Clinical trial NCT03288324
Conditions: Cutaneous Lupus Systemic Lupus Erythematosus
Sponsor: Children's Hospital Medical Center, Cincinnati
Start date: 2017-08-23; Completion date: 2023-12-01
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This 76-week, 3-part Phase 1b/2 study is intended to evaluate the pharmacological properties (pharmacokinetics and pharmacodynamics), safety, tolerability and preliminary effectiveness of TOFA administrated to young adults (18-45 years) with moderately to severely active SLE-CL. Subjects will be studied at the Cincinnati Children's Hospital Medical Center (CCHMC) and in Cleveland at MetroHealth Medical Center.

Detailed description:
Cohort 1 (n=10, weight \> 40kg and age \> 18 years and ≤ 45 years ) will undergo intense PK-sampling to determine exposures following TOFA dosed at 5 mg BID. TOFA dose escalation will not be considered for inadequate response of SLE-CL.

Cohort 2 (n=10, weight \> 40kg and age \> 18 years and ≤ 45 years) will be treated with the same dose as Cohort 1. No PK sampling will occur for Cohort 2. Enrollment of Cohort 2 will only start once Cohort 1 has completed 8 weeks of TOFA and results of PK analyses from Cohort 1 are available.

* Part A (up to week 8) requires stable background medications;
* Part B (up to week 24) allows for tapering of corticosteroids (CS) in the setting of significant clinical improvement of SLE-CL as defined by a decrease in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score by \>50% from baseline , and
* Part C (until week 76) permits tapering of other background medications in subjects with clinical remission of SLE-CL (CLASI activity score=0). TOFA dosing is kept stable during Part C.

Arms: arm 1: open-label study
Interventions: intervention 1: Tofacitinib
Intervention descriptions: intervention 1: Tofacitinib 5 mg twice daily

Protocol documents:
Prot_SAP_000.pdf: 
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STUDY PROTOCOL
Project Name: 
OPEN-LABEL STUDY OF TOFACITINIB FOR MODERATE TO SEVERE SKIN 
INVOLVEMENT IN YOUNG ADULTS WITH LUPUS 
Sponsor:
Hermine Brunner, MD
Coordinating Center:
PRCSG staff
Investigational Medicinal Product/s: 
Tofacitinib
Clinical Trial Working Full Title:
A 3-part open-label study assessing safety, 
tolerability, pharmacokinetic and -dynamic 
profiles, and efficacy of tofacitinib in young 
adults from age 18 to 45 years with moderate 
to severe skin involvement due to lupus
Version Date:
V19 20210322


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Table of Contents
1
Rationale of Trial..................................................................................3
2
Study Design ........................................................................................5
3
Trial Periods -Design ............................................................................6
4
Study description .................................................................................8
4.1
Primary Objective(s) & Endpoint(s) .....................................................8
4.2
Key Secondary Objective(s) & Endpoint(s)...........................................8
4.3
Exploratory Objective(s) & Endpoint(s) ...............................................9
5
Study Participants ..............................................................................10
5.1
Inclusion Criteria................................................................................10
5.2
Exclusion Criteria ...............................................................................11
6
Treatments, Regimens & Control.......................................................13
7
Planned Assessments & Evaluations..................................................18
8
Planned Statistical Analyses...............................................................28
10
Schedule of Assessments...................................................................31
11
References .........................................................................................33
Appendix 1
Tofacitinib Experience in Juvenile Arthritis……………………………………….34
Appendix 2
 Moderate or Potent CYP3A4 Inhibitors and Inducers……………………….35
Appendix 3
 Data Safety Monitoring Plan……………………………………………………………36
Appendix 4         SKINDEX-29 Questionnaire………………………………………………………………55
Appendix 5 
CLASI ………………………………………………………………………………………..………56


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Abbreviations
BILAG
British Isles Lupus Assessment Group index
CLASI
Cutaneous Lupus Disease Area and Severity Index (appendix 5)
CS
Corticosteroid
ESR
Erythrocyte sedimentation rate
JIA
Juvenile Idiopathic Arthritis
PD
Pharmacodynamics
PK 
Pharmacokinetic 
SAE
Serious adverse event 
SLE
Systemic lupus erythematosus
SLEDAI
SLE Disease Activity Index
SLE-CL
 
SLE cutaneous lesions
SOC
Standard of clinical care
TOFA
Tofacitinib
SC-RNA SEQ
Single-cell RNA sequencing of skin 
TD1
Trial day 1


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1. Rationale of Trial 
Janus Kinases (Jak) are tyrosine kinases (Jak1, Jak2, Jak3 and Tyk2) that bind to cell 
receptor subunits and mediate the intracellular signalling initiated by interferons (IFN), 
many interleukins, colony stimulating factors, and hormones such as prolactin, 
erythropoietin and growth hormone. Following receptor ligation, Jak becomes 
activated and phosphorylates the latent transcription factors known as signal 
transducers and activators of transcription (STAT). Then STAT, in homo- or 
heterodimers, translocate into the nucleus and co-/regulate gene transcription. 
Mutations of Jak or STAT in humans are associated with severe immune dysfunction, 
revealing the fundamental role of this pathway in the induction and regulation of 
immune responses 1 (see Figure below). 
Tofacitinib (TOFA), a small molecule that inhibits Jak3, Jak1 and to a lesser degree Jak2, 
has been proven efficacious in rheumatoid arthritis (RA) in phase III trials2,3. Notably, 
a series of Jak-STAT signalling cytokines, especially type I IFNs, IL-10 and IL-6, as well 
as the hormone prolactin, have been implicated in the pathogenesis of systemic lupus 
erythematosus (SLE)4,5. Such immunological abnormalities are thought to be even 
more pronounced among subjects with SLE onset early in life, i.e. with SLE diagnosis 
during childhood and adolescence6. In this context, targeting the Jak-STAT pathway 
may be an attractive approach to manage inflammation and auto-immunity in SLE.
The JAK-STAT signaling pathway. The IL-2 family of cytokines, all sharing a common receptor subunit γ-chain (γc), play a major 
role in promoting and maintaining T, B and natural killer (NK) cell populations. The IL-2 receptor family cytokines, after binding 
their receptor, activate the JAK/STAT signaling pathway. At the cytoplasmic side of the receptor, either JAK1 or JAK3 is 
phosphorylated. Activation of JAKs (~130 kDa) leads to attraction of a specific combination of STATs (70–94 kDa). IL-2, IL-7 and IL-
15 are essential for T cell memory homeostasis, proliferation and survival, while IL-2 and IL-15 are important for NK cell 
development. IL-2 additionally regulates the homeostatic maintenance of Tregs and their function, and stimulates IFN-γ 
production by T-cells upregulating the cytolytic properties of CD8+ cytotoxic T cells. IL-4 activates STAT6 and T helper 2 (Th2) 
development. IL-21, by activating STAT1 and STAT3, induces differentiation of B cells into plasma cells and stimulates cytotoxic T 
cell proliferation. IL-21 also has regulatory effects, inhibits the antigen-presenting function of dendritic cells (DC), and is a pro-
apoptotic factor for NK cells and incompletely activated B cells.
To date, belimumab, hydroxychloroquine, chloroquine and quinacrine are approved 
for adults with systemic lupus erythematosus (SLE). The latter three medications are 
approved also for cutaneous lupus without the system form of the disease, i.e. SLE. 


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Despite these medications, chronic skin disease remains a major problem with SLE7. 
Given the severity of the disease, the unmet medical need, and the low number of 
available subjects in this specific population, it is judged acceptable to assess the 
safety, tolerability and PK as primary objectives; and efficacy as secondary objectives 
in an open-label manner. Subjects with SLE-cutaneous lesions (SLE- CL) will be treated 
with stable standard of care background for SLE and TOFA will be added to treat 
associated active cutaneous lesions with SLE, based on observed improvement of 
inflammatory rashes in previous trials of TOFA in various populations. Isolated 
cutaneous lupus erythematosus without SLE in adults is less common than in older 
adults and will not be studied8. 
With respect to SLE-CL, there is an ongoing clinical trial of TOFA in systemic SLE 
(NCT02535689) where adults with systemic SLE are dosed 5 mg BID. Further, there are 
several studies supporting the efficacy of TOFA in immune mediated alopecia as can 
occur with SLE-CL9,10. Studies  in children with Juvenile Idiopathic Arthritis (JIA)11 
suggest that TOFA is well tolerated. Overall, patients found the taste of the TOFA oral 
suspension to be acceptable (see abstract poster presentation 388 from 2016 ACR 
meeting12 (see Appendix 1).
2. 
Study Design
A scheme of the study design and flow is shown in the figure on the next page.
This 76-week, 3-part Phase 1b/2 study is intended to evaluate the pharmacological 
properties (pharmacokinetics and pharmacodynamics), safety, tolerability and 
preliminary effectiveness of TOFA administrated to young adults (18-45 years) with 
moderately to severely active SLE-CL.  Subjects will be studied at Cincinnati Children’s 
Hospital Medical Center (CCHMC) and Metrohealth Medical Center.

Part A (up to week 8) requires stable background medications; 

Part B (up to week 24) allows for tapering of corticosteroids (CS) in the setting 
of significant clinical improvement of SLE-CL as defined by a decrease in 
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) 
activity score by >50% from baseline , and 

Part C (until week 76) permits tapering of other background medications in 
subjects 
with 
clinical 
remission 
of 
SLE-
CL (CLASI activity score=0). TOFA dosing is kept stable during Part C.
Cohort 1 (n=10, weight > 40kg and age >  18 years and ≤ 45 years) will undergo intense 
PK-sampling to determine exposures following TOFA dosed at 5 mg BID.  TOFA dose 
escalation will not be considered for inadequate response of SLE-CL.
Cohort 2 (n=10, weight > 40kg and age >  18 years and ≤ 45 years) will be treated with 
the same dose as Cohort 1. No PK sampling will occur for Cohort 2.  


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All subjects discontinuing the study after TD1 will enter a 10-Week follow-up period (not shown in figure). TOFA – 
tofacitinib; study visits at trial day 1 (TD1), day 5 of week 1 for Cohort 1 only. Subjects will be discontinued for 
toxicity or lack of response to TOFA at week 8.
3. Trial Periods -Design
It is planned to enroll a total of 20 subjects aged 18 to 45 years with a body weight of 
> 40 kg with active SLE-CL that is not controlled by current standard of care 
medications at tolerable dosages.
Cohort 1 will undergo intense PK-evaluations during the Intense PK Period of Part A. 
As shown in the figure above, subjects move from Part A to Part B to Part C of the 
study, unless they are discontinued from the study (see rescue clause, Section 6.5). 
It is anticipated that almost all subjects will be treated with stable background 
therapy with an antimalarial (hydroxychloroquine, rarely chloroquine), up to 80% are 
treated with corticosteroids (CS), and about 50% of the subjects will also be treated 
with a non-biological DMARD (mostly methotrexate, azathioprine and 
mycophenolate mofetil) for prior multiorgan involvement with SLE.
Screening period
Duration up to 4 weeks; however, subjects should have the TD1 visit as soon as 
possible after the eligibility for the study has been confirmed.  
In the event that a laboratory result does not meet inclusion/exclusion criteria for the 
study, the lab work may be repeated once in the four week period prior to the baseline 
visit to establish elibility for the study. 
TD1     1wk         2wk       3wk      w
5wk       w
7 w
8 w
12w
1 w
20wk    
w
32wk    
w
48wk    52wk                 w
Part – PK of TOFA  
Part – CS 
Part –
Backgroun Drugs Taper
Cohort 
N=10;>40k
Cohort 2:  N=10 ; only for those with confirmed 
Enrollment 
Primar
Endpoint 
Secondar
Endpoint

Rol -over to Part B for CLASI 
End 
Study


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If the subject fails screening for the study,  they may be re-secreened one time after 
the screen failure with permission from the sponsor.  Subject will retain the same 
subject number as assigned at the initial study visit.
If a patient discontinues before the baseline visit, only the demographic information 
and inclusion/exclusion criteria with the primary reason for discontinuation should be 
completed on the eCRF. It is not necessary to complete all the  required evaluations at 
the time of discontinuation unless medically indicated.
Part A (TD1 – week 8)
The primary objective of Part A is to characterize the PK of TOFA at the 5mg dose 
based on Cohort 1 data. Standard of care (SOC) therapies are kept stable during Part 
A. All background medications, including CS remain unchanged.  
Cohort 1 
Intense PK Period: PK sampling will only be done for subjects in Cohort 1. Starting 
at TD1, subject will be monitored at least weekly. PK sampling will occur pre-dose 
on Day 5 (approximately 11-13 hours after the second dose on Day 4) and 0.5, 1, 
2, 4 and 8 hours post first dose on Day 5.  
Cohort 2 
Only if > 1 subject of the Cohort 1 patients has shown partial response of SLE-CL to 
TOFA by week 4, will Cohort 2 be enrolled. 
Cohort 2 subjects will be seen in weekly intervals during Part A.
Cohort 1 and 2 subjects with clinical remission of SLE-CL can enter Part B as early as 
week 4 post baseline. Subjects who move from Part A to Part B prior to Week 8, will 
still be evaluated using the same visit schedule as subjects remaining in Part A until 
week 8.
Part B (week 8* – 24)
The primary objective of Part B is to assess safety and tolerability of TOFA, secondary 
objectives include effectiveness. Specifically, the PK of TOFA at the 5 mg dose based 
on Cohort 1 will be characterized. 

