Sustained Benefits from Ranibizumab for

Central Retinal Vein Occlusion with

Macular Edema: 24-Month Results of the
CRYSTAL Study
Michael Larsen, MD,1 Sebastian M. Waldstein, MD,2 Siegfried Priglinger, MD,3 Philip Hykin, MD,4
Elizabeth Barnes, PhD,5 Margarita Gekkieva, MD,5 Ayan Das Gupta, MSc,6 Andreas Wenzel, PhD,5
Jordi Monés, MD, PhD,7 on behalf of the CRYSTAL Study Group

Purpose: To assess the efficacy and safety profile of an individualized, stabilization criteriaedriven regimen
of ranibizumab 0.5 mg in patients with visual impairment due to macular edema secondary to central retinal vein
occlusion (CRVO).
Design: A 24-month, prospective, open-label, single-arm, multicenter study.
Participants: A total of 357 patients.
Methods: Patients received monthly ranibizumab 0.5 mg injections (minimum, 3 injections) until stable visual
acuity (VA) was maintained for 3 consecutive months. Thereafter, ranibizumab 0.5 mg injections were adminis-
tered if monitoring indicated a loss of VA due to disease activity. The primary outcome results have been
published previously.
Main secondary outcome measures: Mean change from baseline at months 1 through 24 in best-corrected
VA (BCVA) in the overall population and in subgroups categorized according to baseline BCVA, CRVO duration, or
presence of macular ischemia.
Results: The baseline mean BCVA was 53.0 letters and baseline mean CRVO duration was 8.9 months
(median, 2.4 months). The mean (standard deviation) gain in BCVA from baseline with ranibizumab 0.5 mg at
month 24 was 12.1 (18.60) letters (P < 0.0001). Best-corrected VA gains at month 24 were similar in patients with
or without baseline macular ischemia (mean change, 11.1 and 12.9 letters, respectively). The mean BCVA gain at
month 24 was higher in patients with CRVO duration <3 months (13.2 letters) compared with that in those with
CRVO duration >9 months (10.5 letters). Patients with lower baseline BCVA had larger mean BCVA gains at
month 24 (
39 letters; 18.5 letters) than those with higher baseline BCVA (40e59/60 letters; 13.9/7.2 letters),
although the absolute BCVA values at month 24 were higher in patients with higher baseline BCVA. The mean
(standard deviation) and median number of ranibizumab injections up to month 23 were 13.1 (6.39) and 15.0
injections, respectively. No new ocular or nonocular safety events were reported.
Conclusion: An individualized, stabilization criteriaedriven dosing regimen of ranibizumab 0.5 mg led to
sustained BCVA gains for up to 24 months in patients with CRVO. The presence of macular ischemia at baseline
did not influence VA gains. Shorter duration of CRVO at baseline was associated with better VA gains. Safety
findings were consistent with those reported in previous ranibizumab studies in patients with
CRVO. Ophthalmology Retina 2018;2:134-142 ª 2017 by the American Academy of Ophthalmology. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Supplemental material available at http://www.ophthalmologyretina.org.

Central retinal vein occlusion (CRVO) is a sight-threatening
retinal vascular disease with an estimated global prevalence
of 0.08%.1,2 Intravitreal antievascular endothelial growth
factor (VEGF) agents are considered to be the first-line
treatment option for improving visual outcomes in patients
with retinal vein occlusion (RVO).3,4
The long-term efficacy and safety of ranibizumab 0.5 mg
was assessed in the CRYSTAL study in a broad population of
patients with visual impairment due to macular edema
secondary to CRVO. The study did not exclude patients with
retinal ischemia or specify a limit for the duration of CRVO
prior to enrollment. An individualized visual acuity (VA)
stabilization criteriaedriven dosing regimen of ranibizumab
0.5 mg, as recommended in the 2011 European Union Sum-
mary of Product Characteristics,5 was assessed in the study.
The primary outcome (mean change in best-corrected
VA [BCVA] from baseline as measured at month 12) and
other efficacy and safety results up to month 12 have been

134  2017 by the American Academy of Ophthalmology http://dx.doi.org/10.1016/j.oret.2017.05.016

This is an open access article under the CC BY-NC-ND license ISSN 2468-6530/17
(http://creativecommons.org/licenses/by-nc-nd/4.0/). Published by Elsevier Inc.
 Larsen et al 
Sustained Benefits with Individualized Ranibizumab in CRVO
published previously.6 Here we report the 24-month results
of the CRYSTAL study.
Materials and Methods
Study Design and Treatment
The CRYSTAL study (NCT01535261) was a 24-month, phase
IIIb, open-label, single-arm, multicenter study conducted between
February 2012 and March 2015. The study was conducted in
accordance with the Declaration of Helsinki, and the study protocol
was reviewed and approved by the independent ethics committee
or institutional review board of each contributing center. Patients
provided written informed consent before entering the study.
