Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Primary Sjogren's Syndrome; a Phase Ib-IIa Placebo-controlled Clinical Trial and Associated Mechanistic Studies
Phase: PHASE1
Conditions: Sjogren's Syndrome
Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)

1 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
NIH IRB #: 20D0131 
Version Date: 07/01/2024 
Title: Safety of Tofacitinib, an oral Janus Kinase Inhibitor, in primary Sjögren's syndrome Phase 
Ib-IIa placebo-controlled clinical trial and associated mechanistic studies 
NIH Principal Investigator: Blake M. Warner, D.D.S, Ph.D., M.P.H., ABOMP 
 
DIR/OSD NIDCR 
Building 10, Rm 1N110 9000 Rockville Pike 
Bethesda, MD 20892 
Phone: 301-496-4486 
E-mail: blake.warner@nih.gov  
 
Investigational Agents: 
Drug Name: 
Tofacitinib 
IND Number: 
Exempt 
Sponsor: 
NIDCR 
Manufacturer: 
Pfizer 
 
 
 

2 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
TABLE OF CONTENTS  
TABLE OF CONTENTS ................................................................................................................ 2 
STATEMENT OF COMPLIANCE ................................................................................................ 7 
1 
PROTOCOL SUMMARY ...................................................................................................... 8 
1.1.1 
SYNOPSIS ................................................................................................................ 8 
1.2 
Schema ........................................................................................................................... 10 
1.3 
Schedule of Activities (SOA) ......................................................................................... 11 
2 
INTRODUCTION ................................................................................................................ 13 
2.1 
Study Rationale .............................................................................................................. 13 
2.2 
Background .................................................................................................................... 13 
2.2.1 
Sjögren’s Syndrome; description and epidemiology .............................................. 14 
2.2.2 
Current Treatment Paradigms in SS ....................................................................... 14 
2.3 
Risk/Benefit Assessment ................................................................................................ 17 
2.3.1 
Known Potential Risks ............................................................................................ 17 
2.4 
Risk/Benefit Assessment ................................................................................................ 23 
2.4.1 
Risks/discomforts associated with Tofacitinib ....................................................... 23 
2.4.2 
Risks associated with study procedures .................................................................. 27 
2.4.3 
Known potential benefits ........................................................................................ 28 
2.4.4 
Alternatives to participation or other therapies ....................................................... 29 
2.4.5 
Assessment of known potential risks and benefits ................................................. 29 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................... 29 
4 
STUDY DESIGN.................................................................................................................. 33 
4.1 
Overall Design................................................................................................................ 33 
4.2 
Scientific Rationale for Study Design ............................................................................ 33 
4.3 
Justification for Dose ..................................................................................................... 33 
5 
STUDY POPULATION ....................................................................................................... 34 
5.1 
Inclusion Criteria ............................................................................................................ 34 
5.2 
Exclusion Criteria ........................................................................................................... 35 
5.3 
Inclusion of Vulnerable Participants .............................................................................. 36 
5.3.1 
Participation of NIH Staff or family members of study team members ................. 37 
5.4 
Screen Failures ............................................................................................................... 37 
5.5 
Strategies for Recruitment and Retention ...................................................................... 37 

3 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
5.5.1 
Recruitment of women, children, and minorities: .................................................. 38 
5.5.2 
Costs ........................................................................................................................ 38 
5.5.3 
Compensation ......................................................................................................... 38 
6 
STUDY INTERVENTION ................................................................................................... 39 
6.1 
Study Interventions(s) Administration ........................................................................... 39 
6.1.1 
Dosing and Administration ..................................................................................... 39 
6.1.2 
Participant Dosing Considerations .......................................................................... 39 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 40 
6.2.1 
Acquisition and Accountability .............................................................................. 40 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 40 
6.2.3 
Product Storage and Stability.................................................................................. 40 
6.2.4 
Preparation .............................................................................................................. 40 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................... 40 
6.4 
Study Intervention Compliance ...................................................................................... 41 
6.5 
Missing study medication............................................................................................... 41 
6.6 
Concomitant Therapy ..................................................................................................... 41 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 43 
7.1 
Discontinuation of Study Intervention ........................................................................... 43 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 43 
7.3 
Lost to Follow-up ........................................................................................................... 44 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 45 
8.1.1 
STUDY PHASES ................................................................................................... 45 
8.2 
Efficacy Assessments ..................................................................................................... 46 
8.2.1 
Clinical Evaluations ................................................................................................ 46 
8.2.2 
Follow-up/Termination Procedures: ....................................................................... 54 
8.2.3 
Duration of Study Participation .............................................................................. 54 
8.2.4 
Vital Signs Measurement ........................................................................................ 54 
8.2.5 
Adverse event assessment ....................................................................................... 54 
8.2.6 
Assessment of Sjögren's disease activity ................................................................ 54 
8.2.7 
Assessment of Changes in Exocrine Function ........................................................ 55 
8.2.8 
Assessment of changes in oral microbiota .............................................................. 55 

4 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
8.2.9 
Salivary Gland Ultrasound ...................................................................................... 55 
8.2.10 Participant questionnaires ....................................................................................... 55 
8.2.11 Clinical Laboratory Assessments ............................................................................ 55 
8.3 
LABORATORY RESEARCH STUDIES ..................................................................... 56 
8.3.1 
Mechanistic studies ................................................................................................. 56 
8.4 
Biospecimen Evaluations ............................................................................................... 57 
8.4.1 
Correlative Studies for Research/Pharmacokinetic Studies: N/A ........................... 57 
8.4.2 
Samples for Genetic Analysis ................................................................................. 57 
8.5 
Safety and Other Assessments ....................................................................................... 59 
8.6 
Adverse Events and Serious Adverse Events ................................................................. 59 
8.6.1 
Definition of Adverse Event ................................................................................... 59 
8.6.2 
Definition of Serious Adverse Events (SAEs) ........................................................ 59 
8.6.3 
Medical Events Not Qualifying as Adverse Events or Serious Adverse Events: ... 60 
8.6.4 
Clinical Laboratory Test Results Not Qualifying as Adverse Events or Serious 
Adverse Events: .................................................................................................................... 60 
8.7 
Classification of an Adverse Event ................................................................................ 61 
8.7.1 
Severity of Event..................................................................................................... 61 
8.7.2 
Relationship to Study Intervention ......................................................................... 61 
8.7.3 
Expectedness ........................................................................................................... 62 
8.7.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 62 
8.8 
Adverse Event Reporting ............................................................................................... 63 
8.8.1 
Serious Adverse Event Reporting ........................................................................... 63 
8.8.2 
Events of Special Interest........................................................................................ 63 
8.8.3 
Reporting of Pregnancy .......................................................................................... 64 
8.8.4 
Unanticipated Problems (UP) ................................................................................. 64 
8.8.5 
Unanticipated Problem Reporting........................................................................... 65 
9 
STATISTICAL CONSIDERATIONS.................................................................................. 65 
9.1 
Statistical Hypothesis ..................................................................................................... 65 
9.1.1 
SAMPLE SIZE DETERMINATION ..................................................................... 65 
9.2 
Populations for Analyses ................................................................................................ 66 
9.2.1 
Safety Population .................................................................................................... 66 
9.2.2 
Intent to Treat Population ....................................................................................... 66 

5 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
9.2.3 
Toxicity Evaluation ................................................................................................. 66 
9.3 
Statistical Analyses ........................................................................................................ 66 
9.3.1 
General Approach ................................................................................................... 66 
9.3.2 
Analysis of the Primary Endpoints ......................................................................... 66 
9.3.3 
Analysis of the Secondary Endpoint(s)................................................................... 66 
9.3.4 
Safety Analyses ....................................................................................................... 67 
9.3.5 
Baseline Descriptive Statistics ................................................................................ 67 
9.3.6 
Exploratory Analyses .............................................................................................. 67 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 67 
10.1 
Informed Consent Process .......................................................................................... 67 
10.1.1 Consent/Assent Procedures and Documentation .................................................... 67 
10.1.2 Telephone, Remote, and Electronic Consent .......................................................... 68 
10.1.3 Consent of Subjects who are, or become, decisionally impaired ........................... 69 
10.2 
Study Discontinuation and Closure ............................................................................ 69 
10.3 
Confidentiality and Privacy ........................................................................................ 69 
10.4 
Telehealth and Telemedicine ...................................................................................... 70 
10.5 
Outpatient/Outside Clinical Laboratory Testing ........................................................ 70 
10.6 
Future use of Stored Specimens and Data .................................................................. 70 
10.7 
Safety Oversight ......................................................................................................... 71 
10.8 
Clinical Monitoring .................................................................................................... 72 
10.9 
Quality Assurance and Quality Control ...................................................................... 72 
10.10 
Data Handling and Record Keeping ........................................................................... 72 
10.10.1 Data Collection and Management Responsibilities ................................................ 72 
10.10.2 Study Records Retention......................................................................................... 74 
10.11 
Protocol Deviations and Non-Compliance ................................................................. 74 
10.11.1 NIH Definition of Protocol Deviation .................................................................... 74 
10.12 
Publication and Data Sharing Policy .......................................................................... 74 
10.12.1 Human Data Sharing Plan ....................................................................................... 74 
10.12.2 Genomic Data Sharing Plan .................................................................................... 74 
10.13 
Collaborative Agreements .......................................................................................... 75 
10.13.1 Agreement Type...................................................................................................... 75 
10.14 
Conflict of Interest Policy........................................................................................... 75 

6 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
11 ABBREVIATIONS .............................................................................................................. 76 
12 REFERENCES ..................................................................................................................... 77 
13 ATTACHMENTS ................................................................................................................. 81 
 
 
 

7 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

8 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
1 
PROTOCOL SUMMARY 
1.1.1 SYNOPSIS 
Title: 
Safety of Tofacitinib, an oral Janus kinase (JAK) inhibitor, in 
primary Sjögren's syndrome (SS); a Phase Ib-IIa placebo controlled 
clinical trial and associated mechanistic studies 
Study Description: 
As a primary objective, this study represents an innovative 
investigative measure of the safety and tolerability of JAK inhibition 
in participants with primary Sjögren's syndrome. Secondary 
objectives will include investigating the effects of Tofacitinib on 
target tissues (e.g., salivary glands), systemic inflammation, and on 
vascular function in SS participants. We also aim to identify 
biomarkers of response that may be useful as endpoints in future 
studies.  
Objectives: 
 
Primary Objective:   
• 
To determine the safety and tolerability of Tofacitinib in 
participants with SS and mild to moderate disease activity. 
 
Secondary Objectives:    
• 
To assess clinical improvement after treatment with 
Tofacitinib as measured by changes in the European League 
Against Rheumatism (EULAR) Sjögren's syndrome Disease 
Activity Index (ESSDAI) and no worsening on the 
Physician’s Global assessment Scale (PGA). 
• 
To demonstrate that treatment with Tofacitinib is effective 
clinically and biologically in SS individuals with mild to 
moderate disease. 
• 
To investigate the effects of Tofacitinib on systemic 
biomarkers of SS as measures biological effects that can be 
used as outcome measures to power a larger Clinical Trial.  
Endpoints: 
Primary Endpoint:  
• 
Safety and tolerability will be measured by assessment of 
adverse events (AEs) and clinical safety laboratory tests 
throughout the study. Toxicity is defined as any study drug- 
related Grade 3 adverse event or higher (as measured by the 
National Cancer Institute (NCI), Common Terminology 
Criteria for Adverse Events (CTCAE), Version 5.0). 
Secondary Endpoints:  
         Preliminary assessments of clinical response will be measured 
by: 
• 
Changes in the ESSDAI score between Baseline and Day 168 
(end of treatment)  

9 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• 
Changes in the Physician's Global Assessment (PGA) scores 
between baseline and study day 168. 
Study Population: 
Adult patients with Primary Sjögren's syndrome of mild to moderate 
disease activity 
Phase: 
Ib-IIa randomized, double blind, placebo controlled clinical trial 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
 
 
Single-site study to be conducted at NIH Clinical Research Center 
(CRC) 
Description of Study 
Intervention: 
Administration of oral Tofacitinib, 5 mg twice daily, for the 
treatment of SS participants with mild to moderate disease activity. 
 
Study Duration: 
Start Date: 09/20/2020 
End Date: 09/20/2024 (Four (4) years) 
 
Participant 
Duration: 
A maximum of 241+/-45 Days 
 
 
 
 
 

10 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
1.2 SCHEMA 
 

11 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
 
1.3 SCHEDULE OF ACTIVITIES (SOA) 
Procedures 
SCR – 
Visit 1 
-45 days to 
Day 1* 
Baseli
ne 
Visit 2 
D 
1 
D7 
t/call 
(+/- 3 
days) 
Visit 3 
D  
14 
D21 
t/call 
(+/- 3 
days) 
Visit 4 
D  
28 
D42 
t/call(+
/- 3 
days)    
Visit 5 
D  
56 
D70 
t/call(+
/- 3 
days)   
Visit 6 
D  
84 
Visit 7 
D  
112 
Visi
t 
8D 
140 
D154 
t/call  
(+/- 3 
days) 
End 
of Tx. 
Visit 
9 
D 168 
 
End 
of 
Study 
Visit 
10 
D 196 
 
UNSCH 
visit: 
AE or 
other 
reason 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and 
exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurements 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Dental History and Oral and 
Head and Neck Exam 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Saliva Collection 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Salivary Flow Rate  
 
x 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Oral Microbiome/ 
Plaque Collection 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Salivary Gland Ultrasound 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Comprehensive 
Ophthalmic 
Examination, 
Schirmer’s test 
X 
(with fundoscopy 
and MMP-9) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
(with MMP-
9) 
 
X 
 
EKG 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Concomitant medications 
review. 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Minor Salivary Gland Biopsy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Presenting Symptoms-
Abbreviated Medical History 
and physical examination 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Complete blood 
count with 
differential 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Blood/serum chemistries: 
(creatinine, glucose, urea 
nitrogen, total bilirubin, 
alanine aminotransferase, 
aspartate aminotransferase, 
alkaline phosphatase, 
albumin) 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Pregnancy test (serum or 
urine; for females with 
reproductive potential 
only) 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis and Random 
urine 
Protein/Creatinine 
ratio 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
BK virus quantitative PCR- 
urine and blood 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Lipid Panel low density 
lipoprotein (LDL), high 
density lipoprotein 
(HDL), triglycerides (TG) 
and total cholesterol(TC) 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Lipoprotein 
Profile 
(Apolipoprotei
n A-1 
Apolipoprotei
n 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Lymphocyte pheno-TBNK 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Inflammatory 
Markers (hs-
CRP, ESR) 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 

12 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Procedures 
SCR 
Visit 1 
-45 days to Day 
1 
Baseline 
Visit 2 
D 1 
D7 
t/call 
(+/- 3 
days) 
Visit 3 
D 14 
   D21 
t/call  
(+/- 3 
days) 
Visit 4 
D 28 
D42 
t/call 
(+/-  
days) 
Visit 5 
 D 56 
D70 
t/call 
(+/- 3 
days) 
Visit 6 
D 84 
Visit 7 
 
D112 
Visit 8  
D 140 
D154 
t/call 
(+/- 3 
days) 
End of 
Tx. 
Visit 9 
 
D168 
 
End 
of 
Study 
Visit 
10 
 
D196 
 
 
UNSCH 
visit: AE 
or other 
reason 
Serologies: antinuclear 
antibodies, anti-ENA 
panel (anti-RNP, anti- 
SmRNP, anti-SSA, anti-
SSB ) anti- dsDNA 
antibodies, anticardiolipin 
antibodies, lupus 
anticoagulant, anti-beta2-
glycoprotein antibodies, 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
C3 complement, C4 
complement 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Quantitative 
immunoglobulin IgA, 
IgG and IgM  
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Varicella IgG-(antibody) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening serologies for 
hepatitis B, hepatitis C and 
HIV 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Tuberculosis 
using the Quantiferon 
Gold test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-SARS-CoV-2 
antibodies 
 
  X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Research labs 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Cryoglobulins 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum protein electrophoresis 
(SPEP) 
    X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Randomization 
 
 
  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
D1- D168, Dose BID. 1st dose 
at NIH on D1 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Drug Accountability 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Adverse event review 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Assessment of biologic 
effect(s) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Assessment of durability 
of the clinical and 
biologic effects. 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Mechanistic studies: 
(intracellular signaling 
molecules, cytokine 
expression, circulating 
immune cell types and 
autoreactive B cells.) All 
samples can be run 
simultaneously for each 
assay at the end of the study 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Patient 
questionnaires 1. 
SF-36 
2. FSS 
3. PROMIS 
4. Dry Mouth Questionnaire 
5. Xerostomia VAS 
6. OHIP-14 
7. AECG  
symptom 
Questionnai
re 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 

13 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
8. ESSPRI 
Assessment of SS disease 
activity 
1. ESSDAI 
2. Physician Global 
Assessment (PGA) 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Vascular Function Studies 
(SphygmoCOR, CAV1 and 
Endopat) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
All study efficacy dates are ±7 days 
* Screening labs may be used if completed on prior protocols within 30 days of Screening Day.  
 
2 
INTRODUCTION 
2.1 STUDY RATIONALE 
The proposed research is a Phase Ib-IIa clinical trial, whose primary focus is to test the safety of 
Tofacitinib, a JAK inhibitor, in mild to moderate SS. A secondary goal is to perform exploratory 
mechanistic studies as a prologue to future studies in SS and to identify candidate surrogate 
markers that might relate to or predict clinical efficacy of JAK inhibition within this population. 
This clinical trial seeks to address an unmet clinical need: SS is a chronic systemic autoimmune 
disease of unknown etiology, with no cure, and current therapeutic strategies are limited in their 
efficacy.  
2.2 BACKGROUND  
Primary Sjögren’s syndrome (SS) is an autoimmune disease with heterogeneous clinical 
presentation resulting from involvement of multiple biologic pathways. The pathways that lead 
to loss of tolerance in SS include: multiple autoreactive cell types (B, T, dendritic, Th17 and 
regulatory T cells), abnormal cytokine milieus, genetic factors, and environmental and hormonal 
influences, all of which can influence cell differentiation patterns and reset tolerance checkpoints 
(Glauzy et al., 2017). 
Tofacitinib is an orally administered JAK inhibitor that has been approved by the Food and Drug 
Administration for the treatment of moderate to severe rheumatoid arthritis (RA), psoriatic 
arthritis (PsA), and moderate to severe ulcerative colitis (UC). 
The JAKs are a family of intracellular enzymes (JAK1, 2 and 3 and TYK2) that mediate 
signaling through a broad range of cytokine receptors via the signal transducer and activator of 
transcription proteins (STATs) 1,2. Targeting JAKs is an attractive therapeutic possibility for SS 
for many reasons. Many of the inflammatory cytokines implicated in the pathogenesis of SS 
signal via the JAK-STAT pathways. JAK inhibitors have been found to have efficacy in various 
murine models of SS. A mouse model of SS treated with a JAK inhibitor exhibited improvement 
in salivary flow rates and suppression of lymphocyte infiltration in salivary glands. 

14 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
2.2.1 Sjögren’s Syndrome; description and epidemiology 
Sjögren’s syndrome is a systemic autoimmune disease with heterogeneous clinical presentation. 
The disease primarily affects females and is manifested by chronic inflammatory lymphocytic 
infiltration of the exocrine glands leading to their dysfunction and ultimate destruction of the 
tissue. This autoimmune exocrinopathy may occur alone (primary Sjögren’s syndrome) or may 
coexist with other systemic connective tissue disorders (secondary Sjögren’s syndrome). 
Salivary and lacrimal glands are predominantly affected leading to xerostomia (dry mouth) and 
xerophthalmia (dry eyes) although other exocrine gland tissues may be affected including: the 
skin (cutaneous xerosis); the upper respiratory tract causing epistaxis, hoarseness and bronchial 
hyper-responsiveness; and the vagina (vaginal xerosis) that increases the rate of vaginal 
infections and dyspareunia. 
Participants may experience painful recurrent parotid swelling, profound fatigue, widespread 
musculoskeletal pain, and polyarthritis. Patients with SS experience 5-fold higher rates of 
lymphoma than the general population and an 8-fold increased lymphoma- associated risk of 
mortality. 
The prevalence of SS is estimated at 0.5 – 4%, making it one of the most prevalent autoimmune 
diseases1. SS occurs throughout the world and susceptibility is clearly modulated by ethnicity 
and gender1. Although it affects both males and females of all age groups, it most commonly 
affects middle-aged women, typically in the fourth to sixth decades of life, with a striking female 
predilection of approximately 9:1. 
While a precise etiology of SS remains unknown, the pathogenesis is thought to be multifactorial 
including an environmental trigger (i.e., viral) in a genetically predisposed individual. The 
subsequent immune response, involving innate and adaptive immunity, leading to the 
development of autoimmunity and chronic inflammation, are central components of the disease 
process2. Even though concordance in monozygotic twins has not been established, familial and 
monozygotic twins with SS have been reported. For the vast majority of individuals with SS the 
genetic contribution appears to be polygenetic3. Despite rigorous genome wide association 
studies, only a handful of candidate risk loci have been detected and all have been in non-coding 
regions of the genome3. Additionally, non-genetic contributors to disease factors (i.e., hormonal 
and environmental factors) also seem to be important in the pathogenesis of disease. Therefore, 
complex gene-environment interactions driving this disease have not yet been deciphered. 
2.2.2 Current Treatment Paradigms in SS 
The current management of individuals with SS is usually stratified by the degree of internal 
organ involvement; however, most treatment strategies include a variety of immunosuppressive 
medications that are limited in their efficacy and local and systemic approaches to mitigate 
symptoms (e.g., treatment of dry eyes and dry mouth)4. 
Treatment of dry mouth 
The treatment of oral dryness is largely symptomatic4. Artificial saliva preparations (e.g. Saliva 
replacement) are available; the mainstay of replacement therapy consists of frequent sips of 
water or other sugar-free fluids, which are poorly effective. Various fluoride applications 
including prescription-strength toothpaste, fluoride gels and oral rinses are used to prevent dental 
decay. Oral candidiasis, a common consequence of salivary dysfunction and dry mouth related 

15 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
dysbiosis is treated with topical or systemic anti-fungal medications such as nystatin rinse or 
systemic fluconazole. 
If dry mouth is not adequately controlled with replacement methods, pharmacological therapy 
with sialagogue drugs is an option 5. Two drugs are approved for this indication: pilocarpine (5 
mg three times a day) and cevimeline (30-60 mg three times a day). Both act on muscarinic 
receptors and increase exocrine gland secretion. 
However, acceptance and efficacy of muscarinic agonists is only moderate due to unacceptability 
of side effects, including sweating, vision changes, nausea, and flushing. 
Treatment of dry eyes 
Many tear substitutes are available and are commonly used by affected individuals to alleviate 
ocular dryness. Preservative free preparations are preferred especially if used more than four 
times a day. Cyclosporine ophthalmic solution (0.05%, 1 drop every 12 hours) has been 
approved for the treatment of keratoconjunctivitis sicca. 
A frequently used surgical option is the occlusion of the puncta to block tear drainage and 
consequently increase moisture. Pilocarpine and cevimeline can be effective for dry eyes, too, 
especially in individuals with the most severe dryness5. 
Treatment of extra-glandular manifestations 
The treatment of musculoskeletal manifestations of SS is similar to those of other systemic 
rheumatologic diseases6. Antimalarial drugs, such as hydroxychloroquine, are effective for 
arthralgia/arthritis, myalgia and fatigue7. Visceral and neurologic manifestations are treated with 
corticosteroids and immunosuppressive drugs. 
Several randomized case-control studies focused on therapy for SS using biologic agents, such as 
the tumor necrosis factor (TNF) blocking agents, infliximab8 and etanercept9, but none of the 
studies exhibited clinical benefit. 
Treatment of lymphoma in Sjögren’s syndrome is the same as in the general population6. Most 
Sjögren’s syndrome-associated lymphomas are low-grade B cell lymphomas localized in the 
exocrine glands. For these, watchful waiting may be the most appropriate treatment option. 
Higher grade lymphomas require more aggressive treatment with cytotoxic regimen and/or 
radiation therapy. 
Disease pathogenesis; cytokines in Sjögren's syndrome. 
The pathogenesis of SS appears to involve the complex interaction of genetic, environmental, 
and hormonal factors. Activation of several biological pathways belonging to both innate and 
acquired immune systems such as Type I and II interferons (IFN)10-12, aberrant T-regulatory 
activity13, augmented function of helper T-cells14, lymphoneogenesis with germinal center 
formation15, and abnormal B-cell activation with clonal expansion16 have been reported. 
Epithelial damage, due to pathogen, genetic predisposition, or idiopathic insult, and altered 
immune responses may result in apoptosis of salivary (or other target organs) epithelial cells and 
could be responsible for relocalization and release of autoantigens17. 

