Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

36-Month Evaluation of Intravitreous Aflibercept Injection for Wet Age-Related Macular Degeneration in Patients Previously Treated With Ranibizumab or Bevacizumab

Felipe F. Conti, MD; Fabiana Q. Silva, MD; Sunil K. Srivastava, MD; Justis P. Ehlers, MD; Andrew P. Schachat, MD; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVE:

In the ASSESS study, patients with neovascular age-related macular degeneration transitioned from other anti-vascular endothelial growth factor therapies to intravitreous aflibercept (Eylea; Regeneron, Tarrytown, NY) injections (IAI). The purpose was to determine the 36-month outcomes following the change from a fixed 24-month IAI dosing regimen to a routine clinical practice regimen.

PATIENTS AND METHODS:

Patients were treated with a fixed bimonthly regimen for the first 2 years. In the third year, patients were managed according to routine clinical practice.

RESULTS:

A total of 18 patients completed the 36 months and were considered for statistical analyses. At 36 months, a nonsignificant decrease of −37.8 μm in central subfield thickness and a nonsignificant gain of 5.8 letters from baseline were observed.

CONCLUSION:

Despite the significant visual and anatomical gains observed in the 2 years of fixed-dosing IAI, there was gradual decline in these improvements when patients were transitioned to a variable regimen.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:179–185.]

Abstract

BACKGROUND AND OBJECTIVE:

In the ASSESS study, patients with neovascular age-related macular degeneration transitioned from other anti-vascular endothelial growth factor therapies to intravitreous aflibercept (Eylea; Regeneron, Tarrytown, NY) injections (IAI). The purpose was to determine the 36-month outcomes following the change from a fixed 24-month IAI dosing regimen to a routine clinical practice regimen.

PATIENTS AND METHODS:

Patients were treated with a fixed bimonthly regimen for the first 2 years. In the third year, patients were managed according to routine clinical practice.

RESULTS:

A total of 18 patients completed the 36 months and were considered for statistical analyses. At 36 months, a nonsignificant decrease of −37.8 μm in central subfield thickness and a nonsignificant gain of 5.8 letters from baseline were observed.

CONCLUSION:

Despite the significant visual and anatomical gains observed in the 2 years of fixed-dosing IAI, there was gradual decline in these improvements when patients were transitioned to a variable regimen.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:179–185.]

Introduction

Age-related macular degeneration (AMD) is the leading cause of blindness in individuals older than 50 years of age in the developed world.1 Studies have estimated that 8.7% of the population worldwide have AMD, and, with the current aging tendency, projections are that by 2020, there will be 196 million with the disease and 288 million by 2040.2 Intravitreous anti-vascular endothelial growth factor (VEGF) is currently the gold standard treatment for neovascular AMD. The effectiveness of anti-VEGF agents in the treatment of neovascular AMD has been reported in several studies. Aflibercept (Eylea; Regeneron, Tarrytown, NY) was compared to ranibizumab (Lucentis; Genentech, South San Francisco, CA) in the double-masked, multicenter, randomized trials VIEW1 and VIEW 2. The authors reported that intravitreous aflibercept injection (IAI) dosed monthly or every 2 months after three initial monthly doses produced efficacy and safety outcomes comparable to monthly ranibizumab.3 Nevertheless, the successful outcomes of those trials are tempered by the patient's burden of monthly/bimonthly visits.

Because of the challenge that constant office visits and injections represent for patients and their families, the vast majority of retina specialists (98%) prefer to use an as-needed dosing (pro re nata [PRN]) or treat-and-extend (TAE) paradigm.4 TAE strategy was assessed in PRONTO study, a small, single-center, investigator-driven trial. An optical coherence tomography (OCT)-guided variable-dosing regimen with ranibizumab was used, and it reached outcomes comparable with those observed in phase 3 clinical studies.5 A TAE strategy was assessed by the TREX-AMD Study group in a phase 3, multicenter, randomized, controlled clinical trial with 60 patients. The authors reported that visual and anatomic gains with the TAE paradigm were comparable with those obtained with monthly dosing.6 However, well-structured prospective trials that compared different dosing regimen, such as CATT and PIER, indicated that these treatment regimens are inferior to fixed dosing.7,8

