Intravitreal Aflibercept Injection for Macular Edema
`Secondary to Central Retinal Vein Occlusion: 1-Year
`Results From the Phase 3 COPERNICUS Study
`
`DAVID M. BROWN, JEFFREY S. HEIER, W. LLOYD CLARK, DAVID S. BOYER, ROBERT VITTI,
`ALYSON J. BERLINER, OLIVER ZEITZ, RUPERT SANDBRINK, XIAOPING ZHU, AND JULIA A. HALLER
`
` PURPOSE: To evaluate intravitreal aflibercept injec-
`tions (IAI; also called VEGF Trap-Eye) for patients
`with macular edema secondary to central retinal vein
`occlusion (CRVO).
` DESIGN: Randomized controlled trial.
` METHODS: This multicenter study randomized 189
`patients (1 eye/patient) with macular edema secondary
`to CRVO to receive 6 monthly injections of either 2 mg
`intravitreal aflibercept (IAI 2Q4) (n [ 115) or sham
`(n [ 74). From week 24 to week 52, all patients received
`2 mg intravitreal aflibercept as needed (IAI 2Q4 D PRN
`and sham D IAI PRN) according to retreatment criteria.
`The primary endpoint was the proportion of patients who
`gained ‡15 ETDRS letters from baseline at week 24.
`Additional endpoints included visual, anatomic, and
`quality-of-life NEI VFQ-25 outcomes at weeks 24 and 52.
` RESULTS: At week 24, 56.1% of IAI 2Q4 patients
`gained ‡15 letters from baseline compared with 12.3%
`of sham patients (P < .001). At week 52, 55.3% of
`IAI 2Q4 D PRN patients gained ‡15 letters compared
`with 30.1% of sham D IAI PRN patients (P < .001).
`At week 52, IAI 2Q4 D PRN patients gained a mean of
`16.2 letters of vision vs 3.8 letters for sham D IAI
`PRN (P < .001). The most common adverse events
`for both groups were conjunctival hemorrhage, eye pain,
`reduced visual acuity, and increased intraocular pressure.
` CONCLUSIONS: Monthly injections of 2 mg intravitreal
`aflibercept for patients with macular edema secondary to
`CRVO resulted in a statistically significant improvement
`in visual acuity at week 24, which was largely maintained
`through week 52 with intravitreal aflibercept PRN
`dosing. Intravitreal aflibercept injection was generally
`
`Supplemental Material available at AJO.com
`See Accompanying Editorial on page 415.
`Accepted for publication Sep 19, 2012.
`From Retina Consultants of Houston, The Methodist Hospital,
`Houston, Texas (D.M.B.); Ophthalmic Consultants of Boston, Boston,
`Massachusetts (J.S.H.); Palmetto Retina Center, West Columbia, South
`Carolina (W.L.C.); Retina-Vitreous Associates Medical Group, Beverly
`Hills, California (D.S.B.); Regeneron Pharmaceuticals Inc, Tarrytown,
`New York (R.V., A.J.B., X.Z.); Bayer HealthCare, Berlin, Germany
`(O.Z., R.S.); Universita¨tsklinikum Hamburg-Eppendorf, Klinik und
`Poliklinik fu¨r Augenheilkunde, Hamburg, Germany (O.Z.); Department
`of Neurology, Heinrich-Heine-Universita¨t, Du¨sseldorf, Germany (R.S.);
`and Wills Eye Institute, Philadelphia, Pennsylvania (J.A.H.).
`Inquiries
`to Julia A. Haller, 840 Walnut Street, Suite 1510,
`Philadelphia, PA 19107; e-mail: jhaller@willseye.org
`
`2013;155:
`(Am J Ophthalmol
`tolerated.
`well
`429–437. Ó 2013 by Elsevier Inc. All rights reserved.)
`
`T HE MANAGEMENT OF EYES WITH VISION LOSS FROM
`
`macular edema secondary to central retinal venous
`occlusion (CRVO) has been entirely transformed
`in recent years. Both anti–vascular endothelial growth
`factor (VEGF) and steroidal pharmacotherapies have
`been developed, tested, and put into clinical practice,
`targeting the vascular permeability and leakage that
`frequently develops following blockage of the central
`retinal vein.1–7 Intravitreal aflibercept
`injection, also
`known as VEGF Trap-Eye (Regeneron Pharmaceuticals
`Inc, Tarrytown, New York, USA) is a 115-kDa decoy
`receptor fusion protein, composed of the second domain
`of human VEGF receptor 1 and the third domain of
`VEGF receptor 2 fused to the Fc domain of human
`IgG1.8,9 The binding affinity of aflibercept for VEGF is
`substantially greater than that of either bevacizumab or
`ranibizumab,10 and mathematical modeling has predicted
`its potential for a longer duration of action in the eye.11
`The current phase 3 randomized, sham-controlled clin-
`ical trial (COPERNICUS) recently reported that afliber-
`cept, given as a monthly intravitreal injection in eyes
`with macular edema attributable to CRVO,
`improved
`visual acuity (VA) and central retinal thickness, was asso-
`ciated with no progression to neovascularization, and had
`a low rate of ocular adverse events at 24 weeks.6 Beginning
`at week 24, patients in both groups were eligible to receive
`2 mg of intravitreal aflibercept injection (IAI) as needed
`(pro re nata; PRN). Therefore the patients in the sham þ
`IAI PRN group received a different dosing regimen from
`weeks 24 onward compared with the start of treatment in
`those patients who had received intravitreal aflibercept
`initially (every 4 weeks). This report follows these patients
`to 1 year.