16 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
 
Figure 1. Annotated UMAP single cell atlas of the minor salivary glands and JAK1 mRNA expression in minor salivary gland 
cells. 
These autoantigens result in stimulation of intrinsic cellular responses with engagement of toll-
like receptors (TLRs), e.g. TLR3 in epithelial cells, and TLR7 and 
TLR8 in plasmacytoid dendritic cells (pDCs), resulting in local up-regulation of Type I IFNs and 
IL-1218,19. Increases in Type I IFNs induces release of B-cell activating factor (BAFF) 
stimulating B-cell activation, 20 autoantibody production and eventual formation of immune 
complexes that can stimulate pDCs enhanced release of Type I IFN21. 
Interleukin (IL)-12, along with Type I IFNs, stimulates both natural killer cells (innate) and Th1 
cells (adaptive), increasing IFN (Type II IFN) production mediating tissue damage22. Epithelial 
cells, upon TLR stimulation, also produce T-cell homeostatic cytokines, e.g. IL-7, an important 
mediator of T-cell activation, IFN-mediated Th1 response and maintenance of pathogenic Th17 
cells 23,24). These infiltrating CD4+ T cells (Th1 and Th17) show an activated phenotype and 
release pro-inflammatory cytokines such as IFN, IL-17 and IL-6. IFN is involved in epithelial 
cell activation, apoptosis, inflammation and tissue damage25. IL-17 has pro-inflammatory effects 
on epithelial cell by induction of matrix metalloproteinases secretion, dysregulation of tight 
junction proteins and support of ectopic lymphoid tissues26. IL-6 promotes Th17 differentiation 
and is in turn important for the induction of IL-17. 
Although the etiology of SS remains unclear, it is clear that the cytokines play a central role in 
the pathogenesis of SS and exhibit convergent signaling through the JAK-STAT pathway27. 
Therefore, the use of a JAK inhibitor may be beneficial by uncoupling the pathogenic cytokine 
milieu and resultant tissue dysfunction. In support of the proposed study, we have performed 
RNA sequencing (RNAseq) on target tissues (i.e., minor salivary gland biopsies) from SS 
participants and healthy volunteers. 
RNAseq demonstrated enrichment of JAK- STAT pathway genes (e.g., STAT5A, STAT1, 
STAT2, JAK2, and JAK3) including moderate to strong positive correlation of calculated 
interferon scores with clinical variables of SS (e.g., focus scores, salivary flow, and the presence 
of autoantibodies) (Figure 1 unpublished data). Furthermore, we performed a pilot study using 
single cell RNAseq (scRNAseq) on minor salivary glands (MSG) from SS participants (n=3) to 

17 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
investigate the transcriptional state to a single 
cell resolution the expression contribution of 
JAK-STAT pathway genes in SS participants 
(Figure 2 unpublished data). Expectedly, these 
results confirm that JAK1 and TYK2 (and to a 
lesser degree, JAK3), are expressed in the both 
the infiltrating lymphocytes and the epithelia of 
the gland of SS patients. These preliminary 
results indicate the potential for inhibiting 
JAK-STAT pathway may affect the pathogenic 
expression vectors of infiltrating cells while 
allowing normalization of the expression state 
of the secretory epithelium in salivary glands 
and reduction of systemic manifestations of 
SS. 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 Known Potential Risks 
Tofacitinib: Description and Summary of 
Clinical Studies 
Tofacitinib (CP-690550; Pfizer, Inc.) is an 
orally administered JAK inhibitor that has 
recently been approved for the treatment of 
rheumatoid arthritis (RA), ulcerative colitis 
(UC), psoriatic arthritis (PsA), polyarticular 
juvenile idiopathic arthritis, and ankylosing 
spondylitis (AS). Clinical trials of Tofacitinib in RA demonstrate rapid onset of drug efficacy 
with an acceptable safety profile28-32. These clinical trials have used Tofacitinib as 1) 
monotherapy in participants failing non-biologic or biologic disease modifying drugs 
(DMARDS), 2) in combination with methotrexate in participants failing methotrexate or TNF 
inhibitors. The combined results are shown in  
 
Figure 2. JAK-STAT genes upregulated in SS and 
correlate with Focus Score 

18 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Table 1. 
 
 

19 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Table 1. Proportion of Participants with American College of Rheumatology Response 
(20/50/80) Percent 
Monotherapy in Nonbiologic or Biologic DMARD 
Inadequate Respondersc 
MTX Inadequate Respondersd 
TNF Inhibitor Inadequate 
Responderse 
Study I 
Study IV 
Study V 
Na 
PBO 
122 
Tofacitinib 
5 mg Twice Daily 
243 
Tofacitinib 
10mg Twice 
Daily 
245 
PBO 
+ MTX 
160 
Tofacitinib 
5 mg Twice 
Daily + 
MTX 
321 
Tofacitinib 
10 mg 
Twice Daily 
+ MTX 
316 
PBO + 
MTX 
132 
Tofacitinib 
5 mg Twice 
Daily + MTX 
133 
Tofacitinib 
10 mg Twice 
Daily + MTX 
134 
ACR20 
Month 3 
26% 
59% 
65% 
27% 
55% 
67% 
24% 
41% 
48% 
Month 6 
NAb 
69% 
70% 
25% 
50% 
62% 
NA 
51% 
54% 
ACR50 
Month 3 
12% 
31% 
36% 
8% 
29% 
37% 
8% 
26% 
28% 
Month 6 
NA 
42% 
46% 
9% 
32% 
44% 
NA 
37% 
30% 
ACR70 
Month 3 
6% 
15% 
20% 
3% 
11% 
17% 
2% 
14% 
10% 
Month 6 
NA 
22% 
29% 
1% 
14% 
23% 
NA 
16% 
16% 
a N is number of randomized and treated participants. 
b NA Not applicable, as data for placebo treatment is not available beyond 3 months in Studies I and V due to placebo 
advancement. 
c Inadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity. 
d Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria. 
e Inadequate response to a least one TNF inhibitor due to lack of efficacy and/or intolerance. 
 
Improvement with doses of 5 mg twice daily was noted as early as two weeks, with American 
College of Rheumatology (ACR) 20 responses reported in 41-59% and 51- 69% of participants 
at three (3) and six (6) months respectively. Similarly, ACR 50 responses were reported in 26-
31% and 32-42% of participants at three (3) and six (6) months respectively. Similarly, 
Tofacitinib use in PsA also showed a rapid onset of drug efficacy with acceptable safety 
profile33, 34. These clinical trials have used Tofacitinib in combination with a stable dose of 
nonbiologic DMARD (like methotrexate) and the results are summarized in Table 2 and Table 3 
below: 
 
 

20 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Table 2 Proportion of Participants with an ACR Response in Study PsA-I [Nonbiologic 
DMARD Inadequate Responders (TNF Blocker-Naïve)] 
Treatment Group 
Placebo 
Tofacitinib 5 mg Twice Daily 
Tofacitinib 10 mg† Twice Daily 
N‡ 
105 
107 
104 
Response Rate 
Response Rate 
Difference (%) 
95% CI from 
Placebo 
Response Rate 
Difference (%) 
95% CI from 
Placebo 
Month 3 
ACR20 
33% 
50% 
17.1 (4.1, 30.2) 
61% 
27.2 (14.2, 40.3) 
ACR50 
10% 
28% 
18.5 (8.3, 28.7) 
40% 
30.9 (19.9, 41.8) 
ACR70 
5% 
17% 
12.1 (3.9, 20.2) 
14% 
9.7 (1.8, 17.6) 
 
 
Table 3 Proportion of Participants with an ACR Response in Study PsA--II* (TNF Blocker 
Inadequate Responders) 
Treatment Group 
Placebo 
 Tofacitinib 5 mg Twice Daily 
Tofacitinib 10 mg† Twice Daily 
N‡ 
131 
131 
132 
Response Rate 
Response Rate 
Difference (%) 
95% CI from 
Placebo 
Response Rate 
Difference (%) 
95% CI from 
Placebo 
Month 3 
ACR20 
24% 
50% 
26.0 (14.7, 37.2) 
47% 
23.3 (12.1, 34.5) 
ACR50 
15% 
30% 
15.3 (5.4, 25.2) 
28% 
13.5 (3.8, 23.3) 
ACR70 
10% 
17% 
6.9 (-1.3, 15.1) 
14% 
4.5 (-3.4, 12.4) 
Participants with missing data were treated as non-responders. 
* Participants received one concomitant nonbiologic DMARD. 
† The recommended dose of Tofacitinib is 5 mg twice daily. 
‡ N is number of randomized and treated participants 
 
 
In general, Tofacitinib was well tolerated. The most common toxicity reported was infection 
with an overall frequency of 20% in participants who received Tofacitinib 5mg twice daily and 
18% in the participants who received placebo. The most commonly reported infections were 
upper respiratory infections (URI), throat infections and urinary tract infections. Serious 
infections, pneumonia, cellulitis, Herpes zoster, and urinary tract infections due to bacterial or 
opportunistic organisms (Herpes simplex, Cytomegalovirus, Cryptococcus, Pneumocystis, and 
Candida) were observed in 0.4% of participants who received drug for three (3) months or less. 
Other toxicities, including malignancy and gastrointestinal perforation were rare. Laboratory 

21 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
abnormalities, including lymphopenia, neutropenia, anemia, increased transaminases and 
elevated high density lipoprotein (HDL) and low density lipoprotein (LDL) were also considered 
mild and reversible. The lymphopenia (ALC<500 cells/mm3) was associated with an increased 
risk of infection but the neutropenia was not. Pooled data from 2 open-label long-term extension 
studies involving 4102 participants treated for 5963 participant-years reported a cardiovascular 
events incidence rate range from 0.05-0.3 per 100 participant-years 35. Increase in serum 
creatinine of more than 50% from baseline was observed in 3.3 % of the participants35. The 
safety profile observed in participants with active psoriatic arthritis treated with Tofacitinib was 
consistent with the safety profile observed in RA participants 33, 34. 
Recently, our collaborators at the National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS) successfully completed a double-blind randomized placebo- controlled trial 
of Tofacitinib 5 mg BID in patients with Systemic Lupus Erythematosus (SLE). In this trial 20 
participants with mild to moderate SLE took Tofacitinib for 8 weeks. Overall, patients with SLE 
tolerated Tofacitinib well with no withdrawal due to drug intolerance. Most of the adverse events 
were mild to moderate infections, which either self-resolved or treated with short course of oral 
antibiotics (Table 3). No Herpes zoster reactivation or venous thromboembolic events were 
recorded during the study. 
Other safety parameters, including hemoglobin, total white blood cell count and liver function 
tests, did not show any clinically or statistically significant changes in participants on Tofacitinib 
during the study as compared to their baseline or group on placebo. There was a significant 
increase in HDL-C and HDL particle size in Tofacitinib- treated patients at the end of treatment 
phase, accompanied by significant improvements in plasma protein lecithin: cholesterol 
acyltransferase (LCAT) concentration and cholesterol efflux capacity. Arterial stiffness as 
measured by non-invasive vascular function studies decreased in the Tofacitinib-treated group 
but not in the placebo-treated group. 
 
Table 4 Adverse events in clinic al trial of Tofacitinib in SLE 
 
Tofacitinib; mechanism of action: 
The JAKs are a family of intracellular enzymes (JAK1, 2, and 3, and TYK2) that facilitate 
signaling between inflammatory cytokines bound to surface receptors and subsequent gene 
transcription that regulates immune responses36. Specifically, JAKs phosphorylate cytoplasmic 
tails of cytokine receptors once the receptor has been bound by its cognate cytokine. This leads 
to recruitment of appropriate STAT proteins, which are in turn phosphorylated causing 
dimerization and disassociation from the receptor-JAK complex. STATs then translocate to the 
nucleus where they regulate gene transcription. Specific cytokine receptor subunit combinations 
selectively associate with different JAKs and STATs to differentially modulate transcription 
(Fig. 3). JAKs play a critical role in mediating inflammatory responses and pharmacologic 

22 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
intervention modulating JAK function. This modulation represents a promising approach to the 
treatment of autoimmune disease including SS. 
 
 
 
Tofacitinib has been shown to inhibit JAK1, JAK2, and JAK3. Cellular assays measuring 
cytokine-induced STAT phosphorylation have demonstrated partial selectivity of Tofacitinib for 
JAK1 and 3 resulting in greater inhibition of JAK1 and 3 compared to JAK237. JAK1 and JAK3 
mediate intracellular responses for cytokines that use the gamma chain, which are critical for the 
development and function of T, B, and NK cells. Other in vitro studies suggest that the 
effectiveness of Tofacitinib in RA may be attributable to its suppressive effects on the generation 
of Th1 and pathogenic Th17 cells38-40.  
Tofacitinib also inhibits cytokines that provide B cell help such as IL-4, IL-6, and IL- 21 and can 
reduce B cell proliferation41-43.  In addition, Tofacitinib inhibits the effect of IL-6 and IFN-α on 
innate immune cells. 
Rationale for treatment with Tofacitinib:  
Cytokine signaling:  
Targeting JAKs is an attractive therapeutic possibility for SS for many reasons. Many of the 
inflammatory cytokines implicated in SS pathogenesis, in particular Type I IFNs: IL-6, IL-7, IL-
12, IL-21 and IFNγ, signal through JAK/STAT pathways. These molecules mediate tissue 
destruction and contribute to breaking tolerance through effects on B cell activation, 
immunoglobulin production and expression of costimulatory molecules on lymphocytes44,45. 
Following engagement of its receptor, IFNα activates JAKs and STATs leading to increased 
expression of major histocompatibility complex molecules (MHC) Class I, dendritic cell 
maturation, T cell survival and autoantibody production46. Known functions of IL-6 are to 
enhance B cell differentiation into immunoglobulin secreting plasma cells and promote antibody 
production through stimulation of IL-21 by CD4+ T cells47,48. IL-6 is an important factor that 
induces naïve CD4+ cells to differentiate into Th17 cells through activation of STAT3 and 
induction of RAR-related orphan receptor gamma (RORγt)49. Additionally, anti-IL-6 monoclonal 
antibodies are currently being tested in clinical trials for a number of autoimmune diseases. 
 
γ chain cytokines; 
IL-2, 4, 7, 9, 15, 21 
STAT 1, 3, 5, 6 
IL-6, IFNγ 
IL-23, 12, IFNα 
EPO, TPO 
JAK1 
JAK1 
TYK2 
JAK2 
STAT 1, 2, 3  
STAT 4, 3 
STAT 3, 5 
Figure 3.  Associations between JAK kinases, cytokines and  STAT proteins 

23 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Positive anti-inflammatory effects of anti-IL-6 therapy are attributable, in part, to diminished 
support of long- lived plasma cells by IL-6. IL-17 is recognized as an important contributor to SS 
pathogenesis through its effects on neutrophils and monocytes and T cell migration into tissues26. 
Increased numbers of IL-17-producing T cells have been identified in SS participants and in 
salivary gland biopsies from SS participants 14. IL-23 is mainly secreted by antigen presenting 
cells and signals through JAKs and STATs to promote expansion of IL-17 producing cells 
(including Th17 cells), increase IFNγ production, activate memory T cell responses and increase 
production of pro- inflammatory cytokines (comprehensively by Kastelein 50). Given the 
importance of these pro-inflammatory cytokines that signal through JAKs and STAT proteins to 
the inflammatory response in SS, use of Tofacitinib has the potential to block effects of several 
cytokines known to exacerbate inflammatory responses in SS rather than singling out one 
cytokine target at a time. 
T cell pathology in SS and JAK inhibition: 
The importance of T cell contribution to the pathology in SS is well established13. The Class II 
MHC locus remains the strongest genetic association with SS, supporting the role of T cell-
driven autoreactivity3. The plethora of high affinity, class-switched IgG autoantibodies 
characteristic of SS reflect the role of follicular T helper (Tfh) cells in B cell proliferation and 
differentiation giving rise to autoantibody producing plasma cells. Tfh cells are generated from 
naïve CD4+ T cells in the presence of IL-6, IL-21 and inducible T-Cell co-stimulator (ICOS) 
stimulation. Inflammation is locally driven in target organ tissue in response to cytokines that 
regulate vascular permeability and enhance local extravasation of inflammatory cells into tissue. 
Th17 cells are generated from naïve CD4+ T cells in the presence of TGFβ, IL-1β, IL-6, IL-21 
and IL-23 moderating inflammatory responses by releasing the pro-inflammatory cytokines IL-
17 and IL-21. 
Engagement of the IL-17 receptor on target cells leads to chemokine production and results in 
leukocyte recruitment and production of other inflammatory cytokines such as IL-1β and TNFα. 
Th17-related pathology is described in multiple autoimmune diseases including RA, psoriasis, 
inflammatory bowel disease, SLE, and also SS51. 
Ghoreschi et al., have demonstrated, through a series of in vitro cellular assays and in vivo 
animal models, the range of Tofacitinib’s effects on T cell function and inflammatory 
cytokines38. Tofacitinib inhibits JAK3 dependent γc cytokine receptor signaling and other JAK1 
dependent cytokine receptor signaling. These blocking effects manifest as decreased production 
of inflammatory IL-23 dependent Th17 cells. Additionally, Tofacitinib blockade of JAK1 and 
JAK3 inhibit Th1 and Th2 differentiation and block IL-6 signaling. In an animal model of 
collagen-induced arthritis, mice experienced a significant reduction in established arthritis within 
48 hours of treatment with Tofacitinib. Circulating inflammatory markers decreased within 4 
hours, demonstrating a remarkably fast onset of action. These immediate results were not 
associated with leukocyte depletion. Histologic confirmation of leukocyte depletion took seven 
(7) days. 
Others have demonstrated that treatment of human participants with Tofacitinib for prevention of 
graft rejection after kidney transplant results in a differential effect of Tofacitinib on Treg cells 
and Th1 effector cells where the Th1 effector cells proved more susceptible to JAK blockade52. 
These studies have direct implications for the use of JAK inhibition in SS where, similar to the 

24 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
positive results demonstrated in RA, we predict that inhibition of signaling molecules with broad 
effects on inflammatory responses will prove to be beneficial. 
Tofacitinib likely targets pathogenic inflammatory pathways involved in the development and 
maintenance of SS. Additional rationale for a Phase Ib-IIa study of Tofacitinib in SS is the 
exploration of the inhibition of cytokines that may serve a protective role in SS. For example, IL-
2 is an important immunoregulatory cytokine that promotes immune response but it is also 
important for peripheral tolerance53. 
IL-2 promotes expression of Foxp3 in regulatory T (Treg) cells. It also inhibits IL-17 production 
and Bcl6 expression; Bcl6 is important for Tfh cells and germinal center formation. Although no 
evidence exists in mouse models or in humans treated with Tofacitinib that this drug promotes 
autoimmunity, this remains a theoretical possibility. In addition, Tofacitinib can weakly inhibit 
JAK2 and thereby interfere with the action of erythropoietin, GM-CSF and IL-7. Consequently, 
Tofacitinib could theoretically exacerbate the anemia and lymphopenia associated with SS. 
Tofacitinib treatment is also associated with higher rates of BK virus nephropathy. Hence there 
is a possibility of BK virus activation leading to clinically significant disease after starting study 
participants on Tofacitinib. We will include assessment of BK virus infection at baseline and 
throughout the study for an additional safety measure. 
2.4 RISK/BENEFIT ASSESSMENT 
2.4.1 Risks/discomforts associated with Tofacitinib 
Tofacitinib is approved by the Food and Drug Administration (FDA) for treatment of rheumatoid 
arthritis, psoriatic arthritis and ulcerative colitis. However, on September 1, 2021, based on a 
completed review of a large, randomized safety clinical trial, the FDA concluded that there is an 
increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, 
and death with the arthritis and ulcerative colitis medicines Tofacitinib. This lead to the 
requirement of a “Boxed Warning” as follows:  
Boxed Warning 
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE 
CARDIOVASCULAR EVENTS (MACE), AND THROMBOSIS 
Increased risk of serious bacterial, fungal, viral, and opportunistic infections leading to 
hospitalization or death, including tuberculosis (TB).  
Higher rate of all-cause mortality, including sudden cardiovascular death with Tofacitinib vs. 
TNF blockers in rheumatoid arthritis (RA) patients. 
Malignancies have occurred in patients treated with Tofacitinib. Higher rate of lymphomas and 
lung cancers with Tofacitinib vs. TNF blockers in RA patients. 
Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with 
Tofacitinib vs. TNF blockers in RA patients. 
Thrombosis has occurred in patients treated with Tofacitinib. Increased incidence of pulmonary 
embolism, venous and arterial thrombosis with Tofacitnib vs. TNF blockers in RA patients. 

