 |
|
Randomized Controlled Study of an Intravitreous Dexamethasone Drug Delivery System in Patients With Persistent Macular Edema
Baruch D. Kuppermann, MD, PhD;
Mark S. Blumenkranz, MD;
Julia A. Haller, MD;
George A. Williams, MD;
David V. Weinberg, MD;
Connie Chou, PhD;
Scott M. Whitcup, MD; for the Dexamethasone DDS Phase II Study Group
Arch Ophthalmol. 2007;125(3):309-317.
ABSTRACT
| |
Objective To evaluate a dexamethasone intravitreous drug delivery system (DDS) in patients with persistent ( 90 days despite treatment) macular edema.
Methods This 6-month study randomized 315 patients with persistent macular edema with best-corrected visual acuity (BCVA) of 20/40 to 20/200 in the study eye to observation or a single treatment with dexamethasone DDS, 350 or 700 µg.
Main Outcome Measures Proportion of patients achieving a BCVA improvement of 10 or more letters or 15 or more letters, safety measures, change in fluorescein angiographic leakage, and central retinal thickness.
Results At day 90 (primary end point), an improvement in BCVA of 10 letters or more was achieved by a greater proportion of patients treated with dexamethasone DDS, 700 µg (35%) or 350 µg (24%), than observed patients (13%; P<.001 vs 700-µg group; P = .04 vs 350-µg group); an improvement in BCVA of 15 letters or more was achieved in 18% of patients treated with dexamethasone DDS, 700 µg, vs 6% of observed patients (P = .006). Results were similar in patients with diabetic retinopathy, vein occlusion, or uveitis or Irvine-Gass syndrome. During 3 months of observation, 11% of treated patients and 2% of observed patients had intraocular pressure increases of 10 mm Hg or higher.
Conclusion In persistent macular edema, a single dexamethasone DDS treatment produced statistically significant BCVA improvements 90 days after treatment and was well tolerated for 180 days.
Application to Clinical Practice Dexamethasone DDS, 700 µg, may have potential as a treatment for persistent macular edema.
Trial Registration clinicaltrials.gov Identifier: NCT00035906
INTRODUCTION
Macular edema (ME) and its associated reduction in central vision are thought to be caused by abnormal retinal capillary permeability leading to extravascular swelling in the central retina.1 Macular edema is associated with several disorders, including diabetic retinopathy, retinal vein occlusion, and uveitis, and is one of the leading causes of vision loss in patients with diabetes. Diabetic ME develops within 10 years of diabetes diagnosis in 14% to 25% of patients with diabetes (depending on age at onset).2 Left untreated, up to 33% of eyes with diabetic ME will experience moderate vision loss (defined as a loss of 15 letters, or 3 lines, on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) within 3 years.3 Laser photocoagulation has been one of the most common treatments for ME, and the large, 3-year ETDRS clinical trial demonstrated that focal laser therapy reduced the risk of moderate visual loss by 50% in patients with diabetic ME.4
A variety of processes have been implicated in the breakdown of the blood-retinal barrier that leads to ME. These processes include the production of inflammatory mediators (such as prostaglandins and IL-6), increased amounts of vascular permeability factors such as vascular endothelial growth factor,5 and the loss of endothelial tight junction proteins.6 Corticosteroids are thought to have beneficial effects on all of these processes.6-10 It is difficult, however, to deliver therapeutic concentrations of any medication to the retina while limiting systemic exposure. One method is to place the medication directly into the vitreous humor of the eye.11-14 Intravitreal injections of the corticosteroid triamcinolone acetonide have shown promise in the treatment of ME.14-18 Dexamethasone is a more potent corticosteroid than triamcinolone, and intravitreal injections of dexamethasone have been shown to produce high intravitreal drug levels without toxic effects.19-21 Unfortunately, the short intraocular half-life of dexamethasone after intravitreal injection (approximately 3 hours) makes this approach impractical for clinical therapy.20
A novel intravitreal drug delivery system (DDS) (Dexamethasone Posterior Segment Drug Delivery System, Allergan Inc) has been developed that gradually releases 350 or 700 µg of dexamethasone after it has been inserted into the eye through a small pars plana incision or puncture (Figure 1). In preclinical studies of this delivery system, dexamethasone was detected in the vitreous up to 6 months after insertion (Allergan Inc, data on file, 2006-2007). The dexamethasone DDS is composed of a biodegradable copolymer of lactic acid and glycolic acid. These polymers have been used in several medical products, including absorbable sutures.22-24 As dexamethasone is released, the polymer slowly biodegrades into carbon dioxide and water. Since the implant eventually dissolves completely, sequential implants can be placed into the eye over time without the need for surgical removal.
