| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Juvenile Idiopathic Arthritis (sJIA) |
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| E.1.1.1 | Medical condition in easily understood language |
| Systemic Juvenile Idiopathic Arthritis (sJIA) (formerly known as Systemic Juvenile Rheumatoid Arthritis) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| •To assess the sustained efficacy of tofacitinib versus placebo in sJIA patients, as measured by time to sJIA flare in the double blind randomized withdrawal phase. |
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| E.2.2 | Secondary objectives of the trial |
•To assess efficacy of tofacitinib versus placebo in sJIA patients at various time points in the double blind randomized withdrawal phase, as measured by:
a.Percentage of subjects with sJIA disease flares;
b.Percentage of subjects with Adapted JIA ACR 30/50/70/90/100 responses;
c.Changes from baseline in Juvenile Arthritis Disease Activity Score (JADAS 27);
d.Percentage of subjects achieving inactive disease and clinical remission (JIA ACR);
e.Percentage of subjects with inactive disease and minimal disease activity (JADAS 27);
f.Other evaluations specified under “Efficacy endpoints” for the double blind phase.
•To assess the efficacy of tofacitinib in sJIA patients in the open label treatment phase.
See the protocol for a full list of objectives.
•To assess the safety and tolerability of tofacitinib in sJIA patients.
•To assess the pharmacokinetics of tofacitinib in sJIA patients in the open label phase.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study:
1.Male or female aged 2 to <18 years.
2.Diagnosed with sJIA according to International League Against Rheumatism (ILAR) criteria, and, in the opinion of the investigator, have active disease prior to screening. Subjects with first-degree relatives with history of psoriasis, ankylosing spondylitis, enthesis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter's syndrome, or acute anterior uveitis may be allowed for enrollment after consultation with the sponsor. Subjects must have active disease at the time of enrollment, defined as:
a.Documented intermittently spiking temperature >38˚C/100.4˚F for at least 1 day due to sJIA in the screening period and within 1 week before the first dose, and the presence of at least 2 joints with active arthritis at screening and baseline, and an ESR >30 mm/hr [1.5 X ULN] at screening.
OR
b.Only after cohort review is completed and enrollment is opened without restrictions at a particular dose level: The presence of at least 5 joints with active arthritis at screening and baseline, and an ESR >30 mm/hr [1.5 X ULN] at screening. Refer to Section 3.4 of the protocol for details.
3.Treatment with stable doses of methotrexate (MTX) and/or oral CSs is permitted:
•For subjects taking MTX: Treatment for 3 months with MTX and with a stable dose of MTX (dose must be ≤25 mg/wk or ≤20 mg/m2/week, whichever is lower) for at least 46 weeks before the first study drug dose (Day 1). Subjects taking MTX must be taking folic acid or folinic acid in accordance with local standards.
•For subjects taking CS: Treatment with a stable dose of oral prednisone (≤1 mg/kg/day up to a maximum of 30 mg/day), or equivalent, for at least 1 week before the first study drug dose (Day 1).
4.No evidence or history of untreated or inadequately treated active or latent tuberculosis (TB) infection as evidenced by the following:
•A negative QuantiFERON® TB Gold or Glod Plus 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 or Gold Plus 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.
•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.
•No history of either untreated or inadequately treated latent or active TB infection.
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 (see Section 4.4.1 of the protocol).
Country-specific amendment for EU sites (including UK): Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) must agree to use 2 methods of contraception (at least one of which is considered to be highly effective with low user dependency as defined below) throughout the study and for at least 28 days (90 days for male subjects) after the last dose of study drug where there is known or suspected teratogenicity. (see Section 4.4.1 of the protocol).
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/legal guardian has been informed of all pertinent aspects of the study.
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| E.4 | Principal exclusion criteria |
Subjects with any of the following characteristics/conditions will not be included in the study:
1.Previous JIA treatment with tofacitinib.
2.Current symptoms or findings of myocarditis, endocarditis or more than minimal pericardial effusion associated with sJIA.
3.Current symptoms or findings of more than minimal pleuritis with sJIA.
4.Subjects who are still within the washout periods for disallowed nonbiological and biological DMARDs as indicated in the protocol.
5.Infections:
a.Chronic infections;
b.Any 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 within 2 weeks of baseline;
d.A subject known to be infected with Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C (see Section 7.2.8 of the protocol);
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.Diagnosis of active Macrophage Activation Syndrome (MAS) within 3 months prior to the first dose of study drug.
