Purpose
The ROCC study (randomized study comparing ranibizumab to sham in patients with macular edema secondary to central Retinal vein OCClusion [CRVO]) evaluated the short-term effect of intravitreal ranibizumab injections on best-corrected visual acuity (BCVA) and macular edema.
Design
Prospective, multicenter, randomized, double-masked, placebo-controlled trial.
Methods
In this 6-month trial, 32 patients with macular edema secondary to CRVO were randomized to receive monthly intravitreal ranibizumab (0.5 mg/0.05 mL) or sham injections for 3 consecutive months. If macular edema persisted, patients received further monthly injections. Primary outcome measures were BCVA and central macular thickness (CMT) at 6 months.
Results
Twenty-nine patients completed the study. After 3 months, BCVA improved by a mean ± standard deviation (SD) of 16 ± 14 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the ranibizumab group (n = 15), compared with a mean loss of 5 ± 15 ETDRS letters in the sham group (n = 14; P = .001). The mean ± SD change in CMT was −411 ± 200 μm in the ranibizumab group and −86 ± 165 μm with sham ( P < .001). At 6 months, the mean ± SD change in BCVA was 12 ± 20 ETDRS letters in the ranibizumab group compared with −1 ± 17 ETDRS letters in the sham group ( P = .067). The mean ± SD change in CMT was −304 ± 194 μm with ranibizumab and −151 ± 205 μm with sham ( P = .05). Twelve patients (80%) in the ranibizumab group required more than 3 initial injections; mean ± SD number of injections was 4.3 ± 0.9 during the study.
Conclusion
Monthly ranibizumab significantly increased BCVA and decreased macular edema, compared with sham, in patients with CRVO. Repeated consecutive injections are necessary to maintain initial positive results.
Until recently, there has been no effective therapy for macular edema secondary to central retinal vein occlusion (CRVO). Laser photocoagulation has been used without much success, and although intravitreal triamcinolone acetonide has shown some promising results, it is associated with unacceptable ocular complications.
Traditionally, CRVO has been classified as either nonischemic or ischemic, or perfused or nonperfused, depending on the clinical and angiographic findings.
CRVO is characterized by edema of the optic nerve, retinal hemorrhages in all quadrants, and often marked vascular dilation and tortuosity. Ocular neovascularization and associated neovascular glaucoma are rare, but dreaded, complications. The visual decline associated with CRVO depends on the degree of ischemia and the development of secondary macular edema.
Reduced retinal blood flow caused by structural and functional changes in the retinal vasculature leads to varying levels of hypoxia. As with other retinal vascular diseases, there is a marked rise in intravitreal levels of vascular endothelial growth factor (VEGF) after retinal vein occlusions. Intravitreal VEGF levels have been shown to correlate with severity of clinical findings. Intravitreal injections of VEGF in primate eyes induce many of the pathologic findings associated with CRVO. Therefore, inhibiting VEGF seems to be a reasonable approach for treating CRVO. Bevacizumab is an anti-VEGF widely used off-label to treat different neovascular conditions, and has been shown to reduce macular edema and improve visual acuity (VA) in the short term.
Ranibizumab is an anti-VEGF agent currently licensed for the treatment of wet age-related macular degeneration (AMD). Ranibizumab has also been shown to decrease central retinal thickness with a corresponding improvement in VA in patients with diabetic macular edema. Many of the pathologic changes (retinal ischemia and microangiopathy) detected in diabetic retinopathy are also associated with CRVO.
Two studies evaluated the efficacy of intravitreal ranibizumab on macular edema in patients with CRVO; however, neither of these studies was sham controlled. The ROCC study (randomized study comparing ranibizumab to sham in patients with macular edema secondary to central Retinal vein OCClusion) compared the effect of ranibizumab vs sham in patients with macular edema secondary to CRVO.
Methods
This was a 6-month, prospective, multicenter, randomized, double-masked, sham-controlled, monitored study conducted at 4 sites in Norway. The aim of the study was to evaluate the efficacy and safety of intravitreal ranibizumab in patients with macular edema secondary to CRVO.
Patients with macular edema secondary to CRVO in 1 eye, who were previously untreated for this disease, were included in the study. Inclusion criteria included symptom duration ≤6 months, age ≥50 years, and a best-corrected visual acuity (BCVA) score (using the Early Treatment Diabetic Retinopathy Study [ETDRS] chart) between ≤73 and ≥6 letters. Macular edema was confirmed by the presence of intraretinal cysts in the central macular area by optical coherence tomography (OCT) using the Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA) at 3 sites and Topcon 3D OCT 1000 (Topcon Corporation, Tokyo, Japan) at 1 site.
Exclusion criteria included any concomitant ocular disease that could compromise the assessments in the study eye or induce complications such as active extraocular or intraocular infection or inflammation; prior treatment of macular disease; history of uncontrolled glaucoma, filtration surgery, or corneal transplantation; cataract surgery 3 months prior to baseline; aphakia; cataract or diabetic retinopathy in rapid progression; vitreous hemorrhage; or previous rhegmatogenous retinal detachment. Patients were also excluded if they were or could be pregnant, had received other investigational drugs or current treatment for active systemic infection, or had received medication known to be toxic to the eye, or if there were contraindications for the use of an investigational drug. Patients with a history of hypersensitivity or allergy to fluorescein, or an inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed, were also excluded.
All patients underwent a broad ophthalmologic examination, including BCVA examination using ETDRS chart at 4 meters, slit-lamp examination including ophthalmoscopy, fundus photography (baseline and months 3 and 6), fluorescein angiography (FA; baseline and months 3 and 6), and OCT measuring the central macular thickness (CMT). Blood pressure and pulse rate were also monitored.