|
|
|
|
Figure 1. Dexamethasone drug delivery system (DDS). A, Dexamethasone DDS implants. The larger implant is the 700-µg dose, and the smaller implant is the 350-µg dose. B. Approximate location of the dexamethasone DDS (indicated with the arrow; shown larger than actual size for illustrative purposes) after insertion into the eye.
|
|
|
The purpose of this study was to evaluate the safety and efficacy of a single treatment with 1 of 2 different doses of dexamethasone DDS vs observation (no treatment) in patients with ME that had persisted for at least 90 days despite laser treatment or medical therapy. The goal was to explore the potential benefits of this new therapy in a population of patients whose ME had not responded well to currently available treatments. Eligible causes of ME included diabetic retinopathy, retinal vein occlusion, uveitis, or Irvine-Gass syndrome (also referred to as postcataract surgery ME).
METHODS
STUDY DESIGN
This randomized, prospective, multicenter, dose-ranging controlled clinical trial was conducted in compliance with sponsor and investigator obligations, the Declaration of Helsinki, and the institutional review board and informed consent regulations at each investigational site.
STUDY POPULATION
Patients were recruited at 29 retina practices throughout the United States. Patients were at least 12 years of age and had a best-corrected visual acuity (BCVA) of 20/40 (67-73 letters) to 20/200 (34-38 letters) in the study eye because of clinically detectable ME. The most important inclusion criterion was that the patient had persistent ME that continued for 90 days or more after laser treatment or medical therapy. As long as this criterion was met, the underlying cause of ME could be diabetic retinopathy, central or branch retinal vein occlusion, uveitis, or Irvine-Gass syndrome. Patients were stratified according to underlying disease during randomization to treatment to balance any effect of underlying disease on treatment outcome.
Key exclusion criteria included visual acuity worse than 20/200 in the study eye; history of vitrectomy surgery; use of systemic, periocular, or intraocular corticosteroids within 30 days of enrollment; moderate or severe glaucoma; poorly controlled hypertension (defined as systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg), and poorly controlled diabetes (defined as a hemoglobin A1c level >13%).
RANDOMIZATION AND MASKING
Patients were randomized with a 1:1:1 allocation to observation or treatment with dexamethasone DDS, 350 or 700 µg. Randomization was performed centrally and was stratified by underlying cause of the ME. Patients in the treatment groups were masked regarding the dose they received. Key efficacy variables were collected and evaluated by personnel who were masked to patient study treatment.
STUDY TREATMENTS
The investigator selected 1 eye per patient to be the study eye. In patients who were randomized to treatment, dexamethasone DDS, 350 or 700 µg, was surgically implanted into the vitreous cavity of the study eye via a 20-gauge (1.15-mm) trans–pars plana incision (Figure 1B). After placement of the implant, the scleral and conjunctival wounds were closed in layers using absorbable sutures. Patients in the observation group received no study treatment and no sham procedure.
NONSTUDY TREATMENTS
No steroids, immunosuppressants, immunomodulators, or alkylating agents were allowed through day 90 unless medically necessary. If there was an underlying inflammatory condition in the fellow eye, topical steroids or periocular or intravitreal steroid injections could be used. The use of systemic steroid and nonsteroidal anti-inflammatory drugs was permitted as long as the dose remained stable during the first 90 days of the study. The use of topical nonsteroidal anti-inflammatory drugs in the study eye was prohibited. However, any patient who experienced a visual acuity loss of 15 letters or more could be treated with any therapy (including laser photocoagulation) that the investigator deemed appropriate. Because of the inclusion of an observation arm in the study, this provision was deemed necessary to ensure patient safety.
OUTCOME MEASURES AND FOLLOW-UP
The primary outcome measure was the proportion of patients who achieved at least a 10-letter improvement in BCVA at the day 90 follow-up visit. Key secondary outcome measures included the proportion of patients who achieved a 15-letter improvement in BCVA, the proportion of patients who achieved a 3-grade improvement in fluorescein angiographic leakage (standardized 9-grade scale), change in central retinal thickness using optical coherence tomography (OCT) (some investigational sites only; mostly OCT-2 but some OCT-3), and safety parameters. All visual acuity assessments (except at day 1) were based on BCVA obtained using a standardized ETDRS protocol.25 The OCT measurements of central retinal thickness (performed at selected sites only) and fluorescein angiograms were assessed at a central reading center (University of Wisconsin Fundus Photography Reading Center) using standardized procedures and graders masked to study group assignment. The presence of nuclear, cortical, and posterior subcapsular lens opacities was measured during the slitlamp examination using standardized photographs and the clinical lens grading protocol, including the Clinical Lens Grading Protocol slitlamp settings, described in the Age-Related Eye Disease Study reports.26
Patients were evaluated at baseline and days 1, 7, 30, 60, 90, and 180. Intraocular pressure (IOP), slitlamp assessment, and indirect ophthalmologic measurements were performed at every visit, BCVA was assessed at every visit except day 1, and blood pressure was measured at every visit except day 180. Fluorescein angiography and OCT (selected sites) were performed at baseline and days 30 and 90.
