Clinical science
`
`VEGF Trap-Eye for macular oedema secondary
`to central retinal vein occlusion: 6-month results
`of the phase III GALILEO study
`Frank G Holz,1 Johann Roider,2 Yuichiro Ogura,3 Jean-François Korobelnik,4,5,6
`Christian Simader,7 Georg Groetzbach,8 Robert Vitti,9 Alyson J Berliner,9
`Florian Hiemeyer,8 Karola Beckmann,8 Oliver Zeitz,8,10 Rupert Sandbrink8,11
`
`1Department of
`Ophthalmology, University of
`Bonn, Bonn, Germany
`2Department of
`Ophthalmology, University of
`Kiel, Kiel, Germany
`3Department of Ophthalmology
`and Visual Science, Nagoya
`City University Graduate School
`of Medical Science, Nagoya,
`Japan
`4Service d’ophtalmologie,
`Hopital Pellegrin—CHU de
`Bordeaux, Bordeaux, France
`5Université Bordeaux Segalen,
`Bordeaux, France
`6INSERM, ISPED, Centre
`INSERM U897-Epidemiologie-
`Biostatistique, Bordeaux,
`France
`7Department of
`Ophthalmology, Vienna
`Reading Center, Medical
`University of Vienna, Vienna,
`Austria
`8Bayer HealthCare AG, Berlin,
`Germany
`9Regeneron Pharmaceuticals,
`Inc., Tarrytown, New York,
`USA
`10Klinik und Poliklinik für
`Augenheilkunde,
`Universitätsklinikum Hamburg-
`Eppendorf, Hamburg, Germany
`11Department of Neurology,
`Heinrich-Heine-Universität,
`Düsseldorf, Germany
`
`Correspondence to
`Professor Frank G Holz,
`Department of Ophthalmology,
`University of Bonn,
`Ernst-Abbe-Street 2,
`Bonn 53127, Germany;
`frank.holz@ukb.uni-bonn.de
`
`Received 23 April 2012
`Revised 26 November 2012
`Accepted 3 December 2012
`Published Online First
`7 January 2013
`
`To cite: Holz FG, Roider J,
`Ogura Y, et al. Br J
`Ophthalmol 2013;97:
`278–284.
`
`ABSTRACT
`Aim To evaluate intravitreal VEGF Trap-Eye (VTE) in
`patients with macular oedema secondary to central
`retinal vein occlusion (CRVO).
`Methods In this double-masked study, 177 patients
`were randomised (3:2 ratio) to intravitreal injections of
`VTE 2 mg or sham procedure every 4 weeks for
`24 weeks. Best-corrected visual acuity was evaluated
`using the Early Treatment Diabetic Retinopathy Study
`chart. Central retinal thickness (CRT) was measured with
`optical coherence tomography.
`Results From baseline until week 24, more patients
`receiving VTE (60.2%) gained ≥15 letters compared
`with those receiving sham injections (22.1%)
`(p<0.0001). VTE patients gained a mean of 18.0 letters
`compared with 3.3 letters with sham injections
`(p<0.0001). Mean CRT decreased by 448.6 and
`169.3 mm in the VTE and sham groups (p<0.0001).
`The most frequent ocular adverse events in the VTE arm
`were typically associated with the injection procedure or
`the underlying disease, and included eye pain (11.5%),
`increased intraocular pressure (9.6%) and conjunctival
`haemorrhage (8.7%).
`Conclusions VTE 2 mg every 4 weeks was efficacious
`in CRVO with an acceptable safety profile. Vision gains
`with VTE were significantly higher than with observation/
`panretinal photocoagulation if needed. Based on these
`data, VTE may provide a new treatment option for CRVO.
`
`INTRODUCTION
`Macular oedema is the most common cause of
`vision loss for patients with central retinal vein
`occlusion (CRVO).1 Patients suffering from CRVO,
`particularly from non-perfused CRVO,2 have the
`worst prognosis of all RVO patients.3
`A wide variety of strategies have been used for the
`treatment of macular oedema secondary to CRVO
`including surgical procedures,4–6 laser photocoagu-
`lation,7 steroid implants,8 intravitreal steroid injec-
`tions9 and, more recently, antivascular endothelial
`growth factor (anti-VEGF) agents.10–14 Although
`effective in reducing macular oedema secondary to
`CRVO, macular grid laser photocoagulation did not
`appear to improve vision compared with observa-
`tion.2 Treatment with steroids resulted in vision
`gains, but was associated with higher rates of intrao-
`cular pressure (IOP) elevation, cataract formation
`and steroid-induced secondary glaucoma.8 9 15 In
`contrast, intravitreal injections of anti-VEGF agents
`reduced macular oedema and improved vision with
`
`a better safety profile compared with intravitreal
`steroids.10–14 Based on a survey from the American
`Society of Retinal Specialists, over 70% of the
`retinal
`specialists
`(n=619)
`use
`intravitreal
`anti-VEGF agents to treat macular oedema second-
`ary to CRVO.16
`injection;
`aflibercept
`(VTE,
`VEGF Trap-Eye
`Tarrytown,
`Regeneron
`Pharmaceuticals,
`Inc.
