Methotrexate and Mycophenolate Mofetil for UVEITIS

NCT ID: NCT01829295

Last Updated: 2024-04-02

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

216 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-08-31

Study Completion Date

2018-08-09

Brief Summary

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In the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial, the investigators propose to establish which immunosuppressive therapy, methotrexate or mycophenolate mofetil, is more effective as a first-line, corticosteroid-sparing agent for the treatment of non-infectious uveitis in a block-randomized, observer-masked, comparative effectiveness trial.

Detailed Description

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This is a randomized comparative effectiveness trial to determine which treatment, methotrexate or mycophenolate mofetil, is more effective as first-line corticosteroid-sparing treatment for patients with non-infectious intermediate, posterior and panuveitis requiring corticosteroid-sparing therapy. The primary outcome is treatment success assessed at the 6 month visit (Phase 1, 0-6 months). If patients are a treatment success, they continue on the medication for another 6 months (Phase 1, 6-12 months). Patients who are a treatment failure can crossover to the other medication (Phase 2, 0-6 months).

Conditions

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Uveitis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Investigators Outcome Assessors

Study Groups

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Methotrexate

oral methotrexate

Group Type EXPERIMENTAL

Methotrexate

Intervention Type DRUG

For the first two weeks, an introductory dose of 15 mg/week (7.5mg BID once a week) orally. After two weeks, the dose will be increased to 25 mg/week (12.5mg BID once a week)

Prednisone

Intervention Type DRUG

All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg or 60 mg daily, whichever is less. Initial corticosteroid dose will be continued for 2 to 4 weeks at which point prednisone will be gradually tapered. Prednisone will be tapered to and held at 7.5 mg/day for the first 6 months of the study.

Mycophenolate Mofetil

oral mycophenolate mofetil

Group Type EXPERIMENTAL

Mycophenolate mofetil

Intervention Type DRUG

For the first two weeks, an introductory dose of 500 mg twice a day (BID) orally. After two weeks, the dose will be increased to 1.5 g BID.

Prednisone

Intervention Type DRUG

All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg or 60 mg daily, whichever is less. Initial corticosteroid dose will be continued for 2 to 4 weeks at which point prednisone will be gradually tapered. Prednisone will be tapered to and held at 7.5 mg/day for the first 6 months of the study.

Interventions

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Mycophenolate mofetil

For the first two weeks, an introductory dose of 500 mg twice a day (BID) orally. After two weeks, the dose will be increased to 1.5 g BID.

Intervention Type DRUG

Methotrexate

For the first two weeks, an introductory dose of 15 mg/week (7.5mg BID once a week) orally. After two weeks, the dose will be increased to 25 mg/week (12.5mg BID once a week)

Intervention Type DRUG

Prednisone

All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg or 60 mg daily, whichever is less. Initial corticosteroid dose will be continued for 2 to 4 weeks at which point prednisone will be gradually tapered. Prednisone will be tapered to and held at 7.5 mg/day for the first 6 months of the study.

Intervention Type DRUG

Other Intervention Names

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Cellcept

Eligibility Criteria

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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 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.
Minimum Eligible Age

16 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Aravind Eye Hospitals, India

OTHER

Sponsor Role collaborator

Oregon Health and Science University

OTHER

Sponsor Role collaborator

Asociación para Evitar la Ceguera en México

OTHER

Sponsor Role collaborator

Royal Victoria Eye and Ear Hospital

OTHER_GOV

Sponsor Role collaborator

Northwestern University

OTHER

Sponsor Role collaborator

National Eye Institute (NEI)

NIH

Sponsor Role collaborator

King Khaled Eye Specialist Hospital

OTHER_GOV

Sponsor Role collaborator

University of California, San Francisco

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Nisha Acharya, MD, MS

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

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Francis I Proctor Foundation

