Improvement in Vision-Related Function with

Intravitreal Aibercept
Data from Phase 3 Studies in Wet Age-Related Macular
Degeneration
Mitsuko Yuzawa, MD,1 Kyoko Fujita, MD,1 Kim U. Wittrup-Jensen, PhD,2 Christiane Norenberg, MS,2
Oliver Zeitz, MD,2,3 Kenji Adachi, PhD,4 Edward C.Y. Wang, PharmD, MBA,4 Jeffrey Heier, MD,5
Peter Kaiser, MD,6 Victor Chong, MD,7 Jean-Francois Korobelnik, MD8,9
Purpose: To evaluate the effect of intravitreal aibercept injection on visual function in wet age-related
macular degeneration (AMD).
Design: Prospective, multicenter, double-masked, active-controlled, parallel-group, randomized phase 3
clinical studies (VEGF Trap-Eye: Investigation of Efcacy and Safety in Wet AMD [VIEW] 1 and 2 [clinicaltrials.gov
identiers, NCT00509795 and NCT00637377, respectively]).
Participants: Patients (n 2419) with active, treatment-nave, exudative AMD. This analysis included
patients who received intravitreal aibercept 2.0 mg every 8 weeks (2q8; n 607) or ranibizumab 0.5 mg every 4
weeks (0.5q4; n 595).
Intervention: Patients were randomized 1:1:1:1 to receive intravitreal aibercept 2q8 (after 3 initial monthly
doses), intravitreal aibercept 2q4, intravitreal aibercept 0.5q4, or ranibizumab 0.5q4 in the study eye. Patients in
the intravitreal aibercept 2q8 group received a sham injection alternating with active treatment.
Main Outcome Measures: The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25)
was administered at baseline and at weeks 12, 24, 36, and 52. The NEI VFQ-25 subscale scores were compared
between intravitreal aibercept 2q8 and ranibizumab 0.5q4 treatment arms, the approved dosing for each agent
worldwide. Change in composite NEI VFQ-25 score was evaluated based on categorical change in visual acuity
(worsened, unchanged, improved).
Results: Baseline NEI VFQ-25 scores were similar for both treatments in both studies. Mean change from
baseline to 52 weeks was similar for ranibizumab 0.5q4 and intravitreal aibercept 2q8 across all 12 subscales,
with the greatest improvements noted for mental health and general vision (9.0e11.6 points, both treatments,
both studies). Improvement of 4 points or more (both treatments, both studies) also was observed for subscales
near vision, distance vision, role difculties, and dependency. Mean change from baseline to 52 weeks in NEI
VFQ-25 composite score (pooled data) stratied by clinical response showed meaningful improvement only in
patients who gained 5 Early Treatment Diabetic Retinopathy letters or more (7.3 and 7.8 points for intravitreal
aibercept 2q8 and ranibizumab 0.5q4, respectively).
Conclusions: Visual function outcomes were similar across all NEI VFQ-25 subscales over 52 weeks for
intravitreal aibercept 2q8 and ranibizumab 0.5q4, with clinically meaningful improvement recorded in 6 of 12
subscales. Ophthalmology 2015;122:571-578 2015 by the American Academy of Ophthalmology.

Given the increasing prevalence of neovascular (wet or

exudative) age-related macular degeneration (AMD) in the
worlds aging population, the adverse impact of this disease
on quality of life (QoL) in the elderly is of growing public
health signicance.1 With progressive deterioration of the
macula, patients with AMD experience a multitude of visual
problems that signicantly affect their visual function and
QoL. In fact, the reduction in vision-related QoL (VRQoL)
in patients with AMD has been rmly established in natural
history studies2e4 and in treatment trials.5,6 The extent of the
decrement in VRQoL is reected in the seriousness of the
 2015 by the American Academy of Ophthalmology
Published by Elsevier Inc.

burden of illness of AMD.7e9 Central vision, in particular, is

needed for activities such as reading, driving, and facial
recognition. Even in the early stages of AMD, there is
blurring and distortion of central vision, which decreases
functional capacity for these activities.3,10 It is the progressive deterioration of central vision that profoundly impacts disease-specic QoL.8,11
Consequently, the assessment of QoL in AMD clinical
research is a critical component of interventional and observational studies. Clinical measures, such as visual acuity
(VA), and measures of VRQoL, such as the 25-item National
http://dx.doi.org/10.1016/j.ophtha.2014.09.024
ISSN 0161-6420/14

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Ophthalmology Volume 122, Number 3, March 2015

