The RESTORE Study Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema

Article (PDF Available)inOphthalmology 118(4):615-25 · April 2011with115 Reads
DOI: 10.1016/j.ophtha.2011.01.031 · Source: PubMed
Abstract
To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME). A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study. We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME. Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits). Mean average change in BCVA from baseline to month 1 through 12 and safety. Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study. Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.
The RESTORE Study
Ranibizumab Monotherapy or Combined with Laser
versus Laser Monotherapy for Diabetic Macular Edema
Paul Mitchell, MD, PhD,
1
Francesco Bandello, MD, FEBO,
2
Ursula Schmidt-Erfurth, MD,
3
Gabriele E. Lang, MD,
4
Pascale Massin, MD, PhD,
5
Reinier O. Schlingemann, MD, PhD,
6
Florian Sutter, MD,
7
Christian Simader, MD,
8
Gabriela Burian, MD, MPH,
9
Ortrud Gerstner, MSc,
9
Andreas Weichselberger, PhD,
9
on behalf of the RESTORE study group*
Objective: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over
laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic
macular edema (DME).
Design: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
Participants: We included 345 patients aged 18 years, with type 1 or 2 diabetes mellitus and visual
impairment due to DME.
Methods: Patients were randomized to ranibizumab sham laser (n 116), ranibizumab laser (n 118),
or sham injections laser (n 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN);
laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
Main Outcome Measures: Mean average change in BCVA from baseline to month 1 through 12 and safety.
Results: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean
average change in BCVA letter score from baseline to month 1 through 12 (6.1 and 5.9 vs 0.8; both
P0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score 15 and BCVA
letter score level 73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibi-
zumab laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was
significantly reduced from baseline with ranibizumab (118.7
m) and ranibizumab laser (128.3
m) versus
laser (61.3
m; both P0.001). Health-related quality of life, assessed through National Eye Institute Visual
Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined
with laser (P0.05 for composite score and vision-related subscales) versus laser. Patients received 7 (mean)
ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pres-
sure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser
was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
Conclusions: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over
standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant
gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab
laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in
age-related macular degeneration.
Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
Ophthalmology 2011;118:615– 625
© 2011 by the American Academy of Ophthalmology.
*Group members listed online in Appendix (available at http:///aaojournal.org)
Diabetic macular edema (DME) is a leading cause of
visual impairment in patients with diabetic retinopa-
thy.
1–3
Focal/grid laser photocoagulation (hereafter re-
ferred to as laser), the current standard of care in DME,
is mostly associated with only vision stabilization. Some
recent trials, however, have demonstrated useful vision
gain with laser; for example, the Diabetic Retinopathy
Clinical Research Network (DRCR.net) study group re-
cently reported a 10-letter gain in 31% patients, whereas
19% of laser-treated patients exhibited progressive visual
loss (worsening by 2 lines after 2 years follow-up), at
a risk of developing scotomas.
4–7
Vascular endothelial growth factor (VEGF) levels are
elevated in the vitreous of eyes with diabetic retinopathy
making anti-VEGF treatment an attractive therapeutic mo-
dality in DME.
8
Recently, the DRCR.net study group re-
ported that ranibizumab 0.5 mg combined with either
prompt or deferred laser therapy was significantly more
effective than laser alone in improving vision in patients
with DME after 1 year of treatment (best-corrected visual
615© 2011 by the American Academy of Ophthalmology ISSN 0161-6420/11
Published by Elsevier Inc. Open access under CC BY-NC-ND license. doi:10.1016/j.ophtha.2011.01.031
Open access under CC BY-NC-ND license.
acuity [BCVA] letter score of 9 for both ranibizumab
groups vs 3 for laser; P0.001).
9
The RESOLVE study
(phase II randomized multicenter) demonstrated that ranibi-
zumab monotherapy was well-tolerated and significantly
more effective than sham treatment (with rescue laser) in
providing rapid and continuous improvements in BCVA
over 12 months (mean BCVA letter score change from
baseline to month 12, 10.3 for ranibizumab vs 1.4 for
sham; P0.0001).
10
Apart from Ranibizumab for Edema of the mAcula in
Diabetes study (READ-2),
11
there have been no other ran-
domized controlled trials that have assessed the efficacy and
safety of ranibizumab monotherapy compared with laser
monotherapy. Additionally, it is not yet established whether
ranibizumab monotherapy is superior or at least equivalent
to combined therapy. The 12-month, phase III, randomized,
double-masked, multicenter, laser-controlled RESTORE
study was designed to assess whether ranibizumab mono-
therapy or combined with laser was superior to laser alone
in patients with visual impairment due to DME. In addition,
RESTORE is the first study to assess the impact of ranibi-
zumab treatment on health-related quality of life (HRQoL)
outcomes in patients with DME.
Materials and Methods
Study Design
The RESTORE study was a 12-month, double-masked, multi-
center, laser-controlled, phase III study where 345 eligible patients
from 73 centers (10 European countries, Turkey, Canada, and
Australia) were randomized 1:1:1 to 1 of the 3 treatment arms:
Intravitreal ranibizumab (0.5 mg) injection sham laser, adjunc-
tive administration of intravitreal ranibizumab (0.5 mg) injec-
tion active laser, or laser treatment sham injections for 12
months (for details of randomization and masking, see Appendix
1, available online at http://aaojournal.org). One eye was selected
and treated as the study eye. If both eyes were eligible, the eye
with the worse visual acuity (VA; assessed at visit 1) was selected
for treatment, unless, based on medical reasons, the investigator
deemed the other eye more appropriate to receive study treatment.
The study was conducted in accordance with the Declaration of
Helsinki and International Conference on Harmonization Good
Clinical Practice guidelines. Approval was obtained from the eth-
ics committee or institutional review board at each contributing
center. Patients provided written informed consent before entering
the study. The study is registered with clinicaltrials.gov as
NCT00687804.
