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Clinical science
Aflibercept treatment for patients with exudative
age-related macular degeneration who were
incomplete responders to multiple ranibizumab
injections (TURF trial)
Charles C Wykoff, David M Brown, Maria E Maldonado, Daniel E Croft
Retina Consultants of Houston,
Weill Cornell Medical College,
Houston Methodist Hospital,
Houston, Texas, USA
Correspondence to
Dr Charles C Wykoff, Retina
Consultants of Houston, Weill
Cornell Medical College,
Houston Methodist Hospital,
6560 Fannin, Suite 750,
Houston, Texas 77030, USA;
ccwmd@houstonretina.com
Preliminary data from this
study was presented at ARVO
2013, Seattle, WA.
Received 3 December 2013
Revised 26 December 2013
Accepted 18 January 2014
Published Online First
11 February 2014
ABSTRACT
Aim To determine the efficacy of 2.0 mg aflibercept in
the management of patients with recalcitrant exudative
age-related macular degeneration (AMD).
Methods In this prospective, open-label, single-arm
clinical trial, patients were seen monthly and given
mandatory 2.0 mg aflibercept at baseline, months 1, 2
and 4. Pro re nata (PRN) retreatment at months 3 and 5
was performed upon evidence of disease on spectral
domain-optical coherence tomography (SD-OCT). End
point at month 6: mean change in Early Treatment
Diabetic Retinopathy Study best corrected visual acuity
(ETDRS BCVA) and central subfield thickness (CST),
mean number of aflibercept injections, percentage of
PRN injections required, patients with no fluid on SDOCT and patients losing >15 letters.
Results At baseline, 46 patients with a mean of 42
prior antivascular endothelial growth factor-A (antiVEGF) intravitreal treatments had a mean of 74.2 letters
(Snellen equivalent 20/32) and mean CST of 347 mm.
ETDRS letters remained stable throughout the trial; at
month 6, mean BCVA change was +0.2 letters (range
−10 to +13, p=0.71). Anatomically, mean CST
improved significantly from baseline at each study visit
including −23.6 mm at month 1 and −27.3 mm at
month 6 ( p=0.018). Seventy-one of 90 (79%) possible
PRN injections were required and a mean of 5.6
aflibercept injections out of the maximum six were
administered. Ten of 45 (22%) patients had no retinal
fluid on SD-OCT at month 6. No patient lost >15 letters.
Conclusions Aflibercept 2.0 mg treatment maintained
mean visual acuity improvements previously achieved
with high-dose 2.0-mg ranibizumab injections in
recalcitrant wet AMD patients. Aflibercept 2.0 mg
treatment led to significant anatomic improvement and
was required monthly in most patients.
Clinical Trials Registration FDA IND#12462. NCT
01543568.
Trial Details IND 12462, NCT 01543568 http://
clinicaltrials.gov/show/NCT01543568.
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INTRODUCTION
To cite: Wykoff CC,
Brown DM, Maldonado ME,
et al. Br J Ophthalmol
2014;98:951–955.
Neovascular age-related macular degeneration (AMD)
is a leading cause of vision loss around the world.1
Pharmaceutical agents that block vascular endothelial
growth factor-A (VEGF) have revolutionised the management of neovascular AMD and most exudative
retinal diseases. Nevertheless, many eyes treated with
monthly dosing of ranibizumab (Lucentis, Genentech,
South San Francisco, California, USA),2 3 bevacizumab
(Avastin, Genentech, South San Francisco, California,
Wykoff CC, et al. Br J Ophthalmol 2014;98:951–955. doi:10.1136/bjophthalmol-2013-304736
USA),4 or aflibercept (Eylea, Regeneron, Tarrytown,
New Jersey)5 manifest recalcitrant fluid. For example,
in the CATT trial (Comparison of AMD Treatment
Trial), despite monthly treatment with anti-VEGF
agents for 2 years, 51.5% of patients treated with ranibuzumab and 67.4% of patients given bevacizumab
showed evidence of persistent fluid on time-domain
optical coherence tomography (OCT).4 Similarly, in
the VIEW1 and VIEW2 trials (VEGF Trap-Eye:
Investigation of Efficacy and Safety in Wet AMD),
between 27.6% and 32.3% of patients had evidence
of persistent intraretinal or subretinal fluid at the
primary end-point of 1 year despite 2.0 mg aflibercept
treatment.5 Such residual intraretinal or subretinal
fluid likely limits optimal visual improvement,6 and
patients with recalcitrant wet AMD represent a substantial clinical burden.
