Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: A 3-Year Multicenter, Randomized, Controlled Clinical Trial P. Andrew Pearson, MD,1 Timothy L. Comstock, OD,2 Michael Ip, MD,3 David Callanan, MD,4 Lawrence S. Morse, MD, PhD,5 Paul Ashton, PhD,6 Brian Levy, OD,2 Eric S. Mann, MD, PhD,7 Dean Eliott, MD8 Purpose: We studied the 3-year efficacy and safety results of a 4-year study evaluating fluocinolone acetonide (FA) intravitreal implants in eyes with persistent or recurrent diabetic macular edema (DME). Design: Prospective, evaluator-masked, controlled, multicenter clinical trial. Participants: We included 196 eyes with refractory DME. Methods: Patients were randomized 2:1 to receive 0.59-mg FA implant (n ⫽ 127) or standard of care (SOC additional laser or observation; n ⫽ 69). The implant was inserted through a pars plana incision. Visits were scheduled on day 2, weeks 1, 3, 6, 12, and 26, and thereafter every 13 weeks through 3 years postimplantation. Main Outcome Measures: The primary efficacy outcome was ⱖ15-letter improvement in visual acuity (VA) at 6 months. Secondary outcomes included resolution of macular retinal thickening and Diabetic Retinopathy Severity Score (DRSS). Safety measures included incidence of adverse events (AEs). Results: Overall, VA improved ⱖ3 lines in 16.8% of implanted eyes at 6 months (P⫽0.0012; SOC, 1.4%); in 16.4% at 1 year (P⫽0.1191; SOC, 8.1%); in 31.8% at 2 years (P⫽0.0016; SOC, 9.3%); and in 31.1% at 3 years (P⫽0.1566; SOC, 20.0%). The number of implanted eyes with no evidence of retinal thickening at the center of the macula was higher than SOC eyes at 6 months (P⬍0.0001), 1 year (P⬍0.0001; 72% vs 22%), 2 years (P⫽0.016), and 3 years (P⫽0.861). A higher rate of improvement and lower rate of decline in DRSS occurred in the implanted group versus the SOC group at 6 months (P⫽0.0006), 1 year (P⫽0.0016), 2 years (P⫽0.012), and 3 years (P⫽0.0207). Intraocular pressure (IOP) ⱖ30 mmHg was recorded in 61.4% of implanted eyes (SOC, 5.8%) at any time and 33.8% required surgery for ocular hypertension by 4 years. Of implanted phakic eyes, 91% (SOC, 20%) had cataract extraction by 4 years. Conclusions: The FA intravitreal implant met the primary and secondary outcomes, with significantly improved VA and DRSS and reduced DME. The most common AEs included cataract progression and elevated IOP. The 0.59-mg FA intravitreal implant may be an effective treatment for eyes with persistent or recurrent DME. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011;118:1580 –1587 © 2011 by the American Academy of Ophthalmology.
Diabetic retinopathy (DR) is the most common diabetic eye disease and the leading cause of vision loss in American adults.1 The nonproliferative stage of DR is characterized by retinal vascular leakage and retinal ischemia, and the proliferative phase is characterized by neovascularization.1 Clinically significant diabetic macular edema (DME) with reduced vision may result from this leakage. Macular edema, which can occur at any stage of DR, is the leading cause of moderate visual loss (defined as ⱖ15 letters lost on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity [VA] chart, or a doubling of the visual angle) in diabetic patients.2– 4
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The ETDRS determined that focal photocoagulation, when applied using ETDRS treatment guidelines, resulted in a significant reduction in the rate of moderate visual loss for eyes with clinically significant DME.5 However, visual improvement was rare in the ETDRS, as ⬍3% of eyes experienced VA improvement of ⱖ15 letters.6 Despite this, the ETDRS has defined the standard of care (SOC) for DME for ⬎20 years. The recent Diabetic Retinopathy Clinical Research Network study demonstrated that over a 2-year period, focal/grid photocoagulation is more effective and has fewer side effects than 1- or 4-mg doses of preservativefree intravitreal triamcinolone for most patients with DME ISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2011.02.048
Pearson et al 䡠 FA Intravitreal Implant for DME who have characteristics similar to the cohort in this clinical trial.7 Emerging pharmacologic therapies such as anti–vascular endothelial growth factor A agents, including pegaptanib (Macugen, Eyetech Inc., New York, NY), ranibizumab (Lucentis, Genentech USA, Inc., South San Francisco, CA), and bevacizumab (Avastin, Genentech), are currently being evaluated for the treatment of DME and have shown promising results.8 –13 Triamcinolone acetonide, fluocinolone acetonide (FA), and dexamethasone are steroid agents in various stages of clinical development that are being used off-label or in clinical trials to treat DME. Triamcinolone acetonide, when administered through an intravitreal injection, is effective in improving VA and reducing macular thickness in patients with DME.3,14 The effects of this treatment are often transient, and intraocular injections are associated with complications similar to intravitreal surgery, including hemorrhage, retinal detachment, and