Namrata Saroj

Ranibizumab for Macular Edema following Central Retinal Vein Occlusion: Six-Month Primary End Point Results of a Phase III Study

PURPOSE To assess the efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after central retinal vein occlusion (CRVO). DESIGN Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. PARTICIPANTS A total of 392 patients with macular edema after CRVO. METHODS Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. MAIN OUTCOME MEASURES The primary efficacy outcome measure was mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6. Secondary outcomes included other parameters of visual function and central foveal thickness (CFT). RESULTS Mean (95% confidence interval [CI]) change from baseline BCVA letter score at month 6 was 12.7 (9.9-15.4) and 14.9 (12.6-17.2) in the 0.3 mg and 0.5 mg ranibizumab groups, respectively, and 0.8 (-2.0 to 3.6) in the sham group (P<0.0001 for each ranibizumab group vs. sham). The percentage of patients who gained > or =15 letters in BCVA at month 6 was 46.2% (0.3 mg) and 47.7% (0.5 mg) in the ranibizumab groups and 16.9% in the sham group (P<0.0001 for each ranibizumab group vs. sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg = 43.9%; 0.5 mg = 46.9%) had BCVA of > or = 20/40 compared with sham patients (20.8%; P<0.0001 for each ranibizumab group vs. sham), and CFT had decreased by a mean of 434 microm (0.3 mg) and 452 microm (0.5 mg) in the ranibizumab groups and 168 microm in the sham group (P<0.0001 for each ranibizumab group vs. sham). The median percent reduction in excess foveal thickness at month 6 was 94.0% and 97.3% in the 0.3 mg and 0.5 mg groups, respectively, and 23.9% in the sham group. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with CRVO. CONCLUSIONS Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid improvement in 6-month visual acuity and macular edema following CRVO, with low rates of ocular and nonocular safety events.

Ranibizumab for Macular Edema following Central Retinal Vein Occlusion

PURPOSE To assess efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema following branch retinal vein occlusion (BRVO). DESIGN Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. PARTICIPANTS A total of 397 patients with macular edema following BRVO. METHODS Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 mg or 0.5 mg of ranibizumab or sham injections. MAIN OUTCOME MEASURES The primary efficacy outcome measure was mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6. Secondary outcomes included other parameters of visual function and central foveal thickness (CFT). RESULTS Mean (95% confidence interval [CI]) change from baseline BCVA letter score at month 6 was 16.6 (14.7-18.5) and 18.3 (16.0-20.6) in the 0.3 mg and 0.5 mg ranibizumab groups and 7.3 (5.1-9.5) in the sham group (P<0.0001 for each ranibizumab group vs sham). The percentage of patients who gained > or =15 letters in BCVA at month 6 was 55.2% (0.3 mg) and 61.1% (0.5 mg) in the ranibizumab groups and 28.8% in the sham group (P<0.0001 for each ranibizumab group vs sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg, 67.9%; 0.5 mg, 64.9%) had BCVA of > or =20/40 compared with sham patients (41.7%; P<0.0001 for each ranibizumab group vs sham); and CFT had decreased by a mean of 337 microm (0.3 mg) and 345 microm (0.5 mg) in the ranibizumab groups and 158 microm in the sham group (P<0.0001 for each ranibizumab group vs sham). The median percent reduction in excess foveal thickness at month 6 was 97.0% and 97.6% in 0.3 mg and 0.5 mg groups and 27.9% in the sham group. More patients in the sham group (54.5%) received rescue grid laser compared with the 0.3 mg (18.7%) and 0.5 mg (19.8%) ranibizumab groups. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with BRVO. CONCLUSIONS Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid, effective treatment for macular edema following BRVO with low rates of ocular and nonocular safety events.