Patients. The study population consisted of 345 male and
female patients 18 years of age with either type 1 or 2 diabetes
mellitus (as per American Diabetes Association or World Health
Organization guidelines), glycosylated hemoglobin (HbA1c)
10%, and visual impairment due to DME. The key inclusion
criteria were (1) stable medication for the management of diabetes
within 3 months before randomization and expected to remain
stable during the study; (2) visual impairment due to focal or
diffuse DME (definition in Table 1) in at least 1 eye that was
eligible for laser treatment in the opinion of the investigator; (3)
BCVA letter score between 78 and 39, both inclusive, based on
Early Treatment Diabetic Retinopathy Study (ETDRS)-like VA
testing charts administered at a starting distance of 4 meters
(approximate Snellen equivalent 20/32–20/160); and (4) decreased
vision due to DME and not other causes, in the investigator’s
opinion (at visit 1). The key exclusion criteria were (1) concomi-
tant conditions in the study eye that could prevent the improve-
ment in VA on the study treatment in the investigator’s opinion;
(2) active intraocular inflammation or infection in either eye; (3)
uncontrolled glaucoma in either eye (e.g., intraocular pressure
[IOP] 24 mmHg on medication, or from the investigator’s
Table 1. Key Baseline Demographic and Disease Characteristics (Randomized Set)
Variable
Ranibizumab 0.5 mg
(n 116)
Ranibizumab 0.5 mg Laser
(n 118) Laser (n 111)
Mean age SD (years) 62.99.29 64.08.15 63.58.81
Gender, n (% )
Men 73 (62.9) 70 (59.3) 58 (52.3)
Women 43 (37.1) 48 (40.7) 53 (47.7)
Diabetes type, n (%)
Type I 13 (11.2) 15 (12.7) 13 (11.7)
Type II 103 (88.8) 102 (86.4) 97 (87.4)
Not stated 0 1 (0.8) 1 (0.9)
Mean time since first diagnosis of diabetes SD (years) 15.239.91 14.629.84 12.939.02
Mean time since first diagnosis of DME SD (years) 1.801.98 1.993.14 1.581.96
DME type, n (%)*
Focal 64 (55.2) 68 (57.6) 53 (47.7)
Diffuse 45 (38.8) 46 (39.0) 52 (46.8)
Missing 7 (6.0) 4 (3.4) 6 (5.4)
Mean VA SD (letter score) 64.810.11 63.49.99 62.411.11
Patients with VA letter score 73, n (%) 23 (19.8) 19 (16.1) 17 (15.3)
Mean CRT SD (
m) 426.6118.01 416.4119.91 412.4123.95
CRT central retinal thickness; DME diabetic macular edema; SD standard deviation; VA visual acuity.
*Focal DME: More than 67% of leakage originated from leaking microaneurysms (MAs) in the whole edema area or 30%–67% leakage from MAs in the
whole edema area, but 67% of the leakage originated from MAs in the central subfield.
Diffuse DME: Less than 33% of leakage originated from leaking MAs the rest from diffuse leaking capillaries in the whole edema area or 30%–67% leakage
comes from MAs, but 33% of the leakage originated from MAs in the central subfield.
Ophthalmology Volume 118, Number 4, April 2011
616
judgment); (4) panretinal laser photocoagulation (within 6 months)
or focal/grid laser photocoagulation (within 3 months) before
study entry; (5) treatment with antiangiogenic drugs in the study
eye within 3 months before randomization; (6) history of stroke;
and (7) systolic blood pressure (BP) 160 mmHg or diastolic BP
100 mmHg, untreated hypertension, or change in antihyperten-
sive treatment within 3 months preceding baseline.
Study Objectives. The primary objective of this study was to
demonstrate superiority of ranibizumab 0.5 mg as monotherapy or
combined with laser therapy over laser alone (the current standard
of care) with respect to mean average change in BCVA from
baseline over 12 months. Secondary objectives were to evaluate
(1) if ranibizumab 0.5 mg as monotherapy or adjunctive to laser
was superior to laser alone in the proportion of patients with VA
improvement and with BCVA letter score 73 (20/40 Snellen
equivalent) at month 12; (2) the time course of mean change in
BCVA letter score and central retinal (subfield) thickness (CRT);
(3) patient-reported outcomes relative to those associated with
laser treatment; and (4) the safety of intravitreal injections of
ranibizumab 0.5 mg, as monotherapy or adjunctive to laser therapy
relative to laser treatment.
Efficacy and Safety Assessments
Best-Corrected Visual Acuity. We assessed BCVA at every
study visit using ETDRS charts at a starting distance of 4 meters.
The primary efficacy end point was the mean average change in
BCVA letter score from baseline to month 1 through month 12.
Secondary efficacy end points included the mean BCVA letter
score change from baseline to month 12 and proportion of patients
who gained 10 and 15 letters in BCVA and patients with
BCVA letter score 73 at month 12. Mean average change in
BCVA from baseline to month 1 through month 12 was chosen as
the primary efficacy end point as it accounts for both interpatient
and intramonth variability in BCVA and thus gives a more robust
estimate of the VA gained by patients over time compared with the
mean change of BCVA from baseline to study end.
A subgroup analysis of the primary end point was performed on
the basis of demographic and baseline disease characteristics. The
key categories assessed were as follows: DME type (focal/diffuse),
BCVA letter score (60, 61–73, and 73), diabetes type (type
1/type 2), focal and/or grid laser pretreatment (yes/no), CRT
(300, 300 400, and 400
m), ETDRS retinopathy severity
score (10–35, 43 or 47, and 53– 85), macular ischemia (yes/no;
measured by the presence of capillary loss on fluorescein angiog-
raphy according to a modified ETDRS grading scale in the center
subfield of 1000
m diameter, where the capillary loss grades
“moderate,” “severe,” or “completely destroyed” were categorized
as “yes” ischemia, and the grades “none” or “mild” were classified
as “no” ischemia).
Optical Coherence Tomography. Optical coherence tomogra-
phy (OCT) was performed at every study visit using Stratus OCT
(Carl Zeiss, Meditec, Dublin, CA). The images were reviewed by
a central reading center to ensure a standardized evaluation. Ret-
inal thickness was determined using individual A-scans along with
each of 6 B-scans. End points included mean change in CRT
(defined from the central macular area 1000
m in diameter) over
time and the proportion of patients with CRT 275
m.
Stereoscopic Color Fundus Photography and Fluorescein
Angiography. Stereoscopic color fundus photography and fluo-
rescein angiography were performed at baseline, month 6, and
month 12. After pupil dilation and before fluorescein dye injection,
red-free and ETDRS 7-field color photographic images of the
retina of the study eye were taken. Anatomic end points included
the proportion of patients with resolution of leakage and cysts at
month 12 as assessed by the central reading center and the pro-
portion of patients with a 3-step change in the ETDRS severity
score from baseline to month 12 (exploratory end point).
Health-Related Quality of Life. We assessed HRQoL using
the visual-specific National Eye Institute Visual Function Ques-
tionnaire (NEI VFQ-25), as well as generic health assessment
utility tools EuroQoL (EQ-5D), and time trade off (TTO). All
questionnaires were scored by patients at baseline and month 12.
Additionally, the NEI VFQ-25 was scored at month 3 and the
EQ-5D was scored at months 3 and 6. End points included the
absolute change in scores, changes in scores over time, and dif-
ferences in scores between treatment groups.
Drug Exposure. The number of ranibizumab/sham injections
and active/sham laser treatments, and the mean duration of
treatment-free intervals (ranibizumab/sham injection, active/sham
laser) were evaluated over the 12-month assessment period for
each of the treatment arms.