endophthalmitis.15 As an alternative, ophthalmic drug companies have developed sustained-release intravitreal implants containing these agents. Given the solubility and potency of fluocinolone, FA is a good choice for these delivery systems. In addition, differences in lipophilicity among steroids may affect the posterior clearance rate of these drugs through the retina. Less lipophilic compounds, such as triamcinolone acetonide and dexamethasone, could reach higher concentrations in the aqueous humor and, therefore, might cause more problems with intraocular pressure (IOP). Because DME is often difficult to treat and current US Food and Drug Administration–approved therapies are limited, a novel technology that delivers corticosteroid therapy via an intravitreal, polymer-coated, sustained-release implant was studied in DME patients in an earlier smaller feasibility study including 80 eyes (Pearson P, Levy B, Fluocinolone acetonide implant study group. Fluocinolone acetonide intravitreal implant to treat DME: 2-year results of a multi-center clinical trial. Ophthalmol Vis Sci 2005; 46:E-Abstract 4673) and this pilot trial served as the basis for the design of the current study. This intravitreal implant, which has been approved by the US Food and Drug Administration to treat chronic noninfectious posterior uveitis, contains 0.59 mg FA, and is designed to maintain therapeutic drug levels in the vitreous cavity for approximately 30 months. Preclinical and clinical (uveitis) studies have demonstrated that the implant is associated with significantly reduced recurrence of inflammation and, with the noted exception of cataract and increased IOP, was well tolerated, with no measurable systemic drug absorption.16 –18 The objective of this multicenter, randomized, evaluatormasked, controlled trial was to evaluate the efficacy and safety of the 0.59-mg FA intravitreal implant in the treatment of eyes with persistent or recurrent DME. Herein we have presented the 3-year results of this 4-year study.
the investigators and study centers is available online at http:// aaojournal.org). The study protocol (ClinicalTrials.gov identifier: NCT00502541) was approved by the institutional review board/ ethics committee at each study site. The study was conducted in accordance with the Declaration of Helsinki and in compliance with the Food and Drug Administration good clinical practices and all local regulations. Patients with persistent or recurrent unilateral or bilateral DME were enrolled. At baseline, all study eyes had retinal thickening (ⱖ1 disc area in size) involving fixation, and all had undergone macular laser treatment ⬎12 weeks before enrollment. Screening included an ophthalmic examination, optical coherence tomography (OCT), where available, fluorescein angiography, and fundus photography for determination of eligibility and baseline characteristics. Initiation of treatment occurred within 21 days of screening. Inclusion criteria included VA of ⱖ20 letters (20/400) to ⱕ68 letters (20/50). The inclusion and exclusion criteria are presented in Table 1 (available online at http://aaojournal.org). Eyes (n ⫽ 196) were randomized to receive the 0.59-mg FA implant (n ⫽ 127) or SOC (n ⫽ 69) using a 2:1 ratio and with a third-party–masked design (patient and investigator were not masked) to ensure the objectivity of results. The SOC group received focal/grid laser photocoagulation5,19 or observation at the investigator’s discretion. For patients with unilateral DME, the study eye was the affected eye; for patients with bilateral DME, the study eye was the more severely affected eye. In patients with bilateral, symmetric disease, the study eye was determined by a computer-generated randomization code. Implantation surgery was performed on day 1. Because implanted eyes required postoperative anti-inflammatory therapy, both implant and SOC groups received topical corticosteroids for the first study week. Follow-up visits were scheduled on day 2 and weeks 1, 3, 6, 12, 26, 39, and 52; long-term follow-up visits were scheduled every 13 weeks for 3 years. These visits included ophthalmic examinations at every follow-up visit; OCT (where available) at weeks 6, 12, and 26 and years 1, 2, 3, and 4; and fluorescein angiography and fundus photography at weeks 12 and 26 and years 1, 2, 3, and 4. Adverse events (AEs) were reported on day 1 and at each visit thereafter until completion of the study. No elective ocular surgery, such as cataract surgery or grid laser for residual diffuse macular edema in the study eye, was permitted until 6 months postimplantation. If, after implantation, a patient developed focal areas of retinal thickening or clinically significant macular edema or had a patch of residual thickening that the investigator felt was due to leakage from microaneurysms, focal laser treatment was permitted in the study eye during the first 6 months postimplantation. Laser (grid or focal) retreatment in the study and fellow eye after 6 months was left to the discretion of the attending clinician.