If CS are primarily given for SLE-CL, then CS may be decreased for clinically 
significant improvement as defined by a Cutaneous Lupus Erythematosus 
Disease Area and Severity Index (CLASI) activity score by >50% from baseline 
and must be tapered for CLASI activity scores of 0 for > 2 months.
* Roll-over subjects in SLE-CL clinical remission may enter Part B as early as week 4


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
If CS are mainly prescribed for other SLE manifestations besides SLE-CL, then 
CS can be decreased as per the investigator’s decision, based on clinically 
significant findings of improvement.

If the subject has been discontinued from CS and continues to be in SLE-CL 
clinical remission (CLASI activity score = 0), then the subject can enter Part C.  
Subjects who move from Parts B to Part C prior to Week 24 will still be seen using the 
same visit schedule as subjects remaining in Part B until week 24.
Part C (week 24† – 76)
During Part C all therapies can be altered, per investigator discretion, with the 
exception of TOFA.  The TOFA dose will remain stable throughout the study.  Subjects 
who exit Part A or B early due to SLE-CL improvement will remain in Part C until they 
have been in the study for a total of 76 weeks.
4. Study description
4.1 Primary Objective(s) & Endpoint(s)
Primary objective
Part A (Cohort 1 only):
To evaluate the pharmacokinetic (PK) profiles of TOFA in young adults with 
SLE-CL who are on stable treatment for SLE
Part A (Cohort 1 and Cohort 2):

To evaluate the safety and tolerability of TOFA in young adults with SLE-CL
Part B and C:

To evaluate the safety and tolerability of TOFA in young adults with SLE-CL
Primary endpoints
Part A (Cohort 1 only):

Day 5: AUCinf and Cmax of tofacitinib 
Part B: At Week 24:
Nature, severity, and frequency of adverse events
Incidence and severity of laboratory abnormalities
†  as early as week 8 for subjects with clinical remission of SLE -CL and off CS


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4.2 Key Secondary Objective(s) & Endpoint(s)
Secondary objectives

To evaluate the efficacy of TOFA with SLE-CL over time compared to baseline
Secondary endpoint 
Part A and B: 

Proportion of subjects that achieve a skin response (complete or partial 
response) as  per  the validated (CLASI) at weeks 4, 8 and 24 compared to 
baseline at TD114.  Response is defined as follows: 
o
Complete response (CR) : complete resolution of the inflammatory rash 
(CLASI activity score = 0); 
o
Partial response (PR): > 20% improvement of the CLASI activity score. A 
partial response (PR) is considered clinically significant 
o
No response: < 20% improvement or even worsening of the CLASI 
activity score  
o
Cutaneous relapse: a new CLASI activity score >4 in those subjects who 
previously achieved CR of SLE-CL (CLASI=0)
4.3  Exploratory Objective(s) & Endpoint(s)
Exploratory objectives
Part A:  

To evaluate single cell expression patterns of skin biopsies of affected and 
non-affected skin with TOFA therapy

To examine changes in interferon α/γ receptor, STAT phosphorylation 
patterns with TOFA therapy using immunohistochemistry 

To investigate mRNA expression patterns in peripheral blood upon treatment 
with TOFA with focus on interferon regulated genes 
Parts B and C:

To evaluate steroid sparing properties of TOFA for SLE-CL

To evaluate TOFA effect of overall disease activity in SLE as measured by the 
SLEDAI and BILAG

To evaluate effects of TOFA on quality of life as measured by the Skindex 
(appendix 4) and overall well-being
Exploratory endpoints at week 4, 8, 12, 24, 52, and 76 
Part A: Pharmacodynamics (PD)


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
PD parameters include assessment of inhibitory effect of TOFA on expression 
of IL-2 responsive target genes downstream of the JAK/STAT pathway, such as 
FOXP3, SOCS3, IL-2Rα, interferon -γ and granzyme B.
Parts B and C: 

Decrease of absolute dose of systemic CS from baseline

Decrease of body weight adjusted CS dose from baseline
o
CS dosing is measured in prednisone-equivalents
Proportion of subjects who discontinue systemic CS
Proportion of subjects with cutaneous relapse 

Change of BILAG score from baseline13

Absolute value and percent change in plasma: Complement C3 and C4d, 
autoantibodies (anti-dsDNA) 

Change in number of inflamed  joints from baseline14

Change in SKINDEX score from baseline15

Change of CLASI damage score16  from baseline

Change in SLEDAI score at each time point

Change in protein: creatinine ratio at each time point. 

Change in subject’s overall well-being at each time point

Change in subject’s ESR

Proportion of subjects with clinically important reduction in SLE activity at 
each time point, based on CRV changes compared to baseline 

Proportion of subjects with flare of SLE activity at each time point,  as defined 
by the BILAG17
Data of subjects who enter Part B before week 8 and/or Part C before week 24 will be 
considered on a last-observation (LOC) carried forward basis for endpoints of Part A 
and B, respectively.
5.
Study Participants
5.1 Inclusion Criteria
1. Male or female  > 18 years of age and < 45 years of age and > 40 kg body weight.
2. Fulfilled at least 4 out of the 11 Classification Criteria for SLE by the time of 
screening18. 
3. Willing to give written informed consent, must fully understand the requirements 
of the trial, and must be willing to comply with all trial visits and assessments.
4. CLASI activity score of 8 or higher19 at screening and baseline despite standard of 
care therapy.
5. Stable dose of prednisone of ≤ 20 mg/day within 2 weeks of enrollment.


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6. Female subjects of childbearing potential must use a highly effective method of 
contraception to prevent pregnancy (abstinence is considered highly effective) and 
must agree to continue to practice adequate contraception for the duration of 
their participation in the trial and for 28 days after their last dose of TOFA.
7. Female subjects of childbearing potential must have a negative serum pregnancy 
test at screening and a negative urine pregnancy test at Trial Day 1 before dosing.
8. For subjects receiving leflunomide treatment, total daily dose does not exceed 20 
mg.
9. A negative QuantiFERON-TB Gold In-Tube test performed within the 3 months 
prior to screening, or within the screening period prior to baseline. A negative PPD 
test can be substituted for the QuantiFERON-TB.
10. Subjects either have protective varicella titers or evidence of having been 
vaccinated against varicella.
5.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfil any of the following exclusion 
criteria:
1. Mild SLE-CL defined as a CLASI activity score of 7 or lower at screening and baseline.
2. Increase in CS dosing within 2 weeks prior to Trial Day 1, or expected to require an 
increase in CS dosing during the first 4 weeks of the study.
3. Use of i.v. corticosteroids within 4 weeks prior to Trial Day 1.
4. Increase in dosing of methotrexate, leflunomide, within 4 weeks before Trial Day 
1 or expected to require an increase during the first 8-weeks of the study.
5. Increase in dosing of hydroxychloroquine, or chloroquine within 4 weeks before 
Trial Day 1 or expected to require an increase during the first 8-weeks of the study.
6. Rituximab within 1 year of Trial Day 1.
7. Increase in dosing of any medication or herbal treatment considered to have 
immunosuppressive properties with 4 weeks before Trial Day 1. 
8. Prior treatment with or known intolerability of TOFA. 
9. Use of cyclophosphamide (i.v. or oral), cyclosporine, or tacrolimus within 12 weeks 
prior to Trial Day 1. 
10. Treatment with other investigational agents within the last 6 months or 5 half-lives, 
or as per washout requirement from the previous protocol, whichever is longer. 
11. Estimated glomerular filtration rate less than or equal to 60 mL/min /1.73 m2. 
12. Known positive Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), or 
Hepatitis B surface antigen (HBsAg) serology. 


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13. Any condition, including findings in the laboratory tests, medical history, or other 
screening assessments, that, in the opinion of the Investigator, constitutes an 
inappropriate risk or a contraindication for participation in the trial or that could 
interfere with the trial’s objectives, conduct, or evaluation.  
14. Active central nervous system SLE deemed to be severe or progressive and/or 
associated with significant cognitive impairment leading to inability to provide 
informed consent and/or comply with the protocol. 
15. Significant renal disease due to a reason(s) other than Lupus Nephritis (e.g. 
diabetes mellitus, renovascular disease, or antiphospholipid syndrome). 
16. Severely active Lupus Nephritis defined as a renal BILAG A score. 
17. History of dialysis within 3 months prior to Trial Day 1 or expected to need during 
the trial. 
18. History of or planned renal or other organ transplantation. 
19. Known active clinically significant viral, bacterial or fungal infection, or any major 
episode of infection requiring hospitalization or treatment with parenteral anti-
infectives within 8 weeks of screening, or completion of oral anti-infectives within 
2 weeks of Trial Day 1. 
20. Breastfeeding or currently pregnant.
21. Legal incapacity or limited legal capacity to provide informed consent or assent.
22. Blood dyscrasias, including:

Hgb <10 g/dL or Hct <33%.

WBC <3.0 x 109/L.

Neutrophil count <1.2 x 109/L.

Platelet count <100 x 109/L.

Lymphocyte count of <0.5 x 109/L.
23. AST or ALT > 1.5 times the upper limit of normal or any other clinically significant 
laboratory abnormality.
24. History of any other rheumatic autoimmune disease.
25. Infections:

Latent or active TB or any history of previous TB.

Chronic infections.

Any infection requiring hospitalization, parenteral antimicrobial therapy or 
judged to be opportunistic by the investigator within the 6 months prior to 
the first dose of study drug.

Any treated infections within 2 weeks.


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
History of recurrent (more than one episode) herpes zoster or disseminated 
(a single episode) herpes zoster or disseminated (a single episode) herpes 
simplex.

History or current symptoms suggestive of any lymphoproliferative disorder, 
including Cytomegaly Virus (CMV) or Epstein Barr Virus (EBV) related 
lymphoproliferative disorder, history of lymphoma, leukemia, or signs and 
symptoms suggestive of current lymphatic disease.
26. Subjects taking potent and moderate cytochrome P450 3A4 (CYP3A4) inhibitors 
(see Appendix 2).
27. Subjects taking potent and moderate CYP3A4 inducers (see Appendix 2).
28. Subjects who have been vaccinated with live or attenuated vaccines within the 6 
weeks prior to the first dose of study medication. All subjects should be up-to-
date with respect to standard of care vaccinations (as defined by their country 
health ministry) as permitted by past immunosuppressive therapy for SLE. 
29. Subjects with a malignancy or with a history of malignancy with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer 
of the skin or cervical carcinoma in situ.
30. Subjects with a history or current diagnosis of diverticulitis.
6
Treatments, Regimens & Control
This is a 3-part study designed to evaluate the Pharmacokinetics and 
Pharmacodynamics of TOFA in young adults with active SLE-CL (CLASI activity score>8) 
aged 18 to 45 years. Safety and efficacy will be evaluated as secondary objectives. 
Subjects achieving CR of SLE-CL may be permitted to roll-over to subsequent parts of 
the study earlier.
In Part A (baseline – week 8), subjects will be enrolled in an open-label arm to receive 
TOFA orally twice per day. PK analysis will be performed on Cohort 1 only to measure 
PK parameters. Starting week 4, subjects may roll over from Part A to Part B early, if 
there is clinical remission of SLE-CL (CLASI activity score = 0).
In Part B (week 8 – 24), subjects will continue TOFA as in Part A but CS can be decreased 
for clinically significant improvement of SLE-CL by > 50% from baseline. Subjects who 
maintain clinical remission of SLE-CL and succeeded in discontinuing CS, can roll over 
to Part C prior to week 24.
In Part C (week 24 – 76), subjects off CS who are in clinical remission of SLE-CL will be 
able to taper and change other background medications.  TOFA dosage will remain 
stable. 
It is planned to enroll:
Cohorts 1: n=10, weight > 40 kg age >18 up to and including 45 years.


