PSORIATIC ARTHRITIS

To compare the efficacy of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo for the treatment of rheumatological signs and symptoms of PsA, in subjects with active PsA who have had an inadequate response to a traditional non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD). 2. To compare physical function status of subjects with active PsA who have had an inadequate response to a traditional non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD) after administration of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo. 3. To compare the safety and tolerability of two doses (5 mg BID and 10 mg BID) of tofacitinib versus placebo in subjects with active PsA who have had an inadequate response to a traditional non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD).

Xeljanz

Tofacitinib (CP-690,550)

tablet

5

Primary study endpoints of ACR20 responder rate and HAQ-DI will be obtained at Month 3.
All subjects randomized to placebo will receive tofacitinib (5 or 10 mg BID in Treatment
Sequences D and E, respectively) after Month 3 in a blinded manner. During the study,
subjects should remain on a stable dose of one traditional DMARD, eg methotrexate,
sulfasalazine or leflunomide. At the end of Month 12, eligible subjects may enroll into the
open-label, long-term extension study A3921092.

Subject eligibility will be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that
the subject (or a legal representative) has been informed of all pertinent aspects of the
study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
3. The subject has a diagnosis of PsA based upon the CASPAR Criteria17 for at least
6 months and evidence of active arthritis based upon number of tender/painful and
swollen joints detailed in Section 4.1.1 (below).
4. Ongoing treatment with a stable dose of traditional DMARDs (eg, methotrexate,
sulfasalazine or leflunomide) (Section 4.1.2).
5. Meet all other eligibility criteria described in Sections 4.2, 4.3, and 4.4 below
To be eligible for participation in this study, a subject must meet the following criteria:
1. To meet the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria17 a
subject must have inflammatory articular disease (joint, spine, or entheseal) with
3 points from the following 5 categories:
a. Evidence of current psoriasis, a personal history of psoriasis, or a family history
of psoriasis. Current psoriasis is defined as psoriatic skin or scalp disease present
today as judged by a rheumatologist or dermatologist.† A personal history of
psoriasis is defined as a history of psoriasis that may be obtained from a patient,
family physician, dermatologist, rheumatologist, or other qualified health care
provider. A family history of psoriasis is defined as a history of psoriasis in a
first- or second-degree relative according to patient report.
b. Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis
observed on current physical examination.
c. A negative test result for the presence of rheumatoid factor by any method except
latex but preferably by enzyme-linked immunosorbent assay or nephelometry,
according to the local laboratory reference range.
d. Either current dactylitis, defined as swelling of an entire digit, or a history of
dactylitis recorded by a rheumatologist.
e. Radiographic evidence of juxtaarticular new bone formation, appearing as
ill-defined ossification near joint margins (but excluding osteophyte formation) on
plain radiographs of the hand or foot.
† Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.
1. The subject must have active arthritis at both screening and baseline, as defined by
having both:
a. ≥3 tender/painful joints on motion (out of 68 joints assessed); and;
b. 3 swollen joints (out of 66 joints assessed).
2. The subject must have active Plaque Psoriasis which has been diagnosed or
confirmed by a dermatologist or a Sponsor-approved rheumatologist at screening.
4.1.2. Background DMARDs
1. All local standard-of-care practices for the administration of background DMARD
therapy, including laboratory testing, contraceptive requirements, follow-up care and
contraindications should be performed according to local standards of care throughout
the study.
2. Subjects must receive permitted background traditional DMARD and be dosed in
accordance with the local regulatory label. Subjects should remain on a stable dose
of that traditional DMARD throughout the course of the study.
Methotrexate: Maximum dose of 20 mg/week. Minimum duration of therapy
4 months and dose stable for 4 weeks prior to first dose of study drug.
Subjects on methotrexate should be on an adequate and stable dose of folate
supplementation (not less than 5 mg weekly based on folic acid, unless such
doses would violate the local label guidelines or standard of care) for at least
4 weeks prior to the first dose of study drug (see Section 5.5). Subject must
not have had previous serious toxicity while on methotrexate and not be
expected to require evaluation for possible methotrexate toxicity (eg, require a
liver biopsy for methotrexate toxicity) during the study. Sulfasalazine: Maximum dose of 3 gm/day. Minimum duration of therapy
2 months and dose stable for 4 weeks prior to first dose of study drug.
Leflunomide: Maximum dose of 20 mg/day. Minimum duration of therapy 4 months and dose stable for 4 weeks prior to first dose of study drug.
