Methotrexate and Mycophenolate Mofetil for UVEITIS

Uveitis Clinical Trial

— FAST  

Official title:

First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01829295
• Other study ID #: 11-08227
• Secondary ID: 5U10EY021125
• Status: Completed
• Phase: Phase 3
• Start date: August 2013
• Est. completion date: August 9, 2018

Study information

• Verified date: March 2024
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 216
• Est. completion date: August 9, 2018
• Est. primary completion date: February 21, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Uveitis

Intervention

Drug:
• 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.
• 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)
• 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.

Locations

Country	Name	City	State
Australia	Royal Victorian Eye and Ear Hospital	Melbourne	Victoria
India	Aravind Eye Hospital	Coimbatore	Tamil Nadu
India	Aravind Eye Hospital	Madurai	Tamil Nadu
India	Aravind Eye Hospital	Pondicherry	Tamil Nadu
Mexico	Asociacion Para Evita La Ceguera en Mexico	Mexico City	Mexico, D.F.
Saudi Arabia	King Khaled Eye Specialist Hospital	Riyadh
United States	Northwestern University	Chicago	Illinois
United States	Oregon Health and Science University - Casey Eye Institute	Portland	Oregon
United States	Francis I Proctor Foundation	San Francisco	California

Sponsors (8)

Lead Sponsor	Collaborator
University of California, San Francisco	Aravind Eye Hospitals, India, Asociación para Evitar la Ceguera en México, King Khaled Eye Specialist Hospital, National Eye Institute (NEI), Northwestern University, Oregon Health and Science University, Royal Victoria Eye and Ear Hospital

Countries where clinical trial is conducted

United States,  Australia,  India,  Mexico,  Saudi Arabia, 

References & Publications (26)

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. — View Citation

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. — View Citation

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 w — View Citation

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 i — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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 Ant — View Citation

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. — View Citation

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 Wi — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 Firs — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Achieving Treatment Success at 6 Months (Phase I, 0-6 Months)	Controlled ocular inflammation (= 0.5+ anterior chamber cells, = 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and = 2 drops/day of topical 1% prednisolone acetate.	6 Months
Secondary	Number of Participants Achieving Treatment Success at 12 Months on Same Medication (Phase I, 6-12 Months)	Controlled ocular inflammation (= 0.5+ anterior chamber cells, = 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and = 2 drops/day of topical 1% prednisolone acetate in patients who were a treatment success at the primary outcome of 6 months.	12 Months
Secondary	Number of Participants Achieving Treatment Success After Switching to Other Medication (Phase II, 0-6 Months)	Controlled ocular inflammation (= 0.5+ anterior chamber cells, = 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and = 2 drops/day of topical 1% prednisolone acetate for patients who crossed over to other medication following treatment failure at 6 months (or earlier).	6 Months