Sustained Benefits from Ranibizumab for Macular Edema Following Branch Retinal Vein Occlusion: 12-Month Outcomes of a Phase III Study

PURPOSE Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion (BRVO). DESIGN Prospective, randomized, sham injection-controlled, double-masked, multicenter trial. PARTICIPANTS A total of 397 patients with macular edema after BRVO. METHODS Eligible patients were randomized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. After 6 months, all patients with study eye best-corrected visual acuity (BCVA) ≤20/40 or central subfield thickness ≥250 μm were to receive ranibizumab. Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met. MAIN OUTCOME MEASURES The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12. Additional visual and anatomic parameters were assessed. RESULTS Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 16.4 (14.5-18.4) and 18.3 (15.8-20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6-14.6) in the sham/0.5 mg group (P<0.01, each ranibizumab group vs. sham/0.5 mg). The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 56.0% and 60.3% in the 0.3 mg and 0.5 mg groups, respectively, and 43.9% in the sham/0.5 mg group. On average, there was a marked reduction in central foveal thickness (CFT) after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group, which was sustained through month 12. No new ocular or nonocular safety events were identified. CONCLUSIONS At month 12, treatment with ranibizumab as needed during months 6-11 maintained, on average, the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO, with low rates of ocular and nonocular safety events. In the sham/0.5 mg group, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA, but not to the extent of that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Ranibizumab for Macular Edema Due to Retinal Vein Occlusions: Long-term Follow-up in the HORIZON Trial

PURPOSE To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular edema after retinal vein occlusion (RVO). DESIGN Open-label extension trial of the 12-month Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) trials. PARTICIPANTS We included 304 patients who completed BRAVO and 304 patients who completed CRUISE. METHODS Patients were seen at least every 3 months and given an intraocular injection of 0.5 mg ranibizumab if they met prespecified retreatment criteria. MAIN OUTCOME MEASURES Primary outcomes were incidence and severity of ocular and nonocular adverse events (AEs). Key efficacy outcomes included mean change from baseline best-corrected visual acuity (BCVA) letter score by Early Treatment Diabetic Retinopathy Study protocol and central foveal thickness. RESULTS In patients who completed month 12, the mean number of injections (excluding month 12 injection) in the sham/0.5-, 0.3/0.5-, and 0.5-mg groups was 2.0, 2.4, and 2.1 (branch RVO) and 2.9, 3.8, and 3.5 (central RVO), respectively. The incidence of study eye ocular serious AEs (SAEs) and SAEs potentially related to systemic vascular endothelial growth factor inhibition across treatment arms was 2% to 9% and 1% to 6%, respectively. The mean change from baseline BCVA letter score at month 12 in branch RVO patients was 0.9 (sham/0.5 mg), -2.3 (0.3/0.5 mg), and -0.7 (0.5 mg), respectively. The mean change from baseline BCVA at month 12 in central RVO patients was -4.2 (sham/0.5 mg), -5.2 (0.3/0.5 mg), and -4.1 (0.5 mg), respectively. CONCLUSIONS No new safety events were identified with long-term use of ranibizumab; rates of SAEs potentially related to treatment were consistent with prior ranibizumab trials. Reduced follow-up and fewer ranibizumab injections in the second year of treatment were associated with a decline in vision in central RVO patients, but vision in branch RVO patients remained stable. Results suggest that during the second year of ranibizumab treatment of RVO patients, follow-up and injections should be individualized and, on average, central RVO patients may require more frequent follow-up than every 3 months.

Incidence of New Choroidal Neovascularization in Fellow Eyes of Patients Treated in the MARINA and ANCHOR Trials

