Journal Reading Kepada Yth:

Efficacy and Safety of Ranibizumab With or Without Verteporfin

Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: A
Randomized Clinical Trial

Residen : Monika Ayuningrum

Stase : Vitreoretina
Pembimbing : dr. Vanda Virgayanti, M.Ked(Oph), Sp.M
dr. Delfi, M.Ked(Oph), Sp.M(K)
Prof. dr. H. Aslim D. Sihotang, Sp.M (K-VR)

PROGRAM PENDIDIKAN DOKTER SPESIALIS

DEPARTEMEN ILMU KESEHATAN MATA
FAKULTAS KEDOKTERAN UNIVERSITAS SUMATERA UTARA
RUMAH SAKIT UNIVERSITAS SUMATERA UTARA
2021
 Research

JAMA Ophthalmology | Original Investigation

Efficacy and Safety of Ranibizumab

With or Without Verteporfin Photodynamic Therapy
for Polypoidal Choroidal Vasculopathy
A Randomized Clinical Trial
Adrian Koh, MD, FRCS; Timothy Y. Y. Lai, MD, FRCS; Kanji Takahashi, MD; Tien Y. Wong, MD, PhD; Lee-Jen Chen, MD; Paisan Ruamviboonsuk, MD;
Colin S. Tan, FRCS(ED); Chrystel Feller, PhD; Philippe Margaron, PhD; Tock H. Lim, FRCS (ED); Won Ki Lee, MD, PhD; for the EVEREST II study group

Invited Commentary
IMPORTANCE Polypoidal choroidal vasculopathy (PCV) is a common subtype of exudative page 1214
age-related macular degeneration among Asian individuals. To our knowledge, there are no Journal Club Slides and
large randomized clinical trials to evaluate intravitreal ranibizumab, with and without Supplemental content and
verteporfin photodynamic therapy (vPDT), for the treatment of PCV. Supplemental content

OBJECTIVE To compare the efficacy and safety of combination therapy of ranibizumab and
vPDT with ranibizumab monotherapy in PCV.

DESIGN, SETTING, AND PARTICIPANTS A double-masked, multicenter randomized clinical trial

of 322 Asian participants with symptomatic macular PCV confirmed by the Central Reading
Center using indocyanine green angiography was conducted between August 7, 2013, and
March 2, 2017.

INTERVENTIONS Participants were randomized 1:1 to ranibizumab, 0.5 mg, and vPDT
(n = 168; combination therapy group) or ranibizumab, 0.5 mg, and sham PDT (n = 154;
monotherapy group). All participants received 3 consecutive monthly ranibizumab injections,
followed by a pro re nata regimen. Participants also received vPDT/sham PDT on day 1,
followed by a pro re nata regimen based on the presence of active polypoidal lesions.

MAIN OUTCOMES AND MEASURES Step 1 assessed whether combination therapy was
noninferior (5-letter margin) to monotherapy for change in best-corrected visual acuity from
baseline and superior in complete polyp regression. If noninferiority was established, step 2
assessed whether combination therapy was superior to monotherapy measured by
best-corrected visual acuity change at month 12.

RESULTS Baseline demographics of the 322 participants were comparable between the
treatment groups. Mean (SD) age of the patients was 68.1 (8.8) years, and overall, 69.9% of
the patients were men. At baseline, the overall mean best-corrected visual acuity and mean
central subfield thickness were 61.1 letters and 413.3 μm, respectively. At 12 months, mean
improvement from baseline was 8.3 letters with combination therapy vs 5.1 letters with
monotherapy (mean difference, 3.2 letters; 95% CI, 0.4-6.1), indicating that combination
therapy met the predefined criterion for noninferiority as well as being superior to
monotherapy (P = .01). Combination therapy was also superior to monotherapy in achieving
complete polyp regression at month 12 (69.3% vs 34.7%; P < .001). Over 12 months, the
combination therapy group received a median of 4.0 ranibizumab injections compared with
7.0 in the monotherapy group. Vitreous hemorrhage was the only ocular serious adverse
event (combination therapy group, 1 [0.6%]; monotherapy group, 3 [2.0%]). Author Affiliations: Author
affiliations are listed at the end of this
CONCLUSIONS AND RELEVANCE After 12 months, combination therapy of ranibizumab plus article.
vPDT was not only noninferior but also superior to ranibizumab monotherapy in Group Information: The members of
best-corrected visual acuity and superior in complete polyp regression while requiring fewer the EVEREST II study group are listed
at the end of this article.
injections. Combination therapy should be considered for eyes with PCV.
Corresponding Author: Adrian Koh
Hock Chuan, MD, FRCS, Eye and
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01846273.
Retina Surgeons, 13-03 Camden
JAMA Ophthalmol. 2017;135(11):1206-1213. doi:10.1001/jamaophthalmol.2017.4030 Medical Centre, 1 Orchard Boulevard,
Published online October 5, 2017. Singapore 248649 ([email protected]).

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 Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy Original Investigation Research

