Objective: Uveitis refers to intraocular inflammatory diseases that are an important cause of visual loss. Standard systemic immunosuppressive medications for uveitis can cause significant adverse effects and many patients continue to experience disease flare-ups. Sirolimus suppresses cytokine-driven T-cell proliferation and thus, inhibits the production, signaling and activity of many growth factors relevant to uveitis. Subconjunctival sirolimus administration could reduce or eliminate the need for topical and/or systemic immunosuppressive drugs that could result in reduced morbidity. This protocol will investigate subconjunctival sirolimus as a possible treatment for active anterior uveitis. Study Population: Five participants with active anterior uveitis will be initially accrued in this study. Participants must require treatment for their uveitis with systemic and/or topical anti-inflammatory medications at high frequency intervals greater than or equal to three times daily (T.I.D.) or local steroid treatment (periocular steroid injections) is contraindicated because of significant intraocular pressure (IOP) elevation with local steroid treatments in the past (i.e., steroid responder), have at least a grade of 1+ for anterior chamber cells and have visual acuity of at least 20/400 in the study eye. Up to seven participants may be enrolled, as two participants may be replaced if they require the use of additional medications for the treatment of uveitis (other than topical steroids) in their active non-study eye prior to their Week 4 study visit. Design: This is a Phase I, non-randomized, prospective and uncontrolled single-center study to evaluate subconjunctival sirolimus as a treatment for active anterior uveitis. All participants will receive a single 30 L (1,320 g) subconjunctival sirolimus injection in the study eye at baseline and will be followed for 16 weeks post-injection. Outcome Measures: The primary outcome is the number of participants who experience at least a 2-step reduction in inflammation1 within four weeks post-injection. Secondary outcomes include changes in visual acuity and anterior chamber cells,1 the number of participants who experience a disease flare1 within the 16-week study duration and, of the participants who experience a disease flare, the number of days to disease flare from baseline. Secondary outcomes also include the presence or extent of cystoid macular edema, the amount of retino-vascular leakage and changes in retinal thickening. Safety outcomes include the number and severity of systemic and ocular toxicities, adverse events and infections, the proportion of participants who experience vision loss of 15 ETDRS letters and the number of participants who experience a substantial rise in elevated IOP.
|Sen, H Nida; Larson, Theresa A; Meleth, Annal D et al. (2012) Subconjunctival sirolimus for the treatment of chronic active anterior uveitis: results of a pilot trial. Am J Ophthalmol 153:1038-42|
|Larson, Theresa; Nussenblatt, Robert B; Sen, H Nida (2011) Emerging drugs for uveitis. Expert Opin Emerg Drugs 16:309-22|