Central Retinal Vein OcclUsIon (CRUISE) Study - Cruise trial

Journal Club

Presenter : Dr.Niket GandhiModerator: Dr. Devendra Venkatramani

Central Retinal Venous Occlusion

Obstruction of the major outflow channel of the eye, resulting in effects throughout the entire retina

CRVO presents with variable visual loss; the fundus may show retinal hemorrhages, dilated tortuous retinal veins, cotton-wool spots, macular edema, and optic disc edema

Line Of TreatmentVisual morbidity primarily due to:

1. Macular Edema2. Neovascularization

Different approaches studied: 1. Observation2. Laser Grid Photocoagulation3. Intravitreal Steroids 4. Surgery

Central Retinal Vein Occlusion Study

CVOS is a phase III multi-centre RCT that evaluated the efficacy of macular grid photocoagulation in the treatment of macular oedema secondary to central retinal vein occlusion.

Results:1. 155 eyes were included of 155 patients2. 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

SCORETitle: 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

RanibizumabRanibizumab (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 studyAnti VEGF Ranibizumab approved by FDA for

Age related Macular DegenerationStudies showed promising results

1. 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.

2. 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

Financial disclosures

The author(s) have made the following disclosure(s): Genentech, Inc., South San Francisco, California, provided support for the study and participated in study design; conducting the study; and data collection, management, and interpretation. Genentech authors Saroj, Rundle, and Gray would like to report Equity Ownership in Roche

PurposeTo assess the efficacy and safety of intraocular

injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after central retinal vein occlusion (CRVO).

Study Design

The CRUISE was a 6-month Phase IIIMulticenterRandomizedInjection-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,

1. Informed consent provided2. Medical history 3. 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.

Key Inclusion Criteria18 yrs of ageFoveal center-involved macular edema secondary to CRVO

diagnosed within 12 months before study initiation BCVA 20/40–20/320 Snellen equivalent using the ETDRS

chartsMean central subfield thickness >250 u from 2 OCT

measurements (central 1-mm diameter circle with a Stratus OCT )on 2 measurements: 1. 1 at screening confirmed by UWFPRC 2. 1 on day 0 confirmed by the investigating physician

Key Exclusion CriteriaPrior episode of RVOBrisk RAPD10-letter improvement in BCVA between screening and day

0Prior anti-VEGF treatment in study or fellow eye within 3

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

History of radial optic neurotomy or sheathotomy or use of intraocular corticosteroid

H/O wet or dry AMD or diabetic retinopathyCVA or MI within 3 months before day 0

Panretinal scatter photocoagulation or sector laser photocoagulation within 3 months before day 0 or anticipated within 4 months after day 0

Laser for macular edema within 4 months before day 0 ‘inadequate’ laser No foveal laser damage

Randomization

0.3 mg Ranimizumab

0.5 mg Ranimizumab

Sham Injections

Randomization was stratified by baseline BCVA letter score 1. 34 [20/200], 2. 35–54 [20/200 to 20/80]3. 55 [ 20/80])

One eye was chosen as the study eye for each patient. If both eyes were eligible, the eye with the worse BCVA at

screening was selected. Patients, certified BCVA examiners, and 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 and AssesmentStudy visits occurred on days 0 and 7 and months 1 to 6. Each Visit:

1. Complete eye examination with OCT assessment of central foveal thickness (CFT).

2. Patients provided a medical history, vital signs were measured (except for day 7), concomitant medication was reviewed, and safety was assessed.

Any new sign, symptom, illness, or worsening of any 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 measuresThe 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

Exploratory efficacy outcomes includedPercentage of patients with Snellen equivalent BCVA

20/200 or worse at month 6 Mean change from baseline excess foveal thickness (EFT)

over time to month 6 Percentage of patients with Snellen equivalent BCVA of

20/40 at month 6

Additional outcomesMean change from baseline NEI VFQ-25 composite score

over time to month 6Safety outcomes included the incidence and severity of

ocular and non-ocular AEs and SAE

Statistical AnalysisFor each efficacy outcome, 2 pairwise comparisons were

made:1. 0.3 mg ranibizumab versus sham2. 0.5 mg ranibizumab versus sham.

Efficacy outcome analyses were stratified by baseline BVCA letter score (34 vs. 35-54 vs. 55)

Hochberg–Bonferroni multiple comparison modelCochran–Mantel–Haenszel chisquare tests, stratified by

baseline BCVA, were used for secondary and exploratory binary end point group comparisons

Results

Baseline Characterist

ics

Functional Outcomes

Anatomical 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 ofVisual 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

Comparison with SCORE

Treatment of macular edema due to retinal vein occlusions Roomasa Channa Michael Smith Peter A Campochiaro Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Gaps and Unanswered Questions

Does not address whether ranibizumab treatment is beneficial to patients who present with VA 20/40 or better

The duration of ranibizumab treatment required for patients with macular edema following CRVO

What percentage of patients will require treatment beyond the mandated 6 monthly treatments 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.

ObservationWhen would be the ideal time in the course of CRVO

ranibizumab can be used?Role of Ranibizumab in pre existing Iris NeovascularizationBy excluding pts with RAPD it fails the discover the risks/

benefits in advanced cases

THANK YOU