Safety Assessments. Safety was assessed by the 12-month
incidence of adverse events (AEs) and serious AEs (SAEs), by
ophthalmic examinations and IOP measurements, and by changes
in vital signs and laboratory parameters over the 12-month assess-
ment period.
Treatment
Ranibizumab/Sham Treatment. Patients received 3 initial con-
secutive monthly injections of ranibizumab (months 0 –2; treat-
ment initiation phase), followed by further treatment according to
protocol-defined retreatment criteria between and including
months 3 and 11 (continuous/resumed treatment phase; Figure 1,
available online at http://aaojournal.org). Intravitreal ranibizumab
injections were performed by the investigators’ usual routines;
both pre- and postinjection topical antibiotics were used. Sham
ranibizumab injection involved imitation of an injection procedure
using an injection syringe without needle, by applying pressure
against the globe.
Retreatment Criteria During Continuous/Resumed Treat-
ment Phase. As of month 3, the protocol required that 1 injection
per month was to be continued if stable VA was not reached.
Treatment was suspended if either of the following criteria were
met: (1) if the investigator’s opinion was that no (further) BCVA
improvement was attributable to treatment with intravitreal injec-
tion at the last 2 consecutive visits, or (2) BCVA letter score 84
(approximate Snellen equivalent 20/20) was observed at the last 2
consecutive visits. After suspension, injections were resumed pro
re nata (PRN [as required]) if there was a decrease in BCVA due
to DME progression, confirmed by clinical evaluation and/or OCT
or other anatomic and clinical assessments, in the opinion of the
investigator. Patients were treated at monthly intervals until stable
VA was reached again. Thus, reinitiation of intravitreal injections
encompassed 2 successive monthly treatments.
Laser/Sham Laser Treatment. The first laser treatment (active
or sham depending on treatment group; the ranibizumab sham
laser group did not receive active laser treatment) was adminis-
tered on day 1. If required, the first laser administration could be
split into 2 sessions, 4 weeks apart. Retreatments were given in
accordance with ETDRS guidelines at intervals no shorter than 3
months from the previous treatment if deemed necessary by the
evaluating investigator. Patients receiving retreatment with active
or sham laser continued to be treated with monthly ranibizumab or
sham injections as long as the treatment criteria for intravitreal
injection were fulfilled. Decisions on retreatment with laser/sham
were independent of decisions to administer ranibizumab/sham
injections and vice versa. Sham laser was applied under the same
procedure used for laser treatment but without switching on the
laser beam, and by imitating depression of the laser pedal.
Mitchell et al Ranibizumab or Combined With Laser vs Laser for DME
617
Statistical Analysis
The primary analysis was performed on the full analysis set (FAS),
consisting of all patients who received 1 application of the study
treatment ([sham] injection and/or [sham] laser) and had 1
postbaseline assessment for BCVA. The primary end point was the
difference between the average BCVA letter score over all
monthly postbaseline assessments from month 1 to month 12 and
the baseline BCVA letter score ( average change from baseline).
The analysis of the primary end point used the last observation
carried forward approach for the imputation of missing data.
Sensitivity analyses of the primary end point were performed using
(1) an “as documented” approach in the FAS where the average
change from baseline in BCVA was calculated from observed
changes only, and (2) a per-protocol set with missing data being
handled in the same way as for the FAS.
A sample size of 105 randomized patients per treatment group
was considered to have 90% power to detect a 5-letter BCVA
score treatment difference in the mean average change in BCVA
compared with baseline from month 1 through month 12, assuming
a standard deviation (SD) of 10 BCVA letter score with a Bon-
ferroni adjusted 1-sided alpha level of 0.0125 for the 2 compari-
sons. Hypothesis testing of the superiority of ranibizumab mono
and/or ranibizumab/laser combination compared with laser was
done in parallel according to the Hochberg procedure controlling
the overall 1-sided alpha level at 0.025. The statistical hypothesis
testing of the average change from baseline in BCVA was based
on the stratified Cochran–Mantel–Haenszel test using the observed
values as scores and with stratifications according to DME type
(focal, diffuse) and baseline BCVA letter score (60, 61–73,
73). Two-sided 95% confidence intervals for the mean average
changes in BCVA and for the corresponding pair-wise difference
between treatments, were calculated using the least-square means
from an analysis of variance model with treatment, DME type, and
baseline BCVA category (see above) as factors.
The safety analysis was conducted on the safety set that com-
prised all patients who received 1 application of study treatment
and had 1 postbaseline safety assessment.
Results
Patient Disposition and Demographics
A total of 345 patients were randomized to receive ranibizumab
0.5 mg (n 116), ranibizumab 0.5 mg laser (n 118), or laser
(n 111). The efficacy analysis was performed on the FAS that
comprised 115 (ranibizumab 0.5 mg), 118 (ranibizumab laser),
and 110 (laser) patients (1 patient each from the ranibizumab and
laser arm were excluded because they had no postbaseline VA
data). The safety analysis was conducted on the safety set com-
prising 115 (ranibizumab), 120 (ranibizumab laser), and 110
(laser) patients. Three patients (1 in each treatment arm) received
active ranibizumab and active laser in the study eye at baseline
without consideration of the randomization, and all 3 of these were
analyzed under the ranibizumab laser arm for the safety set. The
patient disposition was comparable across the 3 treatment groups
(Fig 2, available online at http://aaojournal.org); 87.9% (ranibi-
zumab), 87.3% (ranibizumab laser), and 88.3% (laser) of the
patients completed the 12-month study period. There were 2 deaths
in each of the 3 treatment arms. Baseline demographics and
diabetes characteristics were comparable across the 3 treatment
arms (Table 1).
Efficacy
Best-Corrected Visual Acuity. The mean average change SD
in the BCVA letter score from baseline to month 1 through month
12 was significantly superior with ranibizumab (6.1 6.4;
P0.0001) and ranibizumab laser (5.9 7.9; P0.0001) than
with laser treatment (0.8 8.6), hence the primary end point was
achieved (Fig 3; Table 2). There was no difference detected
between the 2 ranibizumab treatment arms (P 0.61, Cochran–
Mantel–Haenszel test). Similar results were obtained (data not
shown) for the primary end point using the “as documented”
approach and the per protocol set. The last observation carried
forward calculation of the average level of BCVA letter score over
all monthly post-baseline assessments from month 1 to month 12
was based on 92.6% (ranibizumab), 92.9% (ranibizumab laser),
and 91.4% (laser) observed monthly BCVA assessments.
