An updated analysis of data from an ongoing phase II study of intravitreal ranibizumab treatment for diabetic macular edema shows that functional and anatomic benefits observed at 6-month primary efficacy endpoint are generally maintained at 1 year after switching to a "prn" dosing schedule.
"The results from the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) phase II study demonstrate this anti-vascular endothelial growth factor [VEGF] agent has biological activity in treating DME," said Dr. Do, assistant professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.
"However, more frequent injections may be needed to achieve enhanced visual acuity [VA] benefits. Further study also is needed to determine the role of ranibizumab in combination with other treatment modalities," she said. "We look forward to long-term results from large phase III studies for more information on the efficacy of VEGF blockade with ranibizumab in managing DME."
READ-2 is a prospective, open-label, multicenter clinical trial comparing intravitreal ranibizumab 0.5 mg against standard treatment with focal/grid laser photocoagulation and the combination of the two modalities. Study enrollment was a total of 126 adult diabetic patients at 14 centers.
Patients were eligible for READ-2 if they had an HbA1c level >5.5%, optical coherence tomography (OCT)-measured foveal thickness ≥250 μm, and Snellen equivalent best corrected visual acuity (BCVA) between 20/40 and 20/320.
Initially, patients in the ranibizumab monotherapy group received a series of four injections at baseline and months 1, 3, and 5. In the laser and combination groups, the laser treatment was performed at baseline and again at 3 months if DME was present, and patients in the combination group received combination therapy at baseline and month 3, with intravitreal ranibizumab given 1 week prior to the laser treatment.
Beginning at 6 months, re-treatment was performed on a prn basis based on OCT criteria (treatment given if foveal thickness ≥250 μm). Subjects in the combination and laser only groups could receive ranibizumab alone, laser alone, or combination treatment (for patients in the original combination treatment group only) at the investigator's discretion. Patients in the ranibizumab group could be re-treated no more than once every 2 months and laser re-treatment could be performed no more than once every 3 months.
The three treatment groups were well-matched at baseline in their mean age (~62 years) and mean Snellen equivalent VA (~20/80), HbA1c, and retinal thickness on OCT.
At 6 months, statistically significant differences favoring ranibizumab monotherapy over laser treatment were observed in the primary efficacy analysis of mean change from baseline BCVA (+7.24 letters versus –0.43 letters) as well as in secondary efficacy endpoints of proportions of eyes achieving a ≥3 line BCVA improvement (24% versus 0%) and mean change in excess central subfield thickness (57% versus 11%). Patients in the combination group also showed improvements in all of these endpoints, and had a mean +3.08-letter improvement at month 6 with 12% gaining a ≥3 line BCVA improvement.
"During the first 6 months of the study, monotherapy with ranibizumab provided the most VA benefits," Dr. Do said. "Combination therapy demonstrated VA benefits as well, but the increase in letters read was not as great as was seen in the ranibizumab treatment group."
A total of 112 (88%) patients remained in the study after month 6 and reached month 12. Beginning at 6 months, the majority of subjects had DME and required re-treatment. Nearly all subjects who were initially randomly assigned to laser or combination therapy at baseline were switched to ranibizumab treatment by their study investigators starting at month 6. Eyes that were initially randomly assigned to ranibizumab continued to receive the VEGF inhibitor through 12 months if OCT re-treatment criteria were met.
Comparison of the 6- and 12-month outcomes showed mean BCVA remained relatively stable in the original ranibizumab group. At month 12, the ranibizumab treatment group gained a mean of 6.69 letters. In the groups assigned originally to laser only or combination treatment, most subjects were switched to ranibizumab and BCVA improved from 6 months to 12 months by a mean of 3 and 0.7 letters, respectively.
"At the month 12 visit, we cannot perform a comparison between ranibizumab and laser or combination treatment since the majority of subjects were switched to ranibizumab monotherapy," Dr. Do said. "However, our results demonstrate that VEGF inhibition with ranibizumab is efficacious and safe through 12 months of treatment."
Ongoing phase III studies of ranibizumab for the treatment of DME include the RISE and RIDE trials where ranibizumab is being administered monthly at doses of 0.3 or 0.5 mg and being compared with sham injection.