Purpose
To evaluate intravitreal aflibercept for treatment of macular edema secondary to central retinal vein occlusion (CRVO).
Design
Randomized, double-masked, phase 3 study.
Methods
A total of 177 patients with macular edema secondary to CRVO were randomized to receive 2 mg intravitreal aflibercept (n = 106) or sham (n = 71) every 4 weeks for 20 weeks. From weeks 24 to 48, patients were monitored every 4 weeks; the former group received intravitreal aflibercept as needed (PRN), and the sham group received sham. From weeks 52 to 76, patients were monitored every 8 weeks, and both groups received intravitreal aflibercept PRN. The primary endpoint (proportion of patients who gained ≥15 letters) was at week 24. This study reports exploratory outcomes at week 76.
Results
The proportion of patients who gained ≥15 letters in the intravitreal aflibercept and sham groups was 60.2% vs 22.1% at week 24 (patients discontinued before week 24 were considered nonresponders; P < .0001), 60.2% vs 32.4% at week 52 (last observation carried forward, P < .001), and 57.3% vs 29.4% at week 76 (last observation carried forward; P < .001). Mean μm change from baseline central retinal thickness was −448.6 vs −169.3 at week 24 ( P < .0001), −423.5 vs −219.3 at week 52 ( P < .0001), and −389.4 vs −306.4 at week 76 ( P = .1122). Over 76 weeks, the most common ocular serious adverse event in the intravitreal aflibercept group was macular edema (3.8%).
Conclusions
The visual and anatomic improvements seen after fixed, monthly dosing at week 24 were largely maintained when treatment intervals were extended. Patients with macular edema following CRVO benefited from early treatment with intravitreal aflibercept.
Macular edema is the leading cause of vision loss in patients with central retinal vein occlusion (CRVO). The pathophysiology of CRVO is incompletely understood, but a partial obstruction in blood flow, likely caused by venous thrombosis, increases retinal capillary pressure and results in transudation of fluid into the extravascular space, ultimately leading to macular edema. The proangiogenic protein, vascular endothelial growth factor (VEGF), plays an important role in the pathogenesis of macular edema following CRVO, as evidenced by its ability to initiate intraocular neovascularization and to induce vascular hyperpermeability. Moreover, vitreous levels of VEGF are positively correlated with the severity of macular edema in patients with CRVO. Accordingly, blockade of VEGF following intravitreal injection of anti-VEGF agents improves both visual and anatomic outcomes in patients with macular edema secondary to CRVO.
Intravitreal aflibercept injection (also known in the scientific literature as IAI, IVT-AFL, or VEGF Trap-Eye; Regeneron Pharmaceuticals, Inc; Tarrytown, New York, USA and Bayer HealthCare Pharmaceuticals, Berlin, Germany) is a fusion protein composed of key extracellular domains from human VEGF receptors 1 and 2 and the constant region from human IgG1. The molecule functions as a soluble decoy receptor, binding to multiple VEGF-A isoforms and placental growth factor, thereby preventing these proangiogenic ligands from binding to and activating endothelial VEGF receptors. Intravitreal aflibercept was first approved in the United States for the treatment of neovascular age-related macular degeneration (AMD), based on clinical evidence that it was as effective and safe as ranibizumab in improving visual and anatomic outcomes over a 1-year period. Intravitreal aflibercept has also been investigated for the treatment of macular edema secondary to CRVO in 2 parallel trials, with the COPERNICUS study performed in the United States and the GALILEO study performed in Europe and Asia/Pacific. Twenty-four-week, 52-week, and 100-week results of the COPERNICUS study have been reported, as have the 24-week and 52-week results from the GALILEO study. This report describes the 76-week results of the GALILEO study.
Methods
Study Design
The GALILEO study was a 76-week, randomized, double-masked, phase 3 trial comparing intravitreal aflibercept to sham for the treatment of macular edema secondary to CRVO. The study was carried out at 63 sites across Europe and Asia/Pacific (a list of study investigators is provided in the Appendix , available as Supplemental Material at AJO.com ). Institutional Review Board/Ethics Committee approval was prospectively obtained for the study protocol at each site. All patients signed a written consent form before initiation of the study-specific procedures. The study was registered with ClinicalTrials.gov (identifier no. NCT01012973 ) and was conducted in compliance with ethical guidelines from the Declaration of Helsinki and International Conference on Harmonization. Data for this 76-week report were collected between October 2009 and February 2012.