The mean change SD in BCVA letter score from baseline to
month 12 was 6.8 8.3 (P0.0001) in the ranibizumab arm, 6.4
11.8 (P 0.0004) in the ranibizumab laser arm, and 0.9 11.4
in the laser arm (Table 2). In the ranibizumab and ranibizumab
laser arms, a rapid and clinically relevant improvement in mean
BCVA was observed as of the first assessment posttreatment (at
month 1), which continued up to month 3 and was sustained at
the month 3 level until the last assessment time point at month
12. In the laser arm, mean BCVA stabilized around baseline
level and reached a 0.9 letter gain at month 12 (Fig 4A).
At month 12, 53.0% (vs 19.8% at baseline) of patients in the ranibi-
zumab arm and 44.9% (vs 16.1% at baseline) of patients in the ranibi-
zumab laser arm had a BCVA letter score 73 (20/40 Snellen
equivalent) compared with 23.6% (vs 15.3% at baseline) of patients in the
laser arm (estimated treatment difference vs laser, 29.4% [95% confi-
dence interval, 17.3– 41.5] for ranibizumab and 21.3% [95% confidence
interval, 9.3–33.3] for ranibizumab laser; Table 2; month 3 and 6 data
in Table 3, available online at http://aaojournal.org).
A significantly greater proportion of patients gained 5 BCVA
letters with ranibizumab (65.2% [ranibizumab] and 63.6% [ranibi-
zumab laser]; P0.0001) versus laser alone (33.6%). Similarly,
a significantly greater proportion of patients in either the ranibi-
zumab arm or the ranibizumab laser arm compared with the
laser arm gained a 10 BCVA letter score (37.4% and 43.2% vs
15.5%; P0.0001 for both) and a 15 BCVA letter score (22.6%
[P 0.0005] and 22.9% [P 0.0037] vs 8.2%; Table 2). Con-
Figure 3. Mean average change in best-corrected visual acuity (BCVA)
letter score from baseline to months 1 through 12 (primary end point).
SE standard error.
Ophthalmology Volume 118, Number 4, April 2011
618
versely, a lower proportion of patients lost 10 and 15 letters in
both the ranibizumab arms compared with the laser arm.
The mean average BCVA change from baseline to month 1 through
month 12 by some of the key subgroups including patients with/without
macular ischemia and those with focal/diffuse DME are presented in
Figure 5A–E (Fig 5C–E and Fig 6 [mean average change in BCVA],
available online at http://aaojournal.org). Each of the ranibizumab patient
subgroups did better on average than those on laser alone in terms of the
primary efficacy end point (all categories presented in Table 4 available
online at http://aaojournal.org).
Central Retinal Thickness. The mean CRT change from
baseline to month 12 decreased significantly for ranibizumab
(118.7
m; P 0.0002) and ranibizumab laser (128.3
m;
P0.0001) compared with laser (61.3
m; Fig 4B; Table 2).
At month 12, the proportion of patients with CRT 275
m
was significantly greater in the ranibizumab monotherapy arm
(49.1%; P 0.0408) and the ranibizumab laser arm (55.1%;
P 0.0075) compared with the laser arm (39.1%).
Colour Fundus Photography and Fluorescein
Angiography
At month 12, a significantly larger proportion of patients had
resolution of leakage in the ranibizumab (19.4%; P 0.0002) and
the ranibizumab laser (13.7%; P 0.0114) arms compared with
the laser arm (2.2%).
Health-Related Quality of Life
Visual Functioning Questionnaire. The mean changes in the NEI
VFQ-25 composite scores by treatment arms at months 3 and 12
are presented in Figure 7A (available at online http://aaojournal.
org). For both ranibizumab arms the composite scores increased
from month 3 to 12, whereas it decreased for the laser arm. At
month 12, there was a greater improvement in the composite
scores in the ranibizumab (5.0; P 0.014) and ranibizumab
laser (5.4; P 0.004) arms compared with the laser arm. At month
12, greater differences from baseline in NEI VFQ-25 subscale
scores (general vision, near activities, and distance activities) were
observed for ranibizumab and ranibizumab laser versus laser
alone (all P0.05; Fig 7B–D).
At month 12, excellent to good eyesight was reported by 46%
and 50% of the patients in the ranibizumab and ranibizumab
laser arm compared with 21% and 23% of the patients at baseline
(determined by the individual NEI VFQ-25 question pertaining to
patient’s perception of eyesight posttreatment). Excellent to good
vision was reported by only 24% patients with laser alone at month
12 compared with 22% of the patients at baseline.
Table 2. Best-Corrected Visual Acuity (BCVA) and Central Retinal Thickness (CRT) Outcome at Month 12 (Full Analysis Set,
Last Observation Carried Forward)
Ranibizumab 0.5 mg
(n 115)
Ranibizumab 0.5 mg
Laser (n 118)
Laser
(n 110)
Mean average change in BCVA letter score from baseline to
month 1–12 (primary end point)*
Mean SD 6.16.43 5.97.92 0.88.56
Median (range) 6.1 (10.9–25.2) 6.0 (26.7–27.6) 1.3 (37.8–26.8)
95% CI for mean** (4.9, 7.3) (4.4, 7.3) (0.8, 2.4)
Comparison verus laser
Difference in LS means (vs laser)
5.4 4.9
95% CI for difference
(3.5, 7.4) (2.8, 7.0)
P value
0.0001 0.0001
Proportion of patients with BCVA letter score 73 at month 12
n (%) 61 (53.0) 53 (44.9) 26 (23.6)
95% CI for percentage (43.5, 62.4) (35.7, 54.3) (16.1, 32.7)
Difference in percentage (vs laser) 29.4 21.3
95% CI for difference (17.3, 41.5) (9.3, 33.3)
P value
0.0001 0.0002
Categorized BCVA letter score outcome at month 12, n (%)
Gain of 5 75 (65.2) 75 (63.6) 37 (33.6)
Gain of 10
§
43 (37.4) 51 (43.2) 17 (15.5)
Loss of 10 4 (3.5) 5 (4.2) 14 (12.7)
Gain of 15
§
26 (22.6) 27 (22.9) 9 (8.2)
Loss of 15 1 (0.9) 4 (3.4) 9 (8.2)
Mean CRT change from baseline to month 12,
m
Mean SD 118.7115.07 128.3114.34 61.3132.29
Median (range) 103.0 (514–120) 116.5 (487–103) 60.0 (451–329)
95% CI for mean** (140.1, 97.3) (149.3, 107.3) (86.5, 36.1)
Comparison verus laser
Difference in LS means (vs laser)
61.5 70.6
95% CI for difference
(93.8, 29.2) (102.1, 39.0)
P value
0.0002 0.0001
ANOVA analysis of variance; CI confidence intervals; LS least square; SD standard deviation.
*Missing VA values imputed using last observation carried forward for 7.39% (ranibizumab), 7.06% (ranibizumab laser) and 8.56% (laser) patients.