Evidence suggests that some of these patients
may benefit from a higher dose of anti-VEGF medication or switching to a different pharmacologic
agent. The SAVE trial (Super-dose Anti-VEGF
(SAVE) Trial: 2.0 mg Intravitreal Ranibizumab for
Recalcitrant Neovascular Age-Related Macular
Degeneration) demonstrated significant visual and
anatomic gains in recalcitrant wet AMD eyes at
both 1 and 2 years of treatment.7 8 However, pro
re nata (PRN) retreatments were required at almost
every monthly visit in these aggressive wet AMD
eyes, and retinal fluid was still present in 70% (45/
64) of patients at the end of 2 years.8
The current study aimed to determine if 2.0 mg
aflibercept could maintain or even improve upon
the visual acuity and anatomic gains of the SAVE
trial for these well-characterised recalcitrant exudative AMD eyes.
MATERIALS AND METHODS
This study was a prospective, multicentre, openlabel, single-arm clinical trial (aflibercepT for subjects with exudative AMD who were incomplete
responders to mUltiple Ranibizumab anti-VEGF
injections (TURF trial); Food and Drug
Administration (FDA) Investigational New Drug
#12462). Inclusion criteria were that only patients
who completed the 2-year, prospective SAVE trial
(NCT01025232) in which recalcitrant wet AMD
eyes were treated with 2.0 mg ranibizumab7–9 were
eligible. TURF sample size was determined by
enrolling all consenting patients who enrolled directly into TURF immediately following completion
of the SAVE trial. There was a protocol-mandated
28-day minimum ‘wash-out’ before enrolment in
951
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Clinical science
the TURF study in which patients could not have received any
anti-VEGF medication. No patient had received prior aflibercept
treatment. Exclusion criteria included significant subretinal
fibrosis or geographic atrophy involving the fovea.
After obtaining institutional review board (IRB) approval of
the study protocol and consent, appropriate patients seen at
Retina Consultants of Houston were identified, provided with
informed consent documents, and enrolled. Data was collected
at Retina Consultants of Houston in the Texas Medical Center
(6560 Fannin, Suite 750, Houston, Texas) and in The
Woodlands, Texas (17350 St Luke’s Way, Suite 120).
At all study visits, subjects underwent best corrected Early
Treatment Diabetic Retinopathy Study best corrected visual
acuity (ETDRS BCVA) and comprehensive ophthalmic examination including applanation tonometry, slit-lamp evaluation and
dilated binocular indirect ophthalmoscopy. Fundus photography
and fluorescein angiography were performed at baseline, month
3 and month 6. Spectral domain OCT (SD-OCT) was performed at each visit using the Heidelberg Spectralis HRA+OCT
(Spectralis; Heidelberg Engineering, Heidelberg, Germany). All
patients received 0.05 mL open-label intravitreal injections of
2.0 mg aflibercept administered every 28 days for the first
3 months (baseline, month 1 and month 2), one mandatory
dose at month 4 and, as needed, doses at months 3 and 5. PRN
retreatments at months 3 and 5 were performed in the presence
of intraretinal or subretinal fluid on SD-OCT or if BCVA
decreased >5 letters from the previous visit.
Sterile surgical technique was applied for each intravitreal
injection. Patients self-administered topical antimicrobials four
times daily for 3 days prior to treatment. After topical anaesthesia, the periocular skin, eyelid and eyelashes were treated with
10% povidone iodine swabs, and 5% povidone iodine ophthalmic solution was applied to the conjunctival surface. Following
intravitreal injection, finger-counting testing was performed and
indirect ophthalmoscopy was performed to confirm central
retinal artery perfusion.
