The 1-year Results of CLEAR-IT 2, a
`Phase 2 Study of Vascular Endothelial
`Growth Factor Trap-Eye Dosed As-needed
`After 12-week Fixed Dosing
`
`
`
`Jeffrey S. Heier, MD,’ David Boyer, MD,” Quan Dong Nguyen, MD, MSc,? Dennis Marcus, MD,*
`Daniel B. Roth, MD,°? George Yancopoulos, MD, PhD,° Neil Stahl, PhD,° Avner Ingerman, MD, MSc,°
`Robert Vitti, MD, MBA,° Alyson J. Berliner, MD, PhD,° Ke Yang, PhD,° David M. Brown, MD,’ for the
`CLEAR-IT 2 Investigators
`
`Objective: To evaluate anatomic outcomesandvision, injection frequency, and safety during the as-needed
`(PRN) treatment phase of a study evaluating a 12-weekfixed dosing period followed by PRN dosing to week 52
`with vascular endothelial growth factor (VEGF) Trap-Eye for neovascular (wet) age-related macular degeneration
`(AMD).
`Design: Multicenter, randomized, double-maskedtrial.
`Participants: Weincluded 159 patients with subfoveal choroidal neovascularization (CNV) secondary to wet
`AMD.
`Methods: Patients were randomly assigned to 1 of 5 intravitreal VEGF Trap-Eye treatment groups: 0.5 mg
`or 2 mg every 4 weeksor 0.5, 2, or 4 mg every 12 weeksduring the fixed-dosing period (weeks 1-12). From
`weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or
`4 mg).
`Main Outcome Measures: Changein central retinal/lesion thickness (CR/LT), change in total lesion and
`CNV size, mean changein best-corrected visual acuity (BCVA), proportion of patients with 15-letter loss or gain,
`time to first PRN injection, reinjection frequency, and safety at week 52.
`Results: The decrease in CR/LT at week 12 versus baseline remained significant at weeks 12 to 52 (—130
`um from baseline at week 52) and CNVsize regressed from baseline by 2.21 mm? at 48 weeks. After achieving
`a significant improvement in BCVA during the 12-week,fixed-dosing phaseforall groups combined, PRN dosing
`for 40 weeks maintained improvements in BCVA to 52 weeks (5.3-letter gain; P<0.0001). The most robust
`improvements and consistent maintenanceof visual acuity generally occurredin patientsinitially dosed with 2 mg
`every 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was
`administered after the 12-week fixed-dosing phase, and the meantimeto first reinjection was 129 days; 19% of
`patients received no injections and 45% received 1 or 2 injections. Treatment with VEGF Trap-Eye was generally
`safe and well tolerated, with few ocular or systemic adverse events.
`Conclusions:
`PRN dosing with VEGF Trap-Eye at weeks 16-52 maintained the significant anatomic and
`vision improvements established during the 12-week fixed-dosing phase with a low frequency ofreinjections.
`Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of treatment.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
`Ophthalmology 201 1;118:1098-1106 © 2011 by the American Academy of Ophthalmology.
`
`Vascular endothelial growth factor (VEGF) is a critical
`regulator of normal ocular vasculogenesis and angiogenesis
`during development.!~ Vascular endothelial growth factor
`also plays a central role in the abnormal growth of new
`blood vessels in the retina, as well as in vascular leakage
`that causes retinal edema and thickening, both of which
`characterize diseases such as neovascular (wet) age-related
`macular degeneration (AMD) anddiabetic retinopathy that
`lead to loss of retinal function.*~© Of the various members
`
`of the VEGF gene family, VEGF-A andplacental growth
`factor (PIGF) are the factors implicated in pathologic an-
`giogenesis and the pathogenesis of AMD (Invest Ophthal-
`mol Vis Sci 50 [Suppl]: 2943,2009).7-?