STATISTICAL ANALYSIS
The patient population used for the analysis of primary and secondary efficacy parameters was the intent-to-treat population, which included all randomized patients, with the last observation carried forward for any missing values. The patient population used for the analysis of all safety parameters included all randomized patients who received treatment.
The primary efficacy analysis evaluated the difference between a dexamethasone DDS treatment group and the observation group in the proportion of patients with at least a 10-letter improvement (improvement rate) from baseline BCVA at day 90. Differences in the BCVA improvement rate between each of the dexamethasone DDS treatment groups and the observation group were analyzed separately using the Pearson  2 test. All statistical tests used for the analysis of the primary efficacy parameters were 2-sided with a significance level of  = .025 to maintain the overall type I error rate at .05.
Categorical variables were analyzed using the Pearson 2 or Fisher exact test. Continuous variables were analyzed using analysis of variance. The comparisons for the secondary outcome measures were performed at the = .05 significance level. All tests were 2-sided.
A sample size of 255 patients (85 in each group) was estimated to provide an 80% power to detect a 20% difference between the proportion of patients in a dexamethasone DDS treatment group and the observation group who achieved at least a 10-letter improvement in BCVA at day 90. This calculation was based on a 2-sided z test between 2 proportions, assuming a 10% outcome proportion in the observation group and a significance level of = .025. Assuming a dropout rate of 10%, a sample size of 285 patients (95 in each group) was planned for this study.
RESULTS
Patients were recruited into this study between October 4, 2001, and September 29, 2002. A total of 315 patients (n = 105 in each group) were enrolled. The demographic and baseline characteristics were comparable among the 3 treatment groups (Table 1). The flow of patients through the study is illustrated in Figure 2. Of the 315 patients, 286 (91%) completed the study.
|
|
|
|
Table 1. Patient Baseline Characteristics*
|
|
|
|
|
|
|
Figure 2. Patient flow through the study.
|
|
|
EFFICACY ANALYSIS
Visual Acuity
At baseline, mean visual acuity ranged from 53 to 54 letters (Snellen equivalent: 20/80 to 20/100 in the study eye) in the 3 groups (Table 1). At day 90 (primary end point), a 10-letter or greater improvement in BCVA was achieved in 25 (24%) of 103 patients in the dexamethasone DDS 350-µg group (P = .04 vs observation), 37 (35%) of 105 patients in the dexamethasone DDS 700-µg group (P<.001 vs observation), and 14 (13%) of 105 patients in the observation group (Figure 3). In addition, the proportion of patients achieving a 15-letter (3-line) or greater BCVA improvement at day 90 was 10% (10/103) in the dexamethasone DDS 350-µg group (P = .28 vs observation), 18% (19/105) in the dexamethasone DDS 700-µg group (P = .006 vs observation), and 6% (6/105) in the observation group (Figure 3). At day 180, a significantly greater proportion of patients had achieved at least a 15-letter improvement in the dexamethasone DDS 700-µg group (18% [19/105]; P = .02 vs observation) than in the observation group (8%; 8/105; Figure 3). A statistically significant treatment benefit was first seen at day 60, with a 10-letter or greater improvement in visual acuity in 27 (26%) of 103 patients in the dexamethasone DDS 350-µg group (P = .006 vs observation), 33 (31%) of 105 patients in the dexamethasone DDS 700-µg group (P<.001 vs observation), and 12 (11%) of 105 patients in the observation group. P .025 was considered statistically significant in these analyses. The percentages of patients who lost at least 10 or 15 letters in BCVA and those who achieved improvements of these magnitudes are listed in Table 2.
|
|
|
|
Figure 3. Percentage of patients achieving improvement in best-corrected visual acuity of 10 letters or more or 15 letters or more. P values are for the dexamethasone drug delivery system (DDS) 700-µg group vs the observation group (P.025 was considered statistically significant).
