Highlights
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From baseline to week 76, 65.6% of patients gained ≥15 letters.
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In the treat-and-extend phase, 45.0% of patients achieved a mean treatment interval of ≥8 weeks.
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A last actual treatment interval of ≥8 weeks was achieved by 63.1% of patients.
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Mean BCVA was 51.9 letters at baseline and 72.3 letters at week 76 (+20.3 letters).
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Mean central retinal thickness decreased from 759.9 µm at baseline to 265.4 µm at week 76 (−496.1 µm).
Purpose
To evaluate the efficacy and safety of intravitreal aflibercept (IVT-AFL) treat-and-extend dosing in patients with macular edema secondary to central retinal vein occlusion (CRVO).
Design
CENTERA (Evaluation of a Treat and Extend Regimen of Intravitreal Aflibercept for Macular Edema Secondary to CRVO; NCT02800642) was an open-label, Phase 4 clinical study.
Methods
Patients received 2 mg of IVT-AFL at baseline and every 4 weeks thereafter, until disease stability criteria were met (or until week 20), at which point treatment intervals were adjusted in 2-week increments based on functional and anatomic outcomes.
Results
From baseline to week 76, 105 patients (65.6%) ( P <.0001 [test against threshold of 40%]) gained ≥15 letters; and, during the treat-and-extend phase, 72 patients (45.0%) ( P = 0.8822 [test against threshold of 50%]) achieved a mean treatment interval of ≥8 weeks. A last and next planned treatment interval of ≥8 weeks was achieved by 101 patients (63.1%) and by 108 patients (67.5%), respectively. Mean ± SD best-corrected visual acuity increased from 51.9 ± 16.8 letters at baseline to 72.3 ± 18.5 letters at week 76 (mean change: +20.3 ± 19.5 letters), and central retinal thickness decreased from 759.9 ± 246.0 µm at baseline to 265.4 ± 57.9 µm at week 76 (mean change: −496.1 ± 252.4 µm). The safety profile of IVT-AFL was consistent with that of previous studies.
Conclusions
Clinically meaningful improvements in functional and anatomic outcomes were achieved with IVT-AFL treat-and-extend dosing. Most patients achieved a last actual and last intended treatment interval of ≥8 weeks; therefore, treatment intervals may have been extended even further with a longer study duration.
Retinal vein occlusion is a common cause of vision loss in patients with chronic macular edema. There are 3 different types of retinal vein occlusions, based on the obstruction site: branch retinal vein occlusion, central retinal vein occlusion (CRVO), and hemiretinal vein occlusion. CRVO is an obstruction of the main retinal vein at or posterior to the optic nerve head ; it affects both men and women and occurs most commonly in patients who are 60 years of age or older. , Although CRVO is usually unilateral, approximately 7.8% of patients with CRVO in one eye also have RVO in the fellow eye. CRVO leads to impaired venous drainage from the eye, which in turn may result in increased venous pressure, reduced arterial perfusion, and retinal ischemia. Retinal nonperfusion leads to an increase in vascular endothelial growth factor (VEGF), which increases vascular permeability and can cause macular edema, retinal hemorrhage, and neovascularization.
Treatment of macular edema secondary to CRVO involves the administration of anti-VEGF agents, such as aflibercept and ranibizumab, which have become the standard of care. The efficacy and safety of intravitreal aflibercept (IVT-AFL) were assessed in 2 pivotal Phase 3 studies, COPERNICUS (NCT00943072) , and GALILEO (Vascular Endothelial Growth Factor [VEGF] Trap-Eye: Investigation of Efficacy and Safety in Central Retinal Vein Occlusion; NCT01012973), , in which findings demonstrated that IVT-AFL was beneficial for the treatment of macular edema secondary to CRVO. In these studies, the mean change from baseline to week 24 in best-corrected visual acuity (BCVA) was +17.3 and +18.0 letters for patients treated with IVT-AFL compared with −4.0 and +3.3 letters in patients who received sham injections, respectively. , These studies demonstrate how, if left untreated, patients with macular edema secondary to CRVO lose VA and have a poor prognosis. This was similarly shown in the CRUISE study (A Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion; NCT00485836), in which mean change from baseline BCVA at month 6 was +12.7 letters and +14.9 letters in the 0.3-mg and 0.5-mg ranibizumab groups, respectively, and +0.8 letters in the sham group. Both the COPERNICUS and the GALILEO studies included pro re nata (PRN) dosing from week 24 of treatment to investigate the possibility of extending the treatment interval beyond 4 weeks. Post hoc assessment of the different dosing subgroups demonstrated some de-stabilization of the disease with doses administered PRN. Although the deterioration seen during the study period was minor, possibly due to the regular monitoring schedule implemented in those trials, it is likely to progress over the expected longer-term treatment duration required in the real-world setting for patients with macular edema secondary to CRVO.
The Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) study (ISRCTN13623634) compared IVT-AFL, bevacizumab, and ranibizumab using a PRN dosing regimen and introduced a threshold of treatment success for suspending treatment (>83 Early Treatment Diabetic Retinopathy Study [ETDRS] letters), which allowed a comparative assessment of the treatment burden associated with each treatment arm. Treatment with any of these 3 anti-VEGF agents resulted in improved and sustained VA when patients were monitored regularly and treated promptly (IVT-AFL: +15.1 letters; ranibizumab: +12.5 letters; and bevacizumab: +9.8 letters at week 100). Notably, IVT-AFL was non-inferior to ranibizumab at week 100.
Post hoc analyses of COPERNICUS and GALILEO supported the implementation of proactive treatment to prevent deterioration of functional and anatomic outcomes. “Treat and extend” is a proactive, individualized dose strategy whereby the patient receives an injection at every visit. The treatment interval is decided at every visit and is gradually extended if functional and anatomic stability are maintained and shortened if deterioration is observed, to minimize the risk of disease recurrence rather than in response to it. Additionally, with treat-and-extend dosing regimens, the need for interim monitoring is minimized, which reduces the number of appointments per patient and minimizes the need for monitoring visits. Decreasing the number of visits per patient reduces the treatment burden and the need for scheduling visits, thus benefiting both the patient and the health care providers.
To our knowledge, treat-and-extend dosing regimens have not been evaluated in large-scale studies of IVT-AFL for the treatment of macular edema secondary to CRVO. Therefore, the aim of the CENTERA (Evaluation of a Treat and Extend Regimen of Intravitreal Aflibercept for Macular Edema Secondary to CRVO; NCT02800642) study was to assess the efficacy and safety of IVT-AFL administered in a treat-and-extend dosing regimen in patients with macular edema secondary to CRVO.
Methods
Study Design
CENTERA (NCT02800642) was a 76-week, multicenter, open-label, single-arm, Phase 4 study that assessed the efficacy and safety of IVT-AFL administered using a treat-and-extend dosing regimen in treatment-naive patients with macular edema secondary to CRVO. CENTERA was conducted between June 2016 and July 2019 at 42 study centers in Australia, Canada, Denmark, France, Germany, Italy, Spain, and the UK, in accordance with the Declaration of Helsinki and the International Council for Harmonisation guideline E6: Good Clinical Practice. The protocol and any amendments were reviewed and approved by each study site’s Independent Ethics Committee or Institutional Review Board (IRB) before the start of the study. The name of each study site’s IRB is listed in Supplemental Table 1. All enrolled patients provided written informed consent.
Participants
Treatment-naive patients ≥18 years of age with center-involved macular edema secondary to CRVO for no longer than 3 months were enrolled. Patients were required to have a BCVA of 73-24 ETDRS letters (Snellen equivalent of 20/40-20/320) in the study eye. All patients were scheduled to be treated with IVT-AFL as part of routine clinical practice, with the intent to use a treat-and-extend regimen after the initial dose. Exclusion criteria are listed in the Supplemental material.
Interventions
CENTERA was a single-arm study, and patients received treatment at the discretion of the physician. All patients received 2-mg IVT-AFL injections at baseline and every 4 weeks until disease stability criteria were met or until week 20, whichever occurred first (the initiation phase of the treatment). Starting at week 8, the re-treatment interval was determined, and the frequency of injections could be adjusted by 2-week increments to maintain stable functional and anatomic outcomes (the treat-and-extend phase of treatment).
The stability criteria were no new cysts found on optical coherence tomography; BCVA within a ±5-letter “stability corridor” (defined as no more than a 5-letter gain as the last or second to last visit and no more than a 5-letter loss from best previous BCVA at any visit); and central retinal thickness (CRT) within a ±20% “stability corridor” (defined as no more than 20% thickness reduction as the last or second to last visit and no more than 20% thickening from best previous CRT at any visit). Values of BCVA and CRT outside those “stability corridors” were considered “improvements” for higher BCVA values and lower CRT values and “deteriorations” for lower BCVA values and higher CRT values.
From week 8, at every treatment visit (and at weeks 24, 52, and 76), the physician determined the stability status of each patient, and the following algorithm was used to determine the re-treatment interval: if the condition was stable (all stability criteria met), the treatment interval was extended by 2 weeks. If the condition was improving (no new cysts and improvement in at least 1 of the disease activity criteria [BCVA or CRT] with the other improving or stable), the treatment interval was maintained; and if the condition was deteriorating (new cysts and/or deterioration in at least 1 of the other disease activity criteria [BCVA or CRT]), the treatment interval was reduced by 2 weeks. Injections were not to be administered more frequently than every 4 weeks (minimum re-treatment interval).
