A Study of Baricitinib in Participants From 2 Years to Less Than 18 Years Old With Juvenile Idiopathic Arthritis

Study Overview
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Brief Summary
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The reason for this study is to see if the study drug baricitinib given orally is safe and effective in participants with JIA from 2 years to less than 18 years old.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Withdrawal, Safety and Efficacy Study of Oral Baricitinib in Patients From 2 Years to Less Than 18 Years Old With Juvenile Idiopathic Arthritis (JIA)

Conditions
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Juvenile Idiopathic Arthritis

Intervention / Treatment
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* Drug: Baricitinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have had a diagnosis of active JIA (polyarticular, extended oligoarticular, or enthesitis-related juvenile idiopathic arthritis [ERA] including JPsA). Participants must have had an inadequate response to at least one conventional or biologic disease-modifying antirheumatic drug (DMARD). Exclusion Criteria: Participants must not have systemic JIA, with or without active systemic features. Participants must not have persistent oligoarticular arthritis. Participants must not have been previously treated with a Janus kinase (JAK) inhibitor.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baricitinib<br>Baricitinib was administered QD (once daily) as a 4-mg oral tablet for adolescent participants (12 to <18 years of age) and children ≥9 years of age; and 2 mg for children <9 years of age. Participants <6 years of age received an oral suspension. Participants ≥6 to <12 years old had the option of receiving an oral suspension. Participants >12 years old were supplied tablets. The oral suspension dose was administered as 4-mg, 2-mg, 1-mg, and 0.5-mg as needed. | Drug: Baricitinib<br>* Administered orally.<br>* Other names: LY3009104;|
| Placebo Comparator: Placebo<br>Placebo matched to baricitinib was administered to participants during the DBW period. | Drug: Placebo<br>* Administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Flare | A disease flare is defined as a worsening of 30% or more in at least three of the six core Paediatric American College of Rheumatology (PedACR) criteria for juvenile rheumatoid arthritis (JIA) and an improvement of 30% or more in no more than one of the criteria. The six PedACR criteria are: 1) the number of active joints, 2) the number of joints with limited range of motion, 3) physician's global assessment of disease activity, 4) parent's global assessment of the participant's overall well-being, 5) physical function as measured by the Childhood Health Assessment Questionnaire (CHAQ) and 6) acute-phase reactant (high-sensitivity C-reactive protein [hsCRP] and erythrocyte sedimentation rate [ESR]), the ESR measure is only used as an acute phase reactant in the core criteria. | Week 12 to Week 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving PedACR30 Responder Index | The PedACR30 response is defined as at least 30% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by >30%. The 6 core response variables included in the PedACR criteria are: Number of active joints (defined as a joint that is swollen or in the absence of swelling has loss of passive motion accompanied by either pain on motion or joint tenderness) in 73 joints, Number of joints with limited range of motion in 69 joints, Physician's Global Assessment of Disease Activity (21-circle visual analogue scale [VAS]), Parent's Global Assessment of Patient's Overall Well-being, Physical function as assessed by the CHAQ and Acute-phase reactant (hsCRP and ESR). When PedACR response is analyzed as secondary endpoint, ESR measure is only used as acute-phase reactant in the core criteria. | Week 16, 20, 24, 28, 32, 36, 40 and 44 | 
