 And our last presentation is kind of an update kind of in the cornea world on the dream study. Hi, my name is Shugan Daliwal and I'll be presenting an update on the dream study. This is essentially a study on the use of omega-3 fatty acids as a treatment for dry eye disease. And it was conducted by the dry eye assessment in management study research group and stream study. So dry eye disease is a disease that we're all familiar with. It's one of the top three most prevalent chronic eye diseases but not only is it very common, it's multifactorial, it's complex and it's highly symptomatic. And it presents a great economic burden on a lot of our patients. However, with any complex multifactorial disease, there's no clear cut treatment and a lot of the treatments are often inadequate and expensive. The dream study research group chose to approach dry eye disease here as an inflammatory eye disease. And studies have shown that inflammation plays a significant role in the development and the chronicity of dry eye disease. And it's thought that anti-inflammatory therapies can help break this cycle. One of the proposed anti-inflammatory therapies is polyunsaturated fatty acids. And polyunsaturated fatty acids, specifically omega-3 fatty acids are essential in the human diet, meaning that we cannot synthesize them ourselves and have significant anti-inflammatory properties. And this is specifically via two mechanisms. The omega-3 fatty acid pathway creates anti-inflammatory mediators itself. But it also competes with the omega-6 fatty acid pathway for some shared substrates. So specifically your cyclooxygenases and lipooxygenase. So this shunts away from the production of pro-inflammatory mediators in favor of production of more anti-inflammatory mediators. So this is thought to be the mechanism by which omega-3 fatty acids exert their anti-inflammatory effect. The ideal omega-6 to omega-3 fatty acid ratio in the diet is approximately four to one. However, in our current Western diets, it's closer to 15 to one. So it's thought that if we can approach this ideal ratio of four to one, we could enhance the anti-inflammatory effects of omega-3 fatty acids. And certain studies have shown that omega-3 fatty acids are associated with improvement in dry eye symptoms. In 2005, Miljanovic did a cross-sectional study of approximately 30,000 women. And he showed that there was a 60% decreased incidence of dry eye in those patients who had higher omega-3 fatty acid intake. Vodovich in 2011 showed that omega-3 fatty acid supplementation was associated with increased tear production, with increased tear volume, and improvement in symptomology by the OSDI scores. And Masai in 2008 showed much the same in a randomized control trial. He was able to show that omega-3 fatty acid supplementation improved symptomology by the OSDI score, and then also improved tear breakup time and amybum score. However, despite all this study, there's no real consensus on the dose, the duration of treatment, or the composition of the omega-3 fatty acids to be used. The dream study wanted to design the first large-scale, long-term, multi-center control trial that would evaluate the use of high-dose omega-3 fatty acids at dry eye disease. So as I said, the study, it was designed to be a very clinically rigorous study perspective, multi-center, randomized, double mass, placebo-controlled, and extending over the period of a year. But it was also intended to be a real-world clinical trial that could be applied to our practice day-to-day. So they did this by including a broad spectrum of dry eye. So patients with anywhere from moderate to severe dry eye who simply had to be symptomatic and show consistent signs on exam of dry eye. And other than that, they have very minimally restrictive inclusion and exclusion criteria. So you can see here the eligibility criteria essentially wants patients who have somewhat healthy eyes but consistent evidence of dry eye. People who are symptomatic for at least six months and have consistent evidence on clinical exam of dry eye. It's important to see here that they excluded patients on the far ends of the spectrum of the OSDI score. They did not want patients who were severely symptomatic or minimally symptomatic so that they could, I guess, reduce the incidence of outliers in their data. And then also, this is one of the most novel things that this study did is that it allowed the patients to continue their current dry eye therapies over the course of the study. And this was essentially done so that they would mimic normal clinical practice. They wanted these patients to whatever they happened to be on, if they were on additional tiers, if there were other lubricants to continue that throughout the duration of the study without starting new treatments or stopping that treatment. And you can see here, this is just a list of all the possible additional dry eye therapies patients were allowed to be on. It's pretty extensive. Exclusion criteria, essentially the exclusion criteria just wanted to exclude individuals who had perhaps another reason for their dry eye. And interestingly, they didn't exclude people who recently wore contact lenses or had a history of refractive surgery. So that's a patient population that we probably see a lot that we may not be able to apply these findings to. Beyond