| 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 (JIA) (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 | 20.0 |
| 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 |
| To compare the efficacy of tofacitinib versus placebo for the treatment of signs and symptoms of JIA at Week 44/End of Study (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. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and symptoms of JIA as measured by the percentage of subjects with disease flare (according to PRCSG/PRINTO Disease Flare criteria) at various time points in the double-blind phase;
- To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and symptoms of JIA as measured by time to disease flare in the double-blind phase;
- To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and symptoms of JIA as measured by achievement of JIA ACR 30, 50, 70, 90, 100 response at various time points in the open-label run-in and double-blind phase;
Refer to protocol for complete listing of secondary objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female aged 2 to <18 years.
2. Must meet International League Against Rheumatism (ILAR) JIA classification for one of the following categories and, in the opinion of the investigator, have active disease for at least 6 weeks prior to screening:
- 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 (see Appendix 1); 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:
a. 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.
b. 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.
c. 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 (see Section 7.2.6). 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.
Note: Refer to Section 4.4.1 for additional contraception requirements for investigative sites in UK, Spain, Poland, and Belgium only.
Please refer to the protocol for complete listing of Inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
1. Previous JIA treatment with tofacitinib.
2. Systemic JIA (sJIA) with any active systemic features other than active joints and elevated acute phase reactants within 6 months of enrollment.
3. Persistent oligoarthritis.
4. Undifferentiated JIA.
5. Infections:
a. Chronic infections;
b. 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;
c. Any treated infections within 2 weeks of baseline;
d. A subject known to be infected with Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C (see Section 7.2.7);
e. 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 (see Appendix 6):
a. Hemoglobin <10 g/dL or Hematocrit <33%;
b. White Blood Cell count <3.0 x 109/L;
c. Neutrophil count <1.2 x 109/L;
d. Platelet count <100 x 109/L;
e. 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 (see Appendix 3).
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 or any other clinically significant laboratory abnormality (see Appendix 6).
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 suggestive 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 adequately 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 (Appendix 4).
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.
Please refer to final protocol for complete listing of exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) at Week 44/End of Study (Week 26 of the double-blind phase).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 44 or end of study treatment |
|
| E.5.2 | Secondary end point(s) |
- Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) at various time points in the open-label run-in and double-blind phase;
- Time to disease flare in the open-label run-in and double-blind phase;
- JIA ACR 30, 50, 70, 90, 100 response at various time points in the open-label run-in and double blind-phase;
- Change from baseline in JADAS 27-CRP and JADAS-27 ESR, and occurrence of JADAS minimum disease activity and inactive disease at various time points in the open-label run-in and double-blind phase;
- Presence of JIA ACR inactive disease and clinical remission at various time points in the double-blind phase;
- Change from baseline in each JIA ACR core set variable at various time points in the open-label run-in and double-blind phase;
- Change from baseline in CHQ responses at various time points in the open-label run-in and double-blind phase;
- Change from baseline in CHAQ responses at various time points in the open-label run-in and double-blind phase;
- Occurrence of active uveitis (according to SUN criteria) at various time points in the open-label run-in and double-blind phase;
- In subjects with ERA: Change from baseline in the Tender Entheseal Assessment, Modified Schober’s Test, Overall Back Pain and Nocturnal Back Pain responses at various time points in the open-label run-in and double-blind phase;
- In subjects with PsA: Change from baseline in the BSA affected with psoriasis and PGA of psoriasis assessments at various time points in the open-label run-in and double-blind phase;
- Taste acceptability of tofacitinib oral solution, if applicable, on Day 14 of the open-label run-in phase;
- Safety during the study, with focus on serious infections, cytopenias, malignancies, cardiovascular diseases, and validated assessments of growth and pubertal development;
- Plasma tofacitinib concentrations during the open-label run-in phase.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| various timepoints for each secondary endpoint are defined within the endpoint |
|
| 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 | Yes |
| 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) | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| open label run in followed by double blind placebo control |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Germany |
| Israel |
| Mexico |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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