P
olypoidal choroidal vasculopathy (PCV) is an exuda-
tive retinal disease characterized by an abnormal sub- Key Points
retinal pigment epithelial network of vessels of choroi-
Question Are there any differences in treatment outcomes
dal origin, ending in aneurysmal dilatations, which appear as between combination therapy with intravitreal ranibizumab and
spheroidal polyplike structures.1 Hemorrhage and exudation verteporfin photodynamic therapy compared with ranibizumab
from this vascular network can lead to chronic, multiple, re- monotherapy in polypoidal choroidal vasculopathy?
current serosanguineous detachments of the retinal pigment
Findings In the multicenter EVEREST II randomized clinical trial,
epithelium and retina.1,2 Untreated, the long-term prognosis compared with ranibizumab monotherapy, treatment of
of PCV is poor.3 polypoidal choroidal vasculopathy with ranibizumab plus
The pathogenesis of PCV remains unclear; it was initially verteporfin photodynamic therapy resulted in greater visual acuity
considered a distinct abnormality of the inner choroidal improvement (8.3 vs 5.1 letters) than monotherapy and complete
vasculature2; however, the histopathological evidence suggests resolution of lesions with fewer ranibizumab injections.
that PCV is a variant of type I or occult choroidal neovascular- Meaning These data suggest ranibizumab plus verteporfin
ization seen in neovascular age-related macular degeneration photodynamic therapy should be considered for treatment of eyes
(nAMD), located above or within the Bruch membrane.4-6 Fur- with polypoidal choroidal vasculopathy.
thermore, studies within the past decade show that systemic
and genetic risk factors for PCV and typical nAMD appear to be
fairly similar.7-9 Thus, PCV is considered one of the subtypes tion Good Clinical Practice Guidelines and applicable local
of nAMD.1,10,11 regulations. The study protocol was reviewed and approved by
Indocyanine green angiography (ICGA) is essential for ac- an independent ethics committee or institutional review board
curately diagnosing PCV, helping to visualize the hyperfluo- at each center. All participants provided written informed con-
rescent polypoidal lesions.10,12,13 In general, PCV is reported sent. The trial protocol and statistical analysis plan are avail-
to be more prevalent in certain racial/ethnic groups, espe- able in Supplement 1.
cially in Asian individuals, where the proportion of PCV among
nAMD cases varies from 22.3% to 61.6%.4,14,15 However, with Participants
increased use of ICGA and advances in other diagnostic The study population consisted of treatment-naive partici-
techniques,12,13 a rise in the frequency of PCV diagnosis has pants 18 years and older with symptomatic macular PCV, as de-
been observed across all patient populations.4,16-18 fined by the presence of active macular polypoidal lesions on
The anti–vascular endothelial growth factor agent ranibi- ICGA and by the presence of serosanguineous maculopathy on
zumab, with or without verteporfin photodynamic therapy color fundus photography and fluorescein angiography. The
(vPDT), has shown efficacy in improving visual outcomes and presence of PCV in 1 study eye and eligibility for enrollment were
diminishing polypoidal lesions in patients with PCV.10,19,20 confirmed by the Central Reading Center (Fundus Image Read-
The EVEREST study was a randomized clinical trial in 61 par- ing Centre, Singapore) using a standardized reading protocol
ticipants that showed that combination therapy was signifi- using well-defined grading criteria as in EVEREST.12,19 The eli-
cantly superior to ranibizumab monotherapy in achieving gible BCVA letter score range was between 78 and 24 (approxi-
complete polyp regression over 6 months.19 Although best- mately 20/32 to 20/320 Snellen equivalent), measured using
corrected visual acuity (BCVA) also improved in participants Early Treatment Diabetic Retinopathy Study visual acuity charts
treated with either combination therapy or ranibizumab mono- at 4 m following refraction.
therapy, the study was not powered to compare the effects of Details of the patient inclusion and exclusion criteria are
these treatment modalities on BCVA gains and did not evalu- listed in the eMethods in Supplement 2.
ate results beyond 6 months.19 Therefore, we conducted the
24-month EVEREST II trial to compare the long-term effect of Randomization and Treatment
combination therapy vs ranibizumab monotherapy in a large Participants, evaluating investigators, vision examiners, and
Asian patient population with symptomatic macular PCV. Here, Central Reading Center graders were masked to the treatment.
we report the 12-month primary and secondary outcomes. Separate unmasked investigators (treating physicians) per-
formed the treatments. All eligible participants were random-
ized 1:1 to either combination therapy with ranibizumab, 0.5 mg,
and standard fluence vPDT or ranibizumab, 0.5 mg, mono-
Methods therapy (with sham PDT). Randomization was balanced by site
Study Design (eMethods in Supplement 2).
The EVEREST II trial was a 24-month multicenter, random- All participants were assessed monthly. An intravitreal ra-
ized, double-masked study designed to compare the efficacy and nibizumab injection (0.5 mg/0.05 mL) was administered on day
safety profile of ranibizumab, 0.5 mg, and vPDT combination 1 (baseline) and at months 1 and 2, followed by a pro re nata
therapy with ranibizumab, 0.5 mg, monotherapy in partici- (PRN) regimen according to the protocol-specific retreat-
pants with symptomatic macular PCV from Hong Kong, Japan, ment criteria, with at least a 28-day interval between 2 ranibi-
South Korea, Malaysia, Singapore, Taiwan, and Thailand. The zumab treatments (eMethods and eFigure 1 in Supplement 2).
study was conducted in accordance with the Declaration of On day 1, participants in the combination group were infused
Helsinki and Tripartite International Council on Harmoniza- with intravenous verteporfin (6 mg/m2), and those in the

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 Research Original Investigation Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy

tives included additional functional and anatomical out-

Figure 1. Patient Disposition (Randomized Set)
comes, treatment exposure, and safety and tolerability for both
treatments up to month 12.
491 Total screened

169 Not randomized (34.4%) Efficacy Assessments

due to screening failure Efficacy assessments included both functional (BCVA) and mul-
timodal image (ICGA, fluorescein angiography, color fundus,
and spectral-domain optical coherence tomography) evalua-
322 Patients with PCV enrolled
and randomized tions of the study eye. Disease activity was assessed based on
BCVA loss, spectral-domain optical coherence tomography,
168 Randomized to receive 154 Randomized to receive ICGA, fluorescein angiography, and color fundus anomalies
ranibizumab, 0.5 mg, + vPDT ranibizumab, 0.5 mg (eMethods in Supplement 2).

10 Patients (6.0%) discontinued 18 Patients (11.7%) discontinued

study prior to month 12 study prior to month 12
Safety Assessments
4 Adverse events (2.4%) 5 Adverse events (3.2%) Adverse events (AEs) were assessed at each visit.
1 Patient withdrew consent (0.6%) 6 Patients withdrew consent (3.9%)
1 Lost to follow-up (0.6%) 1 Lost to follow-up (0.6%)
1 Administrative problems (0.6%) 0 Administrative problems Statistical Analysis
1 Death (0.6%) 0 Death A sample size of 160 participants per treatment group was esti-
0 Disease progression 1 Disease progression (0.6%)
2 Protocol deviation (1.2%) 3 Protocol deviation (1.9%) mated to appropriately power the prespecified primary analy-
0 Physician’s decision 2 Physician’s decision (1.3%) sis, with the combined power to achieve a 1-sided noninferior-
ity margin of 5 letters between combination therapy and
158 Completed 12-month study 136 Completed 12-month study ranibizumab monotherapy with respect to the BCVA change from
period (94.0%) period (88.3%)
baseline to month 12, superiority with respect to complete polyp
regression, and superiority with respect to BCVA change from
Randomized set consisted of all randomized participants. Percentages are
based on the total number of participants in the randomized set in the
baseline at the 1-sided level of α = .025 was at least 87.0%.
respective treatment groups. The 5 participants discontinued from the study The primary efficacy objective was tested based on an
owing to protocol deviation were enrolled before the Central Reading Center analysis of covariance model including treatment group as a
confirmed polypoidal choroidal vasculopathy (PCV) diagnosis. One of the 2
factor and (centered) baseline BCVA as a continuous variable
participants whom the physician decided to withdraw did not respond to
treatment and the primary investigator decided to change the treatment. In the for testing noninferiority/superiority of BCVA change from
other case, there were no documented reasons but the participant did not baseline and on a Fisher test to evaluate for superiority with
experience any adverse events. Spectral-domain optical coherence respect to complete polyp regression (eMethods in Supplement
tomography, color fundus photography, fluorescein angiography, and
2). The multiple 1-sided α-level of .025 was to be maintained
indocyanine green angiography were assessed by the Central Reading Center.
by applying a sequentially rejecting multiple testing proce-
dure (steps 1 and 2).
monotherapy group were infused with 5% dextrose solution. Baseline demographics and disease characteristics are pre-
Fifteen minutes after the start of infusion, laser (light dose, 50 sented using descriptive statistics. The primary analysis was
J/cm2; dose rate, 600 mW/cm2; wavelength, 689 nm) was ap- conducted on the full analysis set (FAS) using the last obser-
plied onto the whole lesions in the study eye for 83 seconds. vation carried forward approach for imputation of the miss-
Photodynamic therapy tubing was covered with foil or a blan- ing data. The FAS comprised all participants who were as-
ket. Thereafter, vPDT or sham PDT was administered on a PRN signed to a treatment regimen. The secondary analyses were
basis from month 3 onwards per the protocol-specific retreat- conducted on the study eye of participants in the FAS. The
ment criteria (eMethods and eFigure 1 in Supplement 2), with safety analysis was descriptive and conducted on the safety
at least a 3-month interval between 2 vPDT or sham PDT treat- set that consisted of all participants who received at least 1 ap-
ments. As per protocol criteria, fellow eyes that developed plication of study treatment and had at least 1 postbaseline
macular pathologies were appropriately treated (Trial Proto- safety assessment.
col in Supplement 1).

