ANKYLOSING SPONDYLITIS

Ankylosing Spondylitis (AS) is the most prevalent spondyloarthritis, a group of arthritic conditions affecting the spine. This under recognized disease is often not diagnosed for many years and typically presents in people between 20 and 40 years of age leading to progressive disability and adverse effects on quality of life. Tofacitinib inhibits signaling of cytokines that are integral to lymphocyte activation, proliferation, and function and may thusresult in suppression of multiple aspects of the immune response. This forms the basis of therationale to investigate the effect of tofacitinib in active AS. This study represents the first investigation of tofacitinib in subjects with ankylosing spondylitis. It is designed to obtain more information on the safety, pharmacokinetics and clinical efficacy in this population prior to advancing to large clinical trials. This study will also provide critical information for the design of future tofacitinib studies in the AS population.

Tofacitinib (CP-690550)

2, 5, 10

Primary Efficacy Endpoint:
 ASAS 20 response rate at 12 weeks of treatment.

Subject eligibility should 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. Subject is at least 18 years old (20 years old for subjects in Taiwan) at the Screening
Visit.
4. The subject has a diagnosis of AS based on the Modified New York Criteria for
Ankylosing Spondylitis (1984). See Appendix 2.
5. Subject has active AS at the Screening and Baseline (Day 1) visits defined as:
 BASDAI score of 4; and
 Back pain score (BASDAI Question 2) of 4.
6. Subject has active disease despite nonsteroidal anti-inflammatory drug (NSAID) therapy or is intolerant to NSAIDs as defined by either:
 Subject must have had an adequate trial of at least 2 different oral NSAIDs taken over
a total period of 4 weeks OR Intolerance to NSAID therapy. Intolerance is defined as the subject must have discontinued NSAID treatment due to a related adverse event (eg, allergic reaction, gastrointestinal symptoms or signs, hypertension, etc).
7. Subjects may be receiving the following non-biologic DMARDs at the time of the
Screening visit. These medications should be continued throughout the entire study and
doses should remain unchanged. Any other DMARDs require discussion prior to
enrollment with the sponsor for washout timeframe.
 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
(eg, 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. 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 (Azulfidine
, Salazpyrin ): 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.
8. Subjects who are already taking oral corticosteroids (not injectables) 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 the
first dose of study medication;
 Injected (eg, intraarticular, intramuscular, epidural or intravenous) corticosteroids
must be discontinued 4 weeks prior to the first dose of study medication;
 Topical and intra-rectal corticosteroids will be allowed during the study.
9. Subject has discontinued all disallowed concomitant medication 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.
10. Subjects who are receiving any investigational or marketed treatment for AS, arthritis or back pain not mentioned elsewhere must have that treatment discontinued for 4 weeks or 5 half-lives, whichever is longer.
11. Subjects receiving non-prohibited concomitant medications for any reason must be
willing to stay on a stable regimen as defined in the protocol.
12. 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 the 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 by a qualified radiologist;
 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
(eg, 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.
13. Women of childbearing potential must test negative for pregnancy prior to enrollment in this study.
14. Female subjects who are not of childbearing potential (ie, meet at least one of the
following criteria):
 Have undergone hysterectomy or bilateral oophorectomy;
 Have medically confirmed ovarian failure or;
 Are medically confirmed to be post-menopausal (cessation of regular menses for at
least 12 consecutive months with no alternative pathological or physiological cause);
laboratory confirmation of FSH level indicative of post menopausal according to the
central laboratory may be indicated per investigator’s determination.

Subjects presenting with any of the following will not be included in the study:
1. Subjects who are investigational site staff members or relatives of those site staff
members or subjects who are Pfizer employees directly involved in the conduct of the
trial.
2. Participation in other interventional studies within 4 weeks before the current study
begins and/or during study participation (excluding noninterventional follow-up during
the screening period).
3. Subjects receiving any other DMARDs (other than those allowed), thalidomide
(including previous use) and other prohibited concomitant medications noted in
Appendix 4.
4. Subjects currently receiving or previous use of a TNF inhibitor or other biological agent.
5. Blood dyscrasias at screening or within 3 months prior to the first dose of study drug
including confirmed:
a. Hemoglobin <10 g/dL;
b. Absolute white blood cell count (WBC) <3.0 x 109
/L (<3000 mm3);
c. Absolute neutrophil count (ANC) <1.2 x 109/L (<1200 mm3);
d. Absolute lymphocyte count <1.0 x 109/L (<1000/mm3);
e. Platelet count <100 x 109/L (<100,000/mm3).
One re-testing of a laboratory-acceptable specimen (eg, appropriately labeled, within
stability parameters, not hemolyzed, appropriate type (tube and reagent) and volume) is
allowed of any above parameters if the abnormal lab(s) was an uncharacteristic result(s).
Documentation in the source of the typical results to allow a repeat lab is required.
Re-test must be completed within the screening period.
6. Estimated Creatinine Clearance <40 mL/min based on Cockcroft Gault equation at
Screening visit.
7. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal at screening
visit. (One re-testing with an uncompromised sample is allowed if the abnormal lab
result was an uncharacteristic result and must be completed within the screening period.
Documentation in the source of the typical results to allow a repeat lab is required).
8. History of any other autoimmune rheumatic disease (eg, systemic lupus erythematosis
(SLE), mixed connective tissue disease (MCTD), scleroderma, polymositis) or known
diagnosis of fibromyalgia, without approval by Sponsor.
9. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
10. History of any lymphoproliferative disorder, such as Epstein Barr Virus related
lymphoproliferative disorder (EBV-LPD), history of lymphoma, leukemia, or signs and
symptoms suggestive of current lymphatic disease.
11. History of recurrent (more than one episode) herpes zoster or disseminated/
multi-dermatomal (a single episode) herpes zoster or disseminated (a single episode)
herpes simplex.
12. 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.
13. History of infection requiring antimicrobial therapy within 2 weeks prior to the first dose of study medication.
14. Any prior treatment with alkylating agents (eg, cyclophosphamide or chlorambucil), total lymphoid irradiation, etc.
15. 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 vaccinate with these vaccines at any time during treatment or within 6 weeks after last dose of study drug.
16. 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.
17. History of alcohol or drug abuse unless in full remission for greater than 6 months prior to first dose of study medication.
18. Body weight or body habitus greater than what can be accommodated by the site’s MRI scanner table weight limits or MRI scanner bore.
19. Any contraindication to MRI that in the judgment of the investigator and MRI center
poses a safety risk to the subject such as, but not limited to, cardiac pacemaker; implanted cardiac defibrillator; aneurysm clips; carotid artery vascular clamp; neurostimulator; insulin or infusion pumps; bone growth/fusion stimulator; cochlear, otologic, and ear implants.
20. Subjects with passive implants that may be weakly ferromagnetic in the vicinity of the
RF coil that may cause image artifacts in the spine and SI joints.
21. Severe claustrophobia that would interfere with the ability to undergo an MRI.
22. 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).
23. A subject with a known immunodeficiency disorder or a first degree relative with a
hereditary immunodeficiency.
24. 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.
25. Significant trauma or surgery procedure within 1 month prior to first dose of study
medication, or any planned elective surgery during the study period.
26. A subject requiring prohibited concomitant medications.
27. 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 HBsAg- but 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.
28. A subject who has previously participated in any study of tofacitinib.
29. Pregnant or lactating females, or females planning pregnancy; females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least one ovulatory cycle after last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
30. 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 the judgment of the investigator, would make the subject inappropriate for entry into this study.
31. A subject who, in the opinion of the investigator or Pfizer (or designee), will be
uncooperative or unable to comply with study procedures.