Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.

PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

TYPE 1 VERSUS TYPE 3 NEOVASCULARIZATION IN PIGMENT EPITHELIAL DETACHMENTS ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY: A Prospective Study.

PURPOSE: To evaluate the response to aflibercept therapy for Type 1 and Type 3 neovascularization in pigment epithelial detachments associated with treatment-naive, neovascular age-related macular degeneration. METHODS: In this multicentered, prospective study, eligible eyes underwent an intravitreal aflibercept injection protocol for 12 months. Visual acuity and morphologic features of the pigment epithelial detachments were compared at baseline and follow-up intervals between eyes with Type 1 versus Type 3 neovascularization. RESULTS: Thirty-six eyes were analyzed. At 12 months, Type 1 lesions showed a 4.5 ± 23 Early Treatment of Diabetic Retinopathy Study letter improvement (P = 0.1665) versus a 14 ± 11 (P = 0.0072) letter improvement with Type 3 lesions. Both Type 1 and 3 eyes showed a significant decrease in pigment epithelial detachment size, subretinal fluid, and subretinal hyperreflective material; however, Type 3 eyes had a greater reduction in pigment epithelial detachment size and subretinal hyperreflective material, as well as a reduction in central retinal thickness. Type 1 eyes required an average of 1.636 (range, 1-4) injections to resolve fluid, which was greater than Type 3 eyes, which required an average of 1.143 (range, 1-2) injections (P = 0.0251). CONCLUSION: Intravitreal aflibercept injections were efficacious for pigment epithelial detachments, but baseline and follow-up anatomical and functional outcomes differed in Type 1 versus Type 3 neovascularization. The better response of Type 3 eyes with fewer injections suggests that differentiation of the neovascularization subtype at the initial diagnosis may allow for a more tailored, optimal therapy.

Prospective evaluation of the incidence and risk factors for the development of RPE tears after high- and low-dose ranibizumab therapy.

PURPOSE: To prospectively determine the incidence and risk factors for retinal pigment epithelial (RPE) tears in eyes with vascularized pigment epithelial detachments (PED) and exudative age-related macular degeneration receiving antivascular endothelial growth factor therapy. METHODS: Eyes were prospectively randomized into 1 of 4 arms: 1) 0.5 mg of ranibizumab monthly for 12 months; 2) 0.5 mg of ranibizumab monthly for 3 months and then pro re nata on the basis of clinical and optical coherence tomography-guided indications; 3) high-dose 2.0 mg of ranibizumab monthly for 12 months; or 4) 2.0 mg of ranibizumab monthly for 3 months and then pro re nata thereafter. All PEDs were measured for height, greatest linear diameter, and surface area at baseline. The incidence of RPE tears in the entire 4-arm cohort was determined at the end of 12 months. Eyes were divided into two groups (tear vs. nontear) and statistically compared to determine risk factors for the development of RPE tear. RESULTS: Of 37 eyes, a total of 5 developed postranibizumab RPE tears during the course of the study (incidence 14%). Four of the 5 tears occurred in the high-dose 2.0-mg groups. Baseline PED height, surface area, and greatest linear diameter were significantly greater in the group that developed RPE tears versus the nontear group (P = 0.018, 0.031, and 0.048, respectively). There were significantly more eyes with PED height >550 microns in the RPE tear group (4 of 5, 80%) compared with the nontear group (9 of 32, 18%) (P = 0.042). The presence of PED height >550 microns was associated with an increased tear rate from 14% to 31%. Furthermore, retrospective identification of a ring sign or Grade 1 tear at baseline, in addition to PED height >550 microns, was associated with a further increase in the tear rate to 67%. CONCLUSION: In this study, the prospective incidence of RPE tears was ∼14%. A baseline PED height >550 microns and presence of a Grade 1 tear, or positive ring sign, were identified as high-risk factors for the subsequent development of an RPE tear.

Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial.

Importance: Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden. Objective: To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD. Design, Setting, and Participants: The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021. Interventions: Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 µL) or 2 mg (50 µL) of aflibercept followed by doses at weeks 20 and 32. Main Outcomes and Measures: Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety. Results: All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, -1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, -6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was -159.4 (16.4) vs -137.2 (22.8) µm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, -9.5 [95% CI, -51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, -1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed. Conclusions and Relevance: Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema. Trial Registration: ClinicalTrials.gov Identifier: NCT04126317.

Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial.

PURPOSE: To determine whether prophylactic ranibizumab prevents the development of neovascular age-related macular degeneration (nAMD) in eyes with intermediate age-related macular degeneration (AMD) for patients with preexisting nAMD in their contralateral eye. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Adults aged 50 years and older with intermediate AMD (multiple intermediate drusen [≥63 µm and <125 µm] or ≥1 large drusen [≥125 µm] and pigmentary changes) in the study eye and nAMD in the contralateral eye. INTERVENTION: Intravitreal ranibizumab injection (0.5 mg) or sham injection every 3 months for 24 months. MAIN OUTCOME MEASURES: Conversion to nAMD over 24 months (primary). Change in best-corrected visual acuity from baseline to 24 months (secondary). RESULTS: Among 108 enrolled participants (54 [50%] in each group), all except 2 were non-Hispanic Whites, 61 participants (56%) were female, and the mean age was 78 years. The mean baseline visual acuity was 77.7 letters (Snellen equivalent 20/32). Conversion to nAMD over 24 months occurred among 7 of 54 eyes (13%) in both groups (ranibizumab vs. sham hazard ratio = 0.91 [95% confidence interval (CI), 0.32-2.59]; P = 0.86). At 24 months, the cumulative incidence of nAMD adjusted for loss to follow-up was 14% (95% CI, 4%-23%) in the ranibizumab group and 15% (95% CI, 4%-25%) in the sham group. At 24 months, the mean change in visual acuity from baseline was -2.1 letters (standard deviation, 5.4 letters) with ranibizumab and -1.4 letters (standard deviation, 7.7 letters) with sham (adjusted difference = -0.8 letters [95% CI, -3.7 to 2.2 letters]; P = 0.62). The proportion of eyes that lost at least 10 letters of visual acuity from baseline at 24 months was 2 of 39 (5%) with ranibizumab and 4 of 40 (10%) with sham. There were no serious ocular adverse events in either group. CONCLUSIONS: Quarterly dosing of 0.5 mg ranibizumab in eyes with intermediate AMD did not reduce the incidence of nAMD compared with sham injections; however, the study was likely underpowered given the 95% CI, and a clinically meaningful effect cannot be excluded. There also was no effect on visual acuity at 24 months. Other strategies to reduce neovascular conversion in these vulnerable eyes are needed.

Ranibizumab for choroidal neovascularization secondary to causes other than age-related macular degeneration: a phase I clinical trial.

PURPOSE: To investigate the safety and efficacy of ranibizumab for the treatment of choroidal neovascularization (CNV) secondary to causes other than age-related macular degeneration (AMD). DESIGN: Multicenter, randomized, 12-month clinical trial. PARTICIPANTS: Thirty patients with CNV due to causes other than AMD, including pathologic myopia, ocular histoplasmosis, and angioid streaks. METHODS: Participants were randomly assigned 1:1 to monthly intravitreal injections of 0.5 mg ranibizumab or 3 monthly injections followed by dosing as needed (pro re nata [PRN]) at monthly follow-up visits. MAIN OUTCOME MEASURES: Outcome measures included the incidence of ocular and nonocular adverse events, the percentage of patients gaining ≥ 15 letters of visual acuity (VA) at 6 and 12 months from baseline, the percentage of patients losing ≥ 15 letters of VA at 6 and 12 months from baseline, and mean change in VA and central retinal thickness (CRT) at 6 and 12 months from baseline. RESULTS: No serious ocular or systemic adverse events related to ranibizumab or the injection procedure were reported. Among patients who received monthly ranibizumab injections, 8 of 12 (66.7%) gained ≥ 15 letters of VA at both 6 and 12 months, and among patients who received PRN injections, 9 of 14 (64.3%) and 8 of 14 (57.1%) gained ≥ 15 letters of VA at 6 and 12 months, respectively. No patient in the study lost ≥ 15 letters of VA. Mean VA improved significantly from baseline by 23.9 ± 5.4 (P = 0.001) and 21.1 ± 4.3 letters (P = 0.0003) at 6 months and by 26.9 ± 5.3 (P = 0.0003) and 19.2 ± 3.8 letters (P = 0.0002) at 12 months in the monthly and PRN treatment arms, respectively. Mean CRT decreased significantly from baseline by 103.4 ± 18.9 (P = 0.0005) and 161.1 ± 43.7 µm (P = 0.0034) at 6 months and by 109.3 ± 19.5 (P = 0.0004) and 166.6 ± 38.4 µm (P = 0.001) at 12 months in the monthly and PRN treatment groups, respectively. No statistically significant difference was found between treatment groups in change in VA or CRT at any time point. CONCLUSIONS: Intravitreal ranibizumab, given as monthly injections or as 3 monthly injections followed by PRN dosing, showed a promising efficacy and safety profile in the treatment of CNV due to causes other than AMD.