PURPOSE To explore whether monthly intravitreal ranibizumab injections are associated with a lower rate of new choroidal neovascularization (CNV) in fellow eyes of patients with unilateral neovascular age-related macular degeneration. DESIGN Retrospective data analysis of randomized, controlled clinical trials. METHODS Incidence of new CNV in fellow eyes was calculated at 12 and 24 months from 2 clinical trials (the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration [MARINA] study and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration [ANCHOR] study), based on fluorescein angiographic reading center criteria and investigator evaluation. Patients treated with monthly ranibizumab (0.3 and 0.5 mg) were compared with those receiving a sham injection (MARINA) or photodynamic therapy (ANCHOR). RESULTS In MARINA, new CNV developed in fellow eyes in 20.3% of the 0.3-mg ranibizumab group by 12 months and in 30.4% by 24 months. The conversion rate in the 0.5-mg ranibizumab group was 21.1% and 38.0% by 12 and 24 months, respectively. In the sham group, 26.4% converted by 12 months and 36.3% converted by 24 months. In ANCHOR, fellow eyes in 15.9% of the 0.3-mg ranibizumab group converted by 12 months and fellow eyes in 23.8% converted by 24 months. The conversion rate in the 0.5-mg ranibizumab group was 24.3% and 35.1% by 12 and 24 months, respectively. In the photodynamic therapy group, 25.4% converted by 12 months and 38.8% converted by 24 months. Differences in conversion rates at 12 and 24 months between the 0.3-mg or 0.5-mg ranibizumab groups and respective controls (sham or photodynamic therapy) were not statistically significant. CONCLUSIONS Results of this study do not support the hypothesis that monthly ranibizumab injections reduce the rate of CNV development in untreated fellow eyes.

Intraocular Pressure in Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept or Ranibizumab

PURPOSE To assess change in intraocular pressure (IOP) in patients with neovascular age-related macular degeneration (NVAMD) receiving intravitreal aflibercept injection (IAI) or ranibizumab in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies. DESIGN Analyses from 2 randomized, active-controlled, phase III trials. PARTICIPANTS A total of 2457 patients with NVAMD. METHODS Patients received IAI 2 mg every (q) 4 weeks (2q4), 0.5 mg q4 weeks (0.5q4), 2 mg q8 weeks (after 3 monthly doses; 2q8), or ranibizumab 0.5 mg q4 weeks (Rq4) for 52 weeks. At week 52, patients were switched to a variable regimen requiring at least quarterly dosing and allowing interim injections based on anatomic and visual assessment. MAIN OUTCOME MEASURES Pre-injection IOP was analyzed in study and uninjected fellow eyes from baseline to week 96. Prespecified end points included mean change in IOP from baseline and prevalence of a >21 mmHg and >10 mmHg increase in IOP from baseline. Cumulative incidence of sustained (at 2 consecutive visits) IOP >21 mmHg, a single event of IOP >25 mmHg, and sustained IOP increase from baseline (≥5 mmHg) was also evaluated. RESULTS Mean IOP change from baseline over 96 weeks in all IAI groups was consistently lower than in the Rq4 group, and this finding was replicated in both trials. In an analysis integrating both studies, the proportion of study eyes with IOP >21 mmHg at week 96 was 20.2%, 14.2%, 12.1%, and 12.5% in Rq4, 2q4, 2q8, and 0.5q4, respectively. Reduction in risk, relative to Rq4, of having sustained IOP >21 mmHg over 96 weeks was 62% (95% confidence interval [CI], 36%-78%), 50% (95% CI, 19%-70%), and 69% (95% CI, 45%-84%) for 2q4, 2q8, and 0.5q4, respectively. Risk reduction in the IAI groups for a sustained IOP increase ≥5 mmHg was 31% (95% CI, 8%-48%), 38% (95% CI, 17%-54%), and 47% (95% CI, 27%-61%), respectively. In uninjected fellow eyes, only sustained IOP >21 mmHg events were higher in the Rq4 group compared with all IAI groups. CONCLUSIONS Incidence of elevated IOP in eyes with NVAMD was lower in all IAI groups than in the ranibizumab group.

Intravitreal Aflibercept Injection in Diabetic Macular Edema Patients with and without Prior Anti-Vascular Endothelial Growth Factor Treatment: Outcomes from the Phase 3 Program.

