Non-infectious Uveitis
Conditions
Keywords
Quiescent uveitis, intermediate uveitis, panuveitis, posterior uveitis, uveitis
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.
Interventions
BIOLOGICALAIN457
AIN457 300mg s.c weekly for 3 weeks then every 2 weeks
DRUGPlacebo
Placebo s.c weekly for 3 weeks then every 2 weeks
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Recurrence in Any Eye of Active Intermediate, Posterior, or Panuveitis From Baseline | Baseline to 24 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change (Reduction) From Baseline in Composite Immunosuppressive Medication Score (IMS) From Baseline to 24 Weeks | 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 |
| Mean Change in Best Corrected Visual Acuity From Baseline | Baseline to 24 weeks | 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. |
| Mean Change in Vitreous Haze Grade From Baseline to 24 Weeks | 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 |
Countries
Brazil, Germany, India, Israel, Italy, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Between February 2010 and March 2011, 125 patients were randomized from 51 centers in 9 countries (United States, Germany, Switzerland, India, Spain, United Kingdom, Israel, Brazil and Italy). Recruitment did not reach the target of 340 patients due to early termination of the study.
Participants by arm
| Arm | Count |
|---|---|
| AIN457 300mg s.c Every 2 Weeks AIN457 300mg s.c weekly for 3 weeks, then every 2 weeks | 29 |
| AIN457 300mg s.c Every 4 Weeks AIN457 300mg s.c at baseline and Week 2, then every 4 weeks | 31 |
| AIN457 150mg s.c Every 4 Weeks AIN457 150mg s.c at baseline and Week 2, then every 4 weeks | 31 |
| Placebo s.c Every 2 Weeks Placebo s.c weekly for 3 weeks, then every 2 weeks | 34 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Abnormal test procedure result | 0 | 0 | 1 | 0 |
| Overall Study | Administrative reasons | 5 | 6 | 4 | 4 |
| Overall Study | Adverse Event | 2 | 2 | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 1 | 1 |
Baseline characteristics
| Characteristic | AIN457 300mg s.c Every 2 Weeks | AIN457 300mg s.c Every 4 Weeks | AIN457 150mg s.c Every 4 Weeks | Placebo s.c Every 2 Weeks | Total |
|---|---|---|---|---|---|
| Age, Continuous | 46.2 Years STANDARD_DEVIATION 14.29 | 49.2 Years STANDARD_DEVIATION 11.14 | 47.7 Years STANDARD_DEVIATION 13.5 | 47.3 Years STANDARD_DEVIATION 15.46 | 47.6 Years STANDARD_DEVIATION 13.6 |
| Sex: Female, Male Female | 17 Participants | 16 Participants | 20 Participants | 18 Participants | 71 Participants |
| Sex: Female, Male Male | 12 Participants | 15 Participants | 11 Participants | 16 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 29 | 17 / 31 | 19 / 31 | 14 / 33 |
| serious Total, serious adverse events | 2 / 29 | 1 / 31 | 0 / 31 | 1 / 33 |
Outcome results
Primary
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
Time frame: Baseline to 24 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and have at least one post-baseline assessment for the primary efficacy parameter or any of its components. Following the intent-to-treat principle, patients were analyzed according to the treatment they are assigned to at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AIN457 300mg s.c Every 2 Weeks | Time to First Recurrence in Any Eye of Active Intermediate, Posterior, or Panuveitis From Baseline | NA Days |
| AIN457 300mg s.c Every 4 Weeks | Time to First Recurrence in Any Eye of Active Intermediate, Posterior, or Panuveitis From Baseline | NA Days |
| AIN457 150mg s.c Every 4 Weeks | Time to First Recurrence in Any Eye of Active Intermediate, Posterior, or Panuveitis From Baseline | 178 Days |
| Placebo s.c Every 2 Weeks | Time to First Recurrence in Any Eye of Active Intermediate, Posterior, or Panuveitis From Baseline | NA Days |
Secondary
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
Time frame: Baseline to 24 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and have at least one post-baseline assessment for the primary efficacy parameter or any of its components. Following the intent-to-treat principle, patients were analyzed according to the treatment they are assigned to at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIN457 300mg s.c Every 2 Weeks | Change (Reduction) From Baseline in Composite Immunosuppressive Medication Score (IMS) From Baseline to 24 Weeks | -2.55 Score | Standard Deviation 3.22 |
| AIN457 300mg s.c Every 4 Weeks | Change (Reduction) From Baseline in Composite Immunosuppressive Medication Score (IMS) From Baseline to 24 Weeks | -2.81 Score | Standard Deviation 2.847 |
| AIN457 150mg s.c Every 4 Weeks | Change (Reduction) From Baseline in Composite Immunosuppressive Medication Score (IMS) From Baseline to 24 Weeks | -2.92 Score | Standard Deviation 2.874 |
| Placebo s.c Every 2 Weeks | Change (Reduction) From Baseline in Composite Immunosuppressive Medication Score (IMS) From Baseline to 24 Weeks | -2.13 Score | Standard Deviation 3.049 |
Secondary
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.
Time frame: Baseline to 24 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and have at least one post-baseline assessment for the primary efficacy parameter or any of its components. Following the intent-to-treat principle, patients were analyzed according to the treatment they are assigned to at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIN457 300mg s.c Every 2 Weeks | Mean Change in Best Corrected Visual Acuity From Baseline | 2.9 Letters | Standard Deviation 4.86 |
| AIN457 300mg s.c Every 4 Weeks | Mean Change in Best Corrected Visual Acuity From Baseline | 1.8 Letters | Standard Deviation 6.12 |
| AIN457 150mg s.c Every 4 Weeks | Mean Change in Best Corrected Visual Acuity From Baseline | 1.9 Letters | Standard Deviation 4.46 |
| Placebo s.c Every 2 Weeks | Mean Change in Best Corrected Visual Acuity From Baseline | 1.4 Letters | Standard Deviation 9.42 |
Secondary
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
Time frame: Baseline to 24 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and have at least one post-baseline assessment for the primary efficacy parameter or any of its components. Following the intent-to-treat principle, patients were analyzed according to the treatment they are assigned to at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIN457 300mg s.c Every 2 Weeks | Mean Change in Vitreous Haze Grade From Baseline to 24 Weeks | 0.02 Score | Standard Deviation 0.295 |
| AIN457 300mg s.c Every 4 Weeks | Mean Change in Vitreous Haze Grade From Baseline to 24 Weeks | 0.03 Score | Standard Deviation 0.197 |
| AIN457 150mg s.c Every 4 Weeks | Mean Change in Vitreous Haze Grade From Baseline to 24 Weeks | 0.02 Score | Standard Deviation 0.232 |
| Placebo s.c Every 2 Weeks | Mean Change in Vitreous Haze Grade From Baseline to 24 Weeks | 0.2 Score | Standard Deviation 0.465 |