A3921104 / Tofacitinib in Patients with JIA

Principal Investigator: John Bohnsack
Keywords: IA , Tofacitinib , Arthritis Department: Pediatric Administration
IRB Number: 00082209 Co Investigator: Aimee Hersh
Specialty: Pediatric Rheumatology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Julianna Dorsch
Julianna.Dorsch@hsc.utah.edu
801-587-5200

Brief Summary

The purpose of this research study is to compare the effectiveness of tofacitinib over placebo for treatment of signs and symptoms of JIA.

Primary:
 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.
Secondary:
 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 double-blind phase;
 To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and
symptoms of JIA as measured by changes from baseline in JADAS 27-CRP and
JADAS-27 ESR, and percentage of subjects achieving JADAS minimum disease
activity and inactive disease at various time points in the double-blind phase;
 To evaluate the efficacy of tofacitinib versus placebo for treatment of signs and
symptoms of JIA as measured by the JIA ACR inactive disease and clinical remission
rate 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 changes from baseline in each JIA ACR core set
variable 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 changes from baseline in CHQ responses 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 changes from baseline in CHAQ responses 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 the occurrence of active uveitis (according to SUN
criteria) in the double-blind phase;
 In subjects with ERA: To evaluate the efficacy of tofacitinib for the treatment of ERA
as measured by changes from baseline in the Tender Entheseal Assessment, Modified
Schober’s Test, and Overall Back Pain and Nocturnal Back Pain responses at various
time points in the double-blind phase;
 In subjects with PsA: To evaluate the efficacy of tofacitinib for the treatment of PsA
as measured by changes from baseline in the BSA affected with psoriasis and PGA of
psoriasis assessments at various time points in the double-blind phase;
 To evaluate the efficacy of tofacitinib in the open-label run-in phase;
 To evaluate the taste acceptability of tofacitinib oral solution, if applicable, on Day 14
of the open-label run-in phase;
 To evaluate safety and tolerability of tofacitinib in subjects with JIA during the study;
 To evaluate the PK of tofacitinib in subjects with JIA during the open-label run-in
phase.
Exploratory:
 To evaluate exploratory biomarker and genomic samples to characterize the effect of
tofacitinib.

Inclusion Criteria

Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the
investigator’s study team before subjects are included in the study.
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. 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.


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

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:

  • Chronic infections;
  • 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;
  • Any treated infections within 2 weeks of Baseline visit;
  • A subject know to be infected with Human Immunodeficiency Virus (HIV),
    Hepatitis B, or Hepatitis C;
  • 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:

  • 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 <0.5 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.


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.