To assess long-term efficacy and safety of intravitreal inserts releasing 0.2 μg/d (low dose) or 0.5 μg/d (high dose) fluocinolone acetonide (FAc) in patients with diabetic macular edema (DME).
Two ...randomized, sham injection-controlled, double-masked, multicenter clinical trials.
Subjects with persistent DME despite ≥1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393).
Subjects received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year.
Percentage of patients with improvement of ≥15 letters from baseline. Secondary outcomes included other parameters of visual function and foveal thickness.
At month 36, the percentage of patients who gained ≥15 in letter score using the last observation carried forward method was 28.7% (low dose) and 27.8% (high dose) in the FAc insert groups compared with 18.9% (P = 0.018) in the sham group, and considering only those patients still in the trial at month 36, it was 33.0% (low dose) and 31.9% (high dose) compared with 21.4% in the sham group (P = 0.030). Preplanned subgroup analysis demonstrated a doubling of benefit compared with sham injections in patients who reported duration of DME ≥3 years at baseline; the percentage who gained ≥15 in letter score at month 36 was 34.0% (low dose; P<0.001) or 28.8% (high dose; P = 0.002) compared with 13.4% (sham). An improvement ≥2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7% (low dose) and 10.1% (high dose) compared with 8.9% in the sham group. Almost all phakic patients in the FAc insert groups developed cataract, but their visual benefit after cataract surgery was similar to that in pseudophakic patients. The incidence of incisional glaucoma surgery at month 36 was 4.8% in the low-dose group and 8.1% in the high-dose insert group.
In patients with DME FAc inserts provide substantial visual benefit for up to 3 years and would provide a valuable addition to the options available for patients with DME.
To assess the efficacy and safety of intravitreal inserts releasing 0.2 μg/day (low dose) or 0.5 μg/day (high dose) fluocinolone acetonide (FA) in patients with diabetic macular edema (DME).
Two ...parallel, prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trials.
Subjects with persistent DME despite at least 1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393).
Subjects received study drug or sham injection at baseline and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year.
The primary outcome was the percentage of patients with improvement from baseline best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Trial (ETDRS) letter score of 15 or more at month 24. Secondary outcomes included other parameters of visual function and foveal thickness (FTH).
The percentage of patients with improvement from baseline ETDRS letter score of 15 or more at month 24 was 28.7 and 28.6 in the low- and high-dose insert groups, respectively, compared with 16.2 in the sham group (P = 0.002 for each). Benefit occurred for both doses compared with sham at 3 weeks and all subsequent time points. The mean improvement in BCVA letter score between baseline and month 24 was 4.4 and 5.4 in the low- and high-dose groups, respectively, compared with 1.7 in the sham group (P = 0.02 and P = 0.016). At all time points compared with sham, there was significantly more improvement in FTH. Subjects requiring cataract surgery were more frequent in the insert groups, and their visual benefit was similar to that of subjects who were pseudophakic at baseline. Glaucoma requiring incisional surgery occurred in 3.7%, 7.6%, and 0.5% of the low-dose, high-dose, and sham groups, respectively.
Both low- and high-dose FA inserts significantly improved BCVA in patients with DME over 2 years, and the risk-to-benefit ratio was superior for the low-dose insert. This is the first pharmacologic treatment that can be administered by an outpatient injection to provide substantial benefit in patients with DME for at least 2 years.
To compare aqueous levels of fluocinolone acetonide (FAc) after administration of FAc inserts or FAc implants (Retisert; Bausch & Lomb, Rochester, NY).
Comparison of pharmacokinetics from 2 ...prospective, interventional, clinical trials.
Thirty-seven patients with diabetic macular edema (DME) (Fluocinolone Acetonide in Human Aqueous FAMOUS Study, C-01-06-002) and 7 patients with uveitis (NA-00019318).
Aqueous FAc was measured after administration of FAc implants or 0.2 μg/day (low dose, ILUVIEN; Alimera Sciences Inc., Alpharetta, GA) or 0.5 μg/day (high dose) FAc inserts.
The primary end point was aqueous levels of FAc.