|
|
|
|
|
|
|
Table 2. Patients With Designated Changes in Best-Corrected Visual Acuity at Day 90
|
|
|
We also investigated whether the treatment effect differed by the underlying cause of persistent ME. A subgroup analysis showed that the efficacy results were similar across patients with ME due to different diseases (Table 3). Although the treatment effect appears slightly greater in the patients with Irvine-Gass syndrome or uveitis, the number of patients in this subgroup was small.
|
|
|
|
Table 3. Subgroup Analysis of Visual Acuity Findings (at Day 90) by Underlying Cause of Macular Edema
|
|
|
Patients could be given nonstudy treatments for their ME if the investigator determined it to be medically necessary. A significantly greater proportion of patients in the observation group were given nonstudy treatments for their ME (such as photocoagulation, topical corticosteroidal or nonsteroidal anti-inflammatory agents, periocular corticosteroids, or intravitreal corticosteroids) during the study (24% [25/105]) than were patients in the dexamethasone DDS 350-µg group (12% [13/105]; P = .03 vs observation) or in the dexamethasone DDS 700-µg group (9% [9/105]; P = .003 vs observation).
Other Efficacy Measures
A statistically significant improvement was found in both fluorescein leakage and central retinal thickness in patients receiving dexamethasone DDS compared with patients in the observation group (Table 4). For example, in the dexamethasone DDS 700-µg group, fluorescein leakage decreased by 2 or more levels in a third of patients (34 of 102; P<.001 vs observation) and by 3 or more levels in a quarter of patients (25 of 102; P<.001 vs observation). Mean central retinal thickness decreased by more than 160 µm in the dexamethasone DDS 700-µg group (n = 23), whereas it increased by more than 20 µm in the observation group (n = 30; P<.001).
|
|
|
|
Table 4. Other Efficacy Measures (Day 90)*
|
|
|
SAFETY ANALYSIS
The most common ocular adverse events in the study eye (occurring in 5% of patients in any treatment group during the study and for which the among-group P value was statistically significant) are summarized in Table 5. Statistically significant among-group differences in the frequency of several ocular adverse events were seen. Most ocular adverse events were mild in severity, and most were reported during the first week after surgery. The rates of most ocular adverse events in the treatment and observation groups were similar after day 8. Only 2 adverse events occurred significantly more frequently in a treatment group than in the observation group anytime after day 8: anterior chamber flare (5% in the dexamethasone DDS 700-µg group, 0% in the observation group; P = .03) and increased IOP (6% in the dexamethasone DDS 700-µg group, 0% in the observation group; P = .01) between day 91 and day 180.
|
|
|
|
Table 5. Most Common Ocular Adverse Events (Study Eye)*
|
|
|
Adverse events that can occur after intravitreal surgery or corticosteroid therapy (cataract, retinal detachments, vitreous hemorrhage, endophthalmitis, and elevated IOP) were evaluated specifically. No significant difference was found in the number of reports of cataract among the different study groups. There were 2 cases of extramacular tractional retinal detachments in diabetic patients, 1 in the study eye of a patient in the dexamethasone DDS 350-µg group and 1 in the nonstudy eye of a patient in the observation group, but neither case was considered by the investigator to be related to treatment. Most of the cases of vitreous hemorrhage were reported within the first week after surgery (17 of 21 cases in the dexamethasone DDS 350-µg group; 18 of 22 cases in the dexamethasone DDS 700-µg group), and most (37 of 43 [86%]) were mild in severity. One patient in the dexamethasone DDS 700-µg group with Irvine-Gass syndrome was reported at day 154 to have possible Propionibacterium acnes endophthalmitis. The investigator thought the condition was unrelated to the study treatment since the signs and symptoms preceded enrollment into the study. Culture results from this patient were negative, and the inflammation resolved after topical corticosteroid and topical antibiotic therapy.