`
`METHODS
`
`THE COPERNICUS STUDY IS AN ONGOING 2-YEAR, PHASE 3,
`prospective, randomized, double-masked trial. This multi-
`center study was conducted across 70 sites in the United
`
`0002-9394/$36.00
`http://dx.doi.org/10.1016/j.ajo.2012.09.026
`
`Ó 2013 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
`429
`
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`

`States, Canada, Colombia, India, and Israel. The study
`protocol of the COPERNICUS trial was approved by the
`institutional review board or ethics committee at each
`participating clinical center before the start of the study.
`This trial was registered with ClinicalTrials.gov (identifier
`#NCT00943072). All patients signed a written consent
`form before initiation of the study-specific procedures.
`This study was conducted in compliance with regulations
`of the Health Insurance Portability and Accountability
`Act and the Declaration of Helsinki.
` TREATMENTS: Patients were randomly allocated using
`a 3:2 ratio to receive intravitreal aflibercept injections,
`2 mg (IAI 2Q4), or sham injections, every 4 weeks for
`24 weeks,
`for
`a
`total of 6 monthly
`treatments
`(Supplemental Figure 1, available at AJO.com).6 Between
`weeks 24 and 52, patients in both treatment groups were
`evaluated monthly and were injected with intravitreal afli-
`bercept as needed if they met protocol-specified retreat-
`ment criteria. They received a sham injection if
`retreatment was not indicated. After the first year of
`masked dosing, patients are continuing in a 1-year exten-
`sion phase with PRN dosing. Data for this 52-week report
`were collected between July 2009 and April 2011.
`Randomization was
`stratified by geographic region
`(North America [Canada and the United States] vs the
`rest of the world [Colombia, India, and Israel]) and by using
`a baseline best-corrected visual acuity (BCVA) score
`(>20/200, ie, 35 to 73 Early Treatment Diabetic Retinop-
`athy Study [ETDRS] letters; and <_20/200 ie, 24 to 34
`ETDRS letters). Only 1 eye per patient was included in
`the randomization. All patients were eligible to receive
`panretinal photocoagulation at any time during the study
`if they progressed to neovascularization of the anterior or
`posterior segment.
` PARTICIPANTS: The study enrolled patients aged >_18
`years with center-involved macular edema secondary
`to CRVO diagnosed within 9 months of study initiation.
`All study eyes had mean central subfield retinal thickness
`>_250 mm using optical coherence tomography (OCT)
`from Zeiss Stratus OCT (Version 4.0 or later; Carl Zeiss
`Meditec, Jena, Germany), and protocol refracted ETDRS12
`BCVA of 20/40 to 20/320 (73 to 24 letters).
`Key exclusion criteria for the study eye included: any
`previous
`treatment with antiangiogenic drugs; prior
`panretinal or macular laser photocoagulation; and any
`ocular disorders that could confound interpretation of
`study results. Exclusion criteria with respect to both
`eyes included: previous use of intraocular corticosteroids
`or use of periocular corticosteroids within the 3 months
`prior to day 1; iris neovascularization, vitreous hemor-
`rhage, traction retinal detachment, or preretinal fibrosis
`involving the macula; history or presence of age-related
`macular degeneration (AMD; dry or wet form) that signif-
`icantly affected central vision; diabetic macular edema or
`
`diabetic retinopathy, defined as eyes of diabetic subjects
`with more than 1 microaneurysm outside the area of the
`vein occlusion; and infectious blepharitis, keratitis, scler-
`itis, or conjunctivitis.
` ENDPOINTS AND ASSESSMENTS: The primary efficacy
`endpoint was the proportion of eyes with a gain of >_15
`ETDRS letters in BCVA from baseline to week 24.
`Secondary efficacy endpoints (all assessed at week 24)
`were: change from baseline in BCVA scores; change from
`baseline in central retinal thickness (CRT); proportion of
`patients progressing to neovascularization of anterior
`segment, optic disc, or elsewhere in the retina; and change
`from baseline in the National Eye Institute 25-item Visual
`Function Questionnaire (NEI VFQ-25) in total and subscale
`scores (distance activities, near activities, and vision depen-
`dency). The tertiary efficacy endpoints were all of the
`parameters mentioned above measured at 52 weeks.
