Efficacy Study Of Tofacitinib In Pediatric JIA Population
Condition: Juvenile Idiopathic Arthritis
MeSH terms: Arthritis; Arthritis, Juvenile
Intervention: CP-690,550 (tofacitinib); placebo
Intervention description: 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.; matching placebo tablet or solution for tofacitinib
Intervention MeSH terms: Tofacitinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 225.0
Sex: All
Minimum age: 2 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Arthritis; Pediatric; Long-term; JIA; polyarticular; CP-690,550; tofacitinib; Xeljanz

Summary:

      Evaluate efficacy, safety and tolerability of tofacitinib in pediatric JIA patients.
    

Eligibility criteria:

        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.