Study Objectives
The primary objectives were to demonstrate that combination
Results
therapy was (1) noninferior to ranibizumab monotherapy in par- Patient Disposition and Baseline Characteristics
ticipants with symptomatic macular PCV with respect to change In total, 322 participants were randomized to receive combi-
in BCVA (Early Treatment Diabetic Retinopathy Study letters) nation therapy (n = 168) or ranibizumab monotherapy
from baseline to month 12 with a predefined noninferiority mar- (n = 154; Figure 1). Five participants without active polypoidal
gin of 5 letters and (2) superior with respect to complete polyp lesions were randomized in error before Central Reading Cen-
regression as assessed by ICGA at month 12. Once this was es- ter confirmation.
tablished, the next step was to show the superiority of combi- Baseline characteristics were comparable between groups.
nation therapy vs ranibizumab monotherapy with respect to Overall, the mean (SD) age of participants was 68.1 (8.8) years,
BCVA change from baseline to month 12. The secondary objec- and most participants were men (69.9%; Table). The mean

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 Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy Original Investigation Research

Table. Patient Demographics, Baseline Disease, and Ocular Table. Patient Demographics, Baseline Disease, and Ocular
Characteristics (Randomized Set) Characteristics (Randomized Set) (continued)

No. (%)a No. (%)a

Ranibizumab, Ranibizumab, Ranibizumab, Ranibizumab,
0.5 mg, + vPDT 0.5 mg 0.5 mg, + vPDT 0.5 mg
Parameter (n = 168) (n = 154) Parameter (n = 168) (n = 154)
Age, y No. of polypoidal lesions
No. 168 154 0 0 0
Mean (SD) 68.0 (8.5) 68.2 (9.0) 1 24 (14.3) 34 (22.1)
Age category, y 2 32 (19.0) 33 (21.4)
<50 0 4 (2.6) 3 32 (19.0) 23 (14.9)
50-<65 57 (33.9) 53 (34.4) 4 22 (13.1) 19 (12.3)
65-<75 73 (43.5) 56 (36.4) ≥5 56 (33.3) 42 (27.3)
75-<85 33 (19.6) 34 (22.1) Missing 2 (1.2) 3 (1.9)
≥85 5 (3.0) 7 (4.5) Polyp size, mm2
Sex No. 166 151
Male 109 (64.9) 116 (75.3) Mean (SD) 0.410 (0.426) 0.379 (0.331)
Female 59 (35.1) 38 (24.7) Presence of BVN
Race/ethnicity No 9 (5.4) 7 (4.5)
Chinese 64 (38.1) 59 (38.3) Yes 158 (94.0) 146 (94.8)
Indian (Indian subcontinent) 3 (1.8) 2 (1.3) Cannot grade 1 (0.6) 1 (0.6)
Japanese 46 (27.4) 38 (24.7) BVN size, mm2
Other 55 (32.7) 55 (35.7) No. 158 146
BCVA letter score Mean (SD) 3.140 (2.765) 2.614 (2.231)
No. 168 153
Abbreviations: BCVA, best-corrected visual acuity; BVN, branching vascular
Mean (SD) 61.1 (12.6) 61.2 (13.9) network.
Categorized BCVA letter score a
Percentages are based on total number of participants in the randomized set
(approximate Snellen equivalent) in the respective treatment group.
<39 (Worse than 20/160) 8 (4.8) 11 (7.1)
39 -54 (20/160 to Worse than 34 (20.2) 27 (17.5)
20/80)
baseline BCVA letter score was similar between the combina-
≥54 -<74) (20/80 to Worse than 97 (57.7) 87 (56.5)
20/32) tion (61.1 [approximate Snellen equivalent, 20/63]) and mono-
≥74 (20/32 or Better) 29 (17.3) 28 (18.2) therapy groups (61.2 [approximate Snellen equivalent, 20/
Missing 0 1 (0.6) 63]; Table). Most study eyes had occult with no classic
Central subfield thickness, μm component lesion types at baseline (Table). Overall, 294 par-
No. 159 149 ticipants completed the first 12 months of the study (158 in the
Mean (SD) 415.9 (143.7) 410.4 (170.9) combination arm and 136 in the monotherapy arm; Figure 1).
Type of lesion, No. (%)
100% classic 2 (1.2) 1 (0.6) Efficacy
Predominantly classic 2 (1.2) 0 At 12 months, mean improvement from baseline was 8.3 let-
Minimally classic 9 (5.4) 16 (10.4) ters with combination therapy vs 5.1 letters with mono-
Occult with no classic component 139 (82.7) 124 (80.5) therapy (mean difference, 3.2 letters; 95% CI, 0.4-6.1), indi-
Cannot grade 16 (9.5) 13 (8.4) cating that combination therapy met the predefined criterion
Presence of massive submacular for noninferiority. Combination therapy was statistically su-
hemorrhage perior to ranibizumab monotherapy in improving BCVA from
No 147 (87.5) 135 (87.7) baseline at month 12 (8.3 vs 5.1 letters; P = .01, eTable 1 in
Yes 19 (11.3) 15 (9.7) Supplement 2). Mean change in BCVA from baseline up to
Cannot grade 2 (1.2) 4 (2.6) month 12 is shown in Figure 2. Sensitivity analyses using dif-
Presence of serosanguinous ferent modeling methods and approaches for handling miss-
hemorrhage
ing data and outlier values produced similar results (eTables
No 72 (42.9) 61 (39.6)
2-4 in Supplement 2).
Yes 94 (56.0) 88 (57.1)
At month 12, 24.5% of participants (n = 38) in the combi-
Cannot grade 2 (1.2) 5 (3.2)
nation arm and 14.0% of participants (n = 19) in the mono-
Presence of polypoidal lesions
therapy arm showed a significant BCVA gain of at least 15 let-
No 2 (1.2) 3 (1.9)
ters (P = .03; eFigure 2 in Supplement 2). At month 12, the
Yes 166 (98.8) 151 (98.1)
proportion of participants with BCVA at least 69 letters of the
Cannot grade 0 0
study eye (approximately 20/40 Snellen equivalent) in-
(continued) creased from 32.7% at baseline to 69.0% in the combination