San Francisco, California, United States

Site Status

Northwestern University

Chicago, Illinois, United States

Site Status

Oregon Health and Science University - Casey Eye Institute

Portland, Oregon, United States

Site Status

Royal Victorian Eye and Ear Hospital

Melbourne, Victoria, Australia

Site Status

Aravind Eye Hospital

Coimbatore, Tamil Nadu, India

Site Status

Aravind Eye Hospital

Madurai, Tamil Nadu, India

Site Status

Aravind Eye Hospital

Pondicherry, Tamil Nadu, India

Site Status

Asociacion Para Evita La Ceguera en Mexico

Mexico City, Mexico City, Mexico

Site Status

King Khaled Eye Specialist Hospital

Riyadh, , Saudi Arabia

Site Status

Countries

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United States Australia India Mexico Saudi Arabia

References

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Galor A, Jabs DA, Leder HA, Kedhar SR, Dunn JP, Peters GB 3rd, Thorne JE. Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology. 2008 Oct;115(10):1826-32. doi: 10.1016/j.ophtha.2008.04.026. Epub 2008 Jun 25.

Reference Type BACKGROUND
PMID: 18579209 (View on PubMed)

Siepmann K, Huber M, Stubiger N, Deuter C, Zierhut M. Mycophenolate mofetil is a highly effective and safe immunosuppressive agent for the treatment of uveitis : a retrospective analysis of 106 patients. Graefes Arch Clin Exp Ophthalmol. 2006 Jul;244(7):788-94. doi: 10.1007/s00417-005-0066-8. Epub 2005 Sep 15.

Reference Type BACKGROUND
PMID: 16163494 (View on PubMed)

Teoh SC, Hogan AC, Dick AD, Lee RW. Mycophenolate mofetil for the treatment of uveitis. Am J Ophthalmol. 2008 Nov;146(5):752-60, 760.e1-3. doi: 10.1016/j.ajo.2008.03.004. Epub 2008 May 2.

Reference Type BACKGROUND
PMID: 18455143 (View on PubMed)

Thorne JE, Jabs DA, Qazi FA, Nguyen QD, Kempen JH, Dunn JP. Mycophenolate mofetil therapy for inflammatory eye disease. Ophthalmology. 2005 Aug;112(8):1472-7. doi: 10.1016/j.ophtha.2005.02.020.

Reference Type BACKGROUND
PMID: 16061096 (View on PubMed)

Larkin G, Lightman S. Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye disease. Ophthalmology. 1999 Feb;106(2):370-4. doi: 10.1016/S0161-6420(99)90078-7.

Reference Type BACKGROUND
PMID: 9951492 (View on PubMed)

Baltatzis S, Tufail F, Yu EN, Vredeveld CM, Foster CS. Mycophenolate mofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory disorders. Ophthalmology. 2003 May;110(5):1061-5. doi: 10.1016/S0161-6420(03)00092-7.

Reference Type BACKGROUND
PMID: 12750115 (View on PubMed)

Choudhary A, Harding SP, Bucknall RC, Pearce IA. Mycophenolate mofetil as an immunosuppressive agent in refractory inflammatory eye disease. J Ocul Pharmacol Ther. 2006 Jun;22(3):168-75. doi: 10.1089/jop.2006.22.168.

Reference Type BACKGROUND
PMID: 16808677 (View on PubMed)

Bom S, Zamiri P, Lightman S. Use of methotrexate in the management of sight-threatening uveitis. Ocul Immunol Inflamm. 2001 Mar;9(1):35-40. doi: 10.1076/ocii.9.1.35.3983.

Reference Type BACKGROUND
PMID: 11262666 (View on PubMed)

Dev S, McCallum RM, Jaffe GJ. Methotrexate treatment for sarcoid-associated panuveitis. Ophthalmology. 1999 Jan;106(1):111-8. doi: 10.1016/S0161-6420(99)90011-8.

Reference Type BACKGROUND
PMID: 9917790 (View on PubMed)

Foeldvari I, Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2005 Feb;32(2):362-5.

Reference Type BACKGROUND
PMID: 15693100 (View on PubMed)

Gangaputra S, Newcomb CW, Liesegang TL, Kacmaz RO, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster CS, Kempen JH; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009 Nov;116(11):2188-98.e1. doi: 10.1016/j.ophtha.2009.04.020. Epub 2009 Sep 12.

