Phase II Study to Analyze Sarilumab in Non-Infectious Uveitis

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To evaluate the efficacy of sarilumab at Week 16 in participants with non-infectious uveitis (NIU). Secondary Objectives: To evaluate the change in best corrected visual acuity (BCVA). To evaluate the safety of subcutaneous sarilumab in participants with NIU. To evaluate the change in macular edema. To evaluate the change in other signs of ocular inflammation. To evaluate the effect on retinal vessel leakage. To evaluate the effect of sarilumab on reducing concomitant immunosuppressant therapy. To evaluate the change in ocular inflammation in the anterior chamber. To evaluate the pharmacokinetics of sarilumab in NIU participants. To evaluate the immunogenicity with anti-drug antibodies (ADA).

Detailed Description
-----------------
The total duration per participant was up to 58 weeks, which included a 2 week screening period, 16 weeks principal treatment period (Part A), 34 weeks extension treatment period (Part B) or open label treatment period (Part C), and 6 weeks after last treatment administration. Participants with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 were considered as responders. Participants who did not complete the principal treatment period (Part A) due to lack of efficacy; or no decrease in VH ≥2 and corticosteroids dose ≥10 mg/day at Week 16; or no decrease in VH ≥2 and corticosteroids dose missing at Week 16; or non-responder according to medical review, were considered as non-responders. Responder participants, observed at Week 16 (at the end of Part A), were invited to continue in the extension treatment period (Part B). Non-responder participants, observed within the first 16 weeks, were offered to be treated by open-label sarilumab (Part C).

Official Title
-----------------
A Randomized, Double-Masked and Placebo-Controlled Study to Evaluate the Efficacy and Safety of Sarilumab Administered Subcutaneously Every 2 Weeks in Patients With Non-Infectious, Intermediate, Posterior or Pan-Uveitis (NIU)