Eye Institute Visual Function Questionnaire (NEI VFQ25),12,13 are not interchangeable for assessing patient outcomes and should be viewed as complementary.14 The
VRQoL outcomes demonstrate the real-life value of treatment
to patients and may facilitate discussion between physicians
and patients about treatment progress.15,16 In addition,
VRQoL outcomes data also may be used to demonstrate the
value and cost effectiveness of therapy to payors.7,15,16 The
NEI VFQ-25 has been documented to be responsive to clinical
progression of AMD4,17 and has been used to evaluate change
in VRQoL in many clinical trials of treatments for AMD.18e21
Clinical research using the NEI VFQ-25 has shown that
treatment improves VRQoL. Studies of submacular surgery5
and antievascular endothelial growth factor (VEGF)
therapy20e22 have shown statistically and clinically signicant
improvement in VRQoL. Improvement in both VA and QoL
reported to date have been greatest with ranibizumab14,22 when
compared directly with verteporn photodynamic therapy14
and indirectly with pegaptanib21 and submacular surgery.5
Intravitreal aibercept for injection is a soluble decoy receptor fusion protein that binds with higher afnity to VEGF
than other anti-VEGF agents and also binds to placental
growth factor.23,24 Intravitreal aibercept has been approved
for the treatment of AMD in the United States,25 Europe,26
Japan,27 and Australia26 at a recommended dosing interval of
every 2 months (a monthly dosing interval is also approved in
the United States)27 after initiation with 3 monthly injections.
In the pivotal clinical trials VEGF Trap-Eye: Investigation of
Efcacy and Safety in Wet AMD (VIEW) 1 and 2, efcacy as
measured by VA was demonstrated to be noninferior to
ranibizumab 0.5 mg administered monthly.20 Morphologic
outcomes also were similar between treatments. The VRQoL
as measured by the NEI VFQ-25 was a key secondary
outcome in the VIEW studies. Change from baseline to week
52 in NEI VFQ-25 composite score was reported, showing
similarity across all 3 intravitreal aibercept dosing regimens
and ranibizumab 0.5 mg every 4 weeks. Main outcomes of the
VIEW studies at 52 weeks have been published.20 In brief,
outcomes demonstrated non-inferiority of intravitreal aibercept 2.0 mg every 8 weeks (and every 4 weeks) to ranibizumab 0.5 mg every 4 weeks (0.5q4) in VIEW 1 and 2 on the
primary outcome (proportion with <15-letter loss), and no
difference for the main secondary outcomes (mean change
from baseline in VA and anatomic measures).20
Given the importance of VRQoL to patients and clinicians, as well as to regulatory authorities and payors, we
present here a full analysis of the NEI VFQ-25 data from the
VIEW studies for year 1 for the worldwide intravitreal
aibercept-approved dosing regimen of 2.0 mg every 2
months (2q8; after initiation with 3 monthly injections),
including analysis of outcome data across all subscales and
comparison of this intravitreal aibercept dosing regimen
with ranibizumab therapy.

Methods
Study Design
VIEW 1 (clinicaltrials.gov identier, NCT00509795) and VIEW 2
(clinicaltrials.gov identier, NCT00637377) were comparably

572

designed prospective, multicenter, double-masked, activecontrolled, parallel-group, randomized clinical trials. VIEW 1 was
conducted in 154 centers in the United States and Canada, and
VIEW 2 was conducted in 172 sites in Europe, the Middle East,
Asia-Pacic region, and Latin America between 2007 and 2010.
The trials were approved by national health authorities and the
respective ethics committees and institutional review boards. All
patients provided signed consent for participation, and all United
States sites were in compliance with the Health Insurance Portability and Accountability Act. A detailed description of each trials
methodology has been published previously.20
Patients were randomized in a 1:1:1:1 ratio to 1 of 3 intravitreal
aibercept dosing regimens (0.5q4 or 2.0 mg every 4 weeks; 2.0 mg
every 8 weeks [2q8]) or to ranibizumab 0.5q4; all treatment groups
received injections of the assigned drug at weeks 0, 4, and 8 (sham
injections were given to the intravitreal aibercept 2q8 group at each
interim visit after the initial 3 injections to maintain masking). The
study eye in those with bilateral wet AMD was the worse-seeing
eye. If VA was similar in both eyes, additional criteria were specied to determine the study eye. The fellow eye could be treated
outside of the study according to the prevailing standard of care.
The NEI VFQ-25 assessments were conducted by trained interviewers who were masked to treatment arm assignment. The
NEI VFQ-25 was administered at the following time points:
screening (visit 1) and weeks 12, 24, 36, and 52. In VIEW 1, the
instrument was administered by telephone; in VIEW 2, it was
administered face to face. The NEI VFQ-25 scores were calculated
according to standard scoring protocols published by the instruments developers.28 In both studies, mean change from baseline to week 52 in composite score was a secondary efcacy
outcome and mean change from baseline to week 52 in subscale
scores was an exploratory efcacy outcome measure.