The Implant and Surgical Procedure
Materials and Methods
The sustained-release FA intravitreal implant used in this study and the implantation operative procedure have previously been described elsewhere.17,20 Briefly, the implant was designed to release FA at an initial rate of approximately 0.6 g/d, decreasing over the first month to a steady rate of 0.3 to 0.4 g/d with a duration of approximately 30 months. Surgery was performed under appropriate anesthesia (local or general). If the eye had a previous vitrectomy, a pars plana infusion line was placed to prevent globe collapse.
Study Design
Outcome Measures
This was a 4-year, prospective, multicenter, randomized, evaluator-masked, parallel-group, controlled clinical trial in eyes with DME conducted at 23 study centers in the United States (a list of
The primary efficacy outcome was a ⱖ15-letter increase in VA at 6 months. Visual acuity was measured by masked, certified ETDRS examiners using a standardized ETDRS protocol. Secondary
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measurements included (1) change from baseline in macular edema, including the proportion of eyes with resolution of edema at the center of the macula; (2) score on the ETDRS multistep Diabetic Retinopathy Severity Scale; (3) leakage by fluorescein angiography; and (4) maximum cystoid score. All retinal outcomes were based on assessments of fundus photographs and fluorescein angiograms by a masked reading center, with special masking procedures to prevent all fundus photograph examiners and adjudicators from determining which eyes were implanted.
Safety Analysis We monitored AEs closely throughout the course of the study and assessments were made at follow-up visits. The incidence of treatment-emergent AEs was reported using Medical Dictionary for Regulatory Activities–preferred terms. Ocular AEs were recorded separately for the randomized and nonrandomized eyes for each treatment group.
Statistical Analyses Sample size was determined based on categorical or “responder” assumptions about VA efficacy, where a “responder” was defined as an eye with an improvement in VA of ⱖ15 letters from baseline. Using a 2-sided 2 test without continuity correction and with a 5% significance level, and assuming that the proportion of success in the SOC group would range from 15% to 20%, the study required approximately 180 randomized and treated eyes to provide 80% power for demonstrating a difference of 20% in the proportion of successful implanted eyes compared with SOC eyes. Using a 2:1 randomization ratio, 120 eyes were targeted for randomization to the implant group and 60 for the SOC group.
An analysis of variance model was used to analyze any continuous variables. Categorical data were analyzed using the 2 test. When assumptions for the 2 test were not met, the Fisher exact test was used. Numeric data that were converted to ordinal group data (e.g., Diabetic Retinopathy Severity Score [DRSS]) were analyzed using the Mantel–Haenszel 2 test. All statistical analyses were 2-sided, and significance was recognized at P⬍0.05. The primary analysis compared the proportion of eyes in each treatment group experiencing a clearance of macular edema, as evidenced by resolution of retinal thickening at the center of the macula. All efficacy and safety analyses were performed on the intent-to-treat population, which was defined as all eyes that were randomized to treatment and had ⱖ1 follow-up assessment.
Results Patient enrollment began in September 2001 and completed by 2003. The patient disposition and demographic characteristics for the 196 eyes enrolled in the study are presented in Table 2 (available online at http://aaojournal.org). Demographic characteristics were similar between the implant and SOC groups. The percentage of patients dependent on insulin at baseline was 70.1% (89 of 127) in the implant group and 62.3% (43 of 69) in the SOC group.
