"The treatment groups had virtually no residual macular edema at the primary endpoint of 6 months," said Peter A. Campochiaro, MD, who reported the primary outcome results of the phase III BRAVO Study Group. He is the Eccles Professor of Ophthalmology and Neuroscience at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.
The BRAVO trial was a 12-month, randomized, multicenter, double-masked, sham-controlled study carried out at 93 sites in the United States to evaluate the efficacy and safety of ranibizumab for macular edema associated with BRVO or hemiretinal vein occlusion identified within 12 months of screening for the study.
Patients were eligible if they had a BCVA between 20/40 and 20/400, and a central subfield thickness of 250 μm or greater on optical coherence tomography (Stratus OCT, Carl Zeiss Meditec). Prior treatment was allowed if sufficient time had passed since the last treatment; 4 months for focal/grid laser and 3 months for intraocular injection of a steroid or an anti-vascular endothelial growth factor agent. Patients were excluded if they had a brisk afferent pupil defect in the study eye, gained more than 10 letters of vision between baseline and screening, or if they had had a stroke or myocardial infarction within 3 months of screening.
Patients who met the study criteria were randomly assigned to receive six monthly injections of 0.3 mg (134 patients) or 0.5 mg (131 patients) of ranibizumab or sham injections (132 patients).
At month 3 and beyond, patients who were not doing well were eligible for rescue focal/grid laser. The guideline criteria to identify patients who were not doing well were a BCVA of 20/40 or worse or a central subfield thickness of 250 μm or greater and little improvement over the previous 3 months (less than 5 letters improvement in BCVA or less than 50 μm improvement in foveal thickness).
During the second 6 months of the trial, all patients were eligible to receive ranibizumab if they met re-treatment criteria. Patients who had been assigned to ranibizumab received their previously assigned dose and patients who had been assigned to sham received 0.5 mg of ranibizumab. Starting at month 9, patients were once again eligible for rescue laser if they were not doing well.
The three study groups were well balanced for demographic characteristics, duration of BRVO, and baseline BCVA. The central subfield thickness was slightly greater in the ranibizumab groups compared with the sham group.
The study completion rates in the three groups were good, ranging from 93% to 95%. Most patients received the six treatments mandated by the study protocol. More patients (54.5%) in the sham group received rescue laser therapy compared with the 0.3- and 0.5-mg ranibizumab groups (18.7% and 19.8%, respectively).
"After injection of ranibizumab, there was a very rapid and significant increase in the VA of about eight letters at 1 week after treatment," Dr. Campochiaro said. "This increased to [a mean of] 16.6 and 18.3 letters at the primary endpoint for the 0.3- and 0.5-mg groups, respectively, compared with 7 letters in the sham group.
"There also was a rapid increase in the number of patients who had an increase in BCVA of 15 or more letters (15% to 20% one week after injection of ranibizumab) and this increased to 55.2% and 61.1% at the primary endpoint in the two ranibizumab groups compared with 28.8% in the sham group," he added.
At 6 months, 4.5% of patients in the sham group, none in the 0.3-mg ranibizumab group, and 1.5% of patients in the 0.5-mg ranibizumab group lost 15 or more letters.
"Excess foveal thickness is a measure of macular edema because it takes into account the normal foveal thickness," he said. "At baseline, the mean excess foveal thickness was about 280 μm. At 1 week, this decreased by half in the ranibizumab groups and did not change substantially in the sham group. At the 6-month time point, the excess foveal thickness had decreased to about 50 μm in the two active treatment groups compared with about 180 μm in the sham group. This showed that the macular edema almost completely resolved in the two treatment groups."
Two serious ocular adverse events developed. One case of endophthalmitis developed in the 0.5-mg ranibizumab group, and one patient in the 0.3-mg group had a retinal tear and a retinal detachment.
"Injection of ranibizumab resulted in almost complete elimination of macular edema along with rapid, sustained improvement in BCVA with roughly twice as many patients gaining 15 or more letters compared [with] the sham group. There were no new safety signals in this patient population," Dr. Campochiaro concluded. "Thus, [we find] ranibizumab is an effective treatment for macular edema due to BRVO."
Dr. Campochiaro has received research support from Genentech. The company has an institutional consulting agreement with the Wilmer Eye Institute.