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.
Iluvien
™
(fluocinolone acetonide intravitreal insert, Alimera Sciences, Inc.), a novel injectable intravitreal insert, is being studied to deliver a very low dose of a corticosteroid to the retina ...for up to 3 years as a treatment for diabetic macular edema. Using a proprietary 25-gauge injector system, an ophthalmologist injects the Iluvien insert, which uses the Medidur
™
(Alimera Sciences, Inc.) technology, into the vitreous through a minimally invasive procedure in an out-patient setting. The placement of the device in the inferior vitreous has the potential to maximize drug at the retina while reducing exposure of the anterior chamber. Phase III studies are underway to test the safety and efficacy of Iluvien. This article offers a specific review of the Iluvien technology rather than an overview of the various intravitreal methods of treating posterior eye disease.
The purpose of this study was to evaluate the systemic and ocular pharmacokinetics (PK) of fluocinolone acetonide (FAc) following administration of Iluvien(®) intravitreal implants.
The FAc ...intravitreal implant was administered to rabbits in 3 doses (0.2, 0.5, and 1.0 μg/day). The concentration of FAc was measured by a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method in plasma and ocular tissues at various time points through month 24.
Following administration of the 0.2 μg/day implant, FAc levels peaked in most tissues at day 2 or 8, reached approximate steady state levels by month 3 and very gradually decreased over the duration of the study. The FAc level in the aqueous humor was not measurable at most time points in the rabbit. FAc was still present in most ocular tissues at 2 years. The 0.5 and 1.0 μg/day dose groups followed the same pattern through month 9. The elimination half lives in the tissues for which it was measurable were greater than 83 days. Exposure to FAc was highest in the choroid/retinal pigment epithelium for all doses, followed by lens and retina.
The results of this study demonstrate sustained delivery of FAc from the Iluvien intravitreal implant in the ocular tissue of rabbits. Retina and lens FAc levels with the Iluvien implant were approximately 1/10 those reported with the Retisert(®) implant. FAc levels in the aqueous were not measureable with Iluvien where they were measured for 12 months with Retisert.
To assess whether iris color and eyelash changes occur with the use of unoprostone for 2 years.
The 2 clinical trials described herein were prospective, randomized, double-masked, active-controlled, ...parallel group, multicenter studies.
A total of 1131 patients with primary open-angle glaucoma or ocular hypertension participated in 2 clinical trials and received either unoprostone isopropyl 0.15% (659), timolol maleate 0.5% (331), or betaxolol hydrochloride 0.5% (141), 1 drop per eye twice daily for up to 24 months.
Color photographs (1:1 magnification) were taken of the iris and eyelid of each patient at baseline and at regular intervals thereafter through month 24 using a standardized camera system. Photography included 7 views of each eye plus a calibration photograph and a patient identification photograph, for a total of 16 photographs per patient per visit. Two independent (masked) readers subjectively compared baseline iris colors to subsequent visits. Side view photographs of the upper and lower eyelashes were used for the eyelash length analysis, with each having sufficient depth of field and a sufficient number of eyelashes in focus. Similarly, frontal eyelash views were used for the eyelash density analysis.
Changes from baseline in iris color and eyelash length and density within and between treatment groups.
Seven cases of iris color change (1.06%) were confirmed in patients treated with unoprostone for up to 24 months; no confirmed cases were reported in the timolol or betaxolol groups. In the unoprostone group, cases of iris color change were confirmed at months 12 (1 case), 18 (2 cases), and 24 (4 cases). No clinically relevant differences were observed among treatment groups for changes from baseline in eyelash length or density.
Although iris hyperpigmentation and abnormal eyelash changes may occur after treatment with unoprostone, the incidence of these events appears to be low in the 2-year clinical study.
Iluvien Delta TM (fluocinolone acetonide intravitreal insert, Alimera Sciences, Inc.), a novel injectable intravitreal insert, is being studied to deliver a very low dose of a corticosteroid to the ...retina for up to 3 years as a treatment for diabetic macular edema. Using a proprietary 25-gauge injector system, an ophthalmologist injects the Iluvien insert, which uses the Medidur Delta TM (Alimera Sciences, Inc.) technology, into the vitreous through a minimally invasive procedure in an out-patient setting. The placement of the device in the inferior vitreous has the potential to maximize drug at the retina while reducing exposure of the anterior chamber. Phase III studies are underway to test the safety and efficacy of Iluvien. This article offers a specific review of the Iluvien technology rather than an overview of the various intravitreal methods of treating posterior eye disease.
