| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| JUVENILE IDIOPATHIC ARTHRITIS (JIA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Juvenile Idiopathic Arthritis (formerly known as Juvenile Rheumatoid Arthritis) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059176 |
| E.1.2 | Term | Juvenile idiopathic arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to determine the long term safety and tolerability of tofacitinib for treatment of the signs and symptoms of JIA. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to evaluate the persistence of efficacy of tofacitinib for treatment of the signs and symptoms of JIA. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. JIA subjects aged 2 to <18 years who met entry criteria for qualifying/index study with sufficient JIA disease activity to use tofacitinib.
2. Discontinuation of disallowed concomitant medications for the required time prior to first dose of study drug and only taking concomitant medications in allowable doses/frequencies.
3. Fertile male and female subjects of childbearing potential who are, in the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) must be using a highly effective method of contraception throughout the study and for at least 28 days after the last
dose of study drug.
4. Previously completed participation in a qualifying JIA study of tofacitinib.
5. If receiving MTX, use of MTX orally or parenterally at doses not to exceed 25 mg/week or 20 mg/m2/week, whichever is lower. Must also take folic acid/folinic acid in accordance with local standards.
6. If receiving an oral glucocorticoid, use of glucocorticoids at a max dose of 0.20 mg/kg/day or 10 mg/day, prednisone or equivalent, whichever is lower. For A3921165 subjects, a higher prednisoneequivalent dose may be continued or started.
7. If receiving leflunomide treatment, use of leflunomide at the following doses: 10 mg every other day for subjects weighing <20 kg; 10 mg every day for subjects weighing 20 to 40 kg; 20 mg every day for subjects weighing >40 kg; Or as according to local standards.
8. If receiving sulfasalazine, chloroquine, or hydroxychloroquine treatment, administer according to local standards.
9. Evidence of a personally signed/dated ICD with assent as appropriate indicating that the subject (or a legally acceptable representative/parent(s)/legal guardian) has been informed of all
aspects of the study.
10. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.
11. Subjects for whom, in the Investigator's opinion, treatment with tofacitinib is considered clinically appropriate.
Subjects who enroll outside the 14 day window of the EOS Visit of their qualifying/index study must also meet the below:
12. No evidence of active tuberculosis (TB) or inadequately treated tuberculosis (TB) infection (active or latent) as defined in the protocol. |
|
| E.4 | Principal exclusion criteria |
For subjects who enroll outside the 14 day window of the EOS Visit of their qualifying/index study:
1. 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 <0.75 x 109/L.
2. Estimated GFR <40 mL/min/1.73 m2 per Bedside Schwartz formula at Screening.
3. AST or ALT ≥1.5 x ULN or any other clinically significant laboratory abnormality.
For all subjects:
4. Persistent oligoarthritis and undifferentiated JIA.
5. Current or recent history of uncontrolled clinically significant renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, or neurological disease.
6. History of any other rheumatic autoimmune disease, other than Sjogren's syndrome.
7. History or current symptoms suggestive of any lymphoproliferative disorder.
8. Infections: a. Chronic infections; b. Infection requiring hospitalization,parenteral antimicrobial therapy or judged to be opportunistic by the investigator within the 3 months prior to the first dose of study drug; c. Any treated infections (excluding topical treatment only) within 2 weeks of baseline visit; d. Known infection with HIV, HepB or HepC virus.
9. History of infected joint prosthesis with prosthesis still in situ.
10. History of recurrent (>1 episode) herpes zoster or a single episode of disseminated herpes zoster or a single episode of disseminated (both oral and genital lesions simultaneously, or widespread lesions not contained to oral or genital regions alone) herpes simplex.
11. Taking potent and moderate CYP3A4 inhibitors.
12. Taking potent and moderate CYP3A4 inducers.
13. Participation in studies of investigational compounds within 4 weeks or 5 half lives (whichever is longer) prior to the first dose of study drug.
