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![Need for the study
Anti VEGF Ranibizumab approved by FDA for Age related
Macular Degeneration
Studies 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](https://image.slidesharecdn.com/cruisetrial-140819214050-phpapp02/75/Central-Retinal-Vein-OcclUsIon-CRUISE-Study-Cruise-trial-8-2048.jpg)
![ 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.](https://image.slidesharecdn.com/cruisetrial-140819214050-phpapp02/75/Central-Retinal-Vein-OcclUsIon-CRUISE-Study-Cruise-trial-20-2048.jpg)
Uploaded byLaxmi Eye Institute
Central Retinal Vein OcclUsIon (CRUISE) Study - Cruise trial
Ranibizumab injections led to improved visual acuity and resolution of macular edema compared to sham injections in patients with central retinal vein occlusion. At 6 months, patients receiving 0.3 mg or 0.5 mg ranibizumab were twice as likely to have a visual acuity of 20/40 or better compared to the sham group. Ranibizumab also significantly reduced central foveal thickness within 7 days, suggesting retinal edema in CRVO is primarily VEGF-mediated. While ranibizumab was effective, longer term studies are needed to determine optimal duration of treatment and benefits in less severe cases.
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Central Retinal Vein OcclUsIon (CRUISE) Study - Cruise trial
- 1. Journal Club Presenter :Dr.Niket Gandhi Moderator: Dr. Devendra Venkatramani
- 3. Central Retinal VenousOcclusion 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
- 4. Line Of Treatment Visual morbidity primarily due to: 1. Macular Edema 2. Neovascularization Different approaches studied: 1. Observation 2. Laser Grid Photocoagulation 3. Intravitreal Steroids 4. Surgery
- 5. Central Retinal VeinOcclusion 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 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
- 6. SCORE Title: TheStandard 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
- 7. 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
- 8. Need for thestudy Anti VEGF Ranibizumab approved by FDA for Age related Macular Degeneration Studies 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
- 10. 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
- 11. Purpose To assessthe 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).
- 12. Study Design The CRUISEwas a 6-month Phase III Multicenter Randomized Injection-controlled study Additional 6 months of followup (total 12 months)
- 13.
- 14. The CRUISEstudywas 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.
- 15. Screening And Eligibility Eligibility was determined by the investigating physician During the screening visit, 1. Informed consent provided 2. 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.
- 16. Key Inclusion Criteria 18 yrs 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 the ETDRS charts Mean 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
- 17. Key Exclusion Criteria Prior episode of RVO Brisk RAPD 10-letter improvement in BCVA between screening and day 0 Prior 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 retinopathy CVA or MI within 3 months before day 0
- 18. Panretinal scatterphotocoagulation 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
- 19.
- 20. Randomization wasstratified 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.
- 21. Study Visits andAssesment Study 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.
- 22. Outcome measures The primaryefficacy 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
- 23. Exploratory efficacy outcomesincluded Percentage 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
- 24. Additional outcomes Meanchange from baseline NEI VFQ-25 composite score over time to month 6 Safety outcomes included the incidence and severity of ocular and non-ocular AEs and SAE
- 25. Statistical Analysis Foreach 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) Hochberg–Bonferroni multiple comparison model Cochran–Mantel–Haenszel chisquare tests, stratified by baseline BCVA, were used for secondary and exploratory binary end point group comparisons
- 26.
- 27.
- 31.
- 32.
- 33. Percentage of PatientsWho Gained >15/ Lost <15 ETDRS letters
- 34. Impact on Patient-ReportedOutcomes Because of Visual Function
- 35.
- 36. Change from BaselineCentral Foveal Thickness
- 37.
- 38.
- 39.
- 40. Non Ocular SafetyOutcomes
- 41.
- 42. Author’s Interpretation Monthlyranibizumab 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.
- 43. 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
- 44. Comparison with SCORE Treatmentof 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
- 45. Gaps and UnansweredQuestions 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?
- 46. 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.
- 47. Patients inthe 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.
- 48. Observation When wouldbe the ideal time in the course of CRVO ranibizumab can be used? Role of Ranibizumab in pre existing Iris Neovascularization By excluding pts with RAPD it fails the discover the risks/ benefits in advanced cases
- 49.
Editor's Notes
- #3 the Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein OcclUsIon (CRUISE) Study
- #5 The Central Vein Occlusion Study Group noted that 34% of nonischemic central retinal vein occlusions progressed to become ischemic within 3 years,[12] and 15% of the study group converted within the first 4 months.
- #6 Making Obseravation standard of care for theses patients
- #8 It binds with high affinity to VEGF-A isoforms generated by alternative mRNA splicing, e.g. VEGF121, VEGF165, and their biologically active proteolytic cleavage product VEGF110. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors VEGFR-1 and VEGFR-2 on the surface of endothelial cells. Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage
- #14 Patients who were randomized to the sham group were treated similarly to those in the ranibizumab groups, except that a needleless hub of a syringe was placed against the injection site and the plunger of the syringe was depressed to mimic an injection The study included a 28-day screening period (days 28 to 1); a 6-month treatment period (day 0 to month 6), during which patients received monthly intraocular injections of 0.3 mg or 0.5 mg ranibizumab or sham injections; and a 6-month observation period (month 6 to month 12), during which all patients could receive monthly intraocular ranibizumab if they met prespecified functional and anatomic criteria (i.e., Snellen equivalent study eye best-corrected visual acuity [BCVA] 20/40 according to the Early Treatment Diabetic Retinopathy Study (ETDRS)8 chart or mean central subfield thickness 250 m according to optical coherence tomography [OCT])
- #20 Eligible patients were randomized 1:1:1 to receive monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections, using a dynamic randomization method.
- #22 if it led to death, was life threatening, required prolonged hospitalization, resulted in persistent or significant disability, resulted in congenital anomaly/birth defect, or was considered a significant medical event by the investigator.
- #26 procedure to maintain an overall type I error rate of 0.05 type I and type II errors are respectively incorrect rejection of a true null hypothesis, and incorrect failure to reject a false null hypothesis. More simply stated, a type I error is detecting an effect that is not present, while a type II error is failing to detect an effect that is present
- #31 Mention DA
- #38 The average normal central subfield thickness is 212 m, based on measurements of a population of normal patients.25 Thus, EFT was estimated by subtracting 212 m from the central subfield thickness.
- #46 The CRUISE trial included only patients with BCVA 20/40.The natural history arm of the CVOS demonstrated that 29% of patients present with VA 20/40. Thirty-five percent of patients in the CVOS finished with VA 20/40.
- #47 In patients with CRVO, the mean number of ranibizumab injections during the observation period was 3.9, 3.6, and 4.2 in the 0.3 mg, 0.5 mg, and sham/0.5 mg groups; and the percentage of patients that did not receive any injections during the observation period was 7.0, 6.7, and 4.3, respectively