Patients were randomized 1:1 to receive intravitreal injections of ranibizumab 0.5 mg/0.05 mL (Lucentis; Novartis Inc, Basel, Switzerland) or sham each month for the first 3 months. For the remainder of the 6-month study, treatment was administered at the discretion of the physician if macular edema with cysts in the central macular area persisted. The investigating physician and nurse were masked toward the injecting physician and nurse and vice versa. All patients received chloramphenicol antibiotic eye drops (Kloramfenikol; Nycomed Pharma Inc, Asker, Norway) for 3 days pre- and post-treatment. All treatments were administered after subconjunctival anesthesia with 0.1 mL lidocaine (Xylocain; AstraZeneca Inc, Oslo, Norway). Aseptic technique was used as per the labeling for ranibizumab, and sham treatment was conducted by pressing a plastic syringe against the eyeball.
The primary outcome measures were mean change from baseline in BCVA score and central macular thickness at month 6. Secondary outcome measures included the number of treatments needed, safety and tolerability, and development of neovascularization.
Statistical Methods
The efficacy analysis was done on the per-protocol patient population. This was considered to be appropriate considering the exploratory nature of this trial, and is in accordance with other publications on this topic. Changes in BCVA and macular thickness from baseline to months 3 and 6 were compared between the treatment groups with 2-sample t tests. Within each group, BCVA and macular thickness at months 3 and 6 were compared with baseline using paired t tests. P values less than .05 were considered to be statistically significant. Statistical analysis was performed with SPSS software version 17 (SPSS Inc, Chicago, Illinois, USA).
Results
Baseline Characteristics
Of the 32 patients enrolled, 29 (16 male, 13 female) completed the study. One patient from the ranibizumab group developed retinal artery thrombosis and was withdrawn from the study shortly after the first injection. Two patients from the sham group were also withdrawn from the study, 1 for planned surgery because of cholecystitis and the other following a diagnosis of AMD, a protocol violation.
At baseline, the mean age was 72 years (52–88 years) and the mean duration of CRVO was 78 days (10–163 days). The overall mean ± standard deviation (SD) BCVA score was 43 ± 22 ETDRS letters (20/138 Snellen equivalent); 45 ± 23 ETDRS letters (20/126 Snellen equivalent) in the ranibizumab group (n = 15) and 41 ± 22 ETDRS letters (20/152 Snellen equivalent) in the sham group (n = 14). The overall mean ± SD macular thickness was 625 ± 159 μm; 661 ± 161 μm in the ranibizumab group and 587 ± 154 μm in the sham group ( Table ). FA revealed nonperfusion in an area >5 disc areas in 5 patients (1 patient in the ranibizumab group and 4 patients in the sham group). Three patients (2 in the ranibizumab group [classified as perfused at month 3] and 1 in the sham group [classified as nonperfused at month 3]) were hard to classify at baseline owing to the presence of blood. None of the patients with initially perfused edema became nonperfused during the study. Two patients in the ranibizumab group and 2 in the sham group had diabetes mellitus, but none were reported to have diabetic retinopathy.
| Ranibizumab Group (n = 15) | Sham Group (n = 14) | |
|---|---|---|
| BCVA (ETDRS letters, mean ± SD) at: | ||
| Baseline | 45 ± 23 | 41 ± 22 |
| Month 1 | 57 ± 17 | 33 ± 21 |
| Month 2 | 61 ± 16 | 33 ± 24 |
| Month 3 | 61 ± 19 | 36 ± 24 |
| Month 6 | 56 ± 24 | 39 ± 27 |
| CMT (μm, mean ± SD) at: | ||
| Baseline | 661 ± 161 | 587 ± 154 |
| Month 1 | 369 ± 178 | 566 ± 172 |
| Month 2 | 256 ± 126 | 553 ± 212 |
| Month 3 | 250 ± 121 | 501 ± 209 |
| Month 6 | 357 ± 201 | 436 ± 216 |
a The ROCC Study is a randomized study comparing ranibizumab to sham in patients with macular edema secondary to central Retinal vein OCClusion.
One- and 3-Month Follow-Up
The mean ± SD BCVA in the ranibizumab group had improved by 12 ± 12 ETDRS letters ( P = .002) at month 1 and by 16 ± 14 ETDRS letters ( P = .001) at month 3. In the sham group, the mean ± SD BCVA had worsened by 8 ± 14 ETDRS letters ( P = .055) at month 1 and by 5 ± 15 ETDRS letters ( P = 0.261) at month 3. The improvement in BCVA at 3 months was significantly greater in the ranibizumab group than the sham group ( P = .001). The change in CMT from baseline was −292 ± 226 μm ( P < .001) and −21 ± 87 μm ( P = .384) at month 1, and −411 ± 200 μm ( P < .001) and −86 ± 165 μm ( P = .071) at month 3 in the ranibizumab and sham groups, respectively. The change in CMT during the first 3 months was significantly greater in the ranibizumab group compared with sham ( P < .001).
Six-Month Follow-up
The mean ± SD overall change in BCVA score from baseline to the end of the study was a gain of 12 ± 20 ETDRS letters in the ranibizumab group ( P = .040; Figure 1 ) and a loss of 1 ± 17 ETDRS letters in the sham group ( P = .765; Figure 2 ). The corresponding change in CMT was −304 ± 194 μm in the ranibizumab group ( P < .001) and −151 ± 205 μm in the sham group ( P = .017). The difference in BCVA and CMT between the 2 treatment groups at month 6 approached statistical significance ( P = .067 and P = .05, respectively).