`An improved understanding ofthe pivotal role of VEGF
`in pathologic angiogenesis has resulted in the development
`and use of intravitreal anti-VEGF therapies in wet AMD
`and other eye diseases that have an angiogenesis-based
`etiology.!°-!? Pegaptanib, an oligoribonucleotide aptamer,
`
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`
`© 2011 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/11/$-see front matter
`doi:10.1016/j.ophtha.2011.03.020
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`Heier et al
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`䡠 PRN Treatment of Wet AMD with VEGF Trap-Eye
`
`and ranibizumab, a humanized monoclonal antibody frag-
`ment, are anti-VEGF therapies currently available for intra-
`vitreal treatment of neovascular AMD. In pivotal trials,
`pegaptanib mainly slowed loss of visual acuity, whereas
`ranibizumab improved visual function in a substantial pro-
`portion of patients.13–16 Bevacizumab is an off-label intra-
`vitreal anti-VEGF therapy that has also been shown in less
`rigorous studies to improve visual function.17–20
`The beneficial results with ranibizumab were obtained
`with a fixed-dosing regimen requiring an injection of ranibi-
`zumab 0.5 or 0.3 mg every month for 2 years in the pivotal
`phase 3 studies, Minimally Classic/Occult Trial of the Anti-
`VEGF Antibody Ranibizumab in the Treatment of Neovas-
`cular Age-Related Macular Degeneration (MARINA) and
`Anti-VEGF Antibody for the Treatment of Predominantly
`Classic Choroidal Neovascularization in Age-Related Mac-
`ular Degeneration (ANCHOR).13,15 Several studies were
`undertaken to examine different dosing regimens for ranibi-
`zumab. In a large, randomized study in which patients were
`initially treated with a 3-month loading regimen of ranibi-
`zumab and then dosed at regular quarterly intervals, the
`initial gains after the loading regimen were not maintained
`at a year.21 A 40-patient uncontrolled, open-label, single-
`site, Prospective Optical Coherence Tomography Imaging
`of Patients Treated with
`intra-Ocular
`ranibizumab
`(PrONTO) trial evaluated an as-needed (PRN) dosing reg-
`imen (based on monthly evaluation of changes in retinal
`thickness and edema using optical coherence tomography
`[OCT]) after 3 consecutive monthly injections. Visual acu-
`ity outcomes at 12 and 24 months were comparable with
`those observed in the pivotal phase 3 studies and were
`attained with fewer intravitreal injections.22,23 However, in
`a larger randomized study, the gains in visual acuity after an
`initial 3-month loading regimen of ranibizumab were not
`maintained with subsequent protocol-defined retreatment.24
`Vascular endothelial growth factor Trap-Eye (VEGF
`Trap-Eye) is a potent, specific VEGF antagonist that binds
`and inactivates circulating VEGF and VEGF in the ex-
`travascular space. It was developed specifically as an ultra-
`purified, isoosmotic solution for ophthalmic use.25 Consist-
`ing of extracellular portions of VEGF receptors 1 and 2
`fused to the Fc portion of human immunoglobulin G, VEGF
`Trap-Eye binds both VEGF-A or PlGF and forms an inert 1:1
`complex with the growth factor dimers.24,25 Thus, VEGF
`Trap-Eye has broader anti-VEGF activity compared with
`pegaptanib, which binds only the VEGF-A165 isoform,26 and
`ranibizumab, which neutralizes all active isoforms of
`VEGF-A, but not PlGF.27 Because VEGF Trap-Eye contains
`only human sequences, its potential for immunogenicity is low.
`A key differentiating feature of VEGF Trap-Eye is its pico-
`molar affinity for VEGF ligands, which is substantially higher
`than that of the natural receptors or anti-VEGF monoclonal
`antibodies.25,28,29 The clinical relevance of the higher
`binding affinity of VEGF Trap-Eye remains unknown,
`but it is thought that it might lead to more persistent
`VEGF blockade and a theoretically longer dosing interval
`between injections to maintain visual acuity relative to
`currently available anti-VEGF treatments.30
`The clinical efficacy of VEGF-Trap Eye was initially dem-
`onstrated in the CLinical Evaluation of Anti-angiogenesis in
`
`the Retina Intravitreal Trial (CLEAR-IT 1), a 6-week phase
`1 sequential cohort, single-ascending-dose (0.05 to 4 mg)
`study of intravitreal VEGF Trap-Eye in patients with neo-
`vascular AMD.31 The efficacy and safety of repeated dosing
`with VEGF Trap-Eye were subsequently examined in the
`phase 2 CLEAR-IT 2 study, which consisted of an initial
`12-week fixed dosing period with 1 of 5 monthly or quar-
`terly regimens of VEGF Trap-Eye, followed by PRN dosing
`from weeks 16 to 52. Detailed results to 16 weeks for the
`fixed-dosing phase, including the primary endpoint at week
`12, are presented in the accompanying article (Brown et al.,
`in this issue, pp 1089-97). At 12 weeks, treatment with
`VEGF Trap-Eye resulted in a significant reduction in central
`retinal/lesion thickness (CR/LT) of ⫺119 ␮m and a signif-
`icant improvement in mean BCVA of 5.7 letters for all
`groups combined, and gains of ⬎8 letters in the monthly
`dosing groups. The finding that improvements in visual
`acuity and retinal thickness were greater in the monthly
`dosing groups than in the quarterly dosing groups at week
`12, support the need for an initial intensive monthly loading
`dose phase. Patients were treated with a PRN dosing regi-
`men through week 52 to explore whether the high affinity of
`VEGF Trap-Eye for VEGF-A and PlGF could translate into
`the maintenance of initial visual acuity gains through 1 year
`with less frequent intravitreal injections. Results of the
`continued dosing phase of the CLEAR-IT 2 study are re-
`ported herein.
