A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema.

OBJECTIVE: To evaluate the safety and tolerability of a single subconjunctival (SCJ) or intravitreal (IVT) injection of an ophthalmic sirolimus formulation in eyes with diabetic macular edema (DME). DESIGN: Randomized, open-label, dose-escalating phase I study. PARTICIPANTS: Fifty eyes among 50 patients with DME, retinal thickness ≥ 300 microns and best-corrected visual acuity (BCVA) 20/40 to 20/200. METHODS: A single dose of sirolimus administered SCJ (220, 440, 880, 1320, or 1760 µg) or IVT (44, 110, 176, 264, or 352 µg) on day 0; observation through day 90. MAIN OUTCOME MEASURES: Primary end points were the frequency and severity of ocular and systemic adverse events. Secondary end points were changes in BCVA and retinal thickness. RESULTS: No dose-limiting toxicities were observed and ocular adverse events were mostly mild and transient. Conjunctival hyperemia, hemorrhage, and edema were common after the SCJ injection procedure and conjunctival hemorrhage was common after the IVT injection procedure. Three patients experienced ocular adverse events considered possibly related to study drug: Conjunctival edema and reduced visual acuity were reported in 1 SCJ patient each and iritis was reported in 1 IVT patient. No serious ocular adverse events were reported. No nonocular adverse events were considered related to study drug. Systemic exposure to sirolimus was low, with blood concentrations below levels necessary for systemic immunosuppression. For the SCJ group (n = 25), a median increase in BCVA started at day 7 (5.0 letters) and was 3.0, 4.0, and 4.0 letters at days 14, 45 and 90, respectively. At day 45, median decrease in retinal thickness was -23.7 µm. For the IVT group (n = 25), the median increase in BCVA was 2.0 letters at day 7; at days 14, 45, and 90, the median increase was maintained (4.0 letters); the median decrease in retinal thickness was -52.0 µm at day 45. CONCLUSIONS: Locally administered sirolimus was well-tolerated with minimal systemic exposure at all doses tested in this small phase I population. These findings support advancing the present sirolimus formulation into phase II studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effect of Human Central Nervous System Stem Cell Subretinal Transplantation on Progression of Geographic Atrophy Secondary to Nonneovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the effect of subretinally transplanted human central nervous system stem cells (HuCNS-SC) on the progression of geographic atrophy (GA) in patients with nonneovascular age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, phase 1 open-label clinical trial. PARTICIPANTS: Fifteen patients with bilateral GA solely the result of AMD. METHODS: The eye with the worst best-corrected visual acuity from each patient was selected for treatment and was considered the study eye; fellow eyes served as controls. A total of 0.25 × 106 or 1.0 × 106 HuCNS-SCs were infused directly into the subretinal space, superotemporal to the fovea near the junctional zone, outside the area of GA. All patients underwent spectral-domain OCT and fundus autofluorescence imaging using the Spectralis HRA+OCT (Heidelberg Engineering, Inc., Heidelberg, Germany). Total GA area in both eyes was measured at baseline and month 12 by certified reading center graders using the Spectralis Region Finder software. Sectoral (clock hour) per directional radial GA progression rates with respect to the foveal center in both eyes were calculated using the polar transformation method in Image J software (National Institutes of Health, Bethesda, MD). To facilitate comparative analysis across the cohort, all eyes were transformed to a right-eye orientation. MAIN OUTCOME MEASURES: Total GA area and sectoral per directional GA progression rates were compared in both study and control eyes. RESULTS: No statistically significant difference was found in mean change in total GA area at month 12 between study and fellow eyes (1.07 ± 0.84 mm2 vs. 2.08 ± 1.97 mm2; P = 0.08). However, the month 12 sectoral per directional radial GA growth rate for the superotemporal region (i.e., the location of HuCNS-SC transplantation) showed a significantly slower progression rate in study eyes than in fellow eyes (0.29 ± 0.58 mm vs. 1.08 ± 0.65 mm; P = 0.007). The progression rate in the superotemporal quadrant of the study eye was significantly slower than in the other 3 quadrants combined (P = 0.04). CONCLUSIONS: In this small pilot study, HuCNS-SC transplantation seems to be associated with slower expansion of the GA lesion in the transplanted quadrant. Larger confirmatory studies are required. Sectoral or directional analysis of growth rates of GA may be a useful approach for assessing the efficacy of locally delivered therapies.

Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial.

