Safety and Efficacy of AIN457 in Patients With Quiescent Non-infectious Uveitis

Study Overview
=================
Brief Summary
-----------------
This study will assess the safety and efficacy of AIN457 as adjunctive therapy for the treatment of intermediate uveitis, posterior uveitis, or panuveitis requiring systemic immunosuppression.

Official Title
-----------------
A 24 Week Multi-center, Randomized, Double-masked, Placebo Controlled, Dose-ranging Phase III Study of AIN457 Versus Placebo for Maintaining Uveitis Suppression When Reducing Systemic Immunosuppression in Patients With Quiescent, Non-infectious Intermediate, Posterior or Panuveitis.

Conditions
-----------------
Non-infectious Uveitis

Intervention / Treatment
-----------------
* Biological: AIN457
* Biological: AIN457
* Biological: AIN457
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with quiescent chronic, non-infectious intermediate uveitis, posterior uveitis or panuveitis as evidenced by <1+ anterior chamber cell grade and <1+ vitreous haze in both eyes for at least 6 weeks prior to screening. Requirement for either of the following immunosuppressive therapies at any time within the past 3 months for the treatment or prevention of uveitis which must not have been increased within the 6 weeks prior to screening: Prednisone or equivalent ≥10 mg daily. ≥1 periocular injection or ≥1 intravitreal corticosteroid injection (i.e. triamcinolone) in the study eye within the past 6 months (the last injection must not have been given 6 weeks prior to screening.) Treatment with either cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mycophenolic acid, methotrexate as monotherapy or in combination with or without steroids. (Patients treated with chlorambucil or cyclophosphamide within the past 5 years are ineligible for the study.) Patients not meeting the above specified criteria for immunosuppressive therapies are eligible for enrollment if they are intolerant to systemic immunosuppressive therapy as determined by the study investigator. Exclusion Criteria: Ocular concomitant conditions/disease Patients with a primary diagnosis of Behcet's disease, anterior uveitis or any intermediate uveitis, posterior uveitis or panuveitis in which the manifestation(s) of the active intraocular inflammatory disease may spontaneously resolve or that are not characterized by the presence of either anterior chamber cells or vitritis (vitreous cell and haze) such as the white dot retino-choroidopathies (i.e. Punctate inner choroidopathy (PIC), acute zonal occult outer retinopathy (AZOOR.) Patients with active, non-infectious intermediate, posterior or panuveitis in one or both eyes (≥1+ anterior chamber cells and /or ≥1+ vitreous haze.) Patients receiving or that may require corticosteroids (prednisone or equivalent) ≥1 mg/kg/day to maintain quiescence of their intraocular inflammation. Ocular treatments Treatment with intravitreal anti-VEGF agents administered to the study eye within 3 months prior to screening. Treatment with fluocinolone acetonide implant (Retisert®) in the study eye within the last 3 years, or dexamethasone intravitreal implant and any other investigational corticosteroid implants in the study eye within the last 6 months. Intraocular surgery or laser photocoagulation in the study eye within the last 6 weeks prior to screening except for a diagnostic vitreous or aqueous tap with a small-gauge needle. Systemic conditions or treatments Any systemic biologic therapy (e.g. interferon, infliximab, daclizumab, etanercept, or adalimumab) given intravenously or subcutaneously within 3 months prior to screening. No biologic therapy other than the investigational study treatment will be allowed during the course of the clinical trial. Any prior treatment with systemic alkylating agents (cyclophosphamide, chlorambucil) within the past 5 years prior to screening. Treatment with any live or live-attenuated vaccine (including vaccine for varicella-zoster or measles) within 2 months prior to screening. No treatment with live or live-attenuated vaccines will be allowed during the course of the clinical trial. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AIN457 300mg s.c weekly for 3 weeks<br>AIN457 300mg s.c weekly for 3 weeks then every 2 weeks | Biological: AIN457<br>* AIN457 300mg s.c weekly for 3 weeks then every 2 weeks<br>|
| Experimental: AIN457 300mg s.c at baseline and Week 2<br>AIN457 300mg s.c at baseline and Week 2 then every 4 weeks | Biological: AIN457<br>* AIN457 300mg s.c at baseline and Week 2 then every 4 weeks<br>|
| Experimental: AIN457 150mg s.c at baseline and Week 2<br>AIN457 150mg s.c at baseline and Week 2 then every 4 weeks | Biological: AIN457<br>* AIN457 150mg s.c at baseline and Week 2 then every 4 weeks<br>|
| Placebo Comparator: Placebo s.c weekly for 3 weeks<br>Placebo s.c weekly for 3 weeks then every 2 weeks | Drug: Placebo<br>* Placebo s.c weekly for 3 weeks then every 2 weeks<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Recurrence in Any Eye of Active Intermediate, Posterior, or Panuveitis From Baseline | Kaplan-Meier estimates for the time to the first recurrence in any eye of active intermediate, posterior, or panuveitis from baselineRecurrence of active intermediate, posterior, or panuveitis defined by either: ≥ 2 step increase in vitreous haze with or without an increase in anterior chamber cell grade or decrease in best corrected visual acuity of ≥ 10 ETDRS letters | Baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change (Reduction) From Baseline in Composite Immunosuppressive Medication Score (IMS) From Baseline to 24 Weeks | Participants could have received up to 5 immunosuppresive agents (prednisone, cyclosporine, azathioprine, methotrexate, mycophenolate). Immunosuppressive Medication Score (IMS) is a combined, single numeric score derived on basis of total daily dose of specific immunosuppressive agents / unit body weight, ranged on a scale from 0-9 for the total daily dose in mg per kg. Patients receiving multiple medications, the sum of the grading scores for each drug was used to calculate a total immunosuppression score at each visit. The total IMS is the sum of scores derived from the agents included into the score, and ranged from 0 to 55. Treatment groups compared using analysis of covariance with treatment & baseline IMS as covariate, where the lower IMS (or its reduction from baseline) showed better clinical outcome | Baseline to 24 weeks | 
| Mean Change in Best Corrected Visual Acuity From Baseline | The Best Corrected Visual Acuity (BCVA) is tested using the Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity (VA) testing protocol. VA measurements are taken in a sitting position at an initial test distance of 4 meters using ETDRS charts. The overall BCVA score is calculated using the BCVA worksheet 0-100 letter score. | Baseline to 24 weeks | 
| Mean Change in Vitreous Haze Grade From Baseline to 24 Weeks | The changes in steps (0, 1, or >= 2) from previous visit for vitreous haze, where the score is evaluated based on NEI Vitreous Haze Grading Scale (0 -4). Vitreous haze was recorded as 0-clear; to 4+ as dense opacity obscuring the optic nerve head. A 1 step increase is defined as any of the following changes: 0-1, 0.5-1, 1-2, 2-3, 3-4. A 2 step increase is defined as any of the following changes: 0-2, 0.5-2, 1-3, 2-4. A recurrent episode of active intermediate, posterior or panuveitis was considered to be resolved, if the eye returns and maintains in a quiescent state (<1+ anterior chamber cell grade and <1+ vitreous haze) for at least 2 weeks | Baseline to 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Quiescent uveitis, intermediate uveitis, panuveitis, posterior uveitis, uveitis