At 1 month after administration for subjects who received 1 treatment, mean aqueous FAc levels were 2.17 (low dose) and 3.03 ng/ml (high dose) for FAc inserts and 6.12 ng/ml for FAc implants with maximum levels of 3.83, 6.66, and 13.50 ng/ml, respectively. At 3 months, mean FAc levels were 1.76, 2.15, and 6.12 ng/ml, respectively. Between 6 and 36 months after low-dose inserts, aqueous levels of FAc were remarkably stable, ranging from 1.18 to 0.45 ng/ml. After high-dose inserts, mean FAc levels were stable between 6 and 24 months, ranging from 1.50 to 0.84 ng/ml and then decreasing to 0.35 ng/ml at 30 months and 0.15 ng/ml at 36 months. In implant-containing eyes, mean FAc levels remained >6 ng/ml through 15 months, the last time point with measurements from at least 6 eyes.
Low- and high-dose FAc inserts both provide stable long-term release of FAc with comparable peak levels in the aqueous: slightly >2 ng/ml for approximately 3 months followed by steady-state levels between 1.0 and 0.5 ng/ml through 36 months for low-dose inserts versus levels between 1.5 and 1.1 ng/ml through 24 months for high-dose inserts. Steady-state aqueous levels after FAc implants were >6 ng/ml. These results provide new insights that aid in the interpretation of efficacy trials and indicate that there is a dose effect for steroid-induced ocular hypertension. In susceptible patients, prolonged aqueous levels of FAc >1 ng/ml moderately increased the risk of glaucoma and levels >6 ng/ml posed a markedly increase risk.
To compare Iluvien intravitreal inserts that release 0.2 or 0.5 microg/day of fluocinolone acetonide (FA) in patients with diabetic macular edema (DME).
Prospective, randomized, interventional, ...multicenter clinical trial.
We included 37 patients with DME.
Subjects with persistent DME despite > or = 1 focal/grid laser therapy were randomized 1:1 to receive an intravitreal insertion of a 0.2- or a 0.5-microg/day insert.
The primary end point was aqueous levels of FA throughout the study with an important secondary outcome of the change from baseline in best-corrected visual acuity (BCVA) at month 12.
The mean aqueous level of FA peaked at 3.8 ng/ml at 1 week and 1 month after administration of a 0.5-microg/day insert and was 3.4 and 2.7 ng/ml 1 week and 1 month after administration of a 0.2-microg/day insert. For both inserts, FA levels decreased slowly thereafter and were approximately 1.5 ng/ml for each at month 12. The mean change from baseline in BCVA was 7.5, 6.9, and 5.7 letters at months 3, 6, and 12, respectively, after administration of a 0.5 microg/day-insert and was 5.1, 2.7, and 1.3 letters at months 3, 6, and 12, respectively, after administration of a 0.2-microg/day insert. There was a mild increase in mean intraocular pressure after administration of 0.5-microg/day inserts, but not after administration of 0.2-microg/day inserts.
The FA intravitreal inserts provide excellent sustained intraocular release of FA for > or = 1 year. Although the number of patients in this trial was small, the data suggest that the inserts provide reduction of edema and improvement in BCVA in patients with DME with mild effects on intraocular pressure over the span of 1 year.
Proprietary or commercial disclosure may be found after the references.
This study assessed relationships between best-corrected visual acuity (BCVA), central subfield thickness (CST), and ellipsoid zone (EZ) integrity in macular edema (ME) patients.
Post hoc analysis of ...6 clinical trials, which included verified diagnoses, protocol refractions, and reading center assessment of OCT images.
Participants (n = 1063) were diagnosed with ME from retinal vein occlusion (RVO), diabetic retinopathy (DR; diabetic macular edema, DME), or noninfectious uveitis (NIU).
For CST, 2 clinical trials for each disorder were analyzed. For EZ, 3 studies across 2 disorders were analyzed.
Primary outcomes were correlations between BCVA and CST, and between BCVA and 4 central subfield EZ grades.