Statistical Analysis
All planned analyses were performed in the full analysis set population (subjects who received any study medication and had at
least 1 postbaseline assessment) separately for each study (protocol
specied). One additional analysis was performed in the pooled
data set that compared mean change from baseline with week 52 in
composite and subscale scores, in subgroups of patients, based on
the status of the heterolateral eye.
Missing data were imputed using last observation carried forward; descriptive statistics reported here are mean and standard
deviation. Sensitivity analyses using observed cases were performed to assess the robustness of the analysis.

Results
Key baseline demographic and disease characteristics of VIEW 1
and 2 patient populations are presented in Table 1. There were no
signicant differences between treatment groups within each study.
Small differences in baseline disease severity between studies were
observed. In VIEW 2, best-corrected VA in the treated eye was
lower in the intravitreal aibercept 2q8 arm and central retinal
thickness and choroidal neovascularization lesion size were greater
in both the intravitreal aibercept 2q8 and ranibizumab 0.5q4 arms
than in VIEW 1.
Baseline NEI VFQ-25 overall and subscale scores are displayed
by study in Table 2. Differences between ranibizumab 0.5q4 and
intravitreal aibercept 2q8 were minimal in both studies; just 3 of
13 comparisons in VIEW 1 and 0 of 13 comparisons in VIEW 2
were statistically signicant (P < 0.05). Subscales with highest
scores at baseline in both studies (top 4) included social functioning, color vision, ocular pain, and peripheral vision. Subscales

Yuzawa et al

NEI VFQ-25 Subscale Results from VIEW Trials

Table 1. Patient Demographics and Baseline Characteristics

VEGF Trap-Eye: Investigation of Efcacy
and Safety in Wet AMD 1

VEGF Trap-Eye: Investigation of

Efcacy and Safety in Wet AMD 2

Intravitreal Aibercept 2.0 mg

Every 8 Weeks

Ranibizumab 0.5 mg
Every 4 Weeks

Intravitreal Aibercept 2.0 mg

Every 8 Weeks

Ranibizumab 0.5 mg
Every 4 Weeks

301
77.98.4

304
78.27.6

306
73.88.6

291
73.09.0

287 (95.3)
4 (1.3)
10 (3.3)

296 (97.4)
0 (0.0)
8 (2.6)

217 (70.9)
69 (22.5)
20 (6.5)

213 (73.2)
60 (20.6)
18 (6.2)

178 (59.1)
123 (40.9)
55.712.8
6.575.1
324.4111.2

172 (56.6)
132 (43.4)
54.013.4
6.535.2
315.3108.3

175 (57.2)
131 (42.8)
51.613.9
7.755.5
342.6124.0

169 (58.1)
122 (41.9)
53.813.5
7.595.3
325.9110.9

No. (FAS)
Age (yrs)
Race, no. (%)
White
Asian
Other
Gender, no. (%)
Women
Men
ETDRS BCVA in the study eye
CNV area (mm2)
CRT (mm)

AMD age-related macular degeneration; BCVA best-corrected visual acuity; CNV choroidal neovascularization; CRT central retinal thickness;
ETDRS Early Treatment Diabetic Retinopathy Study; FAS full analysis set; VEGF vascular endothelial growth factor.
Data are mean  standard deviation unless otherwise indicated.

with lowest scores at baseline (lowest 4) included driving, general

vision, mental health, and near activities (VIEW 1) or general
health (VIEW 2). General health was worse in VIEW 2 than in
VIEW 1 (baseline mean, 50 vs. 65), but scores otherwise were
generally similar across studies.
Mean change from baseline to 52 weeks in NEI VFQ-25 subscale scores is shown by study in Table 3. Changes were similar for
ranibizumab 0.5q4 and intravitreal aibercept 2q8 across all subscales, with differences between treatment groups on any subscale
never exceeding 4 points in favor of either treatment. The largest
improvements were observed in the subscales mental health and
general vision for both treatments in both studies.

Mean change in NEI VFQ-25 subscale scores by visit for VIEW 1

and VIEW 2 is shown in Figure 1. Data are presented only for the 6
subscales demonstrating clinically meaningful change (general
vision, near activities, distance activities, mental health, role difculties, and dependency), which has been dened in the literature as a
4- to 6-point change (or more) in the NEI VFQ-25 composite score.22
These data show that the time course of change also was highly similar
between treatments; most improvement was attained by 6 months,
whereas limited further improvement was seen for up to 52 weeks.
Mean change in NEI VFQ-25 composite score stratied by clinical
response (dened as change in VA from baseline to week 52: progression, loss of >5 Early Treatment Diabetic Retinopathy Study

