mal izati o n a n d e xte nsi o n; b o wel wall 
vasc ularit y, l oss of stratificati o n, l oss of c ol o nic ha ustrati o n, str uct ure f or mati o n a n d h y perec h o ge nic rea cti o n a djace nt t o t he 
b o wel wal l.
0 9 0 1 7 7 e 1 9 9 b 0 a 8 7 a\ A p pr o v e d\ A p pr o v e d O n: 2 3- M ar- 2 0 2 2 1 0: 0 7 ( G M T)

T ofaciti ni b
Pr ot o c ol A 3 9 2 1 3 9 5
Fi nal Pr ot oc ol A me n d me nt 2 , 2 2 M arc h 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 4 5 -G S O P -R F 1 5 B 1. 0 L o w -I nter ve nti o nal St u d y 2 ( LI S 2) Pr ot oc ol Te m plate 0 1 -Dec -2 0 2 0
Pa ge 5 5 of 8 7
-
P artici pa nts ac hie vi n g re missi o n ac c or di n g t o I U S assess me nt at W 1 6;
-
P artici pa nts wit h i m pr o ve me nt i n EIM (i n di vi d ual o r cate g orical)‡ ‡ at W 8;
-
P artici pa nts wit h i m pr o ve me nt i n EIM (i n di vi d ual or cate g orical) at W 1 6 .
will be re p orte d wit h t he ass oc iate d 9 5 % Wils o n c o nfi de nce i nter val.5 5
9. 6. I nteri m A n al yses
N ot a p plica ble.
9. 7. D at a M o nit or i n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee
T his st u d y  will n ot use a Data M o nit ori n g C o m mittee .
                                                
‡ ‡ Acc or di n g t o treati n g p h ysicia n’s o bser vati o ns a n d assess me nts.
0 9 0 1 7 7 e 1 9 9 b 0 a 8 7 a\ A p pr o v e d\ A p pr o v e d O n: 2 3- M ar- 2 0 2 2 1 0: 0 7 ( G M T)

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the Sponsor/CRO and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The Sponsor/CRO 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;
The investigator will be responsible for providing oversight of the conduct of the study at the 
site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/EC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations.
Further country specific requirements are described in Appendix 4 10.4.
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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 product under 
study, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Responsible Parties
Sponsor Team 

, MD, PhD,
, UK.

, PhD,
, Switzerland.

, PhD,
, Switzerland.

, PhD,
Pfizer Clinician and medical monitor

, MD
Principal Investigator 

Christoph Matter, MD Senior Gastroenterologist and internist, Intesto, 
Gastroenterologische Praxis Crohn-Colitis Zentrum, Bremgartenstrasse 119, 3012 
Bern.
Study Statistician

, PhD, Pfizer Inc., 
.
Data Management and Statistical analysis

Clinical Trial Unit Bern, Mittelstrasse 43, 3012 Bern.
Monitoring institution

GALSER SA, Swiss CRO, Rue des Beaux-Arts 8, 2000 Neuchâtel.
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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10.1.3. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.
10.1.4. Informed Consent Process
The investigator or his/her representative will explain the nature of the study 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, HIPAA 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 participant’s medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) if the ICD is 
revised during their participation in the study.
A copy of the ICD(s) must be provided to the participant.
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Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples. The investigator or 
authorized designee will explain to each participant the objectives of the additional research.  
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period.
10.1.5. 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 paper 
form and will be password protected and 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. Authorized study staff will be listed and documented 
in a Study Delegation Log, under the investigator’s responsibility.
To protect the rights and freedoms of participants with regards to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. 
Only authorized staff will have access to the code list. 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.
10.1.6. 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 available data from these trials 
24 months after study completion. Patient‑level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
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10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed and/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.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
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 (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, remote, or on- site monitoring), are provided in the central 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing SDV 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, and all applicable regulatory requirements.
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.
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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, the participant’s current medical record must be available.
Definition of what constitutes source data can be found in the Central Clinical Monitoring 
Plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.9. Study and Site Start and Closure
The study site start date is the date on which the clinical study will be open for recruitment of 
participants at the study site, following the SIV.
The first act of recruitment is the date of the first study participant’s first visit and will be the 
study start date.
The sponsor or 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 if requested to do so by the responsible IRB/EC or if such termination is required 
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;
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
Inadequate recruitment of participants by the investigator;