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Cohort 2: n=10; weight > 40 kg and age > 18 years up to and including 45 years. 
Enrollment of subjects into Cohort 2 will commence once enrollment of Cohort 1 
are completed.  


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6.1
Treatment
1. Active drug: 
TOFACITINIB (TOFA)
2. Allowable background anti-inflammatory systemic SLE therapy includes: 
a) Subjects on a stable dose of hydroxychloroquine for at least 1 month prior to 
study entry are permitted to continue use throughout the duration of the study 
with a maximum allowable dose of 400mg.
b) Subjects are permitted ot continue the use of oral corticosteroids (CS), 
methotrexate (MTX), and leflunomide, at allowed doses, as well as NSAIDs and 
ASA.
 
6.2
Dosing
TOFA dosing: Twice daily orally
As documented in the TOFA Investigator brochure (Section 6.1; Version March 2016) 
doses up to 30 mg twice daily were safe and tolerated. However, for the purpose of 
this study only the dose of TOFA approved for rheumatoid arthritis (5 mg PO BID) will 
be tested. 
Based on TOFA PK in the Rheumatoid Arthritis (RA) population [body weight (BW) 
ranging from 40 kg - 140 kg)], clearance (CL) of TOFA is not dependent on body weight 
in adult subjects.  Thus, the starting dose of TOFA will be 5 mg orally twice daily, an 
approved dose of TOFA in adult RA subjects in most countries.  Dose excalation will not 
occur even with lack of SLE-CL improvement.
Corticosteroids (CS):
At study entry, CS dosage must be ≤ 20mg/day. CS should be kept stable up to and 
including week 4.
CS can be decreased starting week 5:

CS may be decreased for improvement of the CLASI activity score by >50% from 
baseline and must be tapered for CLASI activity scores of 0 for > 8 weeks (or 2 
subsequent study visits, whatever is shorter), provided CS are mainly 
prescribed for SLE-CL.  This will minimize morbidity associated with CS use as 
much as possible.

If CS are mainly prescribed for other SLE manifestations besides SLE-CL, then 
CS can be decreased as per the investigator’s decision, even in the setting of 
complete response of SLE-CL, based on continued improvement of clinical 
findings of SLE.
Oral CS may be increased above the baseline level up to max of 60 mg/day for new 
BILAG A or B flares in organ systems other than mucocutaneous organ system (i.e. 
neurologic, ophthalmologic, musculoskeletal, cardiopulmonary, gastrointestinal, 
renal, hematological organ systems)   but must be returned to baseline dose or lower 
within 14 days. If this is not achieved then the subject is considered a treatment failure.


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
Up to 3 doses of pulse methylprednisolone may be given for new BILAG A or B 
flares instead. 

CS increases can occur no more than 3 times during the duration of the study, 
Part A- C.

Subjects requiring more than 3 CS increases will be withdrawn from treatment 
phase of study.  
Other anti-inflammatory medications used as part of standard of care (SOC) for SLE 
These include methotrexate (MTX) or leflunomide or mycophenolate mofetil, 
hydroxychloroquine (HCQ) or chloroquine (CQ), and NSAIDs, which are all allowed 
during the study. All background therapy dosages given prior to Screening must 
have been kept stable according to the specifications in the exclusion criteria for a 
subject to be eligible for the study. These medications must remain stable during 
the Screening period and Part A. SOC medications are part of the subject’s previous 
SLE treatment and thus will not be provided by the Sponsor.
Other permitted Medicine
Vitamin D (≥ 400 IU/day) and calcium supplements (≥ 800 mg/day) may be given 
for prevention of glucocorticoid-induced bone loss (ACR Ad Hoc Committee on 
Glucocorticoid-Induced Osteoporosis, 2001).  
Paracetamol (acetaminophen) may be initiated for pain control of SLE symptoms 
during the study.  This should be titrated off as tolerated, and preferably not taken 
on the day of the clinic visit. Other pain medications, including opiates, may be 
used for temporary relief of symptoms not due to SLE.
Vaccines
Subject should be as up to date with childhood vaccinations as much as previous 
SLE treatments permitted. It is recommended that subjects be vaccinated against 
infectious diseases according to the local standard of care (i.e. influenza, 
pneumococcal vaccine, varicella), preferably at least 2 weeks before TD1. It should 
be noted that live and live-attenuated vaccines are not authorized within 6 weeks 
before TOFA intake, during the trial period, and for 6 weeks following the last dose 
of TOFA.
6.3
Controls
The primary objective of this PK bridging study is safety and tolerability, and thus it is 
acceptable to avoid the use of placebo. 


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6.4
Total duration
76 weeks (part A through C) or until TOFA is considered no longer needed by the 
investigator, whichever is first. 
6.5
Rescue clause, treatment failure & subject withdrawal
A subject will be considered a treatment failure and discontinued from the study if 
he/she experiences one or more of the following:

Serious adverse event that is possibly related to TOFA; 

Important worsening of renal disease defined as a persistent increase in 
proteinuria as measured by the protein: creatinine (PC) ratio to values > 2.0  
after achieving complete response of lupus nephritis, or doubling of proteinuria 
with values PC ratio >3.0 after achieving a partial response of lupus nephritis;

Need to increase current or initiation of new SLE background therapy due to 
non-renal SLE manifestations; 

Life-threatening SLE complications as judged by the investigator;

Need for more than the protocol defined allowable CS rescue therapy as 
determined by the treating physician;

No improvement of SLE-CL as measured by the CLASI by week 8;

Two sequential absolute lymphocyte counts less than  <0.5 x 109 or 500 
cells/mm3;    

Two sequential hemoglobin values <8.0 g/dL (80 g/L) or decreases greater than 
2 g/dL on treatment;

Female subjects that become preganant during the study will discontinue study 
treatment.  They will be continued to be followed in accordance as outlined in 
section 7.3.10.
Subject Withdrawal
Subjects may withdraw from the study at any time at their own/their legal 
guardian’s request, or they may be withdrawn at any time at the discretion of the 
physician investigators for safety, behavioral, or administrative reasons. If a subject 
does not return for a scheduled visit, every effort should be made to contact the 
subject. In any circumstance, every effort should be made to document subject 
outcome, if possible. 
The investigator will inquire about the reason for withdrawal, request the subject 
to return all unused investigational product, request the subject to return for a 
final visit, if applicable, and follow-up with the subject regarding any unresolved 
AEs.


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7
If the subject withdraws from the study, and also 
withdraws consent for disclosure of future information, 
no further evaluations should be performed, and no 
additional data should be collected. The sponsor may 
retain and continue to use any data collected before 
such withdrawal of consent.Planned Assessments & 
Evaluations 
7.1  Evaluations for ALL Subjects
PART A
Cohort 1:    
Subject will be monitored at Day 1 and Day 5 of week 1, and then 
once per week during weeks 2, 3, 4, 5, 6, 7, 8. 
PK samples will be drawn on Day 5 of Trial Week 1: pre-morning 
dose and 0.5, 1, 2, 4 and 8 hours post-morning dose of Day 5.  
Cohort 2: 
TD1, and then once per week during weeks 2, 3, 4, 5, 6, 7, and 8.
PART B‡
Subjects of Cohorts 1 and 2 will be monitored at study visits at 
weeks 10, 12, 16, 20 and 24. CS dosing can be changed during Part 
B.
PART C§ 
Subjects of Cohorts 1 and 2 will be monitored at study visits every 8 
weeks until week 76. Background medications, CS and other 
background medications can be changed during Part C, while TOFA 
remains stable.
Follow-up Period
All subjects who discontinue TOFA treatment at any time post-
baseline will have a follow up phone call 10 weeks after the last 
TOFA dose to monitor for the development of safety events. 
7.1.1 Disease activity

SLEDAI-2K and BILAG-2004 17,20

Physician Global Assessment of SLE activity (visual analog scale ; 0-10)
‡  Roll-over subjects in SLE-CL clinical remission may enter Part B as early as week 4 
§    as early as week 8 for subjects with clinical remission of SLE -CL and off CS


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
CLASI Activity Score16 
7.1.2 Patient-reported outcomes

Well Being Assessment (visual analog scale ; 0-10)

Pain (visual analog scale ; 0-10)

SKINDEX-29 (appendix 4)15 
7.1.3 Other outcome measures

SLICC/ACR damage index21

CLASI Damage Index16
7.1.4 Laboratory parameters

ESR

Hematology

Clinical chemistry

C3,C4, dsDNA-antibodies

Urine PC ratio

Quantitative EBV and CMV PCR
7.2 Evaluations Performed in Select Subjects
7.2.1 Photography & skin biopsy
A subset of up to 3-5 subjects from either Cohort 1 or Cohort 2 will be asked to 
participate in serial photography of lesions on the back, face or the extremities. 
Picture will be obtained three times during the study by a trained individual or 
medical photographer, starting from baseline (also see Schedule of Events).
Subjects agreeing to participate in photography will also be asked to consent to two 
skin biopsies. At each of the two biopsy sessions 2 skin samples will be obtained 
(approximately 3 mm in diameter) by means of punch biopsy. The first two skin 
biopsy samples will be taken from an active SLE-CL lesion located over the back or 
the extremities during week 1. The second two skin biopsy samples will be taken 
from the initial lesion, in close geographical proximity to the site of the initial biopsy, 
between weeks 8 and 15.  


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Prior to taking the skin biopsy the area will be numbed with topical or injectable 
lidocaine.
7.2.2 Pharmacokinetic parameters
Plasma TOFA levels
Cohort 1 will undergo intensive sampling in week 1. 
7.2.3 Exploratory Pharmacodynamic Biomarkers
A subset of subjects will be asked to participate in translational research studies, 
performed 2 or 3 times during the study.

Blood samples for RNA and miRNA level gene expression with focus on 
interferon regulated pathways  

Interferon γ and interferon α levels 

T cell activation of flow – C1 or POLARIS

Urine biomarkers

Single-cell RNA sequencing of skin cells 

Immunohistochemistry of skin cells for phosphorylated STATs and interferons
7.3 
Safety & Adverse Event Reporting
Safety reporting will be completed in accordance with IRB guidelines and FDA 
requirements (21 CFR Part 312) for studies performed under an IND. 
7.3.1. Adverse Events
All observed or volunteered Adverse Events (AE) will be reported as described in the 
following sections.
For all AEs, the site’s investigator must pursue and obtain information adequate both 
to determine the outcome of the AE and to assess whether it meets the criteria for 
classification as a Serious Adverse Event (SAE) requiring immediate notification to the 
IRB and Pfizer or its designated representative. For all AEs, sufficient information 
should be obtained by the investigators to determine the causality of the AE. The 
investigators will assess causality. Follow-up by the investigator may be required until 
the event or its sequelae resolve or stabilize at a level acceptable to the IRB, the 
investigator, and Pfizer concurs with that assessment. 
As part of ongoing safety reviews conducted by the Principal Investigator, any non-
serious adverse event that is determined by the Principal Investigator (PI) to be serious 
will be reported by the PI as a SAE. 


