Objective To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for two years and to describe the impact of switching to as-needed treatment after a year of monthly treatment. Design Multicenter, randomized clinical trial. Participants Patients (N=1107) who were followed during Year 2 among 1185 patients with neovascular age-related macular degeneration (AMD) who were enrolled in the clinical trial. Interventions At enrollment, patients were assigned to four treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At one year, patients initially assigned to monthly treatment were randomly reassigned to monthly or as needed treatment, without changing the drug assignment. Main Outcome Measure Mean change in visual acuity. Results Among patients following the same regimen for two years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference: −1.4 letters; 95% confidence interval (CI): [−3.7, 0.8]; p=0.21). Mean gain was greater for monthly than for as-needed treatment (difference: −2.4 letters; CI: [−4.8, −0.1]; p=0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug p=0.0003; regimen p<0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (−2.2 letters, p=0.03) and a lower proportion without fluid (−19%, p<0.0001). Rates of death and arteriothrombotic events were similar for both drugs (p>0.60). The proportion of patients with ≥1 systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio 1.30; CI [1.07, 1.57]; p=0.009). The majority of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). Conclusions Ranibizumab and bevacizumab had similar effects on visual acuity over a two-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after one year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

BACKGROUND Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. METHODS In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a non-inferiority limit of 5 letters on the eye chart. RESULTS Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. CONCLUSIONS At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.)

on behalf of the HAWK and HARRIER Study Investigators* Purpose: Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a singlechain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD).Design: Double-masked, multicenter, active-controlled, randomized trials. Participants: Patients (N ¼ 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye.Intervention: Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing.Main Outcome Measures: The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes.Results: At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, þ6.6 [6 mg] and þ6.1 [3 mg] letters with brolucizumab vs. þ6.8 letters with aflibercept [HAWK]; þ6.9 [brolucizumab 6 mg] vs. þ7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mgetreated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mgetreated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P ¼ 0.001) and HARRIER (22.7% vs. 32.2%; P ¼ 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean À172.8 mm vs. À143.7 mm; P ¼ 0.001) and HARRIER (LS mean À193.8 mm vs. À143.9 mm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept.Conclusions: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mgetreated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (Clin-icalTrials.gov; NCT02307682, NCT02434328).

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In our trial, adalimumab was found to be associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than was placebo. (Funded by AbbVie; VISUAL I ClinicalTrials.gov number, NCT01138657 .).

A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.