Please select the eligibility criteria that correspond to the clinical trial below.
Title: First-line Antimetabolites as Steroid-sparing Treatment Uveitis Pilot Trial
Brief Summary: The proposed study is a masked trial, with stratified block randomization by site, designed to determine which treatment, methotrexate or mycophenolate mofetil, is more effective as first-line steroid-sparing treatment for patients with non-infectious uveitis requiring corticosteroid-sparing therapy.

One hundred non-infectious uveitis patients in need of corticosteroid-sparing therapy will be randomized to receive either oral methotrexate or oral mycophenolate mofetil at Aravind Eye Hospitals (Madurai and Coimbatore, South India). They will be followed monthly for 6 months after enrollment or until treatment failure. The investigators hypothesize that the proportion achieving corticosteroid-sparing success at 6 months for patients taking mycophenolate mofetil will be improved in comparison with patients taking methotrexate.


Options:
A: Inclusion Criteria:

* All the following criteria must be met at enrollment:

Historical non-infectious intermediate, anterior and intermediate, posterior or panuveitis in at least one eye

Active inflammation within the last 180 days, defined by the presence of any of the following (in at least one eye) according to Standardization of Uveitis Nomenclature (SUN) criteria:

* ≥ 2+ anterior chamber cells
* ≥ 2+ vitreous haze
* active retinal or choroidal lesions

Active inflammation at enrollment, defined by the presence of any of the following (in at least one eye) according to SUN criteria:

* ≥1+ anterior chamber cells and/or
* ≥1+ vitreous haze and/or
* active retinal/choroidal lesions

At least one of the following criteria must be met before or at enrollment:

* Active inflammation after 4 weeks of high-dose (1mg/kg prednisone equivalent) corticosteroid treatment or 4 weeks following a regional corticosteroid injection
* Treatment with oral corticosteroids resulting in a reduction of inflammation, followed by an increase in inflammation (of at least 1 grade in anterior chamber cells or vitreous haze or a change of non-active to active lesions) when corticosteroid is tapered, in the 180 weeks prior to enrollment
* Active inflammation after long-acting corticosteroid injection 4 weeks to 180 days prior to enrollment
* Active inflammation after treatment with \>10mg/day oral prednisone for at least the past 90 days prior to enrollment
* Known chronic condition necessitating corticosteroid-sparing immunosuppressive treatment: Behcet's disease with posterior segment involvement, multifocal choroiditis with panuveitis, serpiginous choroidopathy, birdshot retinochoroidopathy, diffuse retinal vasculitis, Vogt-Koyanagi-Harada with bullous serous retinal detachments and/or choroidal detachments, sympathetic ophthalmia. No prior therapy required for these patients

Willingness to start corticosteroid treatment at 1mg/kg or 60mg a day of prednisone, whichever is less

Willingness to limit alcohol consumption

Willingness to use an acceptable method of contraception during the study period (i.e. pharmacologic medications, devices, barrier methods) or abstinence.

* Exclusion Criteria: Any of the following

Any infectious cause of uveitis

Prior immunosuppressive therapy other than corticosteroids in the past 12 months

Prior intolerability or safety issues with methotrexate or mycophenolate mofetil

Prior failure to control ocular or other inflammation using methotrexate or mycophenolate mofetil

Prior biologic therapy at any time

Media opacity (such as cataract and/or corneal scar) and/or extensive posterior synechiae such that examination of the posterior segment is not possible in both eyes

Chronic hypotony (IOP \< 5 mm Hg for \> 3 months) in both eyes

Periocular or intravitreal corticosteroid injection in the past 4 weeks

Fluocinolone acetonide implant in either eye in \< 3 years

Intraocular surgery in \< 30 days, or planning on getting surgery within the next 6 months

Best spectacle-corrected visual acuity (BSCVA) of hand motions or worse in better eye

\< 16 years of age at enrollment

Planning to conceive during the study period, pregnant or breast-feeding (blood or urine pregnancy test for all females, excluding those who are post-menopausal is mandatory)\*

Any history of cancer (If a patient has a history of non-melanoma skin cancer they can still be considered for inclusion in this study, provided it is not currently active).