For baseline BCVA and CST, Pearson correlation coefficients were: ME from RVO, –0.56 (774 eyes; 95% confidence interval CI, –0.61 to –0.51; P < 0.001); DME, –0.50 (91 eyes; 95% CI, –0.64 to –0.33; P < 0.001); and ME from NIU, –0.38 (198 eyes; 95% CI, –0.49 to –0.26; P < 0.001). Regarding change from baseline to 24 weeks for both BCVA and CST, Pearson correlation coefficients were: ME from RVO, –0.35 (95% CI, –0.43 to –0.27; P < 0.001); DME, –0.30 (95% CI, –0.48 to –0.09; P = 0.006); and ME from NIU, –0.42 (95% CI, –0.53 to –0.29; P < 0.001). Acute and chronic ME showed similar baseline and 24-week change linear correlations. With lower baseline CST, a trend of decreased baseline and 24-week change correlations was found. For central subfield EZ at baseline, mean BCVA progressively worsened with each of 4 EZ grades in 185 eyes with gradable EZ (DME, 41 eyes; NIU, 144 eyes; P ≤ 0.050 for all pairwise comparisons except between normal and questionably abnormal EZ grades). Eyes with normal baseline central subfield EZ showed greater 24-week change in BCVA than those with abnormal baseline EZ (15.00 letters vs. 8.16 letters; P = 0.0005, with baseline BCVA, CST, and age as covariates).
Despite these correlations, CST and EZ integrity, as graded herein, account for the minority of BCVA variation in patients with ME resulting from RVO, DR, and NIU.
Objective To determine if INH-A21, an intravenous immune globulin (IGIV) derived from donors with high titers of antibody to surface adhesins of Staphylococcus epidermidis and S aureus prevents ...late-onset sepsis (LOS) in very low birth weight (VLBW) infants. Study design In this double-blind, placebo-controlled study, infants with birth weights 500 to 1250 g were randomized to receive up to four doses of INH-A21 (Veronate®) or placebo. The primary objective was to determine the safety and efficacy of INH-A21 versus placebo for prevention of S aureus LOS in VLBW infants. Results A total of 1983 infants from 95 neonatal intensive care units were randomized, and received at least one dose of study drug. S aureus LOS developed in 50 of 989 (5%) and 60 of 994 (6%) infants who received placebo or INH-A21, respectively ( P = .34). No differences were found in the frequencies of LOS caused by coagulase-negative staphylococci (CoNS), Candida spp, or overall mortality. No adverse events were statistically significantly associated with INH-A21 infusions compared with placebo. Conclusion INH-A21 failed to reduce the incidence of staphylococcal LOS or candidemia in premature infants.
To present the safety and efficacy of intravitreal implants releasing 0.2 μg/day fluocinolone acetonide (FAc) in patients with chronic versus nonchronic diabetic macular edema (DME). To assess ocular ...characteristics, anatomic changes, and re-treatment and ancillary therapies that may explain the differential treatment effect seen with intravitreal implants releasing FAc 0.2 μg/day in patients with chronic and nonchronic DME. An overall benefit-to-risk assessment for the FAc 0.2-μg/day and FAc 0.5-μg/day doses has been reported previously.
Preplanned subgroup analysis of chronic (duration of diagnosis, ≥3 years) and nonchronic (duration of diagnosis, <3 years) DME in patients from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials.
Patients with persistent DME despite 1 or more macular laser treatment were randomized 1:2:2 to sham injection (n = 185), FAc 0.2 μg/day (n = 375), or FAc 0.5 μg/day (n = 393).
Patients received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on re-treatment criteria, additional masked study drug could be given after 1 year.
Percentage of patients with improvement of 15 letters or more from baseline. Secondary outcomes included other parameters of visual function and foveal thickness.
At month 36, the difference between FAc 0.2 μg/day and sham control in the percentage of patients who gained 15 letters or more was significantly greater in chronic DME patients (FAc 0.2 μg/day, 34.0% vs. sham, 13.4%; P<0.001), compared with patients with nonchronic DME (FAc 0.2 μg/day, 22.3% vs. sham, 27.8%; P = 0.275). The greater response in patients with chronic DME was not associated with baseline ocular characteristics, changes in anatomic features, or differences in re-treatment or ancillary therapies. The ocular adverse event profile for FAc 0.2 μg/day was similar regardless of DME duration.