25 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Notwithstanding, tofacitinib is generally well-tolerated in individuals with Rheumatoid Arthritis. 
The data on adverse events associated with exposure to Tofacitinib are gathered from two Phase 
II and 5 Phase III multi-center, double-blind, placebo controlled clinical trials where participants 
were randomized to Tofacitinib 5 mg twice daily, 10 mg twice daily or placebo, with or without 
concomitant disease modifying drugs (DMARDS); most commonly methotrexate. Adverse 
events associated with Tofacitinib included the following: 
Infections 
Tofacitinib increases the risk of serious bacterial, fungal, viral, and opportunistic infections 
leading to hospitalization or death, including tuberculosis (TB). In the rheumatoid arthritis (RA) 
studies, the overall frequency of infections was 20% in participants who received Tofacitinib 5 
mg twice daily and 18% in participants who received placebo. The most commonly reported 
infections were upper respiratory infections, throat infections and urinary tract infections. The 
most serious side effects reported with Tofacitinib in RA participants were serious infections due 
to bacterial, viral, or fungal organisms. These occurred in 11 out of 2685 participants (0.4%) who 
received drug for three (3) months or less. For participants who experienced 0-12 months of 
exposure to Tofacitinib, serious infections were reported in 34 participants on the 5 mg twice 
daily dose and in 33 participants on the 10 mg twice daily dose. The most common serious 
infections were pneumonia, cellulitis, herpes zoster, and urinary tract infections. Tuberculosis 
was not reported in participants on any dose of Tofacitinib for less than three (3) months. During 
0-12 months of exposure to Tofacitinib, tuberculosis cases were reported in 0 participants 
receiving the 5 mg twice daily dose and 6 participants who received the 10 mg twice daily dose. 
Opportunistic infections were not reported in participants receiving any dose of Tofacitinib for 
less than three (3) months. During 0-12 months of exposure, opportunistic infections were 
reported in four (4) participants receiving 5 mg twice daily dosing and four (4) participants receiving 
10 mg twice daily dosing; the median range for Tofacitinib exposure prior to diagnosis of an 
opportunistic infection was eight (8) months. These opportunistic infections included cryptococcus, 
pneumocystis, herpes virus, cytomegalovirus (CMV) and BK virus and most occurred in participants 
that were also taking corticosteroids and methotrexate. 
Gastrointestinal Perforation 
Rare events of gastrointestinal perforation (GIP) have been reported in clinical studies of 
Tofacitinib in RA participants although the role of JAK inhibition in these events is not known. 
The estimated crude rate of gastrointestinal perforations are very low at 1.29 per 1000-person 
years on Tofacitinib (Xie, 2017). Although slightly higher risk than other biologics used in RA 
such as rituximab, the rate differences compared with various biologics used for RA remain very 
low and appreciably similar (range: 1-3 events per 1000 person-years). Moreover, those patients 
with an increased for GIP tended to be older, had pre-exiting gastrointestinal problems 
(diverticulosis), and prednisone use >7.5 mg/day. 
Malignancy 
Malignancies were reported in clinical studies of Tofacitinib. However, these rates are similar to 
those seen in the general population and generally stable with increasing dose56.A noteworthy 
exception is that higher rates of lung cancer and lymphoma were observed in trials with 
Tofacitinib compared with TNF blockers in RA. In a meta-analyses, there were no apparent or 
consistent association between tofacitinib dose and risk of malignancy except for non-melanoma 

26 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
skin cancer in a long-term extension cohort57. However, numerically higher rates for all 
malignancies, including breast cancer and lymphoma, were observed with the higher 10 mg 
twice daily dose in a phase III study, but not in the long term extension cohort57. Therefore, at 
the 5 mg twice daily dose, currently available evidence does not indicate a significantly 
increased risk of malignancy in RA, the largest collective cohort of patients treated with 
Tofacitinib. In one post marketing study of 5,677 adult patients who participated in phase II, 
phase III, and long-term efficacy studies of Tofacitinib, 107 patients developed malignancies 
(excluding non- melanoma skin cancer). The most common malignancies were lung cancer (n = 
24), followed by breast cancer (n = 19), lymphomas (n = 10), and gastric cancer (n = 6) 57. 
However, it is noteworthy that Sjögren’s syndrome patients have an increased risk of lymphoma 
development58. This is exemplified in a focused case-matched control analysis by Mariette et 
al., examining the incidence rates (IR; events per 100 patient-years) and standardized incidence 
ratios (SIRS) with respect to risk of lymphoma56. Among 19 Tofacitinib studies (Phase I [n=2], 
Phase II [n=9], Phase III [n=6], and long-term extension [n=2]) in patients with moderate-to-
severe rheumatoid arthritis, there were 19 lymphomas in 19,406 patient-years of exposure (IR – 
0.10) and the SIR was 2.656. More patients with lymphomas had a history of Sjögren’s 
syndrome in the context of rheumatoid arthritis and were commonly positive for Anti-cyclic 
citrullinated peptide (anti-CCP). These results indicate that there are minimal differences in 
lymphoma risk for Tofacitinib across all doses and that the increased risk reported likely reflects 
the background disease-specific risk attributable to Sjögren’s syndrome. However, we 
acknowledge that we do not yet know the risk of Tofacitinib administration on lymphomagenesis 
in Sjögren’s syndrome patients. 
Thus, very close clinical follow up in this patient cohort for any changes in patient status is 
essential and will be provided to participants. 
Thrombosis: 
Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial 
thrombosis, have occurred in patients treated with Tofacitinib and other Janus kinase (JAK) 
inhibitors used to treat inflammatory conditions. Many of these events were serious and some 
resulted in death. 
Patients with rheumatoid arthritis 50 years of age and older with at least one cardiovascular risk 
factor treated with Tofacitinib at both 5 mg or 10 mg twice daily compared to TNF blockers in 
RA Safety Study 1 had an observed increase in incidence of these events. The incidence rate of 
DVT per 100 patient-years was 0.22 for Tofacitinib 5 mg twice a day, 0.28 for Tofacitinib 10 mg 
twice a day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.18 
for Tofacitinib 5 mg twice a day, 0.49 for Tofacitinib 10 mg twice a day, and 0.05 for TNF 
blockers. 
In a long-term extension study in patients with UC, five cases of pulmonary embolism were 
reported in patients taking Tofacitinib 10 mg twice daily, including one death in a patient with 
advanced cancer. 
The 10mg twice daily dose of Tofacitinib is not approved for RA and we plan to use only the 
5mg twice daily regimen for this trial. Additionally, patients at high risk or a history of arterial or 
venous thrombosis will be excluded from the study. 

27 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Higher rates of Major Adverse Cardiovascular Events (MACE) 
MACE (i.e., cardiovascular death, myocardial infarction, and stroke) was higher with Tofacitinib 
vs. TNF blockers in RA patients.  
In an RA safety study, RA patients who were 50 years of age and older with at least one 
cardiovascular risk factor treated with Tofacitinib 5 mg twice daily or Tofacitinib 10 mg twice 
daily had a higher rate of major adverse cardiovascular events (MACE) defined as 
cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, compared to 
those treated with TNF blockers. The incidence rate of MACE per 100 patient-years was 0.91 for 
Tofacitinib 5 mg twice a day, 1.11 for Tofacitinib 10 mg twice a day, and 0.79 for TNF blockers. 
The incidence rate of fatal or non-fatal myocardial infarction per 100 patient-years was 0.36 for 
Tofacitinib 5 mg twice a day, 0.39 for Tofacitinib 10 mg twice a day, and 0.20 for TNF blocker. 
Patients who are current or past smokers are at additional increased risk. 
Laboratory Abnormalities  
• Lymphopenia: Lymphopenia below 500 cells/mm3 occurred in 0.04 % of 
participants in both dosing groups of Tofacitinib within the first 3 months. Low 
lymphocyte counts (<500 cells/mm3) were associated with increased risk for 
serious infections. 
• Neutropenia: Neutropenia with an ANC less than 1000 cells/mm3 occurred in 
0.07% of participants in both dosing groups of Tofacitinib during the first 3 
months of exposure. No ANCs less than 500 cells/mm3 were reported and there 
was no clear association between neutropenia and risk of infection. The 
neutropenia was dose related and reversible. 
• Anemia: Although JAK inhibition has potential to affect hematopoiesis through 
interruption of cytokine-induced regulation of hematopoiesis, minimal effects of 
Tofacitinib 5 mg twice daily have been observed in the clinical trials in RA. Mild 
fluctuations in hemoglobin were not different from those observed in the placebo 
group. 
• Liver Function Tests: Increased liver enzyme tests greater than 3 times the upper 
limit of normal were seen in approximately 1.2% of participants overall. No 
differences in the incidence of AST or ALT elevations were observed between the 
placebo, 5 mg and 10 mg twice daily groups in the first three months. 
• Serum Creatinine: In a pooled analysis of five (5) phase III and two (2) long term 
extension studies of Tofacitinib in participants with RA increase in serum 
creatinine was seen predominantly in the first three (3) months of treatment. The 
serum creatinine increases at Month three (3) were 0.07 and 0.08 mg/dl for 5 and 
10 mg twice daily (BID) Tofacitinib doses, respectively, compared with 0.04 
mg/dl in the placebo. In the Tofacitinib 5 mg BID group, 17/1,220 (1.4%) 
participants had a confirmed serum creatinine increase of 33% from baseline in 
Months 0 to 3. Of these participants, only two (2) had serum creatinine elevation 
above the reference range for normal. In the Tofacitinib 10 mg BID group, 
23/1,217 (1.9%) participants had a confirmed serum creatinine increase 33% from 
baseline in Months 0 to 3. Of these 23 participants, only four (4) had serum 
creatinine above the reference range for normal. No continued worsening of serum 
creatinine was noted during the long-term follow-up studies. The published data 

28 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
revealed that these changes plateaued or reversed in long term follow up. 
• Lipids: Dose related elevations of lipid parameters were observed at one month of 
exposure and remained stable thereafter. These were: 
• A mean increase of LDL by 15% in the 5 mg twice daily arm and 19% in the 10 
mg twice daily arm, and 
• A mean increase in HDL by 10 % in the 5 mg twice daily arm and 12% in the 10 
mg twice daily arm. 
However, mean LDL/HDL ratios were unchanged in participants treated with 
Tofacitinib. 
Other Adverse Reactions 
Other adverse reactions reported with Tofacitinib at doses of 5 mg BID include diarrhea (4%), 
nasopharyngitis 3.8%), upper respiratory infections (4.5%, headache (4.3%), high blood pressure 
(1.6%). None of these occurred significantly more frequently than in the participants who were 
treated with placebo. 
Medication Interactions 
Serum Tofacitinib levels can increase when it is co-administered with moderate and potent 
inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole) or CYP2C19 (e.g., fluconazole). 
Potent CYP3A4 inducers (e.g., rifampin) will decrease exposure to Tofacitinib. 
The risk of increased immunosuppression is enhanced if Tofacitinib is co-administered with 
potent immunosuppressive drugs such as azathioprine, tacrolimus, cyclosporine. 
Flare of Sjögren's syndrome: 
There are no data about the use of Tofacitinib in individuals with SS. Tofacitinib may be 
ineffective or may even worsen SS. The potential impact of flares is minimized in this study by 
close monitoring of participants and strict withdrawal criteria for flares. 
2.4.2 Risks associated with study procedures 
Minor Salivary Gland Biopsy 
The biopsy will be performed according to NIDCR SOPs. Local anesthetic will be administered 
to minimize pain during the procedure. Biopsy of the MSG may cause discomfort, pain, and 
swelling at the site (usually lower lip) for several days following the procedure; these symptoms 
can be effectively treated with ibuprofen, acetaminophen, or more potent analgesics as needed. 
Participants may also experience transient paresthesia in the region of the biopsy, permanent 
paresthesia, although reported, are exceedingly rare using the techniques employed by the 
NIDCR. Other possible risks are allergic reactions to the local anesthetic and bleeding and 
infection at the site of biopsy however, such events are rare. 
In a retrospective analysis of biopsies performed in our Clinic, aphthous ulcers developed in less 
than 5% of volunteers who participated in our study. Although the exact cause was not 
identified, this is well-known risk associated with the mucosal biopsy and anesthetic injection. 
Post-operative checks are routinely accomplished 4 to 7 days after the procedure for suture 
removal. Typically, resorbable sutures are used and no follow up is necessary. Rarely a 

29 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
participant will have defective healing, forming an epithelial tag or mucocele. These are 
surgically correctable and will be addressed by an NIDCR dentist or oral surgeon. 
 Salivary Gland Ultrasound 
There are no known risks of salivary gland ultrasounds. This procedure is generally considered 
safe. Patients may experience slight discomfort (cold feeling of the skin) on the areas of the face 
where transduction gel is applied. 
Collection of Saliva/Measurement of Salivary Flow Rate 
There is no known risk associated with this salivary collection. Participants may experience mild 
discomfort due to increased dryness caused by withholding salivary stimulants for 24 hours prior 
to saliva collection. There may be mild discomfort due to positioning of mouth during saliva 
collection. Citric acid (lemon juice) solution used to stimulate salivary flow may cause an 
unpleasant taste and mild discomfort in the salivary glands if the parotid duct is blocked and 
saliva cannot be expressed. 
Vascular function studies: SphygmoCor, CAVI and Endopat 
There is no known risk of these procedures. The procedures are very well tolerated, other than 
potential minimal transient discomfort associated with the inflation of the blood pressure cuff; no 
side effects are expected. 
Dry Eye Examination 
An ophthalmologist measures eye pressure and examines the front part of the eye. Anesthetic eye 
drops will be used in order to measure eye pressure. Occasionally there may be a local allergic 
reaction to any medication such as the anesthetic eye drops. If this should occur, appropriate 
medication to control the allergic reaction will be administered. 
Schirmer’s test performed to evaluate adequate tear production, and MMP-9 simple strip to 
assess presence (positive/negative) of inflammatory protein may be uncomfortable but should 
not be painful. 
Blood draws 
Participants may experience discomfort, bleeding, or bruising at the venipuncture site, which 
should resolve with time. There is also a small risk of fainting. Infection at the site of needle 
insertion may also occur but is rare with the use of sterile disposable needles and aseptic 
technique. 
The amount of blood drawn for clinical care indication and research purposes will be kept within 
the NIH guidelines of 10.5 mL/kg or 550 mL, whichever is smaller, over any 8-week (56 days) 
period for adults. 
2.4.3 Known potential benefits 
There may be no direct benefits to participants. Participants may benefit from a thorough 
evaluation by experts in SS. 
Although the primary endpoint is safety in this double-blind placebo-controlled study, there is 
the possibility that potential participants with mild to moderate disease activity in SS, 

30 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
randomized to drug, may derive a medical benefit. However, this may be a temporary effect 
while patients are on drug and long-term benefits are not anticipated. 
2.4.4 Alternatives to participation or other therapies 
The alternative to study participation is conventional treatment. There are limited treatment 
options available for SS participants with mild to moderate disease activity including higher 
doses of corticosteroids; switching to or adding another immunosuppressant; 
hydroxychloroquine. 
2.4.5 Assessment of known potential risks and benefits 
Unforeseen adverse effects are a risk with every new drug treatment, including new indications 
for approved drugs. The risks of participating in this study are reasonably relative to the potential 
health benefits and generalizable medical knowledge that may be obtained. 
3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
JUSTIFICATION FOR 
ENDPOINTS 
ENDPOINTS 
Primary 
 
 
To determine the safety and 
tolerability of Tofacitinib in 
participants with SS and mild to 
moderate disease activity. 
 
This is an FDA approved drug 
that is not currently approved for 
use in the Sjögren’s syndrome 
population. Tofacitinib has 
demonstrated both clinical and 
molecular potential to be an 
effective treatment for SS, 
however studies are lacking in 
this research population. 
Safety and tolerability will be 
measured by assessment of 
adverse events (AEs) and 
clinical safety laboratory tests 
throughout the study. Toxicity is 
defined as any study drug-related 
Grade 3 or higher adverse event, 
as measured by the National 
Cancer Institute (NCI), Common 
Terminology Criteria for 
Adverse Events (CTCAE), 
Version 5.0). 
Secondary 
 
 
To assess clinical improvement 
after treatment with Tofacitinib as 
measured by  no change or 
improvement in the ESSDAI and no 
worsening on the physician’s global 
PGA. 
The ESSDAI was developed to 
be used as an outcome 
measure in clinical trials 
involving Sjögren's syndrome 
patient cohorts. It allows for 
assessment/scoring of major 
domain activity relevant to a 
SS population. 
Assessments of clinical 
response will be measured by: 
      1) the change in ESSDAI 
between baseline and study 
day 168          2) No 
worsening of PGA between 
baseline and study day 168 
To demonstrate that treatment with 
Tofacitinib is effective clinically 
and biologically in SS individuals 
with mild to moderate disease. 
Data from a randomized placebo-
controlled trial of Tofacitinib in SS 
would yield evidence to further 
pursue JAK/STAT pathway 
targeting in SS. Salivary flow rates 
are an objective measure of organ 
Change in salivary flow rates 
between baseline and study day 
168 

31 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
OBJECTIVES 
JUSTIFICATION FOR 
ENDPOINTS 
ENDPOINTS 
function. Low salivary flow is a 
primary feature of SS and may be 
used as a non-invasive measure of 
therapeutic intervention. 
To investigate the effects of 
Tofacitinib on systemic 
biomarkers of SS as measures of 
biological effects that can be 
used as outcome measures to 
power a larger Clinical Trial. 
The biological effects of 
Tofacitinib in this research 
population are unknown. 
Assessing for changes in major 
biological markers of SS will 
improve the understanding and 
potential uses of Tofacitinib in this 
and other disease states. 
Changes in serum cytokines, 
autoantibody levels (e.g., ANA- 
Hep2 substrate, SSA, SSB 
autoantibody titers), complement 
proteins C3 and C4, markers of 
systemic inflammation such as 
ESR and CRP between baseline 
and study day 168 
Tertiary/Exploratory 
 
 
Identify transcriptional changes 
in affected tissues due to JAK-
STAT inhibition. 
Target tissue (MSG) 
transcriptional landscape 
changes from baseline to Day 
168 with respect to treatment 
allocation. 
Transcriptional alterations and 
pathway analysis using RNA 
sequencing (RNAseq) on 
MSG and/or peripheral blood 
mononuclear cells (PBMC) 
between baseline and study 
day 168. 
Transcriptional and tissue 
compositional changes using 
single cell (sc)RNAseq on 
available tissue collected 
between baseline and study 
day 168. 
Assess target tissue 
histopathological and 
architectural changes as a 
correlative measure with 
functional improvement. 
Target tissue (MSG) changes in 
immune infiltration 
histopathology from baseline to 
Day 168 with respect to 
treatment allocation. 
Change in MSG biopsy 
histopathology including 
focus score, infiltrate area, 
acinar density, and fibrosis. 
Identify changes in infiltrating 
immune cells and the correlation 
with other markers of effect. 
Target tissue (MSG) changes in 
immune infiltration from 
baseline to Day 168 with 
respect to treatment allocation. 
Immunophenotyping of 
immune cell infiltrates in 
minor salivary gland biopsies 
by immunohistochemistry. 
We will specifically focus on 
numbers and or density of 
CD+3, CD20+, CD8+, CD4+, 
CD25+, Foxp3+ 
regulatory subsets and Th17 
cells. 
Identify changes in infiltrating 
immune cells and the correlation 
with other markers of effect. 
Target tissue (MSG) changes in 
immune infiltration from 
When tissue is available, 
alteration in minor salivary 
gland immune cell 

32 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
OBJECTIVES 
JUSTIFICATION FOR 
ENDPOINTS 
ENDPOINTS 
baseline to Day 168 with 
respect to treatment allocation. 
populations by flow 
cytometry with attention to 
CD3+, CD20+ NK, CD8+, 
CD4+, CD19+, 
CD25+, Foxp3+ regulatory 
subsets. 
Identify changes in circulating 
immune cells and the correlation 
with other markers of effect. 
Peripheral blood immune 
compositional measures from 
baseline to Day 168 with 
respect to treatment allocation. 
Alteration in peripheral blood 
immune cell populations by 
flow cytometry with special 
attention to NK, CD8+, 
CD4+, CD25+, Foxp3+ 
regulatory subsets and Th17 
cells. 
Quantify the effect of JAK-
STAT pathway inhibition in 
patient tissues. 
Peripheral blood measures of 
JAK/STAT pathway activation 
state from baseline to Day 168 
with respect to treatment 
allocation. 
Ligand-induced STAT 
phosphorylation in circulating 
T cells and monocytes using 
phosphoflow assessment of 
single cells. 
Quantify the effect of JAK-
STAT pathway inhibition on 
circulating cytokine expression. 
Changes in peripheral blood 
inflammatory biomarkers from 
Baseline through Day 168 with 
respect to treatment arm 
allocation. 
Measures of serum cytokines 
(like IL-2, 4, 6, 7, 9, 15, 
12,17, 23, 
TNFa, TNFb, IFNα and IFNγ) 
 
