| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Juvenile Idiopathic Arthritis (sJIA) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079454 |
| E.1.2 | Term | Systemic juvenile idiopathic arthritis |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 evaluate the efficacy of baricitinib compared to placebo in children with sJIA |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of baricitinib in children with sJIA.
To assess the safety of baricitinib compared to placebo in patients with sJIA. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum I4V-MC-JAHW version 1 dated 18-Apr-2019
A Randomized, Double Blind, Placebo Controlled, Withdrawal, Safety and Efficacy Study of Oral Baricitinib in Patients from 1 Year to Less Than 18 Years Old with Systemic Juvenile Idiopathic Arthritis (sJIA).
This Addendum allows for the radiographic assessment of paediatric patients with systematic juvenile idiopathic arthritis (sJIA) in Study 14-MC-JAHU. This addendum will provide data on joint damage prevention and bone growth to supplement data on physical function and reduction in signs and symptoms.
This addendum is optional. The purpose of the addendum is:
(1) To assess the effect of baricitinib on changes in bone erosion and joint space narrowing, as observed in hand/wrist radiographs, in a subgroup of patients in Study JAHU.
(2) To assess the effect of baricitinib on bone growth in a subgroup of patients in Study JAHU via hand/ wrist radiographs. |
|
| E.3 | Principal inclusion criteria |
[1] Patients are at least 1 year and less than 18 years of age; full date of birth will be collected except in countries in which it is not allowed.
[2] Have a diagnosis of sJIA as defined by International League of Associations for Rheumatology (ILAR) criteria (Petty et al. 2004), with onset before the age of 16 years:
Arthritis in 1 or more joints with or preceded by fever of at least 2 weeks’ duration that is documented to be daily (quotidian) fever for at least 3 days, and accompanied by 1 or more of the following:
o Evanescent (nonfixed) erythematous rash
o Generalized lymph node enlargement
o Hepatomegaly and/or splenomegaly
o Serositis
[4] If participating in the safety/PK period, must have
a diagnosis of sJIA as defined by the ILAR criteria
at least 2 joints with active arthritis
intermittently spiking fever >38°C within the week prior to enrollment
hsCRP levels >1.5 x ULN, and
eGFR ≥60 mL/min/1.73 m2.
[5] Both a parent or legal guardian and the patient (as appropriate) are able to understand and fully participate in the activities of the clinical study and sign their consent and assent, respectively, in accordance with local guidelines.
[6] Male or nonpregnant, nonbreastfeeding female patients
a. Patients of childbearing potential who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) must agree to remain abstinent.
b. Total abstinence is defined as refraining from intercourse during the entirety of the study and for at least 1 week following the last dose of
investigational product. Periodic abstinence such as calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not
acceptable methods of contraception.
c. Otherwise, patients and their partners of childbearing potential must agree to use 2 effective methods of contraception, where at least 1 form
is highly effective for the entirety of the study and for at least 1 week following the last dose of investigational product.
The following contraception methods are considered acceptable (the patient, and their partner, should choose 2, and 1 must be highly effective [defined as less than 1% failure rate per year when used consistently and correctly]):
Highly effective birth control methods:
o Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
o Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or implantable
o Intrauterine device/intrauterine hormone-releasing system
o Vasectomized partner (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
Effective birth control methods:
o Male or female condom with spermicide. It should be noted that the use of male and female condoms as a double-barrier method is not
considered acceptable due to the high failure rate when these methods are combined.
o Diaphragm with spermicide
o Cervical sponge
o Cervical cap with spermicide
Note: When local guidelines concerning highly effective or effective methods of birth control differ from the above, the local guidelines must
be followed.
Adolescent females who have started menses (even 1 cycle and any amount of spotting) are considered to be of childbearing potential.
Female patients of nonchildbearing potential are not required to use birth control and they are defined as:
Females who are infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation) and congenital anomaly such as Müllerian agenesis. |
|
| E.4 | Principal exclusion criteria |
[7] Have polyarticular JIA (positive or negative for rheumatoid factor), extended oligoarticular JIA, enthesitis-related JIA, or juvenile psoriatic arthritis.
[8] Have persistent oligoarticular arthritis as defined by the ILAR criteria.
[9] Have a history or presence of any autoimmune inflammatory condition other than JIA. Exception: For patients with a controlled autoimmune condition, consult the study team.
[10] Have active anterior uveitis or are receiving concurrent treatment for anterior uveitis (patients with a history of uveitis should not be excluded).
[11] Have active fibromyalgia or other chronic pain conditions that, in the investigator’s opinion, would make it difficult to appropriately assess disease activity for the purposes of this study.
