Secukinumab Safety and Efficacy in Juvenile Psoriatic Arthritis (JPsA) and Enthesitis-related Arthritis (ERA)

Study Overview
=================
Brief Summary
-----------------
This was a double-blind, placebo-controlled, event-driven randomized withdrawal study to investigate the efficacy and safety of secukinumab treatment in the Juvenile Idiopathic Arthritis (JIA) categories of Juvenile Psoriatic Arthritis (JPsA) and Enthesitis-related Arthritis (ERA). The study was divided into 3 parts (plus a post-treatment follow-up period) consisting of open-label, single-arm active treatment in Treatment Periods 1 and 3 and a randomized, double-blind, placebo controlled, event-driven withdrawal design in Treatment Period 2

Detailed Description
-----------------
TP1: All eligible subjects entered TP1 to receive 12-weeks of open-label secukinumab at a dose predicted to achieve secukinumab serum levels equivalent to adults administered a 150 mg dose regimen. Secukinumab was administered s.c. weekly for the first 4 weeks (Baseline, Weeks 1, 2, 3, 4) and then every 4 weeks thereafter. Clinical response (JIA ACR 30) was assessed at Week 12. Responders advanced to TP2 and non-responders exited the trial (early termination visit and entered into the Post-treatment follow-up period). TP2: Subjects who were a responder (JIA ACR 30) at Week 12 entered the double-blind withdrawal TP2 and were randomized 1:1 to either secukinumab or placebo on that visit and then every 4 weeks, until either experiencing a disease flare or completion of TP2. TP2 was event driven and was planned to be closed when 33 subjects experienced a disease flare as per JIA definition. Alternatively, the study could be closed when all subjects reached the total study duration of 104 Weeks and therefore subjects who did not experience a disease flare remained in TP2 for the duration of the study and completed the study without entering into TP3 TP3: Subjects experiencing a disease flare in TP2 immediately entered TP3 to receive openlabel secukinumab every 4 weeks until total study duration of 104 weeks for that subject was achieved. Post-treatment follow-up: The post-treatment follow-up period (lasting 12 weeks from the last study drug administration) was required for all subjects, unless they qualified and entered the secukinumab extension trial. All subjects were expected to participate in the post-treatment follow up period, except for those entering the extension study.

Official Title
-----------------
A Three-part Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Secukinumab Treatment in Juvenile Idiopathic Arthritis Subtypes of Psoriatic and Enthesitis-related Arthritis

Conditions
-----------------
Juvenile Psoriatic Arthritis, Enthesitis-related Arthritis