that, trial groups, the trial group division was fairly intuitive. There was an active supplement group and there was a placebo supplement group. The active supplement group received approximately a total daily dose of 2,000 milligrams of EPA and 1,000 milligrams of DHA. The placebo supplement group received 5,000 milligrams of refined olive oil. Specifically, the components of this olive oil were oleic acid, polymitic acid, and linoleic acid. And these patients were examined at three, six, and 12 months for these specific measures. The primary outcome measure of this study was symptoms by the OSDI score, the Ocular Surface Index score. And the secondary outcomes were clinical signs, were compliance with protocol. There were a few exploratory outcomes as well, specifically measuring cytokine levels, markers of inflammation in the tear film. And the results were fairly interesting here. So it showed that in both the placebo and the active supplement group that there was no significant difference between the decrease in OSDI scores. So essentially both groups showed improvement, but there was no difference between the level of improvement between the two. There was a subgroup analysis that was performed as well. Patients were divided in four subgroups based on their OSDI score, the severity of clinical signs, the level of fatty acid levels in their blood, and ocular inflammation. And there was no difference between scores in those subgroups as well. The secondary outcomes showed much of the same as well. There was no significant difference in the clinical signs. There was improvement in both congenital and corneal staining as well as tear breakup time, although there was no improvement in the Shrymer's test and no improvement in visual QT or IVP in both groups. It's interesting that because this was an oral supplement that's systemically absorbed, there was, this study was able to really examine the compliance with this protocol. At the three, six, 12 month intervals, they drew blood levels and were able to show that EPA and DHA levels were higher in the supplement group. And this essentially confirmed that there was a strong level of compliance with their suggested protocol. So to get a little bit more into these results, it's interesting that the symptoms and signs of dry eye disease improved in both the active supplement and the placebo groups. And there was no significant difference in improvement. The dream study research group suggests that their results are highly valid. They essentially created a real world clinical trial, not only with a large scale, and included both academic and private institutions, patients who were both in ophthalmology and optometry practices. They followed up for more than a year so that they could eliminate any seasonality that could contribute to dry eye. And they allowed their patients to continue all other dry eye interventions. And they used a higher dose of omega-3 fatty acids than is typically used in the dry eye clinical trials. At 3,000 milligrams daily, that's pretty significantly high. And they were able to ensure that their patients at a high level of compliance and follow-up by monitoring those blood levels. But it's hard to compare this study to the studies that have been done in the past. And although the results are different, you can't really create a direct head-to-head comparison here. That's partially because the eligibility criteria in this study is so much more lax than it has been in previous studies. There are prior studies that require a specific level of tear osmolarity and really restrictive criteria in that sense. And the omega-3 fatty acid dose as well was significantly higher. One of the controversial aspects of this study is the use of the placebo. In other studies, the placebo is not an actual active ingredient, olive oil. So that also makes a direct comparison somewhat difficult. And of course, there are other large-scale studies that have been indebted in other countries, like India. However, it's hard to compare that diet to the Western diet, which is far lower in omega-3 fatty acids. And that's just that second point is going into the same, that more of the studies that are able to be compared tend to be on a smaller scale and have more restrictive criteria than the dream study did. So limitations of this study. The results on this study are somewhat controversial. Most people do agree that this was a well-designed study. But specifically, the choice of olive oil as a placebo has been a fairly controversial topic. Like I said, the olive oil had three active components, the oleic acid, the phenolic acid, and the pulmitoloic acid. So phenolic acid has been shown to be anti-inflammatory therapy. And given in high doses, has shown to have anti-inflammatory effects in dry eye. However, it was thought that the low phenolic component in refined olive oil would not create any of those benefits. Oleic acid also has anti-inflammatory effect. And this was something that the dream study took into account specifically. They examined RBC levels of oleic acid in the placebo group over the course of the study. And they showed that there was no change in the oleic acid level. Pulmitoloic acid, the third component in olive oil, was not really accounted for. And so this could possibly be a confounding variable in the dream