[12] Have biologic features of MAS such as hemorrhages, central nervous system dysfunction, hepatomegaly, plasma fibrinogen level <2.5 g/L, cytopenia, hypertriglyceridemia, decreased platelet count, increased AST, hyperferritinemia (Ravelli et al. 2005) at screening or a history of recurrent pericarditis, myocarditis, serositis and/or biologic features of MAS over the past 24 weeks.
[13] Have a current or recent (<4 weeks prior to baseline) clinically serious viral, bacterial, fungal, or parasitic infection or any other active or recent infection that, in the opinion of the investigator, would pose an unacceptable risk to the patient if participating in the study.
Note: For example, a recent viral upper respiratory tract infection or uncomplicated urinary tract infection need not be considered clinically serious.
[14] Have had bone or joint infections within 6 months prior to screening.
[15] Have symptomatic herpes simplex at baseline.
[16] Have had symptomatic herpes zoster infection within 12 weeks prior to baseline.
[17] Have a history of multidermatomal herpes zoster, complicated herpes zoster (e.g., ocular or motor nerve involvement or disseminated herpes zoster such as systemic infection).
[18] Have a positive test for hepatitis B virus (HBV) at screening defined as:
a. positive for hepatitis B surface antigen, or
b. positive for hepatitis B core antibody (HBcAb) and positive for HBV deoxyribonucleic acid (DNA)
[19] Have hepatitis C virus (HCV) infection (hepatitis C antibody positive and confirmed presence of HCV ribonucleic acid [RNA]).
[20] Have evidence of human immunodeficiency virus (HIV) infection and/or positive HIV antibodies.
[21] Have had household contact with a person with active tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB.
[22] Have evidence of active TB or untreated/inadequately/inappropriately treated latent TB.
[23] Had major surgery within 8 weeks prior to screening or will require major surgery during the study that in the opinion of the investigator in consultation with Lilly or its designee would pose an unacceptable risk to the patient.
[24] Have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute an unacceptable risk when taking investigational product or interfere with the interpretation of data.
[25] Have a history of a VTE or are considered at high risk of VTE as deemed by the investigator.
[26] Are largely or wholly incapacitated, such as being bedridden.
[27] Have a history of lymphoproliferative disease; or have signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; or have primary or recurrent malignant disease, or have been in remission from clinically significant malignancy for <5 years prior to Visit 2.
[30] Have known hypogammaglobulinemia.
[31] Are using MTX at doses of >20 mg/m2/week, or have received an unstable dose (increasing, reducing, or stopping) within 8 weeks prior to screening.
[32] Are currently receiving concomitant treatment with a combination of >2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (including MTX), or have initiated or changed dosage of concomitant csDMARDs (other than MTX) within 4 weeks prior to screening.
[39] Have received any JAK inhibitors, including, but not limited to, tofacitinib or baricitinib, previously. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| -Time to disease flare (defined as recurrence of fever lasting for 2 or more consecutive days, and/ or worsening of ≥30% in at least 3 of the 6 Pediatric American College of Rheumatology (PediACR) core criteria for JIA and an improvement of ≥30% in no more than 1 of the criteria) from the initiation of the double blind withdrawal period to the end of the double blind withdrawal period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Open Label Lead in Period:
Changes from baseline in each of the 6 individual components of the PediACR Core Set variables as follows, with the addition of absence of spiking fever, as follows:
-Number of active joints
-Number of joints with limited range of motion
-Physician's Global Assessment of Disease Activity
-Parent's Global Assessment of Well-Being
-Physical function as measured by the CHAQ
-Acute-phase reactant hsCRP and erythrocyte sedimentation rate (ESR)
- Proportion of patients without spiking fever
Adapted PediACR 30/50/70/90/100 response rates at the end of the Open label lead in period.
Proportion of patients with inactive disease.
Proportion of patients with minimal disease activity.
Double Blind Withdrawal period:
Changes from the beginning of the OLLI period to the end of the DBW period (due to disease flare or completion) in each of the 6 individual components of the PediACR Core set, plus absence of spiking fever.
Adapted PediACR 30/50/70/90/100 response rates at the end of the DBW period.
Proportion of patients with disease flare.
Proportion of patients with inactive disease
Adverse events including serious AE's. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks (Open label lead in period) and 32 weeks (Double Blind Withdrawal period) |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| A Randomized, Double-Blind, Placebo-Controlled, Withdrawal, Safety and Efficacy Study |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| China |
| India |
| Israel |
| Japan |
| Mexico |
| Russian Federation |
| Turkey |
| Austria |
| Belgium |
| Denmark |
| France |
| Poland |
| United Kingdom |
| Spain |
| Czechia |
| Germany |
| Italy |
|
| 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
|
|
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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