`A masked physician was assigned to assess adverse events
`(AEs), supervise the masked assessment of efficacy, and
`decide on the need for retreatment during the PRN phase.
`Visual acuity assessors were masked as
`to treatment
`assignment.
`Assessments were conducted at regularly scheduled clinic
`visits on day 1 and every 4 weeks from weeks 4 to 52. BCVA
`was evaluated by certified examiners using the ETDRS
`refraction protocol. Retinal characteristics from OCT scans
`were assessed at a masked independent central reading
`center (Duke Reading Center, Durham, North Carolina,
`USA). Central retinal thickness was defined as the thick-
`ness of the center subfield (the area of the retina using
`a 1-mm diameter around the center of the macula). Fundus
`photography and fluorescein angiography were used to eval-
`uate the anatomy of the retinal vasculature. Angiographic
`images were reviewed by masked graders at an independent
`reading center (Digital Angiographic Reading Center, New
`York, New York, USA). Vision-related quality of life was
`assessed using the NEI VFQ-25, which was administered
`by masked site personnel prior to intravitreal injection.
`Eyes were evaluated, starting at week 24, for retreatment
`and received an injection of intravitreal aflibercept if any of
`the following retreatment criteria were met: a >50 mm
`increase in CRT on OCT compared with lowest previous
`measurement; new or persistent cystic retinal changes or
`subretinal fluid on OCT, or persistent diffuse edema
`>_250 mm in the central subfield on OCT; a loss of >_5 letters
`from the best prior measurement in conjunction with any
`increase in CRT on OCT; or an increase of VA between
`the current and most recent visit of >_5 letters. If none of
`these retreatment criteria were met, patients received
`a sham injection.
`Safety was monitored with the recording of ocular and
`nonocular AEs and laboratory measures.
` STATISTICAL ANALYSES: The full analysis set (FAS), on
`which the primary efficacy analyses were conducted, included
`
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`all randomized patients who received any study medication,
`had a baseline efficacy assessment, and had at least 1 postbase-
`line efficacy assessment. In the primary endpoint analysis,
`patients who discontinued prematurely (prior to week 24)
`and had fewer than 5 injections were evaluated as non-
`responders. The last-observation-carried-forward method
`was used to impute missing values. The proportions of
`patients who gained 15 letters were compared with a 2-
`sided Cochran-Mantel-Haenszel test and randomization
`was stratified by region and baseline BCVA. Secondary
`endpoint analyses were conducted sequentially according to
`the order in which the variables were predefined to preserve
`an alpha of 0.05. Proportions were analyzed using the
`Cochran-Mantel-Haenszel test. Time to first injection was
`analyzed using Kaplan-Meier methodology. The Cox propor-
`tional hazards model was used to quantify the differences in
`the rate of time to first injection between treatment groups.
`Continuous variables were analyzed with an analysis of
`covariance main effects model with treatment group,
`region, and baseline BCVA as fixed factors, and the respec-
`tive baseline variable as a covariate.
`Ocular serious adverse events (SAEs) included any AE
`that: caused a decrease in VA of >30 letters (compared
`with the most recent assessment) or a decrease in VA to
`the level of
`light perception or worse that
`lasted
`>1 hour; required medical or surgical intervention to
`prevent permanent loss of sight; or was associated with
`severe intraocular inflammation.
`The sample size calculation was based on the assump-
`tions that the dropout rate would be 9% for each arm and
`the difference in the proportion of eyes gaining at least
`15 letters of vision would be 25% (ie, 15% in the sham
`group13 and 40% in the intravitreal aflibercept 2Q4
`group.14 Therefore, a total sample size of 165 eyes was
`required to detect a difference in the primary analysis
`with 90% power at a significance level of 5% using a 2-sided
`Fisher exact test or a Cochran-Mantel-Haenszel test.
`
`RESULTS
` PATIENT DISPOSITION: A total of 189 patients were
`randomized to intravitreal aflibercept 2Q4 þ PRN
`(n ¼ 115) and sham þ IAI PRN (n ¼ 74). With the excep-
`tion of 1 patient in the IAI 2Q4 þ PRN group, all random-
`ized patients received study drugs. The majority of patients
`(57/74, 77.0% sham þ IAI PRN and 107/115, 93.0% IAI
`2Q4 þ PRN) completed the first 52 weeks of the study
`(Supplemental Figure 2, available at AJO.com). The
`primary reasons for premature discontinuation from the
`study before week 52 were withdrawal of consent (5/115,
`4.3%) for the IAI 2Q4 þ PRN group and adverse event
`(4/74, 5.4%) and treatment failure (4/74, 5.4%) in the
`sham þ IAI PRN group. Treatment failures and AEs
`were the main reasons for the larger proportion of discon-
`
`tinuations in the sham þ IAI PRN group compared with
`the IAI 2Q4 þ PRN patient group, which had no discon-
`tinuations attributable to AEs or treatment failures during
`the first 52 weeks of the study. Adverse events resulting in
`the study discontinuation in the sham þ IAI PRN group
`included vitreous and retinal hemorrhages, reduced visual
`acuity, and iris neovascularization, which all occurred
`before week 24 and were consistent with the complications
`of CRVO.