`New York, USA,
`and
`Bayer HealthCare
`Pharmaceuticals, Berlin, Germany)
`is a fusion
`protein comprising key domains
`from human
`VEGF receptors 1 and 2 with human IgG Fc that
`blocks all VEGF-A isoforms and placental growth
`factor.17 18 Previous studies with VTE have demon-
`strated improvements in visual function for patients
`with neovascular age-related macular degener-
`20
`ation19
`oedema.21
`and
`diabetic macular
`GALILEO is one of two similar trials (with the
`COPERNICUS study)22 designed to evaluate the
`efficacy and safety of intravitreal VTE in patients
`with macular oedema secondary to CRVO.
`
`METHODS
`GALILEO is a phase III, randomised, double-masked,
`multi-centre clinical
`study conducted across 63
`centres in Europe (Austria 3; France 5; Germany 21;
`Hungary 5; Italy 7; Latvia 2) and the Asian/Pacific
`region (Australia 6; Japan 6; Singapore 2; South
`Korea 6). The total study duration is 76 weeks, with
`68 weeks of treatment (figure 1). Herein the results
`from primary analyses at week 24 are reported, while
`the study continues in a masked fashion up to week
`76 with an additional analysis planned at week 52
`(registered as NCT01012973 on clinicaltrials.gov).
`The appropriate institutional review boards/ethic
`committees approved the protocol and all participants
`provided written informed consent.
`Since at
`the time when the GALILEO and
`COPERNICUS studies were started there was no
`approved treatment for CRVO, health authorities
`requested that the duration of the sham treatment
`in GALILEO be extended to a full year (the sister
`study, COPERNICUS, conducted outside the EU
`maintained a
`sham arm for only
`the first
`6 months). Considering this rather long duration of
`sham treatment, the visual acuity and other ocular
`findings were observed carefully by a team of
`masked medical reviewers. If, at any time,
`this
`review team had the impression that a patient
`might not benefit from further study participation
`or might be more adequately treated outside the
`
`278
`
`Holz FG, et al. Br J Ophthalmol 2013;97:278–284. doi:10.1136/bjophthalmol-2012-301504
`
`CELLTRION - EXHIBIT 1071
`
`

`

`Clinical science
`
`Figure 1 GALILEO study design. The
`two study arms consisted of VEGF
`Trap-Eye 2 mg every 4 weeks or sham
`intravitreal injections every 4 weeks.
`BCVA, best-corrected visual acuity;
`CRT, central retinal thickness; CRVO,
`central retinal vein occlusion; ETDRS,
`Early Treatment Diabetic Retinopathy
`Study; OCT, optical coherence
`tomography; PRP, panretinal
`photocoagulation; VTE2Q4, VEGF Trap-
`Eye 2q4. This figure is only reproduced
`in colour in the online version.
`
`study, the investigator was queried and asked to provide a
`reassessment of the patient.
`
`Health Questionnaire, respectively. Selected subscales of NEI
`VFQ-25 were assessed as tertiary efficacy variables.
`
`Participants
`Treatment-naive patients, age ≥18 years, were included if they
`had centre-involved macular oedema secondary to CRVO for a
`maximum of 9 months, with a central retinal thickness (CRT)
`≥250 μm on optical coherence tomography (OCT) and an Early
`Treatment Diabetic Retinopathy Study (ETDRS) best-corrected
`visual acuity (BCVA) of 73 to 24 letters (20/40 to 20/320) in the
`study eye. Patients were excluded if they were pregnant or had
`uncontrolled glaucoma (IOP≥25 mm Hg), filtration surgery,
`bilateral manifestation of RVO, iris neovascularisation, or previ-
`ous treatment with anti-VEGF agents, pan-retinal or macular
`laser photocoagulation, or intraocular corticosteroids.
`
`Treatments
`Patients were randomised in a 3:2 ratio to receive either intravi-
`treal
`injections of VTE 2 mg (VTE2Q4) or sham procedure
`every 4 weeks for 24 weeks. Sham procedure was performed by
`pressing an empty syringe with no needle to the conjunctival
`surface. Randomisation was stratified by region (Europe vs
`and baseline BCVA (≤20/200 vs >20/200).
`Asia/Pacific)
`Pan-retinal photocoagulation was allowed at any time for all
`patients if they progressed to neovascularisation of the anterior
`segment, optic disc or fundus.
