Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration: The MERLOT Randomized Clinical Trial

Abstract

Importance: Although anti-vascular endothelial growth factor (VEGF) treatment offers better outcomes than the natural history of neovascular age-related macular degeneration (ARMD), a less burdensome, less expensive, and more durable treatment is needed.

Objective: To assess the efficacy and safety of epimacular brachytherapy (EMB) for chronic, active, neovascular ARMD.

Design, setting, and participants: The Macular Epiretinal Brachytherapy vs Ranibizumab (Lucentis) Only Treatment (MERLOT) pivotal device trial was conducted at 24 National Health Service hospitals across the UK. Patients who had neovascular ARMD and received intravitreal ranibizumab were enrolled between November 10, 2009, and January 30, 2012. Eligible patients were randomized 2:1 and were stratified by lens status and angiographic lesion type to receive either EMB plus as-needed ranibizumab or as-needed ranibizumab monotherapy. Participants were followed up monthly for 24 months and then assessed at a final visit at month 36. Masking of participants and clinicians was not possible, but best-corrected visual acuity (BCVA) and imaging were analyzed by masked assessors. Analysis followed the intent-to-treat approach.

Interventions: Pars plana vitrectomy with 24 Gy EMB plus as-needed ranibizumab vs as-needed ranibizumab monotherapy.

Main outcomes and measures: Coprimary outcomes were the number of as-needed ranibizumab injections and the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA with a noninferiority margin of -5 ETDRS letters. Secondary outcomes were the percentage of participants losing fewer than 15 ETDRS letters and gaining 0 or more or 15 or more ETDRS letters and the mean change in angiographic total lesion size, choroidal neovascularization size, and foveal thickness on optical coherence tomography.

Results: Of 363 participants, 329 (90.6%) completed 24 months of follow-up (222 participants in the EMB group and 107 in the ranibizumab group). The mean (SD) age of the combined groups was 76.5 (7.4) years. The mean (SD) number of ranibizumab injections was 9.3 (6.7) in the EMB group and 8.3 (4.5) in the ranibizumab group, with a difference of 1.0 injection (95% CI, -0.3 to 2.3; P = .13). The mean (SD) BCVA change was -11.2 (15.7) ETDRS letters in the EMB group and -1.4 (10.9) ETDRS letters in the ranibizumab group, with a difference of 9.8 ETDRS letters (95% CI, -6.7 to -12.9). In the EMB group, 65.6% of participants (160 of 244) lost fewer than 15 ETDRS letters vs 86.6% (103 of 119) in the ranibizumab group, with a difference of 21% (95% CI, 12.4%-29.5%; P < .001). Microvascular abnormalities occurred in 20 of 207 eyes (9.7%) in the EMB group and 1 of 97 eyes (1.0%) in the ranibizumab group. These abnormalities occurred outside the foveal center, and there were no unexpected safety concerns.

Conclusions and relevance: The MERLOT trial found that despite the acceptable safety of EMB, it did not reduce the number of ranibizumab injections and was associated with worse visual acuity than anti-VEGF treatment alone; these results do not support EMB use as an adjunct treatment for chronic, active neovascular ARMD.

Trial registration: ClinicalTrials.gov Identifier: NCT01006538.

Figure 1.. CONSORT Diagram

ARMD indicates age-related macular degeneration; CNV, choroidal neovascularization; and EMB, epimacular brachytherapy. ^aOne participant in the ranibizumab monotherapy group did not receive the intervention as randomized because they withdrew consent prior to baseline and were found to be ineligible because of prior photodynamic therapy. Two participants in the EMB group were enrolled in error; one had previous vitrectomy and the other had visual acuity worse than 6/96.

Figure 2.. Number of As-Needed Ranibizumab Injections From Month 1 to Month 24 by Treatment Group

The top of the box shows the third quartile, and the bottom shows the first quartile, with the median shown as a line across the box. The top error bar represents the observations still within 1½ times of the upper quartile, and the bottom error bar represents the observations within 1½ times the lower quartile. The mean is shown as a square inside the box, and the outliers are shown as circles. The number of injections is represented separately for year 1 and year 2. The baseline ranibizumab given for preexisting disease to participants in both arms is not included.The epimacular brachytherapy (EMB) plus as-needed ranibizumab group comprised 244 participants, whereas the as-needed ranibizumab monotherapy group consisted of 119 participants.

Figure 3.. Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-Corrected Visual Acuity (BCVA) at Month 24

The top of the box shows the third quartile, and the bottom shows the first quartile, with the median shown as a line across the box. The top error bar represents the observations still within 1½ times of the upper quartile, and the bottom error bar represents the observations within 1½ times the lower quartile. The mean is shown as a square inside the box, and the outliers are shown as circles. The epimacular brachytherapy (EMB) plus as-needed ranibizumab group comprised 243 participants, whereas the as-needed ranibizumab monotherapy group consisted of 119 participants.