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 Research Original Investigation Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy

Figure 2. Mean Change in Best-Corrected Visual Acuity (BCVA) Figure 4. Mean Central Subfield Thickness (CSFT) Change
From Baseline to Month 12 (Full Analysis Set)
A Mean CSFT change from baseline
12
0
Mean Change in BCVA From Baseline

Mean CSFT Change From Baseline, μm

10
Ranibizumab, 0.5 mg, + vPDT (n = 168)
Ranibizumab, 0.5 mg (n = 154)
8 –50

6
–100
4

2 –150
Ranibizumab, 0.5 mg (n = 154)

0
Ranibizumab, 0.5 mg, + vPDT (n = 168)
Baseline 1 2 3 4 5 6 7 8 9 10 11 12 –200
Baseline 1 2 3 4 5 6 7 8 9 10 11 12
Time, mo
Time, mo

The total counts presented are the counts of patients in the specific treatment
B Proportion of patients
group who attended the specific visit. These total counts are used as the
denominator for the percentages. Error bars represent 95% CIs. vPDT indicates 100
verteporfin photodynamic therapy.

80
Proportion of Patients, %
Figure 3. Proportion of Participants With Complete Polyp Regression Ranibizumab, 0.5 mg (n = 154)
60
by Study Visits up to Month 12 in Full Analysis Set (FAS)

40
Ranibizumab, 0.5 mg, + vPDT (n = 168)
100
Ranibizumab, 0.5 mg (n = 154)
20
Ranibizumab, 0.5 mg, + vPDT (n = 168)
80
Porportion of Patients, %

60 Baseline 1 2 3 4 5 6 7 8 9 10 11 12
Time, mo
40
Mean CSFT change from baseline to month 12, full analysis set (FAS) (A) and
proportion of participants with disease activity by visit (FAS) (B) as assessed by
20 the investigators. Number values indicate the total number of participants in
the FAS in the respective treatment group. Percentages are computed by
considering the total number of participants in the respective treatment group
0
3 6 12 who attended the specific visit as a denominator. vPDT indicates verteporfin
photodynamic therapy.
Time, mo

Assessed by Central Reading Center using indocyanine green angiography. (least squares mean, −164.9 μm vs −113.4 μm, P < .001). In-
Number values indicate the total number of participants in the FAS in the
vestigator-assessed change in CSFT of the study eye from base-
respective treatment group. Percentages are computed by considering the total
number of participants in the respective treatment group who attended the line is illustrated in Figure 4A.
specific visit as a denominator. vPDT indicates verteporfin photodynamic The proportion of participants with disease activity from
therapy. month 3 to month 11 was lower in the combination arm than
in the monotherapy arm (month 3, 26.4% vs 60.7% and month
arm and from 40.8% at baseline to 58.8% in the mono- 11, 20.5% vs 50.0%; Figure 4B). At month 12, serosanguineous
therapy arm (eFigure 6 in Supplement 2). maculopathy was present in 14.8% of participants in the com-
Combination therapy showed statistically significant su- bination group (n = 23) and in 8.8% of participants in the mono-
periority to ranibizumab monotherapy in achieving com- therapy group (n = 12), whereas submacular hemorrhage (>4
plete polyp regression at month 12 as assessed by ICGA (69.3% disc areas) was reported in 1.3% of participants in the combi-
vs 34.7%; P < .001). The superiority of the combination arm nation group (n = 2) and 0.7% of participants in the mono-
vs the monotherapy arm in achieving complete polyp regres- therapy group 1). The anatomic outcomes can be clearly seen
sion was consistent from months 3 to 12 (Figure 3). In the com- in an example case provided (eFigure 4 in Supplement 2).
bination therapy group, 51.6% of participants showed ab-
sence of leakage on fluorescein angiography at month 12 vs 25% Treatment Exposure
in the monotherapy group (eFigure 3 in Supplement 2). The mean (median) number of ranibizumab injections admin-
The mean reduction in CSFT from baseline to month 12 was istered up to month 12 was 5.2 (4) for combination therapy and
greater in the combination arm than in the monotherapy arm 7.3 (7) for ranibizumab monotherapy, respectively (eTable 5 in

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 Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy Original Investigation Research

