Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.
To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal triamcinolone acetonide (IVT) versus macular laser photocoagulation (MPC) as a primary treatment of diabetic macular edema (DME).
                Randomized 3-arm clinical trial.
                A total of 150 eyes of 129 patients with clinically significant DME and no previous treatment.
                The eyes were randomly assigned to 1 of the 3 study arms: the IVB group, patients who received 1.25 mg IVB (50 eyes); the IVB/IVT group, patients who received 1.25 mg of IVB and 2 mg of IVT (50 eyes); and the MPC group, patients who underwent focal or modified grid laser (50 eyes). Retreatment was performed at 12-week intervals whenever indicated.
                Change in best-corrected visual acuity (VA) at week 24.
                VA changes among the groups were statistically significant at 6 (P<0.001) and 24 (P = 0.012) weeks. The significant treatment effect was demonstrated in the IVB group at all follow-up visits and in the IVB/IVT group at 6 and 12 weeks. VA changes +/- standard deviation at 36 weeks were -0.28+/-0.25, -0.04+/-0.33, and +0.01+/-0.27 logarithm of minimum angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively (P = 0.053). Significant central macular thickness (CMT) reduction was observed in all groups only up to 6 weeks; however, CMT changes were not significant among the groups in all visits. Overall, retreatment was required for 27 eyes up to 36 weeks (14 in the IVB group, 10 in the IVB/IVT group, and 3 in the MPC group). In the IVB group, in which a greater VA improvement was observed, only 1 injection was required in 72% of the cases. VA improvement >2 Snellen lines at 36 weeks was detected in 37%, 25%, and 14.8% of patients in the IVB, IVB/IVT, and MPC groups, respectively.
                Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation. A change in CMT beyond the 6-week time point that corresponded to the vision change was not detected. No adjunctive effect of IVT was demonstrated.
                The author(s) have no proprietary or commercial interest in any materials discussed in this article. To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME).
                Prospective, randomized, interventional, multicenter clinical trial.
                One hundred twenty-six patients with DME.
                Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ.
                The mean change from baseline in best-corrected visual acuity (BCVA) at month 24.
                After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively.
                Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.
                Proprietary or commercial disclosure may be found after the references.
                Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To compare different doses and dosing regimens of Vascular Endothelial Growth Factor (VEGF) Trap-Eye with laser photocoagulation in eyes with diabetic macular edema (DME).
                Randomized, double-masked, multicenter, phase 2 clinical trial.
                Diabetic patients (n = 221) with center-involved DME.
                Participants were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation.
                The change in best-corrected visual acuity (BCVA) at 24 weeks (the primary end point) and at 52 weeks, proportion of eyes that gained 15 letters or more in Early Treatment of Diabetic Retinopathy Study (ETDRS) BCVA, and mean changes in central retinal thickness (CRT) from baseline.
                As previously reported, mean improvements in BCVA in the VEGF Trap-Eye groups at week 24 were 8.6, 11.4, 8.5, and 10.3 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus 2.5 letters for the laser group (P ≤ 0.0085 versus laser). Mean improvements in BCVA in the VEGF Trap-Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus -1.3 letters for the laser group (P ≤ 0.0001 versus laser). Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the VEGF Trap-Eye groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser (P = 0.0031, P = 0.0007, P = 0.1608, and P = 0.0016, respectively, versus laser). Mean reductions in CRT in the VEGF Trap-Eye groups at week 52 were -165.4 μm, -227.4 μm, -187.8 μm, and -180.3 μm versus -58.4 μm for laser (P < 0.0001 versus laser). Vascular Endothelial Growth Factor Trap-Eye generally was well tolerated. The most frequent ocular adverse events with VEGF Trap-Eye were conjunctival hemorrhage, eye pain, ocular hyperemia, and increased intraocular pressure, whereas common systemic adverse events included hypertension, nausea, and congestive heart failure.
                Significant gains in BCVA from baseline achieved at week 24 were maintained or improved at week 52 in all VEGF Trap-Eye groups. Vascular Endothelial Growth Factor Trap-Eye warrants further investigation for the treatment of DME.
                Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).
                A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
                We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
                Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
                Mean average change in BCVA from baseline to month 1 through 12 and safety.
                Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
                Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.
                Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To evaluate the effect of three intravitreal injections of bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular edema (DME).