The detailed study design has been published elsewhere.6
Patients received monthly ranibizumab 0.5 mg injections
(minimum of 3 injections at baseline, month 1, and month 2)
until VA was stable for 3 consecutive months. Thereafter,
ranibizumab 0.5 mg was administered when monitoring indicated
a loss of VA due to disease activity, and treatment was
continued until VA was stabilized (defined as 3 consecutive
visits with stable VA [based on investigator’s judgment],
implying a minimum of 2 further monthly injections). All
patients were to be treated according to an individualized,
stabilization criteriaedriven pro re nata dosing with ranibizumab
0.5 mg, with monthly visits in the first year. As of month 12, if
VA stabilization and the absence of disease activity were
maintained over repeated visits, the monitoring interval could be
increased to every 2 months.
Patients
Patients were 18 years of age with visual impairment due to
macular edema secondary to CRVO with an Early Treatment
Diabetic Retinopathy Study (ETDRS) BCVA letter score ranging
from 73 to 19 (inclusive; approximate Snellen equivalent of 20/40
and 20/400) at screening and at baseline. The detailed study se-
lection criteria have been published elsewhere.6
Objectives
The study objectives up to month 24 included mean change and
mean average change in BCVA; proportion of patients achieving
BCVA improvement of 1, 5, 10, 15, and 30 letters, those
with a BCVA loss of <15 letters, and those reaching a BCVA 73
letters; mean change in central reading center (CRC)eassessed
central subfield thickness (CSFT) from baseline; and safety.
The main study objectives up to month 24 included mean
change in BCVA from month 1 to month 24 compared with
baseline and safety over 24 months. The details of the secondary
objectives have been described previously.6 The exploratory
objectives are provided in Appendix 1 (available at
www.ophthalmologyretina.org).
Assessments
BCVA was assessed at every study visit by certified assessors
using an ETDRS VA testing chart at an initial testing distance of
4 m. Spectral domain OCT was performed by certified operators at
every study visit (for an individual patient, the same machine was
used throughout the study). The images were reviewed by a CRC
to ensure standardized evaluation of CSFT (defined as the average
retinal thickness of the circular area with a 1-mm diameter around
the foveal center) and central foveal thickness (CFT), and to cap-
ture the presence or absence of qualitative parameters (i.e., intra-
retinal cystoid fluid and subretinal fluid). Retinal ischemia was
assessed at baseline and months 3, 12, and 24 using fluorescein
angiography in conjunction with 7-field color fundus photography
performed by certified operators at the site. Here, we present the
results of CRC-assessed macular ischemia, defined as present if the
CRC scored retinal capillary loss (presence or absence of non-
perfusion) as mild, moderate, severe, or completely destroyed in
1 location of the center, inner, or outer subfields of the ETDRS
grid. The specific grading procedure used by the CRC has been
reported in detail previously.6
Treatment Exposure. Information regarding the number of
ranibizumab injections from baseline to month 24 was collected.
Safety Assessments. All adverse events (AEs) and serious AEs
(SAEs) with their type, frequency, severity, and relationship to the
study drug or ocular injection procedure were recorded at all visits
up to 24 months. Vital signs were measured and ophthalmic ex-
aminations were performed at each study visit.
Statistical Analysis
All end points related to the mean change from baseline by visit
and CRC-assessed categorical parameters were descriptively
summarized. The number and proportion of patients with BCVA
letter gain or loss from baseline were assessed using 95% confi-
dence intervals based on binomial distribution. All efficacy ana-
lyses up to 24 months that compared response to baseline were
calculated using a t distribution/t test and 95% confidence intervals,
and P values were 2-sided based on an a significance level of 0.05.
The last-observation-carried-forward approach was used to impute
missing variables. Statistical analysis was performed using SAS
software version 9.2 (SAS Institute, Cary, NC). Three repeated-
measures models were designed to investigate the potential of OCT
in predicting VA outcomes using the observed data at visits
where OCT was assessed by the CRC (details are provided in
Appendix 2, available at http://www.ophthalmologyretina.org).
All efficacy analyses were performed using the full analysis set
(FAS), which included all patients who received 1 administration
of study treatment and underwent 1 assessment of BCVA in the
study eye after baseline. Safety analyses were performed using the
safety set, which included all patients who received 1 adminis-
tration of study treatment and underwent 1 safety assessment
after baseline.
Results
In total, 357 patients were enrolled and 307 (86%) completed the
24-month study. The most common reasons for discontinuation
were withdrawal of consent (n ¼ 14 [3.9%]) and AEs (n ¼ 12
[3.4%]). The safety set included 357 patients, and the FAS
included 356 patients (1 patient with no assessment after baseline
was excluded).
