Juvenile Idiopathic Arthritis (JIA) Associated Uveitis or chronic anterior uveitis Eye Diseases
Conditions
Interventions
Eligible patients in the first stage (biologic refractory patients) will be registered to receive secukinumab. Patients will receive weekly secukinumab injections (75mg if weighing less than 25kg, 150
Sponsors
University Hospitals Bristol and Weston NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Stage 1 1. Children and young people aged = 2 and 30 kgs 40mg every 2 weeks).) during the 12 weeks prior to screening. The participant must have been on MTX or MMF for at least 12 weeks* and have been on a stable dose for 4 weeks prior to screening visit. 4. No Disease modifying immunosuppressive drugs, other than MTX or MMF, in the 4 weeks prior to screening 5. Participant and parent/legal guardian willing and able to comply with protocol requirements and provide written informed consent, and assent where appropriate. 6. For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation. Post pubertal females must have a negative serum pregnancy test within 10 days before the first dose of trial drug. 7. Able to be registered and commence trial treatment within 2 weeks of the screening visit. Stage 2 1. Children and young people aged = 2 and <18 years fulfilling ILAR diagnostic criteria for JIA (all subgroups that have uveitis) with associated uveitis, or chronic anterior uveitis with no known systemic autoimmune disease . 2. SUN grade =1+ or more for two clinic visits during the preceding 12 weeks’ therapy despite MTX and corticosteroid (both systemic and topical) therapy”. The latest date of SUN grade score must be the date of the screening visit. 3. They must have failed MTX (minimum dose of 10-20mg/m2, with a maximum dose of 25mg/participant) or MMF (minimum dose of 300/m2 twice a day to maximum dose 600/m2 twice a day). The participant must have been on MTX or MMF for at least 12 weeks* and have been on a stable dose for 4 weeks prior to screening visit. 4. No Disease modifying immunosuppressive drugs, other than MTX or MMF, in the 4 weeks prior to screening 5. Participant and parent/legal guardian willing and able to comply with protocol requirements and provide written informed consent, and assent where appropriate. 6. For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation. Post pubertal females must have a negative serum pregnancy test within 10 days before the first dose of trial drug. 7. Able to be randomised and commence trial treatment within 2 weeks of the screening visit. * Omission of a maximum of 2 weeks MTX or MMF treatment within the 12 weeks is acceptable and will not render the patient ineligible unless they have missed 2 weeks of treatment in the 4 weeks prior to the screening visit.
Exclusion criteria
Exclusion criteria: Eligibility Criteria for Biologic Refractory Participants (stage 1) 1. Uveitis associated with infection, or history of ocular herpetic disease 2. Active inflammatory disease other than JIA and Uveitis 3. Currently on a biologic agent or has previously received any other biologic agent (other than adalimumab.) 4. Have been on adalimumab within previous 4 weeks 5. Currently on more than 1 disease-modifying anti-rheumatic drug (DMARD) 6. Chronic uncontrolled JIA and/or uveitis for more than 52 weeks 7. More than 6 topical steroid eye drops per eye, per day prior to screening (this dose must have been stable for at least 4 weeks prior to registration) 8. For patients on Prednisone or Prednisone equivalent, dose >0.2mg/kg per day or change of dose within 4 weeks prior to registration 9. Intra-articular joint injections within 4 weeks prior to registration 10. History or current diagnosis of Electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study such as: 10.1. Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker 10.2. History of familial long QT syndrome or known family history of Torsades de Pointes. 11. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions which in the opinion of the Investigator immunocompromises the subject and/or places the subject at unacceptable risk for participation in a study with an immunomodulatory treatment. 12. History of active tuberculosis of less than 24 weeks treatment or untreated latent TB or evidence of Latent TB (positive QuantiFERON or PPD at screening) but unwilling or unable to complete a minimum of 4 weeks of latent TB treatment before initiating treatment with secukinumab 13. Participant has history of central nervous system (CNS) neoplasm, active CNS infection, demyelinating disease, or any progressive or degenerative neurological disease 14. Poorly controlled diabetes or persistently poorly controlled severe hypertension (>95th percentile for height / age) as deemed by the treating physician 15. Previous history of malignancy 16. Intraocular surgery within the 12 weeks prior to screening (cataract/ glaucoma/ vitrectomy) 17. Peri-ocular corticosteroids within 4 weeks prior to screening or intraocular steroid at any time. 18. Pregnant or nursing female 19. Demonstrations of clinically significant deviations in any of the following laboratory parameters: 19.1. Screening total white blood cell (WBC) count 25mm Hg or intraocular pressure requiring systemic acetazolamide 23. Participated in a trial of a medicinal product within 4 weeks prior to screening visit. 24. History of hepatitis B virus 25. Any contra
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| For stage 1 the primary outcome is to determine the response rate of secukinumab at 12 weeks in combination with methotrexate or mycophenolate with regards to controlling disease activity in participants who are refractory* to adalimumab treatment. Each participant will have an assessment of treatment response after 12 weeks of trial treatment. If 3 or more participants show a 2-step improvement in the SUN grade score then the trial will progress to stage 2. For stage 2, we want to determine the response rate at 12 weeks of secukinumab in combination with methotrexate or mycophenolate versus adalimumab in combination with methotrexate or mycophenolate with regard to controlling disease activity in refractory* uveitis associated with juvenile idiopathic arthritis. The primary endpoint is response to treatment, response to treatment is defined as per SUN criteria as a 2 step decrease in the level of inflammation (anterior chamber cells) or decrease to zero between baseline (prior to trial treatment initiation) and after 12 weeks of treatment *refractory refers to active uveitis with SUN =1+ despite treatment with MTX or MMF | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Safety, tolerability and compliance at baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks and 96 weeks: 1.1. Adverse events (AEs), serious adverse events (SAEs) and Adverse Events of Special Interest (AESI) 1.2. Laboratory parameters (haematological and biochemical analysis and urinalysis) 1.3. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 2. Response Rate Determine the response rate at 24 weeks with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis 3. Use of Corticosteroids over duration of study period and throughout follow up (at baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks and 96 weeks): 3.1. Total oral corticosteroid dose 3.2. Reduction in and rate of systemic corticosteroid dose from entry dose 3.3. Topical corticosteroid use (frequency) compared to usage at randomisation. 4. Optic and Ocular at baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks: 4.1. Visual acuity measured by Age-appropriate LogMAR assessment 4.2. Number of participants with resolution of associated optic nerve oedema (as assessed by slit lamp biomicroscopy) or macular oedema (as assessed by optical coherence tomography (OCT). 4.3. Number of patients who are able to reduce topical or systemic agents for ocular hypertension. 4.4. Number of participants with disease control (defined as zero cells, with topical treatment at 12 weeks treatment visit and 24 weeks treatment visit.) 4.5. Number of participants entering disease remission (defined as zero cells, without topical treatment at 12 and 24 weeks treatment visit) 4.6. Duration of sustaining inactive disease (zero cells, with or without topical treatment.) 4.7. Failure to reduce topical steroid eye drops to 2 drops/day by or at the 12 weeks visit 5. Quality of life at baseline, 12 we | — |
Countries
England, Scotland, United Kingdom
Outcome results
None listed