Supplement 2). The difference in the log injection rates be- ticipants receiving combination therapy (either at baseline or
tween the 2 groups was statistically significant (ratio of injec- deferred) had a VA gain of 8.1 and 8.8 letters, respectively.21
tion rates [ranibizumab, 0.5 mg, with vPDT/ranibizumab, 0.5 In contrast, participants with PCV in the DRAGON study
mg], 0.68; P < .001). Approximately 50.6% of participants showed a BCVA gain of 12.7 and 9.4 letters over 12 months with
(n = 87) in the combination arm required 3 or 4 ranibizumab monthly and PRN ranibizumab monotherapy, respectively.22
injections vs 26.2% of participants (n = 39) in the mono- The 12-month VA gains in the PLANET study, which assessed
therapy arm, while 32.2% of participants (n = 48) in the mono- fixed dosing of aflibercept in PCV participants with and with-
therapy arm required 10 to 12 injections over 12 months com- out rescue PDT, were reported to be 10.8 and 10.7 letters,
pared with 8.7% of participants in the combination arm (n = 15) respectively.23 Differences in baseline BCVA across the differ-
(eFigure 5A in Supplement 2). ent studies may account for the differences in BCVA gains be-
The mean (median) number of vPDT treatments in the cause poorer baseline BCVA is an important predictor of su-
combination arm was 1.5 (1), and the mean (median) number perior numerical change in BCVA. The baseline BCVA letter
of sham PDT treatments in the monotherapy arm was 2.3 (2) score for the ranibizumab PRN monotherapy arm in EVEREST
(eTable 1 in Supplement 2). Overall, 61.0% of the participants II (61.2 [approximate Snellen equivalent, 20/63]) was higher
in the combination arm needed only the first vPDT at base- than the baseline BCVA in the ranibizumab PRN arm in
line over the 12 months (eFigure 5B in Supplement 2). DRAGON (54.6 [approximate Snellen equivalent, 20/80])22 and
possibly higher than in the aflibercept and sham rescue PDT
Safety arm in PLANET (57.7).23 Importantly, therapeutic outcomes
Vitreous hemorrhage was the only serious ocular AE re- may be underrepresented by simply evaluating VA gains; other
ported in 1 patient in the combination arm (0.6%) and 3 pa- factors, such as anatomical responses, polyp regression, and
tients in the monotherapy arm (2.0%) (eTable 6 in Supplement treatment burden, need to be taken into account. In EVEREST,
2). No cases of endophthalmitis or retinal break/detachment combination therapy was superior to ranibizumab mono-
were reported in either treatment group. Rates of nonocular therapy in achieving complete polyp regression over 6 months
serious AEs were comparable between both treatment groups (77.8% vs 28.6%, P = .002).19 Similarly, in EVEREST II, com-
(7.6% in the combination arm vs 7.4% in the monotherapy arm). plete polyp regression rates at months 3, 6, and 12 were con-
One patient from the combination group died of chronic ob- sistently higher for combination therapy (71.4%, 71.3%, and
structive pulmonary disease. 69.7%) vs ranibizumab monotherapy (23.3%, 28.0%, and
Ocular AEs of the study eye were reported in 26.7% of par- 33.8%). In FUJISAN, the proportion of participants who showed
ticipants in the combination arm (n = 46) and 25.5% of par- resolution of polypoidal lesions at month 12 was in broad agree-
ticipants in the monotherapy arm (n = 38) (eTable 7 in ment with EVEREST II whether vPDT was given at baseline or
Supplement 2). The most common AEs were intraocular pres- deferred (62.1% vs 54.8%, respectively, P = .53).21 Impor-
sure increase (5.2% and 4.7%), retinal hemorrhage (3.5% and tantly, in contrast to these, complete polyp regression rates at
0.7%), and conjunctivitis (1.7% and 3.4%) in the combination month 12 in PLANET were only 38.9% for the aflibercept and
and monotherapy groups, respectively. Nonocular AEs, re- sham PDT arm and 44.8% for the aflibercept and rescue PDT
gardless of study drug relationship, were reported in 42.4% arm.22 This is substantially lower than combination therapy
(n = 73) and 37.6% (n = 56) of participants in the combination in EVEREST, EVEREST II, or FUJISAN and, in fact, similar to
and monotherapy groups, respectively. the 12-month complete polyp regression rates in the ranibi-
zumab monotherapy arm in EVEREST II. Taken together, these
findings further strengthen the concept that combination
therapy achieves superior BCVA outcomes than anti–
Discussion vascular endothelial growth factor monotherapy along with
The 12-month results of EVEREST II demonstrated that ranibi- concomitant higher polyp closure rates.24,25 Furthermore, the
zumab in combination with vPDT was not only noninferior but overall visual and anatomical outcomes of EVEREST II, the larg-
also superior to ranibizumab monotherapy in improving vi- est combination therapy RCT to our knowledge to date, are in
sion. In addition, combination therapy was found to be supe- concordance with the findings of meta-analyses conducted in
rior to monotherapy in achieving complete polyp regression. 2014 and 2016.16,24
Most patients maintained or reached at least 69 letters with In terms of treatment burden, an increasing concern in the
both treatment modalities at month 12 (eFigure 6 in anti–vascular endothelial growth factor therapy era, the mean
Supplement 2). Despite having high baseline BCVA, partici- number of ranibizumab injections required by the combina-
pants achieved notable BCVA gains of 8.3 letters and 5.1 let- tion arm was significantly lower than the monotherapy arm.
ters in the combination and monotherapy groups, respec- Over 12 months, 50.6% of the participants in the combination
tively. Importantly, over 12 months, the median number of arm required 3 to 4 ranibizumab injections, while only 8.7%
ranibizumab injections was 4 in the combination group com- of participants in this group required 10 to 12 injections. This
pared with 7 in the monotherapy group. This difference in in- reduction in injection number was similar to that observed in
travitreal injections could be significant in terms of cost- other studies evaluating combination therapies for the PCV
effectiveness in many countries. treatment.21,26 In FUJISAN, initial vPDT therapy led to signifi-
Our study should be compared with the few prospective cantly fewer additional ranibizumab treatments after the 3
PCV trials in the literature. In the 12-month FUJISAN study, par- loading doses vs deferred vPDT therapy.22 Combination therapy

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 Research Original Investigation Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy

may thus help reduce overall treatment burden and ulti- sured that only definite PCV cases were recruited. The EVEREST
mately PCV treatment costs. criteria have also been validated in real-world settings.3
In EVEREST II, both treatments showed a considerable 12-
month reduction in the proportion of participants with sero- Limitations
sanguineous mac ulopathy and massive submac ular The study had a few limitations. The administration of 3 ini-
hemorrhage,25,26 thus allaying physician fears about posttreat- tial monthly injections was presumptive because it was based
ment hemorrhage when using vPDT to treat PCV.25-31 The safety on nAMD treatment guidelines, which may not apply to com-
profiles of both treatment groups were comparable and con- bination treatment. Another potential limitation is that only
sistent, with vitreous hemorrhage being the only ocular seri- Asian participants with PCV were included, and the results may
ous AE reported during 12 months and low rates of retinal hem- be ethnospecific. Nevertheless, to our knowledge, no evi-
orrhage in both treatment groups. dence has suggested differential ethnic responses in PCV.
Polypoidal choroidal vasculopathy diagnosis has always
been challenging owing to its clinical and angiographic resem-
blance to other retinal pathologies, such as retinal angioma-
tous proliferation and central serous chorioretinopathy,18 po-
Conclusions
tentially leading to inappropriate therapy. For example, the The 12-month EVEREST II results confirm that combination
efficacy of anti–vascular endothelial growth factor therapy in treatment with ranibizumab and vPDT is effective in improv-
treating central serous chorioretinopathy is unestablished.32 ing vision of participants with symptomatic macular PCV. Im-
Furthermore, in some PCV cases, the polypoidal lesions may portantly, combination of ranibizumab with vPDT also helps
be ill-defined or may have extensive bleeding, which renders to achieve complete polyp regression, a key clinical outcome
diagnosis difficult. One of the strengths of EVEREST II was Cen- for PCV treatment. These functional and anatomical out-
tral Reading Center involvement during screening, using well- comes were achieved with fewer ranibizumab injections over
defined, stringent criteria modified from EVEREST.12,15 This en- 12 months, thereby reducing treatment burden.