In addition, successful outcomes obtained at up to 2 years of fixed anti-VEGF therapy in patients with AMD have been reported.3 However, extension studies from randomized phase 3 trials have shown the difficulty in maintaining the same results with less frequent dosing in later years. During the extension period of the VIEW trial, patients received mandated IAI every 12 weeks (later amended to every 8 weeks) with option to treat monthly based on protocol-defined criteria. Visual acuity declined gradually during the extension period (−3.3 ETDRS letters) but remained improved over the initial baseline.9 During the follow-up phase of the CATT study, patients received treatment according to clinical practice and results indicated that improvements in VA during the first 2 years were not maintained at the end of the follow-up phase, with a loss of 3.3 letters from their presenting vision at of treatment initiation.10 Additionally, clinical research trials do not always express the findings seen in routine clinical practice. These studies enrolled patients with strict entry and exclusion criteria, like the inclusion of only treatment-naïve patients and trial elimination after follow-up loss.

The ASSESS study was a prospective, interventional, single-arm trial that transitioned patients from other anti-VEGF therapies used in everyday practice to IAI in a fixed-dosing regimen. Data through 24 months have been published previously and demonstrated sustained improvements in anatomy and vision in patients over their previous treatment assignments with no new adverse effects noted.11–13 Herein, we report the 36-month clinical outcomes of patients enrolled in the ASSESS study who were treated according the routine clinical practice after being released from the trial.

Patients and Methods

Study Design

The ASSESS trial is a prospective, single-arm, investigator-initiated study ( ClinicalTrials.gov identifier: NCT01617148). It was performed at the Cole Eye Institute, Cleveland, OH, and received approval from the Cleveland Clinic Investigational Review Board. All study related procedures were performed in accordance with good clinical practice (International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use [ICH] E6), applicable U.S. Food and Drug Administration (FDA) regulations, and the Health Insurance Portability and Accountability Act. All patients provided written informed consent for participation in the study.

Participants

Inclusion and exclusion criteria have previously been reported.11–13 In brief, patients were included if they met all of the following criteria: (1) active subfoveal choroidal neovascularization secondary to exudative AMD confirmed by fluorescein angiography; (2) presence of fluid on optical coherence tomography (OCT) (further defined as intraretinal, cystoid, subretinal fluid, or worsening pigment epithelial detachment) or the presence of a new hemorrhage on clinical examination; (3) E-ETDRS vision of 25 to 80 letters (Snellen equivalent of approximately 20/25 to 20/320); (4) prior injection of 1.25 mg bevacizumab (Avastin; Genentech, South San Francisco, CA) or 0.5 mg ranibizumab within 3 months of enrollment; and (5) had an initial response on OCT defined as a decrease of retinal edema and/or subretinal fluid to anti-VEGF injections. The study's inclusion criteria intended to describe a responder population to previous anti-VEGF treatment, which is unlike previous case series that concentrated on evaluating IAI in a nonresponding population. Only one eye per patient was included in the study. Patients who completed the 24-month study were eligible to participate in the 36-month follow-up phase.

Visits and Assessments

In the initial 24 months of the ASSESS study, patients were given 2 mg (0.05 mL) of IAI administered every month for the first 3 months, followed by 2 mg (0.05 mL) once every 2 months until 24 months. Although imaging and clinical values were recorded at follow-up visits, treatment decisions were not based on these values, but instead on a fixed-dosing regimen. Regeneron Pharmaceuticals (Tarrytown, NY) supplied the intravitreous aflibercept. The drug was administered using the standard aseptic intravitreous techniques as detailed in the package insert.14

During the follow-up phase from month 24 to month 36, patients were managed according to routine clinical practice and all treatments were administered according to best medical judgment. A reassessment visit was performed at 36 months. At each reassessment visit, patients were evaluated using an E-ETDRS chart (M&S Technologies, Skokie, IL) and a protocol visual acuity measurement consisting of best-corrected visual acuity (BCVA) using a forced choice paradigm.15 Patients also underwent a comprehensive eye examination and spectral-domain optical coherence tomography (SD-OCT) scanning was performed on both eyes. The scanning protocol consisted of a series of high-definition 6.0 mm linear scans centered on the fovea as well as a macular cube scan (512 × 128) using the Cirrus HD-OCT (software version 6.0; Zeiss, Oberkochen, Germany). Central subfield thickness (CST) was measured using the automated software.