`
`Endpoints
`The primary endpoint was the proportion of patients who gained
`≥15 letters in BCVA at week 24 compared with baseline. The sec-
`ondary endpoints were: (a) the change from baseline to week 24
`in BCVA and CRT, (b) the proportion of patients progressing to
`neovascularisation of anterior segment, optic disc or elsewhere in
`the fundus by week 24 and (c) the changes in vision-related and
`overall health-related quality of life (QoL) as assessed by the
`National Eye Institute Visual Functioning Questionnaire-25 (NEI
`VFQ-25) and European Quality of Life-5 Dimensions (EQ-5D)
`
`Methodology
`Visual function was assessed using the ETDRS charts.23 Retinal
`characteristics were evaluated using OCT (Stratus OCT, Carl
`Zeiss Meditec, Jena, Germany). Baseline retinal perfusion status
`was determined by fluorescein angiography using the central
`vein occlusion study (CVOS) classification.2 Patients were con-
`sidered non-perfused if they had ≥10 disc areas of capillary
`non-perfusion. Vision-related and overall health-related QoL
`was assessed using the NEI-VFQ-25 and EQ-5D Health
`Questionnaires, respectively.
`
`Statistics
`A total of 150 patients (90 VTE/60 Sham) were considered neces-
`sary to detect a between-group difference of 25% in proportion
`of patients gaining ≥15 letters with a power of 90% using a two-
`sided Fisher’s exact test. For the efficacy analyses, the full analysis
`set included all randomised patients who received any study
`treatment and had baseline and at least one postbaseline BCVA
`assessment. The safety analysis set included all patients who
`received any study treatment. For the primary endpoint analysis,
`the between-group difference was evaluated by a two-sided
`Cochran-Mantel-Haenszel (CMH) test at a 5% level stratified for
`regions and baseline visual acuity. In this analysis, patients who
`discontinued prior
`to week 24 were considered as non-
`responders. Several sensitivity analyses for the primary endpoint
`were performed by imputing the missing values with the last
`observation carried forward (LOCF) approach, using observed
`cases, or excluding patients who discontinued study prior to
`week 24 and received fewer than five injections.
`Secondary endpoint analyses were performed sequentially
`according to the order in which the variables were defined to
`preserve an α of 0.05. Proportions were analysed with the
`CMH test. BCVA as a continuous variable was analysed by ana-
`lysis of variance main effects model with treatment group,
`
`Holz FG, et al. Br J Ophthalmol 2013;97:278–284. doi:10.1136/bjophthalmol-2012-301504
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`279
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`

`Clinical science
`
`region and baseline BCVA as fixed factors. A descriptive, post
`hoc analysis using a double-sided Fisher test was conducted to
`evaluate the between-group differences in the proportion of
`patients losing ≥1 and ≥10 letters.
`
`RESULTS
`Patient disposition, demographics and disease
`characteristics
`A total of 240 patients were screened, 177 patients were rando-
`mised and 172 patients were included in the safety analysis set
`(table 1). One patient did not have any postbaseline BCVA assess-
`ment. Therefore, the full analysis set comprised 171 patients
`(table 1). Overall, 86.4% of VTE2Q4 patients and 79.4% of
`sham patients had a perfused retinal occlusion (table 2).
`
`Visual outcomes
`Significantly more VTE2Q4-treated patients gained ≥15 letters
`by week 24 than those receiving sham injections (60.2% vs
`22.1%, p<0.0001) with a CMH-adjusted difference of 38.3%
`(table 3, figure 2). Similar results for the CMH-adjusted differ-
`ence (95% CI) was obtained after imputing the missing values
`with the LOCF approach (41.1% (27.4% to 54.9%)), using the
`observed cases (38.7% (23.5% to 53.8%)), or excluding patients
`who discontinued study prior to week 24 and received fewer
`than five injections (39.2% (25.4% to 53.0%)).
`Patients receiving VTE2Q4 had a significantly greater mean
`change in BCVA than the sham-treated patients at week 24 (18.0
`vs 3.3 letters, respectively; p<0.0001; figure 3) resulting in an
`adjusted between-group difference of 14.7 letters (table 3). The
`
`Table 1 Patient disposition (all randomised patients) and overview
`of analysis sets
`
`n (%)
`
`Patients screened
`Patients randomised
`Patients treated
`Patients (FAS)
`Completed 24 weeks
`Discontinued study before week 24
`Adverse event
`Protocol violation
`Withdrawal of consent
`Lack of efficacy
`Lost to follow-up
`Other
`Discontinued treatment before week 24*
`Adverse event
`Protocol violation
`Withdrawal of consent
`Lack of efficacy
`Lost to follow-up
`Other
`Safety analysis set
`FAS
`Per protocol set
`
`VEGF
`Trap-Eye
`2Q4
`n=106
`
`–
`106 (100)
`104 (98.1)
`103 (97.2)
`96 (90.6)
`10 (9.4)
`0
`5 (4.7)
`3 (2.8)
`0
`1 (0.9)
`1 (0.9)
`11 (10.4)
`2 (1.9)
`5 (4.7)
`3 (2.8)
`0
`1 (0.9)
`0
`104 (98.1)
`103 (97.2)
`87 (82.1)
`
`Sham
`n=71
`
`Total
`n=177
`
`240
`–
`177 (100)
`71 (100)
`68 (95.8) 172 (97.2)
`68 (95.8) 171 (96.6)
`56 (78.9) 152 (85.9)
`15 (21.1)
`25 (14.1)
`4 (5.6)
`4 (2.3)
`2 (2.8)
`7 (4.0)
`3 (4.2)
`6 (3.4)
`5 (7.0)
`5 (2.8)
`0
`1 (0.6)
`1 (1.4)
`2 (1.1)
`18 (25.4)
`29 (16.4)
`8 (11.3)
`10 (5.6)
`2 (2.8)
`7 (4.0)
`3 (4.2)
`6 (3.4)
`4 (5.6)
`4 (2.3)
`0
`1 (0.6)
`1 (1.4)
`1 (0.6)
`68 (95.8) 172 (97.2)
`68 (95.8) 171 (96.6)
`51 (71.8) 138 (78.0)
`
`Percentages are based on all randomised patients.