OBJECTIVE: To compare the treatment effect and safety of photodynamic therapy with verteporfin using a standard (SF) or reduced (RF) light fluence rate with that of placebo therapy in patients with subfoveal minimally classic choroidal neovascularization (CNV) with age-related macular degeneration. DESIGN: Phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial. SETTING: Nineteen ophthalmology practices in North America and Europe. PARTICIPANTS: Patients with initial best-corrected visual acuity of at least 20/250 and a lesion size of no greater than 6 Macular Photocoagulation Study (MPS) disc areas. METHODS: We randomly assigned 117 patients (1:1:1) to verteporfin infusion (6 mg/m(2)) and light application with an RF rate (300 mW/cm(2)) for 83 seconds (light dose of 25 J/cm(2)) or an SF rate (600 mW/cm(2)) for 83 seconds (light dose of 50 J/cm(2)) or to placebo infusion with RF or SF. Treatment was repeated every 3 months if the treating physician noted fluorescein leakage from CNV on angiography. Patients in whom a predominantly classic lesion developed could receive open-label standard verteporfin treatment. Best-corrected visual acuity was measured every 3 months, and angiographic changes were assessed by the Photograph Reading Center through the 3-month examination unless an ocular adverse event or conversion to a predominantly classic lesion was identified by an investigator. Safety was assessed throughout the study. All outcomes were on an intent-to-treat basis. RESULTS: One hundred three (88%) of 117 patients completed the 24-month examination. Twelve (30%) of 40 patients assigned to placebo received open-label standard verteporfin treatment after confirmation of presence of predominantly classic CNV. At month 12, a loss of at least 3 lines of visual acuity occurred in 5 (14%) of 36 eyes assigned to RF and 10 (28%) of 36 eyes assigned to SF, compared with 18 (47%) of 38 eyes assigned to placebo (RF, P = .002; SF, P = .08; RF + SF, P = .004). At month 24, this loss occurred in 9 (26%) of 34 eyes assigned to RF and 17 (53%) of 32 assigned to SF, compared with 23 (62%) of 37 eyes assigned to placebo (RF, P = .003; SF, P = .45; RF + SF, P = .03). Progression to predominantly classic CNV by 24 months was more common in the placebo group (11 [28%] of 39 patients compared with 2 [5%] of 38 in the RF group [P = .007] and 1 [3%] of 37 in the SF group [P = .002]). No unexpected ocular or systemic adverse events were identified. Treatment-related, usually transient visual disturbances were 13% with SF, 10% with placebo, and 5% with RF. CONCLUSIONS: Verteporfin therapy safely reduced the risks of losing at least 15 letters (> or =3 lines) of visual acuity and progression to predominantly classic CNV for at least 2 years in individuals with subfoveal minimally classic lesions due to age-related macular degeneration measuring 6 MPS disc areas or less. Based on the overall evidence available on verteporfin therapy for these lesions, the VIM Study Group would consider recommending verteporfin therapy for relatively small minimally classic lesions similar to those enrolled in the VIM Trial.

A randomized, double-masked clinical trial of Optisol-GS vs Chen Medium for human corneal storage.

OBJECTIVE: To determine whether the clinical outcome of corneal transplantation performed with tissue stored in Chen Medium (CM; Chen Laboratories, Phoenix, Md) is superior to that of Optisol-GS (Chiron Ophthalmics, Irvine, Calif). DESIGN: Randomized, double-masked trial. PARTICIPANTS AND SETTING: Ninety patients undergoing corneal transplantation at a tertiary center. INTERVENTION: Donor cornea pairs were stored, one in CM and the other in Optisol-GS, transplanted, and followed up for 3 months. MAIN OUTCOME MEASURES: Endothelial cell loss (ECL) at 3 months. Secondary outcomes were thickness and epithelialization at days 1, 7, 30, and 90, as well as primary and secondary graft failure. RESULTS: Mean percentages of ECL 3 months after surgery were similar for corneas stored in Optisol-GS and corneas stored in CM. The 95% confidence interval (CI) for the difference was -3.4% to 13.2%. Covariate-adjusted 95% CI was -6.1% to 9.1%. Pachymetry values were similar in the 2 treatment groups. Eighty-eight percent of the corneas stored in each medium achieved epithelialization of 75% to 100% of the surface area within 1 week after transplantation. No primary donor failures occurred in either group. One graft that was preserved in CM failed during the study period. CONCLUSION: The clinical outcomes of corneal transplantation with tissue that was preserved in CM were similar to those of grafts preserved in Optisol-GS.

Outcomes of repeat penetrating keratoplasty and risk factors for graft failure.