| Percentage of Participants Achieving PedACR50 Responder Index | The PedACR50 response is defined as at least 50% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by > 30%. The 6 core response variables included in the PedACR criteria are: Number of active joints (defined as a joint that is swollen or in the absence of swelling has loss of passive motion accompanied by either pain on motion or joint tenderness) in 73 joints, Number of joints with limited range of motion in 69 joints, Physician's Global Assessment of Disease Activity (21-circle VAS), Parent's Global Assessment of Patient's Overall Well-being, Physical function as assessed by the CHAQ and Acute-phase reactant (hsCRP and ESR). When PedACR response is analyzed as secondary endpoint, ESR measure is only used as acute-phase reactant in the core criteria. | Week 16, 20, 24, 28, 32, 36, 40 and 44 | 
| Percentage of Participants Achieving PedACR70 Responder Index | The PedACR70 response is defined as at least 70% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by > 30%. The 6 core response variables included in the PedACR criteria are: Number of active joints (defined as a joint that is swollen or in the absence of swelling has loss of passive motion accompanied by either pain on motion or joint tenderness) in 73 joints, Number of joints with limited range of motion in 69 joints, Physician's Global Assessment of Disease Activity (21-circle VAS), Parent's Global Assessment of Patient's Overall Well-being, Physical function as assessed by the CHAQ and Acute-phase reactant (hsCRP and ESR). When PedACR response is analyzed as secondary endpoint, ESR measure is only used as acute-phase reactant in the core criteria. | Week 16, 20, 24, 28, 32, 36, 40 and 44 | 
| Percentage of Participants Achieving PedACR90 Responder Index | The PedACR90 response is defined as at least 90% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by > 30%. The 6 core response variables included in the PedACR criteria are: Number of active joints (defined as a joint that is swollen or in the absence of swelling has loss of passive motion accompanied by either pain on motion or joint tenderness) in 73 joints, Number of joints with limited range of motion in 69 joints, Physician's Global Assessment of Disease Activity (21-circle VAS), Parent's Global Assessment of Patient's Overall Well-being, Physical function as assessed by the CHAQ and Acute-phase reactant (hsCRP and ESR). When PedACR response is analyzed as secondary endpoint, ESR measure is only used as acute-phase reactant in the core criteria. | Week 16, 20, 24, 28, 32, 36, 40 and 44 | 
| Percentage of Participants Achieving PedACR100 Responder Index | The PedACR100 response is defined as at least 100% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by > 30%. The 6 core response variables included in the PedACR criteria are: Number of active joints (defined as a joint that is swollen or in the absence of swelling has loss of passive motion accompanied by either pain on motion or joint tenderness) in 73 joints, Number of joints with limited range of motion in 69 joints, Physician's Global Assessment of Disease Activity (21-circle VAS), Parent's Global Assessment of Patient's Overall Well-being, Physical function as assessed by the CHAQ and Acute-phase reactant (hsCRP and ESR). When PedACR response is analyzed as secondary endpoint, ESR measure is only used as acute-phase reactant in the core criteria. | Week 16, 20, 24, 28, 32, 36, 40 and 44 | 
| Percentage of Participants With Inactive Disease | Inactive disease is defined as the presence of all of the following: No joints with active arthritis based on Juvenile Arthritis Disease Activity Score (JADAS) - 27 score, No fever, rash, serositis, splenomegaly, hepatomegaly, or generalized lymphadenopathy attributable to JIA as assessed by the investigator, No active uveitis as assessed by the investigator, Normal ESR or hsCRP (i.e., within normal limits in the local laboratory or, if elevated, not attributable to JIA), Physician's Global Assessment of Disease Activity indicating no active disease (Score ranges are 0 to 100 and best possible score on scale is 0) and Duration of morning stiffness ≤15 minutes. | Week 16, 20, 24, 28, 32, 36, 40 and 44 | 
| Percentage of Participants With Minimal Disease Activity | Minimal disease activity is calculated based on the scores from the Physician's Global Assessment of Disease Activity Parent's Global Assessment of Well-Being and the number of swollen joints. If the physician's global assessment of disease activity is ≤3.5 (score range: 0-100), the parent's global rating of patient's overall well-being is ≤2.5 (score range: 0-100), and the swollen joint count is ≤1 (score range: 0-73), then the participant reaches minimal disease activity. if not, minimal disease activity is not reached. | Week 16, 20, 24, 28, 32, 36, 40 and 44 | 