At the primary end point (day 90), only 2 patients (2%) in each of the dexamethasone DDS treatment groups and 1 patient (1%) in the observation group had an IOP increase of 10 mm Hg or more from baseline. The number of patients with an increase in IOP of 10 mm Hg or more from baseline through day 90 was 10 (10%) of 100 in the dexamethasone DDS 350-µg group, 13 (13%) of 101 in the dexamethasone DDS 700-µg group, and 2 (2%) of 100 in the observation group. Most of these patients (7 of 10 in the dexamethasone DDS 350-µg group, 12 of 13 in the dexamethasone DDS 700-µg group, and 1 of 2 in the observation group) had only a single occurrence of an IOP increase of this magnitude or greater. The number of patients with an increase in IOP of 10 mm Hg or more from baseline anytime during the study was 12 (12%) of 100 in the dexamethasone DDS 350-µg group, 17 (17%) of 101 in the dexamethasone DDS 700-µg group, and 3 (3%) of 100 in the observation group. Most of these patients (8 of 12 in the dexamethasone DDS 350-µg group, 14 of 17 in the dexamethasone DDS 700-µg group, and 2 of 3 in the observation group) had only a single occurrence of an IOP increase of this magnitude or greater. The number of patients with an increase in IOP to 25 mm Hg or more anytime during the study was 18 (18%) of 100 in the dexamethasone DDS 350-µg group, 15 (15%) of 101 in the dexamethasone DDS 700-µg group, and 0 in the observation group. No patient had an IOP greater than 22 mm Hg at baseline.
Patients with increases in IOP were successfully managed with either observation or topical IOP-lowering medication. No patient required laser or surgical intervention to control IOP.
Among nonocular adverse events, the only statistically significant among-group differences were in the occurrence of hypertension (dexamethasone DDS 350-µg group, 22%; dexamethasone DDS 700-µg group, 40%; observation group, 26%; P = .02), arthralgia (dexamethasone DDS 350-µg group, 4%; dexamethasone DDS 700-µg group, 1%; observation group, 0%; P = .03), congestive heart failure (dexamethasone DDS 350-µg group, 1%; dexamethasone DDS 700-µg group, 4%; observation group, 0%; P = .049), and tooth infection (dexamethasone DDS 350-µg group, 3%; dexamethasone DDS 700-µg group, 0%; observation group, 0%; P = .03). None of these nonocular adverse events were considered by the investigators to be related to the study medication. No statistically significant changes were found in any laboratory findings (including blood glucose levels) in any of the treatment groups.
COMMENT
This study demonstrated that more patients with persistent ME achieved statistically significant improvements in visual acuity after treatment with dexamethasone DDS than did patients in the observation group. Statistically significant differences between the dexamethasone DDS 700-µg group and the observation group were seen as early as 60 days after treatment and were sustained through at least day 180 (last study visit). The primary end point in this study was the percentage of patients who achieved at least 10 letters of BCVA improvement at day 90 (in the overall population of patients with persistent ME). This was achieved by more patients in both the dexamethasone DDS 350-µg (P = .04) and 700-µg (P<.001) treatment groups than in the observation group.
Moreover, significantly more patients in the dexamethasone DDS 700-µg group than the observation group achieved 15 letters or more of improvement in BCVA at both day 90 (P = .006) and day 180 (P = .02). A patient who improves by 15 letters can read letters half the size of those read at baseline or can read the same size letters from twice as far away. For example, an individual with a baseline visual acuity of 20/80 who improves by 15 letters would achieve 20/40 vision.
Investigators were allowed to administer nonstudy treatments for ME to any study patient if they determined it to be medically necessary. The inclusion of an observation arm in the study protocol required that "escape treatments" be available to ensure good patient care. A significantly greater proportion of patients in the observation group received nonstudy treatments (such as photocoagulation, topical corticosteroidal or nonsteroidal anti-inflammatory agents, periocular corticosteroids, or intravitreal corticosteroids) during the study than did patients in either of the dexamethasone DDS treatment groups. The increased use of these treatments in the observation arm of this study would be expected to improve clinical outcomes in this control group and make it more difficult for the difference between the dexamethasone and observation groups to achieve statistical significance. This lends greater strength to the statistically significant differences that were observed.
In the present study, statistically significant improvements in central retinal thickness and fluorescein leakage were also seen in the dexamethasone DDS 700-µg group at day 90. The improvements seen in these parameters represent the anatomic (central retinal thickness) and physiologic (vascular permeability) correlates of the visual acuity improvements produced by the dexamethasone DDS treatment.
In this study, all efficacy results were qualitatively similar across patients with ME due to different diseases (eg, diabetic retinopathy, retinal vein occlusion, uveitis, or Irvine-Gass syndrome). The study was designed to evaluate the effects of dexamethasone treatment in patients with ME that had persisted for at least 90 days despite laser treatment or medical therapy regardless of the underlying cause of ME. Nonetheless, a preliminary evaluation by disease subtype was conducted to determine if the results in any 1 group were driving the overall results. This analysis showed that all efficacy results were more favorable in the dexamethasone treatment groups than the observation group regardless of the underlying cause of ME. Among patients with ME due to diabetic retinopathy or retinal vein occlusion (87% of all patients), the improvements in all efficacy measures were similar between these 2 study groups and the overall results. The improvement in efficacy measures in patients with uveitis or Irvine-Gass syndrome (13% of all patients) was somewhat greater than for the other patient groups, but because of the relatively small number of such patients, these results did not drive the overall findings. A more detailed analysis of the findings by disease subtype is under way and will be published in a series of separate articles.