Study Endpoints

The follow-up phase of the ASSESS trial aimed to determine the 36-month outcomes following the change from a fixed 24-month IAI dosing regimen to a routine clinical practice regimen. Endpoints evaluated at 36 months were the mean absolute change from baseline in CST as measured by SD-OCT and the mean change from baseline in BCVA. Additional outcomes included the percentage of patients who gained 15 letters of vision or greater, the percentage of patients who lost 15 letters of vision or greater, the percentage of patients who were 20/40 or better, and the percentage of patients who were 20/200 or worse at 36 months. The incidence of ocular and non-ocular adverse events (AEs) and serious AEs (SAEs) were also documented.

Safety Analysis

Safety was monitored through the collection and summary of ocular and non-ocular AEs, SAEs, and ocular assessments. The occurrence of any severe post-injection complications after IAI was recorded, including infection, inflammation, arteriothrombolic events, and death. Nondirective questioning was performed by the study coordinator to prompt AE reports from patients at each study visit. All AEs and SAEs, whether volunteered by the subject; discovered by the study site personnel during questioning; or detected by examination, laboratory testing, or other means, were recorded in case report forms.

Statistical Analysis

Normality was assessed using the Shapiro-Wilk test. No significant deviations from normality were observed. Continuous variables were summarized using means and standard deviations. The changes in macular thickness and visual acuity were assessed using paired t-tests, and mean changes with 95% confidence intervals were reported. Analyses were performed using SAS Software (version 9.4; Cary, NC). Since four time points were evaluated, a Bonferroni corrected significance level of .05/4 = .0125 was assumed, and P values less than this were considered significant.

Results

Eighteen eyes of 18 patients of the initial ASSESS cohort of 32 patients were included, as these 18 patients completed the 36-month assessment. Mean age was 77 years ± 7.8 years. Demographics and baseline ocular characteristics for patients participating the follow-up study are shown in Table 1. Table 2 summarizes the mean absolute changes from baseline in CST and BCVA at 6, 12, 24, and 36 months. The 36-month follow-up phase demonstrated a nonsignificant mean improvement from baseline in CST of −37.9 μm (95% CI, −82.0–6.1; P = .087) at month 36 after statistically significant improvements from baseline at months 6 (−39.4 μm; 95% CI, −67.9 to −10.9; P = .01), 12 (−52.7 μm; 95% CI, −86.6 to −18.8; P = .004), and 24 (−49.9 μm; 95% CI, −84.0 to −15.8; P = .007).

Demographic Characteristics and Outcomes of Patients Enrolled Within the ASSESS Trial

Table 1:

Demographic Characteristics and Outcomes of Patients Enrolled Within the ASSESS Trial

Change From Baseline in CST and BCVA

Table 2:

Change From Baseline in CST and BCVA

There was a nonsignificant mean increase in ETDRS BCVA from baseline of +5.8 letters (95%CI, −2.9–14.6: P = .018) after significant mean increases from baseline at months 6 (+6.6 letters; 95% CI, 3.2–9.9; P < .001), 12 (+10.3 letters, 95% CI, 5.7–15.0; P < .001), and 24 (+10.9 letters; 95% CI, 5.6–16.1; P < .001). Additionally, at month 36, 27.8% of patients gained 15 letters of vision or greater, and 5.6% of patients lost 15 letters or greater from baseline (Figure 2). The percentage of patients whose VA was 20/40 or better increased from 38.9% at baseline to 61.1% at month 24, which was maintained at the 36-month analysis (month 36: 61.1%). Twenty-two percent of patients had VA of 20/200 or worse at baseline. This rate was reduced to 5.5% at month 24, and then increased to 16.7% at month 36 (Figure 3).

Mean change in ETDRS letters and central subfield thickness (CST) in μm during the ASSESS study.

Figure 1:

Mean change in ETDRS letters and central subfield thickness (CST) in μm during the ASSESS study.

Percentage of subjects who gained 15 letters of vision or greater and percentage of subjects who lost 15 letters of vision or greater during ASSESS study years 1, 2, and 3.

Figure 2:

Percentage of subjects who gained 15 letters of vision or greater and percentage of subjects who lost 15 letters of vision or greater during ASSESS study years 1, 2, and 3.

Percentage of patients whose visual acuity was 20/40 or better and 20/200 or worse at baseline and annually during the ASSESS study.

