Two or more dexamethasone intravitreal implants in treatment-naïve patients with macular edema due to retinal vein occlusion: subgroup analysis of a retrospective chart review study.

BACKGROUND: Dexamethasone intravitreal implant (DEX implant) is a biodegradable, sustained-release implant that releases dexamethasone for up to 6 months. We evaluated the efficacy and safety of DEX implant in the treatment of macular edema secondary to retinal vein occlusion (RVO) in treatment-naïve patients. METHODS: A multicenter, retrospective, open-label chart review study investigated the efficacy and safety of DEX implant treatment in 289 patients with macular edema secondary to branch or central RVO (BRVO, CRVO) who received ≥2 treatments with DEX implant in the study eye. Concomitant adjunctive RVO treatments were permitted. Data collected from the time of the first implant (baseline) to 3-6 months after the last implant included best-corrected visual acuity (BCVA) and central retinal thickness measured with optical coherence tomography. In this subgroup analysis, we evaluated outcomes in patients who had received no previous treatment for RVO complications. RESULTS: Thirty-nine patients were treatment-naïve at the time of their first DEX implant (18 BRVO, 21 CRVO). Before the initial DEX implant, the mean duration of macular edema in treatment-naïve patients was 4.9 months, mean central retinal thickness was 550 µm, and mean Early Treatment Diabetic Retinopathy Study BCVA was 8.5 lines (20/125 Snellen). Treatment-naïve patients received a mean of 2.9 implants, either as monotherapy (n = 12) or with adjunctive RVO treatments (n = 27). The mean interval between implants was 177 days. After the first through sixth implants, mean changes from baseline BCVA ranged from +3.0 - +8.0 lines, and mean decreases from baseline central retinal thickness ranged from 241-459 µm. BCVA improved in both BRVO and CRVO and in both phakic and pseudophakic eyes. Overall, 83.8 % of treatment-naïve patients gained ≥2 lines in BCVA, 70.3 % gained ≥3 lines in BCVA, and 56.4 % achieved central retinal thickness ≤250 µm. The most common adverse event was increased intraocular pressure. Fifteen treatment-naïve patients had intraocular pressure ≥25 mm Hg; none required laser or incisional glaucoma surgery. CONCLUSION: Treatment with 2 or more DEX implants had a favorable safety profile and improved visual acuity and anatomic outcomes when used, either alone or with adjunctive RVO therapy, as initial treatment for RVO-associated macular edema. TRIAL REGISTRATION: ClinicalTrials.gov NCT01411696 , registered on August 5, 2011.

Two or more dexamethasone intravitreal implants as monotherapy or in combination therapy for macular edema in retinal vein occlusion: subgroup analysis of a retrospective chart review study.

BACKGROUND: Dexamethasone intravitreal implant (DEX implant) is a sustained-release biodegradable implant approved for treatment of macular edema associated with retinal vein occlusion (RVO). The safety and efficacy of treatment of RVO-associated macular edema with sequential DEX implants in clinical practice was evaluated in patients who received DEX implant as monotherapy compared with patients who received DEX implant in combination with other RVO treatments. METHODS: A multicenter, retrospective, open-label chart review study (one study eye/patient) evaluated use of DEX implant and outcomes in 289 patients with branch or central RVO who received at least 2 DEX implant treatments in the study eye. Data were collected from the time of the first implant (baseline) to 3-6 months after the last implant. Subgroup analysis evaluated outcomes in patients receiving only DEX implant during the study versus patients receiving DEX implant plus adjunctive RVO treatments. Endpoints included best-corrected visual acuity (BCVA) and central retinal thickness (CRT) change from baseline. RESULTS: DEX implant was used as monotherapy in 84 (29.1%) patients and in combination with other therapy in 205 (70.9%) patients. Mean number of DEX implant treatments received was 3.1 in the monotherapy group and 3.3 in the combination therapy group (P = 0.344). Mean time between implants was longer in the combination therapy group (177 vs. 151 days, P < 0.001). Mean change from baseline BCVA after the first through sixth DEX implants ranged from +0.6 to +3.4 lines in the monotherapy group and +1.3 to +2.8 lines in the combination therapy group. Mean decrease from baseline CRT ranged from 165 to 230 µm in the monotherapy group and 136 to 175 µm in the combination therapy group. Increased intraocular pressure was more common in the combination therapy group. CONCLUSIONS: Treatment of RVO-associated macular edema with at least 2 sequential DEX implants was safe and effective both when used alone and when combined with other RVO treatments. Improvements in BCVA and CRT were generally similar in the monotherapy and combined therapy groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT01411696 .