Intervention / Treatment
-----------------
* Drug: secukinumab
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of Enthesitis-related arthritis (ERA) or Juvenile psoriatic arthritis (JPsA) according to the International League of Associations for Rheumatology (ILAR) classification criteria of at least 6 months duration. Active disease (ERA or JPsA) defined as having both: at least 3 active joints at least 1 site of active enthesitis at baseline or documented by history. Inadequate response (at least 1 month) or intolerance to at least 1 nonsteroidal anti-inflammatory drugs(NSAID) Inadequate response (at least 2 months) or intolerance to at least 1 Disease-modifying antirheumatic drugs (DMARD) No concomitant use of second line agents such as disease-modifying and/or immunosuppressive drugs. Exclusion Criteria: Patients fulfilling any ILAR diagnostic JIA category other than ERA or JPsA. Patients who have ever received biologic immunomodulating agents Patients taking any non-biologic DMARD except for MTX (or sulfasalazine for ERA patients only). Patients with active uncontrolled inflammatory bowel disease or active uncontrolled uveitis. Other protocol-defined inclusion/exclusion criteria apply.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Period 2 - active<br>secukinumab (AIN457 - pre-filled syringe) for patients with a minimum American college of Rheumatology (ACR) 30 response in Treatment Period 1 | Drug: secukinumab<br>* secukinumab is a high-affinity fully human monoclonal anti-human antibody that targets IL-17A and neutralizes activity.<br>* Other names: AIN457;|
| Placebo Comparator: Treatment Period 2 - placebo<br>placebo comparator (matched to secukinumab treatment) for patients with a minimum American college of Rheumatology (ACR) 30 response in Treatment Period 1 | Other: placebo<br>* Matched placebo to AIN457 for use in the double blind Treatment Period 2<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Flare During Treatment Period 2 | Survival analysis of time to flare in treatment period 2 (TP2) FAS2 Subjects are either ERA or JPsA | From Week 12 until max Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 30/50/70/90/100 Response at Week 12 - by JIA Category | Summary of JIA ACR 30/50/70/90/100 for all subjects and each JIA category - TP1 (FAS1) The adapted ACR Pediatric 30/50/70/90/100 criteria was used to determine efficacy defined as improvement from baseline of at least 30/50/70/90/100% respectively in at least 3 of the following 6 components Physician's Global Assessment of disease activity on a 0-100 mm VAS from 0 mm = no disease activity to 100 mm = very severe disease activity. Parent's or patient's Global Assessment of Subject's overall wellbeing on a 0-100 mm VAS from 0 mm= very well to 100 mm= very poor. Functional ability: Childhood Health Assessment Questionnaire (CHAQ©) Number of joints with active arthritis using the ACR definition (The ACR definition of active arthritis is any joint with swelling, or in the absence of swelling, limitation of motion accompanied by either pain on motion or tenderness not due to deformity) Number of joints with limitation of motion Laboratory measure of inflammation: CRP (mg/L) | baseline, week 12 | 
| Percent of Participants With Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 30/50/70/90/100 Response at Week 12 - Total | Summary of JIA ACR 30/50/70/90/100 for all subjects - TP1 (FAS1) The adapted ACR Pediatric 30/50/70/90/100 criteria was used to determine efficacy defined as improvement from baseline of at least 30/50/70/90/100% respectively in at least 3 of the following 6 components Physician's Global Assessment of disease activity on a 0-100 mm VAS from 0 mm = no disease activity to 100 mm = very severe disease activity. Parent's or patient's Global Assessment of Subject's overall wellbeing on a 0-100 mm VAS from 0 mm= very well to 100 mm= very poor. Functional ability: Childhood Health Assessment Questionnaire (CHAQ©) Number of joints with active arthritis using the ACR definition (The ACR definition of active arthritis is any joint with swelling, or in the absence of swelling, limitation of motion accompanied by either pain on motion or tenderness not due to deformity) Number of joints with limitation of motion Laboratory measure of inflammation: CRP (mg/L) | baseline, week 12 | 
| Percent Change From Baseline for JIA ACR Core Components in TP1 | Summary of JIA ACR core components for all subjects and each JIA category - Treatment period 1 Negative percent change indicates improvement Physician global assessment of disease activity (VAS mm) 0 (no disease activity) - 100 (very severe); Parent or subject global assessment of overall well-being (VAS mm) 0 (very well) - 100 (very poor); CHAQ (Childhood Health Assessment Questionnaire) 0 - 3 (most severe); Number of joints with active arthritis 0 - 73; Number of joints with limited range of motion 0 - 69. | baseline, week 12 | 
| Percent Change in C-reactive Protein Standardized Value (mg/L) | Median Percent Change from baseline for C-reactive protein standardized value (mg/L) | baseline, week 12 | 
| Change From Baseline Juvenile Arthritis Disease Activity Score (JADAS) Score | JADAS change from baseline for all subjects in Treatment period 1. JADAS-27 (Juvenile Arthritis Disease Activity Score in 27 joints) ranges from 0 to 57 and JADAS-71 ranges from 0 to 101 (higher scores indicate more disease activity). | 12 weeks | 
| Change From Baseline in Total Enthesitis Events - TP1 (FAS1) | Enthesitis swollen joint count range is 0-16. Zero is worst, and 16 is best A total of 16 entheseal sites were assessed for the presence or absence of tenderness of enthesitis. This is the mean (SD) enthesitis count (range 0-16) for FAS subjects A zero score means no enthesitis, so a zero score is better for the patient | Baseline and week 12 | 
| Change From Baseline in Total Dactylitis Count | Summary of total dactylitis count for all subjects - TP1 (FAS1) Total dactylitis count ranges from 0 to 20. A zero score means no dactylitis, so a zero score is better for the patient | baseline, week 12 | 
| Number of Participants With Anti-secukinumab Anitbodies | Blood samples for immunogenicity (anti-AIN457 antibodies) were taken pre-dose at the scheduled time points. In addition, if a subject discontinued from the study at any time, he/she provided a sample at the last visit. All blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. An Electrochemiluminescence method was used for the detection of potential anti-secukinumab antibody formation. | 104 weeks | 
| Secukinumab Serum Concentration | Summary of pharmacokinetic concentrations - Treatment period 1 | baseline, week 12 | 
| Number of Participants With Inactive Disease Status for All Subjects - TP1 (FAS1) | Summary of inactive disease status for all subjects - TP1 (FAS1) Clinical inactive disease definition was adapted from the JIA ACR criteria. All were required to be met: No joints with active arthritis No uveitis CRP value within normal limits for the laboratory where tested or, if elevated, not attributable to JIA Physician's global assessment of disease activity score ≤ 10mm Duration of morning stiffness attributable to JIA ≤15 min | week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
JIA, JPsA, ERA, Secukinumab, ILAR, Arthritis