A significantly higher incidence of certain adverse events was found in the dexamethasone DDS treatment groups than in the observation group. Most of the occurrences of these events, however, were mild, occurred during the first week after surgery, and resolved spontaneously or with treatment. In fact, many of these adverse events, such as hyperemia, pruritus, vitreous hemorrhage, and anterior chamber cells and flare, might be expected as a result of the surgical procedure. The rate of ocular adverse events after day 8 was similar between the treatment and observation groups. Moreover, a novel, simplified sutureless insertion procedure for the dexamethasone DDS has been developed, for which evaluations are currently under way. This procedure should result in fewer insertion-related adverse effects.
Adverse events that are of the greatest concern with corticosteroid therapy include cataract formation27 and increases in IOP.28-29 In the present study, the numbers of reports of cataract were similar in all of the treatment groups. However, treatment-related cataract formation may take longer than 180 days to become apparent. More patients in the dexamethasone DDS groups than the observation group had increases in IOP, but most of these patients had the onset of their increased IOP during the first week after treatment. Moreover, most of these patients had only a single occurrence of increased IOP. This finding suggests that investigators were able to manage increases in IOP when they occurred. All cases of elevated IOP were successfully managed with observation or topical medications, and no patients required surgical or laser treatments to control their IOP.
It is difficult to compare the incidence of increased IOP in the present study with that seen in other studies of intravitreal corticosteroids because each published study to date either enrolled a different patient population or reported the changes in IOP differently, or both.14-17,30 However, in a study by Wingate and Beaumont,30 11% of patients treated with a single 4-mg intravitreal triamcinolone acetonide injection for age-related macular degeneration had a 10–mm Hg or greater increase from baseline IOP at the month 3 visit compared with 2% of patients treated with dexamethasone in the present study (month 3 visit). No strong conclusions can be drawn from the comparison of our study findings regarding IOP changes with those from a different disease state, but it appears that increases in IOP during dexamethasone DDS treatment may be no more frequent (and possibly less frequent) than what has been seen after intravitreal triamcinolone therapy.
Other adverse effects that are of concern with any ophthalmic surgical procedure are endophthalmitis and vitreous hemorrhage. No treatment-related cases of endophthalmitis occurred in this study. Vitreous hemorrhage occurred in some patients in both dexamethasone treatment groups, but most cases were noted during the first week after surgery and were mild in severity.
One of the limitations of this study is the use of an observation arm instead of a sham surgery or placebo control, thereby making it impossible to ensure that the patient was masked with regard to treatment. This limitation was mitigated by ensuring that examiners were masked to the identity of the assigned treatment arm. A masked certified technician performed the visual acuity assessment at days 30, 60, 90, and 180, and patients were advised not to discuss their study group assignment with visual acuity or function assessors. In addition, a central reading facility masked to study group assignment was used for assessing fluorescein angiography and OCT evaluations. Another limitation of the study was that only a single treatment was given and patients were followed up for only 180 days. This study design is appropriate for an early clinical trial of a new treatment but limits the conclusions that can be drawn about the long-term effects of this therapy. Macular edema may persist or recur throughout a long period, and future investigations should include long-term evaluations of multiple dexamethasone DDS implants over time. Moreover, certain adverse effects, such as cataract, may take longer than 6 months to develop, and future studies should follow up patient safety for longer than 6 months.
Macular edema is a major cause of significant visual loss in a variety of different retinal diseases. The findings of this study suggest that dexamethasone DDS, 700 µg, may have potential as a valuable new therapy for this often recalcitrant disease process and support further investigation of its clinical use. Moreover, the statistically significant efficacy findings in this 6-month study suggest that the delivery system that contains 700 µg of dexamethasone is the more appropriate dose for future investigations.
AUTHOR INFORMATION
Correspondence: Baruch D. Kuppermann, MD, PhD, Department of Ophthalmology, University of California, Irvine, 118 Med Surge I, Irvine, CA 92697-4375 (bdkupper{at}uci.edu).
Submitted for Publication: January 18, 2006; final revision received September 28, 2006; accepted September 30, 2006.