At baseline, the mean age of the enrolled patients (n ¼ 357) was
65.5 years (standard deviation [SD], 12.68 years), and a majority of
the patients were men (n ¼ 229 [64.1%]) and white (n ¼ 337
[94.4%]). The mean duration of CRVO was 8.9 months (SD, 20.66
months), and the median duration was 2.4 months (quartile 1, 0.9
months; quartile 3, 8.7 months).6
Efficacy
Best-corrected Visual Acuity. The mean BCVA at baseline in
the study eye was 53.0 letters (SD, 15.00 letters). Rapid gains in
mean BCVA were observed with ranibizumab 0.5 mg treatment at
months 3 and 6, and the gains were maintained until month 24
(65.1 letters [SD, 21.17 letters]; Fig 1). The mean change in BCVA
135
 Ophthalmology Retina Volume 2, Number 2, February 2018
Figure 1. Mean best-corrected visual acuity (BCVA) from baseline to
month 24 in the overall population and by baseline BCVA category (full
analysis set [last observation carried forward]). The full analysis set included
all patients who received 1 administration of study treatment and un-
derwent 1 assessment for BCVA in the study eye after baseline. *P <
0.0001 vs. baseline. All postbaseline comparisons for individual time points
up to month 24 vs. baseline showed a P value <0.0001. D8 ¼ day 8;
ETDRS ¼ Early Treatment Diabetic Retinopathy Study; SE ¼ standard
error of the mean; VA ¼ visual acuity.
from baseline to month 24 was þ12.1 letters (SD, 18.60 letters).
The mean average change in BCVA from baseline to month 1
through month 24 with ranibizumab 0.5 mg treatment was þ12.1
letters (SD, 14.20 letters) (P < 0.0001). At month 24, 45.2% of
study eyes (n ¼ 161) attained a BCVA score 73 letters.
Table 1 shows the proportion of study eyes with categorical
gains in BCVA. The proportion of study eyes with a >15-letters
loss was 5.9% (n ¼ 21) at month 12 and 6.2% (n ¼ 22) at
month 24.
Exploratory subgroup analyses showed that the BCVA gains
from baseline observed at month 24 were similar in study eyes with
and without macular ischemia (mean, 11.1 letters [SD, 17.78 let-
ters] vs. 12.9 letters [18.61 letters], respectively; Fig 2A). In
addition, the VA gains observed were unaffected by the severity
of ischemia at baseline (Fig 2B). Study eyes with a lower
baseline BCVA (
39 letters [Snellen equivalent,
20/200]) had
a higher mean change in BCVA from baseline at month 24 (18.5
letters [SD, 17.38 letters]) compared with those with a higher
baseline BCVA (40e59 letters [Snellen equivalent, 20/160e20/
80]: 13.9 letters [SD, 18.70 letters]; 60 letters [Snellen
equivalent, 20/63]: 7.2 letters [SD, 17.95 letters]). However,
Table 1. Proportion of Study Eyes With Categorical Gains in
Best-Corrected Visual Acuity (Full Analysis Set [Last Observation
Carried Forward])
Categorical Gains in
BCVA (ETDRS Letters) Ranibizumab 0.5 mg (N [ 356), %
1 81.5
5 74.4
10 62.9
15 49.2
30 12.4
BCVA ¼ best-corrected visual acuity; ETDRS ¼ Early Treatment Diabetic
Retinopathy Study.
136
Figure 2. Mean change in best-corrected visual acuity (BCVA) from
baseline to month 24 (full analysis set [last observation carried forward])
(A) by presence of macular ischemia at baseline and (B) by severity of
macular ischemia at baseline. The full analysis set included all patients who
received 1 administration of study treatment and underwent 1 assess-
ment for BCVA in the study eye after baseline. Patients’ ischemic status
was based on the subfield of maximum severity from the center, inner, and
outer subfields. “Severe” includes severe and completely destroyed.
Ischemia was defined as “present” if the central reading center scored
capillary nonperfusion as “mild,” “moderate,” “severe,” or “completely
destroyed” in 1 location of the center, inner, or outer subfields. Mild: up
to one third of the area of the corresponding subfield is not perfused;
moderate: up to two thirds of the corresponding subfield are not perfused;
severe: more than two thirds of the area of the corresponding subfield are
not perfused; completely destroyed: nonperfusion involving the entire
corresponding subfield. ETDRS ¼ Early Treatment Diabetic Retinopathy
Study; SE ¼ standard error of the mean; VA ¼ visual acuity.