`*In the sham group, patients discontinued receiving the sham procedure.
`FAS, full analysis set.
`
`Table 2 Baseline demographics and disease characteristics
`(study eye)
`
`FAS*
`
`Mean age, years (SD)
`Geographic region
`Europe
`Asia/Pacific
`Gender
`Female
`Male
`Race
`White
`Asian
`Not reported
`Renal impairment
`Normal
`Mild
`Moderate
`Severe
`Missing
`Hepatic impairment
`Yes
`No
`Retinal perfusion status
`Perfused
`Non-perfused
`Indeterminable
`Time since CRVO diagnosis
`<2 months
`≥2 months
`Missing
`Mean time since CRVO
`diagnosis in days (SD)
`Mean ETDRS BCVA letter
`score (SD)
`ETDRS BCVA >20/200
`Mean CRT mm (SD)
`Mean IOP (mm Hg) (SD)
`
`VEGF
`Trap-Eye 2Q4
`n=103
`
`Sham
`n=68
`
`Total
`n=171
`
`59.9 (12.4)
`
`63.8 (13.3)
`
`61.5 (12.9)
`
`73 (70.9)
`30 (29.1)
`
`48 (70.6)
`20 (29.4)
`
`121 (70.8)
`50 (29.2)
`
`45 (43.7%)
`58 (56.3%)
`
`31 (45.6%)
`37 (54.4%)
`
`76 (44.4%)
`95 (55.6%)
`
`74 (71.8%)
`26 (25.2%)
`3 (2.9%)
`
`49 (72.1%)
`15 (22.1%)
`4 (5.9%)
`
`123 (71.9%)
`41 (24.0%)
`7 (4.1%)
`
`61 (59.2)
`36 (35.0)
`5 (4.9)
`0
`1 (1.0)
`
`3 (2.9)
`100 (97.1)
`
`89 (86.4)
`7 (6.8)
`7 (6.8)
`
`55 (53.4)
`46 (44.7)
`2 (1.9)
`78.0 (89.6)
`
`37 (54.4)
`17 (25.0)
`9 (13.2)
`2 (2.9)
`3 (4.4)
`
`2 (2.9)
`66 (97.1)
`
`54 (79.4)
`7 (10.3)
`7 (10.3)
`
`35 (51.5)
`33 (48.5)
`0
`87.6 (79.1)
`
`98 (57.3)
`53 (31.0)
`14 (8.2)
`2 (1.2)
`4 (2.3)
`
`5 (2.9)
`166 (97.1)
`
`143 (83.6)
`14 (8.2)
`14 (8.2)
`
`90 (52.6)
`79 (46.2)
`2 (1.2)
`81.8 (85.4)
`
`53.6 (15.8)
`
`50.9 (15.4)
`
`52.2 (15.7)
`
`86 (83.5%)
`683.2 (234.5)
`15.1 (2.8)
`
`56 (82.4%)
`638.7 (224.7)
`14.4 (2.7)
`
`142 (83.0%)
`665.5 (231.0)
`14.9 (2.7)
`
`*n (%) unless otherwise noted
`BCVA, best-corrected visual acuity; CRT, central retinal thickness; CRVO, central retinal
`vein occlusion; ETDRS, Early Treatment Diabetic Retinopathy Study; FAS, full analysis
`set; IOP, intraocular pressure.
`
`VTE2Q4 arm also showed higher proportions of patients with
`vision gains of ≥0, ≥10 and ≥30 letters at week 24 (figure 4). In
`all, 11 (10.7%) patients in the VTE2Q4 group experienced a loss
`of one or more letters during the course of the 24 weeks com-
`pared with 27 (39.7%) patients in the sham arm (p<0.0001). A
`total of 8 patients (7.8%) in the VTE2Q4 group lost 10 or more
`ETDRS letters during the 24 weeks compared with 17 (25.0%)
`for the sham group (p=0.0033).
`Larger numerical differences between VTE2Q4 and sham were
`seen in the subgroup of patients with disease duration <2 months
`compared with the difference noted in the study population as a
`whole (disease duration <2 months: unadjusted difference of
`50.9% ((20.0% sham; 70.9% VTE2Q4)). Within the VTE2Q4
`group, the proportion of patients who gained at least 15 letters at
`week 24 was higher (70.9%) for patients beginning treatment
`within 2 months of diagnosis compared with 50.0% of VTE2Q4
`patients starting treatment ≥2 months after diagnosis.