Efficacy Visual Acuity. Improvements in VA were seen in both treatment groups. The primary endpoint, a ⱖ15-letter increase in VA at 6 months, was met. As illustrated in Fig 1A, the proportion of eyes showing a ⱖ3-line improvement in VA was significantly higher with the FA implant than with SOC at 6 (P⬍0.0012) and 9 months
Figure 1. Proportion of eyes with improvement (ⱖ⫹15) or loss (ⱕ⫺15) of ⱖ15 ETDRS letters in study eye over time (A, 3- to 12-month LVA; B, 15- to 24-month LVA; C, 27- to 36-month and 48-month LVA; P values comparing standard of care and FA implant at each time point above corresponding columns from 2/Fisher exact test). ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FA ⫽ fluocinolone acetonide; LVA⫽ last visit available.
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Figure 2. Proportion of eyes with no evidence of retinal thickening at the center of the macula (P values from 2/Fisher exact test). The n values listed above each bar are the number of eyes with a photo that could be graded available at each interval. FA ⫽ fluocinolone acetonide.
(P⬍0.002) postimplantation. The differences in the percentage of eyes with a ⱖ3-line gain in VA in the FA group compared with the SOC group was not significant at 1 year (P⫽0.119), but it was again significantly higher in FA-treated eyes at 2 years (P⫽0.0016; Fig 1B). By 3 years after implantation, the difference in the rates of ⱖ3-line VA improvements was no longer significant (Fig 1C; P⫽0.1566). Last visit available (LVA) analyses at 48 months postimplantation did not show a difference in the proportion of eyes with a ⱖ3-line VA improvement. Macular Edema. The proportion of eyes showing no evidence of retinal thickening at the center of the macula, as a proportion of eyes with photos that could be graded (all statistical analysis included the indeterminate data of eyes in which photos were unable to be graded), was significantly higher in the implanted group than in the SOC group at 6 months postimplantation (Fig 2; P⬍0.0001). At 1 year postimplantation, there was an increase in both groups in the percentage of eyes showing no evidence of retinal thickening at the center of the macula, but the rate was significantly higher in implanted eyes than in SOC group (P⬍0.0001). At 2 years postimplantation, the proportion of eyes with no evidence of retinal thickening continued to be higher in the implanted group, and the difference remained significant (P⫽0.016). No difference between treatments was seen at 3 years postimplantation (P⫽0.861). No difference in the proportion of eyes showing no evidence of retinal thickening at the center of the macula was found using data from the LVA analysis at 48 months postimplantation. The proportion of eyes with no evidence of retinal thickening at LVA (at 48 months) was 51.2% (65/127 eyes) in the implanted group and 37.7% (26/69 eyes) in SOC eyes (data not shown). The mean ⫾ standard deviation baseline OCT in the small subset of eyes treated where the instrument was available was 419.4⫾109.2 m in implanted eyes (n ⫽ 30) and 368.7⫾96.1 m in SOC eyes (n ⫽ 15). Despite the small sample size, the difference between implanted eyes and SOC eyes in mean change from baseline in macular thickness was significant by 12 weeks (Fig 3; P⬍0.0001). This difference continued to be significant through 2 years (P⫽0.018). The SOC eyes were relatively stable throughout the study until the 3-year visit, when they experienced a slight thinning; the difference between treatments in mean change from baseline in macular thickness was not significant at 3 years (P⫽0.645). Diabetic Retinopathy Severity. Figure 4 shows the changes in DRSS from baseline at 6 months, and 1, 2, and 3 years postimplantation. The ETDRS scale is ranged from 1 (no DR) to 12 (severe DR). There was a higher rate of improvement and a lower rate of decline in DR severity in the implanted group than in the
SOC group at each of these time points (P⫽0.0006 at 6 months postimplantation [Fig 4A]; P⫽0.0016 at 1 year postimplantation [Fig 4B]; P⫽0.012 at 2 years postimplantation [Fig 4C]; and P⬍0.021 at 3 years postimplantation [Fig 4D]). Fluorescein Angiography Leakage. The rate of improvement in fluorescein leakage severity score was greater and the rate of decline lower in the implant group than in the SOC group at 12 weeks (P⫽0.001; Fig 5A, available online at http://aaojournal.org), 6 months (P⬍0.0001; Fig 5B, available online at http://aaojournal.org), and 1 year (P⫽0.006; Fig 5C, available online at http://aaojournal. org) after implantation. Differences in the rate of improvement or decline in fluorescein leakage severity scores between the 2 groups at 2 years (P⫽0.075; Fig 5D, available online at http://aaojournal.org) and 3 years (P⫽0.299; Fig 5E, available online at http://aaojournal. org) postimplantation were not significant. The proportion of eyes with a ⬎2-grade improvement in fluorescein leakage severity score was greater in the implant group than in the SOC group at each time point analyzed. Cystoid Grade. A greater proportion of eyes showed improvement and a lower proportion showed decline from baseline in cystoid grade in the implant group than in the SOC group at 12 weeks (P⬍0.0001; Fig 6A, available online at http://aaojournal.org), and 6 months (P⫽0.001; Fig 6B, available online at http://aaojournal.org) postimplantation. There was no difference between treatment groups in improvement or decline from baseline in cystoid scores at 1 year (P⫽0.059; Fig 6C, available online at http://aaojournal.org), 2 years (P⫽0.213; Fig 6D, available online at http://aaojournal.org), or 3 years (P⫽0.352; Fig 6E, available online at http://aaojournal.org) postimplantation, although the proportion of eyes with a ⱖ1-grade improvement in cystoid scores was higher in the implant group than in the SOC group at all time points analyzed.