Changes in lacrimal function 
Ocular and lacrimal effects are 
main clinical complaints in SS. 
Improvement would reflect 
reduced pathogenic 
inflammation or cytokine 
expression in the lacrimal 
glands and reciprocal 
improvement in ocular surface 
characteristics or lacrimation 
from Baseline through Day 168 
with respect to treatment arm 
allocation. 
Change in corneal surface 
staining, changes in 
Schirmer’s. 
Assess measures of 
cardiovascular status. 
Measures of cardiovascular 
health were improved in a 
recent clinical trial of 
Tofacitinib in SLE patients. We 
are interested in the SS cohort 
from Baseline through Day 168 
with respect to treatment arm 
allocation. 
In addition to the routine lipid 
profile, we may also perform 
measurements of lipoproteins, 
including nuclear magnetic 
resonance (NMR) profile and 
cholesterol efflux capacity 
that have been associated with 
differences in atherosclerotic 

33 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
OBJECTIVES 
JUSTIFICATION FOR 
ENDPOINTS 
ENDPOINTS 
risk in autoimmune diseases 
between baseline and study 
day168. 
Assess changes in insulin 
resistance. 
Insulin resistance changes may 
inform effects on systemic 
health and cardiovascular 
health. 
Change in insulin resistance 
between baseline and study 
day 168. 
To investigate the effects of 
Tofacitinib on participant quality 
of life measures. 
Patient-reported outcomes are a 
way to quantitatively assess 
therapeutic effects of a given 
intervention. There is a need for 
participative and objective 
effectiveness data of Tofacitinib 
in our research population. 
Patient reported outcomes for 
clinical efficacy will be 
measured by changes assessed 
by ESSPRI, 2002 AECG 
Subjective Symptom 
Questionnaire, Subject dry 
mouth questionnaire, OHIP-
14, Xerostomia VAS, FSS, 
PROMIS, and the Short Form 
36 health survey between 
baseline, study days 96, and 
168. 
To investigate the effects of 
Tofacitinib in modulation of 
endothelial responses and 
markers of vascular risk in SS as 
a benefit of improved vascular 
function. 
A recent trial of Tofacitinib in 
SLE patients showed a decrease 
in vascular/ endothelial stiffness 
compared to placebo. Post-
marketing research has shown 
increased risk of PE in RA 
patients treated with 
Tofacitinib. There is a need to 
better understand the vascular 
effects/risks associated with this 
treatment. 
Changes in arterial stiffness in 
Tofacitinib group relative to 
placebo between baseline and 
study day 168. 
Changes in autoantibody levels. 
Changes in autoantibodies due 
to treatment allocation may 
provide future data to perform 
clinical trials as surrogate 
endpoints of efficacy. 
Changes in serum and 
salivary autoantibodies by 
light immunoprecipitation 
system (LIPS) between 
baseline and study day 168. 
Changes in oral microbiome. 
Changes in microbiome may 
reflect restoration of salivary 
function. 
Changes in the microbial 
diversity of oral and salivary 
microbiome between baseline 
and study day 168. 
Saliva Compositional Changes. 
Changes in salivary 
composition may reflect 
changes in glandular 
inflammation. These changes 
Change in collected salivary 
proteins and ionic 
composition as markers of 
improved saliva function 

34 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
OBJECTIVES 
JUSTIFICATION FOR 
ENDPOINTS 
ENDPOINTS 
can be correlated with disease 
response and serve as potential 
biomarkers for future Phase III 
studies. 
between baseline and study 
day 168. 
Assess the durability of clinical 
and biological effects after 
cessation of therapy. 
Any clinical or biological 
changes due to treatment may 
be short-lived after the cessation 
of therapy. 
Understanding the consequence 
of treatment withdrawal may 
help refine future studies and 
the immunology of the diseases. 
Assessment of durability of 
the clinical and biologic 
effects will be measured by 
changes in all of the above 
clinical and biologic measures 
between study days 168 and 
196 except for biopsies which 
will only be obtained at 
before baseline and at end of 
treatment. 
4 
STUDY DESIGN 
4.1 OVERALL DESIGN 
This is a Phase Ib-IIa, randomized, double blinded, placebo controlled clinical trial of orally 
administered Tofacitinib, 5 mg twice daily, for treatment of individuals with mild to moderate SS 
disease activity. The study will aim to screen up to 76 adult participants in order to achieve a 
target study of 30 participants for randomization plus up to 11 participants to replace subjects 
lost to attrition or early withdrawal from the study and to complete enrolment in unfilled 
randomization blocks.  There will be two (2) study arms with 20 participants in Tofacitinib arm 
and 10 participants in placebo arm. The study duration is a maximum of 241 days with a 45-day 
screening period followed by a 168-day treatment period and a 28-day follow-up period. The 
study is a single-site study to be conducted in the NIH Clinical Center. The proposed clinical 
trial is an exploratory study designed to yield preliminary data about the safety, clinical, and 
biologic efficacy of Tofacitinib in SS participants with mild to moderate disease activity. 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed clinical trial is an exploratory study designed to yield preliminary data about the 
safety, and clinical and biologic efficacy of Tofacitinib in SS participants with mild to moderate 
disease activity. If the drug is well tolerated by SS participants, the data can be used to design 
and power a larger study of clinical efficacy and safety. 
4.3 JUSTIFICATION FOR DOSE 
As per the package insert recommendations, each participant will be dosed with 5 mg (1 tablet) 
twice daily for 168 days as is recommended for the treatment of rheumatoid arthritis. 
Tofacitinib and placebo tablets will be supplied by Pfizer Incorporated to the NIH Clinical 
Center Research Pharmacy. 

35 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
5 
STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Adult primary SS participants with mild-to-moderate disease activity will be eligible for this 
study. Enrolled participants can be naïve or failed immunosuppressive therapy beyond 
antimalarials and glucocorticoids; to prevent bias in the cohort of participants with more 
recalcitrant disease. We expect that Tofacitinib is a potential second line therapy, in addition to 
antimalarials and glucocorticoids, depending on the participant’s initial presentation and 
response. Women and members of minority groups, if eligible, will be included in accordance 
with the NIH Policy on Inclusion of Women and Minorities as Participants in Research 
Involving Human Participants. 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. 
Ability of participant to understand and the willingness to sign a written informed 
consent document. 
2. 
Participation and enrollment in companion protocol, 15-D-0051, Characterization of 
Diseases with Salivary Gland Involvement. 
3. 
Stated willingness to comply with all study procedures and availability for the 
duration of the study 
4. 
Male or female, aged between 18-75 years 
5. 
In good general health as evidenced by medical history  
6. 
Meets the 2002 American European Consensus Group classification criteria for 
primary Sjögren's Syndrome or 2016 American College of Rheumatology/European 
League against Rheumatism Classification Criteria (ACR-EULAR) with mild to 
moderate disease activity defined as ESSDAI between 0 to 13 at the screening visit 
and >0 ml/min/gland stimulated saliva flow.  
7. 
Ability to take oral medication and be willing to adhere to the study intervention 
regimen 
8. 
If on glucocorticoids, the dose must be less than 10 mg daily and stable for the 4 
weeks (28 days) prior to screening visit. 
9. 
If on hydroxychloroquine or other antimalarials such as chloroquine or quinacrine, 
the dose must have been stable for the 12 weeks (96 days) prior to screening visit. 
The maximum allowed dose is hydroxychloroquine up to 400 mg/day or 6.5 
mg/kg/day if more than 400 mg/day. The maximum allowed dose for chloroquine 
phosphate is up to 500 mg daily and for quinacrine up to 100 mg daily. 
10. Participants may be on lipid lowering medications if initiated at least 3 months prior 
to the screening visit and dose must be stable for 4 weeks (28 days) prior to study 
entry. 
11. Males and females with potential for reproduction must agree to practice effective 
birth control measures. Females should be on adequate contraception if they are of 
child-bearing potential documented by a clinician, unless participants or spouse have 
previously undergone a sterilization procedure. Adequate birth control measures are: 
intrauterine device (IUD) alone or hormone implants, hormone patches, injectable, 
or oral contraceptives plus a barrier method (male condom, female condom or 
diaphragm), abstinence or a vasectomized partner. 

36 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
12. Agreement to adhere to Lifestyle Considerations (see section 5.4) throughout study 
duration 
5.2 EXCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must not meet any of the 
following criteria: 
1. 
Current or prior treatment with rituximab, belimumab or any other biologic agent in 
the 6 months prior to screening. 
2. 
Current treatment with methotrexate, azathioprine, mycophenolate mofetil, 
cyclosporine, tacrolimus, or other less common immunomodulatory drugs such as 
those falling into the class of disease-modifying antirheumatic drugs (DMARDs), 
not otherwise specified herein. Participants previously on methotrexate, 
azathioprine, mycophenolate mofetil, cyclosporine or tacrolimus, or other DMARDs 
should have withdrawn drug for at least 8 weeks (56 days) at the time of screening. 
3. 
Treatment with cyclophosphamide, pulse methylprednisolone or IVIG within 6 
months prior to screening. 
4. 
Current treatment with potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., 
ketoconazole) or receiving one or more concomitant medications that result in both 
moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., 
fluconazole) that would increase serum availability of Tofacitinib. Past treatment 
with the aforementioned agent is allowed if it was more than a week prior to the 
administration of the first dose of study medication. 
5. 
History of chronic liver disease, not including well-controlled Sjogren’s-related 
chronic liver disease or elevated LFTs: 
▪ 
ALT or AST ≥ 2x upper limit of normal at screening 
▪ 
 Serum unconjugated bilirubin > 2mg/dL at screening 
6. 
Serum creatinine >1.5mg/dL. 
7. 
Protein to creatinine ratio of more than 1mg/dL at screening (repeated and 
confirmed three times or confirmed with 24 hours urine protein of more than 1000 
mg). 
8. 
Active urinary sediment (WBC, RBC or mixed cellular casts 1+ or more /hpf). 
9. 
Hypercholesterolemia: Values after 8-12 hour fasting blood specimen: total 
cholesterol >250 mg/dL or LDL >180 mg/dL or hypertriglyceridemia (triglyceride 
>300 mg/dL) within - 45 days of screening visit. 
10. WBC <2500/µL or ANC <1,000/µL, Hgb <9.0 g/dL or platelets <70,000/µL or 
absolute lymphocyte count < 500/µL. 
11. Pregnant or lactating women. Women of childbearing potential are required to have 
a negative pregnancy test at screening. 
12. A history of drug or alcohol abuse within the 6 months prior to screening. 
13. Currently receiving hemodialysis, peritoneal dialysis, or intestinal dialysis. 
14. Active infection that requires the use of oral or intravenous antibiotics unresolved at 
least 14 days prior to the administration of the first dose of study medication. 
15. Active chronic infections including but not limited to HIV, Hepatitis B, Hepatitis C, 
and BK viremia at screening visit. 

37 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
16. Current or previous diagnosis of malignant disease, except for basal cell or 
squamous cell carcinoma of the skin with complete excision and clear borders or 
adequately treated in situ carcinoma of the cervix. 
17. Known active tuberculosis. Participants with treated latent tuberculosis (LTB) will 
be eligible to participate. Participants with untreated LTB will not be excluded but 
will be evaluated by an infectious disease (I.D.) consultant and may become eligible 
for trial based on infectious disease consultant recommendations.  
18. History of severe or systemic infection caused by common pathogens, or history of 
infection with pathogens that normally do not cause human disease.  
19. Participants with active renal or central nervous system disease or a high activity 
level in any organ system (except articular) in ESSDAI54. 
20. Participants with known increased risk factors for major adverse cardiac event 
(MACE) including a history of: 
• 
Ischemic heart disease (e.g., history of acute myocardial infarction) 
• 
Heart failure 
• 
Cardiomyopathy 
• 
Severe valvular heart disease 
• 
Significant arrhythmias  
• 
Chronic renal failure 
• 
Cerebrovascular accident or transient ischemic attack 
• 
Uncontrolled diabetes mellitus 
• 
Uncontrolled hypertension 
• 
Current smokers or former smokers with less than 3 years since complete 
cessation and/or >20 pack-years of smoking history. 
21. Significant impairment of major organ function (lung, heart, liver, kidney) or any 
condition that, in the opinion of the Investigator, would jeopardize the participant’s 
safety following exposure to the study drug. 
22. Known history of arterial or venous thrombosis or at high risk for clotting disorder 
23. Psychiatric illness or history of medical non-compliance that the study team feels 
will make the patient unlikely to complete the study 
24. Uncontrolled thyroid disease as per PI or medically responsible investigator. 
25. Known allergic reactions to Tofacitinib or its components 
26. Treatment with another investigational drug/intervention within six months except 
for COVID-19 vaccines or therapies that have been granted an FDA emergency 
authorization. 
5.3 INCLUSION OF VULNERABLE PARTICIPANTS 
We do not intend to enroll the following vulnerable populations: children, pregnant women, 
prisoners, or decisionally-impaired adults. 
Spanish speakers and patients who speak other languages may be eligible for participating in this 
study. We will use a Spanish translated version of the long form for enrollment of Spanish 
speaking participants. NIH translators will be provided at study appointments. 

38 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
5.3.1 Participation of NIH Staff or family members of study team members 
NIH staff and family members of study team members may be enrolled in this study as long as 
this population meets the study entry criteria.  Neither participation nor refusal to participate as a 
subject in the research will have an effect, either beneficial or adverse, on the participant’s 
employment or position at NIH. 
We will follow the requirements outlined in Policy 404 Research Involving NIH Staff as Subjects, 
ensuring the guidelines (https://policymanual.nih.gov/3014-404) are met.  
Every effort will be made to protect participant information, but such information may be 
available in medical records and may be available to authorized users outside of the study team 
in both an identifiable an unidentifiable manner. 
The NIH Frequently Asked Questions (FAQs) for Staff Who are Considering Participation in 
NIH Research will be made available. Please see section 10.1.1 for consent of NIH Staff 
Lifestyle Considerations. 
During this study, participants are asked to: 
• Fast overnight (past midnight) for the following visits: Screen, Day 1, Day 84, Day 168 
and Day 196. 
• Withhold salivary stimulants for 24 hours prior to saliva collection. 
• Refrain from eating or drinking anything for 1 ½ hours prior to having a saliva collection. 
Saliva collection is done at the following visits: Screen, Days 1, 84, 168 and 196. 
5.4 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomized to a study arm. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) due to 
failing to meet entry criteria, may be rescreened and considered for study participation. 
Rescreened participants should be assigned the same participant number as for the initial 
screening. 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
Multiple recruitment strategies are planned using the IRB approved recruitment material.   Our 
primary recruitment approach will be to contact participants already known to the Sjögren’s 
syndrome NIDCR clinical protocols (15-D-0051 and 11-D-0172) where participants have 
consented to be contacted regarding future studies. 
Additional methods for recruitment will include contacting patient support groups (e.g., 
Sjogren’s Foundation) as well as contacting referring physician groups to advertise and 
potentially refer participants.  We will utilize the services of NIH Clinical Center Office of 
Patient Recruitment and adhere to the NIH Clinical Center Media Policy. Various NIDCR social 
media platforms which adhere to NIH and the IC’s social media guidelines may also be used.  

39 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
For recruitment, the study team will ensure that social and new media applications and accounts 
are set up and managed in accordance with Section 508 of the Rehabilitation Act of 1973: 
guidance available at http://www.hhs.gov/web/508/index.html and HHS policy available at 
https://intranet.hhs.gov/it/strategy-policy-governance/policies-standards-guides/508-
accessibility-of-technology.html. For all the recruitment strategies, we will use the approved 
recruitment materials.   
Target Patient Samples Size by Gender and Race and Ethnicity: 30 total patients which will 
include approximately 27 females and 3 male participants, which reflects the typical female: 
male distribution of patients in our clinic. We anticipate that 10% of our participants will be non-
white reflecting our current racial-ethnic distribution in our clinic. 
Participants may also be recruited: 
• Outpatient Sjögren’s syndrome and Salivary Disorders Clinic, or Rheumatology Clinic of 
the Clinical Center at the NIH or the NIAMS Community Health Center; 
• Participants referred for treatment and/or second opinion to the NIH; 
• Local area rheumatologists, internists, dental practices, and university hospital clinics; 
• Participants that are referred by their local providers, we will requested to contact the 
research coordinator directly to initiate a release of medical records for review for study 
eligibility. Consistent with our current research protocols in this study population, we 
expect the sending provider has obtained a signed HIPAA authorization or other type of 
signed medical release of information (if under the Privacy Act or outside of the US) to 
be able to share these records or specimens with the study coordinator. 
5.5.1 Recruitment of women, children, and minorities: 
Minors and pregnant women will not be included in this study. This is a Phase Ib-IIa study 
involving greater than a minor increment over minimal risk without the prospect of direct benefit 
to participants based on currently available data. The sex distribution (female: male) for SS is 
9:1; recruitment is expected to support this distribution. 
5.5.2  Costs 
We do not anticipate any direct costs for study participation. 
5.5.3 Compensation 
Participants will receive financial compensation for time required to participate in the research as 
per NIH guidelines. The participants will be paid $130 at each outpatient visit. In addition, 
participants will be paid an additional $100 at the end of study visit Day 196 as a study 
completion bonus. Patients who receive a second (or additional non-diagnostic biopsy) biopsy 
will be paid $220 for each additional salivary gland biopsy. Any participant who withdraws from 
study will be paid for the number of visits completed. For participants living outside a 45-mile 
radius, travel compensation may be provided at discretion of the principal investigator. 
Meal cost will be reimbursed up to $50.00 USD a day per participant per study visit for 
participants travelling from outside a 45-mile radius to the Clinical Center. 

40 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
6 
STUDY INTERVENTION 
6.1 STUDY INTERVENTIONS(S) ADMINISTRATION 
Tofacitinib (Pfizer, Inc.) is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that 
transmit signals arising from cytokine or growth factor-receptor interactions on immune cell 
membranes to influence cellular processes of haematopoiesis and immune cell function. Within 
the signalling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of 
Transcription (STATs) which modulate intracellular activity including gene expression. 
Tofacitinib modulates the signalling pathway at the point of JAKs, preventing the 
phosphorylation and activation of STATs.  
Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-
methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-β-oxo-1- piperidinepropanenitrile, 2-
hydroxy-1,2,3-propanetricarboxylate (1:1) It is freely soluble in water and has a molecular 
weight of 504.5 Daltons. Tofacitinib is supplied for oral administration as 5 mg white round, 
immediate-release film-coated tablets. Each tablet of Tofacitinib contains the appropriate amount 
of Tofacitinib citrate salt and the following inactive ingredients: microcrystalline cellulose, 
lactose monohydrate, croscarmellose sodium, magnesium stearate, HPMC 2910/Hypromellose 
6cP, titanium dioxide, macrogol/PEG3350, and triacetin. 
There will be no IND obtained for the use of any of the investigational agents used in this study.  
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; the drugs are 
already approved and marketed and the investigation is not intended to support a significant 
change in advertising; and the investigation does not involve a route of administration or dosage 
level in use in a patient population or other factor that significantly increases the risks (or 
decreases the acceptability of the risks) associated with the use of the drug product. The Food 
and Drug Administration was contacted on 12/18/2019 for a determination for IND and 
approved a waiver on 01/23/2020; a copy of the FDA IND waiver for IND is provided. 
6.1.1 Dosing and Administration 
The package insert with the recommended dosing is provided. Each participant will be dosed 
with 5 mg (1 tablet) twice daily for 168 days as is recommended for the treatment of rheumatoid 
arthritis. Tofacitinib and placebo tablets will be supplied by Pfizer Incorporated to the NIH 
Clinical Center Research Pharmacy. 
6.1.2  Participant Dosing Considerations 
Participants entering the study will have mild to moderate disease activity. Based on the known 
response to Tofacitinib in RA, animal studies, and cellular assays; we expect a similar rapid 
response in SS participants. 
• Any participants experiencing a flare of glandular or extra-glandular manifestations of 
Sjögren's syndrome, evaluated by the PI or the medically-responsible investigator will be 
re-evaluated in two (2) weeks (14 days). Study drug will be continued during the 
monitoring period. If disease activity continues to worsen, the participant will be 
withdrawn from the study as per Section 7. 

