JOURNAL CLUB

•  Obstruction of the major outflow

CENTRAL channel of the eye, resulting in effects
throughout the entire retina
RETINAL
•  CRVO presents with variable visual loss;
VENOUS the fundus may show retinal hemorrhages,
OCCLUSION dilated tortuous retinal veins, cotton-wool
spots, macular edema, and optic disc edema
 • Visual morbidity primarily due to:
• Macular Edema
• Neovascularization
LINE OF
TREATMEN • Different approaches studied:
T • Observation
• Laser Grid Photocoagulation
• Intravitreal Steroids
• Surgery
CENTRAL RETINAL VEIN
OCCLUSION STUDY
•  CVOS is a phase III multi-centre RCT that evaluated the efficacy of macular
grid photocoagulation in treating macular edema secondary to central retinal vein
occlusion.
• Results:
1. 155 eyes were included in 155 patients
2. There was no statistically significant difference between treatment
• and control visual acuity at any stage of follow-up.
3. Initial visual acuity: 20/160 (treated) vs. 20/125 (control)
4. Final visual acuity: 20/200 (treated) vs. 20/160 (control)
•  Conclusions: Macular grid photocoagulation was effective in reducing
angiographic evidence of macular edema but did not improve visual acuity
in eyes with reduced vision due to macular edema from CVO
SCORE
•  Title: The Standard Care vs Corticosteroid for Retinal
Vein Occlusion (SCORE) Studies compared intraocular
injections of preservative-free triamcinolone acetonide (TA)
to standard care in patients with macular edema due to
CRVO
•  Results: Gain of >15 ETDRS letters– was 6.8%,
26.5% and 25.6% for the observation, 1-mg, and 4-mg
groups.
• No difference in retinal thickness between groups at 12
months
•  Conclusions: Intravitreal triamcinolone is superior to
observation for treating vision loss associated with macular
edema secondary to CRVO .The 1-mg dose has a safety
profile superior to that of the 4-mg dose
RANIBIZUMAB

•  Ranibizumab
(Lucentis, Genentech,
Inc., South San
Francisco, CA) is a
humanized, affinity-
matured VEGF antibody
fragment that binds to
and neutralizes all
isoforms of VEGF-A
and their biologically
active degradation
products
NEED FOR THE STUDY

•  Anti VEGF Ranibizumab approved by FDA for Age related Macular

Degeneration
• Studies showed promising results
• Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular
edema due to retinal vein occlusions: implication of VEGF as a
critical stimulator. Mol Ther 2008;16:791–9. Pieramici DJ, Rabena
M, Castellarin AA, et al.
• Ranibizumab for the treatment of macular edema associated with
perfused central retinal vein
• occlusions [report online only]. Ophthalmology 2008;115:e47–54.
• No randomized control trial yet
 •The author(s) have made the following
disclosure(s):
• Genentech, Inc., South San Francisco,
FINANCIAL California, provided support for the study
and participated in study design;
DISCLOSURE
conducting the study; and data collection,
S management, and interpretation.
Genentech authors Saroj, Rundle, and
Gray would like to report Equity
Ownership in Roche
 •  To assess the efficacy and safety of
intraocular injections of 0.3 mg or 0.5 mg
PURPOSE ranibizumab in patients with macular edema
after central retinal vein occlusion (CRVO).
 •The CRUISE was a 6-month
• Phase III
• Multicenter
STUDY
• Randomized
DESIGN • Injection-controlled study
• Additional 6 months of followup (total 12
months)
STUDY
DESIGN
 The CRUISE studywas registered at www.clinicaltrials.gov
(NCT00485836; accessed December 18, 2009).
 Protocol was approved by the institutional review board at each study
site
 Study was conducted according to the International Conference on
Harmonisation E6 Guideline for Good Clinical Practice and any
national requirements.
 All patients were provided with informed
consent before participation in the study.
 SCREENING AND ELIGIBILITY
• Eligibility was determined by the investigating physician
• During the screening visit,
• Informed consent provided
• Medical history
• Physical examination, a complete eye examination (including
measurement of BCVA), OCT, fluorescein angiography, and
laboratory tests.
•BCVA: ETDRS charts
• OCT : University of Wisconsin Fundus Photograph Reading Center
(UWFPRC; Madison, WI), using the Zeiss Stratus and the FastMac
protocol (Carl Zeiss Meditec, Inc., Dublin, CA)
•If that evaluation and all laboratory tests supported inclusion, the patient was
• scheduled for the day 0 study visit.
 •18 years of age
• Foveal center-involved macular edema
secondary to CRVO diagnosed
• within 12 months before study initiation
• BCVA 20/40–20/320 Snellen equivalent using
KEY the ETDRS charts
INCLUSION • Mean central subfield thickness >250 u
from 2 OCT measurements (central 1-mm
CRITERIA diameter circle with a Stratus OCT )on 2
measurements:
• 1 at screening confirmed by
UWFPRC
• 1 on day 0 confirmed by the
investigating physician
 •Prior episode of RVO
• Brisk RAPD
• 10-letter improvement in BCVA between screening
and day 0

KEY • Prior anti-VEGF treatment in study or fellow eye

within 3 mos before day 0 or systemic anti-VEGF or
EXCLUSION pro-VEGF treatment within 6 mos before day 0

CRITERIA • History of radial optic neurotomy or

sheathotomy or use of intraocular
corticosteroid
•H/O wet or dry AMD or diabetic
retinopathy
•CVA or MI within 3 months before day 0
 • within 3 months before day 0 or
PANRETINAL • anticipated within 4 months after day 0
SCATTER •Laser for macular edema
PHOTOCOAGULATION
OR SECTOR LASER • within 4 months before day 0
PHOTOCOAGULATION
• ‘inadequate’ laser
• No foveal laser damage
RANDOMIZATION