Efficacy and safety of two or more dexamethasone intravitreal implant injections for treatment of macular edema related to retinal vein occlusion (Shasta study).

PURPOSE: To evaluate the efficacy, safety, and reinjection interval of dexamethasone intravitreal implant (DEX implant) in branch retinal vein occlusion and central retinal vein occlusion patients receiving ≥ 2 DEX implant treatments. METHODS: Multicenter (26-site), retrospective chart review study. Data were collected from baseline (at first DEX implant) through 3 months to 6 months after last DEX implant. RESULTS: Patients (n = 289) received 2 to 9 (mean, 3.2) DEX implants as monotherapy (29.1% of patients) or with adjunctive treatments/procedures. Mean duration of macular edema before first DEX implant was 18.4 months. Mean reinjection interval was 5.6 months. Mean peak change in best-corrected visual acuity from baseline through 4 weeks to 20 weeks after final DEX implant was +1.0 line (P < 0.001). Best-corrected visual acuity and central retinal thickness improved significantly from baseline after each of the first 6 DEX implant injections (P ≤ 0.037); 59.7% of branch retinal vein occlusion and 66.7% of central retinal vein occlusion patients achieved ≥ 2-line best-corrected visual acuity improvement. Intraocular pressure increase (≥ 10 mmHg) occurred in 32.6% of patients; 29.1% used intraocular pressure-lowering medication to treat increases associated with DEX implant. Only 1.7% of patients required incisional glaucoma surgery. CONCLUSION: Retinal vein occlusion patients treated with multiple DEX implant injections, either alone or combined with other therapies, had improved central retinal thickness and visual acuity with each subsequent injection. No new safety concerns developed with multiple implants.

End-of-Study Results for the Ladder Phase 2 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the end-of-study results from the Ladder clinical trial of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Multicenter, randomized, active treatment-controlled phase 2 clinical trial. PARTICIPANTS: Patients diagnosed with nAMD with a documented response to anti-vascular endothelial growth factor treatment who received study treatment (N = 220). METHODS: Patients were randomized 3:3:3:2 to treatment with the PDS filled with ranibizumab 10-mg/ml, 40-mg/ml, and 100-mg/ml formulations or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES: End-of-study results for the time to first meeting refill criteria (first refill), mean change from baseline for best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. RESULTS: At study end, the mean time on study was 22.1 months (range, 10.8-37.6 months) for all PDS patients. Median time to first refill was 8.7 months, 13.0 months, and 15.8 months, and 28.9%, 56.0%, and 59.4% of patients went 12 months or longer without meeting refill criteria in the PDS 10-mg/ml, 40-mg/ml, and 100-mg/ml treatment arms, respectively. At month 22, the observed mean BCVA change from baseline was ‒4.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒2.3 ETDRS letters, +2.9 ETDRS letters, and +2.7 ETDRS letters in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg treatment arms, respectively. At month 22, the observed mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg treatment arms. No new safety signals were detected during the additional follow-up. CONCLUSIONS: Over a mean of 22 months on study, vision and anatomic outcomes were comparable between the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms, with a lower total number of ranibizumab treatments with the PDS. The Ladder end-of-study findings were consistent with the primary analysis, and the PDS generally was well tolerated throughout the entire study period. The PDS has the potential to reduce treatment burden in patients with nAMD while maintaining vision.

Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study.

