Central Retinal Vein OcclUsIon (CRUISE) Study - Cruise trial

1. Journal Club
Presenter : Dr.Niket Gandhi
Moderator: Dr. Devendra Venkatramani

3. 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

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 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 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: 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

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 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

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 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).

12. Study Design
The CRUISE was a 6-month
 Phase III
 Multicenter
 Randomized
 Injection-controlled study
 Additional 6 months of followup (total 12 months)

13. Study Design

14.  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.

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 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

19. Randomization
0.3 mg
Ranimizumab
0.5 mg
Ranimizumab
Sham
Injections

20.  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.

21. Study Visits and Assesment
 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 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

23. Exploratory efficacy outcomes included
 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
 Mean change 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
 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)
 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. Results
Baseline
Characteristics
Functional
Outcomes
Anatomical
Outcomes
Safety
Outcomes

27. Demographics

31. Functional Outcomes

32. Change from Baseline BCVA

33. Percentage of Patients Who Gained >15/ Lost
<15 ETDRS letters

34. Impact on Patient-Reported Outcomes Because of
Visual Function

35. Anatomic Outcomes

36. Change from Baseline Central Foveal
Thickness

37. Residual Edema

38. Safety Outcomes

39. Ocular safety Outcomes

40. Non Ocular Safety Outcomes

41. Discussion

42. 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.

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
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

45. 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?

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 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.

48. Observation
 When would be 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. THANK YOU