`
`Materials and Methods
`
`Study Design
`
`The primary objectives of the study were to assess the effect of
`intravitreal VEGF Trap-Eye on CR/LT and to assess the ocular and
`systemic safety and tolerability of repeated doses of VEGF Trap-
`Eye in patients with choroidal neovascularization (CNV) associ-
`ated with wet AMD. A key secondary objective was to assess the
`effect of VEGF Trap-Eye on BCVA.
`This study was a double-masked, prospective, randomized,
`dose- and interval-ranging study in which 5 groups of approxi-
`mately 30 patients each were assigned to a fixed-dose of intravit-
`real VEGF Trap-Eye in the study eye during the first 12 weeks of
`dosing, followed by PRN dosing from weeks 16 to 52 (Fig 1,
`available online at http://aaojournals.org). The VEGF Trap-Eye
`regimens were 0.5 mg or 2 mg at 4-week intervals (0.5q4 or 2q4
`on day 1 and at weeks 4, 8, and 12 for a total of 4 treatments) or
`0.5, 2, or 4 mg every 12 weeks (0.5q12, 2q12, or 4q12 on day 1
`and week 12 for a total of 2 treatments). During the PRN dosing
`phase beginning at week 16, patients received the same dose of
`VEGF Trap-Eye (0.5, 2, or 4 mg) as received during the fixed-
`dosing phase (Fig 2).
`The study protocol was approved by the ethics committee at
`every institution and was conducted according to the recommen-
`dations of Good Clinical Practice and the Declaration of Helsinki.
`The study was compliant with the rules and regulations under the
`Health Insurance Portability and Accountability Act of 1996. All
`patients provided written informed consent to participate in the
`study. The CLEAR-IT 2 study is registered with ClinicalTrials.gov
`(NCT00320788).
`
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`Ophthalmology Volume 118, Number 6, June 2011
`
`were observed by the evaluating practitioner: An increase in CR/LT
`ⱖ100 ␮m as measured by OCT; a loss of ⱖ5 ETDRS letters in
`conjunction with recurrent fluid as indicated by OCT; persistent fluid
`as indicated by OCT; new-onset classic neovascularization; new or
`persistent leak on FA; or new macular hemorrhage.
`
`Endpoints and Assessments
`
`Assessments were performed at scheduled clinic visits on days 1
`and 7, at week 4, and every 4 weeks thereafter to week 52. At each
`visit, patients underwent a full ophthalmologic examination, in-
`cluding visual acuity testing, indirect ophthalmoscopy and slit
`lamp examination, intraocular pressure (IOP) measurement, and
`OCT. Fundus photography and FA were performed at baseline and
`at weeks 4, 12, 24, 36, and 48.
`The primary efficacy endpoint was reduction of CR/LT from
`baseline to 12 weeks, at the end of the fixed-dosing phase. The
`variables assessed during the PRN dosing phase included change
`from baseline in CR/LT and mean change from baseline in CNV size
`determined by FA at 48 weeks, the last mandatory FA in the study;
`BCVA at 52 weeks; proportions of patients with avoidance of mod-
`erate vision loss (loss of ⬍15 letters); stabilization or improvement in
`visual acuity (gain of ⱖ0 letters); and significant vision gain (gain of
`ⱖ15 letters) at 52 weeks; time to first reinjection after week 12; and
`mean number of injections over the PRN period.
`The CR/LT was determined from Stratus OCT (Version 4.0 or
`higher; CarlZeiss, Jena, Germany) scans read at a masked inde-
`pendent central reading center (Digital OCT Reading Center,
`Cleveland, OH). The CR/LT was defined as the distance between
`the inner limiting membrane and posterior border of retinal pig-
`ment epithelial/choriocapillaris complex including any subretinal
`fluid and thickness of any observable choroidal neovascular mem-
`brane or scar tissue in central 1 mm of posterior pole scan.