41 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• Participants with absolute neutrophil count (ANC) 500 to 1000 cells/mm3, will have 
study drug dosing interrupted until absolute neutrophil count (ANC) is greater than 1000 
within 28 days; at that time study drug dosing will resume at 5 mg, orally, twice daily. 
Otherwise, participants will be withdrawn per Section 7. 
• Participants with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL from 
baseline will have study drug dosing interrupted and held until hemoglobin values have at 
least returned to baseline within 28 days at which time study drug will be reintroduced. 
Otherwise, participants will be withdrawn per Section 7.  
• Study drug may be interrupted at the discretion of the investigator if it is in the best 
interest of the participant. 
Drug Administration 
A 35-day supply of study drug or placebo will be dispensed to participants on study days 1, 28, 
56, 84, 112,140 visits as well as unscheduled visits, if required with instructions regarding the 
twice daily dosing regimen and a review of potential side effects. No drug will be dispensed to a 
female participant of reproductive potential until negative pregnancy test results (serum or urine) 
have been obtained within 24 hours of on site visit. 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
Tofacitinib five (5) milligram (mg) tablets are white, round, immediate release film-coated 
tablets, debossed with “Pfizer” on one side and “JKI 5 on the other side. Tofacitinib tablets will 
be stored at 20°C to 5°C 68°F to 77°F) as per manufacturer’s recommendations included in 
labelling. 
6.2.1 Acquisition and Accountability 
Pfizer is providing seventy-count (#70) labelled bottles of 5 mg Tofacitinib and placebo. These 
bottles will be dispensed monthly to the study participants by pharmacy after protocol mandated 
visit is completed and all clinical and study parameters meet approval of the PI or AI seeing the 
participant. 
6.2.2 Formulation, Appearance, Packaging, and Labeling 
Tofacitinib tablets contain 5 mg Tofacitinib. They are white, round, immediate-release film 
coated tablets, debossed with “Pfizer” on one side, and “JKI 5” on the other side. 
6.2.3 Product Storage and Stability 
The drug and placebo will be stored in the NIH Pharmacy according to the 
manufacturer’s suggested storage conditions. 
6.2.4 Preparation 
Study drugs are provided in the expected quantity and preparation. 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Randomization will be done by the NIH Clinical Research Center Pharmacy in conjunction with 
the statistician associated with the study. This is a two-arm, double blind study. 
The study will utilize the stratified block randomization method to ensure that the Tofacitinib 
and placebo groups are balanced with respect to the baseline disease activity level. Eligible 

42 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
subjects will be stratified according to the ESSDAI score (0-1 vs. 2-13). Within each stratum, 
subjects will be randomly assigned by use of computer-generated blocks of size 3 with a 2:1 ratio 
to Tofacitinib or control group. Thus, participants will be randomized to either Tofacitinib or 
placebo in a 2:1 ratio overall. Both participants and investigators will be blinded to treatment 
allocation. Unblinding for analysis will occur once all the collected study data has been entered 
and the database is locked. Participants and local treating physicians will be informed of 
treatment allocation by a letter sent by certified mail, at that time. 
The blind will be held by the statistician and the NIH Clinical Center Research Pharmacy. In 
cases where breaking the blind is necessary to provide clinical care to the participant, as 
determined by the PI and medically responsible team member, Sarthak Gupta, MD, the PI will 
contact the NIH Clinical Center Research Pharmacy and provide the treatment allocation 
information to the treating physician. Such participant(s) would be withdrawn from the study and 
followed up as described in section 4.10 above. 
The Data and Safety Monitoring Committee (DSMC) may also request unblinding of treatment 
allocation or group assignment. These requests will be transmitted to the NIH Clinical Center 
Research Pharmacy by the PI. Data will be provided directly to the DSMC Chair without 
unblinding the investigators before the DSMC determines a plan of action. 
6.4 STUDY INTERVENTION COMPLIANCE 
Compliance with study drug dosing will be assessed during on-site visits, at study day 28, 56, 84, 
112, 140, 168 visits as well as unscheduled visits, if required. Participants will be asked to bring 
their bottles of study drug for a recorded pill count. Participants who have demonstrated less than 
80% compliance at study visits will be withdrawn from the study. Compliance with study 
medication will be determined by the PI based on multiple factors, including but not limited to 
pill count, overall compliance with study procedures, and the reliability of self-reporting of 
compliance based on prior interactions. Study treatment compliance will also be assessed on 
telephone calls on day 7, 21, 42, 70, and 154 (+/- 3 days). A standard scripted conversation will 
be used for telephone calls to determine compliance with protocol requirements. Participants 
withdrawn from the study after receiving study treatment will be asked to follow up to complete 
the study days 168 and 196. 
6.5 MISSING STUDY MEDICATION  
Doses and loss of medication bottle are possible occurrences during the 24-week (168 day) 
dosing period. Missed doses will be documented at each compliance check but will not result in 
a protocol deviation. In the event a dispensed bottle of study drug is lost by a participant, the 
study team will contact pharmacy and dispense a replacement bottle to the participant. A note to 
file will be created describing the event in detail and the incident will be reported to Pfizer. In the 
event the missing study drug is found, participants will be advised to return it.   
6.6 CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form 
(CRF) are concomitant prescription medications, over-the-counter medications and supplements. 
Concomitant therapy information will be recorded at all study visits including screening. 

43 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
The following medications are allowed provided that they are administered at stable doses during 
the study: 
• Antimalarial (hydroxychloroquine 400 mg/day or ≤6.5 mg/kg/day, if more than 400 
mg/day, chloroquine phosphate 500 mg daily, quinacrine 100 mg daily); must already be 
on stable dose of this medication 12 weeks (96 days) prior to study entry. 
• Prednisone or equivalent steroid dose up to 10 mg /day must already be on stable dose of 
this medication four (4) weeks (28 days) prior to study entry. 
• ACE (angiotensin converting enzyme) inhibitors or angiotensin receptor blocking (ARB) 
medications, must already be on stable dose of this medication four (4) weeks (28 days) 
prior to study entry. 
• Prescription medications with oral drying as a known side effect, such as anti- 
cholinergic, anti-histamines, selective serotonin reuptake inhibitors, tricyclic anti- 
depressants, amphetamines, should be stable for 12 weeks (96 days) prior to screening 
visits. 
• Lipid lowering medications if initiated at least three (3) months prior to the screening 
visit. The dose of any of these medications can be decreased (temporally or for the 
duration of the study) if clinically indicated for toxicity. 
The following systemically administered medications and vaccines listed below will not be 
allowed during treatment. A list of prohibited medications which will be provided to the 
participants upon consenting will be reviewed to confirm any of those medications are included 
in their standard treatment regimen. Local administration of prohibited medications may be 
allowed in certain circumstances (e.g., Cyclosporine, locally administered corticosteroid 
injections) at the discretion of the PI or Medically Responsible Investigator. Any clinical 
indication requiring treatment with medications listed below will lead to cessation of study 
treatment. Withdrawn participants will be asked to return according to the follow up phase of the 
study and to complete all study procedures. 
• Rituximab. 
• Any other biologic agent including TNF-α blockers, IL-1 blocking agents, anti-IL-6 
agents, belimumab, abatacept. 
• Cyclophosphamide. 
• Azathioprine. 
• Mycophenolate mofetil. 
• Rapamycin. 
• Cyclosporine.* 
o Topical cyclosporine used for keratoconjunctival sicca will be permitted. 
• Tacrolimus. 
• Methotrexate. 
• Administration of any live virus vaccines. 
• Participants may be on prednisone ≤10 mg/day at study entry. Prednisone may be 
increased as indicated after the end of the treatment period on Day 168 (- 7 days). At the 
investigator’s discretion, glucocorticoids may be tapered during the study. 
• Any other less common DMARDs 

44 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
The study team will make every attempt for the newly enrolled subjects to receive their COVID-
19 vaccine booster from an outside vaccination clinic before randomization. In the event that an 
enrolled subject requires a vaccine booster during the treatment phase, the study team will make 
an accommodation of a 1-week interruption of the study drug. The subject will receive the 
vaccination at their preferred vaccination clinic. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from study intervention does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. Once 
enrolled, should study participant evidence a clinically significant finding, the PI or Medically 
Responsible Investigator will determine if any change in participant management is needed.  
An investigator may discontinue study intervention in a participant for the following reasons: 
• Completion of study intervention 
• Disease progression which requires discontinuation of the study intervention 
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• Investigator discretion as in Sections 6.4, 6.5 and 7.2 
• Positive pregnancy test 
• Lymphocyte count less than 500 cells/mm3, confirmed by repeat testing 
• ANC less than 500 cells/mm3, confirmed by repeat testing 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 14 days (+14 days) following the last dose of study therapy.   Participants are free 
to withdraw consent at any time upon request. Participants may also choose to withdraw 
treatment but remain in the study for follow up. Participants must be withdrawn consistent with 
Section 6.1.2. Additionally, the PI or Medically Responsible Investigator may also choose to 
withdraw treatment or withdraw a participant from the study based on clinical or professional 
judgement. An investigator may withdraw treatment or a participant from study for the following 
reasons: 
• Request by participant to be withdrawn from the study. 
• Flares not resolving within 28 days or if, in the opinion of the medically-responsible 
investigator, the participant requires immediate immunosuppressive therapy that is not 
allowed in the protocol. 
• Any Grade 4 adverse event that is unexpected and at least possibly related to study drug. 
• More than 45 days delay in treatment after the screening visit. 
• More than one (1) “no-show” for a visit. 
• Persistent elevation of LFTs of > 2 times upper limit of normal persistently present on 
repeated samples 14 days +/- 7 days apart. 

45 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• >30% increase in serum creatinine from baseline at enrollment, persistently present on 
repeated samples 14 days +/- 7 days apart. 
• Increase in proteinuria at the time of screening visit to protein to creatinine ratio of more 
than 1.000 mg/dL or more than 1000 mg in a 24 hours urine collection, persistently 
present on repeated samples 14 days +/- 7 days apart. 
• Any other reason that, in the opinion of the responsible Investigator or Medically 
Responsible Physician, poses unacceptable risk to the participant. 
• Infections requiring intravenous antibiotic treatment. 
• Development of any malignancy. 
• Urine BK virus level of more than 10 million copies/ml by quantitative PCR or detection 
of BK virus in serum by quantitative PCR. 
• Non-compliance with treatment (<80% compliance by pill count). 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Voluntary Study Withdrawal Case Report Form (CRF). Participant who signs informed consent 
and are randomized, but do not receive the study drug, may be replaced. 
Participants who sign informed consent, and are randomized and receive the study intervention, 
and subsequently withdraw, or are withdrawn from the study, will be replaced. 
A Participant is considered to have completed the study when he/she has completed 168 days of 
treatment with Tofacitinib and the day 196 follow-up assessments. 
Participants randomized to a study arm who withdraw from the trial prior to starting on study 
drug will be replaced. Participants who withdraw study treatment and/or withdraw from the trial 
for any reason other than drug related adverse events after initiating the first dose of Tofacitinib 
and before completing 112 doses of Tofacitinib (study day 56) will also be replaced in order to 
maintain the sample size of 20 participants on Tofacitinib and 10 participants on placebo, for 
total of 30 evaluable participants. Based on experience with studies in SS participants, we expect 
a withdrawal rate of approximately 25% and therefore plan for a target enrollment of 30 
participants plus 11 participants in event of participant withdrawal.  
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for two (2) scheduled 
visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit within 7 
days and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 

46 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 STUDY ASSESSMENT AND PROCEDURE SCHEDULING 
All the procedures and assessments explained below may be completed within the visit window 
period -45 days for the screening visit and +/- 7 days for follow up visits to accommodate 
scheduling and to reduce burden to participants (i.e., flexibility to optimize time in clinic to 
accommodate patient preferences). 
8.1.1 STUDY PHASES 
PRE-SCREENING VIA PROTOCOL: 15-D-0051 
Participants will be pre-screened on the "Characterization of Diseases with Salivary Gland 
Involvement" protocol (15-D-0051). Those with mild-to-moderately active primary SS and no 
obvious exclusion criteria will be offered the chance to enroll in 20-D-0131.  
NIH participants with SS who are identified from either Protocol 11-D-0172 or Protocol 15-D-
0051 will be offered participation in the study if they are found to have mild to moderate disease 
activity and no obvious exclusion criteria. Pre-screening assessments will be done during routine 
clinical follow up or initial evaluations and will include review of medical history, physical 
examination and laboratory assessment and concomitant medications. All participants referred to 
this study will be enrolled to protocol 15-D-0051. 
Screening Period (-45 days to Day 1): 
Participants may be scheduled for screening visits at the NIH Dental clinic, NIH Outpatient 9 
Clinic or the 5SWS Day Hospital. Screening procedures will be performed as part of this study. 
Any protocol mandated screening parameter greater than 30 days from screening visit must be 
repeated for the screening visit. Subjects will be asked to fast on the day of the appointment and 
to avoid taking saliva stimulants 24 hours prior to the appointment. 
The following procedures will be done during the Screening Period: 
• Informed Consent 
• Review of inclusion and exclusion criteria 
• Medical history and physical examination, 
• Vital sign measurements, 
• Dental history, 
• Oral, and Head and Neck examinations, 
• Saliva Collection 
• Saliva Flow rates  
• Salivary Gland Ultrasound, 
• Comprehensive Ophthalmologic Exam 
o Vision exam  
o Intraocular pressure (IOP)  
o Dilated exam (fundoscopy) 
o Schirmer’s test with and without anesthesia 

47 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
o Ocular surface staining (Fluorescein, Lissamine green) 
• EKG 
• Concomitant medications review 
• Minor Salivary Gland Biopsy. (If participants were previously seen on 15-D-0051 within 
the last twelve months and the appropriate minimum necessary tissues and research 
studies were procured, this biopsy may be used as the baseline biopsy). 
• Assessment of SS activity: ESSDAI, PGA 
• Laboratory studies: 
o Complete blood count with differential, 
o Serum chemistry panel (creatinine, glucose, urea nitrogen, total bilirubin, alanine 
aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin), 
o Pregnancy test (serum or urine; for females with reproductive potential only), 
o Urinalysis and random urine protein/creatinine ratio, 
o Lipid panel: LDH (low density lipoprotein), HDL (high density lipoprotein), TG 
(Triglycerides), Total cholesterol 
o Lipoprotein Profile: Apolipoprotein A-1, Apolipoprotein 
o ANA and anti-ENA panel (anti-RNP, anti-SmRNP, anti-SSA, anti-SSB), 
anticardiolipin antibodies, lupus anticoagulant, and anti-beta2-glycoprotein 
antibodies, anti-dsDNA antibodies, 
o Serum complement components C3 and C4 
o Quantitative Immunoglobulins: IgA, IgG, IgM  
o Serum protein electrophoresis (SPEP) 
 
o Screening serologies for hepatitis B, hepatitis C and HIV (per NIH lab each of these 
tests may only be done once within a six month period) 
o Tuberculosis screening using the QuantiFERON Gold test 
o Anti-varicella IgG 
o BK virus serum and urine quantitative PCR level 
o Cryoglobulins 
After confirmation of eligibility, the PI or otherwise designated AI will contact the Clinical 
Center Research Pharmacy to randomize the Participant. 
8.2 EFFICACY ASSESSMENTS 
8.2.1 Clinical Evaluations 
Clinical assessments will take place the Dental Clinic, Outpatient Clinic (OP), or 5SWS Day 
Hospital. Vascular assessments will be performed in the Vascular Lab of the CRC, Salivary 
assessments will be performed at the Salivary Disorders and Sjögren’s syndrome Clinic at the 
Dental Clinic, Outpatient Clinic 1 (OP1). Subjects will be asked to fast on the day of the 
appointment and to avoid taking saliva stimulants 24 hours prior to the appointment.  
Study Day 1/Visit 2 (on site visit): 
● Concomitant medication review  
● Drug Accountability- Dispense 35-day supply of study drug 
● Vital sign assessments 
● Presenting symptoms, abbreviated medical history, and physical examination 
● Adverse event review 

48 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
● Dental History and Oral and Head and Neck examination 
● Salivary Collection 
● Salivary flow rate 
● Oral Microbiome   
● Laboratory studies: 
o Complete blood count (CBC) with differential, 
o Serum chemistry panel (creatinine, glucose, urea nitrogen, 
total bilirubin, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, albumin), 
o Pregnancy test (urine or serum; for females of reproductive potential 
only), 
o Urinalysis and random urine protein/creatinine ratio, 
o BK virus serum and urine quantitative PCR level, 
o Lipid panel: LDH (low density lipoprotein), HDL (high density 
lipoprotein), TG (Triglycerides), Total cholesterol, 
o Lipoprotein Profile (Apolipoprotein A-1, Apolipoprotein) 
o Lymphocyte pheno-TBNK, 
o Inflammatory markers (hs-CRP, ESR), 
o ANA and anti-ENA panel (anti-RNP, anti-SmRNP, anti-
SSA, anti-SSB), anticardiolipin antibodies, lupus 
anticoagulant, and anti-beta2-glycoprotein antibodies, Anti-
ds DNA antibodies, 
o Serum complement components C3 and C4, 
o Quantitative immunoglobulins (IgA, IgG, IgM), 
o Research Labs - 2 red SST, 6 red/green CPT, 1 PAX 
RNA);  
o Anti-SARS-CoV-2 antibodies  
• 
Mechanistic studies: (intracellular signaling molecules, 
cytokine expression, circulating immune cell types and 
autoreactive B cells) – All samples will be run simultaneously 
for each assay at the end of the study 
• 
Assessment of SS disease activity (ESSDAI, PGA) 
• 
Vascular function studies:  
o Peripheral Wave Analysis (SphygmoCor) 
o Peripheral Arterial Tonometry (Endopat)   
o Cardio-ankle vascular index (CAVI) 
• Patient questionnaires (ESSPRI, Dry Mouth Questionnaire, OHIP-14, 
Xerostomia VAS, FSS, PROMIS-57, SF-36, AECG Symptom Questionnaire) 
• Study drug administration:  
o A 35-day supply of study drug or placebo will be dispensed to 
participants on study day 1 with instructions regarding twice daily dosing 
regimen and a review of potential side effects. No drug will be dispensed 
to a female participant of reproductive potential until negative pregnancy 
test results (serum or urine) have been obtained within 24 hours.  

49 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
o For acute infection(s) requiring antibiotics discovered on Day 1: Any 
participant found to have an acute infection at baseline visit (Day 1 visit) 
will have the study drug withheld and their next visit will be scheduled 
for no more than 30 days later; 
o Infections prior to 14 days of Day 1: study medication may be 
administered 
o Between -14 to Day 1: study drug will be delayed up to the upper limit of 
45 days from screen date 
o If the above stated 14 days puts the patient beyond the limits of protocol 
mandated pre-screening interval, the participant will be excluded from 
study participation and then give the opportunity to be re-evaluated and 
re-enrolled. 
o If the infection resolves, study medication will be started. If infection 
does not resolve within 30 days the participant will be removed from the 
study 
o If a medically significant abnormal lab result (i.e., complete blood count, 
serum chemistries, pregnancy test, urinalysis and random urine 
protein/creatinine ratio) occurs at baseline (Day 1 visit), requiring repeat 
for confirmation, the study drug will be withheld and the next visit will 
be scheduled no more than 30 days later; if repeat testing reveals 
resolution of abnormal results, participants will be instructed to begin 
study medication. If the abnormal lab result does not resolve, participants 
will be removed from the study. Vascular function studies or research 
labs will not be repeated. 
 
Study Days 7, 21, 42, 70, 154 (+/- 3 days) Telephone Calls 
All participants will receive a telephone call from the study coordinator on study days 7, 21, 42, 
70, and 154 (+/- 3 days). These calls will confirm study drug compliance, document any adverse 
events, and record any new or discontinued concomitant medications. A script with standardized 
questions will be used to confirm compliance with study drug. 
Study Day 14/Visit 3: (on site visit) 
All participants will return to the Clinical Center for study day 14 (+/- 7 days); they will be seen 
in either an outpatient clinic or Day Hospital. The following procedures will be performed at this 
visit: 
• Adverse event assessment 
• Concomitant medication review 
• Vital sign measurements 
• Presenting symptoms, abbreviated medical history and, physical 
examination 
• Laboratory studies: 
o Complete blood count with differential, 
o Serum chemistry panel (creatinine, glucose, urea nitrogen, total 
bilirubin, alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase, albumin), 
o Pregnancy test (urine or serum; for females of reproductive potential 
only), 

50 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
o Urinalysis, random urine protein/creatinine ratio, 
o BK virus serum and urine quantitative PCR level 
 
Study Days 28 (Visit 4), 56 (Visit 5), 112(Visit 7), 140 (Visit 8)  
(on site visits): 
All participants will return to the Clinical Center will be seen at the Dental 
clinic, Outpatient 9 Clinic, or the 5SWS Day Hospital on study days 28, 
56,112,140 (all visits +/- 7 days) for a brief visit. Participants will be asked to 
bring study medication bottle to confirm study drug compliance as well as re-
issued of a new 35 day drug supply. The following procedures will be 
performed at this visit: 
• Adverse event assessment 
• Concomitant medication review 
• Drug accountability-Returning used drug bottle 
• Drug accountability- Dispense 35-day supply of study drug 
• Vital sign measurements 
• Presenting symptoms, abbreviated medical history and physical 
examination 
• Laboratory studies: 
o Complete blood count with differential, 
o Serum chemistry panel (creatinine, glucose, urea nitrogen, total 
bilirubin, alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase, albumin), 
o Pregnancy test (urine or serum; for females of reproductive 
potential only), 
o Urinalysis, random urine protein/creatinine ratio 
o Serum complement components C3 and C4, 
o Quantitative immunoglobulins (IgA, IgG, IgM) 
o BK virus serum and urine quantitative PCR level 
o Inflammatory markers (ESR, CRP) 
• Assessment of SS disease activity (ESSDAI, PGA) 
Study Day 84/Visit 8 (on site visit): 
All participants will be seen at the Dental clinic, Outpatient 9 Clinic or the 
5SWS Day Hospital on study day 84 (+/- 7 days). They will be asked to bring 
study medication bottles to assess drug compliance as well as re-issued of a new 
35 day study drug supply. Participants will be asked to fast after midnight the 
night prior for the fasting lipid profile and to avoid taking saliva stimulants 24 
hours prior to the appointment. The following procedures will be performed at 
this visit: 
● Adverse event assessment 
● Concomitant medication review 
● Drug accountability- Returning used drug bottle 
● Drug accountability- Dispense 35-day supply of study drug 
● Vital sign measurements 
● Presenting symptoms, abbreviated medical history and 
physical examination 
● Interim Dental History and Oral, and Head and Neck 
examination 

51 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
● Ophthalmologic Exam 
o Vision exam,  
o Schirmer’s test with/without anesthesia,  
o Ocular surface staining (Fluorescein, Lissamine green) 
● Saliva Collection 
● Salivary Flow Rate 
● Laboratory studies: 
o Complete blood count with differential, 
o Serum chemistry panel (creatinine, glucose, urea nitrogen, total 
bilirubin, alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase, albumin), 
o Pregnancy test (urine or serum; for females of reproductive 
potential only), 
o Urinalysis and random urine protein/creatinine ratio, 
o ANA and anti-ENA panel (anti-RNP, anti-SmRNP, anti-SSA, 
anti-SSB) anticardiolipin antibodies, lupus anticoagulant, and 
anti-beta2-glycoprotein antibodies, Anti-dsDNA antibodies, 
o Serum complement components C3 and C4 
o Quantitative Immunoglobulins, (IgA, IgG, IgM)  
o Serum protein electrophoresis (SPEP) 
o Inflammatory markers (ESR, CRP) 
o BK virus serum and urine quantitative PCR level 
o Lipid panel: LDH (low density lipoprotein), HDL (high density 
lipoprotein), TG (Triglycerides), Total cholesterol, 
o Lipoprotein Profile, 
o Lymphocyte pheno-TBNK, 
o Research Labs (2 red SST, 6 red/green CPT, 1 PAX RNA) 
• Vascular function studies 
o Peripheral Wave Analysis (SphygmoCor) 
o Peripheral Arterial Tonometry (Endopat)  
• Cardio-ankle vascular index (CAVI)Assessment of SS disease activity 
(ESSDAI, PGA) 
• Patient questionnaires (ESSPRI, Dry Mouth Questionnaire, OHIP-14, 
Xerostomia VAS, FSS, PROMIS-57, SF-36, AECG Symptom 
Questionnaire) 
 