| Percentage of Participants in Remission | Remission is defined as inactive disease for at least 24 consecutive weeks. Inactive disease is defined as the presence of all of the following: 1) No joints with active arthritis based on Juvenile Arthritis Disease Activity Score (JADAS)-27 score, 2) No fever, rash, serositis, splenomegaly, hepatomegaly, or generalized lymphadenopathy attributable to JIA as assessed by the investigator, 3) No active uveitis as assessed by the investigator, 4) Normal ESR or hsCRP (i.e., within normal limits in the local laboratory or, if elevated, not attributable to JIA), 5) Physician's Global Assessment of Disease Activity indicating no active disease (best possible score on scale [0]) and 6) Duration of morning stiffness ≤15 minutes. | Week 28, 32, 36, 40 and 44 | 
| Change From Baseline in Juvenile Arthritis Disease Activity Score-27 (JADAS-27) Score | The JADAS-27 score is based on 4 components: 1) Physician's global assessment of disease activity on a 0-100 mm VAS, 2) Parent's global assessment of overall well-being on a 0-100 mm VAS, 3) normalized ESR and 4) number of joints (maximum of 27) with active arthritis (cervical spine, elbows, wrists, metacarpophalangeal joints [from first to third], proximal interphalangeal joints, hips, knees, and ankles). The scores for the each of the first 3 components range from 0 -10; the score for the final component ranges from 0-27. The overall JADAS-27 score is sum of the 4 components and it ranges from 0-57. A higher score indicates more disease activity. Least square (LS) mean was calculated using Analysis of covariance (ANCOVA) model which includes treatment, baseline, prior biologic JIA therapy, combined JIA category and predose exposure ESR category value as fixed factors. | Baseline, Week 44 | 
| Change From Baseline in Arthritis-Related Pain Severity as Measured by the Childhood Health Assessment Questionnaire (CHAQ) Pain Visual Analog Scale (VAS) Item | CHAQ assesses the health status and physical function of children with juvenile arthritis over the past week. The CHAQ consists of a Disability Index and a Discomfort Index. The disability index consisted of 30 items grouped into the following 8 domains: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored from 0 to 3 (0 = no difficulty; 1 = some difficulty; 2 = much difficulty and 3 = unable to do or not applicable). The scores of 8 domains were averaged to calculate the CHAQ-Disability Index total score. A higher score indicates worse physical function. The discomfort index consisted of Parent's Global Assessment of Well-Being and pain assessment due to illness. The intensity of pain is scored on a VAS scale ranging from 0-100 mm, with zero referring to no pain and 100 referring to very severe pain. A higher score indicates a worse outcome. | Baseline, Week 44 | 
| Change From Baseline in Psoriasis Area and Severity Index (PASI) Score | PASI is a combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72 (maximal disease). Body is divided into 4 areas for scoring (head, arms, trunk and legs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area * area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). LS mean was calculated using ANCOVA model which includes treatment, baseline, prior biologic JIA therapy, combined JIA category and predose exposure ESR category value as fixed factors. | Baseline, Week 44 | 
| Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Index | The SPARCC enthesitis is an index used to measure the severity of enthesitis (sites at which tendons and ligaments attach to bones). The SPARCC assesses 16 sites for enthesitis using a score of 0 for no activity or 1 for activity. Sites assessed include Medial epicondyle (left/right [L/R]), Lateral epicondyle (L/R), Supraspinatus insertion into greater tuberosity of humerus (L/R), Greater trochanter (L/R), Quadriceps insertion into superior border of patella (L/R), Patellar ligament insertion into inferior pole of patella or tibial tubercle (L/R), Achilles tendon insertion into calcaneum (L/R), and Plantar fascia insertion into calcaneum (L/R). The SPARCC is the sum of all site scores (range 0 to 16). Higher scores indicate more severe enthesitis. LS mean was calculated using ANCOVA model which includes treatment, baseline, prior biologic JIA therapy, combined JIA category and predose exposure ESR category value as fixed factors. | Baseline, Week 44 | 