` DEMOGRAPHICS AND BASELINE DISEASE CHARACTER-
`ISTICS: Most patients were male (107/187; 57%), white
`(147/187; 78.6%), and originating from North America
`(159/187; 85%) (Table 1). The majority of patients (127/
`187; 67.9%) had fewer than 10 disc areas of nonperfusion
`on reading center evaluation.
`
` EFFICACY: At week 52, the proportion of patients who
`gained at least 15 letters in BCVA was 55.3% in the
`IAI 2Q4 þ PRN group vs 30.1% in the sham þ IAI
`PRN group (Figure 1), demonstrating that IAI 2Q4 þ
`PRN continued to be superior at week 52. For comparison,
`at week 24, 56.1% of patients in the IAI 2Q4 group had
`gained >_15 letters from baseline compared with 12.3% of
`patients in the sham group (P < .001). The majority of
`in both groups gained >_ 0 letters of vision
`patients
`(92.1% of patients in the IAI 2Q4 þ PRN group compared
`with 68.5% of those in the sham þ IAI PRN group at week
`52) (Table 2).
`At week 52, patients in the IAI 2Q4 þ PRN group
`showed a mean change from baseline BCVA of 16.2
`ETDRS letters (Figure 2). For comparison, at week 24,
`the mean change from baseline BCVA was 17.3 ETDRS
`letters in the IAI 2Q4 þ PRN group and 4.0 ETDRS
`letters in the sham group (P < .001). When the sham group
`was
`later eligible to receive intravitreal aflibercept
`(following an as-needed dosing regimen), mean change
`from baseline in BCVA improved in this group from
`4.0 letters at week 24 to þ3.8 letters at week 52, a gain
`of 7.8 letters. The waterfall analysis (Supplemental
`Figure 3, Top and Bottom panels) (Supplemental Material
`available at AJO.com) of
`individual patient responses
`found that only 7.9% of patients who were originally
`randomized to the IAI 2Q4 treatment group experienced
`a loss of vision at week 52 (vs baseline) compared with
`31.5% of patients in the sham þ IAI PRN group.
`At week 52, a gain of >_15 letters was noted in 60.7% vs
`22.2% of patients with a baseline BCVA <_20/200 in the
`IAI 2Q4 þ PRN group vs the sham þ IAI PRN group
`and in 53.5% vs 32.7% of patients, respectively, with a base-
`line BCVA >20/200. For patients with a baseline BCVA
`<_20/200, the mean change from baseline at week 52 in
`BCVA letter score was þ19.9 vs þ5.1 letters for IAI
`2Q4 þ PRN compared with sham þ IAI PRN. Patients
`who had a baseline BCVA of >20/200 had improvements
`in BCVA of þ14.9 compared with þ3.5 letters.
