First-line Antimetabolites as Steroid-sparing Treatment Uveitis Pilot Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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Uveitis, a set of conditions defined by intraocular inflammation, is a significant cause of vision loss and morbidity in the United States and the world. The incidence was recently estimated to be more than 50 cases per 100,000 person-years, with a prevalence of approximately 115 per 100,000 persons. Additionally, uveitis is believed to be the cause of up to 10% of cases of legal blindness in the United States, or approximately 30,000 new cases of blindness per year. In contrast to common age-related eye disorders, uveitis may have a stronger socio-economic impact because it disproportionately affects younger working-age patients. Although the etiology of uveitis is varied, most cases are presumed to be immune-mediated and lack a known infectious cause. Even in developing countries such as India that have a larger burden of infection, the vast majority of cases are non-infectious. The current mainstay of treatment for noninfectious uveitis is corticosteroids (topical, systemic, locally injected, or corticosteroid-eluting implants). Due to the well documented local and systemic side effects associated with corticosteroid therapy, other immunosuppressive therapies are frequently used as corticosteroid-sparing agents in patients who need long-term therapy. These include antimetabolites, calcineurin inhibitors, alkylating agents, and biologic drugs. Cost and morbidity associated with uncontrolled inflammation make the selection of an effective initial steroid-sparing agent extremely important. It is common practice for patients requiring a steroid-sparing agent to be treated first with the less expensive methotrexate and then switched to mycophenolate mofetil in the event of treatment failure. However, results from non-comparative retrospective case series indicate that uveitis patients may be much more likely to achieve controlled inflammation and tolerate treatment with mycophenolate mofetil. Furthermore, approximately half of the patients who fail treatment with methotrexate go on to successful treatment with mycophenolate mofetil. There have been no prospective randomized, controlled trials to systematically determine which antimetabolite is more clinically efficacious as initial corticosteroid-sparing therapy, making it difficult for clinicians to make informed, evidence-based decisions about first-line immunosuppressive treatment. Our contribution is expected to be a definitive understanding of the comparative efficacy, tolerability, and quality of life of these two antimetabolites as initial steroid-sparing therapy for uveitis patients requiring chronic therapy. This contribution is significant because it will enable clinicians to make evidence-based decisions when prescribing first-line immunosuppressive therapy for their uveitis patients. The use of optimal first-line therapy will improve quality of life by reducing the risk of vision loss and complications associated with uncontrolled ocular inflammation and long-term corticosteroid use.

Official Title
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First-line Antimetabolites as Steroid-sparing Treatment Uveitis Pilot Trial

Conditions
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Uveitis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methotrexate<br> | Drug: Methotrexate<br>* All methotrexate doses will be taken orally once per week in a divided dose (half in the morning, half in the evening), and should be taken with food. For the first two weeks, a loading dose of 15 mg/week orally will be administered to assess tolerability. After two weeks, the dose will be ramped up to 25 mg/week until the end of follow-up or until treatment failure due to intolerability, adverse events, or of lack of efficacy. If the study ophthalmologist decides to reduce the study treatment dose due to intolerability, the dose will be reduced to 20 mg per week while maintaining masking. If side effects persist and the study ophthalmologist wishes to reduce the dose a second time, the dose will be reduced to 15 mg per week.<br>|
| Active Comparator: Mycophenolate mofetil<br> | Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil will be taken twice daily on an empty stomach. For the first two weeks, a loading dose of 500 mg/BID orally will be administered to assess tolerability. After two weeks, the dose will be ramped up to 1 g/BID until the end of follow-up or until treatment failure due to intolerability, adverse events, or lack of efficacy. If the study ophthalmologist decides to reduce the study treatment dose due to intolerability, the dose will be reduced to 750 mg/BID while maintaining masking. If side effects persist and the study ophthalmologist wishes to reduce the dose a second time, the dose will be reduced to 500 mg/BID.<br>* Other names: Cellcept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Treatment Success | TREATMENT SUCCESS is defined as controlled ocular inflammation in both eyes with less than or equal to 10 mg/day of prednisone and/or 2 topical steroid drops/day sustained for 2 visits separated by at least 28 days (control of inflammation and prednisone dose must be achieved by 5-month visit and sustained until 6-month visit). Discontinuation of study medication at any time due to efficacy, tolerability, or safety may result in a declaration of TREATMENT FAILURE. Note that all patients will be classified as either a treatment success or failure. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Control of Inflammation |  | 6 months | 
| Change in Best Spectacle-corrected Visual Acuity (BSCVA) | Change in best spectacle-corrected visual acuity (BSCVA) from baseline. Analysis on eye level | 6 months | 
| Number of Eyes With Resolution of Macular Edema |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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uveitis, immunosuppressive, antimetabolite, clinical trial