Efficacy Study Of Tofacitinib In Pediatric JIA Population

This is a randomized withdrawal, double blind, placebo controlled study of pediatric subjects (2 to <18 years of age) with JIA. The primary objective is to compare the efficacy of tofacitinib versus placebo for the treatment of signs and symptoms of JIA at Week 26 of the double blind phase as measured by the percentage of subjects with disease flare (according to PRCSG/PRINTO Disease Flare criteria) after Week 18 of the open label run in phase.All eligible subjects enrolled in the study will initially receive open label tofacitinib for 18 weeks (run in phase). At the end of the 18 week run in phase, only subjects who achieve at least a JIA ACR 30 response will be randomized to the 26 week double blind, placebo controlled phase. Subjects who do not achieve a JIA ACR 30 response at this time point will be discontinued from the study. In addition, subjects who experience a single episode of disease flare at any time during the study (including the open label run in and double blind phase) will also be discontinued from the study. All subjects participating in this study, including those discontinued from the study, will have the option, if eligible (based on inclusion and exclusion criteria), of enrolling in the tofacitinib JIA long term extension study (A3921145).

Subjects who are eligible for the 26 week double blind phase will be randomized (1:1 ratio) to either active tofacitinib or placebo. For subjects with polyarticular course JIA (ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF , systemic JIA with active arthritis but without active systemic features), randomization will be stratified by JIA category and baseline CRP (normal, above normal). For subjects with psoriatic and enthesitis related arthritis, randomization will be stratified by JIA category.

Approximately 210 subjects will be enrolled in the open label run in phase. Among subjects with polyarticular course JIA, stratification will target at least 50% with a baseline CRP above the upper limit of normal. The first cohort (ie, polyarticular course JIA) will have at least 170 subjects enrolled in the run in phase with the minimum number of JIA categories as follows: 24 with extended oligoarthritis, 20 with polyarthritis RF+, 62 with polyarthritis RF-, and no minimum for subjects with systemic JIA with active arthritis but without active systemic features. Additional cohorts (ie, psoriatic and enthesitis related arthritis) will include a minimum of 20 subjects with psoriatic arthritis, and 20 subjects with enthesitis related arthritis. The overall target minimum number of subjects to be enrolled in the study by age is as follows: 20 subjects 2 to <6 years, 20 subjects 6 to <12 years, and 20 subjects 12 to <18 years. The duration of subject participation among those who complete the study (without discontinuation) is expected to be approximately 44 weeks.

• Drug: CP-690,550 (tofacitinib)

  During the open label run in phase, all subjects will receive active tofacitinib oral tablets or oral solution twice daily (BID) orally, at a dosage based on the subject's body weight as specified below.

  During the double blind, placebo controlled phase, subjects will receive either active tofacitinib oral tablets/oral solution or matching placebo oral tablets/oral solution, twice daily (BID), at a dosage specified below.

  Body Weight (Dosage in tablet [BID] or solution [BID]):

  5<7kg (2mg or 2mL); 7<10kg(2.5mg or 2. mL); 10 <15kg (3mg or 3mL); 15<25kg (3.5mg or 3.5mL); 25<40kg (4mg or 4mL); 40kg (5 mg or 5 ml).

  Oral solution (1 mg/mL) is used for subjects <40 kg. Oral tablets (5 mg) are used for subjects >=40 kg.