`
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`TABLE 1. Demographics and Baseline Characteristics of Patients With Macular Edema Secondary to Central Retinal Vein Occlusion
`
`IAI 2Q4 þ PRN
`(n ¼ 114)d
`
`Sham þ IAI PRN
`(n ¼ 73)
`
`Total
`(n ¼ 187)e
`
`65.5 (13.57)
`
`67.5 (14.29)
`
`66.3 (13.85)
`
`45 (39)
`69 (61)
`
`88 (77.2)
`5 (4.4)
`7 (6.1)
`14 (12.3)
`
`95 (83.3)
`19 (16.7)
`
`50.7 (13.90)
`86 (75.4)
`28 (24.6)
`
`77 (67.5)
`17 (14.9)
`20 (17.5)
`
`35 (48)
`38 (52)
`
`59 (80.8)
`5 (6.8)
`2 (2.7)
`7 (9.6)
`
`64 (87.7)
`9 (12.3)
`
`48.9 (14.42)
`55 (75.3)
`18 (24.7)
`
`50 (68.5)
`12 (16.4)
`11 (15.1)
`
`80 (43)
`107 (57)
`
`147 (78.6)
`10 (5.3)
`9 (4.8)
`21 (11.2)
`
`159 (85.0)
`28 (15.0)
`
`50.0 (14.09)
`141 (75.4)
`46 (24.6)
`
`127 (67.9)
`29 (15.5)
`31 (16.6)
`
`Age (y), mean (SD)
`Sex, n (%)
`Female
`Male
`Race, n (%)
`White
`Black
`Asian
`Othera
`Geographic region, n (%)
`North America
`Rest of world
`Visual acuity (ETDRS)
`Mean (SD)
`BCVA >20/200 (letters read >_35)
`BCVA <_20/200 (letters read <_34)
`Retinal perfusion status, n (%)
`Perfusedb
`Nonperfused
`Indeterminate
`Retinal thickness (mm)
`Mean (SD)
`IOP (mm Hg), mean (SD)
`Time since CRVO diagnosis (mo)
`Mean (SD)
`2.73 (3.09)
`1.88 (2.19)
`2.40 (2.796)
`<_2 months
`64 (56.1)
`52 (71.2)
`116 (62.0)
`>2 months
`49 (43.0)
`21 (28.8)
`70 (37.4)
`NEI VFQ-25 total score,c mean (SD)
`77.39 (16.176)
`77.38 (16.602)
`77.39 (16.299)
`NEI VFQ-25 near activities score,c mean (SD)
`69.96 (21.939)
`70.72 (20.222)
`70.25 (21.234)
`NEI VFQ-25 distance activities score, mean (SD)
`75.99 (21.255)
`78.08 (21.258)
`76.80 (21.224)
`Vision dependency score, mean (SD)
`83.26 (25.511)
`82.76 (27.405)
`83.07 (26.195)
`2Q4 ¼ 2 mg once every 4 weeks; BCVA ¼ best-corrected visual acuity; ETDRS ¼ Early Treatment of Diabetic Retinopathy Study; IAI ¼ intra-
`vitreal aflibercept injection; IOP ¼ intraocular pressure; NEI VFQ-25 ¼ National Eye Institute Visual Functioning Questionnaire – 25; PRN ¼ as
`needed; SD ¼ standard deviation.
`aIncluded not reported and multiple races.
`bLess than 10 disc areas of nonperfusion.
`cBaseline total and near activities subscale scores changed slightly from weeks 24 to 52 as a result of multiple-choice options in the ques-
`tionnaires changing from 4 possible responses at week 24 to 5 possible responses at week 52.
`d113 for the time since CRVO diagnosis.
`e186 for the time since CRVO diagnosis.
`Full analysis set.
`
`661.7 (237.37)
`15.1 (3.26)
`
`672.4 (245.33)
`15.0 (2.81)
`
`665.8 (239.82)
`15.1 (3.08)
`
`In eyes with over 10 disc areas of posterior nonperfusion
`(that seen on 7 standard field fluorescein angiogram) at base-
`line, the proportion of eyes gaining >_15 letters at week 24
`was 51.4% vs 4.3% for IAI 2Q4 þ PRN vs sham þ IAI
`PRN treatment and 58.4% vs 16.0% in eyes with less than
`10 disc areas of posterior nonperfusion at baseline, respec-
`tively. At 52 weeks, these proportions were 48.6% vs
`30.4% for IAI 2Q4 þ PRN vs sham þ IAI PRN treatment
`in eyes with posterior nonperfusion, and 58.4% vs 30.0%
`in eyes without posterior nonperfusion eyes, respectively.
`
`If the diagnosis was within 2 months of treatment, the
`proportions of eyes gaining >_15 letters were 64.1% vs
`34.6% for IAI 2Q4 þ PRN vs sham þ IAI PRN treatment
`at 52 weeks (difference of 29.4%), and 42.9% vs 19.0%
`(difference of 23.8%) if the time since diagnosis was greater
`than 2 months.
`The rapid reduction in CRT observed in the IAI 2Q4 þ
`PRN group through week 24 was largely maintained
`through week 52 (457.2 mm and 413.0 mm, respec-
`tively) (Figure 3). At week 52, mean CRT reductions
`
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`FIGURE 1. Proportion of patients with best-corrected visual
`acuity improvement ‡15 letters at weeks 24 and 52 following
`intravitreal aflibercept and/or sham injections for the treatment
`of macular edema secondary to central retinal vein occlusion.
`*P < .001. Missing data were imputed using the last-
`observation-carried-forward method. 2Q4 [ 2 mg every 4 weeks;
`IAI [ intravitreal aflibercept injection; PRN [ as needed.
`
`FIGURE 2. Mean change from baseline in best-corrected visual
`acuity over 52 weeks after intravitreal aflibercept and/or sham
`injections for the treatment of macular edema secondary to
`central retinal vein occlusion. *P < .001. Missing data were
`imputed using the last-observation-carried-forward method.
`2Q4 [ 2 mg every 4 weeks; ETDRS [ Early Treatment Dia-
`betic Retinopathy Study; IAI [ intravitreal aflibercept injec-
`tion; PRN [ as needed.