PURPOSE: To compare repeat penetrating keratoplasty (PKP) with primary PKP with respect to patient characteristics, survival rates, and risk factors for graft failure. METHODS: Retrospective, consecutive, noncomparative case series of 116 patients who underwent repeat PKP and who were identified from a cohort of 696 PKPs performed by one surgeon over a 7.5-year period. RESULTS: Compared with patients who underwent primary PKP, regraft patients were 5 years older, had a higher rate of peripheral anterior synechiae (PAS), were more likely to require intraocular pressure (IOP)-lowering medications prior to surgery, were more likely to develop postoperative corneal neovascularization, were less likely to be phakic, and were more likely to undergo PKP in conjunction with a lens procedure. There was no difference between the two groups with respect to the distribution of original diagnoses leading to PKP and the rate of graft rejection. Two- and 5-year survival rates for repeat PKP were 63.9% and 45.6%, respectively. In a multivariate analysis, the original diagnosis leading to corneal transplantation, the presence of preoperative PAS, intraoperative anterior vitrectomy, and postoperative corneal neovascularization were identified as risk factors for graft failure in patients undergoing a regraft. CONCLUSIONS: Patients undergoing PKP for the first and second time share common risk factors for graft failure, namely, the original diagnosis leading to corneal transplantation, the presence of preoperative PAS, and the occurrence of postoperative corneal neovascularization. The difference in graft survival rates between the two groups can be partially explained on the basis of higher rates of the latter two risk factors among regrafts.

The role of epithelial defects in intralamellar inflammation after laser in situ keratomileusis.

BACKGROUND: A single factor responsible for diffuse lamellar keratitis (DLK) after laser in situ keratomileusis (LASIK) has not yet been identified. Various theories have been proposed to explain what may trigger this condition. We evaluated the role of epithelial defects in interface inflammation and assessed the outcome of eyes with DLK with and without epithelial defects. METHODS: We reviewed the records of all patients with DLK after LASIK performed at the Toronto Gimbel Eye Centre between September 1999 and May 2000. Patients with other epithelial problems, such as punctate epithelial erosions, were excluded. Patients with an epithelial defect and interface keratitis (group 1) were treated with a bandage contact lens and topical steroid therapy; those with interface keratitis alone (group 2) were treated with topical steroid therapy. Variables examined included the onset and duration of DLK, uncorrected visual acuity, best corrected visual acuity, refractive outcome and retreatment rate. RESULTS: A total of 1,436 LASIK procedures were performed during the study period. Thirteen patients (20 eyes) had DLK after LASIK, in all cases of the sporadic type (i.e., nonepidemic). Of the 20 eyes, 8 had an epithelial disturbance. All the patients were followed for at least 3 months. Three eyes (37.5%) in group 1 had uncorrected visual acuity before retreatment of less than 20/25, compared with 2 eyes (16.7%) in group 2. The mean postoperative spherical equivalent was significantly higher in group 1 than in group 2 (-0.60 vs. -0.02 dioptres) (p = 0.01). The retreatment rate was 37.5% (3/8) in group 1 and 16.7% (3/12) in group 2, a nonsignificant difference. After retreatment the uncorrected visual acuity was 20/20 or better in all cases. There were no cases of recurrence of DLK after retreatment. INTERPRETATION: Eyes with interface keratitis and an epithelial defect have a larger deviation from emmetropia before retreatment than eyes with interface keratitis alone. Patients with epithelial defects intraoperatively or who are at risk for such defects postoperatively must be monitored carefully, as they may be at increased risk for DLK.

Correlation between corneal sensitivity, subjective dry eye symptoms and corneal staining in Sjögren's syndrome.

BACKGROUND: Previous studies have shown a poor correlation between dry eye symptoms and objective clinical signs in patients with Sjögren's syndrome. We examined the hypothesis that reduced corneal sensitivity is associated with increased ocular surface disease and reduced symptoms in patients with Sjögren's syndrome. METHODS: Eighteen subjects with a diagnosis of Sjögren's syndrome attending a Sjögren's clinic participated in the study. All participants completed the Ocular Surface Disease Index (OSDI) and the Symptom Severity of Discomfort (SSD) scale and answered a question regarding overall severity of dry eye symptoms. The subjects underwent measurement of best-corrected Snellen visual acuity, corneal sensitivity testing with the Cochet-Bonnet esthesiometer, fluorescein and lissamine green staining of the cornea, Schirmer's test I and determination of the tear film break-up time. The results were analysed using Pearson correlational analysis. RESULTS: Both fluorescein and lissamine green staining of the cornea correlated negatively with central corneal sensation (r = -0.3542, p = 0.034, and r = -0.3748, p = 0.029 respectively), indicating that corneal sensation was reduced with increased ocular surface disease. The overall symptom severity correlated negatively with lissamine green staining of the cornea (r = -0.4310, p = 0.011), suggesting reduced symptoms with increased corneal disease. INTERPRETATION: Reduced corneal sensation correlated with increased ocular surface disease. Ocular surface disease similarly demonstrated a reciprocal relation with patients' dry eye symptoms. Consequently, we found that patients with Sjogren's syndrome with advanced corneal staining tended to have fewer dry eye symptoms than patients with less corneal staining.

Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: primary 6-month results of the SAVE Study.

BACKGROUND: The purpose of this study is to evaluate the ocular tolerability and efficacy of sirolimus administered as subconjunctival or intravitreal injections in patients with non-infectious uveitis. Sirolimus as a Therapeutic Approach for Uveitis (SAVE) is a prospective, randomized, open-label, interventional study. Thirty patients were enrolled and randomized in 1:1 ratio to receive either intravitreal injections of 352 µg sirolimus or subconjunctival injections of 1,320 µg at days 0, 60, and 120, with primary endpoint at month 6. RESULTS: At month 6, all subjects with active uveitis at baseline showed reduction in vitreous haze of one or more steps. Forty percent of subjects showed reduction of two steps or more of vitreous haze (four in each group), and 60% showed a reduction of one-step vitreous haze (seven in group 1 and five in group 2). Changes in the inflammatory indices were statistically significant (p < 0.05) in both study groups. Thirty percent of patients gained one or more lines of visual acuity, 20% lost one or more lines, and 50% maintained the same visual acuity. There were no statistically significant differences between the two study groups at month 6. No serious adverse events were found to be related to the study drug. CONCLUSION: Local administration of sirolimus, either intravitreally or subconjunctivally, appears to be safe and tolerable. No drug-related systemic adverse events or serious adverse events were noted. Sirolimus delivered as either an intravitreal or subconjunctival injection has demonstrated bioactivity as an immunomodulatory and corticosteroid-sparing agent in reducing vitreous haze and cells, improving visual acuity, and in decreasing the need for systemic corticosteroids.

Tolerability and pharmacokinetics of intravitreal sirolimus.

PURPOSE: To evaluate the pharmacokinetics (PK) and tolerability of a proprietary sirolimus depot-forming ocular formulation in rabbits and humans after a single intravitreal (i.v.t.) injection. METHODS: New Zealand White (NZW) rabbits were intravitreally injected in both eyes with an injectable formulation in 5 (3 PK and 2 tolerability) studies. The rabbits received up to approximately 220 µg sirolimus per eye. At the desired timing post-injection, the animals were euthanized; both eyes were enucleated, frozen, and dissected to separate sclera, retina/choroid, and vitreous humor (VH). Whole blood (WB) samples were obtained at each time point before euthanasia. In clinical trials, patients received an i.v.t. injection of approximately 352 µg sirolimus. Sirolimus concentrations in ocular tissues and WB samples were measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS). In both single- and repeat-dose tolerability studies, systemic and ocular adverse effects were evaluated. RESULTS: After i.v.t. administration, sirolimus formed a depot in the VH. During dissolution, concentrations in VH were dose related and exhibited continuous release from the depot. This was characterized by a gradient of sirolimus concentration in the order of VH > retina/choroid > sclera > WB, and the concentrations were maintained for approximately 2 months after the i.v.t. injection. After repeat dosing (132 µg), no drug accumulation was seen in the ocular tissue or systemically. In clinical studies, the highest blood levels were <2 ng/mL at day 2, and half-time (t(1/2)) was 8-9 days. There was no accumulation at day 30 after the i.v.t. injection (up to 352 µg). Safety studies conducted on rabbits indicated good local tolerability. Sirolimus-related effects were limited to minor incipient cataract findings and mild lenticular changes. In the clinical studies where sirolimus was intravitreally administered up to 352 µg, injections were well tolerated. CONCLUSIONS: Sustained i.v.t. delivery was achieved in a dose-dependent fashion after the i.v.t. injection of a proprietary sirolimus depot-forming ocular formulation. Across the tolerability and safety studies, no significant findings were observed for systemic and ocular tolerability. The human WB levels were well below the daily trough systemic blood level range required for systemic immunosuppression. An i.v.t. injection of sirolimus has a PK and safety profile that is favorable for treating inflammatory conditions of the eye, such as non-infectious uveitis, and warrants further investigation in humans.