`Changes in the size of the total lesion and the CNV component
`were evaluated with FA. The CNV size was defined as the area of
`visible CNV (classic or occult) with angiographic evidence of late
`leakage or pooling of dye. Angiographic images were transmitted
`to the masked reading center for review (Digital Angiography
`Reading Center, New York, NY). At least 1 designated photogra-
`pher was certified by the Reading Center before enrollment of the
`first patient at each site.
`Certified examiners assessed BCVA by using the ETDRS pro-
`tocol at 4 m. Examiners were masked to treatment assignment, and
`performed no other study assessments.
`Safety assessments included IOP (measured preinjection and
`approximately 30 minutes postinjection), ophthalmologic exami-
`nations for ocular toxicity, adverse events (AEs), serious AEs
`(SAEs), clinical laboratory tests, and vital signs.
`
`Statistical Analysis
`
`Efficacy assessments were made on the full analysis set, which
`included all patients who received study treatment and had a
`baseline and ⱖ1 postbaseline assessment. Safety assessments were
`performed on all patients who received study treatment.
`The primary analysis was a paired comparison t test of the
`change in CR/LT from baseline to week 12 for all groups com-
`bined. If this was significant, an analysis of covariance was done
`on the 5 individual groups. A similar analysis was done for all
`continuous measures at all time points. Missing values were im-
`puted using the last-observation-carried-forward method for con-
`tinuous measures. The durability of the effect was assessed by
`evaluating all of the endpoints out to week 52. All of the analyses
`shown below were done using the same methods at week 12 and
`week 52 (week 48 for FA parameters).
`
`Figure 2. Study schedule. During the 12-week fixed dosing phase, patients
`in the monthly dosing groups received 0.5 or 2 mg of VEGF Trap-Eye
`every 4 weeks on day 0 and at weeks 4, 8, and 12 for a total of 4 doses;
`those in the quarterly dosing groups received 0.5, 2, or 4 mg of VEGF
`Trap-Eye every 12 weeks on day 0 and at week 12 for a total of 2 doses.
`Beginning at week 16 and continuing to week 52, patients were assessed
`every 4 weeks and, if needed, were retreated with the same dose of VEGF
`Trap-Eye as in the fixed dosing phase. The primary study endpoint was
`assessed at week 12. q ⫽ every; PRN ⫽ as-needed; VEGF ⫽ vascular
`endothelial growth factor; VTE ⫽ VEGF Trap-Eye; 0.5q4 ⫽ 0.5 mg every
`4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12 weeks;
`2q12 ⫽ 2 mg every 12 weeks; 4q12 ⫽ 4 mg every 12 weeks.
`
`Patient Population
`The study enrolled patients ⬎50 years old who had a diagnosis of
`subfoveal CNV secondary to wet AMD and central retinal thick-
`ness ⱖ300 ␮m, Early Treatment of Diabetic Retinopathy Study
`(ETDRS) BCVA of 73 to 34 letters, loss of ⱖ5 ETDRS letters in
`BCVA over the preceding 6 months for previously treated patients
`with minimally classic or occult lesions, linear diameter of lesion
`ⱕ5400 ␮m by fluorescein angiography (FA), subretinal hemor-
`rhage sparing the fovea and comprising ⱕ50% of total lesion, area
`of scar ⱕ25% of total lesion, and sufficient clarity of ocular media
`to allow retinal photography.
`Key exclusion criteria were history of vitreous hemorrhage in
`preceding 4 weeks; aphakia or pseudophakia with absence of a
`posterior capsule (unless as a result of a yttrium aluminum garnet
`capsulotomy); significant subfoveal atrophy or scarring; presence
`of other causes of CNV in either eye; previous treatments for
`AMD in the study eye within 12 weeks for photodynamic therapy,
`8 weeks for pegaptanib sodium, or 24 weeks for intravitreal or
`juxtascleral steroids; no other treatments for AMD (thermal laser,
`surgery, or intraocular/systemic anti-VEGF therapy) were allowed;
`any retinal vascular disease other than CNV in either eye; active
`ocular inflammation or infection; history of trabeculectomy or pars
`plana vitrectomy; history of myocardial infarction, stroke, tran-
`sient ischemic attack, symptomatic peripheral vascular disease, or
`treatment for congestive heart failure within the last 6 months; and
`other conditions or laboratory abnormalities that might interfere
`with patient participation in the study.