The design and eligibility criteria for the GALILEO study have previously been described. Briefly, patients were randomized in a 3:2 ratio to receive either 2 mg intravitreal aflibercept injection (2Q4) or sham in the study eye once every 4 weeks for 20 weeks, for a total of 6 doses. From week 24 to week 48, patients in the intravitreal aflibercept group were evaluated every 4 weeks and received intravitreal aflibercept as needed (2Q4 → PRN) if they met prespecified retreatment criteria. Patients in the sham group continued to receive sham at all scheduled visits through week 48. From week 52 through week 68, patients in both intravitreal aflibercept (2Q4 → PRN) and sham (sham → PRN) groups were monitored every 8 weeks and received intravitreal aflibercept PRN according to the prespecified retreatment criteria. No treatment was administered at week 76 in either group. The prespecified retreatment criteria were as follows: (1) a >50 μm increase in central retinal thickness compared with the lowest previous measurement, (2) new or persistent cystic changes within the neurosensory retina or subretinal fluid, (3) persistent diffuse edema ≥250 μm in the central subfield, (4) loss of ≥5 letters from the best prior measurement in conjunction with any increase in central retinal thickness, or (5) an increase of ≥5 letters in best-corrected visual acuity (BCVA) from the most recent visit in the absence of retinal edema in the central subfield, suggesting potentially further improvements upon a subsequent injection. If none of the retreatment criteria were met, patients received sham to maintain masking. All patients were eligible to receive panretinal laser photocoagulation at any time during the study if they progressed to neovascularization of the anterior segment, optic disc, or elsewhere in the fundus. Only 1 eye from each patient was included in the study and treated as described here.
Outcome Measures
The primary efficacy endpoint was the proportion of patients achieving a gain of ≥15 letters in BCVA from baseline to week 24. Efficacy endpoints at week 76 were all exploratory and included the proportion of patients who gained ≥15 letters in BCVA from baseline; mean change from baseline in BCVA and central retinal thickness; proportion of patients progressing to neovascularization of the anterior segment, optic disc, or elsewhere in the fundus; and change from baseline in the mean National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) total scores. Safety assessments included ophthalmic examinations, adverse events, laboratory measurements, and vital signs. The efficacy and safety endpoints were assessed as described previously. Retinal characteristics were evaluated using time-domain optical coherence tomography.
Statistical Analyses
The efficacy endpoints were analyzed using the full analysis set, which included all randomized patients who received any study treatment and had a baseline and at least 1 post-baseline BCVA assessment. In a prespecified analysis of the primary efficacy endpoint (the proportion of patients who gained ≥15 letters at week 24), patients who discontinued before week 24 were considered to be nonresponders. In the exploratory analysis of proportion of patients with no retinal fluid, observed values were used. In all other efficacy analyses, missing values were imputed by the last observation carried forward method. Between-group differences in the proportion of patients who gained ≥15 letters were evaluated with a 2-sided Cochran-Mantel-Haenszel test. Continuous variables were analyzed with an analysis of covariance, except for BCVA, which was assessed using an analysis of variance. Safety from baseline to week 76 was analyzed in the safety analysis set, which included all randomized patients who received any study treatment. Safety from week 52 to week 76 was analyzed in patients from the safety analysis set who completed week 52.
Results
Patient Disposition, Demographics, and Baseline Characteristics
Of 240 patients screened, 106 patients were randomized to the intravitreal aflibercept group and 71 patients were randomized to the sham group. A total of 104 patients (104/106, 98.1%) in the intravitreal aflibercept group and 68 patients (68/71, 95.8%) in the sham group received treatment and were included in the safety analysis set. The full analysis set included 103 patients (103/106, 97.2%) in the intravitreal aflibercept group (1 patient did not have any post-baseline BCVA score and was therefore excluded from the full analysis set) and 68 patients (68/71, 95.8%) in the sham group. A total of 16 patients (16/106, 15.1%) in the 2Q4 → PRN group and 19 patients (19/71, 26.8%) in the sham → PRN group discontinued the study before week 76. Major reasons for discontinuation in the 2Q4 → PRN group were adverse event (5 of 106 patients, 4.7%), protocol violation (5 of 106 patients, 4.7%), and withdrawal of consent (4 of 106 patients, 3.8%). Major reasons for discontinuation in the sham → PRN group were withdrawal of consent (6 of 71 patients, 8.5%), adverse event (5 of 71 patients, 7.0%), and lack of efficacy (5 of 71 patients, 7.0%). No patient in the 2Q4 → PRN group discontinued the study treatment because of a lack of efficacy. As previously described, demographics and baseline disease characteristics of patients were similar in both treatment groups.