                In this prospective, placebo-controlled, randomized clinical trial, 115 eyes of 101 patients with refractory DME were included. Subjects were randomly assigned to one of the three study arms: 1) three injections of IVB (1.25 mg/0.05 ml) at 6-week intervals, 2) combined IVB and IVT (1.25 mg/0.05 ml and 2 mg/0.05 ml respectively) followed by two injections of IVB at 6-week intervals, and 3) sham injection (control group). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA ) and incidence of potential adverse events.
                Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was -95.7 microm (95% CI, -172.2 to -19.26) in the IVB group, -92.1 microm (95% CI, -154.4 to -29.7) in the IVB/IVT group, and 34.9 microm (95% CI, 7.9 to 61.9) in the control group. There was a significant difference between the IVB and control groups (P = 0.012) and between the IVB/IVT and control groups (P = 0.022). Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. In terms of BCVA change compared to the baseline at 24 weeks, the differences between the IVB and control groups (P = 0.01) and also between the IVB/IVT and control groups (P = 0.006) were significant. No significant differences were detected in the changes of CMT and BCVA between the IVB and IVB/IVT groups (P = 0.99). Anterior chamber reaction was noticed in eight (19.5%) and seven (18.9%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of IOP occurred in three eyes (8.1%) in the IVB/IVT group.
                Three consecutive intravitreal injections of bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the first injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up. The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.
                This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection).
                At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 μm with ranibizumab and 48.4±153.4 μm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab.
                Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety. To report the findings at 1 year of a study comparing repeated intravitreal bevacizumab (ivB) and modified Early Treatment of Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant diabetic macular edema (CSME).
                Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial.
                A total of 80 eyes of 80 patients with center-involving CSME and at least 1 prior MLT.
                Subjects were randomized to either ivB (6 weekly; minimum of 3 injections and maximum of 9 injections in the first 12 months) or MLT (4 monthly; minimum of 1 treatment and maximum of 4 treatments in the first 12 months).
                The primary end point was the difference in ETDRS best-corrected visual acuity (BCVA) at 12 months between the bevacizumab and laser arms.
                The baseline mean ETDRS BCVA was 55.7+/-9.7 (range 34-69) in the bevacizumab group and 54.6+/-8.6 (range 36-68) in the laser arm. The mean ETDRS BCVA at 12 months was 61.3+/-10.4 (range 34-79) in the bevacizumab group and 50.0+/-16.6 (range 8-76) in the laser arm (P = 0.0006). Furthermore, the bevacizumab group gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (P = 0.0002). The odds of gaining > or =10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95% confidence interval, 1.3-19.7; P = 0.019). At 12 months, central macular thickness decreased from 507+/-145 microm (range 281-900 microm) at baseline to 378+/-134 microm (range 167-699 microm) (P<0.001) in the ivB group, whereas it decreased to a lesser extent in the laser group, from 481+/-121 microm (range 279-844 microm) to 413+/-135 microm (range 170-708 microm) (P = 0.02). The median number of injections was 9 (interquartile range [IQR] 8-9) in the ivB group, and the median number of laser treatments was 3 (IQR 2-4) in the MLT group.
                The study provides evidence to support the use of bevacizumab in patients with center-involving CSME without advanced macular ischemia.
                Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients.
                Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies.
                Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT).
                Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria.
                Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months.
                In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8-34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7-31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8-42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3-0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients.
                Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.
                Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia.
                Randomized (1:1), sham-controlled, multicenter, parallel-group trial.
                Subjects with DME.
                Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria.
                The primary efficacy endpoint was the proportion gaining ≥ 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout.
                In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of ≥ 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 [23.3%] vs 53/127 [41.7%], respectively, P = 0.002; week 102, 27/107 [25.2%] vs 45/100 [45.0%], respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups.
                Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population.
                Proprietary or commercial disclosure may be found after the references.
                Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME).
                Randomized, double-masked, multicenter, dose-ranging, controlled trial.
                Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks.
                Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36.
                Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36.
                One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss.
                In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.
There is moderate quality evidence that antiangiogenic drugs provide a definite, but small, benefit compared to current therapeutic options for DMO, i.e. grid laser photocoagulation, or no treatment when laser is not an option. The quality and quantity of the evidence was larger for ranibizumab, but there was little power to investigate drug differences. Most data were obtained at one year, and a long-term confirmation is needed, since DMO is a chronic condition. Safety of both drug and the intravitreal injection procedure were good in the trials, but further long-term data are needed to exclude small, but clinically important differences regarding systemic adverse events.