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7.3.2. Reporting Period
For SAEs, the active reporting period to the IRB and  Pfizer begins from the time that 
the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, i.e., prior to undergoing any study-related procedure and/or 
receiving TOFA, through and including 28 calendar days after the last administration 
of the investigational product.
SAEs occurring to a subject after the active reporting period has ended should be 
reported to the  IRB, FDA, and PFIZER if the investigator becomes aware of them; at a 
minimum, all serious adverse events that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the IRB, FDA 
and PFIZER.
AEs (serious and non-serious) will be recorded on the CRF from the time the subject 
has taken at least one dose of study treatment through last subject visit.
7.3.3 Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage. Examples of AEs include but are not limited 
to:
• Abnormal test findings;
• Clinically significant symptoms and signs;
• Changes in physical examination findings;
• Hypersensitivity;
• Progression/worsening of underlying disease;
• Drug abuse;
• Drug dependency.
Additionally, they may include the signs or symptoms resulting from:
• Drug overdose;
• Drug withdrawal;
• Drug misuse;
• Drug interactions;
• Extravasation;
• Exposure in Utero (EIU);
• Exposure via breast feeding;
• Medication error;
•
Occupational exposure.
7.3.4 Infections
All treated infections occurring during the study, including, but not limited to, 
respiratory infections, cutaneous infections, urinary tract infections and episodes of 
suspicious or febrile diarrhea, should be cultured and any identified organisms noted 


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in the case report form (CRF). Infections should be classified as either serious infections 
or treated infections, as defined below.
Serious Infections
A serious infection is any infection that requires hospitalization for treatment or 
requires parenteral antimicrobial therapy or meets other criteria that require it to 
be classified as a serious adverse event. A subject who experiences a serious 
infection must be discontinued from the study. This infection must be reported as 
a serious adverse event and should be listed as the reason for discontinuation in 
the electronic case report form (eCRF). Appropriate laboratory investigations, 
including but not limited to cultures should be performed to establish the etiology 
of any serious infection. All adverse events, including serious adverse events, must 
be reported as described in Section 7.7.1 on Adverse Event Reporting.
Treated Infections
A treated infection is any infection that requires antimicrobial therapy by any route 
of administration or any surgical intervention (e.g., incision and drainage). A 
subject who experiences a serious infection must be discontinued from the study. 
This information must be noted in the eCRF.
7.3.5 Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows:

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical 
intervention; and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or PI.
Merely repeating an abnormal test, in the absence of any of the above conditions, will 
not constitute an AE. Any abnormal test result that is determined to be an error does 
not require reporting as an AE.
7.3.6 Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:
• Results in death;
• Is life-threatening (immediate risk of death);
• Requires inpatient hospitalization or prolongation of existing hospitalization;
• Results in persistent or significant disability/incapacity (substantial disruption 
of the ability to conduct normal life functions);


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• Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life-
threatening and/or result in death or hospitalization. However, if it is determined that 
the event may jeopardize the subject or may require intervention to prevent one of the 
other AE outcomes, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the 
safety database.
Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase 
(ALT) concurrent with abnormal elevations in total bilirubin that meet the criteria 
outlined below in the absence of other causes of liver injury are considered 
potential cases of drug-induced liver injury (potential Hy’s Law cases) and will 
always be considered important medical events. 
Subjects who subsequently present with AST or ALT ≥3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin ≥2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase ≤2 X ULN or not available are asked to 
return to the investigational site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results. 
This evaluation may include laboratory tests, detailed history and physical 
assessment. In addition to repeating AST and ALT, laboratory tests should include 
albumin, kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, creatinine prothrombin time (PT)/International Normalized Ratio 
(INR) and alkaline phosphatase. 
A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a 
jaundiced patient, surgery, blood transfusion, history of liver or allergic disease, 
and work exposure, will be collected. 
Further testing for acute hepatitis A, B, or C infection and liver imaging (e.g., biliary 
tract) may be warranted. All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above, with no other cause for liver function test 
abnormalities identified at the time should be considered potential Hy’s Law cases 
irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal liver function tests. Such potential Hy’s Law 
cases should be reported as SAEs.


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Study drug will be discontinued if liver injury is noted as defined above.
7.3.7 Hospitalization
AEs reported from studies associated with hospitalization or prolongation of 
hospitalization, are considered serious. Any initial admission (even if less than 24 
hours) to a healthcare facility meets these criteria. Admission also includes transfer 
within the hospital to an acute/intensive care unit (e.g. from the psychiatric wing to a 
medical floor, medical floor to a coronary care unit, neurological floor to a tuberculosis 
unit). Hospitalization does not include the following:
• Rehabilitation facilities;
• Hospice facilities;
• Routine emergency room admissions;
• Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, 
clinical AE is not in itself an SAE. Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (e.g., 
for work-up of persistent pre-treatment lab abnormality); 

Social admission (e.g., subject has no place to sleep); 

Administrative admission (e.g., for yearly physical exam); 

Optional admission not associated with a precipitating clinical AE (e.g., for 
elective cosmetic surgery); 

Hospitalization for observation without a medical AE;  

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, will 
not be reported as AEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE, 
and the resulting appendectomy should be recorded as treatment of the AE.
7.3.8 Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE. For purposes of consistency, 
these intensity grades are defined as follows: 

MILD- Does not interfere with subject's usual function.

MODERATE -Interferes to some extent with subject's usual function.

SEVERE- Interferes significantly with subject's usual function.


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A severe event is not necessarily an SAE. For example, a headache may be severe 
(interferes significantly with subject's usual function) but would not be classified as 
serious unless it met one of the criteria for SAEs, listed above.
7.3.9 Causality Assessment
The investigator’s assessment of causality will be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse 
reporting requirements if applicable. An investigator’s causality assessment is the 
determination of whether there exists a reasonable possibility that the investigational 
product caused or contributed to an AE; generally the facts (evidence) or arguments 
to suggest a causal relationship will be provided.
If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the PI (see Section on Reporting Requirements). 
If the investigator's causality assessment is "unknown but not related to investigational 
product", this will be clearly documented on study records. In addition, if the 
investigator determines an SAE is associated with study procedures, the investigator 
will be record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
7.3.10 Exposure In Utero
If a study subject or study subject’s partner becomes or is found to be pregnant during 
the study subject’s treatment with TOFA, the investigator will submit this information 
to the IRB, and the Pfizer Drug Safety Unit on a Serious Adverse Event Form and 
Exposure in Utero (EIU) Supplemental Form, regardless of whether an SAE has 
occurred. In addition, the investigator must submit information regarding 
environmental exposure to a Pfizer product in a pregnant woman (e.g., a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EIU Form. 
This will be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the exposure. The information submitted should include the anticipated 
date of delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain pregnancy outcome information for all EIU reports 
with an unknown outcome. The investigator will follow the pregnancy until completion 
or until pregnancy termination and notify Pfizer of the outcome as a follow up to the 
initial EIU Form. In the case of a live birth, the structural integrity of the neonate can 
be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure 
test findings are conclusive for a congenital anomaly and the findings are reported).


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If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly [in a live born, a terminated fetus, an intrauterine fetal demise or a neonatal 
death]), the investigator will follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows:

“Spontaneous abortion” includes miscarriage and missed abortion.   

Neonatal deaths that occur within 1 month of birth should be reported, 
without regard to causality, as SAEs. In addition, infant deaths after 1 month 
should be reported as serious adverse events when the investigator assesses 
the infant death as related or possibly related to exposure to investigational 
product.
Further follow-up of birth outcomes will be handled on a case-by-case basis (e.g., 
follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study subject with the EIU Pregnancy 
Partner Release of Information Form to deliver to his partner. The Investigator will 
document on the EIU Form that the subject was given this letter to provide to his 
partner.
7.3.11 Withdrawal Due to Adverse Events (See also section on Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to insufficient 
response, according to the definition of AE noted earlier, and recorded on the 
appropriate AE CRF page.
When a subject withdraws due to an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
7.3.12 Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously 
reported by the study subject. In addition, each study subject will be questioned about 
AEs.
7.3.13 Reporting Requirements
Each AE is assessed to determine if it meets the criteria for SAEs. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness 
of the event. In particular, if the SAE is fatal or life-threatening, notification to Pfizer 
must be made immediately, irrespective of the extent of available AE information. 
This timeframe also applies to additional new information (follow-up) on 
previously forwarded SAE reports as well as to the initial and follow-up reporting 
of EIU and exposure during breast feeding cases. In the rare event that the 


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investigator does not become aware of the occurrence of an SAE immediately (e.g., 
if an outpatient study subject initially seeks treatment elsewhere), the investigator 
is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
The IRB will be notified per institutional policy.
In addition, an investigator may be requested by Pfizer to obtain specific additional 
follow-up information in an expedited fashion. This information collected for SAEs 
is more detailed than that captured on the AE CRF. In general, this will include a 
description of the AE in sufficient detail to allow for a complete medical assessment 
of the case and independent determination of possible causality. Information on 
other possible causes of the event, such as concomitant medications and illnesses 
must be provided. In the case of a subject death, a summary of available autopsy 
findings must be submitted as soon as possible to the IRB and Pfizer or its 
designated representative.
Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the 
form for collection of SAE information is not the same as the AE CRF. Where the 
same data are collected, the forms must be completed in a consistent manner. For 
example, the same AE term should be used on both forms. AE should be reported 
using concise medical terminology on the CRFs as well as on the form for collection 
of SAE information.


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8
Planned Statistical Analyses 
8.1
Pharmacokinetic Analysis 
The PK concentration population is defined as all subjects enrolled and treated for 
whom at least 1 TOFA level or parameters of interest can be determined. 
PK parameters of TOFA following multiple-dose oral administration will be derived 
from the concentration-time profiles using noncompartmental analysis. The observed 
predose concentration will also be used as the 12-hour concentration in these 
calculations, assuming steady state.  Actual PK sampling times will be used in the 
derivation of PK parameters.
The plasma PK parameters from noncompartmental analysis (CL/F, Vz/F, AUCt, Cmax, 
Tmax, and t1/2 (if data permit)) on Day 5 will be summarized descriptively by Visit/Day. 
Plasma concentrations will also be summarized descriptively by PK sampling time. 
Individual subject concentration-time data will be plotted using actual PK sampling 
times. Summary profiles (mean and median plots) of the concentration-time data will 
also be presented. Summary profiles will be presented on both linear-linear and log-
linear scales.
The PK parameters such as CL/F and Vz/F may be compared with historical adult RA 
and JIA patients data using mixed effect modeling approach.
8.2
Safety Analyses
The safety population will be all subjects who received at least 1 dose of TOFA. No 
interim analyses are planned.
AE, SAEs and serious adverse events will be summarized using frequencies and under 
consideration of the number of study subjects affected. Further, in secondary analysis, 
we will use mixed model analysis to assess the relationship between side effects and 
(1) subject weight (2) background therapy with CS; (3) concurrent use of a 
nonbiological immunesuppressant,or (4) a history of lupus nephritis.
8.3
Effectiveness Analyses
Due to the small sample size, results may not show statistical significance.  Statistical 
significance may not be reached in final data analysis.  However, a trend towards 
improved clinical status may assist planning efforts of a larger clinical trial to assess 
efficacy.
The efficacy population will be all subjects who were enrolled in the study and received 
at least 1 dose of TOFA. No interim analyses are planned. We will perform intention-
to-treat analyses, with the last observation carried forward in primary analyses; and 
will also perform analyses on observed data in secondary analyses.  As this is an open-
label study, no control group is available. Efficacy measures are listed under Section 7.   
Data of subjects who enter Part B before week 8 and/or Part C before week 24 will be 


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considered on a last-observation (LOC) carried forward basis for endpoints of Part A 
and B, respectively.
To assess the benefits of TOFA on skin manifestations of SLE, we will use descriptive 
analysis and contingency table analysis, using Chi-square and Fisher Exact test as 
appropriate, to determine the proportion of subjects who are partial or complete 
CLASI responders at weeks 4, 8 and 24 compared to baseline.  To assess the effect of 
TOFA on skin damage, we will compare the change (increase) of CLASI damage score16 
from baseline to the end of Part B and C, respectively, using paired T-tests. 
To assess the steroid –sparing properties of TOFA, we will determine the proportion 
of study subjects who can discontinue steroids at the end of Part B and C, respectively. 
We will also evaluate steroid sparing properties of TOFA for SLE-CL by comparing 
steroid doses (absolute and weight-adjusted) at baseline with those in the end of Part 
B and C, using a paired T-test. 
Similarly, we will assess TOFA effect of overall disease activity in SLE as measured by 
the numeric SLEDAI and BILAG scores, respectively. We will also perform sub-analyses 
and evaluate improvement or resolution of other organ-system activity (e.g. 
serological activity – measured by anti-dsDNA antibodies and low complement levels; 
joint counts) using paired T-tests and contingency table analysis, as appropriate. In a 
similar fashion the change of the other SLE core response variables (CRV) besides 
disease activity (SLEDAI, BILAG) will be assessed at each study visit. 
To explore the effects of TOFA on quality of life, we will compare the SKINDEX score 
(appendix 4), well-being and pain assessments from baseline to the end of Part B and 
C, respectively.
We will also explore single cell expression patterns of skin biopsies of affected and 
non-affected skin with TOFA therapy; and examine changes in interferon α/γ receptor, 
STAT phosphorylation patterns with TOFA therapy using immunohistochemistry; we 
also explore mRNA expression patterns in peripheral blood upon treatment with TOFA 
with focus on interferon regulated genes.
We will also explore at  week 4, 8, 12, 24, 52, and 76,  the relationship of PD 
parameters: the  inhibitory effect of TOFA on expression of IL-2 responsive target 
genes downstream of the JAK/STAT pathway, such as FOXP3, SOCS3, IL-2Rα, interferon 
(IFN)-γ and granzyme B will be studied.