study. Although it was present at such low levels that the argument is made that it's likely not contributing anything here. And of course, it's important to note that these findings don't apply to GLA, gamma-linoleic acid. This is an omega-6 polyunsaturated fatty acid that has been shown to have significant anti-inflammatory effect and significant anti-inflammatory effect specifically in dry eye. So these are some of the limitations to this study. But most people do agree that this was a very well-designed study, that it had a novel approach to creating a clinical dry eye trial that could become the basis of further study in this field in the future. A little bit of an update there on the dream study. Question? Yes? You discussed the limitations very nicely. And when we're looking for an answer in a controversial topic in ophthalmology, we love to see a well-designed, well-done, large study that's going to give us the answer. There is still a lot of controversy on this study. And I don't think that a lot of people agree that this is the answer. And the reason being is the placebo. Yeah. And I know you just discussed that. In addition, this is not a placebo. It's an oil that they're taking it. I wasn't privy to the discussions of the people who were designing this study. But I have no idea why they didn't pick a real placebo instead of an oil placebo that can go up through the result of the study. Because as a result, you do this large study. And there's still a large group of ophthalmologists who say, well, you're next. The placebo group improved. And it's not that neither group improved. They both improved. And in fact, they both improved considerably on the study. It just wasn't a difference between the placebo and the study. And that's because the placebo is not a true placebo. So the problem is, is we went through the time and expense of having this study. And I still don't think the question is answered. And there's a large group of ophthalmologists who still don't believe that using the omega-3 acids are not helpful. And so I'm disappointed in this, the way this study was put together. And I don't think this really answers the question that we wanted it to answer. Yes? So I had a question, though. The way I looked at the data, I thought there was no change from baseline in either placebo or omega-3. Is that correct? I mean, no significant change. I mean, there is a slight decline. But it wasn't, that's not significant, right? My understanding was that there was a significant change in symptoms, the OSDI score. But there was not significant between groups, the level of the delta between the groups. So that's significantly different. I believe so. I'd have to review it, though. Exactly. Both groups showed a significant change. But it wasn't between the two groups. It was both the, I mean, the numbers were large enough to do it, I think. Even though the city overlapped, it's probably some of the largest study that significant. And to go back to Dr. Bamalus's point, I heard one interview from Dr. Aspel, the primary investigator. So they said they chose olive oil because it would stay in the gel capsule better than just water. So I thought that was an interesting, perhaps, that step of the study could have been, if it had shifted differently, perhaps the results and our discussion of the results would be very different. I think it just continues the confusion on dry-eye treatment. What do you do for a patient? Well, you know, based on what it looks like, and it's just trial and error. So you have, I mean, you have some patients who had an OSDI of 40 that went down to zero, potentially, right? So they improved a ton. And so I definitely see that. Well, I have people try it for three, four, six months. And if they have no improvement, I just don't want to stop it. I have the patient who says, they have horrible looking eyes. I can get them on fish oil, and they love it. They're like, my eyes feel great, and their eyes look the exact same. So I think it's just dry-eye, in general, is what it's like. And it is frustrating to not have an answer, but it just continues the saga of trial and error and dry-eye treatment. Dr. Bamalus, this may sound kind of strange, but it's the environmentalist in me. I just have a problem promoting the fish oils as much as we're doing in medicine when there is not a lot of proof that something else could be used instead. Because, and for me, it's a lot of the environmental impact of all the fish oil that we're selling, some of these. There are actually, a lot of people are concerned about the harvesting production of the fish oil. And if we're not really doing anything, I just, I just kind of wonder if they, you know, flaxseed oil or something else. Now, because of the study, actually, tell patients just to have olive oil in their diet. Yeah. Slightly related to the previous question, even though the study is over, is anybody continuing to follow the enrolled participants to see if they're choosing to continue, both in the placebo and the real omega-3 group, to see if they're choosing to continue? No, I don't do that. Not only for dry eye improvement, but also for purported other benefits. I don't believe so. I don't think they've kept in touch with the participants, but that's an interesting point. That could be a major health benefit otherwise. Thank you.