Reference Type BACKGROUND
PMID: 19748676 (View on PubMed)

Holz FG, Krastel H, Breitbart A, Schwarz-Eywill M, Pezzutto A, Volcker HE. Low-dose methotrexate treatment in noninfectious uveitis resistant to corticosteroids. Ger J Ophthalmol. 1992;1(3-4):142-4.

Reference Type BACKGROUND
PMID: 1483126 (View on PubMed)

Shah SS, Lowder CY, Schmitt MA, Wilke WS, Kosmorsky GS, Meisler DM. Low-dose methotrexate therapy for ocular inflammatory disease. Ophthalmology. 1992 Sep;99(9):1419-23. doi: 10.1016/s0161-6420(92)31790-7.

Reference Type BACKGROUND
PMID: 1407973 (View on PubMed)

Taylor SR, Habot-Wilner Z, Pacheco P, Lightman SL. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema. Ophthalmology. 2009 Apr;116(4):797-801. doi: 10.1016/j.ophtha.2008.10.033.

Reference Type BACKGROUND
PMID: 19344827 (View on PubMed)

Daniel E, Thorne JE, Newcomb CW, Pujari SS, Kacmaz RO, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Foster CS, Jabs DA, Kempen JH. Mycophenolate mofetil for ocular inflammation. Am J Ophthalmol. 2010 Mar;149(3):423-32.e1-2. doi: 10.1016/j.ajo.2009.09.026. Epub 2009 Dec 30.

Reference Type BACKGROUND
PMID: 20042178 (View on PubMed)

Sobrin L, Christen W, Foster CS. Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis. Ophthalmology. 2008 Aug;115(8):1416-21, 1421.e1. doi: 10.1016/j.ophtha.2007.12.011. Epub 2008 Jan 25.

Reference Type BACKGROUND
PMID: 18221998 (View on PubMed)

Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005 Sep;140(3):509-16. doi: 10.1016/j.ajo.2005.03.057.

Reference Type BACKGROUND
PMID: 16196117 (View on PubMed)

Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, Nussenblatt RB, Stiehm ER, Tessler H, Van Gelder RN, Whitcup SM, Yocum D. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000 Oct;130(4):492-513. doi: 10.1016/s0002-9394(00)00659-0.

Reference Type BACKGROUND
PMID: 11024423 (View on PubMed)

Reddy AK, Miller DC, Sura AA, Rathinam SR, Gonzales JA, Thundikandy R, Kanakath A, Murugan B, Vedhanayaki R, Lim LL, Suhler EB, Doan T, Al-Dhibi HA, Goldstein DA, Arellanes-Garcia L, Acharya NR. Risk of failing both methotrexate and mycophenolate mofetil from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial. J Ophthalmic Inflamm Infect. 2023 Jun 9;13(1):29. doi: 10.1186/s12348-023-00350-5.

Reference Type RESULT
PMID: 37294447 (View on PubMed)

Chattopadhyay A, Rathinam SR, Gonzales JA, Kelly NK, Thundikandy R, Kanakath A, Murugan SB, Vedhanayaki R, Lim LL, Suhler EB, Al-Dhibi HA, Doan T, Ebert CD, Porco TC, Acharya NR; FAST Research Group. Association between Quality of Life and Visual Acuity in a Randomized Clinical Trial of Patients with Uveitis Taking Antimetabolites. Ocul Immunol Inflamm. 2024 Apr;32(3):301-309. doi: 10.1080/09273948.2023.2169714. Epub 2023 Feb 7.

Reference Type RESULT
PMID: 36749914 (View on PubMed)

Sura AA, Sun Y, Reddy AK, Rathinam SR, Gonzales JA, Thundikandy R, Vedhanayaki R, Kanakath A, Murugan B, Doan TA, Lim LL, Suhler EB, Al-Dhibi HA, Acharya NR; FAST Research Group. Reduced Dose Methotrexate and Mycophenolate Mofetil in Noninfectious Uveitis: A Sub-Analysis from the First-Line Antimetabolites as Steroid Sparing Therapy (FAST) Trial. Ocul Immunol Inflamm. 2024 Aug;32(6):955-960. doi: 10.1080/09273948.2023.2165949. Epub 2023 Jan 26.