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9. Data Safety Monitoring Plan
This study follows procedures for minimizing risks and ensuring the safety and 
confidentiality of human subjects, as established under both the Department of Health 
and Human Services and the Office for Human Research Protections (OHRP). The study 
will be conducted in accordance with the ethical principles of the Declaration of 
Helsinki 
and 
will 
be 
consistent 
with 
Good 
Clinical 
Practices 
(GCP) 
http://www.fda.gov/cder/guidance/959fnl.pdf 
and 
applicable 
regulatory 
requirements. A consent form describing all aspects of the study will  be approved by 
the IRB. The nature of all possible treatment assignments, as well as their risks and 
potential benefits, will be fully explained to all participants. The study sites will take 
appropriate measures to ensure the confidentiality of the data and the well-being of 
the subjects.  Medidata Rave will be used for Electronic Data Capture.   
Please see Appendix 3 for a detailed Data Safety Monitoring Plan. 
Considering the small size of the study and the substantial experience with tofacitinib 
use in humans (see IB; Appendix 3) no Data Safety Monitoring Board will be formed23


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10
Schedule of Assessments 
Trial Period
Screening
Part A  
Part B
Part C
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Trial Week
0
1*1
2
3
4
5
6
7
8
10
12
16
20
24
32
40
48
56
64
72
76/EOS
Time Windows
Day -30 to 
Day -1
Day 1
±1 
day
±1 
day
±1 
day
±1 
day
±1 
day
±1 
day
±1 
day
±2 
day
±2 
day
±3 
day
±3 
day
±3 
day
±5 
day
±5
day
±5
day
±5
day
±5
day
±5
day
±3 
day
Informed Consent
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, medication
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis assessment
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum virology (HBsAg, HCV, HIV, VZV)
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test*2
 X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test*2
X
 
 
X 
 
 
 
X 
 
 X
 
X
 X
X 
X 
X 
X 
X 
X 
 
Vital sign, weight, height*3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Product Dispensing (or as needed)
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Dosing Diary review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete physical examination
X
X
 
 
X
 
 
 
X
 
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology
X
X
X
X
X
X
X
X
X
 
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
 
X
X
X
X
X
X
X
X
X
X
X
Urinalysis incl. sediment
X
X
 
 
X
 
 
 
X
 
X
X
X
X
X
X
X
X
X
X
X
Urine protein: creatinine ratio
X
X
 
 
X
 
 
 
X
 
X
X
X
X
X
X
X
X
X
X
X
Complement C3, C4,
 
X
 
 
X
 
 
 
X
 
X
X
X
X
X
X
X
X
X
X
X
ANA*4 and anti-ds DNA Abs
 
X
 
 
X
 
 
 
X
 
X
X
X
X
X
X
X
X
X
X
X
ESR
 
X
 
 
X
 
 
 
X
 
 
 
 
X
 
 
 
 
 
 
X
Efficacy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Photography (selected)
 
X
 
 
 
 
 
 
X
 
 
 
 
X
 
 
 
 
 
 
 
SLICC/ACR damage index
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
SLEDAI-2K, MD Global Assessments, BILAG
 
X
 
 
X
 
 
 
X
 
X
X
X
X
X
X
X
X
X
X
X
Patient’s  Global Assessment, Skindex
 
X
 
 
X
 
 
 
X
 
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma TOFA-Part A (Cohort 1) *5
 
X*6
Pharmacodynamic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**Gene expression profiling of IL2 mediated genes in 
whole blood
 
X
 
 
 
 
 
 
X
 
 
 
 
X
 
 
 
 
 
 
 
**Phosphospecific flow cytometry of blood T-cells &  
other relevant cells
 
X
 
 
 
 
 
 
X
 
 
 
 
X
 
 
 
 
 
 
 
**SC-RNA SEQ in skin biopsies (selected)
 
X
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
**Skin biopsy (selected) *7
X 
 
 
 
 
 
 
 X *7
 
 
 
 
 
 
Safety
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events/SAE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant  medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TT, diphtheria, varicella, influenza titer; EBV and CMV 
PCR
X
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 


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1*Part A - Day 5 after TD1 
*2Females only
 *3Height only at screening
 *4ANA only at baseline on TD1
*5 A total of 24.5 mL of blood will be taken at these visits for pharmacodynamics tests
 *6PK samples will be drawn on Day 5 of Trial Week 1. re - morning dose for Day 5 and at 0.5, 1, 2, 4 and 8 hours post morning dose.
*7 Two 3mm punch biopsies will be collected.  1st punch collected during week one.  2nd punch colleceted between weeks 8-15.
**Assessment completed only at CCHMC


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11
References
1.
Kalliolias GD, Kirou KA. Type I interferons as biomarkers in autoimmune diseases. 
Biomarkers in medicine. 2012;6(2):137-140.
2.
van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus 
placebo in rheumatoid arthritis. The New England journal of medicine. 2012;367(6):508-
519.
3.
Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib 
monotherapy in rheumatoid arthritis. The New England journal of medicine. 
2012;367(6):495-507.
4.
Yamamoto M, Yokoyama Y, Shimizu Y, et al. Tofacitinib can decrease anti-DNA antibody 
titers in inactive systemic lupus erythematosus complicated by rheumatoid arthritis. 
Modern rheumatology / the Japan Rheumatism Association. 2015:1-2.
5.
Kubo S, Yamaoka K, Kondo M, et al. The JAK inhibitor, tofacitinib, reduces the T cell 
stimulatory capacity of human monocyte-derived dendritic cells. Annals of the rheumatic 
diseases. 2014;73(12):2192-2198.
6.
Silva CA, Avcin T, Brunner HI. Taxonomy for systemic lupus erythematosus with onset 
before adulthood. Arthritis care & research. 2012;64(12):1787-1793.
7.
Bickers DR, Lim HW, Margolis D, et al. The burden of skin diseases: 2004: A joint project 
of the American Academy of Dermatology Association and the Society for Investigative 
Dermatology. Journal of the American Academy of Dermatology. 2006;55(3):490-500.
8.
Mina R, Brunner HI. Update on differences between childhood-onset and adult-onset 
systemic lupus erythematosus. Arthritis Res Ther. 2013;15(4):218.
9.
Jabbari A, Dai Z, Xing L, et al. Reversal of Alopecia Areata Following Treatment With the 
JAK1/2 Inhibitor Baricitinib. EBioMedicine. 2015;2(4):351-355.
10.
Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is 
reversed by JAK inhibition. Nat Med. 2014;20(9):1043-1049.
11.
Ruperto N, Brunner H, Hazra A, et al. AB0879 Pharmacokinetics, Safety, and Tolerability 
of Tofacitinib in Paediatric Patients from Two To Less than Eighteen Years of Age with 
Juvenile Idiopathic Arthritis. Annals of the rheumatic diseases. 2016;75(Suppl 2):1202-
1203.
12.
Brunner HI, Ruperto N, Tzaribachev N, et al. Pharmacokinetics, Safety, and Tolerability of 
Tofacitinib in Pediatric Patients from Six to Less Than Eighteen Years of Age with Juvenile 
Idiopathic Arthritis. Arthritis & Rheumatology. 2015;67:2918-2919.
13.
Brunner HI, Feldman BM, Bombardier C, Silverman ED. Sensitivity of the Systemic Lupus 
Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and 
Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset 
systemic lupus erythematosus. Arthritis Rheum. 1999;42(7):1354-1360.
14.
Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary 
definition of improvement in rheumatoid arthritis. Arthritis & Rheumatology. 
1995;38(6):727-735.
15.
Chren MM, Lasek RJ, Sahay AP, Sands LP. Measurement properties of Skindex-16: a brief 
quality-of-life measure for patients with skin diseases. J Cutan Med Surg. 2001;5(2):105-
110.
16.
Albrecht J, Taylor L, Berlin JA, et al. The CLASI (Cutaneous Lupus Erythematosus Disease 
Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. 
The Journal of investigative dermatology. 2005;125(5):889-894.
17.
Gordon C, Sutcliffe N, Skan J, Stoll T, Isenberg DA. Definition and treatment of lupus 
flares measured by the BILAG index. Rheumatology (Oxford). 2003;42(11):1372-1379.


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18.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the 
classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
19.
Klein R, Moghadam-Kia S, LoMonico J, et al. Development of the CLASI as a tool to 
measure disease severity and responsiveness to therapy in cutaneous lupus 
erythematosus. Arch Dermatol. 2011;147(2):203-208.
20.
Ibanez D, Gladman DD, Urowitz MB. Adjusted mean Systemic Lupus Erythematosus 
Disease Activity Index-2K is a predictor of outcome in SLE. The Journal of rheumatology. 
2005;32(5):824-827.
21.
Gladman DD, Goldsmith CH, Urowitz MB, et al. The Systemic Lupus International 
Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for 
Systemic Lupus Erythematosus International Comparison. The Journal of rheumatology. 
2000;27(2):373-376.


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APPENDIX 1  Tofacitinib Experience in Juvenile Arthritis
ABSTRACT NUMBER: 388
Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Pediatric Patients from Two to 
Less Than Eighteen Years of Age with Juvenile Idiopathic Arthritis
Hermine I. Brunner et al
Meeting: 2016 ACR/ARHP Annual Meeting
Date of first publication: September 28, 2016
Keywords: juvenile idiopathic arthritis (JIA), pharmacokinetics and tofacitinib
SESSION INFORMATION
Background/Purpose: Tofacitinib is an oral Janus kinase inhibitor that is being investigated for 
juvenile idiopathic arthritis (JIA). Here, we report the pharmacokinetics (PK), safety, and taste 
acceptability of tofacitinib following multiple oral doses in patients (pts) 2–<18 years (yrs.) old with
active JIA.
Methods: Data were obtained from an open-label, non-randomized, multicenter, Phase I study 
(NCT01513902) where JIA pts were given 5 mg adult equivalent (based on body weight) of tofacitinib 
(tablet or solution) twice daily (BID) for 5 days (Table). There were 3 cohorts (COH) based on pt age, 
COH1: 12–<18 yrs, COH2: 6–<12 yrs, and COH3: 2–<6 yrs, with a target enrollment per group of ≥8 
JIA pts for N=≥24 evaluable pts completing the study. Pts were enrolled in a stepwise
approach beginning with the older age COH first. Subsequent younger age COH were enrolled 
following confirmation of safety and PK from the previous COH. PK parameters of tofacitinib were 
calculated using non-compartmental analysis of plasma concentration (conc)-time data. Taste 
acceptability of the solution formulation was listed and categorically summarized (frequency and %).
Results: 26 pts (COH1 [N=8], COH2 [N=9], and COH3 [N=9]) were included in this analysis. Pts’ 
age ranged from 2–17 years; all were white except for one; there were 17 females and 9 males. 
Baseline disease characteristics were similar across all COH. All exposure metrics including 
geometric mean (GM) area under the conc-time curves (AUC ), maximum (C ), minimum (C ) and 
predose (C ) conc were lower in COH2 relative to those in COH1; however, due to higher doses in 
COH3 (modified after interim analysis of COH1 and 2), the mean AUC in COH3 was comparable to 
COH1. GM apparent volume of distribution (V /F) decreased with age (COH1=104.9 L, COH2=71.0 
L, COH3=51.4 L). Average terminal half-lives (t) were COH1=2.62 h, COH2=1.95 h,
and COH3=1.77 h. GM tofacitinib CL/F were 53%, 39%, and 11% higher in COH1, COH2, and COH3 
pts, respectively, vs adult RA pts (18.4 L/h) receiving tofacitinib 5 mg BID. GM CL/F and V/F 
parameters were similar between males and females. Tofacitinib, administered over 5 days as
multiple dose tablets or solution formulation, was well tolerated and taste for the solution formulation 
was found acceptable in children with active JIA. No serious adverse events or new safety signals 
were identified.
Conclusion: PK results from this study established dosing regimens for pts aged ≥2 years to be 
used in the upcoming efficacy and safety studies of tofacitinib in JIA pts. Tofacitinib was well tolerated 
in this study in JIA pts. Overall, pts found the taste of the tofacitinib solution formulation
to be acceptable.