0.3 mg
Ranimizumab

0.5 mg
Ranimizumab

Sham
Injections
 • 1. ≤ 34 letter score [< 6/60]
• 35–54 letter score [6/60 to < 6/24]
• ≥ 55 letter score [ ≥ 6/24])
•One eye was chosen as the study eye for each patient.
RANDOMIZATION
•If both eyes were eligible, the eye with the worst BCVA
WAS STRATIFIED at screening
BY BASELINE • was selected.
BCVA LETTER • Patients, certified BCVA examiners, and
SCORE evaluating physicians were masked to treatment and
dose.
•Injecting physicians, who did not perform
examinations or outcome
• assessments, were masked to dose but not treatment.
 • Study visits occurred on days 0 and 7 and months 1 to 6.
• Each Visit:
• Complete eye examination with OCT
assessment of central foveal thickness
(CFT).
STUDY • Patients provided a medical history, measured vital
signs (except for day 7), reviewed concomitant
VISITS AND medication, and assessed safety.
• Any new sign, symptom, illness, or worsening of any
ASSESMENT preexisting
• medical condition was recorded as an adverse event (AE).
•An AE was classified as a serious AE (SAE)
• Patient-reported visual function was assessed with the
National Eye Institute Visual Functioning Questionnaire-25
(NEI VFQ-25) at day 0 and months 1, 3, and 6.
 OUTCOME MEASURES
The primary efficacy outcome measure

BCVA Central Foveal Thickness

Mean Change from baseline % pts with CFT < 250 u
Change over time (Course) Mean change from baseline CFT

% pts gaining 15 letters or more

% pts lost 15 letters or more

 • Mean change from baseline NEI VFQ-25
ADDITIONA composite score over time to
• month 6
L •  Safety outcomes included the
OUTCOMES incidence and severity of ocular and
non-ocular AEs and SAE
 STATISTICAL ANALYSIS
 For each efficacy outcome, 2 pairwise comparisons were made:

1. 0.3 mg ranibizumab versus sham

2. 0.5 mg ranibizumab versus sham.
 Efficacy outcome analyses were stratified by baseline BVCA letter
score (34 vs. 35-54 vs. 55)
 RESULTS
•Baseline
Baseline Functional
•Functiona
Characteristics Outcomes
Characteristics l
Outcomes

Anatomical Safety
• Anatomical Outcomes
Outcomes
Outcomes •Safety
Outcomes
DEMOGRAPHICS
FUNCTIONAL OUTCOMES
CHANGE FROM BASELINE
BCVA
PERCENTAGE OF PATIENTS WHO GAINED >15/ LOST
<15 ETDRS LETTERS
IMPACT ON
PATIENT-
REPORTED
OUTCOMES
BECAUSE
OF VISUAL
FUNCTION
ANATOMIC OUTCOMES
CHANGE FROM BASELINE
CENTRAL FOVEAL THICKNESS
RESIDUAL EDEMA
SAFETY OUTCOMES
OCULAR SAFETY OUTCOMES
NON OCULAR SAFETY OUTCOMES
DISCUSSION
AUTHOR’S INTERPRETATION
• Monthly ranibizumab therapy improved mean BCVA and increased the
proportion of patients gaining 15 ETDRS letters
• Patients treated with ranibizumab were twice as likely to have BCVA of
20/40 compared with the sham group at month 6
• The rapid and significant resolution of macular edema by day 7 in both
ranibizumab groups suggests that the majority of retinal edema in CRVO is
VEGF mediated.
COMPARISON WITH CVOS

•  The CRUISE sham group and the CVOS natural history

cohort had a similar net change in VA of approximately 0
letters
•  19% of patients finish with 20/40 compared with 20.8% in
the CRUISE sham group
 • This implies that patients recruited for the SCORE
CRVO study
• were, on average, different than those enrolled in
COMPARISON CRUISE.
WITH SCORE
• The mean baseline BCVA of CRUISE patients (ETDRS
letter score 48.3) was slightly worse than baseline VA in
the SCORE CRVO study (ETDRS letter score 51.0),
• CRUISE had fewer patients with large capillary dropout
areas than SCORE CRVO.
• Servais and Hayreh’s extensive natural history studies
identified the presence of a relative afferent papillary
defect as one of the most sensitive and specific tests for
differentiating patients with ischemic CRVO.
• Exclusion of patients with a positive relative afferent
papillary defect from CRUISE may have effectively
eliminated patients with extensive capillary dropout and
may explain the differences between CRUISE and
SCORE patient populations with CRVO.
LIMITATIONS
•Does not address whether ranibizumab treatment is beneficial to patients
who present with VA 6/12 or better
• What percentage of patients will require treatment beyond the
mandated 6 monthly treatments that require further exploration?
12 MONTH RESULTS

•If Snellen equivalent BCVA was <20/40 or mean CST was >250 μm, they
received an injection of ranibizumab and patients in the sham group
received 0.5 mg.
• Improvement from baseline in ETDRS letter score very similar to the
month 6 results
• At month 12, 43% of patients in the two ranibizumab groups had a
Snellen equivalent BCVA of 20/40 compared to 35% in the sham/0.5
mg group.
 Patients in the sham group showed substantial improvement during
the observation period when they were able to receive ranibizumab;
improvement from baseline in letter score was 0.8 at month 6 and 7.3
at month 12.
 In the sham group, 33.1% of patients improved from baseline by >15
letters at month 12 compared to 16.9% at month 6.
THANK YOU