PURPOSE To evaluate visual and anatomic outcomes after intravitreal aflibercept injection (IAI) versus laser in diabetic macular edema (DME) patients with and without prior anti-vascular endothelial growth factor (VEGF) treatment for DME. DESIGN Post hoc analysis of eyes from 2 similarly designed, phase 3 trials, VISTA and VIVID. PARTICIPANTS Patients (eyes) with DME with central involvement from VISTA (n = 461) and VIVID (n = 404). METHODS Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or macular laser photocoagulation. MAIN OUTCOME MEASURES This study reports exploratory outcomes through week 100. Analyses focused on VISTA because more patients received prior anti-VEGF therapy in VISTA (42.9%) versus VIVID (8.9%). RESULTS Of 42.9% of patients in VISTA who received prior anti-VEGF treatment, 83.3% to 92.6% received ≥ 1 prior injections of bevacizumab, and 71.4% to 82.4% received bevacizumab only as prior anti-VEGF treatment for a duration ranging from 28 days to 3.9 years. In patients with prior anti-VEGF treatment, mean best-corrected visual acuity (BCVA) changes from baseline in the IAI 2q4, IAI 2q8, and laser groups were +10.4 letters, +10.5 letters, and -0.7 letters at week 52 and +10.9 letters, +10.8 letters, and -0.8 letters at week 100, respectively. Corresponding changes in patients without prior anti-VEGF treatment were +14.1 letters, +11.0 letters, and +0.9 letters at week 52 and +12.0 letters, +11.3 letters, and +2.1 letters at week 100. In patients with prior anti-VEGF treatment, mean reductions in central retinal thickness were 180.2 μm, 192.2 μm, and 90.9 μm at week 52 and 180.1 μm, 196.4 μm, and 94.1 μm at week 100. Corresponding reductions in patients without prior anti-VEGF treatment were 190.3 μm, 175.7 μm, and 61.0 μm at week 52 and 200.0 μm, 186.7 μm, and 76.9 μm at week 100. The most frequent serious ocular adverse event was vitreous hemorrhage (1.3%, 0.7%, and 1.9%, respectively). CONCLUSIONS Visual and anatomic improvements over laser with both IAI regimens were significant and similar through week 100 in subgroups of patients in VISTA with and without prior anti-VEGF treatment for DME.

Dosing regimen and the frequency of macular hemorrhages in neovascular age-related macular degeneration treated with ranibizumab.

Purpose: The purpose of this study was to investigate if monthly intravitreal ranibizumab decreases risk of macular hemorrhages in patients with choroidal neovascularization secondary to age-related macular degeneration. Methods: Incidences of macular hemorrhages in the control and ranibizumab groups from three, multicenter, randomized, clinical trials (MARINA, ANCHOR, and PIER) were compared. Two time intervals (Months 0-3 and 5-17) were evaluated to account for transition from monthly to quarterly injections in PIER. Time interval after Month 17 was excluded because of crossover from control to active treatment in all trials. Results: Months 0-3: All trials showed higher incidence rates of hemorrhages in control compared with ranibizumab groups (ANCHOR: photodynamic therapy [27.3%], 0.3 mg [8.0%], 0.5 mg [8.6%]; MARINA: sham [18.6%], 0.3 mg [8.8%], 0.5 mg [8.8%]; and PIER: sham [16.1%], 0.3 mg [3.4%], 0.5 mg [3.3%]). In ANCHOR and MARINA, data of Months 5-17 showed higher incidence rates in control compared with monthly ranibizumab groups (ANCHOR: photodynamic therapy [47.8%], 0.3 mg [12.5%], 0.5 mg [12.3%]; and MARINA: sham [38.0%], 0.3 mg [13.2%], 0.5 mg [13.0%]), but this was not seen for quarterly ranibizumab groups in PIER (sham [22.4%], 0.3 mg [23.7%], 0.5 mg [28.3%]). Conclusion: Treatment with monthly intravitreal ranibizumab was associated with reduced risk of new macular hemorrhages when compared with photodynamic therapy (ANCHOR) or sham (MARINA and PIER). There was no difference between PIER quarterly ranibizumab-treated and sham patients.

