Eyeworld

EW RETINA 72 July 2016 by Michelle Dalton EyeWorld Contributing Writer Protocol T: Second year results eradicate clear advantages Second year results found perceived superiority of aflibercept over ranibizumab dissipates, leaving all anti-VEGF drugs with similar results W hen the Diabetic Retinopathy Clini- cal Research (DRCR) Network's Protocol T was published last year, all 3 antivascular endothelial growth factor (VEGF) drugs evaluat- ed—aflibercept, bevacizumab, and ranibizumab (0.3 mg)—were roughly the same at 1 year in terms of visual gains in patients with diabetic macu- lar edema (DME) when baseline visual acuity (VA) loss was mild, 20/32–20/40 on an ETDRS chart. But when baseline VA was 20/50 or worse on an ETDRS chart, aflibercept was more effective at improving vision. That changed when the year 2 results were published, and "superi- ority of aflibercept over ranibizumab at the 2-year endpoint of the study … was no longer identified in the worse baseline vision subgroup." 1 As might be expected based on out- comes from other studies on DME, the vision gains were maintained with about 40% fewer injections in the second year and fewer laser treatments in all groups, said John Wells, MD, Palmetto Retina Cen- ter, Columbia, South Carolina, lead author of the 2-year results. "By year 2, there was a dimin- ishing benefit of aflibercept over ranibizumab in the worse baseline vision subgroup," Dr. Wells said. "Vi- sual acuity in the aflibercept group remained fairly flat from year 1 to year 2, while vision in the other 2 groups improved in the worse-seeing eyes." Protocol T now adds to the published literature, but while Dr. Wells said the vision gains reported in Protocol T "were greater than in other protocols," he cautioned that comparing study results is difficult and ill-advised because of the dif- ferent entry criteria and treatment protocols. Marco Zarbin, MD, chair, Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, New Jersey, agreed the Protocol T results were "significantly different" from what had been previously reported but offered an explanation. One potential explanation for the differences between ranibizum- ab and aflibercept in the year 1 outcomes is that ranibizumab was dosed at 0.3 mg. "Whereas previous trials (e.g., Protocol I) have demonstrated the effectiveness of less frequent than monthly treatment using 0.5 mg ranibizumab, the RIDE/RISE registra- tion trials that led to the use of a 0.3 mg ranibizumab dose used a month- ly injection paradigm," Dr. Zarbin explained. Protocol T did not use a monthly injection paradigm, but instead used "a unique paradigm" that permitted less-than-monthly dosing provided certain treatment endpoints were met. 2 "I suspect that if the 0.5 mg dose had been used in Protocol T, it would not have taken approxi- mately 1.5 years for the visual gain with ranibizumab to be equivalent to that observed with aflibercept," Dr. Zarbin said. "I don't think they would have differed at all. Of course, the FDA-approved dose for ranibi- zumab is 0.3 mg, but approval was based on the RIDE/RISE trials, which used a monthly treatment paradigm. In DME trials using 0.5 mg ranibi- zumab PRN, the average monthly dose was approximately 0.35 mg. In Protocol T the average monthly dose was approximately 0.235 mg, which is about two-thirds of the average monthly dose in the trials that ad- ministered 0.5 mg ranibizumab with PRN posology." Dr. Wells disagreed, noting the 0.3 mg was submitted and obtained U.S. approval because it had a more favorable risk profile than the 0.5 mg dose in RISE/RIDE. "In RIDE/ RISE, both the 0.3 mg and the 0.5 mg doses were given monthly for 2 years, and the higher cumula- tive dose with 0.5 mg did not give greater visual improvement than the lower cumulative dose with 0.3 mg." Year 2 results At year 2, Protocol T found no clin- ically important difference in the visual gains observed with afliber- cept, bevacizumab, and ranibizumab for patients with entry-level ETDRS vision of 20/50 or worse. Among pa- tients with entry level best corrected ETDRS visual acuity of 20/50 or worse, there was no statistically sig- nificant difference in visual outcome gains between aflibercept and ran- ibizumab (18.1±13.8 vs. 16.1±12.1 letters improvement for aflibercept and ranibizumab, respectively), nor was there a clinically important difference in visual outcome for any of the 3 agents. 1 "Based on what we learned from Protocol I, 3 it is unlikely that laser had an important impact on vision at year 2 of this study," Dr. Zarbin said. Furthermore, the year 2 data in- dicate that the burden of treatment is the same with all 3 agents. In all 3 treatment cohorts, injections were required in both year 1 and year 2 for most (>80%) patients. There were no real differences in the median number of injections during the 2-year follow-up period (15, 16, and 15 for aflibercept, bevacizumab, and ranibizumab, respectively). 1 Treatment frequency Monthly treatment is simply not necessary in DME, Dr. Wells said. "You can treat until stable, injecting for the first 6 months, per Protocol T. After 6 months, you add laser. Then, after 6 months and after you've added the laser, if 2 consec- utive injections cause no additional improvement in vision or swelling, you basically stop, even if there's edema," he said. Given some of the stringent entry and treatment criteria for Pro- tocol T, one should apply the results of Protocol T to the average patient with care, Dr. Zarbin said. Of neces- sity, clinical trials are much more rigid in their structure and treatment plans than what is found in a typical physician's office, Dr. Zarbin said. For instance, an entry criterion for Protocol T was that patients could Steve Charles, MD, performs a retinal injection on a patient. Source: Steve Charles, MD

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