Discontinuation of further development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
The investigator agrees that the results of the study will be published exclusively under the 
coordination of the sponsor and will include the results of all participating centers. 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 investigator agrees that the first 
publication is to be a joint Publication covering all Study sites, and that any subsequent 
publications will reference that primary Publication.
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.
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10.2. Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
In a LIS2 “product under study” refers to the drug, therapeutic medical device or the vaccine 
product (or any active comparator or placebo) that is under study in the LIS2. Herein, 
“product under study” refers to tofacitinib (Xeljanz®).
10.2.1. 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 the product under study, whether or not 
considered related to the product under study.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of the product under study.
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:
o
Is associated with accompanying symptoms.
o
Requires additional diagnostic testing or medical/surgical intervention.
o
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.
o
Exacerbation of a chronic or intermittent preexisting condition including 
either an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after administration of the product under study 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
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
Signs, symptoms, or the clinical sequelae of a suspected overdose of either the
product under study or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.2.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
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.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization.
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-
pathogenic, is considered serious. The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are considered 
synonymous. These cases are considered unexpected and handled as serious 
expedited cases by pharmacovigilance personnel. Such cases are also considered for 
reporting as product defects, if appropriate.
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g. Research Related Injury
Should a participant, in the investigator’s opinion, suffer a medically important 
research related injury caused by their participation in the study, the designated Pfizer 
clinician or medical monitor must be notified immediately by telephone or email.
A medically important research related injury is any untoward medical occurrence 
that:

Results in death;

Is life threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption 
of the ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an injury is an 
important medical event An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization. However, if it is determined 
that the event may jeopardize the participant or may require intervention to prevent 
one of the other outcomes listed in the definition above, the important medical event 
should be reported as a research related injury.
An investigator may be requested by the designated Pfizer clinician or medical 
monitor to obtain specific additional follow-up information in an expedited fashion. 
In general, this will include a description of the injury in sufficient detail to allow for 
a complete medical assessment of the case and independent determination of possible 
causality. Information on other possible causes of the event, such as concomitant 
treatments, vaccines, and/or 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 or its designated representative.
10.2.3. Definition of Medication Error
A medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the healthcare professional, patient, or consumer. Such events may be 
related to: 
•
Professional practice, 
•
Procedures, 
•
Systems, including:
o
Prescribing;
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o
Order communication;
o
Product labeling, packaging, and nomenclature;
o
Dispensing;
o
Distribution;
o
Administration;
o
Education;
o
Monitoring;
o
Use.
Medication errors also include near-misses involving or not involving a patient directly or 
confusion regarding invented names (eg, trade name, brand name).
10.2.4. Definition of Overdose 
An overdose is an administration of a quantity of a medicinal product given per 
administration or cumulatively that is above the maximum recommended dose according to 
the authorized product information.
10.2.5. 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 adverse events on the CRF and 
for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety throughout 
the active collection period(s). These requirements are delineated for 3 types of events: 
(1) SAEs; (2) non-serious adverse events (AEs); and (3) exposure to the product under study 
or any Pfizer product used under routine care during pregnancy or breastfeeding, or an 
environmental/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.
Table 7.
Reporting of Safety Events
Safety Event
Record on CRF
Report on the CT SAE Report 
Form to Pfizer Safety within 
24 hours of awareness
SAEs
All SAEs occurring during 
the active collection period(s).
All SAEs occurring during the active 
collection period(s). 
Any SAEs (including death) that 
occur after the active collection 
period(s) and the investigator 
suspects may be related to the 
product under study.
Important note: for an SAE where it 
cannot be excluded that the event is 
attributable to the sampling of 
biological material or the collection 
of health-related personal data, the 
event must only be reported on the 
Swissethics Serious Event Report 
form to the CRO immediately upon 
awareness. Refer to Appendix 4
(10.4) for more information.
Non-serious AEs
All non-serious AEs 
occurring during the active 
collection period(s)
None.
Scenarios involving EDP and EDB.
Any AE or SAE associated 
with EDP or EDB.
Note: Instances of EDP or 
EDB not associated with an 
AE/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 
by 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/SAE) must be 
reported.***
* EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer Safety using 
the 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.
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** 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/SAEs associated with occupational exposure are reported 
to Pfizer Safety using the CT SAE Report form.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report Form 
/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are
requested by Pfizer Safety. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will assess intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
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.
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Assessment of Causality

The investigator is obligated to assess the relationship between the product under 
study and each occurrence of each AE/SAE.