Intravitreal Aflibercept Injection in Eyes With Substantial Vision Loss After Laser Photocoagulation for Diabetic Macular Edema: Subanalysis of the VISTA and VIVID Randomized Clinical Trials

Importance Information on the effect of anti–vascular endothelial growth factor therapy in eyes with diabetic macular edema (DME) with vision loss after macular laser photocoagulation is clinically valuable. Objective To evaluate visual and anatomic outcomes in a subgroup of macular laser photocoagulation treatment control (hereafter laser control) eyes with substantial vision loss receiving treatment with intravitreal aflibercept injection. Design, Setting, and Participants This investigation was a post hoc analysis of a subgroup of laser control eyes in 2 phase 3 trials—VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME)—in a multicenter setting. One hundred nine laser control eyes with center-involving DME were included. Interventions Treatment with intravitreal aflibercept injection (2 mg) every 8 weeks after 5 monthly doses with sham injections on nontreatment visits starting at week 24 was initiated on meeting prespecified criteria of at least a 10-letter visual acuity loss at 2 consecutive visits or at least a 15-letter visual acuity loss from the best previous measurement at 1 visit and vision not better than at baseline. Main Outcomes and Measures Visual and anatomic outcomes in a subgroup of laser control eyes receiving treatment with intravitreal aflibercept injection. Results Through week 100, a total of 63 of 154 eyes (40.9%) in VISTA and 46 of 133 eyes (34.6%) in VIVID initially randomized to laser control received treatment with intravitreal aflibercept injection. The median time from week 24 to the first intravitreal aflibercept injection treatment was 34.0 (VISTA) and 83.5 (VIVID) days. In this subgroup, the mean (SD) visual gain from baseline to week 100 was 2.2 (12.5) (VISTA) and 3.8 (10.1) (VIVID) letters. At the time of intravitreal aflibercept injection initiation, these eyes had a mean (SD) loss of 11.0 (10.1) (VISTA) and 10.0 (6.5) (VIVID) letters from baseline, and they subsequently gained a mean (SD) of 17.4 (9.7) (VISTA) and 13.6 (8.6) (VIVID) letters from the initiation of treatment with intravitreal aflibercept injection through week 100. There was a minimal mean change in central subfield thickness from baseline in these eyes at the time of intravitreal aflibercept injection initiation (an increase of 3.9 &mgr;m in VISTA and a decrease of 3.0 &mgr;m in VIVID), after which further mean (SD) reductions of 285.6 (202.6) &mgr;m (VISTA) and 313.4 (181.9) &mgr;m (VIVID) occurred through week 100. Conclusions and Relevance Intravitreal aflibercept injection improves visual and anatomic outcomes in eyes experiencing substantial vision loss after macular laser photocoagulation treatment for DME. Trial Registration clinicaltrials.gov Identifiers: NCT01363440 and NCT01331681

Effect of Fluid Status at Week 12 on Visual and Anatomic Outcomes at Week 52 in the VIEW 1 and 2 Trials

BACKGROUND AND OBJECTIVE To evaluate effect of retinal fluid status at week 12 on visual and anatomic outcomes at week 52 in patients with neovascular age-related macular degeneration from the VIEW studies. PATIENTS AND METHODS Post-hoc analysis included 1,465 eyes treated with intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) 2 mg every 4 weeks (2q4) or every 8 weeks following three initial monthly injections (2q8) or ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg every 4 weeks (Rq4), which had known retinal fluid status at weeks 12 and 52. RESULTS At 12 weeks, 512 (35%) eyes had fluid and 953 (65%) were fluid-free. Two hundred three (41.5%), 148 (29.8%), and 161 (33.5%) eyes had fluid in Rq4, 2q4, and 2q8, respectively. Best-corrected visual acuity (BCVA) change at week 52 from baseline was independent of retinal fluid status at week 12 or treatment assignment. Eyes were more likely to remain fluid-free at week 52 if absent of fluid at week 12. CONCLUSION At week 52, 2q4, 2q8, and Rq4 improved BCVA independent of fluid status at week 12.