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APPENDIX 2.  Moderate or Potent CYP3A Inhibitors and Inducers
NOTE: Topical administration (e.g., 
cutaneous, ophthalmic, or intravaginal) of 
listed concomitant medications, which are 
prohibited if administered systemically, is 
allowed in the study.
Moderate or Potent CYP3A Inhibitors 
Moderate or Potent CYP3A Inducers
HIV antivirals:
efavirenz (Sustiva)
-delavirdine (Rescriptor)
nevirapine (Viramune)
-indinavir (Crixivan)
Barbiturates
-nelfinavir (Viracept)
carbamazepine (Carbatrol, Tegretol)
-ritonavir (Kaletra, Norvir)
modafinil (Provigil)
-saquinavir (Fortovase)
phenobarbital
-atazanavir
phenytoin (Dilantin, Phenytek)
amiodarone (Cordarone, Pacerone)*
rifabutin (Mycobutin) 
cimetidine (Tagamet)
rifampin (Rifadin, Rifamate, Rifater)
clarithromycin (Biaxin, Prevpac)
rifapentine (Priftin)
telithromycin (Ketek)
St. John's Wort
clotrimazole
troglitazone (Rezulin)
chloramphenicol
All Investigational Drugs
diethyl-dithiocarbamate  
DMARDs
diltiazem (Cardizem, Tiazac)
erythromycin 
fluconazole (Diflucan)
fluvoxamine (Luvox)
Grapefruit juice and marmalade
itraconazole (Sporanox)
All Biologics**, such as:
anakinra (Kineret), etanercept 
(Enbrel), adalimumab (Humira), 
infliximab (Remicade), abatacept 
(Orencia), canakinumab (Ilaris), 
tocilizumab (Actemra), golimumab 
(Simponi), rituximab (Rituxan), 
ketoconazole (Nizoral)
mifepristone (Mifeprex, RU486)
nefazodone (Serzone)
norfloxacin (Shibroxin, Noroxin)
mibefradil  
verapamil (Calan SR,Covera HS, Isoptin SR, Tarka, 
Verelan)
voriconazole
Other DMARDs**:
leflunomide, sulfasalazine, 
d-penicillamine, bucillamine, 
mizoribin, azathioprine, cyclosporine, 
tacrolimus, auranofin, 
aurothioglucose, aurothiomalate, 
staphylococcal protein A 
immuno-absorbant pheresis columns


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APPENDIX 3.  Data Safety Monitoring Plan
DATA SAFETY MONITORING PLAN
Tofacitinib for Systemic Lupus Erythematosus 
With Cutaneous Lesions 
 
(IND 132786)


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TABLE OF CONTENTS
A.
SUMMARY OF THE PROTOCOL
38
B.
BRIEF DESCRIPTION OF THE PROTOCOL (STUDY DESIGN)
39
C.
INCLUSION/EXCLUSION CRITERIA
41
D.
SAMPLE SIZE
44
E.
TRIAL MANAGEMENT
44
F.
TARGET POPULATION DISTRIBUTION (WOMEN, MINORITIES, ETC.)
45
G.
INSTITUTIONAL REVIEW BOARD PROTOCOL REVIEW
45
H.
DATA SAFETY AND MONITORING PROCEDURES
46
I.
DATA MANAGEMENT
47
J.
DATA ANALYSIS PLAN
50
K.
REGULATORY ISSUES
50
L.
RISKS & BENEFITS
51
M.
PREMATURE CLOSURE OF STUDY
53
N.
TRIAL EFFICACY
54


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Since there are only 20 subjects, the PI will review all safety events that occur and no formal 
DSMB will be convened for this study.
A.
SUMMARY OF THE PROTOCOL 
This proposed study is an Investigator initiated clinical trial to study the safety and efficacy 
of tofacitinib (TOFA) for systemic lupus erythematosus with cutaneous lesions (SLE-CL).  
TOFA is approved under the brand name (XELJANZ) for the treatment of adult patients 
with moderate to severe rheumatoid arthritis (RA).  Tofacitinib is also being developed for 
the treatment of psoriasis (oral and topical), Crohn’s disease, ulcerative colitis, psoriatic 
arthritis, and ankylosing spondylitis and dry eye disease, and for the prevention of renal 
allograft rejection.
TOFA, a small molecule that inhibits Jak3, Jak1 and to a lesser degree Jak2, has been 
proven efficacious in RA in phase III trials. Notably, a series of Jak-STAT signalling 
cytokines, especially type I IFNs, IL-10 and IL-6, as well as the hormone prolactin, have 
been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Such 
immunological abnormalities are thought to be even more pronounced among subjects 
with SLE onset early in life, i.e. with SLE diagnosis during childhood and adolescence (SLE). 
In this context, targeting the Jak-STAT pathway may be an attractive approach to manage 
inflammation and auto-immunity in SLE.
All type I IFN family members bind a common receptor complex (IFNAR1 and IFNAR2). 
Viral infection rapidly induces leukocyte production of IFN-a and -b, which initiates a 
JAK/STAT signaling cascade leading to transcription of target genes that promote host 
protection and viral elimination. IFN also promotes survival and differentiation of mature 
lymphocytes, class switching at immunoglobulin heavy chain loci, and activation of 
dendritic cells. The primary source of type I IFNs in the body is natural IFN-producing cells 
(NIPCs), also known as plasmacytoid dendritic cells (pDCs). Type I IFNs play a major role in 
the pathogenesis of SLE and have been shown to be associated with lupus-associated skin 
disease in murine studies
TOFA was efficacious in mouse models of skin inflammation induced by imiquimod 
application and IL-23 injection as assessed by clinical, histological and gene expression 
measures in the mouse ear. TOFA was also efficacious in a CD4+CD45RBhighCD25- T-cell 
transfer model that mimics aspects of psoriasis pathology and in a xenograft model where 
human psoriatic skin from psoriasis patients was transplanted onto severe combined 
immunodeficiency (SCID) mice. TOFA was efficacious in rodent and primate models of 
heterotopic heart transplantation and rodent models of arthritis by subcutaneous delivery 
in osmotic pumps (Changelian et al, 2003, Milici et al, 2008). Thus, TOFA shows promise 
in multiple models of autoimmunity and immune dysregulation.
Further, pDCs are actively recruited to inflammatory skin lesions of humans with SLE.
Additionally, blockage of interferon activity has been shown to ameliorate lupus skin 
disease.


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To date, belimumab, hydroxychloroquine, chloroqine and quinacrine are approved for 
adults with systemic lupus erythematosus (SLE). The latter three medications are approved 
also for cutaneous lupus without the system form of the disease, i.e. SLE. Despite these 
medications, chronic skin disease remains a major problem with SLE7.  Given the severity 
of the disease, the unmet medical need, and the low number of available subjects in this 
specific population, it is judged acceptable to assess the safety, tolerability and PK as 
primary objectives; and efficacy as secondary objectives in an open-label manner.
B.
BRIEF DESCRIPTION OF THE PROTOCOL (STUDY DESIGN)
This 76-week, 3-part, Phase 1b/2 study is intended to evaluate the pharmacological properties 
(pharmacokinetics and pharmacodynamics) of TOFA administrated to young adults with 
moderately to severely active inflammatory SLE-CL. 

Part A (up to week 8)requires stable background medications; 

Part B (up to week 24) allows for tapering of corticosteroids (CS), in the setting of significant 
clinical improvement of SLE-CL as defined by a decrease in Cutaneous Lupus 
Erythematosus Disease Area and Severity Index (CLASI) activity score by >50% from 
baseline , and
Part C (until week 76) permits tapering of other background medications in subjects with 
clinical remission of SLE-CL (CLASI activity score=0). TOFA dosing is kept stable during Part C.
Primary Objective
Part A (Cohort 1):

To evaluate the pharmacokinetic (PK) profiles of TOFA  in young adults aged between 
18 and including 45 years with SLE -CL who are on stable treatment for SLE
Part A (Cohort 1 and Cohort 2)

To evaluate the safety and tolerability of TOFA  in young adults with SLE -CL
Part B and C:

To evaluate the safety and tolerability of TOFA in young adults with SLE -CL
Primary endpoints
Part A (Cohort 1 only):

Day 5: AUCinf and Cmax of tofacitinib 
Part B: At Week 24

Nature, severity, and frequency of adverse events

Incidence and severity of laboratory abnormalities
Key Secondary Objective(s) & Endpoint(s)
Secondary objectives

To evaluate the efficacy of TOFA in young adults with SLE -CL


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Secondary endpoint 
Part A and B
Efficacy on SLE skin disease

Proportion of subjects who achieve a skin response (complete or partial response) as  per  the 
validated Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) at weeks 
4, 8 and 24 compared to baseline16.  Response (compared to baseline at TD1) is defined as 
follows: 
o
Complete response (CR) : complete resolution of the inflammatory rash (CLASI activity 
score = 0); 
o
Partial response (PR): > 20% improvement of the CLASI activity score 
o
No response: < 20% improvement or even worsening of the CLASI activity score  (CLASI 
relapse)
Exploratory Objective(s) & Endpoint(s)
Exploratory objectives
Part A: 

To evaluate single cell expression patterns of skin biopsies of affected and non-affected skin 
with TOFA therapy

To examine changes in interferon α/γ receptor, STAT phosphorylation patterns with TOFA 
therapy using immunohistochemistry 

To investigate mRNA expression patterns in peripheral blood upon treatment with TOFA with 
focus on interferon regulated genes 
Parts B and C:

To evaluate steroid sparing properties of TOFA for SLE -CL

To evaluate TOFA effect of overall disease activity in SLE 

To evaluate effects of TOFA on quality of life 
Exploratory endpoints at week 4, 8, 12, 24, 52, and 76 
Part A: 
PD parameters include assessment of inhibitory effect of TOFA on expression of IL-2 
responsive target genes downstream of the JAK/STAT pathway, such as FOXP3, SOCS3, IL-2Rα, 
interferon (IFN)-γ and granzyme B.
Parts B and C: 

Decrease of absolute dose of systemic CS from baseline

Decrease of body weight adjusted CS dose from baseline


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o
CS dosing is measured in prednisone-equivalents

Proportion of subjects who discontinue systemic CS

Proportion of subjects with cutaneous relapse 
o
Cutaneous relapse: a new CLASI activity score  ≥ 4 in those subjects who previously 
achieved CR of SLE -CL (CLASI = 0)  

Change of SLEDAI and BILAG score from baseline

Absolute value and percent change in plasma: Complement C3, C4d, autoantibodies (anti-
dsDNA) 

Change in number of inflamed  joints from baseline14

Change in SKINDEX score from baseline

Change (increase) of CLASI damage score from baseline

Change in the SLE core response variables (CRV) which include
1.
Change in SLEDAI score at each time point
2.
Change in protein: creatinine ratio at each time point. 
3.
Change subject’s overall well-being at each time point
4.
ESR

Proportion of subjects with clinically important reduction in SLE activity at each time point, 
based on CRV changes compared to baseline 

Proportion of subjects with flare of SLE activity at each time point, based on CRV changes 
compared to baseline 
Data of subjects who enter Part B before week 8 and/or Part C before week 24 will be considered 
on a last-observation (LOC) carried forward basis for endpoints of Part A and B, respectively.
C.
INCLUSION/EXCLUSION CRITERIA
INCLUSION CRITERIA
1.
Male or female age 18 to 45 years and >40 kg body weight.
2.
Fulfills at least 4 out of the 11 Classification Criteria for SLE by the time of screening. 
3.
Written informed consent, given before any trial-related procedure. Subjects or their legal 
representative must have read and understood the informed consent form, must fully 
understand the requirements of the trial, and must be willing to comply with all trial visits and 
assessments.
4.
CLASI activity score of 8 or higher at screening and baseline despite standard therapy.
5.
Stable dose of prednisone of ≤ 20 mg/day within 2 weeks of enrollment.
6.
Female subjects of childbearing potential must use a highly effective method of contraception 
to prevent pregnancy (abstinence is considered highly effective) and must agree to continue 


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to practice adequate contraception for the duration of their participation in the trial and for 
28 days following the last dose of TOFA.
7.
Female subjects of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at Trial Day 1 before dosing.
8.
For subjects receiving leflunomide treatment, total daily dose does not exceed 20 mg.
9.
A negative QuantiFERON-TB Gold In-Tube test performed within the 3 months prior to 
screening. A negative PPD test can be substituted for the QuantiFERON-TB.
10. Patients either have protective varicella titers or evidence of having been vaccinated against 
varicella.
EXCLUSION CRITERIA 
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1.
Mild SLE -CL defined as a CLASI activity score of 7 or lower at screening and baseline
2.
Increase in CS dosing within 2 weeks prior to Trial Day 1, or expected to require an increase in 
CS dosing during the first 4 weeks of the study.
3.
Use of i.v. corticosteroids within4 weeks prior to Trial Day 1.
4.
Increase in dosing of methotrexate, leflunomide, within 4 weeks before Trial Day 1 or expected 
to require an increase during the first 8-weeks of the study
5.
Increase in dosing of hydroxychloroquine, or chloroquine within 4 weeks before Trial Day 1 or 
expected to require an increase during the first 8-weeks of the study
6.
Rituximab within 1 year of Trial Day 1.
7.
Increase in dosing of any medication or herbal treatment considered to have 
immunosuppressive properties within 4 weeks before Trial Day 1. 
8.
Prior treatment with or known intolerability of TOFA. 
9.
Use of cyclophosphamide (i.v. or oral), cyclosporine, or tacrolimus within 12 weeks prior to 
Trial Day 1. 
10. Treatment with other investigational agents within the last 6 months or 5 half-lives, or as per 
washout requirement from the previous protocol, whichever is longer. 
11. Estimated glomerular filtration rate (GFR) less than or equal to 60 mL/min per 1.73 m2 
12. Known positive human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B 
surface antigen (HBsAg) serology. 
13. Any condition, including findings in the laboratory tests, medical history, or other screening 
assessments, that, in the opinion of the Investigator, constitutes an inappropriate risk or a 
contraindication for participation in the trial or that could interfere with the trial’s objectives, 
conduct, or evaluation.  