Primary endpoint results of a phase II study of vascular endothelial growth factor trap-eye in wet age-related macular degeneration.

OBJECTIVE: To evaluate the biologic effects and safety of vascular endothelial growth factor (VEGF) Trap-Eye during a 12-week fixed-dosing period in patients with neovascular (wet) age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, randomized, double-masked clinical trial with initial 12-week fixed dosing period. Data were analyzed to week 16. PARTICIPANTS: We included 159 patients with subfoveal choroidal neovascularization secondary to wet AMD. METHODS: Patients were randomized 1:1:1:1:1 to VEGF Trap-Eye during the fixed-dosing phase (day 1 to week 12): 0.5 or 2 mg every 4 weeks (0.5 mg q4wk, 2 mg q4wk) on day 1 and at weeks 4, 8, and 12; or 0.5, 2, or 4 mg every 12 weeks (0.5 mg q12wk, 2 mg q12wk, or 4 mg q12wk) on day 1 and at week 12. MAIN OUTCOME MEASURES: The primary endpoint was change from baseline in central retinal/lesion thickness (CR/LT) at week 12; secondary outcomes included change in best-corrected visual acuity (BCVA), proportion of patients with a gain of ≥ 15 letters, proportion of patients with a loss of >15 letters, and safety. RESULTS: At week 12, treatment with VEGF Trap-Eye resulted in a significant mean decrease in CR/LT of 119 µm from baseline in all groups combined (P<0.0001). The reduction in CR/LT with the 2 mg q4wk and 0.5mg q4wk regimens was significantly greater than each of the quarterly dosing regimens. The BCVA increased significantly by a mean of 5.7 letters at 12 weeks in the combined group (P<0.0001), with the greatest mean gain of >8 letters in the monthly dosing groups. At 8 weeks, BCVA improvements were similar with 2 mg q4wk and 2 mg q12wk dosing. After the last required dose at week 12, CR/LT and visual acuity were maintained or further improved at week 16 in all treatment groups. Ocular adverse events were mild and consistent with safety profiles reported for other intraocular anti-VEGF treatments. CONCLUSIONS: Repeated monthly intravitreal dosing of VEGF Trap-Eye over 12 weeks demonstrated significant reductions in retinal thickness and improvements in visual acuity, and was well-tolerated in patients with neovascular AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Post-hoc analysis of single nucleotide polymorphism profile for eyes with vascularized pigment epithelial detachment due to ARMD.

INTRODUCTION: This post-hoc case-control study compares single nucleotide polymorphism (SNP) profile of eyes with vascularized pigment epithelial detachment (vPED) due to age-related macular degeneration (ARMD) with: (1) Control-1 eyes (no ARMD and AREDS Severity Scale 0); and (2) Control-2 eyes (drusen or AREDS Severity Scale 2). SNP profile of High Responders (HR) was also compared with Low Responders (LR) to ranibizumab. METHODS: Blood samples from 40 patients with vPED treated with ranibizumab were sent for SNP-specific genotype analysis for comparison of variant allele frequencies of 23 SNPs associated with ARMD (VAF) to VAF in 184 Control-1 eyes, and VAF in 85 Control-2 eyes. VAF of HR-50 (⩾50% decrease in PED height) and VAF of HR-75 (⩾75% decrease in PED height) were also compared with VAF of LR. RESULTS: These SNPs were more frequent in vPED than Control-1 eyes: APOE rs4420638 (A/G), HTRA1 rs104904924 (G/T), VEGF rs943080 (T/C), CFH rs1061170 (T/C), CFH rs2274700 (C/T), CFH rs10737680 (A/C), CFH rs10801555 (G/A). These SNPs were more frequent in vPED than Control-2 eyes: APOE rs4420638 (A/G), CFI rs4698775 (G/T), COL15A1/TGFBR1 rs334353 (T/G). FRK rs3812111 (T/A) was more frequent in HR-50 and HR-75 eyes compared with LR. CONCLUSION: Seven SNPs were more frequent in vPED eyes than non-ARMD eyes, and three SNPs were more frequent in vPED eyes than drusen eyes. Adjusting for multiplicity, only CFH rs2274700 (C/T) was significant for first comparison, and only COL15A1/TGFBR1 rs334353 (T/G) was significant for second comparison. APOE rs4420638 (A/G) was the single SNP more frequently linked to vPED eyes for both comparisons. FRK rs3812111 (T/A) was consistently associated with high responders.

Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study.

OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: One hundred twenty-six patients with DME. METHODS: 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. MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24. RESULTS: 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. CONCLUSIONS: 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. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Optical coherence tomography-measured pigment epithelial detachment height as a predictor for retinal pigment epithelial tears associated with intravitreal bevacizumab injections.

PURPOSE: The purpose was to study preinjection optical coherence tomography-related factors in age-related macular degeneration eyes with retinal pigment epithelial detachment (PED) that may predispose retinal pigment epithelial (RPE) tears associated with intravitreal bevacizumab injections. METHODS: This multicenter retrospective case series involving 9 retina specialists and 7 centers investigated Stratus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA) parameters in eyes with vascularized PED (vPED) from February 2006 to February 2007. Of the 1,280 eyes in 1,255 patients receiving 2,890 intravitreal injections, there were 125 eyes with vPED. For every vPED eye that developed an RPE tear (Group 1), 3 or more vPED eyes without RPE tears (Group 2) were randomly selected in each study center during the same time period for comparison. The primary outcome measure was PED height (microm), and the secondary measures included volume index (vPED height x surface area), total macular volume, subretinal fluid, cystoid macular edema, center-point thickness, central 1 mm, and pre- and postinjection best-corrected Snellen visual acuities. RESULTS: Twenty-one vPED eyes in 21 patients among 125 vPED eyes (16.8% of all vPED eyes) developed RPE tears. The 21 Group 1 eyes were compared with the 78 randomly selected Group 2 eyes. The vPED height was significantly higher for Group 1 eyes in comparison to Group 2 eyes (mean: 648.9 +/- 245.0 vs. 338.1 +/- 201.6 microm, P < 0.001). The same was true for the following: volume index (P = 0.001), subretinal fluid (P = 0.002), and total macular volume (P = 0.04). The mean preinjection and post-RPE tear best-corrected visual acuity were 0.92 logMAR (20/166) and 0.84 logMAR (20/137), respectively (P = 0.25). Multivariate analysis showed PED height to be the only significant risk factor associated with RPE tears in Group 1 eyes [odds ratio = 0.995 (95% confidence interval: 0.992-0.997), P < 0.001]. CONCLUSION: Elevated preinjection vPED height is the single most significant predictor for RPE tears after bevacizumab injections for vPED eyes. A vPED height >400 microm is associated with a significant risk for such a complication.

Meticulous multimodal analysis of aflibercept therapy for submacular vascularized pigment epithelial detachment associated with neovascular AMD in a prospective case series, the EVEN study.

