A3921145 / TOFACITINIB & JIA (EXTENSION STUDY)

Principal Investigator: John Bohnsack
Keywords: Idiopathic , Arthritis Department: Pediatric Administration
IRB Number: 00086688 Co Investigator:  
Specialty: Pediatric Rheumatology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

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

Brief Summary

Objectives Primary

  • The objective of this study is to determine the long term safety and tolerability of Tofacitinib for treatment of the signs and symptoms of JIA.

Secondary

  • The secondary objective of this study is to evaluate the persistence of efficacy of Tofacitinib for treatment of the signs and symptoms of JIA.

Exploratory

  • The exploratory objectives of this study are to assess Tofacitinib pharmacokinetic (PK) in pediatric patients on a stable dose of Tofacitinib in the setting of a long-term, open label study, to assess the changes in PK parameters (within patient) with increase in weight in pediatric population and to explore exposure-response relationships of Tofacitinib for various efficacy and safety endpoints after long-term exposure of Tofacitinib in pediatric population.

Endpoints
Primary

  • Standard laboratory safety data and adverse event (AE) reports. Body weight, height and Tanner Stages will be collected to assess growth and physical development.

Secondary
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.
o Parent’s Assessment of Physical Function (CHAQ Disability Index).
o Parent’s Assessment of Child’s Arthritis Pain (CHAQ Discomfort Index, Visual
Analog Scale [VAS]).
o Parent’s Global Assessment of Overall Wellbeing (CHAQ subsection, Visual
Analog Scale [VAS]).
 JIA American College of Rheumatology (ACR) response and occurrence of JIA ACR
disease flare at each visit.
 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.
 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 responses 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.
2.2.3. Exploratory
 Plasma concentration time data for tofacitinib will be analyzed to characterize the PK
in this subject population. Exposure-response relationship will be explored for
various efficacy and safety endpoints after long-term exposure of tofacitinib.

Inclusion Criteria

Subject eligibility should be reviewed and documented by an appropriately qualified member
of the investigator’s study team before subjects are included in the study.
All subjects must meet Inclusion Criteria 1-11 to be eligible for enrollment into the study:


1. Pediatric subjects with JIA aged from 2 to less than 18 years who met entry criteria
for the qualifying/index study and in the opinion of the investigator have sufficient
evidence of JIA disease activity to warrant use of tofacitinib as a DMARD. Subjects
turning 18 years of age during participation in the qualifying/index study or
subsequently will be eligible for participation in this study.

2. The subject has discontinued disallowed concomitant medications for the required
time prior to the first dose of study drug, as defined in Appendix 1, and is taking only
those concomitant medications in doses and frequency allowed by the protocol.


3. Fertile male subjects 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 as outlined in this
protocol throughout the study and for at least 28 days after the last dose of study
medication.


4. Subjects must have previously completed participation in a qualifying study of
tofacitinib for the treatment of JIA. Subjects who have required earlier
discontinuation of treatment in a qualifying study for reasons other than tofacitinib
related serious adverse events may be eligible.


5. For subjects receiving methotrexate (MTX) treatment, MTX may be administered
either orally or parenterally at doses not to exceed 25 mg/week or 20 mg/m2/week,
whichever is lower. Subjects taking methotrexate must be taking folic acid or folinic
acid in accordance with local standards.


6. For subjects receiving an oral glucocorticoid, glucocorticoids may be administered at
a maximum dose of 0.20 mg/kg/day or 10 mg/day, prednisone or equivalent,
whichever is lower.


7. For subjects receiving leflunomide treatment, leflunomide may be administered
according to the following dosing scheme:


 10 mg every other day for subjects weighing less than 20 kg;
 10 mg every day for subjects weighing between 20 and 40 kg;
 20 mg every day for subjects weighing over 40 kg;

Or as according to local standards.


8. For subjects receiving sulfasalazine, chloroquine, or hydroxychloroquine treatment,
these medications may be administered according to local standards.


