Key Findings of Protocol T Study


Experts discuss the results of Protocol T study comparing anti-vascular endothelial growth factor (Anti-VEGF) agents for the treatment of diabetic macular edema (DME).


Ehsan Rahimy, MD: Veeral, the results of Protocol T demonstrated that the different anti-VEGF agents all have differing degrees of efficacy. Fortunately they all work well in treating DME [diabetic macular edema]. Can you briefly [discuss] the key findings from that study and what were the take home points?

Veeral Sheth, MD, MBA, FASRS, FACS: This was a great study done by the DRCR [Diabetic Retinopathy Clinical Research Network] that’s relevant because it was free of industry bias. We like to see these studies because we think they are going to fairly look at these things. And the question at the time was, going back to how we compare to the CATT study, we’ve got these 3 great agents, are they different or not? Or are they about the same and interchangeable? And what we saw was with patients who had pretty good vision to start, 20/40 or better, all 3 worked very similarly when given in the same way. However, at [vision of] 20/50 or worse, we did see a tendency to favor aflibercept over ranibizumab and bevacizumab. I think for the first time we had seen, in an independent way, that there might be some differences with these anti-VEGFs. That’s kind of the primary finding.

The other finding I thought was interesting in Protocol T is that we still had a lot of patients, despite getting every month injections or every 4-week injections, after 6 months still had residual fluid. We still had about 40% to 50%, and even up to 60% in the bevacizumab group, who at that time point still needed some degree of rescue therapy. That just shows you that they work well, but there’s still room for improvement. [It goes] back to the other questions of, how do we get better? This is the way we’re looking at getting better, better drying, longer acting. This was a study that kind of showed us we’ve got good treatments, but there’s still room for improvement.

Ehsan Rahimy, MD: In your clinical practice, do you still use that benchmark of 20/50 or worse [when] you’re thinking of aflibercept earlier, and at 20/40 or better you could use any of the agents? How are you guys incorporating that in your practices?

Jonathan Jonisch, MD: My clinical impression is that aflibercept is a superior drug to bevacizumab in our diabetics. When you have a 2-year trial showing noninferiority, I think all of us have a lot longer-term experience with these drugs. We see it on a daily basis. We see it over many years. I think if these trials were longer and with more patients, there [would be] more subtleties that you could find. My clinical impression is that it’s a better drug. And it was shown even in this limited subset to be superior for the first time in 20/50. So outside of payer mandates that require me to use bevacizumab, my preference is to use aflibercept in this population. Specifically, I find [that] to be the biggest delta between our therapies.

Veeral Sheth, MD, MBA, FASRS, FACS: I agree with that. I think you put Protocol T, that’s kind of what got us thinking about it, but we’ve had many years of practice since then, and I think plenty of us have seen patients where you just know that aflibercept is working better. We’re forced to think about it with step therapy and things like that now. But time and time again, we see that patients tend to do better. And there’s a predictability to it. We’ve had some issues with Avastin [bevacizumab] and compounding pharmacies, you can name a bunch of issues with it. I think that in a world, again, going back to safety and how important safety is today, and predictability and efficacy, you combine all those things, and we tend to gravitate toward things that we know are more of a sure bet for our patients.

Ehsan Rahimy, MD: Veeral, you brought up 2 key points from Protocol T that don’t get discussed as much. No. 1, I think we all know, and the nice thing in these studies is, you’re free of [pharmaceutical industry] bias. But on the flip side, the bevacizumab at this stage is not the same bevacizumab that we’re giving that comes from compounding pharmacies. [This one is] straight out of the bottle from Genentech. There’s a reliability in terms of the potency and the amount of medication they’re giving in those studies that, I think we’d all agree, we can’t entirely trust that on a day-to-day basis. Then I like what you mentioned about the rescue therapy. Rescue was focal laser [therapy], we don’t talk about that as much. But the aflibercept-treated arms, correct me if I’m wrong, had the lowest rate of requiring rescue compared to the other treatment arms. I think that does speak to something, be it fluid control or durability. Ali, do you have any thoughts on that?

Ali Khan, MD, FACS, FASRS: If your retreatment criteria is based on anatomy to some degree, the drug that has the better anatomic results will result in [fewer] retreatments. I think that bore out in Protocol T and now the subsequent studies. With your initial question, I do consider that 20/50 mark. A lot of the clinical trials have ETDRS [Early Treatment of Diabetic Retinopathy Study] vision [testing], which isn’t really what we do in clinical practice. This gave it a very easy, Snellen visual acuity [test] to frame our thought process. And honestly, I think what got a lot of people to start using aflibercept more comfortably and earlier in the disease process, was this trial, at least in diabetics. I still think of the 20/50 mark because it is the Snellen visual acuity measurement. And I think, whether you do step therapy or start with Avastin on your own accord, meaning not payer mandated, I’ve paid attention to how many patients I switch. I do think a good number of them I switch, whether that’s from suboptimal anatomic response or simply trying to gain durability.

This trial looked at noninferiority in terms of visual outcomes as a 2-year mark, which everyone says [is] equivalent. But the durability aspect to me, is what has helped push me toward probably more use of aflibercept, whether they’re 20/50, or better or worse, or not. But the durability effect alone, I’ve noticed. Luckily, like we said, all efficacy is not always created equal in terms of the anatomy, but for a patient, especially with diabetes, durability, makes a big difference. And aflibercept has been good in that respect, at least in my practice.

Veeral Sheth, MS, MBA, FASRS, FACRS: You brought up a good point, that bevacizumab in that study was different than what we use today. And I can argue, all 4 of us were in the clinic earlier today, we all probably used bevacizumab, but all 4 of us probably used a slightly different version of the bevacizumab, whether it was packaged differently, whether it was sitting in your fridge for 2 months, or in my fridge for 2 days. All of that matters, it has been shown to matter. So I think that variability is a little tricky these days too, especially when we know that the aflibercept you used was probably the same exact one that I used. I think it’s a tradeoff that you have to think about as well.

Ehsan Rahimy, MD: Great point. I do like to [mention] a positive take home [message] to Protocol T too, at the end of the day is, we have 3 great drugs that work. They all did improve vision, patients did do well on all of them, and I think that is important for us to take home that point because as we’ll discuss, access is different for everybody.

Transcript edited for clarity.

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