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.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to administration of the 
product under study, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is very 
important that the investigator always assess causality for every event before the 
initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the product under study caused the 
event, then the event will be handled as “related to product under study” 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. 
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This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Pfizer Safety with a copy of any postmortem 
findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.2.6. Reporting of SAEs
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.
The country specific requirements for the recording and reporting of SAE occurring during 
the active collection period(s) are outlined in Appendix 4 (10.4).
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10.3. Appendix 3: Liver Safety: Suggested Actions and Follow up Assessments -
Potential Cases of Drug Induced Liver Injury
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with
clinical signs/symptoms, such LFT results should be managed and followed as described 
below.
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
o
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).
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o
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized
initial abnormalities to determine etiology. A detailed history, including relevant information, 
such as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or overthecounter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum samples for acetaminophen/paracetamol drug and/or protein adduct levels may be 
warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 
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10.4. Appendix 4: Country Specific Requirements
10.4.1. Switzerland 
Local regulations/Declaration of Helsinki
This study will be conducted in accordance with the protocol, the Declaration of Helsinki,§§
the principles of Good Clinical Practice, the HRA*** and the HRO,††† as well as other local 
relevant regulations. The Project Leader acknowledges his responsibilities as both the Project 
Leader and the Sponsor.
Research legislation:
Ordinance on human research with the exception of Clinical 
trials (HRO).
Type of Research Project:
Research project involving human subjects 
Risk Categorization:
Risk category A acc. to ordinance HRO Art.7
Project Leader/Sponsor:
Pfizer AG, Schärenmoosstrasse 99, 8052 Zürich, Switzerland
GCP Training
Before enrolling any participants, the investigator and any sub-investigators will complete a 
Good Clinical Practice training course recognized by Swissethics (“GCP Training”) or
training deemed equivalent by Pfizer. Any investigators who later join the study will do the 
same before performing study related duties. For studies of applicable duration, the 
investigator and sub-investigators will complete GCP Training or equivalent every 3 years 
during the term of the study, or more often if there are significant changes to the ICH GCP 
guidelines or course materials. 
Study Intervention 
No participants or third-party payers will be charged for study intervention. Study 
intervention does not refer to product under study (Xeljanz®), which will be charged to 
participant’s health insurance as per routine practice.
                                                
§§ Declaration of Helsinki.
(https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-
subjects).
*** Human Research Act (HRA).
http://www.admin.ch/opc/en/classified-compilation/20121176/201401010000/810.305.pdf.
††† Ordinance on Human Research with the Exception of Clinical trials (HRO) https://www.admin.ch/opc/en/classified-
compilation/20121177/index.html.
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Liability Coverage
This study is exempt from liability coverage requirements according to Art. 12 HRO.
Obligations of safety communication to Ethics Committee

Notification of safety and protective measures (HRO Art. 20).
The investigator notifies the CRO and the Sponsor, within 24 hours, in case immediate safety 
and protective measures have to be taken during the conduct of the study. The Ethics 
Committee will be notified via BASEC of these measures and of the circumstances 
necessitating them within 7 days.

Serious events (HRO Art. 21)
If a serious event‡‡‡ occurs, the investigator should notify the CRO and the Sponsor within 
24 hours of awareness. The CRO will notify the Ethics Committee via BASEC within 7 days. 
In addition, the investigator shall assess the connection between the event and the collection 
of health-related personal data or the sampling of the biological material. At the same time, 
proposals concerning the corrective and preventive measures to be taken should be 
submitted. The Ethics Committee shall reach a decision on the continuation of the study 
within 30 days after receipt of the report. 
Serious events will be recorded using the Swissethics Serious Event Report form for HRO 
research projects and submitted to the Ethics Committee.
Compensation to study participants
Participants will not be compensated for their participation in the study. However, if the 
study participant is asked to come to the study site for any procedures related only to the 
study and which are not part of regular medical care, he/she will be reimbursed for expenses 
that result from the travel to the site (for example, transportation fees or parking), 
 
.
                                                