 Other traditional DMARDs not listed as a prohibited concomitant medication
(see Appendix 3) may be considered after discussion with the Pfizer Study
Clinician.
4.2. A3921091 Specific PsA Patient Population
1. Subject had an inadequate response to at least one traditional DMARD due to lack of
efficacy or toxicity/lack of toleration and must not have received any previous TNFi
treatment.
2. Subjects who are not contraindicated for treatment with adalimumab in accordance
with the approved local label. Subjects who do not meet the New York Heart
Association Class III and Class IV Congestive Heart Failure are eligible.
 Class III: subjects with marked limitation of activity; they are comfortable only at
rest.
 Class IV: subjects who should be at complete rest, confined to bed or chair, any
physical activity brings on discomfort and symptoms occur at rest.
3. Subjects without a history of hypersensitivity or infusion reactions to biologic agents.
4.3. Other Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Subject must be at least 18 years old (20 years old for subjects in Taiwan) at the
screening visit.
2. No evidence of active or latent or inadequately treated infection with Mycobacterium
tuberculosis (TB) as defined by all of the following:
A negative QuantiFERON-TB Gold (QFT-G) In-Tube test performed at or within
3 months prior to a given Screening visit. A negative PPD test can be substituted
for the QuantiFERON Gold (QFT-G) In-Tube test only if the central laboratory is
unable to perform the test or cannot determine the results to be positive or
negative and the Pfizer Study Clinician approves it, on a case by case basis.
Subjects with a history of Bacille Calmette Guérin (BCG) vaccination will be
tested with the QFT-G test. No local QFT-G testing will be accepted for meeting
this inclusion criterion.
A chest radiograph taken at or within the 3 months prior to screening without
changes suggestive of active TB infection as determined (and documented) by a
qualified radiologist or pulmonologist as per local standard of care.
No history of either untreated or inadequately treated latent or active
TB infection.
If a subject has previously received an adequate course of therapy for either latent
(9 months of isoniazid in a locale where rates of primary multi-drug resistant
TB infection are <5% or an acceptable alternative regimen) or active (acceptable
multi-drug regimen) TB infection, neither a PPD test nor a QuantiFERON
TB Gold In-Tube®™ (QFT Gold test) need be obtained, but a chest radiograph
must still be obtained if not done so within the prior 3 months. A subject who is
currently being treated for either latent or active TB infection can only be enrolled
with confirmation of current incidence rates of multi-drug resistant TB infection,
documentation of an adequate treatment regimen, and prior approval of the
Sponsor.
3. Subject has discontinued all disallowed concomitant medications for the required
time prior to the first dose of study medication and is taking only those concomitant
medications in doses and frequency allowed by the protocol (see Appendix 3).
Subjects who are receiving any investigational or marketed treatment for PsA or
psoriasis not mentioned elsewhere must have that treatment discontinued for 4 weeks
or 5 half lives, whichever is longer. Discontinuation criteria for biologics not
otherwise mentioned must be discussed with the Sponsor.
4. Subjects who are already taking oral corticosteroids (but not injectable) may
participate in the study:
 Oral corticosteroids: Subjects who are already receiving oral corticosteroids must
be on a stable dose of 10 mg/day of prednisone or equivalent for 4 weeks prior
to first dose of study drug.
 Injected (eg, intraarticular, intramuscular or intravenous) corticosteroids:
Discontinued 4 weeks prior to the first dose of study drug.
5. Subjects who are already taking NSAIDs/COX-2 inhibitors may participate in the
study provided that that the dose is stable for one week prior to first dose of study
drug.
6. Subjects are to discontinue active psoriasis treatment prior to being enrolled in the
study.
 Biologics: Investigational biologics should be discussed with the Pfizer Clinician
to confirm eligibility and period of discontinuation required.
 Ustekinumab (Stelara) must be discontinued for at least 12 weeks prior to
first dose of study drug.
 Alefacept (Amevive) must be discontinued for at least 8 weeks prior to first
dose of study drug.
 Topical treatments that could affect psoriasis including: corticosteroids, tars,
keratolytics, anthralin, vitamin D analogs, and retinoids must be discontinued for
at least 2 weeks prior to the first dose of study drug.
 Exceptions: the following topical treatments are allowed: non-medicated
emollients for use over the whole body; topical steroids including hydrocortisone
and hydrocortisone acetate ≤1% for the palms, soles, face, and intertriginous areas
only; tar and salicylic acid preparations for the scalp only and shampoos free of
corticosteroid for the scalp only.
 UVB (narrowband or broadband) phototherapy must be discontinued at least
2 weeks prior to the first dose of study drug. Psoralens + UVA phototherapy
(PUVA) must be discontinued for at least 4 weeks prior to the first dose of study
drug.