Table 2. Baseline 25-Item National Eye Institute Visual Function Questionnaire Composite and Subscale Scores
VEGF Trap-Eye: Investigation of Efcacy
and Safety in Wet AMD 1

No. (FAS with baseline NEI VFQ-25 score)

Composite score
Subscale score
General vision
Near activities
Distance activities
Mental health
Social functioning
Dependency
Role difculties
Driving
Color vision
Peripheral vision
Ocular pain
General health

VEGF Trap-Eye: Investigation of Efcacy

and Safety in Wet AMD 2

Intravitreal Aibercept 2.0 mg

Every 8 Weeks

Ranibizumab 0.5 mg
Every 4 Weeks

Intravitreal Aibercept 2.0 mg

Every 8 Weeks

Ranibizumab 0.5 mg
Every 4 Weeks

293
69.616.8

303
71.817.2

306
71.319.1

291
72.919.1

59.417.2
61.321.4
65.322.3
57.525.6
82.621.8
73.324.9
64.825.0
55.830.3
85.122.2
76.123.5
82.418.1
65.222.5

60.017.4
62.822.6
69.122.7*
62.025.4*
85.019.5
75.327.0
66.327.8
58.030.5
88.719.0*
77.323.3
84.518.2
64.221.6

56.116.5
60.926.4
70.625.7
60.527.6
83.122.8
76.728.8
60.331.5
55.436.3
89.720.2
79.125.8
84.020.0
49.521.2

57.017.0
63.725.5
70.827.1
62.626.5
85.422.1
80.028.8
64.131.2
57.735.3
90.119.8
81.024.2
82.421.0
50.221.1

AMD age-related macular degeneration; FAS full analysis set; NEI VFQ-25 25-item National Eye Institute Visual Function Questionnaire;
VEGF vascular endothelial growth factor.
Data are mean  standard deviation.
*P<0.05 for comparison of ranibizumab 0.5 mg every 4 weeks with intravitreal aibercept 2.0 mg every 8 weeks.

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Ophthalmology Volume 122, Number 3, March 2015

Table 3. Mean Change from Baseline to Week 52
VEGF Trap-Eye: Investigation of Efcacy
and Safety in Wet AMD 1
25-Item National Eye Institute Visual
Function Questionnaire Subscale
No. (range)*
General visiony
Near activitiesy
Distance activitiesy
Mental healthy
Role difcultiesy
Dependencyy
Social functioning
Driving*
Color vision
Ocular pain
Peripheral vision
General health

VEGF Trap-Eye: Investigation of

Efcacy and Safety in Wet AMD 2

Intravitreal Aibercept 2.0 mg

Every 8 Weeks

Ranibizumab 0.5 mg
Every 4 Weeks

Intravitreal Aibercept 2.0 mg

Every 8 Weeks

Ranibizumab 0.5 mg
Every 4 Weeks

288e292
10.119.0
6.122.2
6.221.8
10.124.1
7.126.7
3.422.9
2.622.1
2.224.4
0.622.3
1.220.0
4.423.9
4.922.1

296e300
9.518.8
7.223.1
2.523.1
9.821.8
5.829.3
5.422.6
3.020.0
0.122.0
1.919.1
1.317.7
5.525.3
3.620.4

297e301
9.117.0
7.021.3
4.321.8
10.422.0
7.824.1
4.125.2
1.519.9
1.024.0
0.421.2
3.119.4
2.525.7
1.519.0

286e287
9.518.1
7.221.1
7.621.6
11.223.9
6.929.9
4.525.5
4.920.0
0.123.2
3.118.2
5.122.7
3.126.2
0.820.6

AMD age-related macular degeneration; VEGF vascular endothelial growth factor.

*For all subscales except driving; for driving, n 229, n 254, n 121, and n 122, respectively.
y
Clinically meaningful improvement.

[ETDRS] letters; maintenance, change of 5 ETDRS letters;