**Two-sided 95% CI are based on the t-distribution.
Differences in LS means and the 2-sided 95% CIs are estimated from pair wise ANOVA (stratified) model.
P-values for treatment difference are from the 2-sided stratified Cochran-Mantel-Haenszel test using the row means score.
§
Specified gain, or BCVA letter score of 84.
Mitchell et al Ranibizumab or Combined With Laser vs Laser for DME
619
EQ-5D Scores. None of the differences from baseline in the
mean EQ-5D visual analog scores between the ranibizumab treat-
ment groups and laser alone were statistically significant at any
time point (Fig 8, available online at http://aaojournal.org).
TTO Scores. Patients were asked what proportion of their life
expectancy they would be willing to trade off to avoid their current vision
impaired health state, the resulting proportion representing the utility of
their current health state. An improvement of 0.13 in the utility score was
observed for ranibizumab monotherapy (baseline score 0.69), 0.032 for
ranibizumab laser (baseline score 0.73), and 0.023 for laser alone
(baseline score 0.73; Fig 9, available online at http://aaojournal.org); these
differences were not significant versus laser.
Figure 4. A, Mean change in best-corrected visual acuity (BCVA) letter score from baseline to month 12. B, Mean change in central retinal thickness
(CRT) from baseline to month 12. SE standard error.
Figure 5. Mean change in best-corrected visual acuity (BCVA) from baseline over 12 months by key baseline characteristics, (A) best-corrected visual
acuity and (B) central retinal thickness. BCVA best-corrected visual acuity; CRT central retinal thickness; SE standard error.
Ophthalmology Volume 118, Number 4, April 2011
620
Drug Exposure
Ranibizumab Injections. The mean number of ranibizumab/sham
injections received was similar for all treatment groups (6.8 –7.3
injections; Table 5). Between months 3 and 11, patients received
an average of 4.1 ranibizumab intravitreal injections in the ranibi-
zumab arm, 3.8 in the ranibizumab laser arm, and 4.5 sham
injections in the laser-treated arm.
Treatment-Free Interval for Ranibizumab or Sham Injec-
tions. A greater proportion of patients in the ranibizumab (85.2%)
and ranibizumab laser arms (81.7%) had their dose interrupted due
to disease improvement compared with the laser arm (68.2%), which
received sham injections only (Table 6 available online at http://
aaojournal.org). According to the protocol, the first possible time
point to stop injections (ranibizumab or sham) because of stability was
month 3. At month 3, more patients in the ranibizumab arms (32.2%
[ranibizumab] and 30.8% [ranibizumab laser]) than the laser arm
(20.9%) were not treated because of stability of VA.
After treatment interruption, the mean duration of the treatment-free
interval was approximately 2 months in both the ranibizumab and
the laser arms and approximately 2.5 months in the ranibizumab
laser arm (Table 7 available online at http://aaojournal.org). Fewer
patients received monthly treatment in the ranibizumab (8.0%) and
ranibizumab laser (7.6%) arms compared with the laser arm
(17.8%). The proportion of patients with a maximum treatment-
free interval of 3 months was similar across treatment arms
(57.9%– 61.9%).
Laser Treatment. The mean number of active/sham laser
treatments was similar for all treatment groups (1.7–2.1 adminis-
trations; Table 8 available online at http://aaojournal.org). From
month 3 to month 11, patients received 0.9 sham laser adminis-
trations in the ranibizumab arm, 0.7 active laser administrations in
the ranibizumab laser arm, and 1.1 in the laser-treated arm
(Table 8, available online at http://aaojournal.org). During this
period, 49.6% (ranibizumab) and 44.5% (ranibizumab laser) of
the patients received a sham/active laser treatment compared with
63.9% patients in the laser arm.
Safety
Serious Adverse Events. No ocular SAEs were reported in the
ranibizumab arm, whereas there were 2 cases each reported in the
ranibizumab laser (cataract) and laser only (cataract and macu-
lopathy) arms; none suspected to be related to study drug or
procedure (Table 9 available online at http://aaojournal.org). There
were no cases of endophthalmitis reported in any of the treatment
arms (7 ranibizumab or sham injections over the 12-month
treatment period). There were 23 (20%) patients with nonocular
SAEs in the ranibizumab arm, 17 (14.2%) in the ranibizumab
laser arm, and 15 (13.6%) in the laser arm (Table 9, available
online at http://aaojournal.org). The nonocular SAEs that were
suspected by the investigator to be related to a study drug or
procedure included intestinal obstruction (0.9%), hypoglycemia
(0.9%), pulmonary embolism (1.7%), dyspnea (0.9%), and arterial
thrombosis limb (0.9%) in the ranibizumab arm, coronary artery
occlusion (0.8%) in the ranibizumab laser arm. There were 6
deaths reported during the study (2 per treatment arm), none of
which were considered to be related to the study drug by the
investigator (Table 9, available online at http://aaojournal.org).
Adverse Events. The most frequently occurring ocular and
nonocular AEs are summarized in Table 10 (available online at
http://aaojournal.org). The most common ocular AE was eye pain
in all 3 treatment arms. Eye pain was also the most common ocular
AE suspected to be related to study drug (10 –12 cases) followed
by conjunctival hemorrhage, which was reported in the ranibi-
zumab arms only (8–9 cases). One patient each in the ranibizumab
arms experienced IOP increase, which was suspected to be related
to study drug or procedure (Table 11 available online at http://
aaojournal.org). Nasopharyngitis was the most common nonocular
AE observed in all 3 treatment arms. Some of the nonocular AEs
that were suspected to be related to study drug or procedure
included pulmonary embolism (n 2), limb arterial thrombosis
(n 1), arthralgia (n 1), and hypertension (n 1), all in the
ranibizumab arm, coronary artery occlusion (n 1) in the ranibi-
zumab laser arm, and hypertension (n 1) in the sham arm
(Table 11). Hypertension, the most common AE potentially related
to systemic VEGF inhibition, was comparable in all treatment
arms (Table 12). Arterial thromboembolic events were reported by
6 patients in the ranibizumab arm and 1 patient each in the
ranibizumab laser and laser arms. These included 1 case each of
myocardial infarction in the ranibizumab and ranibizumab laser
arm, and 1 case of cerebrovascular accident in the ranibizumab arm.
At the end of the study, there was no clinically significant differ-
ence between treatment arms for either mean BP or IOP, and the
values of clinical laboratory evaluations were similar among the
study arms (details in Appendix 3, available online at http://
aaojournal.org).