`
`Retreatment Criteria
`During the fixed-dosing phase, 1 eye was designated as the study
`eye and all evaluations were conducted on that eye as described
`previously (Brown et al, in this issue, pp 1089-97). Beginning at
`week 16, patients were evaluated every 4 weeks to determine the
`need for continued dosing. After week 16, the study eye was
`reinjected with VEGF Trap-Eye if any of the following changes
`
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`Heier et al
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`䡠 PRN Treatment of Wet AMD with VEGF Trap-Eye
`
`Table 2. Baseline Demographic and Clinical Characteristics
`
`Characteristic
`
`All Treated Patients
`(n ⴝ 157)
`
`Age, y (mean [range])
`Gender (%M:%F)
`Disease duration, months (mean [range])
`Previous treatment
`Lesion size (mean ⫾ SD) in disc area
`Lesion type (n [%])
`Predominantly classic
`Minimally classic
`Occult lesions
`Disease status (mean [range])
`Central retinal/lesion thickness (␮m)
`Foveal thickness (␮m)
`Best-corrected visual acuity (ETDRS letters)
`
`78.3 (53–94)
`38:62
`3.9 (0–67)
`20 (12.7%)
`3.11 ⫾ 2.12
`
`60 (38.2)
`37 (23.6)
`60 (38.2)
`
`456 (186–1316)
`327 (116–1081)
`56 (27–83)
`
`ETDRS ⫽ Early Treatment of Diabetic Retinopathy Study; F ⫽ Female;
`M ⫽ Male; SD ⫽ standard deviation.
`
`Results
`
`Patient Disposition
`Of 159 patients who were randomized, 157 were treated and 134
`(85.4%) completed 52 weeks in the study (Table 1 available online
`at http://aaojournal.org). For the 23 patients (14.6%) who were
`withdrawn before completion of 52 weeks, 6 (3.8%) withdrawals
`were at the request of the patient.
`
`Baseline Characteristics
`The study population was representative of the AMD population in
`the United States. Patients ranged in age from 53 to 94 years
`(mean, 78.3) and the majority were women (62%; Table 2). The
`mean time from diagnosis was 3.9 months (range, 0 – 67), and
`12.7% of patients had received previous treatment. The distribu-
`tion of CNV lesions was 38.2% predominantly classic, 23.6%
`minimally classic, and 38.2% occult with no classic. The treatment
`groups were well-balanced overall for baseline disease severity,
`but mean CR/LT and mean foveal thickness were somewhat higher
`in the 4 mg q12wk group (Table 3).
`
`Change in Central Retinal/Lesion Thickness
`The primary efficacy endpoint of the study was mean change in
`CR/LT at week 12. In all treatment groups combined, the signif-
`icant decrease from baseline in CR/LT observed at week 12 (⫺119
`␮m) was maintained to week 52 (⫺130 ␮m; P⬍0.0001) after 40
`weeks of PRN dosing with VEGF Trap-Eye (Fig 3A). The de-
`
`Figure 3. Mean change in central retinal/lesion (CR/LT) thickness in
`(A) all treatment groups combined and (B) individual treatment groups.
`The CR/LT was measured with optical coherence tomography. Change in
`CR/LT from baseline at 12 weeks was the primary study endpoint. In the
`combined treatment group, a significant (*P⬍0.0001) decrease in CR/LT
`at week 12 was maintained to week 52 (⫺130 ␮m). The decrease in
`CR/LT in individual treatment groups was maintained between weeks 12
`and 52 with PRN dosing was significant (*P⬍0.0001; †P ⫽ 0.0002)
`compared with baseline values. The last-observation-carried-forward
`method was used to impute missing data. CR/LT ⫽ central retina/lesion
`thickness; PRN ⫽ as-needed; 0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg
`every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12 weeks; 2q12 ⫽ 2 mg every 12
`weeks; 4q12 ⫽ 4 mg every 12 weeks.
`
`crease in CR/LT was also maintained in all individual dosing
`groups after PRN dosing and was significant compared with base-
`line values. The greatest decreases in CR/LT at week 52 versus
`baseline occurred in the 4 mg q12wk group (⫺161 ␮m; P ⫽
`0.0002) and the 2 mg q4wk group (⫺143 ␮m; P⬍0.0001; Fig 3B).
