Diabetes, and its related ocular conditions like diabetic macular edema (DME), is a chronic condition. And as such, patients must be monitored and treated over long periods of time.
However, clinical trials generally don’t have that long-term (or lifetime) follow-up. Eventually, patients are released from strictly regimented medical studies and thrust back into the real world, where they may or may not continue treatment. So, it’s a known fact that clinical results don’t always align with the real world.
Of course, this fact is not lost on ophthalmologists and researchers. As such, results from one recent extension study were published in March 2020: Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study).1
During the 37th World Ophthalmology Congress (WOC2020 Virtual®), study co-author Jennifer Sun, MD, from the Joslin Diabetes Center at Harvard Medical School (USA), shared results and insights from this study which asked, “What happened after Protocol T patients were released from the study and into traditional clinical care?”
Protocol T Extension: Results
The original Protocol T study compared efficacy and safety of aflibercept, bevacizumab and ranibizumab, where all three groups were found to have visual improvements from baseline to two years patients with center-involved DME.2 Dr. Sun pointed out that the Protocol T Extension study’s main objectives did not include a comparison of treatment groups after 2 years, as treatment between 2 and 5 years was managed at clinician discretion.
According to Dr. Sun, there were several main questions researchers investigated in the Protocol T Extension — below, we investigate the answers to these questions further.
1) Did patients continue treatment with a retina specialist?
Of the original Protocol T study, 317 of 463 eligible participants or 68% completed the 5-year visit. And between years 2 and 5, 217 of 317 (68%) of study eyes received at least 1 anti-VEGF treatment.
2) What treatments were given and how often were they received?
Regarding treatment provided over those three years, Dr. Sun said, “Thirty-eight percent received aflibercept; 32% bevacizumab; 19% ranibizumab; 10% corticosteroids; 8% focal grid laser; and 10% PRP.
“The mean number of visits among participants was 14 between 2 and 5 years, suggesting that they were being followed fairly frequently — at least 4 times per year in many cases,” continued Dr. Sun. “We saw that 98% of these visits were conducted at the Protocol T clinical site, so these patients were experiencing good continuity of care with what seemed like reasonable follow-up.”
She explained that the distribution of anti-VEGF agents received after two years was pretty widely distributed: “So, whereas 32% had no injections after 2 years, the rest of the patients — although they had a median number of injections of 4 (which was very similar to what we saw in Protocol I) — saw a very large range of patients who were getting very few treatments to patients who were still getting monthly [treatment] over that timeframe.”
3) How did participant VA change from baseline and between 2 and 5 years?
“As you may remember, during the randomized trial, the overall group gained a fair amount of vision, about 12 letters or more,” shared Dr. Sun. “During the observational study, we saw that at the end of 5 years, these eyes still had a positive gain of 7.4 letters from baseline, so they were still better off from where they started.”
At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years.
“This was very similar when we looked at groups broken up by treatment assignment. All three groups had declines in vision of approximately one line or so during the 2 to 5 2024 visits,” said Dr. Sun.
“When we look at those with baseline VA of 20/32 to 20/40, we see that again on average the eyes gained in vision from baseline to 2 years — and then there was a slight decline in vision, and the decline was fairly similar among the treatment groups,” she continued. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline, but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years.
“We also had a consistent change in the baseline groups that started with vision of 20/50 or worse, all of these three groups have a decline in vision from the 2 year visit, but at 5 years they’re all still better off than they were at the beginning of the study,” shared Dr. Sun. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline, but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years.
4) How did participant central subfield thickness (CST) change from baseline and between 2 and 5 years?
Mean CST decreased from baseline to 5 years by 154μm (95% CI, 142-166) and was stable between 2 and 5 years (-1μm; 95% CI, -12 to 9).
“Indeed, we saw basically a one micron difference between the 2 and 5 year visits,” said Dr. Sun, adding that this again, was very consistent among the three treatment groups.
Limitations and conclusions
As with any study, there can be limitations. In this instance, the researchers said that only two-thirds of eligible participants completed year 5 of the study. Plus, treatment from years 2 to 5 was at clinician discretion, so treatment cannot be compared during that time. It’s also important to note that this data was retrospective.
“However, we can conclude that after Protocol T ended and patients were released to standard care, 95% of our patients continued to receive retinal care and at least 68% received at least one intravitreal anti-VEGF injection,” said Dr. Sun.
She explained that on average, patients had visual gains from baseline but their mean VA worsened between years 2 and 5. Meanwhile, there weren’t significant CST changes in the long-term follow-up.
“These results are different from prior clinical trials in DME that have demonstrated better maintenance of visual gains,” she said, explaining that Protocol I clearly demonstrated much better maintenance than what was observed in this extension study.
“This suggests that studies to improve long-term visual outcomes in clinical care among eyes with DME are still needed,” concluded Dr. Sun.
References
- Glassman AR, Wells JA, Josic K, et al. Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study). Ophthalmology. 2020;S0161-6420(20)30304-3.
- Wells, JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123(6):1351-1359.