Figure 3:

Percentage of patients whose visual acuity was 20/40 or better and 20/200 or worse at baseline and annually during the ASSESS study.

The mean number of visits in year 3 following the fixed dosing phase in years 0 to 2 was 8 ± 1.71, with a mean number of injections of 3.7 ± 2.2 among the 18 patients. Twelve patients were followed in a PRN fashion in the third year, with an average BCVA of 59.1 ± 20.2 ETDRS letters, an average of 8.75 ± 1.48 visits, and 2.6 ±1.8 injections (bevacizumab or aflibercept) in the period. Six patients were followed bimonthly with fixed IAI, with an average BCVA of 67.7 ± 21.8 ETDRS letters, an average of 6.5 ± 1.08 visits, and 6 ± 0.6 injections in the period.

Serious Adverse Events

One SAE was encountered during the 36-month study and was documented as not attributable to IAI. A patient was admitted for atrial fibrillation with rapid ventricular response at month 12 and for pneumonia and chronic heart failure at month 16.

Discussion

The first 2 years of the ASSESS trial investigated the effect of a fixed-dosing paradigm with IAI in patients previously treated with anti-VEGF injections in an as-needed fashion. By the end of year 2, there was a sustained improvement in anatomy and vision from baseline and stability when compared to baseline.13 The follow-up phase of the ASSESS trial evaluated the outcomes of those patients after their return to a routine clinical practice regimen. At the end of the follow-up phase, the mean VA declined 5.1 ETDRS letters from month 24. Similarly, the mean CST increased 11.9 μm from month 24. Yet, VA and CST measurements of month 36 were slightly better than baseline (+5.8 letters, P = .18; −37.9 μm, P = .087, respectively).

As patients were transitioned back to a routine clinical regimen, there was no significant improvement in the burden related to the number of clinic visits (follow-up phase: 8 ± 1.71 visits/year vs. fixed-dose treatment period: 7 ± 1.71 visits/year). Additionally, the loss of visual and anatomical improvements obtained in the first two years of fixed dosing regimen may imply that flexible regimens and undertreatment endanger the gains obtained during bimonthly-visits phase.

These results are comparable to the outcomes of other extension trials. In the SEVEN-UP study, 65 patients with AMD originally enrolled at fixed-dosed treatment had their long-term outcomes (7 years to 8 years) assessed, after switching to any regimen deemed appropriate. A mean loss of 8.6 letters was reported (P < .005) after this transition.16 The follow-up phase of the CATT trial reported similar results. Clinical outcomes of 647 patients were assessed 5 years after the original CATT study. During the follow-up phase, patients received a mean number of 4.4 anti-VEGF injections/year. Results indicate that improvements in VA during the first 2 years were not maintained through 5 years, with a mean VA change of −3.3 letters from the initial baseline and −5.1 letters from month 24.10 The VIEW 1 extension study reported the outcomes of 323 patients who had received intravitreous ranibizumab or aflibercept on fixed-interval dosing regimens during the 96-week VIEW1 study period. During the extension study period, patients received intravitreous aflibercept every 12 weeks (later amended to every 8 weeks) on a capped PRN dosing regimen (PRN dosing in addition to the fixed injection at 12 weeks or 8 weeks). Patients received an average of 6.08 injections/year. Visual acuity declined gradually during the extension period (−3.3 ETDRS letters from the extension study start) but remained improved over the initial baseline (+7.1 letters from the initial study baseline).9 Thus, to reduce the risk of under treatment, close clinical monitoring of exudative AMD patients on anti-VEGF therapy must be maintained over the course of treatment, even many years after initiation, and it may be beneficial to develop a standard follow-up protocol.

Unlike other studies that focused on inadequate responders,17–20 our trial transitioned patients who showed visual and anatomical gains with other anti-VEGF agents. The achievement of superior outcomes with another treatment strategy may not necessarily reflect drug superiority but likely the benefit of a fixed-dosing paradigm in treating patients in an FDA-approved manner over the possible undertreatment of variable-dosing regimens. Several studies report the conversion of patients to IAI from other therapeutics.17–20 The drawbacks of such experiments include their retrospective nature, lack of standardized treatment interval, and their analyses. The ASSESS study attempted to avoid some of these potential biases; however, there are still drawbacks to our study, such as the small sample size, and the absence of a non-transitioned comparison group. Nevertheless, this trial does have significant strengths including its prospective nature, continuous treatment, long-term follow-up with good retention, and meticulous evaluation of anatomical and visual results that surpass these drawbacks.