`
`Change in Angiographic Measures
`Fluorescein angiography (FA) was performed at baseline and at
`weeks 4, 12, 24, 36, and 48. In all groups combined and in each
`treatment group, there were no significant changes in total lesion
`
`Table 3. Baseline Disease Status by Treatment Group
`
`Mean (Range)
`
`0.5q4
`(n ⴝ 32)
`
`2q4
`(n ⴝ 31)
`
`0.5q12
`(n ⴝ 32)
`
`2q12
`(n ⴝ 31)
`
`4q12
`(n ⴝ 31)
`
`All Groups
`(n ⴝ 157)
`
`CR/LT (␮m)
`Foveal thickness (␮m)
`BCVA (ETDRS letters)
`
`434 (282–710)
`329 (212–509)
`54 (27–76)
`
`453 (232–960)
`307 (171–524)
`58 (32–83)
`
`442 (186–762)
`319 (116–559)
`56 (30–72)
`
`447 (265–948)
`334 (186–762)
`57 (32–72)
`
`507 (240–1316)
`360 (177–1081)
`53 (28–80)
`
`456 (186–1316)
`327* (116–1081)
`56 (27–83)
`
`BCVA ⫽ best-corrected visual acuity; CR/LT ⫽ central retinal/lesion thickness; ETDRS ⫽ Early Treatment of Diabetic Retinopathy Study; q ⫽ every.
`*In all groups (n ⫽ 157), 25 patients at week 52 showed foveal thickness measurements of ⬍150 ␮m.
`
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`size from baseline to week 12 and week 48 (data not shown). The
`decrease in total lesion size for the 2 mg q4wk group at week 12
`(⫺0.75 mm2; ⫺0.30 disc area [DA]) and week 48 (⫺1.75 mm2;
`⫺0.69 DA; P⬍0.04) achieved significance.
`The area of CNV (defined as classic and/or occult CNV dem-
`onstrating angiographic evidence of late leakage or pooling of dye)
`was also measured. In all treatment groups combined, PRN treat-
`ment with VEGF Trap-Eye resulted in a consistent decrease in the
`CNV size versus baseline at weeks 12 and 48, with a decrease of
`⫺2.21 mm2 (⫺0.87 DA) at week 48 (P⬍0.001; Fig 4A, available
`online at http://aaojournal.org). All treatment groups other than the
`0.5 mg q12wk group experienced a decrease in active CNV size at
`48 weeks (⫺1.42 to ⫺3.41 mm2; ⫺0.56 to ⫺1.34 DA), with the
`greatest reduction in the 2 mg q4wk group (⫺3.41 mm2, ⫺1.34
`DA; P⬍0.001; Fig 4B).
`
`Change in Visual Acuity
`The significant improvement from baseline in BCVA that was
`noted at 12 weeks was maintained through the PRN dosing phase
`to week 52. The combining of all treatment groups showed a mean
`gain of 5.7 letters at week 12 and 5.3 letters at week 52 (P⬍0.0001
`vs baseline; Fig 5A). The greatest improvement in BCVA occurred
`
`Figure 5. Mean change in best-corrected visual acuity (BCVA) in (A) all
`treatment groups combined and (B) individual treatment groups. The BCVA
`was assessed with the Early Treatment of Diabetic Retinopathy Study protocol
`at 4 m. Significant improvements from baseline in BCVA were noted in all
`treatment groups combined at week 12 (5.7 letters) and were maintained to
`week 52 (5.3 letters; ¶P⬍0.0001). The 2 mg q4wk group showed the greatest
`gain in BCVA at 12 weeks, which was maintained to 52 weeks (9.0 letters;
`*P⬍0.0001; †P ⫽ 0.085; ‡P ⫽ 0.0412; §P ⫽ 0.0154; and 储P ⫽ 0.344 for
`individual groups versus baseline). The last-observation-carried-forward
`method was used to impute missing data. ETDRS ⫽ Early Treatment of
`Diabetic Retinopathy Study; PRN ⫽ as-needed.
`
`1102
`
`Figure 6. Visual acuity changes at week 52. The proportions of patients
`who avoided moderate vision loss (ⱖ15 letters), had an improvement in
`visual acuity (gain of ⱖ0 letters), or had a significant vision gain (ⱖ15
`letters) in the treatment groups combined and individual dosing groups at
`week 52 are shown. In the treatment groups combined, only 8% of patients
`experienced moderate loss of vision, whereas 22% showed a significant
`gain in vision of ⱖ15 letters at week 52 after 40 weeks of as-needed (PRN)
`dosing. The last-observation-carried-forward method was used to impute
`missing data. 0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks;
`0.5q12 ⫽ 0.5 mg every 12 weeks; 2q12 ⫽ 2 mg every 12 weeks; 4q12 ⫽
`4 mg every 12 weeks.
`
`in the 2 mg q4wk treatment group, with a mean increase of 8.3
`letters at week 12 and of 9.0 letters at week 52 (P⬍0.0001 vs
`baseline; Fig 5B). Visual acuity improvements compared with
`baseline were also maintained in all other treatment groups at
`week 52.