Safety Ocular Adverse Events. There was a higher rate of treatmentemergent ocular AEs in eyes treated with the 0.59-mg FA implant (100%) than in eyes that received SOC (88.4%) during the study. Ocular AEs reported for ⬎20% of implanted eyes are presented in Table 3. The most frequent AEs in implanted eyes were elevated IOP (88 of 127 eyes [69.3%]), worsening cataract (71 of 127 eyes [55.9%]), vitreous hemorrhage (51 of 127 eyes [40.2%]), pruritus (49 of 127 eyes [38.6%]), and abnormal sensation in the eye (47 of 127 eyes [37.0%]). The most frequent AEs in SOC eyes were macular edema (25 of 69 eyes [36.2%]), DR (19 of 69 eyes
Figure 3. Mean change in macular thickness from baseline (as measured by OCT in a subgroup of eyes). The n values listed above each bar are the number of eyes measured at each interval. FA ⫽ fluocinolone acetonide; OCT ⫽ optical coherence tomography.
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Figure 4. Change in Diabetic Retinopathy Severity Scores (A, 6 months; B, 1 year; C, 2 years; D, 3 years; P values from Mantel–Haenszel 2 test). FA ⫽ fluocinolone acetonide.
[27.5%]), reduced VA (16 of 69 eyes [23.2%]), worsening cataract (15 of 69 eyes [21.7%]), pruritus (15 of 69 eyes [21.7%]), and photophobia (15 of 69 eyes [21.7%]). Eye pain was observed in 34 of 127 eyes (26.8%) in the implanted group compared with 11 of 69 eyes (15.9%) in the SOC group. To relieve elevated IOP, 43 of 127 eyes (33.8%) underwent ⱖ1 surgical intervention (40 of 127 eyes [31.5%] underwent filtering surgeries and 3 of 127 eyes [2.4%] had the implant removed to relieve IOP). Nonocular Adverse Events. The most frequent nonocular AEs in the implant group were blood glucose increase (seen in 29 of 127 patients [22.8%]), anemia (19 of 127 patients [15.0%]), coronary artery disease (17 of 127 patients [13.4%]), and headache (15 of 127 patients [11.8%]). Nearly all of these AEs were unrelated to treatment, and the rates were similar in the SOC group. In the SOC group, the most frequent AEs were blood glucose increase (16 of 69 patients [23.2%]), renal impairment (9 of 69 Table 3. Ocular Treatment-Emergent Adverse Events Study Eye, n (%) Adverse Event
0.59-mg Implant (n ⫽ 127)
Standard of Care (n ⫽ 69)
Elevated intraocular pressure Cataract (aggravated) Vitreous hemorrhage Pruritus Abnormal sensation in the eye Macular edema Eye pain Diabetic retinopathy Reduced visual acuity Eye irritation Increased lacrimation Photophobia Blurred vision Vitreous floaters
88 (69.3) 71 (55.9) 51 (40.2) 49 (38.6) 47 (37.0) 44 (34.6) 34 (26.8) 29 (22.8) 29 (22.8) 28 (22.0) 28 (22.0) 27 (21.3) 27 (21.3) 27 (21.3)
8 (11.6) 15 (21.7) 13 (18.8) 15 (21.7) 8 (11.6) 25 (36.2) 11 (15.9) 19 (27.5) 16 (23.2) 7 (10.1) 6 (8.7) 15 (21.7) 11 (15.9) 6 (8.7)
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patients [13.0%]), congestive cardiac failure (8 of 69 patients [11.6%]), arthralgia (8 of 69 patients [11.6%]), and hypertension (8 of 69 patients [11.6%]). Intraocular Pressure. An IOP of ⱖ30 mmHg at any time during the entire 4-year postimplantation period was recorded in 61.4% of implanted eyes (78 of 127 eyes) and in 5.8% of SOC eyes (4 of 69 eyes). Hypotony (IOP ⱕ7 mmHg) was observed in 22.0% of implanted eyes (28 of 127 eyes) and in 8.7% of SOC eyes (6 of 69 eyes) at any time during the 4-year postimplantation follow-up. Hypotony was generally transient as demonstrated by the lower proportion of eyes with hypotony at the 3 year visit, 4.3% of implanted eyes (4 of 92 eyes), and in 0% of SOC eyes (0 of 50 eyes). Cataracts. Cataracts, primarily nuclear and posterior subcapsular, and progression of preexisting cataracts were commonly reported for the implanted study eyes. Cataracts were extracted in 91% of implanted phakic eyes and in 20% of SOC phakic eyes by 4 years postenrollment. Laser (grid or focal) retreatment data in the study and fellow eye showed 5 implanted eyes had 8 laser treatments and 9 SOC eyes had 12 laser treatments by 6 months; 20 implanted eyes had 32 laser treatments, and 28 SOC eyes had 52 laser treatments by 3 years.