Study Day 168/Visit 9 (end of treatment visit): 
All participants will be seen at the Dental clinic, Outpatient 9 Clinic or the 5SWS 
Day Hospital on study day 168 (+/- 7 days). Study participants will be asked to 
return medication bottles to confirm compliance with study drug and to fast 
overnight for lab tests. Subjects will be asked to avoid taking saliva stimulants 24 
hours prior to the appointment. 
• Adverse event assessment 
• Concomitant medication review 
• Drug accountability-Returning used drug bottle 
• Vital sign measurements 
• Interim Dental History and Oral and Head and Neck examination 
• Saliva Collection 

52 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• Salivary flow rate 
● Oral Microbiome Collection 
● Ophthalmologic Exam 
o Vision exam 
o Schirmer’s test with/without anesthesia 
o Ocular surface staining (Fluorescein, Lissamine green) 
o Pentagraph for tear breakup time, redness scale, tear lake if available 
o MMP-9 simple strip test 
● Minor Salivary Gland Biopsy 
● Salivary Gland Ultrasound 
● Presenting symptoms, abbreviated medical history and physical 
examination 
● Laboratory studies: 
o Complete blood count with differential, 
o Serum chemistry panel (creatinine, glucose, urea nitrogen, total 
bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, albumin), 
o Pregnancy test (urine or serum; for females of reproductive potential 
only), 
o Urinalysis and random urine protein/creatinine ratio, 
o Inflammatory markers (CRP, ESR), 
o ANA and anti-ENA panel (anti-RNP, anti-SmRNP, anti-SSA, anti-
SSB), anticardiolipin antibodies, lupus anticoagulant, and anti-beta2-
glycoprotein antibodies, Anti-dsDNA antibodies, 
o Serum complement components C3 and C4 
o Quantitative Immunoglobulins, (IgA, IgG, IgM) 
o Serum protein electrophoresis (SPEP) 
o Lipid panel LDL (low density lipoprotein), HDL (high density 
lipoprotein), TG (triglycerides), total cholesterol 
o Lipoprotein Profile 
o Lymphocyte pheno-TBNK 
o BK virus serum and urine quantitative PCR level 
o Anti-SARS-CoV-2 Antibodies 
o Mechanistic studies: (intracellular signaling molecules, cytokine 
expression, circulating immune cell types and autoreactive B cells) – 
All samples will be run simultaneously for each assay at the end of the 
study 
• Assessment of SS disease activity (ESSDAI, PGA, Salivary flow) 
• Patient questionnaires (ESSPRI, Dry Mouth Questionnaire, OHIP-14, 
Xerostomia VAS, FSS, PROMIS-57, SF-36, AECG Symptom 
Questionnaire) 
• EKG 
• Assessment of biologic effect  
• Assessment of durability of the clinical and biological effects  
Study Day 196 (end of study visit): 

53 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
All participants will be seen at the Dental clinic, Outpatient 9 Clinic or the 5SWS Day Hospital. 
They will be asked to bring their bottles of study drug to account for any remaining study drug at 
the end of study visit (+/- 7 days). Participants will be asked to fast after midnight the night prior 
for the fasting lipid profile. Subjects will be asked to avoid taking saliva stimulants 24 hours 
prior to the appointment. The following procedures will be performed at this visit: 
• Adverse event assessment 
• Concomitant medication review 
• Vital sign measurements 
• Interim Dental History and Oral, Head and Neck Exam  
• Saliva Collection 
• Saliva Flow rates 
• Ophthalmologic Exam 
o Vision exam 
o Intraocular pressure (IOP)  
o Schirmer’s test with/without anesthesia 
o Ocular surface staining (Fluorescein, Lissamine green) 
o Pentagraph for tear breakup time, redness scale, tear lake (if available) 
• Presenting symptoms, abbreviated medical history, and physical 
examination 
• Laboratory studies: 
o Complete blood count with differential, 
o Serum chemistry panel (creatinine, glucose, urea nitrogen, total 
bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase), 
o Pregnancy test (urine or serum; for females of reproductive potential 
only), 
o Urinalysis and random urine protein/creatinine ratio, 
o Inflammatory markers (CRP, ESR), 
o ANA and anti-ENA panel (anti-RNP, anti-
SmRNP, anti-SSA, anti-SSB) anticardiolipin 
antibodies, lupus anticoagulant, and anti-beta2-
glycoprotein antibodies, Anti-dsDNA antibodies, 
o Serum complement components C3 and C4 
o Quantitative Immunoglobulins, (IgA, IgG, IgM) 
o Serum protein electrophoresis (SPEP)Lipid panel 
LDL (low density lipoprotein), HDL (high 
density lipoprotein), TG (Triglycerides), total 
cholesterol 
o Lipoprotein Profile 
o Lymphocyte pheno-TBNK 
o BK virus serum and urine quantitative PCR level 
o Research Labs (2 red SST, 6 red/green CPT, 1 PAX RNA) 
o Mechanistic studies: (intracellular signaling molecules, 
cytokine expression, circulating immune cell types and 
autoreactive B cells) – All samples will be run 

54 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
simultaneously for each assay at the end of the study 
● EKG 
● Assessment of SS disease activity (ESSDAI, PGA) 
● Patient questionnaires (ESSPRI, Dry Mouth Questionnaire, 
OHIP-14, Xerostomia VAS, FSS, PROMIS-57, SF-36, 
AECG Symptom Questionnaire). 
● Vascular function studies 
o Peripheral Wave Analysis (SphygmoCor) 
o Peripheral Arterial Tonometry (Endopat) 
o Cardio-ankle vascular index (CAVI) 
• Assessment of biologic effect  
• Assessment of durability of the clinical and biological effects  
 
Unscheduled Visits: 
In the event of an adverse event or other reason that results in an unscheduled visit and will take 
place at the Dental clinic, Outpatient 9 Clinic, the 5SWS Day Hospital. Clinically appropriate 
assessments from the list below will be completed at the discretion of the principal investigator 
and medically responsible investigator at this visit: 
● Adverse event assessment (AE) 
● Concomitant medication review 
● Vital sign measurements 
● Medical history and physical examination 
● Laboratory studies 
o 
Complete blood count with differential, 
o 
Serum chemistry panel (creatinine, glucose, urea nitrogen, total 
bilirubin, alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase) 
o 
Pregnancy test (urine or serum; for females of reproductive potential 
only) 
o 
Urinalysis and random urine protein/creatinine ratio, 
o 
Inflammatory markers (CRP, ESR), 
o 
anti-ENA (Sm, RNP, SSA, SSB), serum complement components 
C3 and C4 
o 
Quantitative Immunoglobulins (IgA, IgG, IgM) 
o 
Serum protein electrophoresis (SPEP) 
o 
Lipid panel LDL (low density lipoprotein), HDL (high density 
lipoprotein), TG (Triglycerides), total cholesterol 
o 
Lipoprotein Profile 
o 
Lymphocyte pheno-TBNK 
o 
BK virus serum and urine quantitative PCR level 
o 
Research Labs (2 red SST, 6 red/green CPT, 1 PAX RNA) 
● 
EKG 
● 
Assessment of SS disease activity (ESSDAI, PGA) 

55 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
● 
Patient questionnaires Patient questionnaires (ESSPRI, Dry Mouth 
Questionnaire, OHIP- 14, Xerostomia VAS, FSS, PROMIS-57, SF-36, 
AECG Symptom Questionnaire) 
● 
Drug accountability 
8.2.2 Follow-up/Termination Procedures: 
While on this study, participants will continue to receive regular medical care from their primary 
physicians. Any AEs reported will be followed by the investigators as described in Section 
16.1.8. Following completion of the study or after withdrawal from the study, participants will 
return to the care of their referring physicians. Participants may continue their follow up visits on 
protocol 15-D-0051 as appropriate. A summary of the participants’ course in the study will be 
sent to the referring physician. 
Participants who withdraw or are withdrawn from the study after receiving study treatment will 
be asked to complete the day 168 and 196 for close out safety assessments. Participants are 
deemed ineligible before study day 1 or randomization will resume care with their referring 
physician with no further evaluation in this protocol. 
8.2.3 Duration of Study Participation 
Study participation will be a maximum of 241 days, comprised of a 45 day screening period 168 
days treatment period, and 28 day follow up period. All study time periods are inclusive of a 
window of +/- 7 days for study days 1, 28, 56, 84, 112, 140 , -7 days for study day 168and +/- 3 
days for telephone calls to accommodate any potential variability in participant scheduling (see 
Schedule of Events). 
8.2.4 Vital Signs Measurement 
Vital signs measurements will include pulse rate, systolic and diastolic blood pressure, 
respiratory rate, and temperature. These measurements will be performed at all study visits and 
recorded on CRF. 
8.2.5 Adverse event assessment 
Adverse events will be assessed by reviewing the interim medical history, performing a physical 
evaluation, asking open-end question of how the participant’s feeling and reviewing laboratory 
results at each visit, as well as part of the clinical monitoring telephone calls on study days 7, 21, 
42, 70, and 154 (+/- 3 days) as per Section 5.1.2.. After completing screening assessments, any 
adverse event (AE) or serious adverse event (SAE) reported by a subject, whether or not study 
drug has been administered, will be recorded by the investigators. Any AE/SAE prior to dosing 
will be categorized as “Baseline” and any AE/SAE after dosing will be categorized as 
“treatment-emergent.” 
8.2.6 Assessment of Sjögren's disease activity 
SS disease activity will be assessed with the following measures: 
• Clinical Labs 
• ESSDAI: This validated disease activity measure reflects clinical events that occurred 
within 28 days and includes physical findings and laboratory measures. 
• Physician Global Assessment (PGA) assess global disease activity 

56 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
8.2.7 Assessment of Changes in Exocrine Function 
Changes in salivary flow will be assessed by measuring whole unstimulated saliva flow (WUS) 
and glandular parotid and submandibular/sublingual unstimulated and 0.2% citric acid stimulated 
flow rates. 
Changes in lacrimal flow will be measured by Schirmer’s test. 
8.2.8 Assessment of changes in oral microbiota 
Supragingival plaque oral microbiome will be collected from three sites on posterior teeth. 
Decayed, missing, filled teeth (DMFT) scores and periodontal charting will be procured at 
plaque collection. 
8.2.9 Salivary Gland Ultrasound 
An ultrasound of the salivary glands may be done in the SS clinic for research purposes. Changes 
in ultrasonographic findings will be assessed at baseline and at the study day 168. Salivary gland 
ultrasound can be used to assess the echogenicity and homogeneity of the salivary glands 
including the submandibular and parotid glands. Validated scoring criteria will be used to assess 
ultrasonographic feature parameters. 
8.2.10 Participant questionnaires 
The following assessments will be utilized to assess participant reported outcomes: 
1. 
EULAR Sjögren’s syndrome patient reported index (ESSPRI) 
2. 
2002 American-European Consensus Group (AECG) Criteria Subjective Symptoms 
3. 
Patient Dry Mouth questionnaire 
4. 
Xerostomia visual analog scale [VAS] 
5. 
Fatigue as measured by FSS 
6. 
PROMIS-57 Profile version 2.0 
7. 
Quality of life by the Short Form 36 (SF36) questionnaire 
8. 
Oral health related quality of life by the OHIP-14. 
8.2.11 Clinical Laboratory Assessments 
The CLIA certified clinical laboratories at the NIH Clinical Center (Department of Laboratory 
Medicine) will be the central laboratories for all routine clinical laboratory parameters. A serum 
or urine pregnancy test will be performed for female participants at screening, as per study 
efficacy evaluation measures, unless postmenopausal (no menstrual period for 2 years or more), 
had a previous hysterectomy or removal of the ovaries. Some of the testing may be performed at 
an outside commercial laboratory for patient convenience. Participants will be asked to complete 
safety visits and further follow-up will be done under the Pathogenesis and/or Natural History of 
Sjögren’s syndrome Protocol (11-D-0172) and/or by their local physicians. Participants will have 
blood samples drawn through phlebotomy. The laboratory at the NIH Clinical Center will be the 
central laboratory for all clinical laboratory parameters. Routine testing for various viral 
infections, including hepatitis B and C and HIV, will be done, since these viruses have been 
shown to be a cause of salivary gland dysfunction. A positive test for any of these viruses will 

57 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
affect healthy subjects’ participation in this protocol (5.2). Additional testing for COVID-19 
antibodies will be done, since Sjogren’s Syndrome patients may be at greater risk for infection 
with COVID-19. Moreover, COVID-19 is now known to cause a plurality of post-infection 
complications including local effects on the mouth such as taste loss and dry mouth, as well as 
systemic affects including malaise, fatigue, and joint pain. These are also common clinical 
complaints in the study population. Participant’s participation will not be affected by the results 
of these tests, but may be used to clinically contextualize interval changes in symptom severity 
(ESSDAI) in the event of symptomatic or asymptomatic (unknown) infection 
8.3 LABORATORY RESEARCH STUDIES 
8.3.1 Mechanistic studies 
Mechanistic studies will be conducted to investigate effects of Tofacitinib on intracellular 
signaling molecules, cytokine expression, circulating immune cell types and autoreactive B cells. 
Results of these mechanistic studies will be used to compare responses in participants on 
Tofacitinib versus placebo. 
All samples for the mechanistic assays will be collected at baseline or study day 1, prior to 
treatment, and study days 84, 168, and 196. For unscheduled visits, samples for mechanistic 
studies may be collected when possible. These assays will be performed in laboratories at the 
NIH. However, all samples will be processed for immediate use or cryopreserved and stored in 
freezers located in Building 10 (1N). To reduce confounding from variability between multiple 
assays, all of the samples will be treated appropriately, frozen and stored until all samples can be 
run simultaneously, for each assay, at the end of the study. 
The following is a list of the planned mechanistic studies: 
▪ 
Change in inflammation in the MSG (i.e., focus score), numbers of infiltrating 
lymphocytes, and the immunophenotypic distribution in the tissues using 
immunohistochemistry, flow cytometry, and (when tissue is available) single cells 
RNA sequencing. 
▪ 
Changes in levels of SS-related autoantibodies (e.g., anti-Ro52, -Ro60, -la, -CCP, -
Sm, -TRIM38, -IFN, and others) using LIPS; 
▪ 
Ligand-induced STAT phosphorylation in circulating T cells and monocytes using 
phosphoflow assessment of single cells; 
▪ 
Expression of STAT-related target genes; expression of pro-inflammatory and 
immunoregulatory cytokines in T cells and monocytes using RNAseq; 
▪ 
RNA sequencing of MSG to detect dominant pathway alterations including, but not 
limited to inflammatory (e.g., “interferon signature”, “granulocyte signature”) and 
secretory pathways. 
▪ 
RNAseq in PBMCs to detect dominant pathway alterations including, but not 
limited to inflammatory pathways (like “interferon signature”, “granulocyte 
signature”); measures of CD3+ T cell expression of IFN regulatory factor-related 
genes using RNAseq; 

58 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
▪ 
Alteration in peripheral blood immune cell populations with special attention to 
CD4+, CD25+, Foxp3+ regulatory subsets, and Th17 cells. 
▪ 
Measures of serum cytokines (IL-2, 4, 6, 7, 9,12, 15, 17, 23, TNFa, TNFb, IFNα 
and IFNγ); 
▪ 
Measurement of cholesterol efflux capacity and NMR lipoprotein profile (particle 
size and number) and insulin resistance. 
▪ 
Changes in vascular function, as assessed by the reactive hyperemia index (RHI) 
using Endopat device, and arterial stiffness using cardio-ankle vascular index 
(CAVI). Both are surrogate markers of vascular damage and future atherosclerosis 
development which are amenable to change within this duration of treatment. 
Additional biomarker studies: Unused biological samples from above (e.g., whole blood, plasma, 
serum, and saliva) from the planned mechanistic studies will be frozen and stored for future use. 
Consent for storage is addressed in informed consent document. 
8.4 BIOSPECIMEN EVALUATIONS 
Research samples will be collected and stored in locked secure freezers in Building 10 and 
Building 50 on the NIH campus. Only study investigators and participating research personnel 
will have access to the samples. Samples will be kept indefinitely unless there is a significant 
justification for destroying them. The PI will report the loss or destruction of samples collected 
under this protocol to the Institutional Review Board (IRB). 
All samples will be coded and will not have personal identifiers. The codes for identifiers will be 
contained in a secure, password protected, electronic database (Clinical Trials Data Base 
(CTDB)) and a participant identification log will be maintained in secure research files 
maintained in secure and locked offices of the research team... 
Coded samples may be shared with collaborators within and outside the NIH. Any remaining 
samples will be stored in the NIDCR or NIAMS locked freezers. Stored samples may be used for 
studies related to SS or other autoimmune or disorders affecting salivary glands. Approval from 
the IRB will be obtained prior to any research use of stored samples beyond the scope of this 
study. 
All participant samples will be coded and used for research purposes without sharing identifying 
information. This information will be stored on password protected computers. 
8.4.1 Correlative Studies for Research/Pharmacokinetic Studies: N/A 
8.4.2 Samples for Genetic Analysis 
Tissues to be collected for possible genetic analyses include: whole blood and/or PBMCs, and 
minor salivary gland tissues. 
Description of the scope of genetic/genomic analysis 
These studies may include, but are not limited to, RNA sequencing, epigenetic sequencing 
analyses, and whole genome sequencing. Specifically, we may conduct the following sequencing 
analyses: 
RNA sequencing (pending tissue availability): 

59 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• Bulk RNA sequencing of peripheral blood mononuclear cells and minor salivary glands. 
• Single cell, single nuclei, or spatial-transcriptomics RNA sequencing of minor salivary 
glands and peripheral blood mononuclear cells. 
Epigenetic sequencing analyses (pending tissue availability): 
• ATAC-Sequencing or other epigenetic sequencing techniques on peripheral blood 
mononuclear cells and minor salivary glands 
Whole genome sequencing (WGS): 
• WGS of minor salivary gland or peripheral blood mononuclear cells. 
Description of how privacy and confidentiality of medical information/biological samples will 
be maximized 
As part of this study, certain genetic studies, such as whole genome, exome, whole transcriptomic, 
or epigenomic sequencing may be utilized to understand the effect of Tofacitinib in SS. These 
studies will not be completed until after data lock. Genetic material (DNA, RNA) will be extracted 
from PBMCs or tissues and used for sequencing (DNA whole genome, RNA whole transcriptome, 
or other sequencing methodologies). The samples will be de-identified and coded in a password 
protected database. Data linking individual sequencing results with individual patients will be 
available to only the PI and co-investigators. De-identified sequencing data may be shared with 
collaborators through approved NIDCR Data Transfer Agreements (DTA). Genetic material will 
not be used for other specific but unrelated investigations unless permission is first granted by the 
NIH IRB as well as the subject. 
The expression profile of mRNA and non-coding RNAs may be analyzed from various tissues and 
body fluids, such as whole blood, blood components, saliva, urine and biopsy samples (e.g., 
salivary gland biopsies). 
NIH’s policy for data-sharing for federally funded genome-wide association studies requires that 
genotypic and phenotypic information from such studies will be made available through the NIH 
GWAS data repository designated as database of Genotypes and Phenotypes (dbGAP). Only coded 
de-identified data will be submitted to dbGAP. The data include the results of the GWAS and 
selected demographic and clinical variables. We anticipate that similar requirements may be put 
in place in the future for whole genome sequencing/whole transcriptome data, too. 
Medical information and biological samples relating to genomic material will follow the same 
protections as other biospecimens and medical information collected in this study and as outlined 
in sections 8.4 Biospecimens, 10.1.5 Confidentiality and Privacy and 10.2 Future Use of Stored 
Specimens and Data. Data related to genomic analysis will be shared in accordance with NIH 
Genomic Data Sharing Policy as described in in section, 10.9.2, Genomic Data Sharing Plan. 
Whole genome association studies (GWAS), whole genome sequencing, RNA sequencing, and 
data deposition into dbGaP. 
Management of Results 
It is not expected that any of the genomic testing would result in a clinically actionable gene 
variant. The data obtained will be handled with confidentiality. However, if mutation(s) is/are 
found that seem to cause or contribute to the disease or phenotype under study, we will verify the 