Key outcome measures included mean change in ETDRS
BCVA from baseline, mean change in central subfield thickness
(CST), mean number of 2.0 mg intravitreal aflibercept injections
administered, percentage of PRN injections required, percentage
of patients with no intraretinal, subretinal, or subretinal
pigment epithelial (RPE) fluid on SD-OCT at month 6 and percentage of patients who lost >15 letters BCVA. All SD-OCT segmentations were manually confirmed and corrected as needed
to follow the internal limiting membrane and Bruch’s membrane
prior to computation of SD-OCT change maps and CST
(MEM, CCW). Statistical comparisons were performed with
paired Student t tests where appropriate.
RESULTS
Patient characteristics
Forty-six patients enrolled directly from the SAVE trial into the
TURF trial between April and September 2012.7–9 Baseline
demographics and clinical findings are described in table 1.
Forty-five of 46 (98%) patients completed the 6-month trial. At
baseline, patients had received a mean of 42 (range 19–67)
prior anti-VEGF intravitreal treatments including a mean of 21
(range 13–24) prior 2.0 mg ranibizumab treatments out of a
maximum 24 during the immediately preceding 24 months of
the SAVE trial. Median time from prior anti-VEGF treatment to
the first aflibercept treatment was 28 days (mean 33.3, range 28
to 68 days).
952
Table 1
Baseline patient demographics
Baseline demographics
Patients
Sex (male/female)
Age m(r)
Prior anti-VEGF injections m(r)
2.0 mg ranibizumab injections m(r)
Washout period in days m(r)
ETDRS BCVA m(r)
Snellen equivalent (r)
SD OCT CST μm m(r)
Intraretinal fluid n(%)
Subretinal fluid n(%)
Sub-RPE fluid n(%)
No intraretinal, subretinal, or Sub-RPE fluid n(%)
46
22/24
77.8 (55–95)
42 (19–67)
21 (13–24)
33 (28–68)
74.2 (41–92)
(20/100–20/16)
347 (188–565)
17 (37)
21 (46)
18 (39)
8 (17)
anti-VEGF, anti-vascular endothelial growth factor-A; CST, central subfield thickness;
ETDRS BCVA, Early Treatment Diabetic Retinopathy Study best corrected visual acuity;
m, mean; OCT, optical coherence tomography; r, range; sub-RPE, subretinal pigment
epithelial.
Visual outcomes
At enrolment, mean BCVA was 74.2 ETDRS letters (Snellen
equivalent 20/32, range 41–91, 20/100–20/16). BCVA remained
stable throughout the 6-month trial with no significant fluctuation; at month 6, mean change was +0.2 ETDRS letters (range
−10 to +13, p=0.71) (figure 1). At 6 months, 4 eyes (9%)
improved by ≥5 ETDRS letters and 1 eye (2%) improved by
≥10 ETDRS letters, gaining 13 letters within the first month of
treatment; PRN retreatment was required at both PRN visits in
3 of 4 of these patients, while 1 patient received neither PRN
retreatment. At month 6, 4 eyes (9%) lost ≥5 letters or more
with 1 eye (2%) receiving neither PRN retreatment and losing
10 letters associated with collapse of a pigment epithelial
detachment (PED) and progression of geographic atrophy
(figure 2A); PRN retreatment was required at both PRN visits in
2 of 4 of these patients, and 2 patients received neither PRN
retreatment. No patient lost >15 letters BCVA.
Anatomic outcomes
At enrolment, mean CST was 347 μm (range 188–565 mm).
Mean CST improved significantly from baseline at all study
visits including −23.6 mm at month 1 (−5%, range −384 to
+32 mm), and −27.3 mm at month 6 (−6%, range −381 to
+59 mm, p=0.018) (figure 3).