Discussion This study was conducted to determine the efficacy and safety of the FA intravitreal implant in the treatment of eyes with persistent or recurrent DME. The primary efficacy outcome was the percentage of eyes with a ⱖ15-letter increase in VA at 6 months. VA increases of ⱖ3 lines were observed in 16.8% of implanted eyes compared with 1.4% of SOC eyes at 6 months (P⫽0.0012), thus meeting the primary endpoint of the study. Significant improvement in VA was also observed in the implant group at 9, 18, and 24 months.
Pearson et al 䡠 FA Intravitreal Implant for DME The implant provided effective treatment of DME, as indicated by an increase in the proportion of eyes with no evidence of retinal thickening at the center of the macula from baseline. Compared with SOC, the FA implant group had a significantly higher proportion of eyes showing no evidence of retinal thickening at the center of the macula at 6 months, 1 year, and 2 years; however, the difference was not significant at 3 years postimplantation, probably owing to the 30-month life span of the FA implant,21 and the gradually increased rates for SOC eyes getting better over the same time period. Significant improvements in secondary endpoints such as DRSS and OCT measurements also suggest that the implant provided an effective treatment for DME. Worsening of the DRSS by ⱖ2 steps has been associated with an increased risk of visual loss5; however, it is unclear what impact an improved DRSS has on the risk of either visual loss or gain. To the best of our knowledge, this is the first study conducted involving an ocular treatment that demonstrates a reversal of nonproliferative DR severity. In a study of the FA intravitreal implant in the treatment of posterior uveitis, significant improvements in VA were reported, and these improvements were attributed to the reduction of cystoid macular edema.18 Other studies have indicated that the reduction of macular edema in DME and other retinal vascular diseases is accompanied by improvements in VA.14,22 It is likely that the effective resolution of macular edema by the FA implant in the current study led to the observed improvements in VA. The VA fluctuated more from visit to visit in the FA-implanted group than in the SOC group. This suggests that, in addition to the resolution of macular edema by the FA implant, the development of cataracts had a temporal impact on the VA of implanted eyes. Improvement in VA was significant in the implant group at 6 months postimplantation, before observable cataract progression (P⫽0.0012). The time during which VA worsened (1 year postimplantation) and then improved (2 years postimplantation) corresponds with the period in the study during which a majority of cataracts developed and were extracted. These findings are consistent with the Beaver Dam Eye Study, in which VA improved after cataract surgery.23 Similar observations also have been noted in the use of the FA implant for the treatment of noninfectious posterior uveitis.16 The lack of a difference in the proportion of eyes with ⱖ3 lines of VA gained at the 3-year visit likely reflects drug depletion in the implant, the recurrence of macular edema in some eyes, and the finding that SOC eyes had a gradual increase in VA at each time point. By 3 years postimplantation, 20% of SOC eyes had an improvement in VA of ⱖ3 lines. Although the ETDRS demonstrated that an improvement of ⱖ3 lines was uncommon (⬍3%), many of the ETDRS eyes had better baseline VA. The beneficial response to early focal treatment in the ETDRS was most apparent in eyes with CSDME and worse VA at baseline (⬍20/40) as compared with those with better baseline VA.5 This improvement by SOC eyes should be a consideration in future trials looking to show a significant benefit of a pharmacologic treatment of DR.