improvement, gain >5 ETDRS letters) is displayed by VIEW study in
Figure 2. Only the subgroup with clinical improvement had a sizable
gain in NEI VFQ-25 score. In this subgroup, the intravitreal aibercept 2q8 and ranibizumab 0.5q4 groups in VIEW 1 demonstrated
increases of 7.2 and 8.5 points, respectively, and 7.1 and 7.0 points,
respectively, in VIEW 2. In contrast, in the subgroup with clinical
progression, there was a small decrease in NEI VFQ-25 composite
scores in both treatment arms in both studies (Fig 2). Results were
intermediate in the clinical maintenance subgroup. Results of analyses
for the other 2 intravitreal aibercept dosing regimens (2q4 and 0.5q4)
were qualitatively similar to those presented here (data not shown).
The study population was divided according to the status of the
heterolateral eye into 3 subgroups: heterolateral eye without active
disease (group 1), heterolateral eye with macular scar (group 2),
and heterolateral eye with active disease (group 3). Per protocol, the
worse-seeing eye was to be selected as the study eye. Therefore, in
general in group 1 and group 3, the heterolateral eye was better
seeing. The baseline NEI VFQ-25 composite and subscale scores
and the mean change from baseline to week 52 are shown in
Table 4. The groups differed on nearly all baseline scores
(P <0.001), group 1 having the highest scores and group 2 the
lowest scores. The mean changes in scores at week 52 were
consistently greater in group 2 than in group 1 or group 3. Notably,
we observed approximately 2-fold mean improvement in distance
activities, 3-fold mean improvement in peripheral vision, and 4fold mean improvement in social functioning in group 2 compared
with group 1 or group 3. Overall, those with heterolateral macular
scar (group 2) showed a more than 1.5-fold mean improvement on
the NEI VFQ-25 composite score than those with no active disease
in the heterolateral eye (group 1) or those with bilateral disease
(group 3). Nevertheless, the absolute values at week 52 were uniformly higher for group 2 than the comparator groups (Table 4).

Discussion
The major nding of this analysis of NEI VFQ-25 subscale
data from the VIEW 1 and 2 studies is that there was virtually

574

no difference between the group receiving intravitreal aibercept every other month (after 3 initial monthly injections)
and the group receiving continuous monthly ranibizumab
treatment. Neither the magnitude of improvement at week 52
nor the timing of changes was different, despite approximately 5 fewer doses of intravitreal aibercept having been
administered. The VRQoL improvement was most evident
for both treatments for the following 6 subscales: mental
health, general vision, near activities, role difculties, distance activities, and dependency. For all of these subscales,
the degree of improvement was clinically meaningful, using
the generally accepted threshold of 4 to 6 points as an indicator of clinically meaningful improvement.22 We also
showed that the subset of patients with a good clinical
response, as dened by improvement in VA of more than 5
ETDRS letters, showed the greatest improvement in the
composite NEI VFQ-25 score.
These results extend previously published ndings. To
the best of our knowledge, this is the rst published report
that presents NEI VFQ-25 subscale data directly comparing
change in NEI VFQ-25 scores between different anti-VEGF
therapies for AMD. As has already been shown for clinical
and morphologic outcomes in the treatment of AMD,20
intravitreal aibercept and ranibizumab seem to provide
equivalent benet in VRQoL. Second, the results in the
ranibizumab 0.5q4 arm of the VIEW studies provide
convincing replication of NEI VFQ-25 subscale data from
the Minimally Classic/Occult Trial of the Anti-VEGF
Antibody Ranibizumab in the Treatment of Neovascular
Age-Related Macular Degeneration (MARINA) and AntiVEGF Antibody for the Treatment of Predominantly Classic
Choroidal Neovascularization in Age-Related Macular
Degeneration (ANCHOR) studies of ranibizumab in the
treatment of AMD,14,19,22 including the fact that subscales
showing the most improvement in the present analysis are
the same as those that did so in the prior analyses (mental

Yuzawa et al

NEI VFQ-25 Subscale Results from VIEW Trials

IVT-AFL 2q8

VIEW 1

12

10

10

2
Week 52

0
Baseline

10

2
Week 12

Week 24

Week 36

Week 52

0
Baseline

12

12

10

10

2
Week 12

Week 24

Week 36

Week 52

0
Baseline

12

12

10

10

2
Week 12

Week 24

Week 36

Week 52

0
Baseline

12

12

10

10

0
Baseline

Week 36

12

0
Baseline

Week 24

10

0
Baseline

Week 12

12

0
Baseline

VIEW 2

12

0
Baseline

Ranibizumab 0.5q4

Week 12

Week 24

Week 36

Week 52

0
Baseline

12

12

10

10

0
Baseline

Week 12

Week 24

Week 36

Week 52

0
Baseline

Week 12

Week 24

Week 36

Week 52

Week 12

Week 24

Week 36

Week 52

Week 12

Week 24

Week 36

Week 52

Week 12

Week 24

Week 36

Week 52

Week 12

Week 24

Week 36

Week 52

Week 12

Week 24

Week 36

Week 52

Figure 1. Graphs showing clinically meaningful change from baseline to week 52 in the 25-item National Eye Institute Visual Function Questionnaire (NEI
VFQ-25) subscale scores: (A) mental health, (B) general vision, (C) role difculties, (D) near activities, (E) distance activities, and (F) dependency. IVT-AFL
2q8 intravitreal aibercept 2.0 mg every 8 weeks; VIEW VEGF Trap-Eye: Investigation of Efcacy and Safety in Wet AMD; 0.5q4 0.5 mg every 4 weeks.