the absolute mean BCVA values at month 24 were higher in
study eyes with higher baseline BCVA than in those with a
lower baseline BCVA (Fig 1); the mean BCVA at month 24 was
47.8 letters (SD, 18.14 letters) among study eyes with baseline
BCVA
39 letters, and 73.9 letters (SD, 18.22 letters) among
those with baseline BCVA 60 letters. Study eyes with a BCVA
of 70 to 73 letters (Snellen equivalent, 20/40) at baseline (mean,
71.8 letters [SD, 0.93 letters]) had an absolute mean BCVA of
79.8 letters (SD, 13.65 letters) at month 24 (mean gain from
baseline of 8.0 letters [SD, 13.60 letters]). At month 24, study
eyes with shorter disease duration of CRVO at baseline (<3
months) exhibited slightly higher mean BCVA gains (13.2
letters) than those with longer disease duration at baseline (3e9
months: 11.3 letters; >9 months: 10.5 letters; Fig 3).
Anatomical Outcomes. The mean CSFT in the study eye
decreased from baseline to month 24 with ranibizumab 0.5 mg
treatment (693.7 mm [SD, 231.64 mm] vs. 344.6 mm [178.23 mm]).
The maximum reduction in CSFT from baseline was reached by
 Larsen et al 
Sustained Benefits with Individualized Ranibizumab in CRVO
Figure 3. Mean change in best-corrected visual acuity (BCVA) from
baseline to month 24 by duration of central retinal vein occlusion (CRVO)
at baseline (full analysis set [last observation carried forward]). The full
analysis set included all patients who received 1 administration of study
treatment and underwent 1 assessment for BCVA in the study eye after
baseline. ETDRS ¼ Early Treatment Diabetic Retinopathy Study; VA ¼
visual acuity.
month 3, and the reduction was maintained up to month 24
(Fig 4).
The proportion of study eyes with CRC-assessed CSFT and
CFT
450 mm (predefined cutoff value) increased from baseline to
month 24, whereas the proportion of study eyes with visible
intraretinal cystoid fluid and subretinal fluid decreased (Table 2;
available at www.ophthalmologyretina.org).
Other Efficacy Analyses. At baseline, CRC-assessed
macular ischemia was present in 107 of the 356 study eyes
(30.1%) in the FAS population. The proportion of study eyes
with macular ischemia decreased over time with ranibizumab
treatment and was 16.3% (n ¼ 58) at month 3, 17.1% (n ¼ 61) at
month 12, and 12.9% (n ¼ 46) at month 24. Figure 5 shows
fluorescein angiography images of a study eye with capillary
nonperfusion that was graded as moderate to severe at baseline
and as questionable to mild at month 24. In addition, the
proportion of study eyes in the FAS (observed, n ¼ 356) with
investigator-assessed nonperfusion within the 3-mm perifoveal
subfield decreased from baseline (19.4% [n ¼ 69]) to month 24
(4.5% [n ¼ 16]).
Moreover, an inverse correlation was observed between the
mean CRC-assessed CSFT decrease in the study eye and the mean
BCVA increase from baseline up to month 24. Most of the
decrease in CSFT and improvement in BCVA had occurred by
month 1. The parameter estimates for associations between BCVA
(letters) and CRC-assessed CSFT in the study eye up to month 24
were 0.0260 (P < 0.0001) for model 1, 0.0272 (P < 0.0001)
for model 2, and 0.0021 (P ¼ 0.0401) for model 3. Similar results
were observed for CFT.
Treatment Exposure
The mean number of ranibizumab injections received in the study
eye was 13.1 (SD, 6.39 injections [median, 15.0 injections]) before
month 24 (Fig 6), of which 8.1 injections (SD, 2.77 injections
[median, 9.0 injections]) were received before month 12. The
first visit at which an injection was not given due to disease
stabilization was month 3 for 141 study eyes (39.5%) and month
23 for 1 study eye (0.3%). During the study, 33 study eyes
Figure 4. Mean change in central subfield thickness (CSFT) from baseline
to month 24 (full analysis set [last observation carried forward]). The full
analysis set included all patients who received 1 administration of study
treatment and had 1 assessment for best-corrected visual acuity in the
study eye after baseline. *P < 0.0001 vs. baseline, as assessed by the central
reading center. SE ¼ standard error of the mean.
(9.2%) received only 3 injections, whereas 5 (1.4%) received the
maximal exposure of 24 injections (Fig 6). The number of
ranibizumab injections was similar in study eyes with or without
macular ischemia (mean, 12.2 injections [SD, 6.51 injections] vs.
13.1 injections [6.74 injections], respectively).
In the second year, when treatment was interrupted because of
stabilization criteria and monitoring could be bimonthly (skipped
visit), monitoring for 122 patients (34.3%) could be extended to
bimonthly visits; 84 of these 122 patients (23.6% of all patients)
did not need re-treatment at the subsequent visit following the start
of bimonthly monitoring (i.e., they had a successfully skipped
visit).