| Change From Baseline in Juvenile Spondyloarthritis Disease Activity (JSpADA) Index | The JSpADA index is used to evaluate the disease activity of juvenile spondyloarthritis. The JSpADA index scores will be determined by following 8 components: active joint count, active enthesitis count, pain over the past week, CRP level related to juvenile spondyloarthritis activity, morning stiffness greater than 15 minutes, clinical sacroiliitis, uveitis and back mobility. All items are transformed to values of 0, 0.5, or 1, and the total score ranges from 0 to 8, where higher scores indicate more disease activity. LS mean was calculated using ANCOVA model which includes treatment, baseline, prior biologic JIA therapy, combined JIA category and predose exposure ESR category value as fixed factors. | Baseline, Week 44 | 
| Pharmacokinetics (PK): Maximum Plasma Baricitinib Concentration at Steady-State (Cmax, ss) | Maximum Plasma Baricitinib Concentration at Steady-State | For Safety/PK period: Day 1, Day 4, Day 14 (pre dose) and Day 14 (post dose). For OLLI period: Day 1, Day 14, Day 28, Day 56 and 84 (pre dose) | 
| PK: Area Under the Baricitinib Concentration-Time Curve During a Dosing Interval at Steady-State (AUCτ,ss) | Area under the concentration-time curve of Baricitinib during a dosing interval at steady state. | For Safety/PK period: Day 1, Day 4, Day 14 (pre dose) and Day 14 (post dose). For OLLI period: Day 1, Day 14, Day 28, Day 56 and 84 (pre dose) | 
| Change From Baseline in Immunoglobulin Levels | Change from baseline in Serum Immunoglobulin A, Serum Immunoglobulin G and Serum Immunoglobulin M levels at week 12 are presented. | Baseline, Week 12 | 
| Number of Participants With Change of Immunoglobulin G (IgG) Titers | Number of participants with change of IgG titers eligible for tetanus / diphtheria / acellular pertussis (tDaP) vaccine and pneumococcal conjugate are presented. Participants who were immunized with tDaP or pneumococcal conjugate vaccine had their IgG antibody titers to the antigens evaluated preimmunization and at 4 and 12 weeks postimmunization. A primary immune response was assessed in participants who had never received tDaP or pneumococcal conjugate vaccines previously and secondary/booster responses were assessed if the participants had previously received the vaccines. For pneumococcal conjugate vaccine, number of participants with >= 2-fold increase from baseline in >=6 pneumococcal serotypes at week 4 and 12 is presented. For tDaP vaccine, number of participants with >= 4-fold increase from baseline in participants with baseline titer >=0.1 IU/mL at week 4 and 12 is presented. | Pre-Vaccination to 4 and 12 Weeks Post-Vaccination | 
| Number of Participants With Product Acceptability and Palatability Assessment | The questionnaire for product acceptability and palatability assessed the participants ability to swallow the tablet, experience relating to the taste, smell and ease of administering and taking the suspension. The questionnaire contained following Questions: Question 1) How did you (your child) like the taste of the medicine? Question 2) How did you (your child) like the smell of the medicine? Question 3) How easy was it for you (your child) to take the medicine today? Question 4) How easy was it for you to use the oral syringe to give your child the dose today? and Question 5) How easy was it for you (your child) to swallow the medicine today? Responses: Liked Very Much, Liked, Neither Liked nor Disliked, Disliked, Disliked Very Much, Very Easy, Easy, Neither Easy nor Hard, Difficult (or Hard) and Very Difficult (or Hard). The number of participants with these responses are presented. Data is presented as Question Number-Response-Time point. | Baseline and week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polyarticular JIA, Oligoarthritis, Juvenile psoriatic arthritis (JPsA), Enthesitis-related juvenile idiopathic arthritis (ERA)