Panretinal Photocoagulation for Diabetic Retinopathy in the RIDE and RISE Trials: Not "1 and Done".

PURPOSE: To evaluate panretinal photocoagulation (PRP) treatment and re-treatment patterns in patients with diabetic retinopathy (DR) and diabetic macular edema (DME). DESIGN: Post hoc analysis of the phase 3 RIDE (clinicaltrials.gov identifier, NCT00473382) and RISE (clinicaltrials.gov identifier, NCT00473330) clinical trials of ranibizumab for the treatment of DME. PARTICIPANTS: Seven hundred fifty-nine patients were randomized for treatment. METHODS: Panretinal photocoagulation treatment patterns and clinical experiences were assessed by baseline PRP treatment status. MAIN OUTCOME MEASURES: Number and timing of on-study PRP treatment sessions undergone through month 24. Time to new proliferative event (composite end point) was also assessed. RESULTS: At baseline, approximately 25% of patients in RIDE and RISE had undergone PRP treatment before enrollment (22.2%, 24.4%, and 25.4% of patients in the sham, ranibizumab 0.3 mg, and ranibizumab 0.5 mg arms, respectively). In patients without prior PRP at baseline (n = 577), 9.5% of sham-treated patients underwent 1 or more PRP treatments through month 24, compared with 1.1% and 1.6% of patients receiving ranibizumab 0.3 mg and ranibizumab 0.5 mg, respectively (P < 0.001 for both ranibizumab arms vs. sham). In patients with prior PRP at baseline (n = 182), 19.3% of sham-treated patients underwent 1 or more PRP treatments through month 24. No ranibizumab-treated patients with prior PRP at baseline required additional on-study PRP through month 24 (P < 0.001 for both ranibizumab arms vs. sham). Ranibizumab treatment also significantly reduced clinical DR progression among patients who underwent prior PRP. By month 24 in patients with prior PRP at baseline, the probability of experiencing a new proliferative event was 10.3% and 9.9% in patients receiving ranibizumab 0.3 mg and ranibizumab 0.5 mg treatment, respectively, compared with 39.4% in sham-treated patients (P < 0.0001). Overall, sham-treated patients, including those patients who were PRP naïve at baseline who went on to require PRP, experienced more clinical events than ranibizumab-treated patients. CONCLUSIONS: In RIDE and RISE, PRP treatment was not a "1 and done" procedure, with on-study PRP re-treatment occurring in patients both with and without prior PRP treatment at baseline. Ranibizumab treatment reduced on-study PRP treatment and DR progression regardless of prior PRP treatment status at baseline.

YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale.

Purpose: Faricimab is a novel anti-angiopoietin-2 and anti-vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME. Design: Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE). Participants: Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus. Methods: These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden. Main Outcome Measures: We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab. Results: YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately. Conclusions: YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.

Impact of Delayed Time to Treatment on Visual Outcomes in Neovascular AMD: Data From the HARBOR Study.

BACKGROUND AND OBJECTIVE: To determine the potential impact on visual outcomes of delayed treatment initiation in patients with neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: Post hoc analysis of anti-vascular endothelial growth factor treatment-naïve patients with nAMD from HARBOR. Time to treatment was defined as first ranibizumab injection date minus screening date. Comparisons were made between the prompt (≤ 6 days) versus delayed (> 10 days) treatment groups. Main outcome measures were best-corrected visual acuity (BCVA) change over time, BCVA, number of ranibizumab injections, and proportion of 3-line gainers/losers. RESULTS: In HARBOR, more than 50% of patients received their first injection within 7 days of screening, with mean (median) time to treatment of 4.6 (5) and 15.9 (14) days for the prompt and delayed treatment groups, respectively. Mean (95% confidence interval [CI]) BCVA change from baseline to Month 24 was 9.1 (7.4-10.8) and 8.8 (6.7-10.8) Early Treatment Diabetic Retinopathy Study letters in the prompt (n = 395) and delayed (n = 230) treatment groups, respectively. Mean (95% CI) total number of ranibizumab injections for the as-needed arms was 12.4 (11.6-13.3) and 11.4 (10.3-12.4) for the prompt and delayed treatment groups, respectively. CONCLUSION: In HARBOR, time from screening to first ranibizumab injection did not seem to significantly affect mean BCVA change or number of injections. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:62-69.].