This is the first published analysis correlating duration of diagnosis of DME with treatment effect. In patients with chronic DME, FAc 0.2 μg/day provides substantial visual benefit for up to 3 years and would provide an option for patients who do not respond to other therapy.
Background
This post hoc analysis compared the efficacy and safety of suprachoroidally administered triamcinolone acetonide (CLS‐TA) to other commonly available treatments for non‐infectious uveitis.
...Methods
Results from the PEACHTREE study were compared between subjects randomised to CLS‐TA not requiring rescue therapy and those subjects randomised to control, who subsequently required rescue therapy. Endpoints included best corrected visual acuity (BCVA), central subfield thickness (CST), treatment emergent adverse events and intraocular pressure (IOP) related safety findings.
Results
In this analysis, there were 83 unrescued CLS‐TA subjects and 46 rescued control subjects. At Week 24, 51.9% of the unrescued CLS‐TA subjects gained ≥15 letters in BCVA, compared to 37.0% of the rescued control subjects (p = 0.115). Unrescued CLS‐TA subjects showed a mean gain of 15.7 versus 10.9 letters in rescued control subjects (p = 0.080). A significantly greater mean reduction in CST was observed for unrescued CLS‐TA subjects versus rescued control subjects (174.0 and 148.5 μm; p = 0.040). Of unrescued CLS‐TA subjects, 4.9% experienced IOP elevations ≥30 mm Hg at any visit versus 10.9% of rescued control subjects. Further, use of IOP‐lowering medications appeared lower in unrescued CLS‐TA subjects versus rescued control subjects (7.2% vs. 13.0%). There were no IOP‐lowering surgical interventions in either group.
Conclusion
CLS‐TA subjects experienced significantly greater reduction in CST and tended towards greater improvement in BCVA, compared with rescued control subjects. Suprachoroidally administered CLS‐TA showed a lower incidence of IOP‐related safety findings.
To present the safety and efficacy of intravitreal implants releasing 0.2 μg/day fluocinolone acetonide (FAc) in patients with chronic versus nonchronic diabetic macular edema (DME). To assess ocular ...characteristics, anatomic changes, and re-treatment and ancillary therapies that may explain the differential treatment effect seen with intravitreal implants releasing FAc 0.2 μg/day in patients with chronic and nonchronic DME. An overall benefit-to-risk assessment for the FAc 0.2-μg/day and FAc 0.5-μg/day doses has been reported previously.
Preplanned subgroup analysis of chronic (duration of diagnosis, ≥3 years) and nonchronic (duration of diagnosis, <3 years) DME in patients from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials.
Patients with persistent DME despite 1 or more macular laser treatment were randomized 1:2:2 to sham injection (n = 185), FAc 0.2 μg/day (n = 375), or FAc 0.5 μg/day (n = 393).
Patients received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on re-treatment criteria, additional masked study drug could be given after 1 year.
Percentage of patients with improvement of 15 letters or more from baseline. Secondary outcomes included other parameters of visual function and foveal thickness.
At month 36, the difference between FAc 0.2 μg/day and sham control in the percentage of patients who gained 15 letters or more was significantly greater in chronic DME patients (FAc 0.2 μg/day, 34.0% vs. sham, 13.4%; P<0.001), compared with patients with nonchronic DME (FAc 0.2 μg/day, 22.3% vs. sham, 27.8%; P = 0.275). The greater response in patients with chronic DME was not associated with baseline ocular characteristics, changes in anatomic features, or differences in re-treatment or ancillary therapies. The ocular adverse event profile for FAc 0.2 μg/day was similar regardless of DME duration.
This is the first published analysis correlating duration of diagnosis of DME with treatment effect. In patients with chronic DME, FAc 0.2 μg/day provides substantial visual benefit for up to 3 years and would provide an option for patients who do not respond to other therapy.
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