Overall, 275 patients had a treatment interruption (due to dis-
ease stabilization) followed by a reinitiation of treatment (after a
drop in BCVA due to disease activity); of these, 263 patients
(95.6%) recovered BCVA to the level prior to treatment interrup-
tion (mean [SD] difference between before interruption vs.
following reinitiation, 1.1 letters [8.36 letters]).
Safety
Serious Adverse Events. Ocular SAEs in the study eye were
reported in 10 patients (2.8%) up to month 24 (Table 3; available at
www.ophthalmologyretina.org). Glaucoma, retinal ischemia, and
reduced VA were reported as SAEs in 2 patients (0.6%) each. All
other ocular SAEs were reported in 1 patient (0.3%) each. Four
SAEs reported in 2 patients were suspected to be related to the
ocular injection procedure; these occurred in the first 12 months,
and the results have been previously reported.6 Study treatment
discontinuation due to SAEs was reported in 2 patients (retinal
ischemia and glaucoma [reported term: neovascular glaucoma] in 1
patient [0.3%] each). The investigator did not suspect a
relationship between the events and the study medication or
injection procedure.
Nonocular SAEs were reported in 54 patients (15.1%; Table 3;
available at www.ophthalmologyretina.org). Atrial fibrillation,
cardiac failure, congestive cardiac failure, myocardial infarction,
lower respiratory tract infection, and pneumonia were reported in 3
patients (0.8%) each; moreover, acute pancreatitis, femoral neck
fracture, bladder cancer, breast cancer, cerebrovascular accident,
137
 Ophthalmology Retina Volume 2, Number 2, February 2018

Figure 5. Fluorescein angiography images from the same eye at baseline and month 24 showing improvement in capillary perfusion and reduction in retinal
vascular leakage with ranibizumab treatment. Images shown are of a study eye with capillary nonperfusion graded as (A) moderate to severe at baseline and
(B) questionable to mild at month 24.

anxiety, acute renal failure, pleural effusion, and hypertension were accident [n ¼ 2], cardiac failure [n ¼ 2], and chest pain [n ¼ 1])
reported in 2 patients (0.6%) each. All other nonocular SAEs were were suspected by the investigator to be related to the study
reported in 1 patient (0.3%) each. Three SAEs (cerebrovascular treatment. Of these, 1 event of cerebrovascular accident and 1 event

138
 Larsen et al 
Sustained Benefits with Individualized Ranibizumab in CRVO
Figure 6. Ranibizumab treatment exposure during the study (safety set). The safety set included all patients who underwent 1 safety assessment after
baseline and received 1 administration of study treatment. The total number of injections per study eye was calculated, and per-study eye values are
summarized.
of cardiac failure occurred in the first 12 months; both of these events
were reported previously.6 The other cardiac failure event was severe,
resulting in hospitalization and nondrug therapy; the other
cerebrovascular accident event was severe, resulting in study drug
discontinuation and hospitalization; and the chest pain event was
also severe, resulting in hospitalization and concomitant medication
administration.
Five patients died during the study, of which 2 deaths occurred
in the first 12 months; these deaths were reported previously.6 The
causes for the remaining 3 deaths were multiorgan failure (n ¼ 1),
gangrene (n ¼ 1; patient had underlying conditions of diabetes
mellitus, obesity, and arterial hypertension), and peripheral artery
aneurysm (n ¼ 1; patient had underlying conditions of
dyslipidemia, myocardial ischemia, ventricular tachyarrhythmia,
and prostatomegaly). All the deaths were judged by the
investigator as not related to either the study treatment nor the
ocular injection procedure.
Adverse Events. Ocular AEs in the study eye were reported in
210 patients (58.8%; Table 4). The most commonly reported ocular
AEs were intraocular pressure (IOP) increase (44 patients [12.3%]),
ocular hypertension (26 patients [7.3%]), and eye pain (25 patients
[7.0%]; Table 4), most of which were related to the injection
procedure and were transient. Neovascular glaucoma was reported
as an AE in 2 patients (0.6%); both events were moderate in
severity and were considered by the investigator to be not related
to either the study treatment or ocular injections. Eight neovascular
complication events were reported in 7 patients (2.0%): 3 patients
experienced retinal neovascularization, 3 experienced iris
neovascularization, and 1 patient experienced both events. Of the 8
events, 7 were mild to moderate in severity and 1 event was
categorized as severe (iris neovascularization). The severe event
and 1 moderate event (of retinal neovascularization) led to
permanent discontinuation of the study drug, at the investigator’s
discretion. None of the neovascular complication events were
suspected by the investigator to be related to study treatment or
ocular injections. Nonocular AEs were reported in 228 patients
(63.9%). The most commonly reported nonocular AEs were
hypertension (42 patients [11.8%]) and nasopharyngitis (39 patients
[10.9%]; Table 4). A majority of all reported ocular (>90%) and
nonocular (>80%) AEs were mild or moderate in severity.