Conclusion

Switching patients from variable to a fixed-dosing regimen can produce visual and anatomical gains. However, the maintenance of these gains may be jeopardized by undertreatment and loss of follow-up. Future controlled studies, with a larger number of patients and longer follow-up periods may help to develop an effective but less burdensome follow-up protocol.

References

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Demographic Characteristics and Outcomes of Patients Enrolled Within the ASSESS Trial

Baseline

N (full set analysis) 18

Age, mean (SD) 77.7 years (±7.8 years)

Length of time since diagnosis of exudative AMD prior to enrollment, mean (SD) 24 months (± 25.8 months)

Previous treatment, % (n) Bevacizumab: 22% (4) Ranibizumab: 66.7% (12) Both: 11.1% (3)

Average number of treatments prior to study entry, mean (SD) 12 (± 6.3) Range: 4 to 23 injections

36 month E-ETDRS BCVA letter score, mean (SD) 56 ±18.1; Range: 24–69
  Snellen equivalent, mean 20/80
  PRN Group 52 ± 17.8; Range: 24–73; 20/100
  Fixed bimonthly Group 65 ± 16.8; Range: 32–80; 20/50
Outcomes

Number of visits, mean
  PRN 8.75 ± 1.48
  Fixed bimonthly 6.5 ± 1.08

Number of injections, mean
  PRN 2.6 ± 1.8
  Fixed bimonthly 6 ± 0.6

E-ETDRS BCVA letter score, mean (SD)
  PRN 59.1 ± 20.2
  Fixed bimonthly 67.7 ± 21.8

Change From Baseline in CST and BCVA

Factor Baseline Mean (95% CI) Time Point Mean (95% CI) Difference Mean (95% CI) Difference (P Value)
CST: 6 Months 302.4 (263.5–341.4) 263.0 (240.3–285.7) −39.4 (−67.9 to −10.9) .010
CST: 12 Months 302.4 (263.5–341.4) 249.7 (235.4–264.0) −52.7 (−86.6 to −18.8) .004
CST: 24 Months 302.4 (263.5–341.4) 252.6 (230.9–274.2) −49.9 (−84.0 to −15.8) .007
CST: 36 Months 302.4 (263.5–341.4) 264.5 (229.8–299.2) −37.9 (−82.0–6.1) .087
BCVA: 6 Months 56.1 (47.1–65.2) 62.7 (54.5–70.8) 6.6 (3.2–9.9) < .001
BCVA: 12 Months 56.1 (47.1–65.2) 66.4 (58.7–74.2) 10.3 (5.7–15.0) < .001
BCVA: 24 Months 56.1 (47.1–65.2) 67.0 (60.1–73.9) 10.9 (5.6–16.1) < .001
BCVA: 36 Months 56.1 (47.1–65.2) 61.9 (51.8–72.1) 5.8 (−2.9–14.6) .18
Authors

From Cole Eye Institute, Cleveland Clinic, Cleveland.

This study was accepted for presentation at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting in Baltimore, May 7–11, 2016.

Dr. Srivastava has received personal fees from Regeneron and grants and personal fees from Bausch + Lomb, Sanofi, Santen, and Allergan outside the submitted work. Dr. Ehlers has received grants from Regeneron and grants and personal fees from Genentech, Alcon, and Thrombogenics outside the submitted work. Dr. Schachat is a part-time employee of the State of Ohio, receives royalties from Elsevier, receives honorarium from the American Academy of Ophthalmology, and will receive possible future payments from Eastern Capital. Dr. Singh has received grants and personal fees from Regeneron and Genentech, personal fees from Shire, and grants from Apellis and Alcon. The remaining authors report no relevant financial disclosures.

Dr. Singh did not participate in the editorial review of this manuscript.

Support for this study was provided by a research trial grant from Regeneron.

Address correspondence to Rishi P. Singh, MD, 9500 Euclid Avenue, Desk i32, Cleveland, OH 44195; email: SINGHR@ccf.org.

Received: May 24, 2017
Accepted: August 03, 2017

10.3928/23258160-20180221-05

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