health and general vision). In addition, the baseline demographics, disease characteristics, and NEI VFQ-25
subscale scores of the ranibizumab-treated patients in the
VIEW studies were similar to those reported in the prior
studies.14,19,22 These observations provide reassurance that

the ranibizumab arms in the VIEW trials comprised patient

populations comparable with those studied in MARINA and
ANCHOR and that they performed as expected. Finally, the
study completion rate in all study arms was more than
98%, almost entirely eliminating potential for bias from

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Ophthalmology Volume 122, Number 3, March 2015

Ranibizumab 0.5q4
IVT-AFL 2q8

NEI VFQ-25 Mean Composite Score*

10
8
6
4
2
0
2
4

Loss of >5
EDTRS letters

Change of

Gain of >5
EDTRS letters

EDTRS letters
R 0.5q4
IVT-AFL 2q8

n=32
n=34

n=63
n=73

n=192
n=192

*SD range 12.3 to 16.6, too large for display

B
NEI VFQ-25 Mean Composite Score*

8
7
6
5
4
3
2
1
0
1
2
3

Loss of >5
EDTRS letters

Change of

Gain of >5
EDTRS letters

EDTRS letters
R 0.5q4
IVT-AFL 2q8

n=40
n=38

n=70
n=72

n=190
n=182

*SD range 12.1 to 16.5, too large for display

Figure 2. Bar graphs showing change from baseline to week 52 in the 25item National Eye Institute Visual Function Questionnaire (NEI VFQ-25)
composite scores by visual acuity responder status: (A) VEGF Trap-Eye:
Investigation of Efcacy and Safety in Wet AMD (VIEW) 1, (B) VIEW 2.
ETDRS Early Treatment Diabetic Retinopathy Study; IVT-AFL 2q8
intravitreal aibercept 2.0 mg every 8 weeks; NEI VFQ-25 National Eye
Institute Visual Function Questionnaire; R ranibizumab; SD standard
deviation.

imputation of missing data using the last observation carried

forward method; consequently, results of the sensitivity
analyses (observed cases) were almost identical.
We did 1 additional analysis to investigate whether these
data support the hypothesis that improvement in visual
function is greater when the better-seeing eye is treated, as
has been documented in prior studies.18,29 Indeed, we found
that patients with macular scar in the heterolateral (fellow)
eye, in which the study eye was the better-seeing eye (group
2), showed consistently greater improvement on all subscales
and the composite score of the NEI VFQ-25 compared with
the subgroup with unilateral active disease (group 1) and the

576

subgroup with bilateral active disease (group 3), in which the

study eye was the worse-seeing eye. This outcome supports
the hypothesis, and suggests that the VRQoL benet of
treatment for patients in groups 1 or 3 may have been greater
had the better-seeing eye been selected for treatment.
It is important to translate what these improvements in
NEI VFQ-25 subscale scores actually mean in terms of the
daily life of patients.16 With respect to mental health, it
suggests the potential for less worrying, less dysphoria, and a
decreased risk of depression. Improvements in near activities
refer to gains in reading, writing, and the ability to engage in
arts and crafts; improvements in distance activities may
indicate better mobility, decreased falls, and the ability to
venture outside the home.9,16 Taken together, these improvements in visual function also may result in the reduced
need of informal caregiving, professional in-home help, or
medical care transportation, as well as improved productivity
in paid work or volunteer activities.8,11 Intravitreal aibercept 2q8 may be expected to provide these potential
benets while requiring fewer visits, fewer injections, and
reduced monitoring compared with ranibizumab.
Although patients in the intravitreal aibercept 2q8 group
received active treatment every other month after the 3
monthly loading doses, they still had the same number of
visits, the same intensity of monitoring, and the same number
of injections as those receiving ranibizumab because of the
need in a randomized clinical trial to preserve masking of the
study treatment. Therefore, the treatment burden was not
actually lower for intravitreal aibercept- versus ranibizumab-treated patients in the VIEW studies. We hypothesize
that patients treated with intravitreal aibercept in routine
clinical settings, according to the approved dosing and
monitoring schedule, may experience an even greater
improvement in QoL than that observed in the VIEW studies.
Specically, this may be reected in a more robust
improvement in subscales associated with reduced treatment
burden, such as the dependency subscale, than what was
observed in the VIEW studies, in which modest (4e5 points)
and similar improvement was observed in both the intravitreal aibercept and ranibizumab treatment groups.
This analysis has several limitations. Because the VIEW
studies were active controlled but not placebo controlled, there
were no placebo data with which to compare the active treatments. However, data from prior studies have shown a substantial decline in NEI VFQ-25 composite and subscale scores
over 1 year in placebo-treated populations similar to those
studied in VIEW 1 and 2, providing very strong historical
evidence that there is minimal placebo effect.14,19,21 Also,
because the treatment regimens in both VIEW studies changed
after week 52, the analysis is limited to 1 year. No inferential
statistical testing was performed because the analyses were
post hoc and the studies were not powered for these analyses,
and therefore all testing would be of an exploratory nature. In
addition, the magnitude of the differences between study arms
for the NEI VFQ-25 composite and all subscale measures was
less than 4 points, indicating lack of clinical signicance.
In conclusion, this analysis of VRQoL outcomes in the
VIEW 1 and 2 studies showed similar results in NEI VFQ-25
scores across all subscales over 52 weeks of treatment with
intravitreal aibercept 2q8 and ranibizumab 0.5q4. Benet