Overall, 111 ocular AEs (31.1%) and 17 nonocular AEs (4.8%)
were suspected by the investigator to be related to the study
treatment or ocular injections (Table 5; available at
www.ophthalmologyretina.org). Increased IOP (33 patients
[9.2%]), eye pain (22 patients [6.2%]), conjunctival hemorrhage
(18 patients [5.0%]), ocular hypertension (16 patients [4.5%]),
vitreous floaters (13 patients [3.6%]), and injection-site pain (11
patients [3.1%]) were the most common ocular AEs related to
treatment or ocular injection that were reported in the study eye. Of
these, most were suspected to be related to ocular injections alone.
Only 1.4% (n ¼ 5) of IOP increase, 0.6% (n ¼ 2) of ocular hy-
pertension, and 0.6% (n ¼ 2) of vitreous floaters events were
suspected to be related to the study medication. All instances of
conjunctival hemorrhage or injection-site pain were suspected to be
related to ocular injections alone. Headache (7 patients [2.0%]) was
the most commonly reported nonocular AE suspected to be related
to the study treatment or ocular injections.
In all, 14 ocular AEs resulted in 6 patients (1.7%)
discontinuing study treatment (Table 6; available at
www.ophthalmologyretina.org). Glaucoma, retinal ischemia, and
vitreous hemorrhage were the events resulting in treatment
discontinuation in 2 patients each. All other events resulted in
treatment discontinuation in 1 patient each (Table 6; available at
www.ophthalmologyretina.org). Only the event of vitreous
hemorrhage was suspected by the investigator to be related to the
study medication (but not to the injection procedure); the study
drug was permanently discontinued for this patient because of
this event, and nondrug therapy was administered. Eleven
nonocular AEs resulted in 10 patients (2.8%) discontinuing study
treatment; of these, 3 (2 SAEs of aforementioned cerebrovascular
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 Ophthalmology Retina Volume 2, Number 2, February 2018

Table 4. Ocular (Study Eye) and Nonocular Adverse Events Discussion

Regardless of Study Treatment Relationship (Safety Set)
The 24-month results of the CRYSTAL study demonstrate
Ranibizumab 0.5 mg
Preferred Term (N [ 357), n (%) the sustained benefits of an individualized, VA stabilization
criteriaedriven dosing regimen of ranibizumab 0.5 mg in
Ocular AEs, total 210 (58.8) patients with CRVO. The significant BCVA gain with
Intraocular pressure increased 44 (12.3)
ranibizumab 0.5 mg observed at month 12 compared with
Ocular hypertension 26 (7.3)
Eye pain 25 (7.0) that at baseline (primary end point)6 was maintained through
Conjunctival hemorrhage 24 (6.7) month 24. The functional improvements were associated
Visual acuity reduced 23 (6.4) with a reduction in the mean CSFT.
Dry eye 22 (6.2) As seen in the first year,6 ranibizumab treatment in the
Macular edema 19 (5.3) second year provided BCVA gains irrespective of baseline
Vitreous floaters 19 (5.3) BCVA. Patients with a lower baseline BCVA exhibited
Vision blurred 18 (5.0)
Cataract 16 (4.5) higher mean BCVA gains than did those with higher
Macular fibrosis 15 (4.2) baseline BCVA, although the absolute BCVA at month 24
Glaucoma 13 (3.6) was higher in patients with higher baseline BCVA. Best-
Blepharitis 12 (3.4) corrected VA gains were numerically greater in patients
Vitreous detachment 12 (3.4) with shorter disease duration, supporting early intervention
Injection site pain 11 (3.1) with ranibizumab. Similar findings with ranibizumab were
Conjunctivitis 10 (2.8)
Ocular discomfort 10 (2.8)
observed in patients with branch RVO.7 The benefits of
Eyelid edema 9 (2.5) early intervention have also been reported with other
Ocular hyperemia 9 (2.5) treatments in patients with RVO.8,9
Corneal abrasion 7 (2.0) The presence of retinal ischemia is a major determinant
Lacrimation increased 7 (2.0) of visual outcomes in patients with CRVO, and it causes
Nonocular AEs, total 228 (63.9) poorer vision at baseline and during follow-up.1,10,11 The
Hypertension 42 (11.8)
CRYSTAL study suggests that macular ischemia has a
Nasopharyngitis 39 (10.9)
Headache 21 (5.9) minimal impact on functional outcomes and need for re-
Influenza 17 (4.8) treatment. Hence, the results of the CRYSTAL study add
Bronchitis 15 (4.2) to the existing findings from other anti-VEGF studies that
Fall 15 (4.2) patients with retinal nonperfusion or macular ischemia do
Back pain 13 (3.6) benefit from anti-VEGF therapy.12e14
Cough 13 (3.6) Overall, the results of the CRYSTAL study demonstrate
Upper respiratory tract infection 12 (3.4)
Diarrhea 11 (3.1) the sustained efficacy of ranibizumab 0.5 mg for 2 years,
Dizziness 11 (3.1) with a decreasing injection frequency, in patients with
Pneumonia 10 (2.8) CRVO of different duration and including those with mac-
Arthralgia 9 (2.5) ular ischemia (i.e., in a subset of patients that is represen-
Lower respiratory tract infection 9 (2.5) tative of the general population). These results add to the
Sinusitis 9 (2.5) existing data from other ranibizumab studies in patients with
Tooth infection 9 (2.5)
Urinary tract infection 9 (2.5)
macular edema secondary to CRVO,15e18 further validating
Atrial fibrillation 8 (2.2) the benefits of long-term therapy with ranibizumab 0.5 mg.