9. Evidence of a personally signed and dated informed consent document with assent as
appropriate indicating that the subject (or a legally acceptable representative/
parent(s)/legal guardian) has been informed of all pertinent aspects of the study.


10. Subjects who are 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 while also taking into consideration currently
available therapies and prior response to these therapies.


Subjects who enroll outside the 14 day window of the EOS Visit of their qualifying/index
study must also meet Inclusion Criterion 12 to be eligible for enrollment into the study:


12. No evidence of active tuberculosis (TB) or inadequately treated tuberculosis (TB)
infection (active or latent) as evidenced by all of the following:


a. A negative QuantiFERON-TB Gold In-Tube test4 performed within the
3 months prior to screening. A negative purified protein derivative (PPD) test
with a result of <5 mm induration 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 approves it, 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 (see
Section 7.2.4).


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 7.2.4).
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 (<5%), documentation of an adequate treatment regimen, and prior
approval of the Sponsor.

Exclusion Criteria

Subjects presenting with any of the following will not be included in the study:
For subjects who enroll outside the 14 day window of the EOS Visit of their qualifying/index
study (1-3):


1. Blood dyscrasias, including:

a. Hgb <10 g/dL or Hct <33%.
b. WBC <3.0 x 109/L.
c. Neutrophil count <1.2 x 109/L.
d. Platelet count <100 x 109/L.
e. Lymphocyte count of <0.75 x 109/L.


2. Estimated glomerular filtration rate [GFR] <40 mL/min/1.73 m2 calculated using
Bedside Schwartz formula (Appendix 4) at the Screening Visit.


3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 1.5 times the
upper limit of normal or any other clinically significant laboratory abnormality.


For all subjects:
4. Systemic JIA (sJIA) with active systemic features other than active joints and
elevated acute phase reactants, 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, such as
Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma,
leukemia, or signs and symptoms suggestive of current lymphatic disease.


8. 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 visit.
d. A subject known to be infected with human immunodeficiency virus (HIV),
hepatitis B or hepatitis C virus.
e. History of infected joint prosthesis with prosthesis still in situ.


9. History of recurrent (more than one episode) herpes zoster or disseminated (a single
episode) herpes zoster or disseminated (a single episode) herpes simplex

10. Subjects taking potent and moderate cytochrome P450 3A4 (CYP3A4) inhibitors
(Appendix 5).


11. Subjects taking potent and moderate CYP3A4 inducers (Appendix 5).


12. Participation in studies of investigational compounds (excluding qualifying/index
study with tofacitinib) within 4 weeks or 5 half-lives (whichever is longer) prior to
the first dose of study drug. Subjects cannot participate in studies of other
investigational compounds at any time during their participation in this study.
Exposure to investigational biologics should be discussed with the Pfizer Medical
Monitor.


13. Any 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.


14. Pregnant or nursing females are excluded.


15. Intramuscular or intravenous corticosteroids in the 4 weeks preceding first dose of
study medication.


16. Subjects who have been vaccinated with live or attenuated vaccines within the
6 weeks prior to the first dose of study medication. All study participants should be
up-to-date with respect to standard of care vaccinations (as defined by their country
health ministry). (See Life Style Guidelines for further information regarding
avoidance of household contacts who may be vaccinated).


17. Use of prohibited prescription or nonprescription drugs and dietary supplements
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study
medication.


18. Herbal supplements must be discontinued at least 4 weeks prior to the first dose of
study medication.


19. Subjects with a first degree relative with a hereditary immunodeficiency; IgA
deficiency not exclusionary.


20. Subjects with a malignancy or with a history of malignancy with the exception of
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the
skin or cervical carcinoma in situ.


21. Recent (within 28 days prior to first dose of study drug) significant trauma or major
surgery.

22. Unwilling or unable to comply with the Life Style Guidelines described in this
protocol.


23. 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.


24. 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.