Yuzawa et al

NEI VFQ-25 Subscale Results from VIEW Trials

Table 4. Mean Change From Baseline in Selected 25-Item National Eye Institute Visual Function Questionnaire Scores at Week 52
(Last Observation Carried Forward)*
25-Item National
Group 1: Unilateral Disease,
Eye Institute
Fellow Eye Better Seeing (n [ 961)
Visual Function
Questionnaire
Week 52
Change
Subscale
No.y Baseline
Composite score
General vision
Near activities
Distance activities
Mental health
Role difculties
Dependency
Social functioning
Peripheral vision

950
944
950
945
945
944
944
940
939

72.717.9
59.117.1
64.024.0
70.524.6
62.425.6
66.228.3
78.126.8
85.220.7
79.124.1

77.917.6 5.114.2
68.716.1 9.517.8
71.323.9 7.321.4
75.423.5 4.821.9
72.724.3 10.222.5
73.227.0 6.826.7
82.625.1 4.322.9
87.819.7 2.619.8
82.822.5 3.624.5

Group 2: Unilateral Disease,

Fellow Eye with Macular Scar (n [ 41)

Group 3: Bilateral
Disease (n [ 200)

No.y

Baseline

Week 52

Change

No.y

Baseline

41
41
41
40
41
41
41
41
41

58.817.0
49.316.2
42.422.8
51.428.8
49.226.5
41.528.4
57.732.0
70.428.6
65.828.7

67.219.5
62.418.0
51.024.7
65.028.5
61.728.1
52.730.7
62.831.4
82.322.0
76.825.9

8.416.1
13.217.7
8.620.5
12.822.5
12.524.7
11.335.0
5.133.0
11.922.0
11.032.6

197
196
197
196
197
197
197
197
194

67.817.9
55.316.4
57.522.5
65.124.1
54.628.5
57.330.0
71.627.9
81.222.6
77.323.4

Week 52

Change

72.916.2 5.115.9
64.016.6 8.720.2
62.321.8 4.724.5
70.223.1 5.022.9
65.325.3 10.724.5
63.628.7 6.429.9
76.225.8 4.527.3
84.120.9 2.923.4
81.122.3 3.927.4

*Differences in baseline values were statistically signicant for the composite score and all subscale scores shown in this table.
y
Number of patients with baseline and week 52 values, equal to the number of patients included in calculation of change.

was similar in both treatment groups and was comparable with

that observed for ranibizumab 0.5q4 in prior clinical trials.
These data extend and strengthen the evidence demonstrating
that intravitreal aibercept 2q8 provides equivalent benet to
ranibizumab 0.5q4 in the rst year of AMD treatment with 5
fewer active doses administered. In clinical settings, intravitreal aibercept 2q8 also would be associated with reduced
treatment burden compared with ranibizumab 0.5q4, possibly
providing additional benet in QoL.

10.

Acknowledgments. Medical writing support was provided

by Bill Kadish, MD, of PAREXEL, and was funded by Bayer
Pharma AG.

11.

8.

9.

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Footnotes and Financial Disclosures

Originally received: February 17, 2014.
Final revision: September 12, 2014.
Accepted: September 16, 2014.
Available online: November 6, 2014.

Manuscript no. 2014-278.

Department of Ophthalmology, Nihon University School of Medicine,

Surugadai, Kanda, Chiyoda-ku, Tokyo, Japan.

Bayer Pharma AG, Berlin, Germany.

Klinik und Poliklinik fr Augenheilkunde,

Hamburg-Eppendorf, Hamburg, Germany.

Universittsklinikum

Health Economics and Outcomes Research, Bayer Yakuhin Ltd, Umeda,

Kita-ku, Osaka, Japan.

Ophthalmic Consultants of Boston and Tufts University School of Medicine, Boston, Massachusetts.

Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Oxford Eye Hospital, University of Oxford, Oxford, United Kingdom.

Service dophtalmologie, Hpital PellegrindCHU de Bordeaux and

Universit Bordeaux Segalen, Bordeaux, France.

INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique,

Bordeaux, France.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): K.U.W-J.: Employee
e Bayer Pharma AG, Berlin, Germany.
C.N.: Employee e Bayer Pharma AG, Berlin, Germany.

O.Z.: Employee e Bayer Pharma AG, Berlin, Germany.

K.A.: Employee e Bayer Yakuhin Ltd, Umeda, Kita-ku, Osaka, Japan.
E.C.Y.W.: Employee e Bayer Yakuhin Ltd, Umeda, Kita-ku, Osaka,
Japan.
J.H.: Consultant e Acucela, Seattle, WA, Aerpio, Blue Ash, OH, Alimera,
Alpharetta, GA, Allergan, Irvine, CA, Bausch & Lomb, Bridgewater, NJ,
Bayer HealthCare, Whippany, NJ, Dutch Ophthalmic, Exeter, NH, Endo
Optiks, Little Silver, NJ, Forsight, Long Grove, IL, Genzyme, Cambridge, MA,
Heidelberg Engineering, Carlsbad, CA, Kala Pharmaceuticals, Waltham, MA,
Kanghong, Chengdu, China, LPath, San Diego, CA, Nicox, Fort Worth, TX,
Notal Vision, Tel Aviv, Israel, Ohr Pharmaceutical, New York, NY, Ophthotech, New York, NY, Oraya, Newark, CA, QLT, Vancouver, BC, Regeneron Pharmaceuticals, Rensselaer, NY, Roche, Nutley, NJ, Sequenom, San
Diego, CA, Thrombogenics, Leuven, Belgium, Vertex, Boston, MA, Xcovery,

578

West Palm Beach, FL; nancial support e Acucela, Seattle, Washington,

Aerpio, Blue Ash, OH, Alcon, Fort Worth, TX, Alimera, Alpharetta, GA,
Allergan, Irvine, CA, Bayer HealthCare, Whippany, NJ, Fovea, Cambridge,
MA (acquired by Sano), Genentech, South San Francisco, CA, Genzyme,
Cambridge, MA, GlaxoSmithKline, Middlesex, United Kingdom, LPath, San
Diego, CA, Neovista, San Francisco, CA, Notal Vision, Tel Aviv, Israel,
Novartis, Basel, Switzerland, Ohr Pharmaceutical, New York, NY, Ophthotech, New York, NY, Paloma, Nagoya, Aichi, Japan, Regeneron Pharmaceuticals, Tarrytown, NY; Travel support e Regeneron Pharmaceuticals,
Tarrytown, NY.
P.K.: Consultant e Alcon, Fort Worth, TX, Bayer HealthCare, Whippany,
NJ, Genentech, South San Francisco, CA, Novartis, Basel, Switzerland,
Regeneron Pharmaceuticals, Tarrytown, NY.
V.C.: Consultant e Allergan, Irvine, CA, Bayer HealthCare, Whippany,
NJ, Novartis, Basel, Switzerland, Quantel, New York, NY; Financial support e Allergan, Irvine, CA, Novartis International AG, Basel, Switzerland;
Lecturer e Bayer HealthCare, Whippany, NJ, Heidelberg, Ladenburg,
Germany, Novartis International AG, Basel, Switzerland; Travel support e
Bayer HealthCare, Whippany, NJ.
J.-F.K.: Consultant e Bayer HealthCare, Whippany, NJ, Carl Zeiss Meditec, Dublin, CA, Novartis International AG, Basel, Switzerland, Roche,
Nutley, NJ, Thea, Clermont-Ferrand, France; Advisory board e Alcon, Fort
Worth, TX, Allergan, Irvine, CA; Travel support e Regeneron Pharmaceuticals, Tarrytown, NY.
Supported by Bayer Pharma AG, Berlin, Germany. The sponsor or funding
organization participated in study design, data collection, data management,
data analysis, and approval of the manuscript.
Abbreviations and Acronyms:
AMD age-related macular degeneration; ETDRS Early Treatment
Diabetic Retinopathy; NEI VFQ-25 25-item National Eye Institute Visual
Function Questionnaire; QoL quality of life; VA visual acuity;
VEGF vascular endothelial growth factor; VIEW VEGF Trap-Eye:
Investigation of Efcacy and Safety in Wet AMD; VRQoL vision-related
quality of life; 0.5q4 0.5 mg every 4 weeks; 2q8 2.0 mg every 8 weeks.
Correspondence:
Mitsuko Yuzawa, MD, Department of Ophthalmology, Nihon University
School of Medicine, Surugadai Nihon University Hospital, 1-8-13, Kandasurugadai, Chiyoda-Ku, Tokyo, Japan 101-8309. E-mail: yuzawa.
mitsuko@nihon-u.ac.jp.