‡‡‡ A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the sampling 
of biological material or the collection of health-related personal data, and which:
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay;
b. results in permanent or significant incapacity or disability; or
c. is life-threatening or results in death.
A SE may also be a RRI as defined in APPENDIX 2 10.2.2 and should be reported to the Pfizer clinician immediately.
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Substantial and non-substantial amendments 
Substantial amendments to the study set-up, the protocol and relevant study documents will 
be submitted to the Ethics Committee for approval according to HRO Art. 18 before
implementation. Exceptions are measures that have to be taken immediately in order to 
protect the participants. Substantial amendments are changes that affect the safety, health, 
rights and obligations of study participants, changes in the protocol that affect study 
objective(s), changes of study site(s) or of study leader and sponsor.
End of study
Upon project completion or discontinuation, the Ethics Committee is notified within 
90 calendar days. All biological materials and health-related data are anonymized upon 
termination of data analysis.
Funding, publication policy and declaration of interest
The study is initiated and funded by Pfizer AG. 
A description of the study will be available on www.kofam.ch (n°SNCTP xxx) as required 
by Swiss law. 
Participating investigators declare no conflict of interest. 
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10.5. Appendix 5: Protocol Specific Appendices
Sidekick Health IBD App
At the end of the study (ie, after completing Week 16), study participants will be asked to 
complete the user version of the Mobile Application Rating Scale (uMARS)54 to rate the
Sidekick Health IBD App used in this study. A shortened version of the uMARS including 
only sections A-E will be used. Thus, the questionnaire will include 23 questions separated 
into 5 sections including App engagement, functionality, aesthetics, information and 
participants’ subjective App quality assessment. Completion of this questionnaire will not be 
mandatory as per study protocol, ie, study participants can choose to not respond to this 
questionnaire. Missing data will therefore not be considered protocol deviation. 
All study related data collected on the App will be stored on the App provider’s cloud-based 
platform in Belgium during the entire study duration and will be imported to the study 
database in Switzerland on a regular basis. Study related will be transferred to the Sponsor in a 
coded form and data are entirely owned by the Sponsor of the study. At the end of the study, 
the data will be deleted from the Sidekick Health database and this data destruction will be 
documented in a relevant certificate of destruction. Data collected on the App and transferred 
to the study database, will be archived together with other study data according to applicable 
regulations. 
Participants who choose to use the functionalities from the native (non-research) version of 
the Sidekick Health IBD App (eg, IBD-specific modules, activity logging, food diary), which 
are freely accessible to study participants via their App research account, and thereby choose 
to provide personal information, such as information about their diet, physical activity, vital 
signs, etc., will be informed that all these non-research data will be collected and stored by 
Sidekick Health. Importantly, these non-research data collected via native App functionalities 
will not be linked to the research data or to individual study participants. Sidekick Health 
might, at the end of the study, use the data collected via native App functionalities to assess 
the usability of these App features by the study participants during the study duration. All 
data collected and assessed will be anonymized and expressed in an aggregated form.
The Full Terms and Conditions and Privacy Policy of Sidekick Health are available under the 
following links: https://legal.sidekickhealth.com/2/en/terms.html and 
https://legal.sidekickhealth.com/2/en/privacy.html, respectively.
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10.6. Appendix 6: Abbreviations
The following is a list of abbreviations used in the protocol:
Table 8.
Abbreviations
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
App
mobile application
AST
aspartate aminotransferase
BASEC
Business Administration System for Ethical 
Committees
BMI
body mass index
CD
Crohn’s Disease
CIOMS
Council for International Organizations of Medical 
Sciences
CK
creatine kinase
CRF
case report form
CRO
contract research organization
CRP
C-reactive Protein
CSR
Clinical Study Report
CT
clinical trial
DILI
drug-induced liver injury
eCRF
electronic case report form
EDB
exposure during breastfeeding
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Abbreviation
Definition
EDC
electronic data capture
EDP
exposure during pregnancy 
EIM
extra-intestinal manifestation
EMA
European Medicines Agency
EU
European Union
EudraCT
European Union Drug Regulating Authorities
Clinical Trials Database
FACIT-F
Functional Assessment of Chronic Illness Therapy -
Fatigue
fCAL
fecal calprotectin
FMS
Full Mayo score
FOPH
Federal Office of Public Health
GCP
Good Clinical Practice 
GGT
gamma glutamyl transferase
HCP
healthcare provider
HIPAA
Health Insurance Portability and Accountability Act
HRA
Human Research Act
HRO
Human Research Ordinance
HRQL
health-related quality of life
IBD
inflammatory bowel disease
IBDQ
inflammatory bowel disease questionnaire
IBS
irritable bowel syndrome
ICD
informed consent document
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Abbreviation
Definition
ICH
International Council for Harmonisation
ID
identification 
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IUS
intestinal ultrasound
JAKi
Janus Kinase inhibitor
LFT
liver function test
LIS2
low-Interventional Study 2
MCID
minimal clinically important difference
MSR
Medical & Scientific Relations manager
NA
not applicable
NRS
numerical rating scale
pCRF
paper case report form
PMS
Partial Mayo score
POC
point of care
PP
per-protocol
PRO
patient reported outcome
PT
prothrombin time
QoL
quality of life
RRI
research related injury
RW
real world
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Abbreviation
Definition
RWD
real world data
RWE
real world evidence
SAE
serious adverse event
SAP
Statistical Analysis Plan
SDV
source data verification
SIV
site initiation visit
SNCTP
Swiss National Clinical Trials Portal
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBili
total bilirubin
TLS
Transport Layer Security
TNF
tumor necrosis factor
TNFi
tumor necrosis factor inhibitor
UC
ulcerative colitis
ULN
upper limit of normal
VAS
visual analogue scale
W# (where # is a number)
Week # of study
WOCBP
woman of childbearing potential 
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