CST decreased >10% in 9 of 46 patients (19.6%) at month
3, and in 7 of 45 patients (15.6%) at month 6. For these eyes,
the mean decrease in CST at month 6 was −149 mm (−31%,
range −48 to −381 mm). Of the 7 patients with CST decrease
>10% at month 6, 4 had complete, or near complete, resolution of PED (figure 2B); 94% of the decrease in CST in these
patients was realised within the first 2 months of aflibercept
treatment. At month 3, no patient gained >10% CST, but at
month 6, 2 patients gained >10% CST, gaining either significant subretinal (60 mm) or intraretinal (92 mm) fluid after not
receiving a PRN injection.
In total, 71 of 90 (79%) possible PRN injections were administered and a mean of 5.6 aflibercept injections out of the
minimum 4 and maximum 6 total injections were administered.
PRN retreatment was required at both PRN visits in 33 of 46
(72%) patients due to SD-OCT findings, and neither of the
PRN injections were given in 8 of 46 (17%) patients. At months
Wykoff CC, et al. Br J Ophthalmol 2014;98:951–955. doi:10.1136/bjophthalmol-2013-304736
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Clinical science
Figure 1 Change in mean
best-corrected visual acuity (best
corrected visual acuity (BCVA); Early
Treatment Diabetic Retinopathy Study
(ETDRS) letters) over 6 months with
standard error (SE) bars.
3 and 6, 17 (37%) and 10 (22%) patients had no intraretinal,
subretinal, or sub-RPE fluid, respectively.
Adverse events
Ocular and systemic adverse events are reported in table 2.
There were no cases of endophthalmitis, intraocular inflammation, new subretinal haemorrhage, or traumatic cataract. In
total, three patients were noted to have increased geographic
atrophy (3/46, 7%). No systemic arterial thromboembolic events
were identified. One (1/46, 2%) patient died at month 5 related
to complications of acute onset leukaemia.
DISCUSSION
Eyes with recalcitrant exudative AMD are a substantial clinical
burden, representing approximately a quarter to one-third of all
new wet AMD eyes. In such patients, 2.0 mg ranibizumab, a
fourfold higher dose than the FDA approved 0.5 mg dose for
wet AMD management, appears capable of additional anatomic
and visual benefit based on the SAVE trial outcomes at month 3,
year 1 and year 2,7–9 as well as the LAST study (evaLuation of
high-dose rAnibizumab (2.0 mg) in the management of AMD in
patients with perSistent/recurrenT macular fluid).10 In the
HARBOR study, 2.0 mg ranibizumab demonstrated no clinical
advantage over the 0.5 mg ranibizumab dosing in treatment
naive eyes11 and Genentech discontinued further development
and clinical trials of the 2.0 mg dose. As the SAVE cohort had
demonstrated sustained clinical benefit from the higher dose, we
were reticent to switch these patients back to 0.5 mg ranibizumab. With FDA approval of aflibercept for therapeutic use, the
TURF trial was designed to assess if the anatomic and BCVA
Figure 2 Case examples. Baseline late-phase fluorescein angiograms (FA) with associated spectral domain optical coherence tomography
(SD-OCT) orientations (white dashed line) followed by sequential SD-OCT images at baseline (left), 1 month (centre) and 6 months (right). (A)
flattening of pigment epithelial detachment (PED) from baseline associated with retinal pigment epithelial and outer retinal atrophy. (B) flattening of
PED with residual subretinal fluid under the fovea at month 6.
Wykoff CC, et al. Br J Ophthalmol 2014;98:951–955. doi:10.1136/bjophthalmol-2013-304736
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Figure 3 Change in central subfield
thickness (spectral domain optical
coherence tomography (SD-OCT)) over
6 months with standard error (SE)
bars. Central subfield thickness was
evaluated monthly as well as 7 days
after the first aflibercept treatment.
gains could be maintained with this alternative pharmacologic
agent. The TURF trial consisted entirely of patients exiting the
SAVE trial, and demonstrates that commercially available 2.0 mg
aflibercept treatment maintained the mean visual gains attained
with 2.0 mg ranibizumab treatment and led to significant mean
anatomic improvement. These anatomic gains were primarily
driven by a minority of patients (20%, 9 of 45), many with dramatic flattening of PED. Despite no mean change in BCVA
including all TURF patients, one patient gained 13 ETDRS
letters within 1 month of aflibercept initiation, a patient who
required both PRN retreatments.