PURPOSE: This prospective case series investigates the visual and anatomical outcomes including detailed volumetrics of eyes with vascularized pigment epithelial detachments (PED) treated with aflibercept in eyes with neovascular age-related macular degeneration (nAMD) through meticulous analysis in a reading center setting. METHODS: We conducted a single-arm multicenter, prospective, open-labeled, interventional case series, comparing visual and anatomic outcomes at 12 months with baseline for intense aflibercept therapy. Eyes with submacular vascularized PED due to AMD received 2.0 mG of intravitreal aflibercept at baseline and then monthly for 6 months. During the subsequent 6 months, mandatory aflibercept therapy was given for every other month, while additional aflibercept injections were allowed between mandatory injections if necessary, at 4 weeks after last injection, contingent on pre-defined visual and anatomic re-treatment criteria. Standardized ETDRS vision measurement, anterior and posterior segment examination, and high-density spectral-domain optical coherence tomography scans were obtained at baseline and monthly, while fundus photography and fluorescein angiography were obtained at baseline, 3,6, and 12 months. Indocyanine-green angiography was obtained at baseline and 3 months. Meticulous multidimensional assessment of the scanned multimodal serial images was then performed by Doheny Image Reading Center. RESULTS: Of 36 eyes and patients with mean age of 80, mean baseline and 12-month-ETDRS BCVA was 59 ± 8.9 letters (20/66), and 65 ± 27 letters (20/50), respectively; (6.5 letters improvement, p = 0.02). Significant reductions from baseline to month-12 were noted for multiple anatomic measures, including PED maximum height, entire lesion and central 1-mm subfield of PED mean thickness and volume, and mean subretinal hyperreflective material (SHRM) thickness and volume, also entire lesion of retinal thickness, retinal volume, and mean subretinal fluid (SRF) thickness (mean reductions in magnitude ranging from 37.5 to 91.7%, all p < 0.001). FA measurements also showed significant decrease from baseline to month-12, including area and greatest linear diameter (GLD) of fibrovascular PED, area and GLD of NV area and leakage (mean reductions in magnitude from 41.9 to 87.7%, p value from 0.002 to <0.001). This case series shows that while majority of reductions in SRF volume occurred during first month from baseline, majority of reduction in retinal, PED, and SHRM volumes occurred during first 2 months after onset of anti-VEGF injections. RPE tears developed in 5 eyes (13.9%) correlating with eyes with large PED height and volume at baseline (mean height >800 µm, mean volume >4 mm3). Geographic atrophy (GA) was noted in only 1 eye at baseline, but in 16 eyes (44.4%) by 12 months. CONCLUSIONS AND IMPORTANCE: Significant improvement in vision and anatomic measures including volumetrics of vPED were noted at 12 months after aflibercept therapy. Besides substantial PED height, large PED volume at baseline also correlated with RPE tears in 13.9% of eyes with vPED after anti-VEGF therapy. Reduction in SHRM correlated directly with decrease in PED, and more than 40% of study eyes developed GA by 12 months following intense anti-VEGF therapy.

Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study.

OBJECTIVES: To compare ranibizumab with focal/grid laser or a combination of both in diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: A total of 126 patients with DME. METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg of ranibizumab at baseline and months 1, 3, and 5 (group 1, 42 patients), focal/grid laser photocoagulation at baseline and month 3 if needed (group 2, 42 patients), or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 (group 3, 42 patients). MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at month 6. RESULTS: At month 6, the mean gain in BCVA was significantly greater in group 1 (+7.24 letters, P = 0.01, analysis of variance) compared with group 2 (-0.43 letters), and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. For patients with data available at 6 months, improvement of 3 lines or more occurred in 8 of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 (P = 0.002, Fisher exact test) and 3 of 40 (8%) in group 3. Excess foveal thickness was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively. CONCLUSIONS: During a span of 6 months, ranibizumab injections by the current protocol had a significantly better visual outcome than focal/grid laser treatment in patients with DME.

Clinical evaluation of the safety and efficacy of preservative-free triamcinolone (triesence [triamcinolone acetonide injectable suspension] 40 mg/ml) for visualization during pars plana vitrectomy.

PURPOSE: To evaluate the safety and efficacy of preservative-free triamcinolone (TRIESENCE(R) suspension) for visualization during pars plana vitrectomy. METHODS: This phase III, observer-masked study was conducted in 6 centers by 10 surgeons and enrolled 60 patients undergoing pars plana vitrectomy. Preservative-free triamcinolone (up to 4 mg) was administered to all patients to enhance visualization of vitreous and membranes. During each surgery, video recordings captured visualization pre- and postinstillation of preservative-free triamcinolone. An independent, masked reader evaluated the videos for the degree of visualization using a five-point scale ranging from 0 (not visible) to 4 (clearly delineated). Surgeons used a five-point scale ranging from "strongly disagree" to "strongly agree" to assess whether preservative-free triamcinolone improved visualization. RESULTS: In 59 of 60 cases, the masked reader's scores for visualization of posterior segment structures were higher (i.e., structures were more clearly visible) after instillation of preservative-free triamcinolone. The preinstillation mean visualization score was 0.5 compared to 3.7 postinstillation (P < 0.0001). Greater than 90% of surgeon evaluations agreed or strongly agreed that preservative-free triamcinolone enhanced visualization of posterior segment structures. No safety issues were identified. CONCLUSIONS: Preservative-free triamcinolone (TRIESENCE(R) suspension) was well tolerated and effectively enhanced visualization of posterior segment structures during pars plana vitrectomy.

Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1.

PURPOSE: To evaluate the efficacy and safety of ranibizumab administered monthly for three months and then quarterly in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic CNV lesions. METHODS: Patients were randomized 1:1:1 to 0.3 mg ranibizumab (n = 60), 0.5 mg ranibizumab (n = 61), or sham (n = 63) treatment groups. The primary efficacy endpoint was mean change from baseline visual acuity (VA) at month 12. RESULTS: Mean changes from baseline VA at 12 months were -16.3, -1.6, and -0.2 letters for the sham, 0.3 mg, and 0.5 mg groups, respectively (P < or = .0001, each ranibizumab dose vs sham). Ranibizumab arrested CNV growth and reduced leakage from CNV. However, the treatment effect declined in the ranibizumab groups during quarterly dosing (e.g., at three months the mean changes from baseline VA had been gains of 2.9 and 4.3 letters for the 0.3 mg and 0.5 mg doses, respectively). Results of subgroups analyses of mean change from baseline VA at 12 months by baseline age, VA, and lesion characteristics were consistent with the overall results. Few serious ocular or nonocular adverse events occurred in any group. CONCLUSIONS: Ranibizumab administered monthly for three months and then quarterly provided significant VA benefit to patients with AMD-related subfoveal CNV and was well tolerated. The incidence of serious ocular or nonocular adverse events was low.

Treatment outcomes of conventional or high-dose ranibizumab for vascularized pigment epithelial detachment based on lesion subtypes.

INTRODUCTION:: A post hoc study was conducted to compare visual and anatomic outcomes of vascularized serous pigment epithelial detachment (Group 1) with fibrovascular pigment epithelial detachment (Group 2) due to age-related macular degeneration treated with either 0.5 or 2.0 mg ranibizumab injections. METHODS:: A prospective, randomized trial was performed with the following regimens for 12 months: (1) 0.5 mg monthly, (2) 0.5 mg monthly for 4 months followed by pro re nata injections, (3) 2.0 mg monthly, and (4) 2.0 mg monthly for 4 months followed by pro re nata injections. Primary measure was best-corrected standardized vision. Secondary measures included central subfield, thickness surface area A2, greatest linear diameter, heights of pigment epithelial detachment and choroidal neovascularization (CNV), subretinal fluid, cystoid macular edema, and adverse events. RESULTS:: For 36 eyes (8 in Group 1 and 28 in Group 2), follow-up time was 12 months. There were no differences in baseline features between groups except for pigment epithelial detachment A2 (Group 2 > Group 1). Two-way analysis of variance showed comparable improvements in anatomic and vision outcomes. Three-way analysis of variance also showed similar responses for both lesion subtypes with high-dose treatment. There was a trend toward greater pigment epithelial detachment resolution in Group 1 eyes. There were no differences in retinochoroidal angiomatous proliferation (Type-3 CNV) and cataracts between groups, although greater percentages of eyes in Group 1 developed retinal pigment epithelial tears (25% vs 10.7%). CONCLUSION:: There were no differences in vision and anatomic outcomes between lesion subtypes, and similarly, more rapid responses to high-dose than conventional-dose ranibizumab occurred for eyes with both lesion subtypes. More retinal pigment epithelial tears may develop in eyes with vascularized serous pigment epithelial detachment.

Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2.