`
`280
`
`Holz FG, et al. Br J Ophthalmol 2013;97:278–284. doi:10.1136/bjophthalmol-2012-301504
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`

`

`Clinical science
`
`Table 3 Primary and secondary endpoints
`
`FAS
`Primary endpoint
`No (%) of patients who gained at least 15 letters in BCVA at week 24
`Difference,* %
`CMH adjusted difference*,† % (95% CI)
`p Value‡
`Secondary endpoint
`1. Change in BCVA letter score from baseline to week 24§,**
`2. Change in CRT from baseline to week 24¶,**
`3. Percentage of patients progressing to any neovascularisation by week 24‡,**
`4. Change in total NEI VFQ-25 score from baseline to week 24¶,**
`5. Change in EQ-5D score from baseline to week 24¶,**
`
`VEGF Trap-Eye 2Q4
`
`n=103
`
`62 (60.2)
`38.1
`38.3 (24.4 to 52.1)
`<0.0001
`p Value
`<0.0001 (favours VTE2Q4)
`<0.0001 (favours VTE2Q4)
`0.5947
`0.0013§
`0.0627§
`
`Sham
`
`n=68
`
`15 (22.1)
`–
`
`–
`
`–
`Adjusted difference between treatment groups (95% CI)
`14.7 (10.8 to 18.7)
`−239.42 (−286.31 to −192.53)
`−1.5 (−7.4 to 4.4)
`4.2 (1.7 to 6.8)
`0.044 (−0.002 to 0.090)
`
`*Difference is VTE2Q4 minus sham.
`†Estimate and CI are calculated using CMH weights adjusted for region (Europe vs Asia/Pacific) and baseline BCVA category (>20/200 vs ≤20/200).
`‡p Value is calculated using two-sided CMH test adjusted by region and baseline BCVA category. This applied for the primary endpoint and the third secondary endpoint (percentage of
`patients progressing to any neovascularisation by week 24).
`§ANOVA with treatment group, geographic region and baseline BCVA category as fixed factors.
`¶Analysis of covariance (ANCOVA) with treatment group, geographic region and baseline BCVA category as fixed factors and the respective baseline variable as a covariate.
`**The hierarchical testing of the secondary endpoints had to be stopped after the testing of the proportion of patients progressing to any neovascularisation; the p values provided in
`this table for the subsequent steps (test #4 and test #5) were for descriptive purposes only.
`ANOVA, analysis of variance; BCVA, best-corrected visual acuity; CMH, Cochran-Mantel-Haenszel; CRT, central retinal thickness; FAS, full analysis set; NEI VFQ-25, National Eye Institute
`Visual Functioning Questionnaire-25; VTE2Q4, VEGF Trap-Eye 2 mg every 4 weeks.
`
`Anatomical outcomes
`The difference between the treatment groups in mean changes
`in CRT at week 24 was 279.3 mm (figure 5) (difference between
`least
`squares mean changes 239.4; p<0.0001,
`table 3).
`Neovascularisation was developed in three VTE2Q4 patients
`(2.9%) (two anterior segment neovascularisation and one neo-
`vascularization elsewhere (NVE)) and three sham patients
`(4.4%) (one anterior segment neovascularisation and two NVE)
`(p=0.5947, table 3). Only one case of iris neovascularisation in
`the VTE2Q4 group required treatment with pan-retinal laser
`photocoagulation. The other cases reported to be neovasculari-
`sation in the VTE2Q4 group did not require therapy. All of the
`
`three sham patients with neovascularisation received pan-retinal
`laser photocoagulation. No further rescue laser treatment was
`applied until week 24.
`
`QoL outcomes
`The mean change from baseline to week 24 in total NEI-VFQ
`scores was 7.5 for the VTE2Q4 group and 3.5 for the sham
`group. The between-group difference
`in both the total
`NEI-VFQ score and the near-activities subscore was significant
`at week 24 (p=0.0013 and p=0.0003, respectively, table 3).
`A trend was observed between groups in favour of VTE2Q4
`for the distance-activities subscore, dependency subscore and
`overall mean EQ-5D score at week 24 (p=0.0689, p=0.2552,
`p=0.0627, respectively).
`
`Figure 2 Percentage of patients who gained ≥15 letters over the
`course of 24 weeks. Full analysis set; patients who discontinued prior
`to respective visit evaluated as non-responders. VEGF Trap-Eye 2Q4,
`n=103; sham, n=68. Difference between groups at week 24=38.1%.
`*p<0.0001 VEGF Trap-Eye versus sham was calculated using two-sided
`Cochran-Mantel-Haenszel test adjusted by region and baseline
`best-corrected visual acuity category.
`
`Figure 3 Mean change in visual acuity (Early Treatment Diabetic
`Retinopathy Study (ETDRS) letters). Full analysis set; LOCF. VEGF
`Trap-Eye 2Q4, n=103; sham, n=68. Difference between groups at
`week 24=14.7 letters. *p<0.0001 VEGF Trap-Eye versus sham based on
`treatment difference of the least squares mean changes derived from
`analysis of variance.