`
`Frequency of Patients with Visual Acuity Changes
`
`In all treatment groups combined, moderate loss of vision (loss of
`ⱖ15 letters) was avoided in 98% of patients at week 12 and 92%
`at week 52 after treatment with VEGF Trap-Eye. In the individual
`treatment groups, 88% to 100% of patients avoided moderate loss
`of vision at week 52 (Fig 6). Overall, 12 patients experienced
`moderate vision loss at week 52, including 4 in the 0.5 mg q4wk
`group, 4 in the 0.5 mg q12wk group, 3 in the 2 mg q12wk group,
`and 1 in the 4 mg q12wk group. None of the patients in the 2 mg
`q4wk group experienced moderate vision loss.
`Stabilization or improvement in visual acuity (gain of ⱖ0
`letters) occurred in 74.5% of patients in all treatment groups
`combined at week 12 and in 73% of patients at week 52. In the
`individual treatment groups, the proportion of patients experienc-
`ing stable or improved visual acuity ranged between 59% and
`81%, with the highest proportion in the 2 mg q4wk group. Overall,
`these proportions remained steady from week 12 to week 52.
`The frequency of patients in all treatment groups combined
`with a significant gain in vision (ⱖ15 letters) was 18.5% at week
`12 and 22% at week 52. Groups treated with 2 mg, either monthly
`or quarterly, had the highest frequency of patients with significant
`visual gain (26% and 16%, respectively, at week 12, and 29% in
`each group at week 52).
`The proportion of patients with ⱕ20/200 vision in all treatment
`groups combined was 11.5% at baseline and remained stable at
`10.8% at week 52. The proportion of patients with ⱖ20/40 vision
`increased from baseline (15%) to week 52 (41%) for all groups
`combined, with the 0.5mg q4wk and 2mg q4wk groups increasing
`from 13% and 16% to 47% and 45%, respectively (Fig 7, available
`online at http://aaojournal.org).
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`䡠 PRN Treatment of Wet AMD with VEGF Trap-Eye
`
`Table 4. Retreatment Outcomes with VEGF Trap-Eye
`
`Mean No. of Injections
`over PRN Phase
`(Weeks 12–52)
`
`Mean No. of Days to
`First Injection over
`PRN Phase
`(Weeks 12–52)
`
`Median No. of Days
`to First Injection
`over PRN Phase
`(Months 3–12)
`
`2.52
`1.55
`1.84
`2.48
`1.7
`2.01
`
`102
`160
`133
`113
`138
`129
`
`85
`150
`86
`86
`111
`110
`
`Treatment Regimen
`
`0.5 mg q4
`2 mg q4
`0.5 mg q12
`2 mg q12
`4 mg q12
`All groups
`
`PRN ⫽ as-needed.
`
`Reinjection Outcomes
`Beginning at week 16, patients were evaluated monthly for the
`need for reinjection. Over the 40-week PRN dosing phase, the
`mean number of reinjections received for all groups combined was
`2.01, ranging from 1.55 injections in the 2 mg q4wk group to 2.52
`in the 0.5 mg q4wk group (Table 4). During the PRN dosing phase,
`29 patients (19%) did not receive any injections of VEGF Trap-
`Eye, 45% received 1 to 2 injections, and only 5% of patients
`received ⱖ5 injections (Fig 8). The most common reason for
`retreatment was the presence of persistent fluid on OCT examina-
`tion (63%); in 26% of patients who needed retreatment, a new or
`persistent leak was noted on FA, and 25% of patients had a loss of
`BCVA of ⱖ5 ETDRS letters with recurrent fluid on OCT (Table
`5 available online at http://aaojournal.org).
`The average time from the last mandatory injection at week 12
`to the first PRN injection was 129 days for all treatment groups
`combined. The longest initial treatment-free interval was in the 2
`mg q4wk group (160 days; Table 4). This calculation accounts for
`the 29 patients who were not reinjected by assigning them a
`reinjection time at 52 weeks and is therefore an underestimate of
`the true mean. Kaplan–Meier analysis of the time to first reinjec-
`tion showed a median time to reinjection for all groups combined
`of 110 days. The longest median time to reinjection was 150 days
`in the 2 mg q4wk group (Fig 9, available online at http://
`aaojournal.org; Table 4).
