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document
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 .
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Intervention_Pharmacological
sirolimus
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Intervention_Pharmacological
single subconjunctival ( SCJ )
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Intervention_Pharmacological
intravitreal ( IVT ) injection
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Intervention_Pharmacological
sirolimus
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Outcome_Other
safety and tolerability
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Outcome_Adverse-effects
Conjunctival hyperemia , hemorrhage , and edema
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Outcome_Physical
conjunctival hemorrhage
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Outcome_Adverse-effects
ocular adverse events
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Outcome_Adverse-effects
Conjunctival edema
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Outcome_Adverse-effects
reduced visual acuity
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Outcome_Adverse-effects
serious ocular adverse events
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Outcome_Adverse-effects
nonocular adverse events
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Participant_Condition
diabetic macular edema