60 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
finding in a CLIA-certified laboratory. After consultation with the IRB the subjects will be 
informed and instructed that these genetic findings may require further analysis. A medical genetic 
counselor will be utilized as appropriate to communicate the genetic findings to the subjects. 
It is conceivable that during traditional genetic studies we identify genes associated with Sjögren’s 
syndrome which are also associated with other disorders unrelated to Sjögren’s syndrome. This 
information will not be placed in the medical records, nor will it be discussed with subjects unless 
there is clear scientific evidence that this finding will have a clinically significant impact on the 
subject’s prognosis or treatment. Sequencing may also identify variant genes that increase the 
subject’s risk for other diseases or may have an impact on the prognosis of other diseases. The PI 
of this protocol (or his/her staff clinician, nurse, or genetic counselor) will be responsible for 
communicating that result to the participant. It is essential that this communication include a clear 
message that the absence of such a finding does not confidently exclude the presence of such a 
mutation and that if there is an indication for specific testing for any of the genes or disorders 
covered by current ACMGG secondary findings standards. 
We will make no attempts to identify any of these variants and will not inform the subjects unless 
such variants are identified in our association studies of Sjögren’s syndrome and there is clear 
scientific evidence that this finding will have a clinically significant impact on the subject’s 
prognosis or treatment. In that case, we will contact all subjects and inform them that we have 
identified such a genetic variant in our cohort and ask them if they want to be informed about their 
individual result. Then, we will provide the data and appropriate counseling to the subjects who 
wish to be informed. The details of this process (such as the letter to the subjects) will be submitted 
to the IRB for approval. Since this is an evolving field, it is possible that we will identify sequence 
variants associated with Sjögren’s syndrome, which may have an effect on the subject’s treatment 
and or prognosis but for which there is no consensus in the medical community. In these cases, we 
will seek guidance from experts in the field (geneticists, ethicists and the appropriate 
subspecialists) and will provide a plan of action to the IRB based on their recommendations. 
8.5 SAFETY AND OTHER ASSESSMENTS 
Patient safety will be assessed through clinical assessments and laboratory studies during 
scheduled follow up visits (SOA), symptom assessment during interim phone calls (SOA), and 
assessment of AEs. 
8.6 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.6.1 Definition of Adverse Event 
Adverse events (AE) are any unfavorable and/or unintended diagnosis, symptom, sign (including 
an abnormal laboratory finding), syndrome, or disease that occurs during the study, having been 
either absent at baseline, or if present at baseline, appears to worsen. 
Events will be reported as AE’s as described in section 8.2.5. 
All AEs will be graded for intensity (severity) according to CTCAE version 5.0 and relationship 
to study drug as described below. 
8.6.2 Definition of Serious Adverse Events (SAEs) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator, sponsor, or Pfizer, it results in any of the following outcomes: 

61 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• Results in death 
• A life-threatening adverse event, (defined as a participant at immediate risk of death at 
the time of the event; it does not apply to an AE which hypothetically might have caused 
the death if it were more severe), 
• Requires or prolongs hospitalization (i.e. the AE required at least a 24-hour inpatient 
hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion), 
• Results in a congenital anomaly or birth defect (i.e., an adverse outcome in a child or 
fetus of a Participant exposed to the trial drug prior to conception or during pregnancy), 
• Causes a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, 
• Any other condition that, in the judgment of the investigator, represents a significant 
hazard or does not meet any of the above serious criteria but may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
8.6.3 Medical Events Not Qualifying as Adverse Events or Serious Adverse 
Events: 
Signs and symptoms of pre-existing medical conditions will not be recorded or reported as AEs 
or SAEs, unless they represent a clinically significant change from the baseline disease status 
documented at the Pre-screening Visit. In addition, hospitalization for elective procedures or 
surgeries will not be considered SAEs, nor will inpatient hospitalizations for convenience. 
8.6.4 Clinical Laboratory Test Results Not Qualifying as Adverse Events or 
Serious Adverse Events: 
A clinically significant laboratory result that is present at baseline and does not change 
significantly during the study will not be reported as an AE or SAE. The clinical significance of 
a change in a laboratory result will be determined by the PI or medically responsible medical 
investigator. 
The PI, along with the medically responsible investigator will evaluate all clinical laboratory and 
imaging results for clinically significant abnormalities and document the evaluation in the 
medical record and case report form. A clinically significant laboratory abnormality will be 
documented as an adverse event using the following criteria: 
The abnormality, 
• is not already encompassed by a reported adverse event (e.g., elevated AST need not be 
reported as an AE if Liver Failure has already been reported as an AE). 

62 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• is considered clinically significant by the Investigator.  
• necessitates study drug dosing modification (i.e., dose reduction, interruption or 
discontinuation); and/or 
• requires a therapeutic intervention (e.g., concomitant medication, blood transfusion or 
dialysis); and 
• is unexplainable by the participant’s current and past medical conditions 
• is related to a SS flare. 
o A SS flare is any significant worsening of the signs, symptoms, and laboratory test 
abnormalities associated with SS. Any increase in the ESSDAI index of >3 or more 
will be considered as a SS flare59. 
8.7 CLASSIFICATION OF AN ADVERSE EVENT 
8.7.1 Severity of Event 
The intensity (severity) of AEs and SAEs will be graded according to a descriptive scale based 
on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 
8.7.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
investigator who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect. 
For all AEs and SAEs, the investigator will provide his best estimate of the causal relationship 
between the event and study drug, and the causal relationship between the event and study 
procedures. The degree of certainty about causality will be graded according to the following 
criteria. 
o Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
o Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
o Possibly Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 

63 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
o Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
o Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
8.7.3 Expectedness 
For reporting purposes, the medically responsible investigator will be responsible for 
determining whether an adverse event (AE) is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or Physicians’ Desk 
Reference (PDR), published medical literature, protocol, informed consent document or not 
identified. This includes adverse events for which the specificity or severity is not consistent 
with the description in the P.I. or PDR. For example, under this definition, hepatic necrosis 
would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
For consistency of labeling and categorizing adverse events, the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 will be used in this 
study. 
8.7.4 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 
The severity of an AE will be documented at its highest level of severity. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
Any time after informed consent is obtained, AEs and SAEs will be recorded and reported until 7 
(for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. 

64 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
8.8 ADVERSE EVENT REPORTING 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor.  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF) and will be reported to the IRB according to the NIH-
OHSRP Policy 801: Reporting Research Events. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
8.8.1 Serious Adverse Event Reporting 
Serious Adverse Events will be reported to: 
• The NIH IRB according to NIH-OHSRP Policy 801: Reporting Research Events and 
Policy 802: Non-Compliance in Human Participants Research NIH-OHSRP Policy 801: 
Reporting Research Events and Policy 802: Non-Compliance in Human Participants 
Research, NIDCR Clinical Director’s Office within 7 calendar days based on NIDCR 
DIR Reporting guidance. 
• Pfizer Safety within twenty-four (24) hours of Institution’s first awareness of an SAE, or 
immediately upon Institution’s awareness if the SAE is fatal or life-threatening,  
according to Pfizer guidance and instructional material and templates. The study 
investigator will report to the Pfizer any serious adverse event, whether or not considered 
study intervention related, including those listed in the protocol or investigator brochure 
and must include an assessment of whether there is a reasonable possibility that the study 
intervention caused the event. Study endpoints that are serious adverse events (e.g., all-
cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death 
from anaphylaxis). In that case, the investigator must immediately report the event to 
Pfizer. 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by  Pfizer, if applicable and should be provided as 
soon as possible. 
8.8.2 .Events of Special Interest 
The following instances will be reported to Pfizer Safety as SAEs: 
• Exposure to the Pfizer Product during pregnancy (see section 8.8.3) or lactation 
• Drug overdose 
• Medication error 
• Occupational exposure to the Pfizer Product and 
• Lack of effect of the Pfizer Product 

65 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• Potential drug-induced liver injury as assessed by if a Study subject develops abnormal 
values in aspartate transaminase (“AST”) or alanine transaminase (“ALT”) or both, 
concurrent with abnormal elevations in total bilirubin and no other known cause of liver 
injury, that event would be classified as a Hy’s Law Case. 
8.8.3 Reporting of Pregnancy 
This study includes pregnancy information as safety data and pregnancies will be recorded if they 
begin any time after enrollment. Information about any pregnancy should be reported promptly 
as SAE’s to Pfizer within 24 hours of the Institution becoming aware of the pregnancy according 
to Pfizer guidance and instruction and to the NIDCR Office of Clinical Director (OCD) within 7 
working days; the DSMC will not receive an expedited report. All pregnancies identified during 
the study must be followed to conclusion and the outcome of each must be reported. The 
investigator should be informed immediately of any pregnancy in a study participant or a partner 
of a study participant. A pregnant participant should be instructed to stop taking study 
medication. The investigator should counsel the participant and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. Tofacitinib has a pregnancy risk factor 
Category C; there are no adequate and well controlled studies in pregnant women. Pregnancy 
outcome should be determined and submitted to Pfizer Safety and the NIDCR, Office of Clinical 
Director. When possible, similar information should be obtained for a pregnancy occurring in a 
partner of a study participant. Should the pregnancy result in a congenital abnormality or birth 
defect Pfizer Safety and the NIDCR, Office of Clinical Director should be notified. 
Sexually active participants with a partner able to become pregnant, will also be advised their 
partner should not become pregnant during study participation and 3 months following study 
completion. Participants and partners must agree to use effective birth control to be considered 
for study participation. The principal investigator or the medically responsible investigator will 
include discussion with participants or partners considering pregnancy after study participation 
during initial study participation discussions. 
8.8.4 Unanticipated Problems (UP) 
Definition of Unanticipated Problems (UP) 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected. 

66 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
8.8.5  Unanticipated Problem Reporting  
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 
(IRB) as per Policy 801. 
9 
STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESIS 
All analyses in this trial are descriptive and exploratory in nature. No formal statistical inferences 
are planned. 
• Primary Endpoint(s): The primary objective is to evaluate the safety and tolerance of 
Tofacitinib in participants with SS. The primary endpoints include number and rates of 
adverse events (serious adverse events, Grade 3 and 4 toxicities not fulfilling the criteria 
for SAE, and non-serious adverse events) and number and rates of SS disease flares. 
• Secondary Endpoint(s): Secondary endpoints will be analyzed by comparisons between 
the treatment (all SS participants receiving Tofacitinib) and placebo groups once the last 
participant completes the 28 weeks (196 days). 
• Exploratory Endpoint(s): 
For the following exploratory endpoints, all changes will be assessed between baseline and end 
of treatment, unless otherwise specified. 
• 
Changes in salivary glands as assessed by histopathology including focus  score, 
inflammation quantification and immunophenotyping of infiltrates 
• 
Global transcriptomic changes in peripheral blood monocytes and minor salivary glands 
with specific interrogation of IFN regulated genes and other inflammatory pathways 
using software tools like Ingenuity Pathway Analysis. 
• 
Differences between the treatment/placebo groups in changes in individual disease 
activity measures (ESSDAI, PGA, tear production, salivary flow) at the end of Study Day 
168 will be analyzed as repeated measures with change from baseline as the dependent 
variable. 
• 
Changes in participant reported outcomes such as: ESSPRI, SF-36, FSS, PROMIS 
• 
Changes in non-invasive vascular studies 
• 
A change will be analyzed using the appropriate statistical test per each type of data 
collected between baseline and at Day 168.  
9.1.1 SAMPLE SIZE DETERMINATION 
This is a pilot, Phase Ib-IIa study intended to study predominantly the tolerability/toxicity of 
Tofacitinib.  The number of participants for this study is arbitrary and is based primarily on the 
conventional numbers in Phase II studies and our experience with similar studies conducted 
previously. The primary endpoint is safety and tolerability. 15- 20 participants are commonly 
used as the sample size for open label safety studies. Our plan to have 20 Participants dosed with 
Tofacitinib to evaluate for safety and a placebo group of additional 10 participants for 
comparison is consistent with Phase I studies. 

67 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
9.2 POPULATIONS FOR ANALYSES 
9.2.1 Safety Population 
All participants who receive at least one dose or part of a dose of the study intervention and 
complete a safety follow-up, whether withdrawn prematurely or not, will be included in the 
safety population. All data relating to safety will be listed and summarized separately for the 
treatment period and for the entire study. All safety reports will be reviewed by the Principal 
Investigator. 
9.2.2 Intent to Treat Population 
Anyone randomized and receiving at least one dose of study drug will be included in the intent to 
treat population.   
9.2.3 Toxicity Evaluation  
All participants will be evaluable for toxicity from the time of their first dose of study drug, 
Tofacitinib 5 mg, orally, twice daily. 
9.3 STATISTICAL ANALYSES 
9.3.1 General Approach 
Demographics and clinical variables will be summarized by treatment group for each study visit. 
For continuous variables, descriptive statistics includes mean, standard deviation, median, and 
range. For categorical variables, counts and percentages will be reported. Due to exploratory 
nature of this study, statistical testing will be performed at the two-sided 5% level for the 
efficacy variables. The 95% confidence interval will be provided as well. 
9.3.2 Analysis of the Primary Endpoints 
The primary goal is to evaluate the safety and tolerance of Tofacitinib in participants with SS. 
For the safety population, the number and percentage of subjects with any AE, any related AE, 
any SAE, any Grade 3 and 4 toxicities not fulfilling the criteria for SAE, and non-serious adverse 
events and SS disease flares, as well as the total number of events for each category will be 
summarized by treatment group. AE’s/SAE’s will be reported from the time of consent.  Events 
that are reported prior to the first treatment will be considered non-treatment emergent in 
analyses.  
9.3.3 Analysis of the Secondary Endpoint(s) 
Secondary endpoints listed in Section 3.0 will be analyzed for the ITT population. Continuous 
endpoints (e.g. change from baseline (Day 1) to end of treatment (Day 168) will be compared 
between treatments using analysis of covariance (ANCOVA) model with baseline as a covariate 
if normality assumption holds. Otherwise, the nonparametric alternative will be adopted. For 
repeated measures, linear mixed models will be used. For multi-omics data, transcriptional 
pathway analysis, graphical data visualization (heat maps, cluster analysis), and differential gene 
expression analysis will be performed. 
Secondary endpoints will be analyzed by comparisons between the treatment (all SS participants 
receiving Tofacitinib) and placebo groups once the last participant completes the 28 weeks (196 
days) of study. 

68 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
• 
Change in the ESSDAI score between baseline and Day 168 (end of treatment). 
• 
Change in the Physician's Global Assessment (PGA) scores between baseline and study 
day 168 (end of treatment). 
9.3.4 Safety Analyses 
The primary endpoint of this study is safety. Please refer to 9.2.2. 
9.3.5 Baseline Descriptive Statistics 
See 9.2.1 General Approach. 
9.3.6 Exploratory Analyses 
Exploratory endpoints are listed in Section 3.0 and analyses are listed in 9.2.1 General Approach. 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1 INFORMED CONSENT PROCESS 
10.1.1 Consent/Assent Procedures and Documentation 
The principles of informed consent obtained by IRB authorized study team members will be in 
compliance with all IRB requirements. Informed consent will be completed prior to initiation of 
any study activities. All participants will receive an IRB approved and current consent form 
containing the purposes, procedures, benefits, and potential hazards of the study. This 
information will be reviewed with participant by either the principal or a qualified associate 
investigator. All prospective participants will be given ample time to read the consent form, and 
ask questions, before signing. 
Individual potential participants are required to sign an informed consent document. The original 
forms will become part of the permanent medical record and kept on file in the participant’s 
medical record, available for inspection by study monitors, auditors, and regulatory authorities, 
both federal and institutional. Copies will be provided to participants and a copy will be filed in 
participant’s research records. As per regulatory and IRB requirement, informed consent 
documentation note will be placed in the individual participant electronic record, Clinical 
Research Information System (CRIS) documenting consent and process used to obtain consent. 
The PI will be responsible to ensure that informed consent is obtained in accordance with the 
relevant Federal regulations and NIH Policy 301. The informed consent will be obtained by the 
PI or designated investigators that have taken NIMH informed consent course. 
All the relevant research information necessary to make an informed decision will be disclosed 
to the prospective participants. The IRB approved research team member obtaining informed 
consent is responsible for assuring all potential participant questions have been appropriately 
answered and the potential participant comprehends information discussed. The individual 
obtaining the informed consent will make every effort to minimize any possibility of therapeutic 
misconception. 
Consent for NIH staff will be obtained as detailed above with following additional protections: 
Consent from staff members will be obtained by an individual independent of the staff member’s 
team whenever possible.  Otherwise, the consent procedure will be independently monitored by 

69 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
the CC Department of Bioethics Consultation Service in order to minimize the risk of undue 
pressure on the staff member. 
10.1.2 Telephone, Remote, and Electronic Consent 
 The informed consent document will be provided well in advance as a physical or electronic 
document to the participant or consent designee as applicable for review prior to consenting. A 
designated study investigator will carefully explain the procedures and tests involved in this study, 
and the associated risks, discomfort and benefits. In order to minimize potential coercion, as much 
time as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to any research activities 
taking place. 
Informed consent may take place in person or remotely (e.g., via telephone or other NIH approved 
remote platforms used in compliance with policy, including NIH HRPP Policy 303) per discretion 
of the designated study investigator and with the agreement of the participant/consent designee(s). 
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed. If the consent process is occurring remotely, participants and 
investigators will view individual copies of the approved consent document on screens at their 
respective locations; the same screen may be used when both the investigator and the participant 
are co-located but this is not required. 
For telephone consent: When the research team study member is satisfied that the potential 
participant has been given an opportunity to ask questions and all questions have been 
satisfactorily answered the potential participant will sign and date the informed consent, with the 
actual date of consent. The original informed consent document will be sent back to the consenting 
investigator who will sign and date the consent form with the date the consent was returned. A 
fully executed copy will be sent to medical records and filed in the participant’s medical records; 
a copy will be filed in the research records and a final copy will be returned via mail for the 
participant’s records. Consent documentation will be entered in CRIS with a progress note to the 
individual participant medical record. 
For electronic consent: The study team will confirm with the subject that they are comfortable 
using the electronic consenting before proceeding with obtaining consent. If not, other methods 
will be utilized. When an electronic document with a digital signature is used for the 
documentation of consent, this study will use the iMedConsent™ platform which is 21 CFR, Part 
11 compliant to obtain the required signatures. During the consent process, participants and 
investigators will view the same approved consent document simultaneously in their respective 
locations.  The identity of the participant will be determined by verifying a government issued 
identification card via the telehealth platform, prior to obtaining the signature. Electronic signature 
with a timestamp will be provided by required parties through system prompts. Once the completed 
consent has been saved, it will post to CRIS within a few minutes. All consents completed in 
iMedConsent™ will post to both the Documents tab and the Consents tab in CRIS.  If the research 
participant has a FollowMyHealth™ account a copy of the completed consent will be posted to 

70 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
their account within two business days. The study team will provide the research participant with 
a printed copy of the signed document.  
10.1.3 Consent of Subjects who are, or become, decisionally impaired 
Adults unable to give consent are excluded from enrolling in the protocol. Adults presenting with 
representative with legally authorized representation (LAR) documentation will also be excluded 
from study participation 
10.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. If the study is prematurely terminated or suspended, the PI will promptly 
inform study participants, the Institutional Review Board (IRB), and Pfizer to provide the 
reason(s) for the termination or suspension. Written notification, documenting the reason for 
study suspension or termination, will be provided by the suspending or terminating party to study 
participants, Pfizer, NIDCR Division of Intramural Research Data and Safety Monitoring 
Committee (DSMC), and regulatory authorities. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Institute DSMC and/or IRB. 
10.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the Institute and its designees. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Institute and 
Pfizer. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Institute, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
Pfizer requirements. 

71 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Study participant research data will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by 
clinical sites and by research staff will be secured and password protected. At the end of the 
study, all study databases will be de-identified and archived at the NIDCR. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
10.4 TELEHEALTH AND TELEMEDICINE  
During extreme situations when travel to the NIH CC may not be feasible or advisable (e.g., 
inclement weather, pandemics), telehealth visits may be utilized to include follow-up and 
unscheduled visits.  
ThinkAndor® will be utilized for the conduct of synchronous telehealth/telemedicine visits 
between NIH healthcare providers and their patients. The provider will document all clinically 
relevant information collected during the patient encounter in CRIS, just as they do for an onsite 
visit, and note in the documentation that the encounter occurred via telehealth/telemedicine. 
Obtaining remote consent via telehealth is explained in 10.1.2.  
10.5 OUTPATIENT/OUTSIDE CLINICAL LABORATORY TESTING 
Outpatient/Outside Clinical Laboratory Testing may be performed by local CLIA-certified 
laboratories for study visits for non-local participants that are unable to have laboratory testing 
performed at the NIH. Participants will be given a laboratory order by the NIH heath team to be 
used at their local CLIA-certified laboratory. Participants and the CLIA-certified lab will be 
instructed to have lab results sent to NIH via fax within 7 business days (± 7 days) to the 
research team. Additional outpatient blood or urine tests may be ordered as clinically indicated. 
Lab work to be obtained at local CLIA-certified lab will follow required protocol visit labs. 
BLOOD SPECIMENS FOR RESEARCH ASSAYS WILL NOT BE PERFORMED BY OUTSIDE 
LABORATORIES. FOR REMOTELY COMPLETED SAFETY LABS NOT COVERED BY THE PATIENT’S 
INSURANCE, WE WILL COVER THE COST FOR COMMERCIAL LABORATORY TESTING.  
10.6 FUTURE USE OF STORED SPECIMENS AND DATA 
Research samples collected from participants consenting to this protocol will be stored in locked 
secure freezers belonging to NIDCR and NIAMS. The freezers are located in Building 10 and 
Building 50 at the NIH. Only study investigators and participating research personnel will have 
access to the samples. Samples will be kept indefinitely unless there is a significant justification 
for destroying them. The Principal Investigator will report the loss or destruction of samples 
collected under this protocol to the Institutional Review Board (IRB). 