Hypotension 8 (2.2) Patients with CRVO are believed to require more
Blood pressure increased 7 (2.0) frequent follow-ups and more injections to control edema
Insomnia 7 (2.0) and maintain visual benefits compared with those with
Laceration 7 (2.0) branch RVO.10,19 Consistent with these findings, the mean
number of ranibizumab 0.5 mg injections up to month 23
The safety set included all patients who underwent 1 safety assessment was higher in patients with CRVO in the CRYSTAL study
after baseline and received 1 administration of study treatment. (13.1 injections [mean of 5 injections needed in the second
Adverse events (AEs) reported in 2% of patients are presented. Preferred
terms are sorted in descending frequency. A patient with multiple occur-
year]) compared with that in patients with branch RVO in
rences of an AE under 1 treatment is counted only once in the AE category the BRIGHTER study (11.4 injections).
for that treatment. A patient with multiple AEs within the primary system In the HORIZON-RVO study,18 an open-label extension
organ class (eye disorders) is counted only once in the total row. trial that included patients who completed Central Retinal
AEs were coded using the Medical Dictionary for Regulatory Activities Vein Occlusion Study: Evaluation of Efficacy and Safety
(version 17.1).
Trial (CRUISE),20 and in the COPERNICUS study with
aflibercept,21 monitoring of patients every 3 months in the
second year showed worsening of outcomes.
accident [including the 1 that occurred before month 12] and The 24-month results of CRYSTAL revealed that in
transient ischemic attack [that occurred before month 12]) were approximately 35% of patients, the investigator considered
suspected by the investigator to be related to the study treatment extending the visit interval to 2 months appropriate, at least
or ocular injections. once, and approximately two thirds of these patients did not

140
 Larsen et al 
Sustained Benefits with Individualized Ranibizumab in CRVO
need re-treatment following the skipped visit. Results from
this and previous studies suggest that bimonthly monitoring
may be sufficient to achieve successful outcomes with an
individualized ranibizumab dosing regimen in carefully
selected patients, whereas visit intervals beyond 2 months
are not advisable during the initial 2 years of therapy.
When CRYSTAL study was designed, the 2011 Euro-
pean Union Summary of Product Characteristics5 was in
effect, and the disease stability and re-treatment criteria
were based on VA loss as a consequence of disease activity.
Re-treatment could not be applied when CSFT remained
abnormal or increased but VA was still unchanged. In most
patients who had a treatment interruption due to disease
stabilization, once treatment was reinitiated, VA recovered
to the level prior to treatment interruption. A similar finding
was observed in patients with CRVO in the SHORE
study,17 where after mandatory monthly injections, VA
declined upon transition to a pro re nata regimen but
BCVA recovered subsequently. This recovery of lost
BCVA in CRVO is different from neovascular age-related
macular degeneration (nAMD), where lost BCVA cannot
completely be restored by treatment reinitiation22;
interestingly, retinal thickness in these nAMD patients is
not deteriorating in line with BCVA.22 The underlying
mechanism for this differential behavior in response to
reinitiation of anti-VEGF treatment between CRVO with
its pathology of intraretinal vessels and nAMD in which
leakage comes from newly formed choroidal vessels re-
mains to be determined. It may be speculated that the local
cellular environment around a choroidal neovascularization
is more detrimental to photoreceptors and retinal pigment
epithelium than that created by leakage from natural vessels
of the retina that are leaking as a consequence of venous
congestion.