Author Contributions: Dr Kuppermann had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The Dexamethasone DDS Phase II Study Group Investigators: Carl Awh, MD, Nashville, Tenn; Brian Berger MD, Austin, Tex; Paul Bernstein, MD, PhD, Salt Lake City, Utah; Herbert Cantrill, MD, Minneapolis, Minn; Thomas Chang, MD, Los Angeles, Calif; Stanley Chang, MD, New York, NY; Robert Diaz-Rohena, MD, McAllen, Tex; Bernard Doft, MD, Pittsburgh, Pa; Pravin Dugel, MD, Phoenix, Ariz; Kurt Gitter, MD, New Orleans, La; Bert Glaser, MD, Chevy Chase, Md; Stuart Green, MD, New Brunswick, NJ; Julia A. Haller, MD, Baltimore, Md; Dennis Han, MD, Milwaukee, Wis; Bradley Jost, MD, Dallas, Tex; Baruch D. Kuppermann, MD, PhD, Irvine, Calif; Hilel Lewis, MD, Cleveland, Ohio; Helen Li, MD, Galveston, Tex; Peter Liggett, MD, Hamden, Conn; Travis Meredith, MD, Chapel Hill, NC; George Novalis, MD, Tucson, Ariz; Steven Sanislo, MD, Palo Alto, Calif; Steven Schwartz, MD, Los Angeles; Lawrence Singerman, MD, Cleveland; Alan Wagner, MD, Virginia Beach, Va; George A. Williams, MD, Royal Oak, Mich; David Wilson, MD, Portland, Ore; Keye Wong, MD, Sarasota, Fla; Lucy H. Young, MD, PhD, Boston, Mass.
Financial Disclosure: None reported.
Funding/Support: This study was sponsored by Oculex Pharmaceuticals Inc. Additional data analysis and interpretation were provided by Allergan Inc, which supervised the preparation of the manuscript and approved the final version. Allergan Inc also supervised a secondary analysis of all of the data by an independent statistician. The independent statistician was Ronald W. Helms, Department of Biostatistics, University of North Carolina; he received compensation from Allergan Inc for his participation.
Author Affiliations: Departments of Ophthalmology, University of California, Irvine (Dr Kuppermann), Stanford University, Stanford, Calif (Dr Blumenkranz), and Wilmer Eye Institute, Johns Hopkins University, Baltimore, Md (Dr Haller); Associated Retinal Consultants, Beaumont Eye Institute, Royal Oak, Mich (Dr Williams); The Eye Institute, Medical College of Wisconsin, Milwaukee (Dr Weinberg); and Allergan Inc, Irvine (Drs Chou and Whitcup).
REFERENCES
| |
1. Ferris FL III, Patz A. Macular edema: a complication of diabetic retinopathy. Surv Ophthalmol. 1984;28(suppl):452-461.
FULL TEXT
|
ISI
| PUBMED
2. Klein R, Klein BE, Moss SE, Cruickshanks K. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, XV: the long-term incidence of macular edema. Ophthalmology. 1995;102:7-16.
ISI
| PUBMED
3. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: ETDRS report number 4. Int Ophthalmol Clin. 1987;27:265-272.
FULL TEXT
|
ISI
| PUBMED
4. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103:1796-1806.
FREE FULL TEXT
5. Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol. 2002;133:70-77.
FULL TEXT
|
ISI
| PUBMED
6. Antonetti DA, Barber AJ, Khin S; et al. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Diabetes. 1998;47:1953-1959.
ABSTRACT
7. Leopold IH. Nonsteroidal and steroidal anti-inflammatory agents. In: Sears M, Tarkkanen A, eds. Surgical Pharmacology of the Eye. New York, NY: Raven Press; 1985:83-133.8. Nauck M, Karakiulakis G, Perruchoud A, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol. 1998;341:309-315.
FULL TEXT
|
ISI
| PUBMED
9. Tennant JL. Cystoid maculopathy: 125 prostaglandins in ophthalmology. In: Emery JM, ed. Current Concepts in Cataract Surgery: Selected Proceedings of the Fifth Biennial Cataract Surgical Congress: Section 3. St Louis, Mo: CV Mosby; 1978:360-362.10. Antonetti DA, Wolpert EB, Maio L, Harhaj NS, Scaduto RC Jr. Hydrocortisone decreases retinal endothelial cell water and solute flux coincident with increased content and decreased phosphorylation of occludin. J Neurochem. 2002;80:667-677.
FULL TEXT
|
ISI
| PUBMED
11. Lee VHL, Pince KJ, Frambach DA, Martini B. Drug delivery to the posterior segment. In: Ogden TE, Schachat AP, eds. Retina. Vol 1. St Louis, Mo: CV Mosby; 1989:483-498.12. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin. 1992;10:505-512.