The incidence of ocular AEs was higher in the implant group than in the SOC group. The AEs most frequently experienced in implanted eyes were elevated IOP, cataract formation, vitreous hemorrhage, pruritus, and abnormal sensation in the eye. Ocular AEs such as abnormal sensation in the eye and pain may be attributed to the implantation surgery. Corticosteroids can cause an elevation of IOP through all routes of administration,24 and it is well established that prolonged local or systemic administration of corticosteroids is associated with a higher incidence of elevated IOP and cataract formation.25,26 These effects, which were the 2 most frequently reported AEs in this study, may be related; one study found a strong association between corticosteroidinduced IOP rises and the subsequent development of cataract.27 Elevation of IOP and cataract formation have been hypothesized to share the same mechanism, possibly involving activation of a common steroid receptor that may be located in the trabecular meshwork and the lens.27 In this study, 33.8% of patients required either filtration surgery or explantation for uncontrolled IOP. Despite these AEs, the risk– benefit ratio of the FA implant seems favorable for many eyes with persistent or recurrent DME who are losing vision despite laser treatment. Future treatments should consider a reduced dose of FA or provide other mechanisms to reduce the incidence of IOP elevation. It is possible that a different delivery mechanism for FA (or a different steroid) may be as efficacious as the 0.59-mg FA implant but have fewer side effects. In conclusion, this is the first study to demonstrate that sustained (⬎6 months) drug delivery to the posterior segment is efficacious in the treatment of diabetic retinal disease. Specifically, improvements of ⱖ3 lines of VA in the FA group were significant at 6 (primary endpoint), 9, 18, and 24 months compared with SOC. The results of this study indicate that sustained drug delivery is beneficial for DME, because effects of treatments such as IVTA do not persist in the long term and need to be repeated.28 This study also demonstrates that sustained delivery of steroids can result in resolution of DME and improvement in DRSS. With careful monitoring of IOP and lens clarity, the 0.59-mg FA intravitreal implant may be an effective treatment for eyes with persistent or recurrent DME. There is no evidence from this study that long-term exposure of the retina to low concentrations of steroids has any deleterious effect; in fact, the opposite may be true, as demonstrated by the improvement in DRSS. In clinical practice, when the implant is depleted of drug (30 months), the stimulus responsible for the development of DME may persist or may have significantly lessened, and close follow-up is therefore indicated.
References 1. Aiello LP. The potential role of PKC beta in diabetic retinopathy and macular edema. Surv Ophthalmol 2002;47(suppl 2):S263–9.
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2. Gardner TW, Sander B, Larsen ML, et al. An extension of the Early Treatment Diabetic Retinopathy Study (ETDRS) system for grading of diabetic macular edema in the Astemizole Retinopathy Trial. Curr Eye Res 2006;31:535– 47. 3. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002;109:920 –7. 4. Tranos PG, Topouzis F, Stangos NT, et al. Effect of laser photocoagulation treatment for diabetic macular oedema on patient’s vision-related quality of life. Curr Eye Res 2004;29: 41–9. 5. ETDRS. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796 – 806. 6. Emerson MV, Lauer AK. Emerging therapies for the treatment of neovascular age-related macular degeneration and diabetic macular edema. BioDrugs 2007;21:245–57. 7. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115:1447–9. 8. Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 2007;114: 1860 –7. 9. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 2007;114: 743–50. 10. Chun DW, Heier JS, Topping TM, et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 2006;113:1706 –12. 11. Cunningham ET, Jr., Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an antivascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005;112:1747–57. 12. Fraser-Bell S, Kaines A, Hykin PG. Update on treatments for diabetic macular edema. Curr Opin Ophthalmol 2008;19: 185–9. 13. Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 2006;26:999 –1005. 14. Bakri SJ, Shah A, Falk NS, Beer PM. Intravitreal preservativefree triamcinolone acetonide for the treatment of macular oedema. Eye 2005;19:686 – 8.