No new safety findings were observed during the 24-
month study period, and safety results were consistent
with the already well-established safety profile of ranibizu-
mab in patients with CRVO.16,18,20 The study limitations are
reported elsewhere.6
Results of the 24-month CRYSTAL study support an
individualized, VA stabilization criteriaedriven dosing
regimen (3 mandatory injections followed by dosing as
needed) of ranibizumab 0.5 mg for a broad population of
patients with CRVO regardless of disease duration, baseline
VA, or presence of macular ischemia. In addition, the study
findings support early intervention with ranibizumab. No
new safety concerns were identified, and safety results up to
24 months were consistent with the well-established safety
profile of ranibizumab in patients with CRVO.
Acknowledgments. The authors thank Lakshmi Venkatraman
(Scientific Services Practice, PLS, Novartis Healthcare Pvt Ltd,
Hyderabad, India) for medical writing and editorial assistance.
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Footnotes and Financial Disclosures
Originally received: March 3, 2017.
Accepted: May 31, 2017.
Available online: September 9, 2017. Manuscript no.: ORET_2017_130.
1
Department of Ophthalmology, Rigshospitalet and Faculty of Health and
Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2
Department of Ophthalmology, Vienna Reading Center, Medical Uni-
versity of Vienna, Vienna, Austria.
3
Department of Ophthalmology, Ludwig-Maximilians-University, Munich,
Germany.
4
Moorfields Eye Hospital, London, United Kingdom.
5
Novartis Pharma AG, Basel, Switzerland.
6 A.W., E.B., M.G.: Employees d Novartis Pharma AG, Basel, Switzerland.
Novartis Healthcare Pvt Ltd, Hyderabad, India.
7
Institut de la Màcula, Centro Médico Teknon, and Barcelona Macula
Foundation, Barcelona, Spain.
Meeting presentations: Data from this study were previously presented at
the 15th European Society of Retina Specialists Congress, September
17e20, 2015, Nice, France; and at the 15th European School for Advanced
Studies in Ophthalmology Retina Academy Conference, October 22e24,
2015, Barcelona, Spain.
Financial disclosures:
The multicenter CRYSTAL study was funded and managed by Novartis
and is registered with www.clinicaltrials.gov (NCT01535261).
The authors made the following disclosures:
M.L.: Lecturing and advisory board participation, principal investigator in
clinical trials d Alcon, Allergan, Bayer, Novartis, Novo Nordisk, Roche.
S.W.: Consultant d Bayer, USA; Novartis, Switzerland; Research
support d Genentech, USA; Grant support d Christian Doppler Research
Society, Austria.
142
occlusion: two-year results from the COPERNICUS study.
Ophthalmology. 2014;121:1414e1420.
22. Richard G, Mones J, Wolf S, et al. Scheduled versus pro re
nata dosing in the VIEW trials. Ophthalmology. 2015;122:
2497e2503.
J.M.: Consultant/advisor d Novartis, Switzerland; Bayer, Germany;
Ophthotech, USA; Notal Vision, Israel; Alimera, USA; Stock options d
Notal Vision, Israel; Ophthotech, USA. Grant support d Novartis,
Switzerland; Bayer, Germany; Alcon, USA; Roche, Switzerland; Oph-
thotech, USA; Lecture fees e Novartis, Switzerland; Allergan, USA;
Ophthotech, USA.
S.P.: Lecture fees d Technolas, Germany; Alcon, Germany; Novartis,
Germany; Örtli, Switzerland; Zeiss, Germany; Meeting expenses d
Novartis, Switzerland; Abbott, Germany; Zeiss, Germany.
P.H.: Grant funding, honoraria, travel expenses d Allergan, Bayer, and
Novartis.
A.D.G.: Employee d Novartis Healthcare Pvt Ltd, Hyderabad, India.
Human Subjects: This study includes human subject/tissues. The study was
conducted in accordance with the Declaration of Helsinki, and the study
protocol was reviewed and approved by the independent ethics committee
or institutional review board of each contributing center. Patients provided
written informed consent before entering the study.
Abbreviations and Acronyms:
AE ¼ adverse event; BCVA ¼ best-corrected visual acuity; CFT ¼ central
foveal thickness; CRC ¼ central reading center; CRVO ¼ central retinal
vein occlusion; CSFT ¼ central subfield thickness; ETDRS ¼ Early
Treatment Diabetic Retinopathy Study; FAS ¼ full analysis set;
IOP ¼ intraocular pressure; nAMD ¼ neovascular age-related macular
degeneration; RVO ¼ retinal vein occlusion; SAE ¼ serious adverse event;
SD ¼ standard deviation; VA ¼ visual acuity; VEGF ¼ vascular endo-
thelial growth factor.
Correspondence:
Prof Michael Larsen, MD, Department of Ophthalmology, Rigshospitalet
and Faculty of Health and Medical Sciences, DK-2600 Glostrup,
Denmark. E-mail: miclar01@regionh.dk.