乌鸦传媒

At the annual Digestive Disease Week conference, researchers reported results from of the T3MPO-2 study of tenapanor (Ibsrela) in adult patients with irritable bowel syndrome with constipation (IBS-C) to examine the relationship between patient-reported satisfaction (as measured by adequate and degree of relief) and improvement in abdominal symptoms.

In this exclusive 乌鸦传媒 video, Anthony Lembo, MD, director of research for the Cleveland Clinic's Digestive Disease & Surgery Institute, explained the study design and clinical significance of the results.

Following is a transcript of his remarks:

My name is Dr. Anthony Lembo, I'm actually now at the Cleveland Clinic Digestive Disease & Surgery Institute. Although as you see from this abstract, this was done when I was at the Beth Israel Deaconess in Boston, Massachusetts. And I was joined with some of my colleagues, Darren Brenner, [MD]; Brian Lacy, [MD, PhD]; and Suling Zhao, [PhD]; Susan Edelstein, [PhD]; and David Rosenbaum, [PhD] -- employees at Ardelyx, the manufacturer of tenapanor.

But I'm really excited to talk to you about this study because what we did was look at a new endpoint that we think is clinically important and will be important for future clinical trials. And we dove into this a little further to figure out what was the minimally clinically significant difference that you need to see in this endpoint, and look how it correlates with other global measures. And it's another way of thinking about how clinically significant it is.

So again, the title is the analysis of the patient-reported treatment satisfaction of abdominal pain score, which is what the new score is called in patients with IBS-C. And we used the results of patients treated with tenapanor. And we specifically used the results from the second of the two phase III trials. This was the , also published back in the Red Journal [American Journal of Gastroenterology]; it was called T3MPO-2. Not important, but it's a 26-week trial.

And for those of you that aren't familiar with tenapanor, it's a blocker of the NHE3 [sodium-hydrogen exchanger 3] receptor. That is a receptor that absorbs sodium. So you get an increase in sodium inside the gut that causes increase in fluids and presumably increase in motility.

Tenapanor, like several of the other products in this category of increase in fluids in the gut in patients with IBS, also reduced visceral sensitivity in the animal model. And tenapanor also has been shown in an animal model to reduce permeability.

So it has some really interesting properties, and I think we all realize that it's FDA approved for the treatment of IBS with constipation, a dose of 50 milligrams twice daily. And that was really based on the two phase III trials.

But we're taking results only from one of the phase III trials, and we're only looking at the group of patients that received the medication. Again, we're not looking at efficacy in this trial. We're really trying to compare this look at this endpoint. So let's talk about the endpoint that's in question here.

So this is a recently FDA-validated, three-item abdominal symptom score. And this was created in conjunction with the FDA. And importantly, it was recently studied in a [phase] IIIB trial with patients with linaclotide [Linzess] and showed that it was very responsive to change. And again in the PRO [patient-reported outcome] development, these symptoms are abdominal pain on a 0-10 scale, bloating 0-10, and discomfort. But those were the key abdominal features that patients reported to be clinically meaningful to them.

So seeing changes in the abdominal symptoms is important. Again, we're not going to look at the bowel symptoms in this analysis; we're really going to focus on this abdominal symptom score, or sometimes known as AS score.

And then we use two other global endpoints, adequate relief as well as the degree of IBS symptom relief as a 7-point scale that has three of the scales as improvement and three are worse, and one in the middle of, unchanged. So somewhat relieved, considerably relieved, or completely relieved. And then vice versa, for those that are getting worse, just the opposite was getting worse.

So we had a group of patients that received just tenapanor, and in total there are different subgroups that -- and again the exact number is not important -- but not all the patients answered adequate relief. So the ends are gonna be a little bit different. But again, the endpoints are the global messages where they're trying to get across.

In the first table, we just show you those people with adequately versus non-adequately and looked at the demographics showing that they're pretty similar, which isn't a big surprise, at the bottom of table 1, one of the things which is important is the baseline abdominal symptom score. And they were somewhat different between those that had adequate relief and those that did not have adequate relief -- again, suggesting that the lower the score, the more likely you are to have adequate relief.

In the second table, we looked at the two global endpoints as anchors, so either whether you had adequate relief or if you had some relief based on a degree of relief symptoms -- either complete, considerably, or somewhat relieved. And again, you'll notice that the ends are different just because of the percentage of patients.

But really the take-home points here are a couple. One is if you focus on the right-hand side, the percent change from baseline to week 26, that the difference is about 30%, and the change from the AS score, the three-item score. And if you look down below at the degree of relief questionnaire, again if you look at the minimum, which is like the minimally clinically significant improvement, is somewhat relieved -- it's about 30%. So 32% for this. And then it goes up higher; you have to have more improvement in AS scores to have considerably or completely [relieved] -- again, exactly what you'd expect from this.

The importance of this is that the 30% -- and remember for the FDA endpoint they're asking for a 30% improvement in the worst abdominal pain, so one of the three scores is to meet the FDA endpoint -- here we're showing that that is probably the minimum threshold to see clinically significant improvement based on these two anchors that were used for the AS score.

So in figure 2 if you look at it, this shows you the percentage of patients that had the different degrees of relief, their symptoms including those that got worse. So if you look, they broke the patients down based on whether they had adequate relief or no adequate relief. And again, it shows that those that had adequate relief tended to report somewhat considerably or completely relieved.

And again, the downside to adequate relief is it doesn't tease it apart. So you don't actually know if somebody had considerably or complete relief -- as you can see it's about a third almost for those three for somewhat, considerably, or completely relieved.

So that's one of the benefits of having this degree of relief. And those that didn't have adequate relief, you can see the percentages are much smaller, but there still is a significant group of about 45% of people that had somewhat relief but didn't think they had adequate relief.

So again, it shows you how patients are thinking about these endpoints slightly differently.

And then finally on figure 3, here we looked at the AS score or the abdominal symptom score -- again those three feelings of pain, bloating, and discomfort. And looked at it to see what the best sensitivity and specificity was for looking at the change from baseline in the anchor of having any release.

So what's the minimally clinically significant difference? And you can see on the left-hand side, the change would be a change of two and a half points of that AS score. Again, don't forget, 0-10 range, so it's in the range of 0-3.

And then most importantly on the right-hand side, the optimal value is being just around 30%, just under 30%. Again, consistent with the fact of what I said earlier, that that's probably the right number for being the minimal clinically significant difference using this AS score.

So this AS score is a new score. It was a standard PRO development with the FDA. It's something that we're going to see more and more as we look at IBS clinical trials in this current study. Using the tenapanor data, we were able to show what we believe is the minimal clinically significant difference in the AS score, which is a difference of about 2.5 points on that scale or about approximately 30% change from baseline in the abdominal symptom score.

So we think that this is going to be helpful for all of us going forward, particularly in the clinical trials. And again as I said, you'll probably see this score being used more and more.

Thank you very much for your attention.

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