15. Jager RD, Aiello LP, Patel SC, Cunningham ET, Jr. Risks of intravitreous injection: a comprehensive review. Retina 2004; 24:676 –98. 16. Callanan DG, Jaffe GJ, Martin DF, et al. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol 2008;126:1191–201. 17. Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirtyfour-week results of a multicenter randomized clinical study. Ophthalmology 2006;113:1020 –7. 18. Jaffe GJ, Yang CH, Guo H, et al. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device. Invest Ophthalmol Vis Sci 2000;41:3569 –75. 19. Shahidi M, Ogura Y, Blair NP, Zeimer R. Retinal thickness change after focal laser treatment of diabetic macular oedema. Br J Ophthalmol 1994;78:827–30. 20. Jaffe GJ, McCallum RM, Branchaud B, et al. Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology 2005;112:1192– 8. 21. Retisert prescribing information. Rochester, NY: Bausch & Lomb, Inc.; April 2005. 22. Patelli F, Fasolino G, Radice P, et al. Time course of changes in retinal thickness and visual acuity after intravitreal triamcinolone acetonide for diffuse diabetic macular edema with and without previous macular laser treatment. Retina 2005;25:840 –5. 23. Klein BE, Klein R, Moss SE. Change in visual acuity associated with cataract surgery. The Beaver Dam Eye Study. Ophthalmology 1996;103:1727–31. 24. Bandi N, Kompella UB. Budesonide reduces vascular endothelial growth factor secretion and expression in airway (Calu-1) and alveolar (A549) epithelial cells. Eur J Pharmacol 2001;425:109 –16. 25. Becker MD, Smith JR, Max R, Fiehn C. Management of sight-threatening uveitis: new therapeutic options. Drugs 2005;65:497–519. 26. Holekamp NM, Thomas MA, Pearson A. The safety profile of long-term, high-dose intraocular corticosteroid delivery. Am J Ophthalmol 2005;139:421– 8. 27. Gillies MC, Kuzniarz M, Craig J, et al. Intravitreal triamcinolone-induced elevated intraocular pressure is associated with the development of posterior subcapsular cataract. Ophthalmology 2005;112:139 – 43. 28. Yilmaz T, Weaver C, Gallagher M, et al. Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: a systematic review. Ophthalmology 2009;116:902–11.
Footnotes and Financial Disclosures Originally received: February 9, 2010. Final revision: February 23, 2011. Accepted: February 28, 2011.
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Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Manuscript no. 2010-224.
1
Department of Ophthalmology and Visual Science, University of Kentucky, Lexington, Kentucky.
2
Bausch & Lomb, Inc., Rochester, New York.
3
University of Wisconsin Medical School, Madison, Wisconsin.
4
Texas Retina Associates, Arlington, Texas.
5
University of California–Davis Medical Center, Davis, California.
6
pSivida, Watertown, Massachusetts.
7
The Retina Group Ltd., Fairview Heights, Illinois.
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A list of principle investigators and board members is available at http:// aaojournal.org. Presented in part at: the Association for Research in Vision and Ophthalmology Annual Meeting, April 30 –May 4, 2006. Financial Disclosure(s): The authors have made the following disclosures: At the time the study was conducted, Dr. Brian Levy, and Dr. Timothy Comstock were employees of Bausch & Lomb Inc., Rochester, New York, the sponsor of this study. Dr. Dean Eliott, Dr. Michael Ip, Dr. David Callanan, Dr. Lawrence Morse and Dr. Eric Mann had no proprietary interest in the firm. Dr. Paul Ashton is the CEO of pSivida, the company that invented Retisert, and is
Pearson et al 䡠 FA Intravitreal Implant for DME one of the inventors listed on the patent; Dr. Andrew Pearson had a financial interest in the product. Dr. Dean Eliott was a pSivida stockholder, and he is an ad hoc consultant for Alcon, Allergan, Bausch & Lomb, Genentech, and Glaukos. None of the other investigators had a proprietary interest in fluocinolone acetonide intravitreal implant. Financial support for this research was provided by Bausch & Lomb Incorporated, Rochester, New York. The sponsor participated in the design
of the study; conducting the study; data collection, management, and analysis; interpretation of the data; and preparation, review, and approval of the manuscript. Correspondence: Dean Eliott, MD, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, 243 Charles St., Boston, Massachusetts 02114. E-mail:
[email protected].
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