`
`Holz FG, et al. Br J Ophthalmol 2013;97:278–284. doi:10.1136/bjophthalmol-2012-301504
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`Figure 4 Proportion of patients who gained vision at week 24
`compared with baseline. Full analysis set; patients who discontinued
`prior to week 24 evaluated as non-responders. VEGF Trap-Eye 2Q4,
`n=103; sham, n=68.
`
`Safety
`The most common treatment-emergent adverse events (AEs) for
`the VTE2Q4 patients were eye pain, increased IOP and conjunc-
`tival haemorrhage (table 4). A slight imbalance was seen in
`IOP-increased AEs between VTE2Q4 (10 (9.6%)) and sham
`(4 (5.9%)). Of note, 5 (4.8%) of these IOP-related AEs were
`procedure-related in the VTE2Q4 group, while only 1 (1.5%)
`in the sham group was related to procedure. Three incidents
`(2.9%) of increased IOP in the VTE2Q4 group were judged to
`be drug-related compared with 1 (1.5%) for the sham group.
`The IOP-increased events for reasons other than the injection
`procedure were well balanced across the arms (table 5). The pro-
`portions of patients experiencing predefined elevations in IOP
`(ie, ≥10 mm Hg
`change
`from baseline, >21 mm Hg or
`≥35 mm Hg) were low and similar between treatment groups at
`all time points.
`There were no incidences of endophthalmitis or cases of rheg-
`matogenous detachment in either treatment group. There was
`one incidence of uveitis in the VTE2Q4 arm that was consid-
`ered to be mild and resolved without change of therapy. There
`
`Figure 5 Mean change in central retinal thickness. Full analysis set;
`LOCF. VEGF Trap-Eye 2Q4, n=103; sham, n=67. Difference between
`groups at week 24=279.3 mm. *p<0.0001 VEGF Trap-Eye versus sham
`is based on treatment difference of the least-squares mean changes
`derived from analysis of covariance (ANCOVA).
`
`Table 4 Treatment-emergent adverse events. Those events with
`an incidence ≥3% in either study group are shown
`VEGF Trap-Eye 2Q4
`n=104
`n (%)
`
`Safety analysis set
`
`Sham
`n=68
`n (%)
`
`12 (11.5)
`9 (8.7)
`7 (6.7)
`6 (5.8)
`6 (5.8)
`5 (4.8)
`5 (4.8)
`4 (3.8)
`4 (3.8)
`4 (3.8)
`3 (2.9)
`3 (2.9)
`2 (1.9)
`1 (1.0)
`0 (0.0)
`
`Eye disorders (study eye)
`Eye pain
`Conjunctival haemorrhage
`Retinal exudates
`Foreign body sensation
`Retinal vascular disorder
`Ocular hyperaemia
`Vitreous floaters
`Macular oedema
`Macular ischaemia
`Optic disc vascular disorder
`Eye irritation
`Lacrimation increased
`Papilloedema
`Retinal ischaemia
`Visual acuity reduced
`Investigations
`10 (9.6)
`IOP increased*
`General disorder and administrative site conditions
`Injection site pain
`5 (4.8)
`Non-ocular events
`Nasopharyngitis
`Headache
`Hypertension
`Back pain
`Arthralgia
`Fall
`
`8 (7.7)
`7 (6.7)
`4 (3.8)
`3 (2.9)
`1 (1.0)
`0 (0.0)
`
`3 (4.4)
`3 (4.4)
`5 (7.4)
`5 (7.4)
`6 (8.8)
`4 (5.9)
`0 (0.0)
`11 (16.2)
`3 (4.4)
`3 (4.4)
`7 (10.3)
`4 (5.9)
`3 (4.4)
`3 (4.4)
`7 (10.3)
`
`4 (5.9)
`
`2 (2.9)
`
`6 (8.8)
`4 (5.9)
`3 (4.4)
`3 (4.4)
`5 (7.4)
`3 (4.4)
`
`*The adverse event could occur prior to the injection or shortly after the injection,
`when the IOP was checked after the procedure. The postinjection IOP check had to
`occur approximately 30 min after the injection. In total 13 patients (therefore six in
`the VTE2Q4 arm) had at least a single IOP measurement of >21 mm Hg preinjection.
`One patient in each of the arms had neovascularisation of the chamber angle as the
`underlying cause and were treated. Two patients in the VTE2Q4 arm had a history of
`glaucoma and were treated accordingly. One patient in the sham arm had newly
`diagnosed ocular hypertension or glaucoma and treatment was initiated. All other
`cases (three in the VTE2Q4 and five in the sham arm) had IOPs >21 mm Hg at not
`more than two visits and had no therapy documented, with one exception (IOP of
`24 mm Hg) who received an acute short-term treatment.
`IOP, intraocular pressure; VTE2Q4, VEGF Trap-Eye 2 mg every 4 weeks.