`
`TABLE 2. Proportions of Patients With Vision Gains and
`Losses at Weeks 24 and 52 Following Sham and/or
`Intravitreal Aflibercept Injections for the Treatment of
`Macular Edema Secondary to Central Retinal Vein Occlusion
`
`IAI 2Q4 þ
`PRN
`(n ¼ 114)
`
`Week 24
`Sham þ IAI
`PRN
`(n ¼ 73)
`
`IAI 2Q4 þ
`PRN
`(n ¼ 114)
`
`Week 52
`Sham þ IAI
`PRN
`(n ¼ 73)
`
`9 (12.3)
`16 (21.9)
`29 (39.7)
`38 (52.1)
`
`63 (55.3)
`88 (77.2)
`93 (81.6)
`105 (92.1)
`
`22 (30.1)
`34 (46.6)
`43 (58.9)
`50 (68.5)
`
`Letter gain, n (%)
`>_15 lettersa
`64 (56.1)
`>_10 letters
`87 (76.3)
`>_5 letters
`97 (85.1)
`>_0 letters
`107 (93.9)
`Letter loss, n (%)
`>0 letter
`7 (6.1)
`35 (47.9)
`9 (7.9)
`23 (31.5)
`>_5 letters
`5 (4.4)
`29 (39.7)
`8 (7.0)
`17 (23.3)
`>_10 letters
`2 (1.8)
`22 (30.1)
`6 (5.3)
`13 (17.8)
`>_15 letters
`2 (1.8)
`20 (27.4)
`6 (5.3)
`11 (15.1)
`2Q4 ¼ 2 mg once every 4 weeks; IAI ¼ intravitreal aflibercept
`injection; PRN ¼ as needed.
`aWeek 24 completers within full analysis set.
`Full analysis set unless indicated otherwise.
`
`FIGURE 3. Mean change from baseline in central retinal thick-
`ness (CRT) over 52 weeks after intravitreal aflibercept and/or
`sham injections for the treatment of macular edema secondary
`to central retinal vein occlusion. CRT was measured with
`optical coherence tomography. A significant decrease from base-
`line in CRT was observed at week 24 in the IAI group compared
`with the sham-treated group (*P < .001). Missing data were
`imputed using the last-observation-carried-forward method.
`2Q4 [ 2 mg every 4 weeks; IAI [ intravitreal aflibercept injec-
`tion; PRN [ as needed.
`
`Mantel-Haenszel test). Panretinal photocoagulation was
`performed for 4 of the patients (5.5%) in the sham þ
`IAI PRN group.
`
`were similar in both treatment groups (413.0 mm for IAI
`2Q4 þ PRN vs 381.8 mm for sham þ IAI PRN).
`During the first 52 weeks, no eyes in the IAI 2Q4 þ
`PRN group developed any neovascularization compared
`with 5 eyes (6.8%, all
`in the anterior segment) for
`the sham þ IAI PRN group (P ¼ .006 by Cochran-
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`FIGURE 4. Mean change from baseline in NEI VFQ-25 scores
`at weeks 24 and 52 following intravitreal aflibercept and/or
`sham injections for the treatment of macular edema secondary
`to central retinal vein occlusion. Missing data were imputed using
`the last-observation-carried-forward method. Week 24, IAI
`2Q4 D PRN n [ 104, sham D IAI PRN n [ 59. *P < .05.
`P values for sham D IAI PRN vs IAI 2Q4 D PRN: Total,
`P [ .001; near-activities subscores, P [ .071; distance-
`activities subscores, P [ .032; dependency subscores, P [
`.083. Week 52, IAI 2Q4 D PRN n [ 109, sham D IAI PRN
`n [ 59. P values for sham D IAI PRN vs IAI 2Q4 D PRN:
`Total, P [ .216; near-activities subscores, P [ .338;
`distance-activities subscores, P [ .085; dependency subscores,
`P [ .415. P values are based on least square mean changes using
`an analysis of covariance model. 2Q4 [ 2 mg once every 4 weeks;
`IAI [ intravitreal aflibercept injection; NEI VFQ-25 [
`National Eye Institute Visual Functioning Questionnaire - 25;
`PRN [ as needed.
`
`The between-group differences in the mean NEI VFQ-
`25 total and subscale scores were significant at week 24.
`A clinically relevant improvement in the mean NEI
`VFQ-25 total score was observed in both IAI 2Q4 þ
`PRN (7.5 points) and sham þ IAI PRN (5.1 points) groups
`at week 52 (Figure 4). A significant difference between the
`treatment arms was not seen at week 52 because of the
`crossover to intravitreal aflibercept PRN in the sham group.