Discussion
The results from the RESTORE study demonstrate that
treatment with ranibizumab as monotherapy and combined
with laser treatment is superior to laser treatment in rapidly
improving and sustaining VA in patients with visual im-
Table 5. Number of Ranibizumab/Sham Injections Received (Safety Set)
Ranibizumab 0.5 mg
(n 115)
Ranibizumab 0.5 mg Laser
(n 120)
Laser
(n 110)
Total number of injections Ranibizumab Ranibizumab Sham
Total 800 816 802
Mean SD 7.02.81 6.82.95 7.33.22
Median (Range) 7.0 (1–12) 7.0 (2–12) 7.0 (1–12)
Distribution of injections, n (%)
1–3 16 (13.9) 23 (19.2) 19 (17.3)
4–6 37 (32.2) 34 (28.3) 32 (29.1)
7–9 40 (34.8) 35 (29.2) 22 (20.0)
10–12 22 (19.1) 28 (23.3) 37 (33.6)
SD standard deviation.
Mitchell et al Ranibizumab or Combined With Laser vs Laser for DME
621
pairment due to DME. There were no efficacy differences
detected between the ranibizumab and ranibizumab com-
bined with laser treatment arms. A greater proportion of
patients treated with ranibizumab gained 5, 10, and 15
BCVA letter scores from baseline compared with the laser-
treated patients.
Ranibizumab treatment consistently demonstrated signif-
icant and superior VA benefit in all subgroups of DME
patients, including patients with focal or diffuse DME and
those with or without prior laser as compared with laser
treatment alone. The functional improvements in BCVA
were accompanied by significant improvements in anatomic
end points, CRT on OCT, and resolution of leakage on
fluorescein angiography. At month 12, 49.1% (ranibi-
zumab), 55.1% (ranibizumab laser), and 39.1% (laser)
patients had CRT 275
m, whereas 50.9%, 44.9%, and
60.9%, respectively, had CRT 275
m.
The efficacy results with ranibizumab treatment from the
RESTORE study are consistent with the recently published
DRCR.net and RESOLVE studies.
9,10
Results from the
DRCR.net study showed that ranibizumab used in conjunc-
tion with laser therapy (prompt or deferred) was signifi-
cantly more effective than laser alone in improving VA in
patients with DME after 1 year of treatment (9 [both] vs
3 BCVA letter score; P0.001).
9
In the DRCR.net study,
approximately 30% of the ranibizumab laser patients
gained a 15 BCVA letter score from baseline compared
with 15% of the laser-treated patients.
The RESOLVE study demonstrated that ranibizumab
provided rapid and continuous improvements in BCVA
compared with sham over a period of 12 months (mean
average change in BCVA letter score from baseline to
month 12, 7.8 for ranibizumab vs 0.1 for sham;
P0.0001).
10
At month 12, approximately 32% of the
ranibizumab-treated patients gained a 15 BCVA letter
score compared with 10% in the sham control arm.
The observed numerical differences in the BCVA out-
come between RESTORE and RESOLVE may be partly
attributed to the differences in eligibility criteria and as a
consequence to baseline characteristics of the enrolled pa-
tients. Additionally, the 2 studies had different retreatment
criteria, which led to an average of 10 ranibizumab injec-
tions in the RESOLVE study and 7 injections in the
RESTORE study.
Visual impairment or reduced VA adversely impacts pa-
tients’ independence (activities like reading, interacting so-
cially, watching TV, driving, etc) and HRQoL.
12–14
The
RESTORE trial is the first to assess the impact of ranibizumab
treatment on HRQoL, particularly using the NEI VFQ-25
questionnaire. Ranibizumab showed progressive and sustained
improvements in HRQoL as assessed by the NEI VFQ25
composite scores. The mean change in VFQ-25 composite
scores was significant, with ranibizumab monotherapy and
combined with laser (5.0 and 5.4 point) versus laser. These
results are consistent with those reported for ranibizumab in the
neovascular AMD studies Anti-VEGF Antibody for the Treat-
ment of Predominantly Classic Choroidal Neovascularization
in Age-Related Macular Degeneration (ANCHOR) and Min-
imally Classic/Occult Trial of the Anti-VEGF Antibody
Ranibizumab in the Treatment of Neovascular Age-Related
Macular Degeneration (MARINA), where a 4- to 6-point im-
provement in mean NEI VFQ-25 scores represented a clini-
cally meaningful change corresponding with a 15-letter im-
provement in BCVA.
15
The strongest evidence of HRQoL
benefit for ranibizumab compared with laser alone was ob-
served for general vision, near, and distance activities NEI
VFQ-25 subscales. Adding to the HRQoL outcomes are the
data on the proportion of patients who had a BCVA letter score
73 (20/40 Snellen equivalent, the legal minimum for driving in
the United States and the United Kingdom) in the study eye at
month 12. In RESTORE, at month 12, 44.9% (ranibizumab
laser) and 53.0% (ranibizumab) patients had a BCVA letter
score 73 versus 16.1% and 19.8% patients at baseline,
whereas with laser 23.6% patients had a BCVA letter score
73 versus 15.3% at baseline. For the EQ-5D scores, none
of the differences between the ranibizumab treatment arms
and laser arm at any time point were significant. This is not
surprising given that EQ-5D does not contain any vision-
related domains, and has known ceiling effects,
16
so the
scale may lack sensitivity in detecting changes in DME
outcomes.
For the TTO scores, the change in mean utility score of
0.13 with ranibizumab was not statistically different from
laser alone at month 12 (P 0.10). Results from the TTO
utility measurement indicate a numerical improvement with
ranibizumab vs laser alone, and hence a possible impact on
the quality-adjusted life years associated with ranibizumab
therapy.
Table 12. Adverse Events Potentially Related to Systemic Vascular Endothelial Growth Factor
Inhibition (Safety Set)
Preferred Term, n (%)
Ranibizumab 0.5 mg
N 115
Ranibizumab 0.5 mg Laser
N 120
Laser
N 110
Total 14 (12.2) 7 (5.8) 11 (10.0)
Arterial thromboembolic events 6 (5.2) 1 (0.8) 1 (0.9)
Angina pectoris 2 (1.7) 0 0
Pulmonary embolism 2 (1.7) 0 1 (0.9)
Cerebrovascular accident 1 (0.9) 0 0
Myocardial infarction 1 (0.9) 1 (0.8) 0
Hypertension 9 (7.8) 6 (5.0) 9 (8.2)
Non-ocular hemorrhage 1 (0.9) 0 1 (0.9)
Epistaxis 1 (0.9) 0 1 (0.9)
Proteinuria 1 (0.9) 1 (0.8) 0
Ophthalmology Volume 118, Number 4, April 2011
622
The RESTORE study used retreatment criteria that were
designed to enable an individualized treatment regimen based
on patients’ disease stability. Patients were assessed monthly to
observe disease stability/activity and to guide treatment inter-
ruption or reinitiation through changes in VA, supported by
clinical and anatomic evaluations attributable to the progres-
sion of DME. The validity of this approach was confirmed by
the efficacy outcome, which showed that the PRN retreatment
regimen could maintain the BCVA gained at the end of the
treatment initiation phase. Furthermore, this was achieved with
an average of 4 injections in the 9-month continuous/resumed
treatment phase. However, it is unknown whether or not VA
gains would have been greater if monthly treatment had been
maintained over 12 months. Ongoing ranibizumab clinical
trials, such as the Ranibizumab Injection in Subjects with
clinically significant macular Edema with center involvement
secondary to diabetes mellitus (RISE, NCT00473330)
17
and
the Ranibizumab Injection in subjects with clinically signifi-
cant macular Edema with center involvement secondary to
Diabetes mellitus (RIDE, NCT00473382)
18
where monthly
injections are mandated for 24 months will provide data on
maximal VA gains in DME with monthly therapy. Overall, a
greater proportion of patients interrupted treatment due to
disease stability with ranibizumab than laser (85% [ranibi-
zumab] and 82% [ranibizumab laser] vs 68%), which was
expected because the laser arm received sham injections only.