ISI
| PUBMED
13. Maurice DM. Micropharmaceutics of the eye. Ocular Inflammation Ther. 1983;1:97-102.
14. Jonas JB, Kreissig I, Sofker A, Degenring RF. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol. 2003;121:57-61.
FREE FULL TEXT
15. Sutter FKP, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment. 3-month efficacy and safety results of a prospective, randomized, double-masked, placebo-controlled clinical trial. Ophthalmology. 2004;111:2044-2049.
FULL TEXT
|
ISI
| PUBMED
16. Young S, Larkin G, Branley M, Lightmann S. Safety and efficacy of intravitreal triamcinolone for cystoid macular oedema in uveitis. Clin Experiment Ophthalmol. 2001;29:2-6.
FULL TEXT
|
ISI
| PUBMED
17. Martidis A, Duker JS, Greenberg PB; et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920-927.
FULL TEXT
|
ISI
| PUBMED
18. Ip MS, Gottlieb JL, Kahana A; et al. Intravitreal triamcinolone for the treatment of macular edema associated with central retinal vein occlusion. Arch Ophthalmol. 2004;122:1131-1136.
FREE FULL TEXT
19. Nabih M, Peyman GA, Tawakol ME, Naguib K. Toxicity of high-dose intravitreal dexamethasone. Int Ophthalmol. 1991;15:233-235.
ISI
| PUBMED
20. Kwak HW, D’Amico DJ. Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection. Arch Ophthalmol. 1992;110:259-266.
FREE FULL TEXT
21. Maxwell DP Jr, Brent BD, Diamond JG, Wu L. Effect of intravitreal dexamethasone on ocular histopathology in a rabbit model of endophthalmitis. Ophthalmology. 1991;98:1370-1375.
ISI
| PUBMED
22. Kobayashi H, Shiraki K, Ikada Y. Toxicity test of biodegradable polymers by implantation in rabbit cornea. J Biomed Mater Res. 1992;26:1463-1476.
FULL TEXT
|
ISI
| PUBMED
23. Moritera T, Ogura Y, Honda Y, Wada R, Hyon SH, Ikada Y. Microspheres of biodegradable polymers as a drug-delivery system in the vitreous. Invest Ophthalmol Vis Sci. 1991;32:1785-1790.
FREE FULL TEXT
24. Visscher GE, Robison RL, Maulding HV, Fong JW, Pearson JE, Argentieri GJ. Biodegradation of and tissue reaction to 50:50 poly(dl-lactide-co-glycolide) microcapsules. J Biomed Mater Res. 1985;19:349-365.
FULL TEXT
|
ISI
| PUBMED
25. Early Treatment Diabetic Retinopathy Study Research Group. Early Treatment Diabetic Retinopathy Study Design and baseline patient characteristics: ETDRS report number 7. Ophthalmology. 1991;98:741-756.
ISI
| PUBMED
26. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS report no. 4. Am J Ophthalmol. 2001;131:167-175.
FULL TEXT
|
ISI
| PUBMED
27. Butcher J, Austin M, McGalliard J, Bourke R. Bilateral cataracts and glaucoma induced by long term use of steroid eye drops. BMJ. 1994;309:43.
FREE FULL TEXT
28. Armaly ME. Statistical attributes of the steroid hypertensive response in the clinically normal eye, I: the demonstration of three levels of response. Invest Ophthalmol. 1965;4:187-197.
FREE FULL TEXT
29. Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol. 1965;4:198-205.
FREE FULL TEXT
30. Wingate RJB, Beaumont PE. Intravitreal triamcinolone and elevated intraocular pressure. Aust N Z J Ophthalmol. 1999;27:431-432.
FULL TEXT
|
ISI
| PUBMED
SECTION EDITOR: ROY W. BECK, MD, PhD
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Poly-{epsilon}-Caprolactone Intravitreous Devices: An In Vivo Study
Silva-Cunha et al.
IOVS 2009;50:2312-2318.
ABSTRACT
| FULL TEXT
Dexamethasone Inhibits High Glucose-, TNF-{alpha}-, and IL-1{beta}-Induced Secretion of Inflammatory and Angiogenic Mediators from Retinal Microvascular Pericytes
Nehme and Edelman
IOVS 2008;49:2030-2038.
ABSTRACT
| FULL TEXT
Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations
Short
Toxicol Pathol 2008;36:49-62.
ABSTRACT
| FULL TEXT
From the Library
Br. J. Ophthalmol. 2007;91:846-846.
FULL TEXT
|
