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Quan Dong Nguyen, Mohamed Ibrahim, Anthony Watters, Millena Bittencourt, Jithin Yohannan, Yasir J. Sepah, Joel Naor, Naveed K. Shams, James P. Dunn, Diana V. Do; Primary Endpoint Results Of The SAVE Study - Sirolimus As Therapeutic Approach To UVEItis: A Randomized Study To Assess The Safety And Bioactivity Of Intravitreal And Subconjunctival Injections Of Sirolimus In Patients With Non-infectious Uveitis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2251.
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To evaluate the safety and bioactivity of sirolimus as an immunomodulatory therapeutic (IMT) agent, delivered subconjunctivally (SCJ) or intravitreally (IVT), in patients with non-infectious posterior, intermediate, or panuveitis.
30 patients were stratified at baseline (BL) into 3 categories/groups: (1) active disease receiving no treatment; (2) active disease receiving prednisone ≥10 mg/day and/or at least 1 other IMT; (3) inactive disease receiving prednisone <10 mg/day and/or at least 1 other IMT. Patients in each category were randomized into SCJ or IVT arm (1:1). Study eyes received SCJ (1320 µg) or IVT (352 µg) injections at days 0, 60, and 120, with primary endpoint at day-180. Study subjects may be followed and treated until M12. Beyond safety, study parameters include change in visual acuity (VA), vitreous cells/haze, and reduction in dosage of systemic corticosteroid (CS) compared to BL. Visual Function Questionnaire (VFQ) was also performed at BL, M6, and M12.
28 subjects completed the 6-month primary endpoints; 2 subjects discontinued. Both SCJ and IVT sirolimus injections were well tolerated. None of the adverse events (AE) were deemed to be related to sirolimus. At M6, VA improved in 39% (SCJ=43%; IVT=36%) and stabilized in 39% of all patients. Vitreous haze improved in 82% of patients (SCJ=79%; IVT=86%). 20 patients , were on systemic CS therapy at BL; all had their doses of CS reduced at M6. 7/20 were, in addition to CS, on systemic IMT, which was discontinued prior to screening. 1/7 patients required re-initiation of IMT, albeit for systemic disease reactivation. In group 2, CS dose was successfully reduced to <10mg/day in 85% of subjects, (median dose: BL=20mg/day; M6=8mg/day). In group 3, median CS dose was reduced from 9 (BL) to 3mg/day (M6). VFQ scores increased for both SCJ and IVT groups at M6 compared to BL.
Locally administered (subconjunctival or intravitreal) sirolimus appears to be safe in patients with non-infectious uveitis. Sirolimus has demonstrated bioactivity by reducing vitreous haze and cells, improving VA, and in decreasing need for systemic CS. Additional clinical trials are indicated to confirm the role of locally-delivered sirolimus and to determine its appropriate dosage and frequency of administration.
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