` TREATMENT EXPERIENCE: Beginning at week 24, all
`patients were eligible to receive an injection of aflibercept
`if any of the protocol-defined retreatment criteria were
`met. During the PRN phase of the study, 57 of the 60
`patients in the sham þ IAI PRN group and 102 of the
`110 patients in the IAI 2Q4 þ PRN group had at least 1
`injection (Figure 5, Top panel). Eighty-three percent of
`the sham þ IAI PRN patients compared with 30% of IAI
`2Q4 þ PRN patients had their first injection at week 24.
`The median time to first injection in the PRN phase was
`29 days for the sham þ IAI PRN group and 68 days for
`
`FIGURE 5. Cumulative incidence of time to first intravitreal
`aflibercept injection and distribution of injections in patients
`with macular edema secondary to central retinal vein occlusion.
`(Top panel) The cumulative incidence of time to first injection
`was compared between the treatment groups. The P value from
`the log-rank test was <.01. (Bottom panel) Exposure to study
`drug (excluding sham) from weeks 24 to 52 is shown for the
`week-24 completers within safety analysis set. 2Q4 [ 2 mg
`once every 4 weeks; IAI [ intravitreal aflibercept injection;
`PRN [ as needed.
`
`the IAI 2Q4 þ PRN group. The mean numbers of injec-
`tions were 3.9 (SE ¼ 0.3) and 2.7 (SE ¼ 0.2) in the
`sham þ IAI PRN and IAI 2Q4 þ PRN groups, respectively
`(Figure 5, Bottom panel).
` SAFETY: From baseline to week 52, the proportion of
`patients that experienced at least 1 ocular treatment-
`emergent adverse event (TEAE) in the study eye was
`similar between treatment groups (Supplemental Table 1,
`available at AJO.com). The most common ocular TEAEs
`in the IAI 2Q4 þ PRN and sham þ IAI PRN groups,
`respectively, were reduced visual acuity (18.4% and
`21.6%), conjunctival hemorrhage (16.7% and 18.9%),
`eye pain (15.8% and 9.5%), and increased intraocular pres-
`sure (12.3% and 13.5%).
`Ocular-SAEs reported more than once in the study eye
`all occurred in the sham þ IAI PRN group (Table 3).
`The 1 case of endophthalmitis
`in the intravitreal
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`TABLE 3. All Ocular Serious Adverse Events From Baseline to Weeks 24 and 52 Occurring in Patients With Macular Edema Secondary
`to Central Retinal Vein Occlusion Who Were Treated With Sham and/or Intravitreal Aflibercept Injections
`
`Weeks 0-24a
`
`IAI 2Q4
`(n ¼ 114)
`
`Sham
`(n ¼ 74)
`
`IAI 2Q4 þ PRN
`(n ¼ 110)
`
`Weeks 24-52b
`Sham þ IAI PRN
`(n ¼ 60)
`
`3 (2.7)
`
`2 (3.3)
`
`4 (3.5)
`
`10 (13.5)
`
`Number of patients with at least 1 ocular serious
`TEAE in study eye, n (%)
`Eye disorders, n (%)
`2 (1.8)
`10 (13.5)
`3 (2.7)
`2 (3.3)
`Vitreous hemorrhage
`0
`4 (5.4)
`1 (0.9)
`1 (1.7)
`Glaucoma
`0
`2 (2.7)
`0
`1 (1.7)
`Iris neovascularization
`0
`2 (2.7)
`0
`0
`Retinal hemorrhage
`0
`2 (2.7)
`0
`0
`Visual acuity reduced
`1 (0.9)
`1 (1.4)
`0
`0
`Retinal artery occlusion
`1 (0.9)
`0
`0
`0
`Retinal tear
`0
`1 (1.4)
`0
`1 (1.7)
`Retinal vein occlusion
`0
`1 (1.4)
`1 (0.9)
`0
`Cataract
`0
`0
`1 (0.9)
`1 (1.7)
`Cystoid macular edema
`0
`0
`1 (0.9)
`0
`Infections and infestations, n (%)
`1 (0.9)
`0
`0
`0
`Endophthalmitis
`1 (0.9)
`0
`0
`0
`Injury, poisoning and procedural complications, n (%)
`1 (0.9)
`0
`0
`0
`Corneal abrasion
`1 (0.9)
`0
`0
`0
`2Q4 ¼ 2 mg once every 4 weeks; IAI ¼ intravitreal aflibercept injection; PRN ¼ as needed; SAE ¼ serious adverse event; TEAE ¼ treatment-
`emergent adverse event.
`aSafety analysis set.
`bWeek 24 completers within the safety analysis set.
`
`aflibercept group was culture-positive for coagulase-
`negative Staphylococcus and was considered by the investi-
`gator to be related to the intravitreal injection. It occurred
`before week 24, 44 days after starting study medication, and
`10 days after the last intravitreal injection. From weeks 24
`to 52, only 3 patients in the IAI 2Q4 þ PRN group and 2 in
`the sham þ IAI PRN group experienced any ocular serious
`adverse events.