PURPOSE: To evaluate efficacy and safety of quarterly (and then monthly) ranibizumab during the 2-year Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled study of the efficacy and safety of ranibizumab in subjects with subfoveal CNV with or without classic CNV secondary to AMD (PIER) study. DESIGN: Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled trial in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). METHODS: Patients were randomized 1:1:1 to sham injection (n = 63) or 0.3 mg (n = 60) or 0.5 mg (n = 61) intravitreal ranibizumab monthly for 3 months and then quarterly. During study year 2, eligible sham-group patients crossed over to 0.5 mg ranibizumab quarterly. Later in year 2, all eligible randomized patients rolled over to 0.5 mg ranibizumab monthly. Key efficacy and safety outcomes of the 2-year trial are reported. RESULTS: At month 24, visual acuity (VA) had decreased an average of 21.4, 2.2, and 2.3 letters from baseline in the sham, 0.3 mg, and 0.5 mg groups (P < .0001 for each ranibizumab group vs sham). VA of sham patients who crossed over (and subsequently rolled over) to ranibizumab decreased across time, with an average loss of 3.5 letters 10 months after crossover. VA of 0.3 mg and 0.5 mg group patients who rolled over to monthly ranibizumab increased for an average gain of 2.2 and 4.1 letters, respectively, 4 months after rollover. The ocular safety profile of ranibizumab was favorable and consistent with previous reports. CONCLUSIONS: Ranibizumab provided significant VA benefit in patients with AMD-related CNV compared with sham injection. Ranibizumab appeared to provide additional VA benefit to treated patients who rolled over to monthly dosing, but not to patients who began receiving ranibizumab after >14 months of sham injections.

Retinal pigment epithelial tears after intravitreal bevacizumab injection for neovascular age-related macular degeneration.

PURPOSE: To study retinal pigment epithelium (RPE) tears after off-label intravitreal bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) injection for neovascular age-related macular degeneration. Eyes with a vascularized pigment epithelial detachment (PED) that developed an RPE tear were compared with eyes with a vascularized PED but without an RPE tear. METHODS: Nine retina specialists across the United States and in Europe participated in this retrospective case series. All eyes that received intravitreal bevacizumab injection for choroidal neovascularization (CNV) over 12 months (October 2005 to September 2006) were included. Eyes without all three confirmed tests (fluorescein angiography, fundus photography, and optical coherence tomography) were excluded from analysis. Statistical analyses were performed on multiple characteristics of eyes with a vascularized PED that did and did not develop an RPE tear. RESULTS: Among 2,785 intravitreal bevacizumab injections for 1,064 eyes, RPE tears were found in 22 eyes in 22 patients (2.2%). A vascularized PED was present in 21 of 22 eyes that developed an RPE tear (17.1% of PED eyes; 15, 100% occult CNV; 6, predominantly occult CNV). Mean interval from bevacizumab injections to RPE tears was 37.3 days. Mean follow-up time was 124.9 days. Mean subfoveal PED size was larger for eyes with tears than for those without tears (13.97 mm vs 9.9 mm, respectively; P = 0.01; odds ratio, 1.09). There was substantially smaller mean ratio of CNV size to PED size for eyes with tears than for those without tears (27.9% vs 67.6%, respectively; P = 0.005). Mean pre-bevacizumab injection best-corrected Snellen visual acuity was 20/162, and mean post-RPE tear best-corrected visual acuity was 20/160 (P = 0.48). CONCLUSION: Large PED size is a predictor for RPE tears, and a small ratio of CNV size to PED size (<50%) is more common in eyes with RPE tears. Vision may be preserved despite RPE tears.

Intravitreal bevacizumab (avastin) in central retinal vein occlusion.

PURPOSE: To describe the effects of intravitreal bevacizumab in eyes with macular edema resulting from central retinal vein occlusions (CRVO). METHODS: Retrospective consecutive case series of patients diagnosed with macular edema from CRVO who received intravitreal bevacizumab. RESULTS: Thirty eyes of 29 patients with an average age of 72 years (range, 54-87 years) had intravitreal bevacizumab injections. Mean follow-up was 18.1 weeks. Initial mean visual acuity was 20/394. At the 1- and 2-month follow-up, mean visual acuity improved to 20/237 (n = 26, P = 0.04) and 20/187 (n = 21, P = 0.008), respectively. At the 3- and 4-month follow-up, visual acuity improved from 20/228 to 20/157 (n = 15, P = 0.05) and from 20/313 to 20/213 (n = 11, P = 0.03), respectively. No significant changes in visual acuity were found after 4 months though the number of patients in this group was small. Duration of treatment effect following an injection appears to be limited to 2 months for most patients. No ocular or systemic adverse reactions were noted. CONCLUSIONS: The visual benefits of intravitreal bevacizumab for macular edema due to CRVO are apparent early but are not sustained without repeated injections. Larger clinical studies with long-term follow-up will be necessary to better elicit the best regimen for this therapy.