`
`were none in the sham group. Two patients in the VTE2Q4
`group and four patients in the sham group had ocular SAEs
`(table 6). There were no arterial thromboembolic events or
`deaths reported in either treatment group during the 24-week
`study period.
`
`DISCUSSION
`VTE 2 mg every 4 weeks resulted in significantly better visual
`acuity outcomes than sham. Clinically relevant improvements in
`visual acuity in the VTE2Q4 group could be seen as early as the
`first post-treatment assessment (week 4) and reached a stable
`level, on average, around week 16. The better visual acuity
`outcome was accompanied by more favourable vision-related
`QoL measures in the VTE2Q4 group than in the sham group.
`Several
`studies have investigated the efficacy of other
`anti-VEGF agents for the treatment of macular oedema second-
`ary to CRVO. The CRUISE study reported that patients receiv-
`ing monthly injections of 0.5 mg ranibizumab (n=130)
`experienced a mean change from baseline BCVA of 14.9 letters
`
`282
`
`Holz FG, et al. Br J Ophthalmol 2013;97:278–284. doi:10.1136/bjophthalmol-2012-301504
`
`

`

`Table 5 Mean IOP prior to injection and the proportion of
`patients experiencing predefined elevation in IOP during the study
`
`Safety analysis set
`
`VEGF Trap-Eye 2Q4
`n=104
`
`Sham
`n=68
`
`Total
`n=172
`
`–
`
`–
`
`–
`
`–
`
`–
`
`–
`
`Mean IOP (SD)
`14.4 (2.7)
`15.1 (2.7)
`Baseline
`15.0 (2.9)
`14.6 (3.0)
`Week 4
`15.0 (3.1)
`14.6 (2.8)
`Week 8
`15.0 (3.4)
`14.8 (2.8)
`Week 12
`15.0 (3.8)
`15.1 (3.1)
`Week 16
`15.2 (4.1)
`15.3 (3.3)
`Week 20
`15.6 (5.1)
`15.3 (3.5)
`Week 24
`–
`No. (%) of patients with an increase of ≥10 mm Hg from baseline in preinjection
`IOP
`1 (1.5)
`0 (0.0)
`Week 16
`2 (2.9)
`2 (1.9)
`Week 20
`2 (2.9)
`3 (2.9)
`Week 24
`No. (%) of patients with a preinjection IOP absolute value of ≥21 mm Hg
`Week 4
`2 (1.9)
`1 (1.5)
`Week 8
`1 (1.0)
`2 (2.9)
`Week 12
`1 (1.0)
`2 (2.9)
`Week 16
`1 (1.0)
`3 (4.4)
`Week 20
`2 (1.9)
`3 (4.4)
`Week 24
`5 (4.8)
`4 (5.9)
`No. (%) of patients with a preinjection IOP absolute value of ≥35 mm Hg
`Baseline
`1 (1.0)
`0 (0.0)
`Week 8
`1 (1.0)
`0 (0.0)
`Week 12
`0 (0.0)
`1 (1.5)
`Week 16
`1 (1.0)
`0 (0.0)
`Week 24
`0 (0.0)
`1 (1.5)
`Mean (SD) IOP
`
`1 (0.6)
`4 (2.3)
`5 (2.9)
`
`3 (1.7)
`3 (1.7)
`3 (1.7)
`4 (2.3)
`5 (2.9)
`9 (5.2)
`
`1 (0.6)
`1 (0.6)
`1 (0.6)
`1 (0.6)
`1 (0.6)
`
`IOP, intraocular pressure.
`
`at 6 months.10 Furthermore, 47.7% of patients gained ≥15
`letters at 6 months. A relatively smaller, randomised, double-
`masked study of bevacizumab (n=30) found a mean increase of
`14.1 letters from baseline to week 24 in BCVA of patients
`receiving bevacizumab every 6 weeks.24 The proportion of
`patients gaining ≥15 letters in the bevacizumab study was 60%
`at 24 weeks.24 These findings compare favourably with the
`results of the current study as the mean increase in BCVA was
`18.0 letters and 60.2% of patients gained ≥15 letters in the
`VTE2Q4 group (n=103) at week 24. Improvements in visual
`
`Table 6 Percentage of patients with treatment-emergent ocular
`SAEs (Study eye)
`
`Safety analysis set
`
`At least 1 SAE
`Glaucoma
`Macular oedema*
`Retinal tear
`Vitreous detachment
`Investigations
`Intraocular pressure increased
`
`n (%)
`
`VEGF Trap-Eye 2Q4
`(n=104)
`
`2 (1.9)
`0 (0.0)
`1 (1.0)
`1 (1.0)
`1 (1.0)
`
`0 (0.0)
`
`Sham
`(n=68)
`
`4 (5.9)
`2 (2.9)
`1 (1.5)
`0 (0.0)
`0 (0.0)
`
`1 (1.5)
`
`*Macular oedema could be reported as an adverse event, if worsening of macular
`oedema was observed.
`SAE, serious adverse event.