Systemic autoimmune disease anticipated to dictate treatment course

Abnormal Complete blood count (≤ 2,500 white blood cells and/or ≤ 75,000 platelets and/or ≤9 hemoglobin) within 4 weeks prior to enrollment\*

Abnormal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥ 2 times the upper limit of normal for the lab and/or creatinine ≥ 1.5 within 4 weeks prior to enrollment\*

Evidence of active tuberculosis, HIV infection, syphilis, or hepatitis B or C (patients must have a tuberculin skin test, or interferon-gamma release assay, a chest radiograph, Rapid plasma reagin / Venereal disease research laboratory test (RPR/VDRL), fluorescent treponemal antibody absorption test (FTA-ABS), or other treponemal tests, Hepatitis B surface antigen, Hepatitis C antibody tests, and HIV test within 90 days prior to enrollment)\*\*

\*Testing required within 4 weeks prior to enrollment; \*\*Testing required within 90 days prior to enrollment.
B: Inclusion Criteria:

* Patients with Behçet's disease and with a history of recurrent uveitis in a least one eye.
* Documented evidence of \>2 recurrent exacerbations of either intermediate uveitis, posterior uveitis or panuveitis in the study eye within the past 6 months (this could include the current exacerbation for patients having an acute exacerbation at screening). Exacerbations fulfilling the study inclusion criteria must have one or more of the following recorded in the patients patients medical record for each recurrent exacerbation:

  * \>2+ vitreous haze with \<2+ anterior chamber cell grade (intermediate or posterior uveitis) or \>2+ vitreous haze with \>2+ anterior chamber cell grade (panuveitis)
  * presence of retinal infiltrates or vasculitis or hemorrhages
  * documented \>10 ETDRS letter or 2 line Snellen decrease in visual acuity attributed to ocular inflammation secondary to the recurrent exacerbation of Behçet's disease.
* Requirement for either of the following immunosuppressive therapies for at least 3 of the past 6 months for the treatment of or to prevent an exacerbation of ocular inflammation related to Behçet's disease:

  * Prednisone or equivalent \>10 mg daily
  * The need for at least \>1 periocular injection or \>1 intravitreal corticosteroid injection in the study eye within the past 6 months (the last injection must have not been given within 6 weeks of screening)
  * Treatment with cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mycophenolic acid or methotrexate either as monotherapy or in combination with or without steroids. (Patients treated at any time with chlorambucil or cyclophosphamide are not eligible for the study.)
* Patients not meeting the above specified criteria for immunomodulatory therapies are eligible for enrollment if they are intolerant to systemic immunomodulatory therapy as determined by the study investigator.

Exclusion Criteria:

* Subjects with infectious uveitis, uveitis due to other causes than Behçet's disease, or uveitis of unknown etiology.
* Less severe (i.e. anterior) uveitis associated with Behçet's disease.

Ocular treatments

* Treatment with intravitreal anti-VEGF agents administered to the study eye within 3 months prior to study screening.
* Treatment with any injected or implantable corticosteroid releasing device (i.e., flucinolone acetonide implant, Retisert®) in the study eye within the last 3 years.
* 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

* Treatment with any live or live-attenuated vaccine (including vaccine for varicella-zoster virus or measles) within 2 months prior to screening.
* Any systemic biologic therapy (e.g. interferon, infliximab, daclizumab, etanercept, or adalimumab) given intravenously or subcutaneously within 3 months prior to screening and no prior treatment with AIN457.
* Any prior treatment with systemic alkylating agents (cyclophosphamide, chlorambucil).

Other protocol-defined inclusion/exclusion criteria may apply
C: 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
D: Inclusion Criteria:

* Non-infectious anterior, intermediate, posterior or panuveitis
* Active uveitis within the last 60 days (defined by the presence of any of the following according to SUN criteria: ≥ 1+ anterior chamber cells, anterior vitreous cells, vitreous haze, active retinal or choroidal lesions)
* Prednisone dose ≥ 15 mg/day
* History of corticosteroid taper failure (inability to taper to prednisone 10 mg or less) or obvious chronic disease necessitating corticosteroid-sparing immunosuppressive treatment

Exclusion Criteria:

* Any infectious cause of uveitis
* Tuberculosis: Evidence of active TB (PPD and CXR required - latent TB patients are still eligible)
* Positive for Hepatitis: HBsAg and/or Hep C antibody
* Positive for Syphilis: RPR/VDRL and/or FTA-ABS
* Abnormal CBC (\<2500 WBC or \<75,000 Plts or \<10 Hgb)
* Abnormal liver and/or kidney tests (ALT/AST \>2x normal or CR\>1.5)
* Pregnancy or breast-feeding (blood or urine pregnancy test for all females, excluding those who are post-menopausal)
* Chronic hypotony (IOP \< 5 mm Hg for \> 3 months)
* Prior use of any immunosuppressive drug for the treatment of uveitis in the past 6 months
* Prior failed treatment with methotrexate or mycophenolate mofetil
* Periocular or intravitreal corticosteroid injection in the past 3 months
* Fluocinolone acetonide implant surgery in either eye in \< 3 years
* Intraocular surgery in \< 30 days, or any ocular surgery scheduled during the 6-month study period
* VA of hand motions or worse in better eye
* \< 16 years of age at enrollment

Answer: D