  Other Name: Matching placebo to tofacitinib (same tablet or solution as the active arm).
• Other: placebo
  matching placebo tablet or solution for tofacitinib
  Other Name: Placebo for tofacitinib

• Experimental: CP-690,550
  Treatment arm: Tofacitinib tablets or solution, according to subjects' body weights
  Intervention: Drug: CP-690,550 (tofacitinib)
• Placebo Comparator: Placebo
  Control arm: matching placebo tablets or solution for tofacitinib
  Intervention: Other: placebo

Inclusion Criteria:

1. Male or female aged 2 to <18 years.

2. Must meet International League Against Rheumatism (ILAR) JIA diagnostic criteria for one of the following categories with active disease for at least 6 weeks:

   • Extended oligoarthritis;
   • Polyarthritis (RF+);
   • Polyarthritis (RF-);
   • Systemic JIA with active arthritis but without active systemic features in the prior 6 months and at the time of enrollment;
   • Psoriatic arthritis;
   • Enthesitis related arthritis. Subjects with polyarticular course JIA (ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF , systemic JIA with active arthritis but without active systemic features) must have a minimum of 5 active joints (an active joint is defined as a joint with swelling or, in the absence of swelling, limited range of motion accompanied by either pain on motion or tenderness) at screening and baseline to be eligible for study entry.

   Subjects with psoriatic or enthesitis related arthritis must have a minimum of 3 active joints (an active joint is defined as a joint with swelling or, in the absence of swelling, limited range of motion accompanied by either pain on motion or tenderness) at screening and baseline to be eligible for study entry.

   Treatment with stable doses of a Non Steroidal Anti inflammatory Drug (NSAID) and/or a stable dose of an oral glucocorticoid, and/or a stable dose of methotrexate is permitted.

   For subjects receiving an oral glucocorticoid: Glucocorticoids may be administered at a maximum dose of 0.2 mg of prednisone equivalent per kilogram per day or 10 mg per day for ? 2 weeks before baseline, whichever is lower.

   For subjects receiving methotrexate (MTX) treatment: MTX may be administered either orally or parenterally at doses not to exceed 25 mg/wk or 20 mg/m2/week (whichever is lower); participants must have taken MTX for 3 months and be at a stable dose for at least 6 weeks before baseline. Subjects taking MTX must be taking folic acid or folinic acid in accordance with local standards.

   For subjects with psoriatic arthritis, the following topical treatments for psoriasis 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, salicylic acid preparations, and shampoos free of corticosteroids are permitted only for the scalp

3. Inadequate response or intolerance to at least one Disease Modifying Anti Rheumatic Drug (DMARD), which may include MTX or biologic agents; in the case of ERA and psoriatic arthritis, inadequate response to Non Steroidal Anti Inflammatory Drugs (NSAIDs).

4. No evidence or history of untreated or inadequately treated active or latent tuberculosis (TB) infection as evidenced by the following:

   1. A negative QuantiFERON ®TB Gold In Tube test performed within the 3 months prior to screening. A negative purified protein derivative (PPD) test can be substituted for the QuantiFERON® TB Gold 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 medical monitor is informed and agrees on a case by case basis.
   2. Chest radiograph without changes suggestive of active tuberculosis (TB) infection within 3 months prior to screening is recommended and should be performed according to local standards of care or country-specific guidelines.
   3. 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-Gold®TM test need be obtained. A chest radiograph should be obtained if not done within the 3 months prior to screening. To be considered eligible for the study, the chest radiograph must be negative for active tuberculosis infection.

   A subject who is currently being treated for latent 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.

5. Fertile males and females who are, in the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) must be willing and able to use a highly effective method of contraception as outlined in this protocol during the study and for at least 28 days after the last dose of study medication.

6 Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

7. Evidence of a personally signed and dated Informed Consent document and Assent document (as appropriate) indicating that the subject and a legally acceptable representative/parent(s)/legal guardian has been informed of all pertinent aspects of the study.

Exclusion Criteria

Subjects with any of the following characteristics/conditions will not be included in the study:

1. Previous JIA treatment with tofacitinib.
2. Systemic JIA (sJIA) with active systemic features (including subjects with characteristic sJIA fever and rash or serositis within 6 months of enrollment).
3. Persistent oligoarthritis.
4. Undifferentiated JIA.