Study Endpoints
The pre-determined co-primary endpoints were the proportion of patients who gained ≥15 letters from baseline to week 76 and the proportion of patients with a mean treatment interval of ≥8 weeks from the last initiation phase visit to week 76. These endpoints were met if significantly ≥40% of patients gained ≥15 letters and if significantly ≥50% of patients had a mean treatment interval of ≥8 weeks.
Secondary endpoints included mean change in BCVA and CRT from baseline to weeks 24, 52, and 76; the number of injections from baseline to week 76; and the mean treatment interval from baseline to week 76. Other endpoints reported included the proportion of patients who lost <15 letters. The following post hoc analyses were also conducted: the proportion of patients who achieved a last actual (defined as the length of the interval before study end [last]) and last intended treatment interval (defined as the next planned interval [next planned]) of ≥8 weeks and the proportion of patients who had a BCVA of ≥70 letters at all mandatory study visits. Safety was assessed throughout the study period. Adverse events (AEs) were treatment-emergent if they occurred or worsened after the first IVT-AFL dose and, at most, 30 days after the last dose. All AEs were reported in case report forms and coded using Medical Dictionary for Regulatory Activities, edition 22.0. An adjudication of AEs according to the Antiplatelet Trialists’ Collaboration criteria was also performed.
Statistical Analysis
Study success required that a gain of ≥15 letters at week 76 was reached by significantly more than 40% of patients and that a mean treatment interval of ≥8 weeks was reached by significantly more than 50% of patients during the treat-and-extend phase. The exact 1-sample binomial test was used to assess each of the co-primary efficacy variables at a significance level of 5% (2-sided test) using the full analysis set (FAS), and 95% confidence intervals (CIs) were provided. A sample size of 150 patients was calculated to provide a power of ≥90% to meet both co-primary endpoints, assuming a true probability for gaining ≥15 letters of 55% and a true probability to reach a mean treatment interval of ≥8 weeks of 65%. All other variables were analyzed by descriptive statistical methods, and frequency tables were generated for categorical data.
The safety analysis set included all enrolled patients who received IVT-AFL. The FAS included all enrolled patients who received IVT-AFL, had a baseline BCVA assessment, and had at least 1 post-baseline BCVA assessment. The primary efficacy analysis was conducted using the FAS. The per-protocol set (PPS) included all enrolled patients who received IVT-AFL, had a BCVA assessment at study baseline, had at least 1 BCVA assessment at week 24 or later, and did not have a major protocol deviation. The co-primary efficacy variable sensitivity analysis was conducted using the PPS. Statistical evaluation was performed using Statistical Analysis System version 9.4 software (SAS Institute, Cary, North Carolina, USA).
Results
Patients
Of the 244 patients who were enrolled, 162 completed screening and entered the treatment period. Two patients had no post-baseline assessments available and were not included in the FAS. Overall, 150 patients (92.6%) completed the study. The reasons for study discontinuation were death (n = 4), withdrawal by patient (n = 3), AEs (n = 2), physician decision (n = 2), and lost to follow-up (n = 1). In total, 147 patients were included in the PPS ( Figure 1 ).
The overall mean ± SD age was 66.2 ± 13.4 years, and 60.0% of patients were male ( Table 1 ). At baseline, mean ± SD BCVA was 51.9 ± 16.9 letters and CRT was 759.9 ± 246.0 µm.
Characteristic | IVT-AFLN=160 |
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Mean age, years (SD) | 66.2 (13.4) |
Age range, years, n (%) | |
18–64 | 62 (38.8) |
65–84 | 87 (54.4) |
≥85 | 11 (6.9) |
Sex, n (%) | |
Male | 96 (60.0) |
Race, n (%) | |
White | 152 (95.0) |
Asian | 3 (1.9) |
Black | 1 (0.6) |
Not reported | 4 (2.5) |
Mean BVCA ETDRS letters, (SD) | 51.9 (16.9) |
Mean CRT, µm (SD) a | 759.9 (246.0) |
Weeks since CRVO diagnosis, n (%) b | |
0 | 3 (1.9) |
1 | 35 (22.3) |
2 | 43 (27.4) |
3 | 21 (13.4) |
4 | 13 (8.3) |
5 | 8 (5.1) |
6 | 9 (5.7) |
7 | 5 (3.2) |
8 | 3 (1.9) |
9 | 3 (1.9) |
≥10 | 17 (10.8) |
Mean refraction sphere, diopters (SD) | 1.8 (1.7) |
Capillary non-perfusion on FA, n (%) | |
No | 149 (93.1) |
Yes | 11 (6.9) |
Location of capillary non-perfusion on FA, n (%) | |
Q1, Q2, Q3, Q4 | 6 (3.8) |
Q2, Q3 | 3 (1.9) |
Q3 | 2 (1.3) |
Gonioscopy, n (%) | |
Normal | 148 (92.5) |
Abnormal | 9 (5.6) |
Missing | 3 (1.9) |