`The incidence of nonocular TEAEs was similar in both
`treatment groups
`from baseline to week 52.
`In the
`sham þ IAI PRN and IAI 2Q4 þ PRN groups, the
`most commonly reported nonocular TEAEs were hyper-
`tension (9.5% vs 14.9%, respectively), nasopharyngitis
`(6.8% vs 7.9%, respectively), and upper respiratory infec-
`tions (5.4% vs 7.9%,
`respectively). Nonocular SAEs
`occurred in a small group of patients with a similar
`frequency in the IAI 2Q4 and sham groups from weeks
`0 to 24 (5.3% vs 8.1%, respectively) and in the IAI
`2Q4 þ PRN and sham þ IAI PRN groups from weeks
`24 to 52 (6.4% vs 8.3%, respectively) (Supplemental
`Table 2, available at AJO.com). The incidence of Anti-
`Platelet Trialists’ Collaboration and arterial thromboem-
`bolic events were 2.7% in the sham group (1 acute
`myocardial infarction and 1 carotid artery stenosis) and
`0.9% in the IAI 2Q4 þ PRN group (1 myocardial infarc-
`tion). There were 2 vascular deaths (2.7%) (1 attributable
`to acute myocardial infarction and 1 to arrhythmia), both
`
`occurring in the sham group before receiving intravitreal
`aflibercept at week 24.
`
`DISCUSSION
`
`THE COPERNICUS STUDY RESULTS FROM WEEK 24 THROUGH
`week 52 demonstrate that the robust elimination of retinal
`edema on OCT and the concomitant BCVA gains
`achieved after 6 monthly intravitreal aflibercept injections
`in the IAI 2Q4group can be largely maintained with less
`frequent dosing of a mean 2.7 injections. It must be noted
`that patients continued to be evaluated monthly during the
`PRN phase. Careful monitoring in clinical practice may be
`critical to achieve this result in a reactive PRN treatment
`setting. In real-world practice, clinicians may choose
`a ‘‘treat and extend’’ regimen, although this has not been
`formally tested in CRVO to circumvent the requirement
`for monthly monitoring and to stay in a proactive treat-
`ment mode. A prolonged injection interval, ie, reduced
`injection frequency, after an initial period of monthly
`dosing is consistent with the use of intravitreal aflibercept
`injection in neovascular AMD, where a Q8-week dosing
`regimen has been shown to be as efficacious as a monthly
`regimen for the treatment of neovascular AMD (Nguyen
`QD et al.
`IOVS 2011;52:ARVO E-Abstract 3073;
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`Schmidt-Erfurth U et al. IOVS 2011;52:ARVO E-Abstract
`1650). Similarly, the DA VINCI study also reported signif-
`icant gains in BCVA and reductions in CRT at 24 and
`52 weeks for patients with diabetic macular edema who
`were treated with 3 initial monthly 2 mg doses of intravi-
`treal aflibercept followed by injections every 8 weeks or
`as needed.15
`The eyes originally randomized to sham therapy
`benefited from crossover to active therapy both anatomi-
`cally and with improvements in visual acuity. While the
`anatomic improvement experienced in the delayed
`sham þ IAI PRN cohort appeared almost as robust as for
`those who were originally randomized to IAI 2Q4, none
`of the VA parameters (percent of 15-letter gainers, net
`letter gainers, and mean improvement from baseline)
`ever approached those seen with the proactive dosing
`regimen with an earlier treatment onset. In fact, all of these
`parameters were still statistically below those of the orig-
`inal IAI 2Q4 group at 52 weeks. This occurred even though
`from weeks 24 to 52, the sham þ IAI PRN group of patients
`received 3.9 injections on average compared with 2.7 for
`those on the IAI 2Q4 þ PRN regimen. The waterfall anal-
`ysis demonstrates that the final disposition of the patients
`that were originally randomized to the IAI 2Q4 cohort
`was positive but the sham crossover group had mixed
`results, with over 30% of patients having a net vision loss
`at week 52 compared to baseline. The marked difference
`in outcomes implies that a 6-month delay in providing
`intravitreal aflibercept therapy may be too long and that
`irreversible damage from chronic edema may limit VA
`gains at 1 year. An alternative explanation for relative
`lack of efficacy in the crossover arm is that the sham group
`was treated with a reactive PRN regimen instead of 6 initial
`
`monthly doses in weeks 24 to 52. It is possible that VA
`gains could have been better in this group with a proactive,
`fixed dosing schedule of anti-VEGF suppression. However,
`higher proportions of eyes gained >_15 letters at 52 weeks in
`the subgroup of patients who received intravitreal afliber-
`cept <_2 months afte