Approximately 33% of the ranibizumab-treated patients
interrupted treatment for the first time at month 3 due to
treatment efficacy. The proportion of patients with a
maximum treatment-free interval of 3 months was sim-
ilar across treatment arms (57.9%– 61.9%).
The results from the RESTORE study have assessed the
treatment effect of ranibizumab monotherapy in DME, as well
as the potential benefit of combining it with laser therapy. Over
the 1-year study period, the results from RESTORE show that
there were no significant efficacy differences detected between
the ranibizumab and the ranibizumab combined with laser treat-
ment arms with respect to improvements in BCVA, as well
as the number of injections. Overall, the retreatment criteria
based on disease stability used in the RESTORE study
allowed a reduction in the number of injections compared
with the RESOLVE study, through monthly monitoring to
assess patients’ need for retreatment.
Ranibizumab as monotherapy or combined with laser was
well-tolerated in patients with visual impairment due to DME
over 12 months. There were no ocular SAEs observed in the
ranibizumab arm. There were no incidences of glaucoma re-
ported in any of the treatment arms and only 1 patient in each
ranibizumab arm reported increased IOP. Both cases of IOP
increase resolved on their own, without treatment, and the
investigator considered these events to be related to injection
procedure and not to the drug. Ranibizumab treatment was not
found to be associated with an increased risk of cerebrovascu-
lar or cardiovascular events in DME patients over 12 months;
there were no cases of endophthalmitis reported in the study.
The pooled analysis of the 2 pivotal studies, RESOLVE and
RESTORE, resulted in an incidence rate of 1.4% for endoph-
thalmitis at 1 year, which is consistent with the incidence rate
of 1.6% found in the pooled analysis of the pivotal AMD
studies, ANCHOR, MARINA, and PIER (A Phase IIIb,
multicenter, randomized, double-masked, sham Injection-
controlled study of the Efficacy and safety of Ranibizumab;
unpublished data, July 21, 2008). The incidence of AEs
potentially related to systemic VEGF inhibition (hyperten-
sion, proteinuria, and nonocular hemorrhage) were low and
did not differ compared with the laser control cohort. Fur-
thermore, ranibizumab treatment did not negatively influ-
ence the VA outcome or the progression of macular isch-
emia, as confirmed by assessing the BCVA at month 12 in
the subgroups with or without the presence of ischemia at
baseline, as well as by the degree of capillary loss in the
central subfield from baseline to month 12 (Appendix 2,
available online at http://aaojournal.org). The safety find-
ings from this study are consistent with the safety profile of
other studies with ranibizumab treatment in DME
9,10
and
neovascular AMD.
19,20
In summary, data from the 3 randomized clinical trials
RESOLVE, DRCR.net and RESTORE involving 1000
patients provide robust evidence for the efficacy and
tolerability of ranibizumab in DME.
9,10
Furthermore, the
24-month results from DRCR.net and the recently pub-
lished READ-2 study have shown that ranibizumab sus-
tains efficacy
9,11
through year 2 of treatment and was
well-tolerated.
9
These reports may lead to a shift in
treatment paradigm for DME, from laser, to newer ap-
proaches using ranibizumab. Results from the 2-year
extension of the RESTORE study will add to the data
from studies REVEAL (NCT00989989),
21
RIDE,
18
RISE,
17
and RETAIN (NCT01171976),
22
and DRCR.net
(4-year follow-up) and are expected to further enhance
the evidence for ranibizumab therapy in DME in the
coming years.
In conclusion, RESTORE is the first study to demon-
strate that ranibizumab monotherapy provides significantly
superior benefit over standard-of-care laser in patients with
visual impairment due to DME, rapidly improving and
sustaining BCVA over the 12-month treatment period.
Ranibizumab therapy was administered using an individu-
alized PRN regimen with monthly monitoring and retreat-
ment based on disease stability. During the 12-month study
period combining laser with ranibizumab did not seem to
provide any advantage compared with ranibizumab mono-
therapy in terms of improving BCVA and treatment expo-
sure. However, longer follow-up may be required to assess
the benefit of combining laser with ranibizumab. Ranibi-
zumab consistently improved BCVA across all the sub-
groups of patients, including patients with focal or diffuse
DME. Ranibizumab treatment was also associated with
progressive and sustained improvements in HRQoL com-
pared with laser alone, as assessed by the NEI VFQ-25
scores. Ranibizumab was well-tolerated in patients with
visual impairment due to DME with a safety profile similar
to the well-established safety profile in neovascular
AMD.
19,20
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Footnotes and Financial Disclosures
Originally received: November 3, 2010.
Final revision: January 10, 2011.
Accepted: January 10, 2011. Manuscript no. 2010-1525.
1
Centre for Vision Research (Westmead Millennium Institute), University
of Sydney, Sydney, Australia.
2
Department of Ophthalmology, University Vita-Salute Scientific Insti-
tute, San Raffaele, Milano, Italy.
3
Universitätsklinik für Augenheilkunde und Optometrie, University of
Vienna, Waehringer Guertel, Vienna, Austria.
4
Division of Medical Retina and Laser Surgery, Department of Ophthal-
mology, University Eye Hospital Ulm, Ulm, Germany.
5
Assistance Publique des Hôpitaux de Paris, Ophthalmology Department,
Hôpital Lariboisière, Paris, France.
6
Department of Ophthalmology, Academisch Medisch Centrum Univer-
siteit van Amsterdam, Amsterdam, The Netherlands.
7
Universitätsspital Zürich, Augenklinik, Nordtrakt II, Zürich, Switzerland.
8
Vienna Reading Center, Department of Ophthalmology, Medical Univer-
sity of Vienna, Vienna, Austria.