`
`Safety
`The types and frequencies of ocular AEs occurring in the study eye
`were consistent with AEs previously reported with intravitreal
`
`Figure 8. Number of injections after loading phase. Numbers of patients
`receiving 0 to 9 injections of VEGF Trap-Eye during the as-needed dosing
`period are shown. Overall, 19% of patients required no retreatment, 45%
`received 1 or 2 retreatments, and only 5% required 5 to 9 retreatments.
`VEGF ⫽ vascular endothelial growth factor.
`
`anti-VEGF treatment and were generally related to the intravitreal
`injection procedure (Table 6). In all treatment groups combined,
`conjunctival hemorrhage (38.2%) was the most frequently reported
`AE in the study eye. Most ocular AEs in the study eye were mild
`(58%), with 4 events considered severe (conjunctival hemorrhage,
`reduced visual acuity, uveitis, and increased IOP). Seven patients
`(4.5%) had an increase in IOP in the study eye that was considered
`related to study treatment, but the increased IOP was not consid-
`ered an SAE and did not lead to withdrawal of patients from the
`study. Most ocular events that occurred in the fellow eye were mild
`(41.4%) or moderate (12.7%); the most frequently reported AE in
`the fellow eye was vitreous detachment (8.9%).
`The number of patients with systemic AEs was similar among
`treatment groups. The most commonly reported systemic AEs
`were urinary tract infection (10.2%), bronchitis (9.6%) and upper
`respiratory tract infection (9.6%). A total of 58 systemic SAEs
`were reported in 35 patients, but none of the events was deemed to
`be related to study treatment. Two deaths occurred during the
`study, one from pancreatic carcinoma and the other from preex-
`isting pulmonary hypertension. Four ocular SAEs were reported:
`Culture-negative endophthalmitis/uveitis (0.5 mg q4wk group) and
`decreased visual acuity (0.5 mg q12wk group) in the study eye and
`increased IOP (4 mg q12wk group) and retinal detachment (0.5 mg
`q12wk group) in the fellow eye. Stroke was reported in 1 patient
`in the 0.5 mg q4wk group who had a history of stroke. No cases of
`vascular death were reported in this study.
`Adverse events resulted in withdrawal of 7 patients from the
`
`Table 6. Ocular Adverse Events in the Study Eye (Frequency
`ⱖ5% in All Groups Combined*)
`
`Adverse Event
`
`Number (n) Percent (%)
`
`Conjunctival hemorrhage
`Increased IOP (transient postinjection)
`Refraction disorder
`Retinal hemorrhage
`Visual acuity reduced (patient reported)
`Vitreous detachment
`Eye pain
`Vitreous floaters
`Detachment of retinal pigment epithelium
`Retinal edema
`Visual disturbance
`Blepharitis
`Subretinal fibrosis
`
`60
`29
`26
`22
`21
`18
`15
`14
`12
`10
`8
`8
`8
`
`IOP ⫽ intraocular pressure.
`*Patients receiving treatment with VEGF Trap-Eye (n ⫽ 157).
`
`38.2
`18.5
`16.6
`14.0
`13.4
`11.5
`9.6
`8.9
`7.6
`6.4
`5.1
`5.1
`5.1
`
`1103
`
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`Ophthalmology Volume 118, Number 6, June 2011
`
`study: Three ocular (retinal edema and retinal hemorrhage in the
`study eye and increased IOP in the fellow eye) and 4 systemic
`(non-Hodgkin’s lymphoma, hip fracture, colon cancer, and bron-
`chitis). There were no differences in frequency of AEs or SAEs
`between the treatment groups.
`
`Discussion
`
`Among patients with neovascular AMD, PRN dosing with
`VEGF Trap-Eye maintained efficacy established during a
`12-week monthly or quarterly fixed-dosing phase for an
`additional 40 weeks. For all groups combined, a clinically
`significant improvement in visual acuity achieved at 12
`weeks (5.7-letter gain) was maintained to 52 weeks (5.3-
`letter gain), accompanied by a decrease in CR/LT (⫺119
`␮m at week 12 and ⫺130 ␮m at week 52). Among patients
`in all treatment groups combined, 22% experienced a gain
`of ⱖ15 letters and only 8% of patients had a loss of ⱖ15
`letters at the end of the study period. These improvements
`were achieved with an average of only 2 additional injec-
`tions of VEGF Trap-Eye over the 40-week PRN phase;
`notably, 44% of patients required either no retreatment or
`only 1 reinjection, suggesting a long duration of effect in
`these patients. Repeated intravitreal dosing of VEGF Trap-
`Eye was generally safe and well tolerated. The overall
`safety profile was s