The FDA approved labelling for aflibercept use in the management of wet AMD includes two options: 2 mg every 8 weeks
after 3 initial monthly doses or 2 mg monthly. While both treatment regimens led to clinically equivalent mean visual outcomes
in treatment-naive patients, there is evidence that continued
monthly therapy after the first 3 monthly doses translates into
better visual outcomes in some patients, particularly those with
recalcitrant exudative disease activity. For example, when eyes
with persistent macular oedema during each of the first 4 visits
in VIEW1 and VIEW2 were considered, continued monthly aflibercept achieved superior outcomes compared with every
8-week dosing.12 The current TURF trial employed every other
month dosing after the first 3-monthly doses, but was designed
to permit PRN dosing at the intervening months. Supporting
Table 2
Ocular and serious systemic adverse events (AEs)
Ocular adverse event (%)
Patients with ocular AEs
Cataract progression
Geographic atrophy progression
Serious adverse events (%)
Patients with SAEs
Total SAEs
Death
Atrial fibrillation
Squamous cell carcinoma
Upper respiratory tract infection
Urinary tract infection
6 (13)
3 (7)
3 (7)
9 (20)
11 (24)
1 (2)
1 (2)
2 (4)
5 (11)
2 (4)
the observation that aflibercept does not maintain maximal
retinal deturgesence for 2 months in many patients, and indicative of the recalcitrant exudative nature of the study eyes in
TURF, 72% of eyes required retreatment at both PRN visits,
and 79% of PRN retreatments were required. Furthermore, the
only two patients who experienced a >10% gain in CST during
the TURF trial both did not receive a PRN treatment the month
prior.
In the treatment-naive eyes included in the VIEW1 and
VIEW2 trials, aflibercept and ranibizumab treatment resulted in
clinically equivalent visual outcomes.5 While both pharmacologic agents neutralise VEGF-A, aflibercept has a distinct mechanism of action and also inhibits VEGF-B and placental growth
factor.13 As such, eyes with recalcitrant exudative AMD may
respond differently to these medications. Indeed, many analyses
have recently reported positive anatomic benefit, and in some
cases visual benefit, with aflibercept in recalcitrant wet AMD
eyes previously treated with ranbizumab or bevacizumab.14–18
The strength of this study is its prospective design involving a
well-defined patient cohort who had received rigorous previous
treatment with anti-VEGF therapies, as well as its standardised
treatment and follow-up intervals. The limitations of this trial
include the lack of a control group, relatively small sample size,
and the limited duration of 6 months.
This study provides evidence that aflibercept treatment may
be anatomically valuable in some recalcitrant exudative AMD
eyes, while maintaining prior visual gains. Such value may be
apparent relatively quickly after initiation of aflibercept treatment. However, a substantial majority of the patients in this
prospective trial required monthly aflibercept dosing to achieve
maximal anatomic and visual benefit. Longer-term data will be
valuable to guide the ongoing management of patients with
recalcitrant wet AMD.
Contributors CCW: concept, design, PI, writing of the manuscript (guarantor);
DMB: concept, design, revision of the manuscript; MEM: data collection, analysis,
writing of the manuscript. DEC: data collection, analysis, writing of the manuscript.
Funding Research grant from Regeneron Pharmaceuticals. The funding organisation
had no role in the design or conduct of this research.
Competing interests Yes. ICMJE conflicts of interest forms have been attached.
Ethics approval Sterling IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
954
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Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/3.0/
9
10
11
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Downloaded from http://bjo.bmj.com/ on June 16, 2016 - Published by group.bmj.com
Aflibercept treatment for patients with
exudative age-related macular degeneration
who were incomplete responders to multiple
ranibizumab injections (TURF trial)
Charles C Wykoff, David M Brown, Maria E Maldonado and Daniel E
Croft
Br J Ophthalmol 2014 98: 951-955 originally published online February
11, 2014
doi: 10.1136/bjophthalmol-2013-304736
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