Conditions
-----------------
Uveitis

Intervention / Treatment
-----------------
* Drug: Sarilumab
* Drug: Prednisone
* Drug: Methotrexate
* Drug: Folic/folinic acid
* Other: Placebo (for Sarilumab)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: ≥18 years of age. Non-infectious intermediate, posterior, or pan-uveitis in the study eye. Active disease at screening or evidence of activity within the 3 months prior to screening visit. Following the approval of amendment-2, only participants with active disease as defined above were enrolled in the study. Starting oral prednisone dose must be greater than or equal to 15 mg/day and less than 80 mg/day. At screening, participants must be receiving oral prednisone (≥15 mg and <80 mg/day [or equivalent oral corticosteroid]) as single immunosuppressive therapy or in combination with MTX (≤25 mg/week) orally or intravenously or intramuscular or subcutaneous). - Participants could be receiving one or several of the following therapies: Azathioprine (≤2.5 mg/kg/day), Mycophenolate mofetil (≤2 g daily, orally), Cyclosporine (≤4 mg/kg daily, orally), Tacrolimus (≤4 mg daily, orally). The doses might not had been increased for at least 4 weeks prior to the randomization visit. At randomization, participants had been receiving oral prednisone (≥15 mg and <80 mg/day [or equivalent oral corticosteroid]) as single immunosuppressive therapy or in combination with MTX (≤25 mg/week) orally or intravenously or intramuscular or subcutaneous). Azathioprine, mycophenolate mofetil, cyclosporine and tacrolimus had to be permanently discontinued at least 48 hours prior to the first study treatment injection, or longer as per Investigator's judgment. These immunomodulatory therapies (IMTs) were not permitted anytime during the treatment period. Signed written informed consent. Exclusion criteria: Participants with best-corrected visual acuity (BCVA) worse than 20 early treatment diabetic retinopathy study (ETDRS) letters in at least one eye. Participants with confirmed or suspected uveitis of infectious etiology or uveitis of traumatic etiology. Participants with primary diagnosis of anterior uveitis. Prior treatment with anti-interleukin-6 (IL-6) or interleukin-6 receptor complex (IL-6R) antagonist therapies, including tocilizumab and sarilumab. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (for Sarilumab) subcutaneous (SC) injection every 2 weeks (q2w) for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with Methotrexate (MTX) 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). | Drug: Sarilumab<br>* Pharmaceutical form: Prefilled syringes; Route of administration: Subcutaneous<br>* Other names: SAR153191/REGN88;Drug: Prednisone<br>* Pharmaceutical form: Tablet or Capsule; Route of administration: Oral<br>Drug: Methotrexate<br>* Pharmaceutical form: Tablet or Capsule or Suspension; Route of administration: Orally or intravenously or intramuscular<br>Drug: Folic/folinic acid<br>* Pharmaceutical form: Tablet or Capsule; Route of administration: Oral<br>Other: Placebo (for Sarilumab)<br>* Pharmaceutical form: Prefilled syringes; Route of administration: Subcutaneous<br>|
| Experimental: Sarilumab 200 mg q2w<br>Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). | Drug: Sarilumab<br>* Pharmaceutical form: Prefilled syringes; Route of administration: Subcutaneous<br>* Other names: SAR153191/REGN88;Drug: Prednisone<br>* Pharmaceutical form: Tablet or Capsule; Route of administration: Oral<br>Drug: Methotrexate<br>* Pharmaceutical form: Tablet or Capsule or Suspension; Route of administration: Orally or intravenously or intramuscular<br>Drug: Folic/folinic acid<br>* Pharmaceutical form: Tablet or Capsule; Route of administration: Oral<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least 2-step Reduction in Vitreous Haze (VH) or Prednisone Dose <10 mg/Day at Week 16 | At least 2-step reduction in VH per central review from baseline was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 [low opacity] to 8 [more opacity]) images (in increasing order of opacity) are equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Participants with prednisone dose <10 mg/day (or equivalent oral corticosteroid) were also evaluated. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in VH Scale at Week 16 | Change from baseline in VH scale was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 [low opacity] to 8 [more opacity]) images (in increasing order of opacity) were equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Least squares (LS) mean was calculated using mixed model for repeated measurements (MMRM) model with treatment groups, visits and visit-by-treatment groups interaction as fixed categorical effects as well as fixed continuous covariate of baseline adjudicated VH. | Baseline to Week 16 | 
| Percentage of Participants With Anterior Chamber (AC) Cell Score = 0 or At Least 2-step Reduction in Score at Week 16 | Participants with AC cell score = 0 or with ≥2 step reduction from baseline at Week 16 were evaluated. Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm × 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: grade 0 = no cells; grade +0.5 = 1 - 5 cells; grade +1 = 6 - 25 cells; grade +2= 26 - 50 cells; grade +3 = too many to count. | Week 16 | 
| Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Week 16 | BCVA score is based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters, and then at 1 meter. The range of ETDRS is 0 to 100 letters. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline BCVA. | Baseline to Week 16 | 
| Change From Baseline in Central Retinal Thickness (CRT) At Week 16 | CRT was measured by spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT. | Baseline to Week 16 | 
| Percent Change From Baseline in CRT at Week 16 | CRT was measured by SD-OCT, a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT. | Baseline to Week 16 | 
| Percentage of Participants With CRT Thickness <300 Microns at Week 16 |  | Week 16 | 
| Percentage of Participants Without Retinal Vessel Leakage on Fluorescein Angiography (FA) at Week 16 |  | Week 16 | 
| Percentage of Participants With Prednisone Dose of ≤5 mg/Day (or Equivalent Oral Corticosteroid) at Week 16 | Participants with prednisone dose ≤5 mg/day (or equivalent oral corticosteroid) at Week 16 were evaluated. | Week 16 | 
| Pharmacokinetics (PK) Assessment: Serum Functional Sarilumab Concentration | Serum functional (unbound) sarilumab concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) method with a lower limit of quantification (LLOQ) of 294 ng/mL. Concentrations below LLOQ were set to zero for samples at predose. Post-treatment concentrations below LLOQ were replaced by LLOQ/2. The samples were considered non-eligible for the analysis if the previous dosing time was <11 days or >17 days before the sampling time for every other week regimens. | Predose on Day 1 (Baseline), Week 2, 4, 8, 12, 16, 24, 36, 52, and end of study (EOS) (Week 56) |