Subjects presenting with any of the following will not be included in the study:
1. Currently have non-plaque forms of psoriasis, eg erythrodermic, guttate or pustular,
with the exception of nail psoriasis, which is allowed.
2. Subjects who are investigational site staff members directly involved in the conduct
of the trial and their family members, site staff members otherwise supervised by the
Investigator, or subjects who are Pfizer employees directly involved in the conduct of
the trial.
3. Participation in other studies involving investigational drug(s) (Phases 1-4) within
4 weeks before the current study begins and/or during study participation.
Participation in any observational studies during study participation.
4. Pregnant females, breastfeeding females, females of child-bearing potential not using
highly effective contraception or not agreeing to continue highly effective
contraception for at least one ovulatory cycle after last dose of investigational product
or females planning pregnancy. Women of childbearing potential must test negative
for pregnancy prior to enrollment in this study. (Further description of the
requirements and a list of contraceptives considered highly effective and acceptable
for use in this study will be found in Section 4.6.6).
5. Current or recent history of a severe, progressive or uncontrolled renal, hepatic,
hematological, gastrointestinal, metabolic (including hypercholersterolemia),
endocrine, pulmonary, cardiovascular, or neurologic disease.
6. Blood dyscrasias within 3 months prior to the first dose of study drug including
confirmed:
a. Hemoglobin <10 g/d
b. White blood cell count <3.0 x 109 (<3000/mm3);
c. Absolute neutrophil count ≤1.5 x 109(<1500/mm3);
d. Absolute lymphocyte count <1.0x109(<1000/mm3);
e. Platelet count <100 x 109(<100,000/mm3).
7. Estimated Creatinine Clearance <40 ml/min based on Cockcroft-Gault equation (see
Appendix 2).
8. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal at
screening visit.
9. Have a known immunodeficiency or a first-degree relative with a hereditary
immunodefiency.
10. Also excluded are subjects with history of any autoimmune rheumatic disease other
than PsA (including systemic lupus erythematosis, mixed connective tissue disease,
scleroderma, polymyositis) or known diagnosis of fibromyalgia, without approval by
Sponsor. Prior history of, or current rheumatic inflammatory disease other than PsA
(eg, gout, reactive arthritis, chronic Lyme disease) without approval by Sponsor.
11. Functional Class IV as defined by the American College of Rheumatology
classification of functional status for RA, ie, limited in ability to perform usual
self-care, vocational and avocational activities.
12. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
13. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV)
related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and
symptoms suggestive of current lymphatic disease.
14. History of recurrent (more than one episode) herpes zoster or disseminated (a single
episode) herpes zoster or disseminated (a single episode) herpes simplex.
15. History of infection requiring:
 Hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically
significant by the investigator, within the 6 months prior to the first dose of study
medication.
 Oral antimicrobial therapy within 2 weeks prior to the first dose of study
medication.
16. Any prior treatment with non-B cell-specific lymphocyte depleting agents/therapies
[eg, alemtuzumab (Campath®
), efalizumab (Raptiva®
)], alkylating agents (eg,
cyclophosphamide or chlorambucil), or total lymphoid irradiation. Subjects who
have received rituximab or other selective B-lymphocyte depleting agents (including
experimental agents) are eligible if they have not received such therapy for at least
1 year prior to first dose of study drug and have normal CD19/20+ counts by FACS
analysis.
17. Any subject who has been vaccinated with live or attenuated vaccines within the
6 weeks prior to the first dose of study medication or is to be vaccinated with these
vaccines at any time during treatment or within 6 weeks following discontinuation of
study medication. (See Section 4.6.2 Vaccine Guidelines for further information
regarding avoidance of household contacts who may be vaccinated).
18. A subject with any condition possibly affecting oral drug absorption, eg,
gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of
bariatric surgery such as gastric bypass. Procedures such as gastric banding, that
simply divide the stomach into separate chambers, are NOT exclusionary.
19. History of alcohol or drug abuse unless in full remission for greater than 6 months
prior to first dose of study medication.
20. Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant
abnormalities which may affect subject safety (eg, pattern of acute myocardial
infarction, acute ischemia or serious arrhythmia) or interpretation of study results
(eg, continuously paced ventricular rhythm or complete left bundle branch block).
21. A subject 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.
22. Significant trauma or surgery procedure within 1 month prior to first dose of study
medication, or any planned elective surgery during the study period.
23. A subject requiring prohibited concomitant medications (See Appendix 3).
24. A subject known to be infected with human immunodeficiency virus (HIV),
hepatitis B virus or hepatitis C virus or any chronic infection. HBsAg+ is exclusionary; subjects who are HBsAgbut HBcAb+ must undergo
further testing for HBsAb to be considered for enrollment. If HBsAb+, subject may enroll; if HBsAb- , subject is excluded. Subjects who are HCV Ab+ must undergo further testing for HCV RNA. Subjects who are HCV RNA- may enroll.
25. A subject with evidence of skin conditions (eg, eczema) at the time of the screening
or baseline visit that would interfere with evaluation of psoriasis.
26. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in judgement of investigator, would make subject inappropriate for
entry into study.
27. A subject who has previously participated in any study of tofacitinib.
28. A subject who, in the opinion of the investigator or Pfizer (or designee), will be
uncooperative or unable to comply with study procedures.