Reference Type RESULT
PMID: 36701644 (View on PubMed)

Tsui E, Rathinam SR, Gonzales JA, Thundikandy R, Kanakath A, Balamurugan S, Vedhanayaki R, Lim LL, Suhler EB, Al-Dhibi HA, Doan T, Keenan J, Ebert CD, Kim E, Madow B, Porco TC, Acharya NR; FAST Research Group. Outcomes of Uveitic Macular Edema in the First-line Antimetabolites as Steroid-Sparing Treatment Uveitis Trial. Ophthalmology. 2022 Jun;129(6):661-667. doi: 10.1016/j.ophtha.2022.02.002. Epub 2022 Feb 8.

Reference Type RESULT
PMID: 35143800 (View on PubMed)

Kelly NK, Chattopadhyay A, Rathinam SR, Gonzales JA, Thundikandy R, Kanakath A, Murugan SB, Vedhanayaki R, Cugley D, Lim LL, Suhler EB, Al-Dhibi HA, Ebert CD, Berlinberg EJ, Porco TC, Acharya NR; FAST Research Group. Health- and Vision-Related Quality of Life in a Randomized Controlled Trial Comparing Methotrexate and Mycophenolate Mofetil for Uveitis. Ophthalmology. 2021 Sep;128(9):1337-1345. doi: 10.1016/j.ophtha.2021.02.024. Epub 2021 Mar 4.

Reference Type RESULT
PMID: 33675850 (View on PubMed)

Kong CL, Kelly NK, Sundararajan M, Rathinam SR, Gonzales JA, Thundikandy R, Vedhanayaki R, Kanakath A, Murugan B, Doan T, Goldstein D, Al-Dhibi HA, Acharya NR. Comparison of CD4 Counts with Mycophenolate Mofetil versus Methotrexate from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial. Ocul Immunol Inflamm. 2022 Jan 2;30(1):198-202. doi: 10.1080/09273948.2020.1774906. Epub 2020 Aug 11.

Reference Type RESULT
PMID: 32779952 (View on PubMed)

Rathinam SR, Gonzales JA, Thundikandy R, Kanakath A, Murugan SB, Vedhanayaki R, Lim LL, Suhler EB, Al-Dhibi HA, Doan T, Keenan JD, Rao MM, Ebert CD, Nguyen HH, Kim E, Porco TC, Acharya NR; FAST Research Group. Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With Uveitis: A Randomized Clinical Trial. JAMA. 2019 Sep 10;322(10):936-945. doi: 10.1001/jama.2019.12618.

Reference Type RESULT
PMID: 31503307 (View on PubMed)

Bui AD, Kong CL, Kelly NK, Rathinam SR, Gonzales JA, Thundikandy R, Kanakath A, Murugan B, Vedhanayaki R, Lim LL, Suhler EB, Al-Dhibi HA, Doan T, Acharya NR; First-Line Antimetabolites as Steroid-Sparing Treatment Research Group. Time to Uveitis Control with Methotrexate and Mycophenolate Mofetil. Ophthalmology. 2022 Jun;129(6):721-723. doi: 10.1016/j.ophtha.2022.01.020. Epub 2022 Jan 25. No abstract available.

Reference Type RESULT
PMID: 35085661 (View on PubMed)

Sundararajan M, Rathinam SR, Thundikandy R, Kanakath A, Balamurugan S, Vedhanayaki R, Miller DC, Lim LL, Suhler EB, Al-Dhibi HA, Arellanes-Garcia L, Reddy AK, Feng S, Doan T, Porco TC, Shantha JG, Acharya NR, Gonzales JA. Association Between Baseline Macular Morphologic Features on Optical Coherence Tomography and Visual Outcomes in Patients with Vogt-Koyanagi-Harada Disease. Ocul Immunol Inflamm. 2025 Feb;33(2):263-270. doi: 10.1080/09273948.2024.2391420. Epub 2024 Aug 27.

Reference Type DERIVED
PMID: 39190826 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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5U10EY021125

Identifier Type: NIH

Identifier Source: secondary_id

View Link

11-08227

Identifier Type: -

Identifier Source: org_study_id

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