Primary:* 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.Secondary:* To assess efficacy of tofacitinib versus placebo in sJIA…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Time to sJIA disease flare in the double-blind randomized withdrawal phase.
Secondary outcome
Efficacy endpoints:
* 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 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 6
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 and clinical remission at every visit
from Day 7 onward (JIA ACR) in the open-label and double-blind phase.
Exploratory
* Change from baseline in various genomic and serum biomarkers following
treatment with tofacitinib.
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.
Background summary
The safety and effectiveness of tofacitinib for the treatment of rheumatoid
arthritis (RA) has been demonstrated in adult subjects. The Sponsor is
conducting a pediatric investigational program to determine the safety and
efficacy of tofacitinib in subjects 2 to <18 years of age for the treatment of
Juvenile Idiopathic Arthritis (JIA). As part of this pediatric investigational
program, study A3921165 will evaluate efficacy, safety, tolerability and
pharmacokinetics of tofacitinib as treatment for systemic (s)JIA. In this
study, after 12 to 40 weeks of treatment with open-label tofacitinib, sJIA
patients who are able to taper corticosteroids (CS) while maintaining an
Adapted JIA ACR 30 response will be identified as *responders*. These
responders will proceed to a double-blind withdrawal phase in which they will
be randomized to either continue with tofacitinib treatment or start placebo
treatment. Sustained efficacy of tofacitinib to prevent disease flare will be
evaluated in the randomized withdrawal phase.
It is expected that Tofacitinib will demonstrate a reduction in signs and
symptoms of sJIA compared to placebo.
Study objective
Primary:
* 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.
Secondary:
* 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,
as measured by:
a. Percentage of subjects with successful corticosteroids tapering per protocol
at the end of the open-label phase in subjects with sJIA receiving
corticosteroids at start of open-label phase;
b. Percentage of subjects with Adapted JIA ACR 30/50/70/90/100 responses at
every visit from Day 7 onward;
c. Other evaluations specified under *Efficacy endpoints* for the open-label
phase.
* 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.
Exploratory Objective
* To evaluate exploratory biomarker and genomic samples to characterize the
effect of
tofacitinib.
Study design
This is a 2-phase randomized withdrawal study to evaluate efficacy, safety and
tolerability, and pharmacokinetics of tofacitinib as a treatment for sJIA.
The first phase will be open-label were all subjects receive tofacitinib. The
second phase will be double-blind placebo controlled.
Intervention
Open-label phase: All subjects <40 kg will receive tofacitinib 5 mg BID oral
tablets, and all subjects <40 kg will receive a weight-based lower dose of
tofacitinib oral solution (1 mg/mL) BID. Each dose must be taken two times per
day, about 12 hours apart
Double-blind phase: Eligible subjects will be randomized in a 1:1 ratio to
either continue on the same dose of tofacitinib that they received in the
open-label phase or start placebo.
Study burden and risks
The patients will need to do/undergo the following for the study:
-Visit the hospital 16 times
- 22 times blood tests
-Urine test
-Physical exam, vital signs, demographic and medical history
-Pregnancy tests in women of childbearing potential
-An X-ray only if required to determine tuberculosis
-examination of the joints
-questions about pain and stiffness
-questions about possible immobilization, surgery or heart conditions
-Female patients: no breastfeeding allowed. Effective methods of birth control
must be used from the time of signing the ICF, throughout the entire study and
for X days following the last dose of the study drug.
Male patients: due to the potential risk of the effect on the sperm appropriate
method of contraception must be used starting at screening and continuing for
at least x days following the last dose of study drug.
-Parents of the patients will be asked to complete a questionnaire about their
child's condition
The nature and degree of the risk varies with the patient population; however,
these potentially important risks include lipid elevations, decreases in
hemoglobin, decreases in neutrophil and lymphocyte counts, increases in serum
creatinine, increases in serum creatine kinase, infection risk,
lymphoproliferative disorder/lymphoma risk, malignancy risk, non-melanoma skin
cancer, gastrointestinal perforations, viral reactivation, including herpes
zoster, tuberculosis, transaminase elevations, drug hypersensitivity and
effects on pregnancy and the fetus. Additionally, venous thromboembolism (VTE)
has been identified as an important identified risk associated with tofacitinib.
Safety assessments, including physical examinations, clinical laboratory tests,
adverse event monitoring vital signs and VTE risk assessment will be performed
in Study A3921165. Safety assessments, inclusion/exclusion criteria, monitoring
and discontinuation criteria including newly added criteria for the
discontinuation of a subject with a VTE event were designed to manage and
mitigate the safety risks associated with tofacitinib therapy.
Based on the totality of the data, the sponsor is of the opinion that the
overall risk-benefit assessment for this study is favorable for children with
sJIA. Thorough safety monitoring and staggering of cohorts based on age for
index studies will be used to minimize risk in the pediatric population.
De Entrée 99-197
Amsterdam 1101 HE
NL
De Entrée 99-197
Amsterdam 1101 HE
NL
Listed location countries
Age
Inclusion criteria
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, 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 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.
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 Section 5.8.1.2 of 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 (see Section 4.5.2
Vaccination in Household Members) during treatment or during the 6 weeks
following discontinuation of study drug.
15.Current malignancy or history of 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 see paragraph 4.2. Exclusion
Criteria of the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002018-29-NL |
| CCMO | NL75258.041.20 |