8.Blood dyscrasias, including (see Appendix 7 of the protocol):
a.Hemoglobin <9 g/dL;
b.White Blood Cell count <3.0 x 109/L;
c.Absolute Neutrophil count <1.2 x 109/L;
d.Platelet count <100 x 109/L;
e.Absolute 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 4 of the protocol).
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 7 of the protocol).
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 there are household members that require oral polio vaccination during treatment or during the 6 weeks following discontinuation of study drug.
15. Current malignancy or history any malignancy with the exception of adequately treated or excised basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ.
16.Subjects with a first degree relative with a hereditary immunodeficiency; IgA deficiency not exclusionary.
17.Recent (within 28 days prior to first dose of study drug) significant trauma or major surgery.
18.Subjects receiving potent and moderate CYP3A4 inhibitors or inducers (Appendix 5 of the protocol).
19.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.
20.Use of prohibited prescription or non prescription drugs and dietary supplements listed in Appendix 1 and Appendix 5 of the protocol within the specified time frame prior to the first dose of study medication.
21.Herbal supplements, unless discontinued at least 28 days prior to the first dose of study medication.
22.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.
To see the full list of exclusion criteria, please refer to the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Time to sJIA disease flare in the double blind randomized withdrawal phase. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Defined within the endpoint. |
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| E.5.2 | Secondary end point(s) |
•Occurrence of disease flares in the double blind phase at each visit.
•Achievement of corticosteroid tapering per protocol at the end of the open label active treatment period in applicable subjects receiving corticosteroids on study Day 1 of the open label phase.
•Achievement of a corticosteroid dose of ≤0.2 mg/kg/day or 10 mg/day (whichever is lower) at the end of the open label treatment period in subjects receiving corticosteroids on Day 1 of the open label phase.
•Adapted sJIA ACR 30/50/70/90/100 response at every visit from Day 7 onward in the open label and the double blind phase.
•Fever (Temp >38 Degrees Celsius) attributed to sJIA at Day 3, Day 7 and Day 14 of the open label phase.
•CRP ≤10 mg/L at every visit of the open label phase.
•“Absence of fever”, defined as absence of fever due to sJIA in the week preceding the assessment at every visit from Day 7 onward in the open label and double blind phase.
•Time to first Adapted JIA ACR 30 response in Part 1 of the open label phase.
•Change from baseline in Juvenile Arthritis Disease Activity Score (JADAS 27) at every visit from Day 7 onward in the open label and double blind phase.
•Change from baseline in each JIA ACR core variable at every visit from Day 7 onward in the open label and double blind phase.
•Change from baseline in Child Health Questionnaire (CHQ) responses at the end of Part 1 and Part 2 of the open label phase, at randomization and every 3 months thereafter.
•Change from baseline in Child Health Assessment Questionnaire (CHAQ) at every visit from Day 7 onward in the open label and double blind phase.
•Occurrence of inactive disease status and minimal disease activity at every visit from Day 7 onward (JADAS 27) in the open label and double blind phase.
•Occurrence of inactive disease status at every visit from Day 7 onward (JIA ACR) in the open label phase.
•Occurrence of inactive disease status and clinical remission at every visit in the double-blind phase.
Safety Endpoints
•All adverse events (AEs), including Serious Adverse Events (SAEs).
•Macrophage activation syndrome (MAS) events.
•Serious infections, including tuberculosis, varicella and herpes zoster and opportunistic infections.
•Clinically significant abnormal laboratory parameters, including abnormal hematology parameters, lipid parameter changes, liver enzymes, serum creatinine elevation.
•Malignancies, including lymphoma and non melanoma skin cancer.
•Gastrointestinal perforations.
•Cardiovascular diseases.
•Assessments of growth and pubertal development.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| various timepoints for each secondary endpoint are defined within the endpoint |
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| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 phase followed by double blind placebo controlled withdraw phase |
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| 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 | 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 |
| Brazil |
| Canada |
| China |
| Costa Rica |
| India |
| Israel |
| Mexico |
| South Africa |
| United States |
| Poland |
| Sweden |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Belgium |
| Hungary |
| Russian Federation |
| Slovakia |
| Turkey |
| Ukraine |
| United Kingdom |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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