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14. Active central nervous system SLE deemed to be severe or progressive and/or associated with 
significant cognitive impairment leading to inability to provide informed consent and/or 
comply with the protocol. 
15. Significant renal disease due to a reason(s) other than LN (e.g. diabetes mellitus, renovascular 
disease, or antiphospholipid syndrome). 
16. Severely active Lupus Nephritis defined as a renal BILAG A score 
17. History of dialysis within 3 months prior to Trial Day 1 or expected use during the trial duration. 
18. History of or planned renal or other organ transplantation. 
19. Known active clinically significant viral, bacterial or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 8 weeks 
of screening, or completion of oral anti-infectives within 2 weeks before trial Day 1. 
20. Breastfeeding or currently pregnant.
21. Legal incapacity or limited legal capacity to provide informed consent or assent.
22. Blood dyscrasias, including:

Hgb <10 g/dL or Hct <33%.

WBC <3.0 x 109/L.

Neutrophil count <1.2 x 109/L

Platelet count <100x 109/L.

Lymphocyte count of <0.5 x 109/L.
23. AST or ALT > 1.5 times the upper limit of normal or any other clinically significant laboratory 
abnormality.
24. History of any other rheumatic autoimmune disease.
25.  Infections:

Latent or active TB or any history of previous TB.

Chronic infections.

Any infection requiring hospitalization, parenteral antimicrobial therapy or judged to 
be opportunistic by the investigator within the 6 months prior to the first dose of study 
drug.

Any treated infections within 2 weeks.

History of recurrent (more than one episode) herpes zoster or disseminated (a single 
episode) herpes zoster or disseminated (a single episode) herpes simplex.

History or current symptoms suggestive of any lymphoproliferative disorder, including 
Cytomegaly Virus (CMV) or Epstein Barr Virus (EBV) related lymphoproliferative 
disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current 
lymphatic disease.
26. Patients taking potent and moderate cytochrome P450 3A4 (CYP3A4) inhibitors.


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27. Patients taking potent and moderate CYP3A4 inducers.
28. Patients who have been vaccinated with live or attenuated vaccines within the 6 weeks prior 
to the first dose of study medication. All study participants should be up-to-date with respect 
to standard of care vaccinations (as defined by their country health ministry) as permitted by 
past immunosuppressive therapy for SLE. 
29. Patients with a malignancy or with a history of malignancy with the exception of adequately 
treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical 
carcinoma in situ.
30.  Subjects with a history or current diagnosis of diverticulitis.
D.
 SAMPLE SIZE
This is a 3-part study designed to evaluate the PK-PD of TOFA in subjects 18-45 years with at least 
moderately active SLE -CL. Safety and efficacy will be evaluated as secondary objectives.  No formal 
sample size estimation was done but previous TOFA studies in other populations suggest that 20 
subjects are sufficient to achieve the objectives of this study.  
It is planned to enroll:
Cohorts 1: n=10, weight > 40 kg and age > 18 years up to and including age 45 years. 
Cohort 2: n=10; weight > 40 kg and age > 18 years up to and including age 45 years.  
Enrollment of subjects into Cohort 2 will commence once enrollment of Cohort 1 are 
completed and at least 1 subject in Cohort 1 showed at least partial improvement of SLE-
CL. i.e. a 20% reduction of the CLASI activity score, between baseline and week 4.
E.
TRIAL MANAGEMENT
For this study, all subjects will be recruited and followed at CCHMC and  Metrohealth Medical 
Center.
It is planned to enroll:
Cohorts 1: n=10, weight > 40 kg and age > 18 years and ≤ 45 years. 
Cohort 2: n=10; n=10, weight > 40kg and age > 18 years and ≤ 45 years . 
Enrollment of subjects into Cohort 2 will commence enrollment of Cohort 1 are completed and at 
least 1 subject in Cohort 1 showed at least partial improvement of SLE-CL. i.e. a 20% reduction of 
the CLASI activity score, between baseline and week 4. 
The general approach to evaluation is to enroll a total of 20 subjects aged 18 to 45 years with a 
body weight of > 40 kg. Besides population PK-sampling, Cohort 1 will undergo intense PK-
evaluations during the Intense PK Period of Part A. Enrollment of subjects into Cohort 2 will 
commence once enrollment of Cohort 1 are completed and at least 1 subject in Cohort 1 showed 
at least partial improvement of SLE-CL. i.e. a 20% reduction of the CLASI activity score, between 
baseline and week 4. Subjects move from Part A to Part B to Part C of the study, unless they are 
discontinued from the study (see rescue clause Section 6.5 in the clinical protocol). 


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It is anticipated that almost all subjects are on stable background therapy with an antimalarial 
(hydroxychloroquine, rarely chloroquine), up to 80% are treated with corticosteroids (CS), and 
about 50% of the subjects will also be treated with a non-biological DMARD (mostly methotrexate, 
azathioprine and mycophenolate mofetil) for prior multiorgan involvement with SLE.
Based on TOFA PK in the RA population (body weight ranging from 40 kg-140 kg), clearance (CL) 
of TOFA is not dependent on body weight in adult subjects.  Thus, the dose of TOFA in adults with 
body weight (BW) 40 kg was set to 5 mg twice daily (BID), an approved dose of TOFA in adult RA 
patients in most countries. 
This clinical trial is the only one planned to be conducted this year under the IND. The trial will 
take 4 years.
F.
TARGET POPULATION DISTRIBUTION (WOMEN, MINORITIES, ETC)
Twenty adult subjects diagnosed with SLE will be enrolled in this study. All subjects regardless of 
race and socioeconomic class will be considered potential study subjects.  
This study follows procedures for minimizing risks and ensuring the safety and confidentiality of 
human subjects, as established under both the Department of Health and Human Services and the 
Office for Human Research Protections (OHRP). The study will be conducted in accordance with 
the ethical principles of the Declaration of Helsinki and will be consistent with Good Clinical 
Practices (GCP) http://www.fda.gov/cder/guidance/959fnl.pdf and applicable regulatory 
requirements. 
A common consent and assent form describing all aspects of the study will be used. Each 
participant and their legal guardian will be education about their risks and potential benefits. We 
will take appropriate measures to ensure the confidentiality of the data and the well-being of 
participants. 
G.                 INSTITUTIONAL REVIEW BOARD PROTOCOL REVIEW
The protocol, informed consent, and assent will be reviewed and approved by the IRB.
Recruitment & Consent Procedures  
The recruitment procedures for the trial will include a thorough explanation of the study, time 
commitments, possible risks and benefits, and alternative treatments. The patient must sign an 
informed consent forms that meets all current criteria of the FDA and local health regulations. 


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H.
             DATA SAFETY AND MONITORING PROCEDURES
All questionnaires and the results of the physical examination will be recorded on study forms. All 
forms will be assessed for completeness by the Clinical Research Coordinator. The Division of 
Rheumatology at Cincinnati Children’s Hospital Medical Center will serve as study Coordinating 
Center.  
ACTIONS TO ACHIEVE DATA SAFETY
All data will be entered into the Medidata Rave database on PCs in the Division of Rheumatology, 
CCHMC, stored and accessed in accordance with the HIPPA Standards [www.hhs.gov], HCFA’s 
Internet Security Policy and other state and local requirements. The Medidata Rave database is 
maintained on servers by Medidata and back up is performed as outlined by medidata information 
security and privacy white paper.  The Division of Biomedical Informatics at CCHMC distributes 
numerous computer packages for research purposes, including SAS [SAS Inc., Cary, North Carolina) 
and Microsoft software [see http://info.chmcc.org).  Data monitoring of data collected at the 
CCHMC will be performed by the Division of Rheumatology research staff with assistance from the 
CCHMC Office for Clinical and Translational Research (OCTR).
MONITORING OF SITES
The PI will monitor the database of both CCHMC and Metrohealth Medical Center with assistance 
from CCHMC OCTR.
REPORTING OF ADVERSE EVENTS
Reporting of Adverse events will occur as part of the safety assessment of the study drug. We will 
use the National Cancer Institute (NCI) Common Toxicity Criteria, Version II for reporting. 
All severe adverse events communicated to CC within one working day will be reported to the IRB 
within 2 working days. Based on the requirements for IND amendments outlined in the CFR 
§312.32, Dr. Brunner will be responsible for IND safety reporting including reporting of life-
threatening and serious adverse events, unexpected adverse drug experience and the writing of 
the annual IND safety report. 
CRITERIA FOR STUDY DISCONTINUATION
A subject will be considered a treatment failure and discontinued from the study if he/she 
experiences one or more of the following:

Serious adverse event that is possibly related to TOFA;

Important worsening of renal disease defined as a persistent increase in proteinuria as 
measured by the protein: creatinine (PC) ratio to values > 2.0  after achieving complete 
response, or doubling of proteinuria with values PC ratio >3.0 after achieving a partial 
response;

Need to increase current or initiation of new SLE background therapy due to non-renal SLE; 


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
Life-threatening SLE complications as judged by the investigator;

Need for more than the allowable CS rescue therapy as determined by the treating physician.

No response of SLE-CL by Week 8
INTERIM ANALYSIS & SAFETY REVIEWS
No interim analyses are planned.   The PI will continuously monitor the study for safety.  An internal 
review of the study will be completed by CCHMC OCTR  as outlined in the monitoring plan.
I.
DATA MANAGEMENT 
GENERAL INSTRUCTIONS FOR COMPLETING FORMS. 
All data recorded on forms must be verifiable in the source documents maintained according to 
FDA and Good Clinical Practice (GCP) guidelines.  
 Subjects must not be identified by name on any study document submitted with the forms (i.e. 
lab reports).  Replace subject names with subject initials and ID number.  
Source documentation will comply with the following: 

HEADER:  Complete the header information on every page, including pages for 
which no study data are recorded. Record subject’s first, middle, and last initials 
(use a hyphen if no middle name).   All dates must be verifiable by source 
documentation.  Estimates are not acceptable. 

ABBREVIATIONS:  Use of abbreviations not specifically noted in the instructions 
for completing the forms can be problematic and should be held to a minimum. 

EXTRANEOUS WRITING: Comments written extraneously on forms cannot be 
captured for monitoring and data analysis; thus, write only in the spaces indicated. 

CORRECTING ERRORS:  If an error has been made on the study forms, place a 
single line through the erroneous entry and record the data and your initials.  
Indicate the correct response.  

Do not leave forms incomplete or unused without explanation.  Do not leave 
items blank without explanation.  Do not skip any items.  Some items may carry 
“unknown” or “not applicable” response choices that should be checked when 
necessary.  Incomplete forms that do not have adequate explanation compromise 
the integrity of the entire study. 

INCOMPLETE DATA: Errors, such as incomplete and illegible forms, are problems 
that require time and energy to resolve. Data may not be available to complete 
the form for various reasons.  Circle the item for which data is not available and 
indicate the reason near the appropriate field:
o
If an evaluation was not done,  write “ND” and provide a reason
o
If the information is not available, but the evaluation was done, write 
“NAV”.  Every effort should be made to obtain the information requested.  


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Only in rare circumstances, as in the case of lost documentation, should 
NAV be recorded on the form.

If an evaluation is not applicable, write “NA”. 

INCOMPLETE FORMS: If an entire page of the forms cannot be completed (all have 
no responses), and it is unlikely that it will be completed, draw a diagonal line 
through the form and write “NOT DONE, NOT AVAILABLE, or NOT APPLICABLE.” 
The header information must be completed even though no data was recorded 
on the form.
RETENTION OF STUDY DOCUMENTATION
NIH policy requires that studies conducted under a grant retain participant forms for 3 years (7 
years if under contract). Individual IRBs may have different requirements for record retention.  
FDA requires that informed consent forms be retained for 2 years after a marketing application is 
approved for a product or, if an application is not approved, until 2 years after shipment and 
delivery of the product is discontinued for investigational use and the FDA is notified.  Investigators 
should retain forms for the longest applicable period.
SOURCE DOCUMENTATION
Patient data are collected on source documents [a paper case report form (CRF)].  Source 
documents are any documents on which study data are recorded for the first time. The PI must 
retain all study documents.  The following are considered subject file documents:

Case report forms 

Data correction forms (see QRF under Administrative Forms)

Worksheets

Source documents

Signed subject consent/assent forms

Hard copies of lab reports will be placed in the CRF binder kept on site.  Lab data 
will be sent directly electronically to the Methodology Core for updating the 
database.
LOCUS OF COMPUTING

The Data Management Center (DMC) at CCHMC will design and manage the Medidata Rave 
database.