14. Any prior treatment with non B cell specific lymphocyte depleting agents/therapies.
15. Pregnant or nursing females.
16. IM or IV corticosteroids in the 4 weeks prior to first dose of study
drug.
17. Vaccination with live or attenuated vaccines within 6 weeks prior to first dose of study drug.
18. Use of prohibited prescription/nonprescription drugs and dietary
supplements within 7 days or 5 half lives (whichever is longer) prior to first dose of study drug.
19. Herbal supplements must be discontinued at least 4 weeks prior to
first dose of study drug.
20. First degree relative with a hereditary immunodeficiency; IgA deficiency not exclusionary.
21. Malignancy or history of malignancy except adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
22. Recent (within 28 days prior to first dose of study drug) significant trauma or major surgery.
23. Unwilling/unable to comply with the Lifestyle Guidelines in the protocol.
24. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality.
25. Child 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.
26. Any factors or clinical characteristics potentially related to the risk of VTE that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results.
27. History of allergies, intolerance or hypersensitivity to lactose or tofacitinib, or any other excipients of the IMP. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Standard laboratory safety data and adverse event (AE) reports. Body weight, height and Tanner Stages will be collected to assess growth and physical development. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary end points consist of 4 items:
1) Standard Lab Safety Data
2) AE assessment
3) body weight and height
4) Tanner Stage
Standard Lab Safety Data is performed at Baseline, and Months 1, 3, 6, 9, and 12. During study years 2 - 10 lab is collected at 6 month intervals. AE assessment is performed at Baseline, and Months 1, 3, 6, 9, and 12. During study years 2 - 10 AE assessment is completed at 6 month intervals. Body weight and height is recorded at Baseline, and Months 1, 3, 6, 9, and 12. During study years 2 - 10 body weight and height is collected at 6 month intervals. Tanner stage is assessed at Baseline and annually thereafter. |
|
| E.5.2 | Secondary end point(s) |
The following efficacy parameters will be assessed:
• Physician global evaluation of disease activity at each visit.
• Number of joints with active arthritis at each visit.
• Number of joints with limitation of motion at each visit.
• Index of inflammation (C reactive protein [CRP]) and Erythrocyte Sedimentation Rate [ESR]) at each visit.
• Childhood Health Assessment Questionnaire (CHAQ) at each visit.
• Parent's Assessment of Physical Function (CHAQ Disability Index).
• Parent's Assessment of Child's Arthritis Pain (CHAQ Discomfort Index, Visual Analog Scale [VAS]).
• Parent's Assessment of Overall Wellbeing (CHAQ subsection Visual Analog Scale [VAS]).
• • JIA American College of Rheumatology (ACR) response at each visit and occurrence of JIA ACR disease flare after Month 3.
• JIA ACR Clinical Inactive Disease status and Clinical Remission on Medication at each visit.
• Change from baseline in Juvenile Arthritis Disease Activity Score (JADAS) 27-CRP and JADAS 27-ESR, and occurrence of JADAS minimum disease activity and inactive disease at each visit.
•Eligibility of tapering defined per protocol for corticosteroids, MTX/lefluomide, and tofacitinib.
•In subjects with sJIA: “Absence of Fever”, defined as absence of fever due to sJIA in the week preceding the assessment at each visit.
• In subjects with Enthesitis Related Arthritis (ERA): Change from baseline in the Tender Entheseal Assessment, Modified Schober's Test, Overall Back Pain and Nocturnal Back Pain response at various visits.
• In subjects with psoriatic arthritis (PsA): Change from baseline in body surface area (BSA) affected by psoriasis and Physician's Global Assessment (PGA) of psoriasis) at various visits.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The Secondary endpoints (section 2.2.2) will be assessed at Baseline, and Months 1, 3, 6, 9, and 12. During study years 2 - 10 the assessments will be completed at 6 month intervals. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Costa Rica |
| India |
| Israel |
| Mexico |
| South Africa |
| United States |
| Poland |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Belgium |
| Hungary |
| Russian Federation |
| Slovakia |
| Turkey |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS, according to the Protocol.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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