72 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
All samples will be coded and will not have personal identifiers. The codes for identifiers will be 
contained in a secure electronic database (CTDB) and a participant code log that is maintained in 
secure research files. An electronic record log with identifiers of all collected research specimens 
will be kept. These will be stored in secure NIH computers. 
Coded samples may be shared with collaborators within and outside the NIH. Any remaining 
samples will be stored in the NIDCR or NIAMS locked freezers. Stored samples may be used for 
studies related to SS or other autoimmune or disorders affecting salivary glands. Approval from 
the IRB will be obtained prior to any research use of stored samples beyond the scope of this 
study. 
All participant samples will be coded and used for research purposes without sharing identifying 
information and all collaborators will follow federal rules for clinical research. 
10.7 SAFETY OVERSIGHT 
In addition to the PI’s responsibility for oversight, this study will be monitored by the NIDCR 
Division of Intramural Research Data and Safety Monitoring Committee (DSMC). The DSMC 
will include members with expertise in a broad range of areas, including, but not limited to, 
human subjects’ protection, clinical trial implementation, biostatistics, rheumatology, and 
medical bone and mineral metabolism. The DSMC will meet periodically to assess safety and 
efficacy data (if applicable), study progress, and data integrity for the study. The DSMC will 
determine frequency of review at the first meeting, but typically will meet at least once a year. 
The DSMC may also choose to electronically review periodic data and safety reports in addition 
to convening data review meetings. If safety concerns arise, more frequent meetings may be 
held. In addition, unscheduled meetings can be requested by any party with responsibility of 
overseeing the study. The DSMC will provide recommendations to the NIDCR concerning the 
continuation, modification, or termination of the trial. The DSMC will operate under the rules of 
an NIDCR-approved charter. The roles and responsibilities of committee members and meeting 
procedures will be formally described in the charter. 
The DSMC will provide its input to the National Institute of Dental and Craniofacial Research, 
Clinical Director and the PI. 
The DSMC will be alerted if any of the following situations occur: 
• 
An unexpected fatal or life-threatening event assessed as related to the use of study drug. 
• 
Three or more participants with similar severe AEs (Grade 3 or 4) assessed as related to 
the use of study drug. 
The Principal Investigator will be responsible for monitoring the accruing safety data related to 
suspension guidelines and for alerting the DSMC chair when a criterion is met. The DSMC 
chair, through the DSMC Executive Secretary, will be alerted by email within 7 calendar days of 
determination that a criterion has been met. The DSMC will issue a recommendation on study 
continuation to the NIDCR Clinical Director or designee after reviewing data related to the 
suspension guideline. If the study is stopped, participants will receive conventional care for any 
study-related AEs and continue to be followed for clinical and safety outcomes. Otherwise, the 
study will continue per the DSMC recommendations. The Principal Investigator and the Clinical 
Director will provide the recommendations of the DSMC to the IRB. 

73 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
10.8 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and/or other operating procedures, 
and that the quality and integrity of study data and data collection methods are maintained. 
Monitoring for this study will be performed by the NIDCR Clinical Research Operations and 
Management Support (CROMS) contractor. The monitor will evaluate study processes and 
documentation based on the International Council for Harmonization (ICH), E6: Good Clinical 
Practice guidelines (GCP). 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP). The 
CMP will specify the frequency of monitoring, monitoring procedures, the level of clinical site 
monitoring activities (e.g., the percentage of participant data to be reviewed), and the distribution 
of monitoring reports. Some monitoring activities may be performed remotely, while others will 
take place at the study site(s). Staff from the NIDCR CROMS contractor will conduct 
monitoring activities and provide reports of the findings and associated action items in 
accordance with the details described in the CMP. Documentation of monitoring activities and 
findings will be provided to the study PI, NIDCR-OCTOM, and NIDCR Office of the Clinical 
Director (OCD) staff. 
10.9 QUALITY ASSURANCE AND QUALITY CONTROL 
Internal quality assurance activities will include study team meetings, where the protocol team 
will review any new consents, unanticipated problems, and adverse events, and quarterly 
reporting of quality assurance/quality improvement activities to the NIDCR Office of the 
Clinical Director Clinical Operations Manager and NIDCR-OCTOM. 
The study team will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
The data will be further validated via a series of manual edit checks, and all relevant data queries 
will be raised and resolved on an ongoing basis. Complete, clean data will be frozen to prevent 
further inadvertent modifications. All discrepancies will be reviewed and any resulting queries 
will be resolved with the investigators and amended in the database. All elements of data entry 
(i.e., time, date, verbatim text, and the person performing the data entry) will be recorded in an 
electronic audit trail to allow all data changes in the database to be monitored and maintained in 
accordance with federal regulations. 
10.10 
DATA HANDLING AND RECORD KEEPING 
10.10.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 

74 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study. Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into Clinical Trials Data Base 
(CTDB), a 21 CFR Part 11-compliant data capture system provided by the Research Nurse 
Coordinator. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
Study staff will complete electronic case report forms (eCRFs) via a web-based electronic data 
capture (EDC) system (Clinical Trials Database, CTDB) that is compliant with Part 11 Title 21 
of the Code of Federal Regulations. Participant electronic medical records in the Clinical 
Research Information System (CRIS) will be used as source documents for these eCRFs. 
Participants will also complete periodic questionnaires as outlined in the study procedures 
through the Clinical Trial Survey System (CTSS) – an ancillary web-based application 
associated with CTDB. These participant-completed questionnaires in CTSS will be used as 
source documents for the study. The CTSS is accessible outside the NIH and allows participants 
to remotely respond to clinical questionnaires with secure passwords administered by CTDB. 
Security of the database system is maintained through an application firewall, military grade 
encryption and SSL certificates, removal of personal identifiers consistent with HIPAA 
requirements (45 C.F.R.164.514(a),(b)&(c)), and the incorporation of audit trails. The servers are 
physically located in a secured NIH data center with controlled limited access. If for any reason, 
the CTSS system is unavailable for use by a participant, questionnaires may be completed in 
paper form.  The paper form will be used as the source. Study team member(s) will enter data 
into the CTDB database.  
Paper-based CRFs and physician assessments may be completed in addition to completion of 
web-based CRFs. Completed paper-based forms will be imputed into appropriate CTDB 
database. CRFs, participant questionnaire data will be kept in the CTDB database. 
Research records and all source documents will be kept in locked cabinets or rooms, and 
computer research databases will be stored in a secure, password-protected environment, per 
standard NIH policies. Only study investigators and participating research personnel will have 
access to the data. 
In the future, other investigators (at the NIH) may wish to study these samples and/or data. In 
that case, IRB approval must be sought prior to any sharing of samples. Any clinical information 
shared about the sample without participant identifiers would similarly require prior IRB 
approval. 
The research use of stored, unlinked or unidentified samples may be exempt from the need for 
prospective IRB review and approval. Exemption requests will be submitted in writing to the 
NIH Office of Human Participants Research, which is authorized to determine whether a 
research activity is exempt. 

75 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
10.10.2 
Study Records Retention 
Study documents should be retained for a minimum of 3 years after the last approval of a 
marketing application in an International Council on Harmonization (ICH) region and until there 
are no pending or contemplated marketing applications in an ICH region or until at least 2 years 
have elapsed since the formal discontinuation of clinical development of the study intervention, 
or as per the NIH Intramural Records Retention schedule. No records will be destroyed without 
the written consent of Pfizer Incorporated, if applicable. It is the responsibility of the Pfizer, to 
inform the investigator when these documents no longer need to be retained. 
10.11 
PROTOCOL DEVIATIONS AND NON-COMPLIANCE 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations to the NIH Institutional Review Board as per Policy 801. 
Deviations must be addressed in study source documents and reported to NIDCR Office of 
Clinical Director. The investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. 
10.11.1 
NIH Definition of Protocol Deviation 
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol.  
• Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study. 
• Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study. 
10.12 
 PUBLICATION AND DATA SHARING POLICY 
10.12.1 
 Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer- reviewed journals. 
10.12.2 
 Genomic Data Sharing Plan 
This study will be conducted in accordance with the National Institutes of Health (NIH) 
Genomic Data Sharing (GDS) Policy to ensure the broad and responsible sharing of genomic 

76 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
research data. NIH has longstanding policies to make data publicly available in a timely manner 
from the research activities that it funds. Once study database is locked, analysis of 
genomic/transcriptomic data may commence. RNA sequencing, and data deposition into dbGaP 
(adults only). 
NIH’s policy for data-sharing for federally funded genome-wide association studies requires that 
genotypic and phenotypic information from such studies will be made available through the NIH 
data repository designated as database of Genotypes and Phenotypes (dbGAP). Only coded de-
identified data will be submitted to dbGAP. The data include the results of the transcriptomic 
data and selected demographic and clinical variables. dbGaP is divided into an open access area 
and a controlled access area. The open access area contains summary data only. Individual-level 
data and complete genomic summary data are kept in the controlled access area. Investigators 
who want access to data kept under controlled access (e.g., individual-level data) must submit a 
Project Request through dbGaP. Project Requests are reviewed by an NIH Data Access 
Committee, which focuses on whether the proposed research use of the requested data is 
consistent with data use limitations provided by the Institution that submitted the data to dbGaP. 
10.13 
COLLABORATIVE AGREEMENTS  
10.13.1 
Agreement Type 
For the purpose of this trial, we have an executed clinical trial agreement (CTA), 
CTA#56584687, with Pfizer Inc.   
A Memorandum of Understanding has been executed with the Clinical Research Center 
Department of Biostatics for biostatistical support for this study. 
10.14 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the NIDCR has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
The NIH guidelines on conflict of interest will be distributed to all investigators. 
The NIH and Dr. John O’Shea have a patent related to JAK inhibitors and receive royalties. The 
NIH and Dr. O’Shea have had a collaborative agreement and development award (CRADA) with 
Pfizer that pertains to JAK inhibition and tofacitinib. The NIH and Dr. O’Shea have an ongoing 
CRADA for new JAK inhibitors. We will submit appropriate information to the Deputy Ethics 
Committee (DEC) of the Clinical Center to determine conflict of interest in Dr. O’Shea’s 
participation in this study. 
No other investigators on the study team have any financial conflicts of interest to report. 
The Principal Investigator will seek prospective and continuing NIH IRB review and approval 
for research collaborations in which coded samples (for which the investigators maintain the 

77 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
key) are sent to non-NIH investigator(s). The PI will identify the names of the collaborating 
researchers and their affiliated institutions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 ABBREVIATIONS 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DMARDS 
Disease modifying anti rheumatic drugs 
DSMC 
Data Safety Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 

78 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIDCR 
National Institute of Dental and Craniofacial Research 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
12 REFERENCES  
1. Qin, B. et al. Epidemiology of primary Sjögren's syndrome: a systematic review and 
meta-analysis. Ann. Rheum. Dis. 74, 1983–1989 (2015). 
2. Holdgate, N. & St Clair, E. W. Recent advances in primary Sjögren's syndrome. 
F1000Res 5, (2016). 
3. Imgenberg-Kreuz, J., Rasmussen, A., Sivils, K. & Nordmark, G. Genetics and epigenetics 
in primary Sjögren's syndrome. Rheumatology (Oxford) (2019). 
doi:10.1093/rheumatology/key330. 
4. Vivino, F. et al. Sjögren's syndrome : An update on disease pathogenesis, clinical 
manifestations and treatment. Clin. Immunol. 203, 81–121 (2019). 
5. Petrone, D. et al. A double-blind, randomized, placebo-controlled study of cevimeline in 
Sjögren's syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis 
Rheum. 46, 748–754 (2002). 
6. Mavragani, C. P., Moutsopoulos, N. M. & Moutsopoulos, H. M. The management of 
Sjögren's syndrome. Nat Clin Pract Rheumatol 2, 252–261 (2006). 
7. Fox, R. I. et al. Treatment of primary Sjögren's syndrome with hydroxychloroquine. 
Am. J. Med. 85, 62–67 (1988). 
8. Mariette, X. et al. Inefficacy of infliximab in primary Sjögren‘s syndrome: results of the 
randomized, controlled Trial of Remicade in Primary Sjögren’s syndrome (TRIPSS). 
Arthritis Rheum. 50, 1270–1276 (2004). 
9. Sankar, V. et al. Etanercept in Sjögren's syndrome: a twelve-week randomized, double-
blind, placebo-controlled pilot clinical trial. Arthritis Rheum. 50, 2240–2245 (2004). 

79 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
10. Brkic, Z. et al. Prevalence of interferon type I signature in CD14 monocytes of patients 
with Sjögren's syndrome and association with disease activity and BAFF gene 
expression. Ann. Rheum. Dis. 72, 728–735 (2013). 
11. Davies, R. et al. Aberrant cell signaling in PBMCs upon IFN-α stimulation in primary 
Sjögren's syndrome patients associates with type I interferon signature. Eur. J. Immunol. 
48, 1217–1227 (2018). 
Ha, Y.-J. et al. Increased expression of interferon-λ in minor salivary glands of patients 
with primary Sjögren's syndrome and its synergic effect with interferon-αon salivary 
gland epithelial cells. Clin. Exp. Rheumatol. 36 Suppl 112, 31–40 (2018). 
12. Christodoulou, M. I., Kapsogeorgou, E. K., Moutsopoulos, N. M. & Moutsopoulos, 
H. M. Foxp3+ T-regulatory cells in Sjögren's syndrome : correlation with the grade of the 
autoimmune lesion and certain adverse prognostic factors. Am. J. Pathol. 173, 1389–1396 
(2008). 
13. Fei, Y. et al. Clinical parameter and Th17 related to lymphocytes infiltrating degree of 
labial salivary gland in primary Sjögren's syndrome. Clin. Rheumatol. 33, 523– 529 
(2014). 
14. Katsifis, G. E., Rekka, S., Moutsopoulos, N. M., Pillemer, S. & Wahl, S. M. Systemic 
and local interleukin-17 and linked cytokines associated with Sjögren's syndrome 
immunopathogenesis. Am. J. Pathol. 175, 1167–1177 (2009).  
15. Theander, E. et al. Lymphoid organisation in labial salivary gland biopsies is a possible 
predictor for the development of malignant lymphoma in primary Sjögren's syndrome. 
Ann. Rheum. Dis. 70, 1363–1368 (2011). 
16. Kapsogeorgou, E. K., Abu-Helu, R. F., Moutsopoulos, H. M. & Manoussakis, M. N. 
Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins. 
Arthritis Rheum. 52, 1517–1521 (2005). 
17. Gottenberg, J.-E. et al. Activation of IFN pathways and plasmacytoid dendritic cell 
recruitment in target organs of primary Sjögren's syndrome. PNAS 103, 2770–2775 
(2006). 
18. Kawakami, A. et al. Toll-like receptor in salivary glands from patients with Sjögren's 
syndrome: functional analysis by human salivary gland cell line. J. Rheumatol. 34, 1019–
1026 (2007). 
19. Ittah, M. et al. Viruses induce high expression of BAFF by salivary gland epithelial cells 
through TLR- and type-I IFN-dependent and -independent pathways. Eur. J. Immunol. 
38, 1058–1064 (2008). 
20. Wildenberg, M. E., van Helden-Meeuwsen, C. G., van de Merwe, J. P., Drexhage, 
H. A. & Versnel, M. A. Systemic increase in type I interferon activity in Sjögren's 
syndrome: a putative role for plasmacytoid dendritic cells. Eur. J. Immunol. 38, 2024–
2033 (2008). 
21. Nocturne, G. & Mariette, X. Advances in understanding the pathogenesis of primary 
Sjögren's syndrome. Nat Rev Rheumatol 9, 544–556 (2013). 
22. Bikker, A. et al. Increased expression of interleukin-7 in labial salivary glands of patients 
with primary Sjögren's syndrome correlates with increased inflammation. Arthritis 
Rheum. 62, 969–977 (2010). 
23. Jin, J.-O., Kawai, T., Cha, S. & Yu, Q. Interleukin-7 enhances the Th1 response to 
promote the development of Sjögren's syndrome-like autoimmune exocrinopathy in mice. 
Arthritis Rheum. 65, 2132–2142 (2013). 

80 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
24. Abu-Helu, R. F., Dimitriou, I. D., Kapsogeorgou, E. K., Moutsopoulos, H. M. & 
Manoussakis, M. N. Induction of salivary gland epithelial cell injury in Sjögren's 
syndrome . 17, 141–153 (2001). 
25. Verstappen, G. M., Corneth, O. B. J., Bootsma, H. & Kroese, F. G. M. Th17 cells in 
primary Sjögren's syndrome: Pathogenicity and plasticity. J. Autoimmun. 87, 16–25 
(2018). 
26. Lee, J. et al. JAK-1 Inhibition Suppresses Interferon-Induced BAFF Production in 
Human Salivary Gland: Potential Therapeutic Strategy for Primary Sjögren's Syndrome. 
Arthritis Rheumatol 70, 2057–2066 (2018). 
27. Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid 
arthritis. N. Engl. J. Med. 367, 495–507 (2012). 
28. Kremer, J. M. et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib 
(CP-690,550) versus placebo in combination with background methotrexate in patients 
with active rheumatoid arthritis and an inadequate response to methotrexate alone. 
Arthritis Rheum. 64, 970–981 (2012). 
29. Riese, R. J., Krishnaswami, S. & Kremer, J. Inhibition of JAK kinases in patients with 
rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract Res Clin 
Rheumatol 24, 513–526 (2010). 
30. van Vollenhoven, R. F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid 
arthritis. N. Engl. J. Med. 367, 508–519 (2012). 
31. O'Shea, J. J., Laurence, A. & McInnes, I. B. Back to the future: oral targeted therapy for 
RA and other autoimmune diseases. Nat Rev Rheumatol 9, 173–182 (2013). 
32. Gladman, D. et al. Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate 
Response to TNF Inhibitors. N. Engl. J. Med. 377, 1525–1536 (2017). 
33. Mease, P. et al. Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis. N. 
Engl. J. Med. 377, 1537–1550 (2017). 
34. Wollenhaupt, J. et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for 
the treatment of rheumatoid arthritis in open-label, long term extension studies. J. 
Rheumatol. 41, 837–852 (2014). 
35. Murray, P. J. The JAK-STAT signaling pathway: input and output integration. J. 
Immunol. 178, 2623–2629 (2007). 
36. Meyer, D. M. et al. Anti-inflammatory activity and neutrophil reductions mediated by the 
JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond) 7, 
41 (2010). 
37. Ghoreschi, K. et al. Modulation of innate and adaptive immune responses by tofacitinib 
(CP-690,550). J. Immunol. 186, 4234–4243 (2011). 
38. Maeshima, K. et al. The JAK inhibitor tofacitinib regulates synovitis through inhibition 
of interferon-γ and interleukin-17 production by human CD4+ T cells. Arthritis Rheum. 
64, 1790–1798 (2012). 
39. Tanaka, Y., Maeshima, K., Maeshima, Y. & Yamaoka, K. In vitro and in vivo analysis of 
a JAK inhibitor in rheumatoid arthritis. Ann. Rheum. Dis. 71 Suppl 2, i70–4 (2012). 
40. Rizzi, M. et al. Impact of tofacitinib treatment on human B-cells in vitro and in vivo. 
J. Autoimmun. 77, 55–66 (2017). 
41. Piscianz, E. et al. Fate of lymphocytes after withdrawal of tofacitinib treatment. 
PLoS ONE 9, e85463 (2014). 

81 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
42. Martina, M. N. et al. Inhibition of JAK3 and PKC via Immunosuppressive Drugs 
Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes 
In Vitro. Transplant. Proc. 48, 3046–3052 (2016). 
43. Navarro-Mendoza, E. P. et al. Cytokine markers of B lymphocytes in minor salivary 
gland infiltrates in Sjögren's syndrome. Autoimmun Rev 17, 709–714 (2018). 
44. Davies, R. et al. Single Cell Based Phosphorylation Profiling Identifies Alterations in 
Toll-Like Receptor 7 and 9 Signaling in Patients With Primary Sjögren's syndrome. 
Front Immunol 10, 281 (2019). 
45. Rönnblom, L. The type I interferon system in the etiopathogenesis of autoimmune 
diseases. Ups. J. Med. Sci. 116, 227–237 (2011). 
46. Dienz, O. et al. The induction of antibody production by IL-6 is indirectly mediated by 
IL-21 produced by CD4+ T cells. J. Exp. Med. 206, 69–78 (2009). 
47. Naka, T., Nishimoto, N. & Kishimoto, T. The paradigm of IL-6: from basic science to 
medicine. Arthritis Res. 4 Suppl 3, S233–42 (2002). 
48. Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 
1beta and 6 but not transforming growth factor-beta are essential for the differentiation of 
interleukin 17-producing human T helper cells. Nat. Immunol. 8, 942–949 (2007). 
49. Kastelein, R. A., Hunter, C. A. & Cua, D. J. Discovery and biology of IL-23 and IL- 27: 
related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 
221–242 (2007). 
50. Waite, J. C. & Skokos, D. Th17 response and inflammatory autoimmune diseases. 
Int J Inflam 2012, 819467–10 (2012). 
51. Sewgobind, V. D. K. D. et al. The Jak inhibitor CP-690,550 preserves the function of 
CD4CD25FoxP3 regulatory T cells and inhibits effector T cells. Am. J. Transplant. 10, 
1785–1795 (2010). 
52. Bernard, F., Romano, A. & Granel, B. [Regulatory T cells and systemic autoimmune 
diseases: systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's 
syndrome]. Rev Med Interne 31, 116–127 (2010). 
53. Seror, R. et al. Defining disease activity states and clinically meaningful improvement in 
primary Sjögren‘s syndrome with EULAR primary Sjögren’s syndrome disease activity 
(ESSDAI) and patient-reported indexes (ESSPRI). Ann. Rheum. Dis. 75, 382–389 (2016).  
54. McMahon, M. et al. Dysfunctional proinflammatory high-density lipoproteins confer 
increased risk of atherosclerosis in women with systemic lupus erythematosus. Arthritis 
Rheum. 60, 2428–2437 (2009). 
55. Mariette, X., Chen, C., Biswas, P., care, K. K. A. 2018. Lymphoma in the tofacitinib 
rheumatoid arthritis clinical development program. Wiley Online Library 
56. doi:10.1002/acr.23421 
57. Curtis, JR., et al., Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies 
across the rheumatoid arthritis clinical development programme 
58. Harigai, M. Growing evidence of the safety of JAK inhibitors in patients with rheumatoid 
arthritis. Rheumatology (Oxford) 58, i34–i42 (2019). 
59. Theander, E., Rheumatism, R. M. A.2004. Mortality and causes of death in primary 
Sjögren's syndrome: a prospective cohort study. Wiley Online Library 
doi:10.1002/art.20176 
60. Seror, R. et al. EULAR Sjögren's syndrome disease activity index (ESSDAI): a user 
guide. RMD Open 1, e000022–e000022 (2015). 

82 
Abbreviated Title: Tofacitinib in Sjögren's syndrome 
Version Date: 07/01/2024 
 
Template version date 10.27.2020 
 
13 ATTACHMENTS 
Attachment A: Ocular Surface Disease Index© (OSDI) 
 
Attachment B: Participant Weekly Medication chart  
Attachment C: COVID-19 Safety and NIH Clinical Trial Information Card