5. Infections:

   1. Chronic infections;
   2. 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;
   3. Any treated infections within 2 weeks of Baseline visit;
   4. A subject know to be infected with Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C;
   5. History of infected joint prosthesis with prosthesis still in situ.
6. History of recurrent (more than one episode) herpes zoster or disseminated (at least one episode) herpes zoster, or disseminated (at least one episode) herpes simplex.
7. Active uveitis (according to SUN criteria) within 3 months of enrollment.

8. Blood dyscrasias, including:

   1. Hemoglobin <10 g/dL or Hematocrit <33%;
   2. White Blood Cell count <3.0 x 109/L;
   3. Neutrophil count <1.2 x 109/L;
   4. Platelet count <100 x 109/L;
   5. Lymphocyte count <0.75 x 109/L.
9. Estimated glomerular filtration rate [GFR] <40 mL/min/1.73 m2 at Screening. GFR will be calculated by the central lab using the bedside Schwartz formula.
10. Current or recent history of uncontrolled clinically significant renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease.
11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ?1.5 times the upper limit of normal.
12. History of any other rheumatologic disease, other than Sjogren's syndrome..
13. History or current symptoms suggestive of lymphoproliferative disorders (eg, Epstein Barr Virus [EBV] related lymphoproliferative disorder, lymphoma, leukemia, or signs and symptoms of current lymphatic disease).
14. Vaccinated or exposed to a live or attenuated vaccine within the 6 weeks prior to the first dose of study drug, or is expected to be vaccinated or to have household exposure to these vaccines during treatment or during the 6 weeks following discontinuation of study drug.
15. Subjects without documented evidence of having received at least one dose of the varicella vaccine in countries where the vaccine is approved and standard of care or those who do not have evidence of prior exposure to varicella zoster virus (VZV) based on serological testing (ie, VZV IgG Ab).
16. Current malignancy or history of any malignancy with the exception of adequate treated or excised basal cell or squamous cell or cervical cancer in situ.
17. Subjects who have previously failed more than 3 biologic therapies (with different mechanisms of action) for JIA.
18. Subjects with a first degree relative with a hereditary immunodeficiency; IgA deficiency not exclusionary.
19. Recent (within 28 days prior to first dose of study drug) significant trauma or major surgery.
20. Subjects receiving potent and moderate CYP3A4 inhibitors or inducers.
21. Prior treatment with non B cell specific lymphocyte depleting agents/therapies (eg, almetuzumab [CAMPATH], alkylating agents [eg, cyclophosphamide or chlorambucil], total lymphoid irradiation, etc.). 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 study baseline and have normal CD 19/20+ counts by FACS analysis.
22. Use of prohibited prescription or non prescription drugs and dietary supplements listed in Appendix 1 and Appendix 4 within the specified time frame prior to the first dose of study medication.
23. Herbal supplements must be discontinued at least 28 days prior to the first dose of study medication.
24. Use of certain biologic and non biologic DMARDs are disallowed at any time during this study (Appendix 1).
25. For subjects with PsA, oral and topical medications and alternative treatments that could affect psoriasis are prohibited (see Inclusion Criterion 2 for exceptions). This includes topical corticosteroids, tars, keratolytics, anthralin, vitamin D analogs, and retinoids which must be discontinued at least 2 weeks prior to first dose of study drug. Also prohibited is ultraviolet B (UVB) (narrowband or broadband) phototherapy that must be discontinued at least 2 weeks prior to first dose of study drug. Psoralens + ultraviolet A (UVA) phototherapy (PUVA) must be discontinued at least 4 weeks prior to first dose of study drug.
26. Subjects who are children of or related to investigational site staff members, site staff members otherwise supervised by the investigator, or Pfizer employees directly involved in the conduct of the study.
27. Participation in other studies involving investigational drug(s) within 4 weeks or 5 half lives (whichever is longer) prior to study entry and/or during study participation. Exposure to investigational biologics should be discussed with the Sponsor.
28. 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.
29. Pregnant or nursing females are excluded.