ARTICLE INFORMATION Ruamviboonsuk, Tan, Feller, Margaron, Lim, Lee. for the conduct of the study and oversight of the
Accepted for Publication: August 15, 2017. Statistical analysis: Takahashi, Wong, Feller, collection and management of data.
Margaron. Group Information: The EVEREST II study group
Published Online: October 5, 2017. Administrative, technical, or material support: Lai,
doi:10.1001/jamaophthalmol.2017.4030 members are Kanji Takahashi, MD, Kansai Medical
Takahashi, Tan, Margaron, Lim. University Hospital, Hirakata-city, Osaka, Japan;
Open Access: This article is published under the Supervision: Koh, Takahashi, Ruamviboonsuk, Kunihiko Shiraki, MD, Osaka City University
JN-OA license and is free to read on the day of Margaron, Lim. Hospital, Osaka-city, Osaka, Japan; Yasuo Yanagi,
publication. Conflict of Interest Disclosures: All authors have MD, The University of Tokyo Hospital, Bunkyo-ku,
Author Affiliations: Eye and Retina Surgeons, completed and submitted the ICMJE Form for Tokyo, Japan; Satoshi Kato, MD, PhD, The
Camden Medical Centre, Singapore, Singapore Disclosure of Potential Conflicts of Interest. Dr Koh University of Tokyo Hospital, Bunkyo-ku, Tokyo,
(Koh); Department of Ophthalmology and Visual is a consultant for Novartis, Allergan, Carl Zeiss, Japan; Hiroko Terasaki, MD, Nagoya University
Sciences, The Chinese University of Hong Kong, Meditec, and Heidelberg Engineering. Dr Lai is a Hospital, Nagoya-city, Aichi, Japan; Masahito Ohji,
Hong Kong, China (Lai); Department of consultant for Allergan, Bayer, Novartis, and MD, Shiga University of Medical Science Hospital,
Ophthalmology, Kansai Medical University, Hirakata Genentech. Dr Takahashi is a consultant for Bayer Ohtsu-city, Shiga, Japan; Tetsuju Sekiryu, MD,
Hospital, Osaka, Japan (Takahashi); Singapore Eye and Novartis. Dr Wong received travel grants, Fukushima Medical University Hospital,
Research Institute, Singapore National Eye Centre, writing/reviewing fees, and consultancy fees from Fukushima-city, Fukushima, Japan; Shoji Kishi, MD,
Duke-NUS Medical School, National University of Novartis and Bayer during the conduct of the study Gunma University Hospital, Maebashi-city, Gunma,
Singapore, Singapore (Wong); Department of and consultancy fees from Abbott, Allergan, Japan; Masahiro Morimoto, MD, Gunma University
Ophthalmology, Mackay Memorial Hospital, Taipei, Genentech, Roche, and Pfizer outside the Hospital, Maebashi-city, Gunma, Japan; Tatsuro
Taiwan (Chen); Department of Ophthalmology, submitted work. Dr Chen receives financial support Ishibashi, MD, Kyushu University Hospital, Fukuoka
Rajavithi Hospital, Bangkok, Thailand from Novartis and Bayer and is a consultant for city, Fukuoka, Japan; Yuji Oshima, MD, Kyushu
(Ruamviboonsuk); Fundus Image Reading Centre, Bayer. Dr Ruamviboonsuk is a consultant for University Hospital, Fukuoka city, Fukuoka, Japan;
National Healthcare Group Eye Institute, Singapore Allergan, Bayer, and Novartis. Dr Tan receives Koh Hei Sonoda, MD, Kyushu University Hospital,
(Tan, Lim); National Healthcare Group Eye Institute, conference support from Bayer, Heidelberg Fukuoka city, Fukuoka, Japan; Rvusaburo Mori, MD,
Tan Tock Seng Hospital, Singapore (Tan, Lim); Engineering, and Novartis. Ms Feller and Dr Surugadai Nihon University Hospital, Kanda
Novartis Pharma AG, Basel, Switzerland (Feller, Margaron are employees of Novartis Pharma AG, surugadai, Chiyoda, Tokyo, Japan; Ayame Annabelle
Margaron); Department of Ophthalmology, Seoul Basel, Switzerland. Dr Lim receives travel support Okada, MD, Kyorin University Hospital, Shinkawa,
St Mary’s Hospital, The Catholic University of Korea, from Heidelberg Engineering and Novartis. Dr Lee is Mitaka, Tokyo, Japan; Tomohiro lida, MD,Tokyo
Seoul, Korea (Lee). a consultant for Alcon, Allergan, Bayer, Novartis, Women's Medical University Hospital, 8-1
Author Contributions: Drs Koh and Margaron had and Santen and is a trustee/board member for Kawada-cho, Shinjuku-ku, Tokyo, Japan; Takayuki
full access to all the data in the study and take Alcon, Allergan, Bayer, and Novartis. No other Baba, MD, Chiba University Hospital, lnohana
responsibility for the integrity of the data and the disclosures were reported Chuo-ku Chiba-shl Chiba, Japan; Fumio Shiraga,
accuracy of the data analysis. Funding/Support: This study was funded and MD, Okayama University Hospital, Shikata-cho,
Concept and design: Koh, Lai, Chen, managed by Novartis Pharma AG. Kita-ku, Okayama, Okayama, Japan; Hideyasu Oh,
Ruamviboonsuk, Tan, Lim, Lee. MD, Hyogo Prefectural Amagasaki General Medical
Role of the Funder/Sponsor: In conjunction with Center, Higashinaniwa-cho, Amagasaki-city, Hyogo,
Acquisition, analysis, or interpretation of data: Lai, the EVEREST II Steering Committee, Novartis
Takahashi, Wong, Chen, Ruamviboonsuk, Tan, Japan; Toshiya Sakurai, MD, Tane Memorial Eye
Pharma AG participated in the design of the study; Hospital, Sakaigawa, Nishi-ku, Osaka, Japan;
Feller, Margaron, Lim, Lee. analysis and interpretation of the data; preparation,
Drafting of the manuscript: Lai, Wong, Nagako Kondo, MD, Miyake Eye Hospital, Ozone,
review, and approval of the manuscript; and Kita- ku, NagOya City, Japan; Shigeru Honda, MD,
Ruamviboonsuk. decision to submit the manuscript for publication.
Critical revision of the manuscript for important Kobe University Hospital, 7-5-2, Kusunoki-cho,
Additionally, Novartis Pharma AG was responsible Chuo-ku, Kobe, Hyogo, Japan; Mineo Kondo, MD,
intellectual content: Koh, Lai, Takahashi, Chen,

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 Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy Original Investigation Research