The DMC at CCHMC will program the database with integrated query management.  Data 
can be queried based on field settings, programmed logical checks, and manual checks.  

An audit trial will be maintained on all data entry.  All changes made to a data point are 
tracked by the audit trail.  The audit trail is viewable based on role permissions.  Information 
collected in the audit trail includes: action, user name and ID, and date /time performed.  A 
more detailed audit trail report can be generated by DMC as required.


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DATA ENTRY
Only properly trained persons directly involved with the study protocol will begranted access. The 
DMC will invite users to the study with the appropriate role and site assignment.  Users must 
create an iMedidata account.  The iMedidata account is owned and controlled by the individual.  
The DMC requires role specific online Rave training before gaining access to the study database.
Double data entry will not be used for this study.  Edit procedures are in place during data entry.
HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT (HIPAA)
Medidata Rave complies with Health Insurance Portability and Accountability Act of 1996 (HIPPA) 
guidelines, by storing all data in protected areas, assigns all users roles that control data access 
and read/write privileges and tracks any changes. Moreover, IRB approval and patient consent is 
required before any data can be entered. 
MEDIDATA RAVE AUDIT TRAIL:

Creation of data: The data can only be entered by authorized personnel.  These individuals 
must log onto the system with their iMedidata account username and individually selected 
password.  Individuals should log off the system after each session to prevent unauthorized 
entries. 

Modification of data: Data modification can only be done by authorized personnel.  Reasons 
for changes to the data will be collected. Individuals should log off after each session to prevent 
unauthorized entriesDeletion of data: Deletion of data can only be done by authorized 
personnel. However, subjects, forms, and log lines cannot be truly deleted. A request would 
need to be made to the DMC to inactivate an entire subject. The subject will be made inactive 
and inaccessible in EDC and will not be a part of data exports. Similarly, log lines and individual 
forms may also be made inactive. Users with data entry privileges are able to inactivate log lines 
and forms. The data will still be viewable in EDC, but will not be a part of the data export. All 
inactive data can be reactivated as appropriate.An audit trail is recorded.  The audit trail includes 
information on: action, user name and ID, and date/time performed.
J.
DATA ANALYSIS PLAN
Pharmacokinetic/dynamic analysis will occur on de-identified data by PFIZER. In brief, NONMEM 
modeling will be done and exposures to TOFA analyzed under consideration of patient weight and 
concomitant medications (steroids yes/no). All other analyses will be done by a trained 
biostatistician working at CCHMC . 
See details in Protocol Section 8, Planned Statistical Analyses.
Categorical outcomes parameters will be summarized in frequencies/ rates and numeric outcomes 
will be assessed using paired t-tests. In analyses that adjust for concomitant medications, ANOVA 
will be done and least-square means calculated.
Frequencies of adverse events by seriousness will be summarized per MEDDRA lower level term 
and/or NCI Common Toxicity Criteria lower-level term.


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K.
REGULATORY ISSUES
ADVERSE EVENT REPORTING DEFINITIONS
Adverse Event (AE) 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.
Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence at any dose that:
• Results in death;
• Is life-threatening (immediate risk of death);
• Requires inpatient hospitalization or prolongation of existing hospitalization;
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
• Results in congenital anomaly/birth defect.
Requires or Prolongs Hospitalization: Hospital admissions scheduled prior to the study, are not 
considered serious adverse events unless the hospitalization is prolonged due to an adverse event.  
Planned admissions as part of a study, hospitalizations for scheduled treatment of a pre-existing 
condition that has not worsened, and hospitalization for an elective procedure are not considered 
serious adverse events.
AE/SAE DATA COLLECTION AND REPORTING
Adverse Event Data Collection and Reporting Procedures.  During a clinical trial, the reporting of 
adverse experience information can lead to important changes in the way a new treatment is 
developed, as well as provide integral safety data.  All AEs will be reported on the AE pages of the 
CRF.  All serious adverse events that occur, regardless of causality, will require immediate 
reporting (within 24 hours of knowledge to Pfizer. For any adverse event meeting the definition 
of fatal or “life threatening,” the investigator will notify Pfizer immediately.  The  IRB will be 
notified per IRB policy of SAE/AE that is both related to study drug and unexpected.  All other AEs 
not fitting related/unexpected criteria will be reported to per IRB policy.  Subjects or subjects’ 
partners who become pregnant during subject’s TOFA treatment will be reported on an SAE form 
with the addition of an Exposure in Utero (EIU) Supplemental Form, regardless of whether an SAE 
has occurred.  Pregnancy SAE and EIU form will be submitted to Pfizer within 24 hours of 
awareness of the exposure and to the IRB per IRB policy. 
See Protocol Section 7.7 Safety & Adverse Event Reporting for additional information.


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WOMEN OF CHILDBEARING POTENTIAL 
Patients must not be and should not become pregnant during exposure to study drug. Sexually 
active female participants must use an effective method of birth control during the study. The 
informed consent form will indicate that the investigator has reviewed information about 
pregnancy prevention for all women of childbearing potential. A serum or urine -HCG will be 
performed at randomization. Pregnancy testing will be repeated throughout the study as deemed 
necessary by the treating physician.
L.
RISKS & BENEFITS
1.
RISKS

Privacy and confidentiality risks:  All study results will be kept confidential. All patient 
identifiers will be removed prior to data transmission to the CC at CCHMC. The study and 
study information will follow regulations of the Good Clinical Practice Guidelines.

Financial risks: Patients will not be charged for the study procedures and study blood draws.  
The patient’s insurance company will be charged for continuing medical care and/or 
hospitalization including tests and treatments of any side effects of tofacitinib. In the event 
that the patient insurance does not cover cost, the patient may incur additional costs 
because of treatment side effects.

Blood draws may cause discomfort when the needle passes through the skin and may cause 
bruises and even infections. The study personnel will attempt to combine study blood draws 
with those necessary for all subjects.
The following side-effects are associated with Tofacitinib: 

Very common side effects (≥10%): upper respiratory tract infection (nasopharyngitis, 
common cold).

Common side effects (< 10%): lung infection (pneumonia and bronchitis), shingles (herpes 
zoster), influenza (flu), sinusitis, urinary bladder infection (cystitis), sore throat 
(pharyngitis), viral infections affecting the gut, increased liver enzymes, muscle enzymes 
or cholesterol, weight gain, stomach (belly) pain (which may be from inflammation of the 
stomach lining), vomiting, diarrhoea, nausea, indigestion,  pain in the muscles and joints, 
low white blood cell count, low red blood cell count (anaemia), fever, fatigue (tiredness), 
swelling of the feet and hands, headache, high blood pressure (hypertension), poor sleep, 
shortness of breath or difficulty breathing, cough, rash, itching.

Uncommon side effects (1%): blood infection (sepsis), tuberculosis, kidney infection, skin 
infection, herpes simplex or cold sores (oral herpes), blood creatinine increased (a 
possible sign of decreased kidney function), dehydration, muscle strain, tendonitis, joint 
swelling, joint infection, ligament sprain, abnormal sensations, sinus congestion, skin 
redness, fatty liver, inflammation of outpouchings of the intestine (diverticulitis), tears in 
the stomach or intestines, viral infections, some types of skin cancers (nonmelanoma-
types).

Rare side effects (0.1%): tuberculosis involving the brain and spinal cord, bones and other 
organs, and other unusual infections.


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
Serious infections 

Tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread 
throughout the body. Some people have died from these infections.  

 Viral reactivation, including herpes zoster, in Asian people may be higher than for non-
Asian people.  This higher risk has been seen in people with rheumatoid arthritis and 
psoriasis who have been treated with tofacitinib.

Cancer and immune system problems 

Skin cancers, lymphoma and other cancers including lung, breast, melanoma, prostate and 
pancreatic cancer.  

Some people who have taken oral tofacitinib with certain other medicines to prevent kidney 
transplant rejection have had a problem with certain white blood cells growing out of 
control (Epstein Barr Virus-associated post transplant lymphoproliferative disorder). 

Tears or holes (perforation) in the stomach or intestines 

Gastrointestinal perforation has been observed in clinical trials in patients with rheumatoid 
arthritis.

Changes in certain laboratory test results 

Changes in lymphocytes, neutrophils counts, hemoglobin, liver enzymes and lipids. 
Based upon the information provided above, the risks associated with the study are rated to be 
low to moderate. 
ACTIONS TAKEN TO MINIMIZE RISKS
This study follows procedures for minimizing risks and ensuring the safety and confidentiality of 
human subjects, as established under both the Department of Health and Human Services and 
the Office for Human Research Protections (OHRP). The study will be conducted in accordance 
with the ethical principles of the Declaration of Helsinki and will be consistent with Good Clinical 
Practices (GCP) http://www.fda.gov/cder/guidance/959fnl.pdf and applicable regulatory 
requirements.  
To mitigate these risk, we plan to:

Exclude participants who may be at an increased risk for these side effects 

Prohibit the use of immunizations using live vaccines during study participation

Prohibit the use of medications with known drug interactions with tofacitinib

Conduct subject monitoring during the course of the study to assess safety of 
participants, including laboratory monitoring. 

Con-medication monitoring for potential drug interactions

Conduct follow up safety visits and discontinuation of treatment

Reporting of Adverse Events:  Reporting of Adverse events will occur as part of the safety 
assessment of the study drug. We will use the National Cancer Institute (NCI) Common 


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Toxicity Criteria, Version II for reporting. All severe adverse events communicated to CC 
within 48 hours and reported to the IRB within 2 working days. 

Based on the requirements for IND amendments outlined in the CFR §312.32, Dr. Brunner 
will be responsible for IND safety reporting including reporting of life-threatening and 
serious adverse events, unexpected adverse drug experience and the writing of the 
annual IND safety report. 
2.
BENEFITS
Subjects may or may not receive benefit from this study.  
M.
PREMATURE CLOSURE OF STUDY
CRITERIA FOR STUDY DISCONTINUATION 
A subject will be considered a treatment failure and discontinued from the study if he/she 
experiences one or more of the following:

Serious adverse event that is possibly related to TOFA;

Important worsening of renal disease defined as a persistent increase in proteinuria as 
measured by the protein: creatinine (PC) ratio to values > 2.0  after achieving complete 
response, or doubling of proteinuria with values PC ratio >3.0 after achieving a partial 
response;

Need to increase current or initiation of new SLE background therapy due to non-renal SLE; 

Life-threatening SLE complications as judged by the investigator;

Need for more than the allowable CS rescue therapy as determined by the treating 
physician.
N.
TRIAL EFFICACY
No interim analysis is planned to assess efficacy of tofacitinib.


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APPENDIX 4
The Skindex-29 Dermatology Survey of Quality of Life (Patient)
These questions concern your feelings about the skin condition that has bothered you the most.  
How often during the past FOUR weeks do these statements describe you?
Check the answer that comes closest to the way you have been feeling.
Never
1
Rarely
2
Sometimes
3
Often
4
All the time
5
1.
My skin hurts
2.
My skin condition affects how well I sleep
3.
I worry that my skin condition may be serious
4.
My skin condition makes it hard to work or do hobbies
5.
My skin condition affects my social life
6.
My skin condition makes me feel depressed
7.
My skin condition burns or stings
8.
I tend to stay at home because of my skin condition
9.
I worry about getting scars from my skin condition
10. My skin itches
11. My skin condition affects how close I can be with those I love
12. I am ashamed of my skin condition
13. I worry that my skin condition may get worse
14. I tend to do things by myself because of my skin condition
15. I am angry about my skin condition
16. Water bothers my skin condition (bathing, washing hands)
17. My skin condition makes showing affection difficult
18. I worry about side effects from skin medications/treatments
19. My skin is irritated
20. My skin condition affects my interactions with others
21. I am embarrassed by my skin condition
22. My skin condition is a problem for the people I love
23. I am frustrated by my skin condition
24. My skin is sensitive
25. My skin condition affects my desire to be with people
26. I am humiliated by my skin condition
27. My skin condition bleeds
28. I am annoyed by my skin condition
29. My skin condition interferes with my sex life
30. My skin condition makes me tired


Tofacitinib in SLE
Clinical Trial Synopsis
Version 19 20210322
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APPENDIX 5


Tofacitinib in SLE
Clinical Trial Synopsis
Version 19 20210322
57/57