OBJECTIVE: To assess safety of repeated intravitreal injections of ranibizumab in treating neovascular age-related macular degeneration (AMD), and to assess changes in visual acuity (VA) and AMD lesion characteristics. DESIGN: Multicenter, controlled, open-label, clinical trial. PARTICIPANTS: Sixty-four patients with subfoveal predominantly or minimally classic AMD-related choroidal neovascularization. METHODS: In part 1, subjects were randomized to monthly intravitreal ranibizumab for 3 months (4 injections of 0.3 mg or 1 injection of 0.3 mg followed by 3 injections of 0.5 mg; n = 53) or usual care (UC; n = 11). In part 2, subjects could continue their regimen for 3 additional months or cross over to the alternative treatment. MAIN OUTCOME MEASURES: Adverse events (AEs), intraocular pressure (IOP), VA, and lesion characteristics assessed by fluorescein angiography and fundus photography. RESULTS: Of the 64 randomized subjects, 62 completed the 6-month study. Twenty of 25 subjects (80%) randomized to 0.3 mg, and 22 of 28 subjects (79%) randomized to 0.5-mg ranibizumab in part 1 continued on that treatment in part 2; 9 of 11 (82%) subjects randomized to UC in part 1 crossed over to ranibizumab treatment in part 2. The most common AEs with ranibizumab were reversible inflammation and minor injection-site hemorrhages. Serious AEs were iridocyclitis, endophthalmitis, and central retinal vein occlusion (1 subject each). Postinjection, IOP increased transiently in 22.6% of ranibizumab-treated eyes in parts 1 and 2. After 4 ranibizumab injections (day 98), mean (+/- standard deviation) VA had increased 9.4+/-13.3 and 9.1+/-17.2 letters in the 0.3- and 0.5-mg groups, respectively, but had decreased 5.1+/-9.6 letters with UC. In part 2 (day 210), VA increased from baseline 12.8+/-14.7 and 15.0+/-14.2 letters in subjects continuing on 0.3 and 0.5 mg, respectively. Visual acuity improved from baseline > or =15 letters in 26% (day 98) and 45% (day 210) of subjects initially randomized to and continuing on ranibizumab, respectively, and areas of leakage and subretinal fluid decreased. No UC subject had a > or =15-letter improvement at day 98. CONCLUSIONS: Repeated intravitreal injections of ranibizumab had a good safety profile and were associated with improved VA and decreased leakage from choroidal neovascularization in subjects with neovascular AMD.

Patterns of Early and Delayed Visual Response to Ranibizumab Treatment for Neovascular Age-Related Macular Degeneration.

IMPORTANCE: Understanding the range of temporal responses to ranibizumab is critical for the assessment of individualized treatment regimens for neovascular age-related macular degeneration. OBJECTIVE: To examine patterns of visual and anatomical response to ranibizumab treatment. DESIGN, SETTING, AND PARTICIPANTS: This study is a retrospective subanalysis of HARBOR (a phase 3, double-masked, multicenter, randomized, active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg ranibizumab administered monthly or on an as-needed basis (PRN) in patients with subfoveal neovascular age-related macular degeneration). A total of 1097 patients with neovascular age-related macular degeneration were randomized to intravitreal ranibizumab, 0.5 or 2.0 mg, administered monthly or as needed (PRN) with monthly monitoring. Of the 1097 patients, 1057 were included in the analysis for early responders (best-corrected visual acuity [BCVA] obtained at baseline and month 3), and 988 patients were included in the analysis for delayed responders (BCVA obtained at baseline, month 3, and month 12). The HARBOR study began July 7, 2009, with the primary 12-month end point completed on August 5, 2011, ongoing to 24 months. Data analysis for the subgroup was performed from January 4, 2013, through December 17, 2015. INTERVENTIONS: Patients were categorized based on BCVA outcomes as early 15-letter responders (gained ≥15 letters from baseline at month 3) or delayed 15-letter responders (did not gain ≥15 letters from baseline at month 3 but did so at month 12). MAIN OUTCOMES AND MEASURES: Changes from baseline in BCVA and central foveal thickness (CFT). RESULTS: In total, 266 early and 135 delayed 15-letter responders were identified. In the 0.5-mg monthly, 0.5-mg PRN, 2.0-mg monthly, and 2.0-mg PRN treatment groups, 63 (24.0%) of 263, 65 (24.6%) of 264, 68 (25.7%) of 265, and 70 (26.4%) of 265 patients were early responders, respectively, and 40 (16.3%) of 246, 31 (12.6%) of 247, 35 (14.1%) of 248, and 29 (11.7%) of 247 patients were delayed responders, respectively. By month 12, early vs delayed responders in the PRN treatment groups received 7.5 vs 7.4 ranibizumab injections, respectively (P = .84). More than 80% of early responders receiving PRN treatment maintained 15-letter or greater gains at month 24. At baseline, early vs delayed responders had worse BCVA (49.8 vs 55.4 letters; P < .001) and greater CFT (374.9 vs 339.0 µm; P = .02), although anatomical results were comparable by month 3 (CFT, 187.7 vs 188.9 µm). CONCLUSIONS AND RELEVANCE: Improvement of 15 letters or more from baseline occurred in 266 (25.2%) of 1057 patients within 3 months of beginning ranibizumab treatment, whereas an additional 135 (13.7%) of 988 patients achieved this gain by 12 months. The 2 cohorts had similar anatomical temporal response patterns. PRN treatment with monthly monitoring was effective in maintaining early vision gains and allowing delayed vision gains. These results suggest that vision improvement can continue in some patients after macular edema resolves and CFT decreases stabilize.