9
Novartis Pharma AG, Basel, Switzerland.
Presented in part at: WOC 2010, EURETINA 2010, and AAO 2010.
Appendix 4 contains a list of the primary investigators who participated in
this study (available online at http://aaojournal.org).
The authors thank Aditi Gandhe (Novartis Healthcare Private Ltd., India)
for her medical writing and editorial assistance and Shivani Mittra (No-
vartis Healthcare Private Ltd., India) for her contribution toward various
drafts of this manuscript.
Financial Disclosure(s):
The authors have made the following disclosures:
P. Mitchell Novartis Consultant, Lecturer; Pfizer Consultant, Lec-
turer; Allergan Consultant; Solvay Consultant; Bayer Consultant.
Ophthalmology Volume 118, Number 4, April 2011
624
F. Bandello Novartis Consultant, Lecturer; Allergan Consultant,
Lecturer; Thea Consultant, Lecturer.
U. Schmidt-Erfurth Alcon Laboratories, Inc. Consultant, Lecturer;
Bayer Healthcare Consultant, Lecturer; Novartis Consultant, Lecturer;
Regeneron Lecturer; Pfizer Lecturer.
P. Massin Novartis Consultant, Lecturer; Allergan Consultant,
Lecturer; Fovea Pharmaceutical Consultant; Sanofi Aventis – Consultant;
Takeda Consultant, Lecturer.
R.O. Schlingemann – Novartis – Consultant, Lecturer; Bayer Healthcare –
Consultant.
F. Sutter Novartis Consultant.
G. Burian Novartis Pharma Employee.
O. Gerstner Novartis Pharma Employee.
A. Weichselberger Novartis Pharma Employee.
Sponsored by Novartis Pharma AG, Switzerland. The study is registered
with www.clinicaltrial.gov under number NCT00687804.
Correspondence:
Prof. Paul Mitchell, Centre for Vision Research, University of Sydney
(Westmead Hospital), Sydney, Australia. E-mail: paul.mitchell@sydney.
edu.au.
Mitchell et al Ranibizumab or Combined With Laser vs Laser for DME
625
    • "The rate of angina was 0.8% in the IVR group [28]. Myocardial infarction was reported in 3 trials, with a rate of 1.9% in the IVA group, 0.5% in the IVB group [27], and 1.2% in the IVR group [27, 39, 42]. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: To compare the efficacy and safety of current treatments in diabetic macular edema (DME). Methods: PubMed, Embase and CENTRAL were systematically reviewed for randomized controlled trials of current treatments in DME through August 2015. Data on the mean change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) were extracted, and adverse events (AEs) were collected. Results: A total of 21 trials were included in our network meta-analysis. Intravitreal ranibizumab improved BCVA most significantly (OR: +7.01 95%CI (2.56 to 11.39)) in 6 months and intravitreal aflibercept (+8.19 (5.07 to 11.96)) in 12 months. Intravitreal triamcinolone combined with LASER decreased CMT most significantly (-111.34 (-254.61 to 37.93)) in 6 months and intravitreal aflibercept (-110.83 (-190.25 to -35.27)) in 12 months. Compared with the relatively high rate of ocular AEs in the groups with administration of steroids, systematic AEs occurred more frequently in the groups with vascular endothelial growth factor inhibitors involved. Conclusions: Our analysis confirms that intravitreal aflibercept is most favorable with both BCVA improvement and CMT decrease than other current therapies in the management of DME within 12 months. Vascular endothelial growth factor inhibitors for DME should be used with caution due to systematic AEs. Combined intravitreal triamcinolone with LASER has a stronger efficacy in decreasing CMT than the other interventions in the early stage after injection. More high-quality randomized controlled trials will be necessary.
    Full-text · Article · Jul 2016
    • "The model was based on the advection and diffusion of the simplest known limiting factor, oxygen, rather than dealing with, say, removal of lactate or carbon dioxide. The model treats only one cytokine, a single VEGF isoform without consideration of other larger VEGF isoforms , PEDF, PDGF, erythropoietin, angiopoetin-1, angiopoetin-2 or angiopoetin-like 4, all of which likely play at least some role in vascular changes in diabetic retinopathy [117,[140][141][142]. In this case the level of therapeutic efficacy of the anti-VEGF injectable agents such as ranibizumab or aflibercept supports VEGF being a major [12, 100,143] if not the only important factor, supporting its relevancy and use in the model. "
    [Show abstract] [Hide abstract] ABSTRACT: An explanatory computational model is developed of the contiguous areas of retinal capillary loss which play a large role in diabetic maculapathy and diabetic retinal neovascularization. Strictly random leukocyte mediated capillary occlusion cannot explain the occurrence of large contiguous areas of retinal ischemia. Therefore occlusion of an individual capillary must increase the probability of occlusion of surrounding capillaries. A retinal perifoveal vascular sector as well as a peripheral retinal capillary network and a deleted hexagonal capillary network are modelled using Compucell3D. The perifoveal modelling produces a pattern of spreading capillary loss with associated macular edema. In the peripheral network, spreading ischemia results from the progressive loss of the ladder capillaries which connect peripheral arterioles and venules. System blood flow was elevated in the macular model before a later reduction in flow in cases with progression of capillary occlusions. Simulations differing only in initial vascular network structures but with identical dynamics for oxygen, growth factors and vascular occlusions, replicate key clinical observations of ischemia and macular edema in the posterior pole and ischemia in the retinal periphery. The simulation results also seem consistent with quantitative data on macular blood flow and qualitative data on venous oxygenation. One computational model applied to distinct capillary networks in different retinal regions yielded results comparable to clinical observations in those regions.
    Full-text · Article · Jun 2016
    • "Visual impairment in diabetic retinopathy (DR) is most commonly associated with diabetic macular edema (DME), which affects about 20% of these patients [1] . Recently, anti- VEGF agents have been widely used in the treatment of DME based on the results of clinical trials [2][3][4]. However, decreasing the VEGF levels alone is not sufficient to reduce DME, and repeated anti-VEGF injections create a burden for patients [5]. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose . To evaluate the real-world efficacy and safety of the dexamethasone implant (DEX implant) in patients with diabetic macular edema (DME). Methods . Retrospective, multicenter, and noncomparative study of DME patients who were treated with at least one DEX implant. A total of 186 eyes from 165 patients were included. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), complications, and number of retreatments were collected. Data at baseline and monthly for 6 months were analyzed. Results. The average baseline BCVA and CRT were 0.60 LogMAR and 491.6 μ m, respectively. The mean BCVA improved until 3 months and then decreased up to 6 months of follow-up (0.53, 0.49, and 0.55 LogMAR at 1, 3, and 6 months; p = 0.001
    Full-text · Article · May 2016
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