`
`Clinical science
`
`acuity were observed in the CRUISE study as early as at the
`7-day time point.10 The efficacy with VTE was not measured
`until the fourth week; however, both studies suggest that the
`effect of anti-VEGF agents on macular oedema secondary to
`CRVO occurs very soon after the initiation of treatment.
`In parallel with the increases in BCVA, patients in the
`VTE2Q4 arm experienced a substantial reduction in CRT. Like
`visual acuity, the onset of the effect on CRT occurred immedi-
`ately after the first treatment resulting in a rapid restoration of
`macular morphology. The CRUISE and bevacizumab studies
`found reductions in central foveal thickness consistent with the
`current study.10 24
`Since VEGF is a known stimulator of angiogenesis,25 VEGF
`blockade is expected to reduce neovascularisation secondary to
`CRVO. Numerically, a lower percentage of patients in the
`VTE2Q4 than the sham group progressed to any neovascularisa-
`tion. However, this effect was not significant due to the gener-
`ally low incidence of neovascularisation in both study arms. Of
`note, investigators treated all three patients with neovascularisa-
`tion in the sham arm, but only one of the three patients in the
`VTE2Q4 arm. None of the neovascularisation events were
`serious. No unexpected safety findings were reported. The key
`AEs were either due to the injection procedure or to the under-
`lying disease. The slight imbalance in the rate of increased IOP
`in VTE-treated eyes might reflect transient IOP increases after
`the injection procedure, as an indepth analysis of preinjection
`IOP did not reveal a relationship between increased IOP and the
`drug therapy.
`The sham group had a higher percentage of patients discon-
`tinuing study primarily due to AEs and lack of efficacy; this had
`no major impact on the analysis of the primary endpoint (with
`discontinued patients before week 24 judged as non-
`responders), as similar results were obtained after imputing the
`missing values with the LOCF approach, using observed cases,
`or excluding patients who discontinued prior to week 24 and
`received fewer than five injections.
`The week 24 results using VTE2Q4 from the GALILEO
`study are consistent with those seen in the sister
`study,
`COPERNICUS,22 which also compared CRVO patients receiv-
`ing VTE2Q4 with patients receiving monthly sham injections.
`The visual outcomes in the sham group were more slightly
`favourable in GALILEO than in COPERNICUS.22
`In conclusion, the GALILEO study demonstrated efficacy of
`VTE in the treatment of macular oedema due to CRVO with a
`generally favourable safety and tolerability profile. Therefore,
`VTE may have the future potential to contribute to the manage-
`ment of patients with this sight-threatening condition.
`
`Acknowledgements The authors thank the members of the Independent Data
`Monitoring Committee, Marc de Smet, Yit Yang, Finn Waagstein and Walter
`Lehmacher, for their review of safety data and their recommendations during the
`conduct of the trial. Editorial assistance for the preparation of this manuscript was
`provided by Julie Crider, PhD.
`Contributors All authors, FGH, JR, YO, J-FK, CS, GG, RV, AB, FH, KB, OZ and RS,
`were involved in the conception and design, acquisition of data, or analysis and
`interpretation of data in the GALILEO study. Additionally, all authors were involved
`in the drafting and revision of the article for intellectual content and the approval of
`the final version to be published.
`Funding The GALILEO study was supported by Bayer HealthCare, Berlin, Germany
`and Regeneron Pharmaceuticals, Inc. Tarrytown, New York, USA.
`Competing interests Dr Holz is a consultant to Acucela, Bayer HealthCare,
`Boehringer-Ingelheim, Heidelberg Engineering, Genentech, GlaxoSmithKline, Neuron,
`Novartis and Pfizer and has received research funding from Bayer HealthCare,
`Genentech, Novartis and Pfizer. He has also received travel support from Bayer
`HealthCare and lecture fee from Novartis and Pfizer. Dr Roider is a consultant to
`Bayer HealthCare. Dr Ogura is a consultant to and has received travel support and
`
`Holz FG, et al. Br J Ophthalmol 2013;97:278–284. doi:10.1136/bjophthalmol-2012-301504
`
`283
`
`

`

`Clinical science
`
`lecture fee from Bayer HealthCare. Dr Korobelnik is a consultant to Alcon, Bayer
`HealthCare, Carl Zeiss Meditec and Thea. He is also an advisory board member in
`Allergan and Novartis. Dr Simader is a consultant to Bayer HealthCare. Dr
`Groetzbach is an employee of Bayer HealthCare. Dr Vitti is an employee of
`Regeneron Pharmaceuticals, Inc. Dr Berliner is an employee of Regeneron
`Pharmaceuticals, Inc. Hiemeyer is an employee of Bayer HealthCare. Beckmann is an
`employee of Bayer HealthCare. Dr Zeitz is an employee of Bayer HealthCare. Dr
`Sandbrink is an employee of Bayer HealthCare.
`Patient consent Obtained.
`Ethics approval Institutional Review Boards and Ethics Committee.
`Provenance and peer review Not commissioned; externally peer reviewed.
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