Over the past 200 years of written records, the Hawaiian Islands have experienced tens of tsunamis generated by earthquakes in the subduction zones of the Pacific ‘Ring of Fire’ (for example, ...Alaska–Aleutian, Kuril–Kamchatka, Chile and Japan). Mapping and dating anomalous beds of sand and silt deposited by tsunamis in low‐lying areas along Pacific coasts, even those distant from subduction zones, is critical for assessing tsunami hazard throughout the Pacific basin. This study searched for evidence of tsunami inundation using stratigraphic and sedimentological analyses of potential tsunami deposits beneath present and former Hawaiian wetlands, coastal lagoons, and river floodplains. Coastal wetland sites on the islands of Hawai΄i, Maui, O΄ahu and Kaua΄i were selected based on historical tsunami runup, numerical inundation modelling, proximity to sandy source sediments, degree of historical wetland disturbance, and breadth of prior geological and archaeological investigations. Sand beds containing marine calcareous sediment within peaty and/or muddy wetland deposits on the north and north‐eastern shores of Kaua΄i, O΄ahu and Hawai΄i were interpreted as tsunami deposits. At some sites, deposits of the 1946 and 1957 Aleutian tsunamis are analogues for deeper, older probable tsunami deposits. Radiocarbon‐based age models date sand beds from three sites to ca 700 to 500 cal yr bp, which overlaps ages for tsunami deposits in the eastern Aleutian Islands that record a local subduction zone earthquake. The overlapping modelled ages for tsunami deposits at the study sites support a plausible correlation with an eastern Aleutian earthquake source for a large prehistoric tsunami in the Hawaiian Islands.
IMPORTANCE: Intravenous magnesium sulfate administered to pregnant individuals before birth at less than 30 weeks’ gestation reduces the risk of death and cerebral palsy in their children. The ...effects at later gestational ages are unclear. OBJECTIVE: To determine whether administration of magnesium sulfate at 30 to 34 weeks’ gestation reduces death or cerebral palsy at 2 years. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial enrolled pregnant individuals expected to deliver at 30 to 34 weeks’ gestation and was conducted at 24 Australian and New Zealand hospitals between January 2012 and April 2018. INTERVENTION: Intravenous magnesium sulfate (4 g) was compared with placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years’ corrected age) or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a pediatrician) at 2 years’ corrected age. There were 36 secondary outcomes that assessed the health of the pregnant individual, infant, and child. RESULTS: Of the 1433 pregnant individuals enrolled (mean age, 30.6 SD, 6.6 years; 46 3.2% self-identified as Aboriginal or Torres Strait Islander, 237 16.5% as Asian, 82 5.7% as Māori, 61 4.3% as Pacific, and 966 67.4% as White) and their 1679 infants, 1365 (81%) offspring (691 in the magnesium group and 674 in the placebo group) were included in the primary outcome analysis. Death or cerebral palsy at 2 years’ corrected age was not significantly different between the magnesium and placebo groups (3.3% 23 of 691 children vs 2.7% 18 of 674 children, respectively; risk difference, 0.61% 95% CI, −1.27% to 2.50%; adjusted relative risk RR, 1.19 95% CI, 0.65 to 2.18). Components of the primary outcome did not differ between groups. Neonates in the magnesium group were less likely to have respiratory distress syndrome vs the placebo group (34% 294 of 858 vs 41% 334 of 821, respectively; adjusted RR, 0.85 95% CI, 0.76 to 0.95) and chronic lung disease (5.6% 48 of 858 vs 8.2% 67 of 821; adjusted RR, 0.69 95% CI, 0.48 to 0.99) during the birth hospitalization. No serious adverse events occurred; however, adverse events were more likely in pregnant individuals who received magnesium vs placebo (77% 531 of 690 vs 20% 136 of 667, respectively; adjusted RR, 3.76 95% CI, 3.22 to 4.39). Fewer pregnant individuals in the magnesium group had a cesarean delivery vs the placebo group (56% 406 of 729 vs 61% 427 of 704, respectively; adjusted RR, 0.91 95% CI, 0.84 to 0.99), although more in the magnesium group had a major postpartum hemorrhage (3.4% 25 of 729 vs 1.7% 12 of 704 in the placebo group; adjusted RR, 1.98 95% CI, 1.01 to 3.91). CONCLUSIONS AND RELEVANCE: Administration of intravenous magnesium sulfate prior to preterm birth at 30 to 34 weeks’ gestation did not improve child survival free of cerebral palsy at 2 years, although the study had limited power to detect small between-group differences. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12611000491965
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