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Japan; Masahiro Miura, MD, Tokyo Medical Polypoidal choroidal vasculopathy: simultaneous efficacy and safety of verteporfin photodynamic
University Ibaraki Medical Center, Inashiki-gun indocyanine green angiography and eye-tracked therapy in combination with ranibizumab or alone
Ibaraki, Japan; Chieko Shiragami, MD, Kagawa spectral domain optical coherence tomography versus ranibizumab monotherapy in patients with
University Hospital, Kita-gun, Kagawa Japan; Yasuo findings. Retina. 2012;32(6):1057-1068. symptomatic macular polypoidal choroidal
Kurimoto, MD, Kobe City Medical Center General 6. Rosa RH Jr, Davis JL, Eifrig CW. Clinicopathologic vasculopathy. Retina. 2012;32(8):1453-1464.
Hospital, Kobe-city, Hyogo, Japan; Yuk Yau Timothy reports, case reports, and small case series: 20. Oishi A, Kojima H, Mandai M, et al. Comparison
LAI, MD, FRCS(Ed), FRCOphtha, FHKAM, Chinese clinicopathologic correlation of idiopathic of the effect of ranibizumab and verteporfin for
University of Hong Kong, Hong Kong; Lan Y. H. polypoidal choroidal vasculopathy. Arch Ophthalmol. polypoidal choroidal vasculopathy: 12-month
Wong, MMed, FRCS(Ed), FRCOphthaHK, FHKAM, 2002;120(4):502-508. LAPTOP study results. Am J Ophthalmol. 2013;156
Queen Mary Hospital, Hong Kong; Wonki Lee, MD, (4):644-651.
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Bundang Hospital, Bundang Seongnam, Korea; 19-29. polypoidal choroidal vasculopathy: The Fujisan
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Hospital, Seoul, Korea; Eung Suk Kim, MD, PhD, of smoking and cardiovascular risk factors with 22. Li X, Zhu A, Egger A, et al. Ranibizumab 0.5 mg
Kyung Hee University Hospital, Seoul, Korea; polypoidal choroidal vasculopathy and age-related in patients with polypoidal choroidal vasculopathy:
Dongwon Lee, MD, PhD, Kim's Eye Hospital, Seoul, macular degeneration in Chinese persons. results from the DRAGON study. Paper presented
Korea; Taegon Lee, MD, Kim's Eye Hospital, Seoul, Ophthalmology. 2011;118(5):846-852. at: American Academy of Ophthalmology; October
Korea; Nikolle Tan, MMed, FRCS(Ed), Tan Tock Seng 9. Cheung CM, Laude A, Yeo I, et al. Systemic, 17, 2016; Chicago, IL.
Hospital, Ophthalmology, Singapore; Rajesh ocular, and genetic risk factors for age-related 23. Iida T. Results of the Planet Study. Paper
Rajagopalan, MBBS, FRCS(Ed), Tan Tock Seng macular degeneration and polypoidal choroidal presented at: Asia-Pacific Vitreo-retina Society
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Cheung, MBBS, FRCOphtha, Singapore National Eye 41386. Thailand.
Centre, Singapore; Caroline Ka Lin Chee, MMed,
FRCS(Ed), National University Hospital, Singapore; 10. Koh AH, Chen LJ, Chen SJ, et al; Expert PCV 24. Wang W, He M, Zhang X. Combined intravitreal
Shih-Jen Chen, MD, PhD, Taipei Veterans General Panel. Polypoidal choroidal vasculopathy: anti-VEGF and photodynamic therapy versus
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Gung Memorial Hospital Linkou, Lin-Ko, Taiwan; treatment. Retina. 2013;33(4):686-716. choroidal vasculopathy: a systematic review and
Lee-Jen Chen, MD, MacKay Memorial Hospital, Taipei, 11. Wong CW, Yanagi Y, Lee WK, et al. Age-related meta-analysis of comparative studies. PLoS One.
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Changhua Christian Hospital, Changhua, Taiwan; 107-139. Three-year visual outcomes of intravitreal
Shwu-Jiuan Sheu, MD, Kaohsiung Veterans General 12. Tan CS, Ngo WK, Chen JP, Tan NW, Lim TH; ranibizumab with or without photodynamic
Hospital, Kaohsiung, Taiwan; Paisan Ruamviboonsuk, EVEREST Study Group. EVEREST study report 2: therapy for polypoidal choroidal vasculopathy. Acta
MD, Rajavithi Hospital, Bangkok, Thailand; Prut imaging and grading protocol, and baseline Ophthalmol. 2016;94(8):e765-e771.
Hanutasaha, MD, Ramathibodi Hospital, Bangkok, characteristics of a randomised controlled trial of 26. Akaza E, Yuzawa M, Matsumoto Y, Kashiwakura
Thailand; Patama Bhurayanontachai, MD, polypoidal choroidal vasculopathy. Br J Ophthalmol. S, Fujita K, Mori R. Role of photodynamic therapy in
Songklanagarind Hospital, Songkla, Thailand; Nor 2015;99(5):624-628. polypoidal choroidal vasculopathy. Jpn J Ophthalmol.
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Additional Contribution: We thank Mayuri Shinde,
Scientific Services Practice, Product Lifecycle genetic predisposition. Ophthalmologica. 2014;231 28. Lee WK, Lee PY, Lee SK. Photodynamic therapy
Services, Novartis Healthcare Pvt Ltd, Hyderabad, (2):59-74. for polypoidal choroidal vasculopathy:
India, and Steven Cartmell, Product Lifecycle 15. Iida T. Polypoidal choroidal vasculopathy with vaso-occlusive effect on the branching vascular
Services, Novartis Ireland Ltd, Dublin, Ireland for an appearance similar to classic choroidal network and origin of recurrence. Jpn J Ophthalmol.
medical writing and editorial assistance towards the neovascularisation on fluorescein angiography. Br J 2008;52(2):108-115.
development of this article, and Mitsuko Yuzawa, Ophthalmol. 2007;91(9):1103-1104. 29. Lee YH, Lee EK, Shin KS, Lee KM, Kim JY.
MD, Department of Ophthalmology, Nihon 16. Tang K, Si JK, Guo DD, et al. Ranibizumab alone Intravitreal ranibizumab combined with verteporfin
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work as first chair of the steering committee. photodynamic therapy for polypoidal choroidal choroidal vasculopathy. Retina. 2011;31(7):1287-1293.
vasculopathy: a systematic review and 30. Hirami Y, Tsujikawa A, Otani A, et al.
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2. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. polypoidal choroidal vasculopathy: the group features and follow-up results of pulsating
Idiopathic polypoidal choroidal vasculopathy experience with digital fundus photography and polypoidal choroidal vasculopathy treated with
(IPCV). Retina. 1990;10(1):1-8. confocal scanning laser ophthalmoscopy. Retina. photodynamic therapy. Acta Ophthalmol. 2010;88
3. Cheung CM, Laude A, Wong W, et al. Improved 2014;34(12):2397-2406. (6):660-668.
specificity of polypoidal choroidal vasculopathy 18. Tan CS, Ngo WK, Lim LW, Tan NW, Lim TH; 32. Lim JW, Ryu SJ, Shin MC. The effect of
diagnosis using a modified EVEREST criteria. Retina. EVEREST Study Group. EVEREST study report 3: intravitreal bevacizumab in patients with acute
2015;35(7):1375-1380. diagnostic challenges of polypoidal choroidal central serous chorioretinopathy. Korean J
4. Kokame GT. Polypoidal choroidal vasculopathy: vasculopathy: lessons learnt from screening failures Ophthalmol. 2010;24(3):155-158.
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 Supplementary Online Content