Efficacy
The proportion of patients in the 2Q4 → PRN and sham → PRN groups who gained ≥15 letters in BCVA was 60.2% vs 22.1% at week 24 (patients who discontinued before week 24 were considered to be nonresponders; P < .0001), 60.2% vs 32.4% at week 52 (last observation carried forward; P < .001), and 57.3% vs 29.4% at week 76 (last observation carried forward; P < .001). The mean change from baseline BCVA in the 2Q4 → PRN and sham → PRN groups was 18.0 vs 3.3 letters ( P < .0001) at week 24, 16.9 vs 3.8 letters ( P < .0001) at week 52, and 13.7 vs 6.2 letters ( P < .01) at week 76 ( Figure 1 ).
The mean change from baseline central retinal thickness in the 2Q4 → PRN and sham → PRN groups was −448.6 vs −169.3 μm ( P < .0001) at week 24, −423.5 vs −219.3 μm ( P < .0001) at week 52, and −389.4 vs −306.4 μm ( P = .1122) at week 76 ( Figure 2 , Top). The proportion of patients in the 2Q4 → PRN and sham → PRN groups who had no retinal fluid was 80.4% vs 25.5% at week 24, 66.7% vs 30.0% at week 52, and 60.2% vs 52.0% at week 76 ( Figure 2 , Bottom).
During the 76-week study, 8 patients (7.8%) in the 2Q4 → PRN group and 6 patients (8.8%) in the sham → PRN group developed neovascularization. In the 2Q4 → PRN group, neovascularization occurred in the anterior segment in 7 patients (6.8%), in the optic disc in 1 patient (1.0%), and elsewhere in the fundus in 2 patients (1.9%) (neovascularization occurred in more than 1 location in 2 patients). In the sham → PRN group, neovascularization occurred in the anterior segment in 1 patient (1.5%), in the optic disk in 2 patients (2.9%), and elsewhere in the fundus in 4 patients (5.9%) (neovascularization occurred in more than 1 location in 1 patient). Panretinal photocoagulation was performed for 2 patients (1.9%) in the 2Q4 → PRN group and for 3 patients (4.4%) in the sham → PRN group.
Vision-related quality of life, as measured by mean changes in NEI VFQ-25 total scores from baseline, demonstrated a clinically relevant improvement (≥4-point increase) in the 2Q4 → PRN group at weeks 24, 52, and 76 (7.5, 7.8, and 7.4 points, respectively). In the sham → PRN group, improvements in NEI VFQ-25 total scores were 3.5 points at week 24, 4.5 points at week 52, and 4.9 points at week 76. The between-group differences in these scores significantly favored the 2Q4 → PRN group at all 3 visits ( P = .0013 at week 24; P = .0049 at week 52; P = .0445 at week 76).
Study Drug Injections
Between week 24 and week 52, the 2Q4 → PRN group received a mean (±SD) of 2.5 ± 1.7 injections (safety analysis set) ( Table 1 ). Between week 52 and week 76, the mean (±SD) number of intravitreal aflibercept injections in the 2Q4 → PRN group was 1.3 ± 1.1, compared with 1.7 ± 1.1 in the sham → PRN group (safety analysis set). Distribution of injections from week 52 to week 76 is presented in Figure 3 .
| Mean Number of Intravitreal Aflibercept Injections | |||
|---|---|---|---|
| Baseline to Week 24 | Week 24 to Week 52 | Week 52 to Week 76 | |
| Sham → intravitreal aflibercept PRN | NA | NA | 1.7 ± 1.1 c |
| Intravitreal aflibercept 2Q4 → PRN | 5.7 ± 0.9 a | 2.5 ± 1.7 b | 1.3 ± 1.1 c |
b Safety analysis set, n = 97.
c Safety analysis set, n = 52 for Sham → PRN, and n = 91 for 2Q4 → PRN.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