Koh A, Lai TYY, Takahashi K, et al; the EVEREST II Study Group. Efficacy and safety of
ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal
vasculopathy: a randomized clinical trial. JAMA Ophth. Published online October 5, 2017.
doi:10.1001/jamaophthalmol.2017.4030

eMethods.
eFigure 1: Retreatment Algorithm
eFigure 2: Categorized Change in BCVA at Month 12 (FAS)
eFigure 3: Proportion of Patients With No Leakage in the Study Eye, by Visit From Months 3 to
12 (FAS)
eFigure 4: Example Case of PCV Patient Treated With Ranibizumab 0.5 mg + vPDT
Combination Therapy – Baseline OCT
eFigure 5. Frequency of Ranibizumab Injections Administered Over 12 Months (Safety Set)
eFigure 6: Proportion of Patients With BCVA ≥69 letters at Baseline and Month 12 (FAS)
eTable 1: Treatment Comparison For Change in the Best-Corrected Visual Acuity From
Baseline at Month 12 (FAS, LOCF)
eTable 2: Treatment Comparison for Change in the Best-Corrected Visual Acuity From
Baseline at Month 12 (Per Protocol Set, LOCF)
eTable 3: Treatment Comparison for Change in the Best-Corrected Visual Acuity From
Baseline at Month 12 (FAS)
eTable 4: Treatment Comparison for Change in the Best-Corrected Visual Acuity From
Baseline at Month 12 (FAS)
eTable 5: Number of Ranibizumab Injections and PDT Treatments Administered Over 12
Months (Safety Set)
eTable 6: Ocular and Nonocular Serious Adverse Events Regardless of Study Drug
Relationship Up to Month 12 (safety set)
eTable 7: Ocular and Nonocular Adverse Events Regardless of Study Drug Relationship Up to
Month 12 by Preferred Term

eReferences
This supplementary material has been provided by the authors to give readers additional
information about their work. 

© 2017 American Medical Association. All rights reserved. 
eMethods
Patient inclusion and exclusion criteria
 
Inclusion criteria for patients 
 Patients must provide written informed consent before any assessment is performed 
 Male or female aged ≥18 years 
Inclusion criteria for the study eye 
 Confirmed diagnosis of symptomatic macular PCV defined by 
o Active macular polypoidal lesions shown by ICGA and 
o Presence of serosanguinous maculopathy (i.e. exudative or hemorrhagic features 
involving the macula on CF photography and FA) 
 BCVA letter score between 78‐24 (approximately 20/32 to 20/320 Snellen equivalent) 
using ETDRS VA chart measured at 4 m 
 GLD of the total lesion area (BVN + polyps) < 5400 μm (approximately 9 Macular 
Photocoagulation Study disc areas) as delineated by ICGA 
Exclusion criteria for patients 
 Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test 
 Women of child‐bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. 
Exclusion criteria for systemic medical history or conditions 
 Any type of systemic disease or its treatment, including any medical condition 
(controlled or uncontrolled) that over the duration of the study could be expected to 
progress, recur, or change to such an extent that it may bias the assessment of the 
clinical status of the patient to a significant degree or put the patient at special risk 
 History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases 
 Stroke or myocardial infarction within the past 3 months prior to screening 
 History of porphyria 
 Uncontrolled blood pressure defined as systolic value of >160 mm Hg or diastolic value 
of >100 mm Hg while sitting at screening or baseline 
 Known hypersensitivity to any of the study drugs (ranibizumab or verteporfin) or any 
component of their formulations or to drugs of similar chemical classes and to 
fluorescein or indocyanine green 
Exclusion criteria for prior or current systemic medication 
 Use of other investigational drugs within 30 days or 5 half‐lives prior to screening, 
whichever is longer 

© 2017 American Medical Association. All rights reserved. 
  Previous treatment with systemic anti‐VEGF drugs within 6 months prior to screening 
(e.g., sorafenib , sunitinib, bevacizumab) 
 Use of systemic corticosteroids for more than 30 consecutive days during the past 3 
months prior to screening 
 Current or planned use of systemic medications known to be toxic to the lens, retina or 
optic nerve including deferoxamine, chloroquine/hydroxychloroquin, tamoxifen, 
phenothiazines, and ethambutol 
 
Exclusion criteria for ocular medical history and conditions 
 Presence of angioid streaks, macular fibrosis, presumed ocular histoplasmosis 
syndrome, or pathologic myopia (evidence of posterior segment abnormalities 
consistent with pathologic myopia) 
 Tear (rip) of the retinal pigment epithelium involving the fovea at the time of screening 
or baseline 
 Fibrosis or geographic atrophy involving the fovea 
 Active ocular inflammation or infection (ocular or periocular) at the time of screening or 
baseline 
 Uncontrolled intraocular hypertension or glaucoma (IOP≥ 30 mmHg) despite treatment 
with anti‐glaucoma medication at the time of screening or baseline 
 History of rhegmatogenous retinal detachment or macular hole (stage 3 or 4) 
 Ocular disorders in the study eye (e.g. cataract, retinal vascular occlusion, diabetic 
retinopathy) that in the opinion of the investigator, may confound the interpretation of 
study results or compromise VA or require medical or surgical intervention during the 
study period 
 Inability to obtain photographs, FAs, ICGAs, or OCTs to document the lesion (e.g. due to 
media opacity, insufficient pupillary dilation, or lack of venous access) 
 
Exclusion criteria for prior or current ocular treatment 
 Prior treatment with verteporfin PDT, external‐beam radiation, subfoveal or extrafoveal 
focal laser photocoagulation, submacular surgery, or transpupillary thermotherapy 
 Prior treatment with any anti‐VEGF compound or any investigational treatment 
 History of intraocular surgery in the study eye including pars plana vitrectomy and 
intraocular hemorrhage displacement (e.g. injection of gas with or without tissue 
plasminogen activator) 
 Cataract surgery within 60 days prior to screening or prior complicated cataract surgery 
 History of YAG laser posterior capsulotomy in the study eye within 30 days prior to 
screening 
 Treatment with intravitreal or subtenon corticosteroid injection or device implantation 
within 90 days prior to screening 

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