Managing Your Adult Patients’ IBS-D Symptoms Transcript

Managing Your Adult Patients’ IBS-D Symptoms

Host: Christina J. Hanson, FNP, South Denver Gastroenterology
Featuring Kim Orleck, PA-C, Atlanta Gastroenterology Associates

Welcome to Clinical Conversations: Managing Your Adult Patients’ IBS-D Symptoms.

Christina Hanson and Kimberly Orleck received payment from Salix Pharmaceuticals for their testimonies.

Christina: Hi, I’m Christina Hanson and thanks for tuning in to Clinical Conversations. Today we’re going to be talking about managing symptoms in your adult patients with IBS-D. I’m joined by Kim Orleck, who is a practicing physician assistant and is the nurse practitioner and physician assistant supervisor at Atlanta Gastroenterology Associates. Welcome, Kim!

Kim: Thanks, Christina, happy to be here!

Christina: Kim, we know that irritable bowel syndrome, or IBS, is classified into subtypes, with irritable bowel syndrome with diarrhea, or IBS-D, being the most common. Let’s start by talking about the typical symptoms experienced by patients with IBS-D.

Kim: Patients with IBS-D experience recurring abdominal pain, and have loose, mushy, or watery stools at least 25% of the time.

It’s important to note that IBS-D is a chronic relapsing disorder where patients’ symptoms can vary over time. In terms of their symptoms, sometimes they’ll have good days, and sometimes they’ll have bad days.

Because their symptoms can be hard to predict, some patients have to make plans with the bathroom in mind—they feel like they need to know where the closest bathroom will be wherever they go.

There was an interesting survey conducted in 2014 that looked at characteristics of IBS-D symptoms. Of the 1094 patients in this survey with an IBS-D diagnosis, 61% reported diarrhea as a disruptive symptom and 32% reported their discomfort or pain as disruptive. Additionally, bloating was reported as a disruptive symptom in 19% of these patients.

For context, this was an online survey of people with IBS-D symptoms. There were 1094 individuals in this survey who had an IBS-D diagnosis and 830 individuals had IBS-D symptoms that were consistent with Rome III criteria but with no formal diagnosis. Disruptiveness of symptoms was rated on a 7-point scale, with 1 being not at all disruptive and 7 being extremely disruptive.

Christina: I’ve found that to be the case with my patients. What can be challenging, too, is that IBS-D is a difficult topic to talk about. The quality and consistency of your bowel movements is not something that you chat about around the dinner table, so what’s your general approach, or mindset, when you’re working with these patients?

Kim: There are really two main things I try and do. First, I think one of the most important things clinicians can do is remind patients that we’re truly listening, and that IBS-D is a legitimate diagnosis. A lot of what I see is that patients with IBS come to us for second, third, fourth, or fifth opinions—not necessarily because they don’t believe the diagnosis but because they feel like they weren’t listened to. They were told “it's just IBS.” Their condition was minimized, as being just a functional issue. So, it’s important to validate what these patients are saying—that they are feeling abdominal pain. That they are having diarrhea and experiencing bloating, which can be quite disruptive for them. So, I think the most important thing is that clinicians are there to listen and explain to patients that we do understand that they are truly hurting. It’s not “in their heads”. Patients with a functional bowel disorder can be suffering in similar ways to how patients with other chronic conditions are suffering.

The second part to that is to remind patients that we have so many options for treatment now. We need to reassure them that there are treatments available to help manage their IBS-D and we’re going to work with them and help them to find an IBS-D treatment that works for them.

Christina: Kim, you bring up IBS-D treatment, which we’ll get to later, but I’m wondering if you could expand a little more on that first part, and give our audience some examples of things you say to help reassure patients and get to a point to understand their goals and how to help manage their symptoms with pharmacologic treatment.

Kim: One of the things that’s most helpful to me—and I always remind new PAs and NPs of this—is asking the patient: “What is the biggest issue to you? If we could help address one thing, what would it be? Is it the abdominal pain? The diarrhea? The bloating?”

If we ask that of patients and really listen, it makes them really know that, (A) we care. We want to listen. We want to help them. And (B) we’re going to focus on the biggest factor—the thing that bothers them the most—and we’ll work on that first.

Christina: Yeah, I think that’s a great place to start. It can be really challenging to manage IBS-D symptoms. Patients often try strategies to manage their abdominal pain and diarrhea without medication, like exercising, meditation, relaxation techniques, or cognitive-behavioral therapy. They may try different dietary measures like taking fiber. There’s a lot of interest in the low FODMAP diet. For those who might not be familiar, FODMAP stands for Fermentable, Oligo-, Di-, Mono-saccharides, and Polyols. This covers a large class of small nondigestible carbohydrates that are in so many common foods like fruits, vegetables, legumes and cereals, honey, milk and dairy products, and sweeteners. So, understandably, there are challenges with a low FODMAP diet. It can be restrictive and hard for patients with IBS-D to adhere to over time, and they may not get all of the nutrients they need. Patients with IBS-D may also try different over-the-counter medications or supplements. Kim, I know that you have a background in nutrition, what do you think about some of these interventions?

Kim: Yeah, I’m actually a dietician, and I think it really depends on the patient. Some patients will say, “I really want to try the natural way, the dietary way.” We don’t do food allergy testing, but I will try to support them in any way I can. While FODMAP may work for some patients, it may be a little restrictive, like you said. It may also be time consuming and may take a lot of work with the dietician.

And to the other point you made, patients with IBS-D may try multiple medications. In addition, they may not always be satisfied with their IBS-D treatment regimen. I want to talk again about that 2014 survey I mentioned earlier that included patients with and without an IBS-D diagnosis. The 1094 patients who had an IBS-D diagnosis reported trying an average of 4.9 different treatments for IBS-D—so nearly 5—and about 80% said they were not satisfied with their treatments.

As a reminder, this was an online survey of people with IBS-D symptoms. Some had a previous diagnosis of IBS-D, and others had IBS-D symptoms that were consistent with Rome III criteria but had no formal diagnosis. There were 1094 individuals in this survey who had an IBS-D diagnosis and 830 individuals had IBS-D symptoms that were consistent with Rome III criteria but with no formal diagnosis. Regarding treatment satisfaction, people in the survey rated how satisfied they were with their current treatment on a 7-point scale, with 1 being extremely unsatisfied and 7 being extremely satisfied.

Christina: IBS-D is a chronic condition. As with any chronic condition, we want to help our patients find relief from their ongoing symptoms. This is where it can be helpful to consider a treatment like XIFAXAN. XIFAXAN is indicated for the treatment of irritable bowel syndrome with diarrhea in adults and contraindicated in patients with a hypersensitivity to rifaximin, rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Kim, can you talk a little bit about how XIFAXAN is thought to work?

Kim: Sure. XIFAXAN is the only FDA-approved IBS-D treatment that alters the microbiome in the gut. It’s a nonsystemic antibiotic, and less than 1% is normally absorbed from the gut. This means most of XIFAXAN doesn’t get into the bloodstream, so it works primarily in the gut to inhibit the growth of bacteria. Although additional studies are needed to further understand the role of gut microbiota in IBS, evidence suggests that XIFAXAN directly attacks bacteria in the gut that may be linked to IBS-D symptoms. It’s important to note that the mechanism of action of XIFAXAN is not completely known and does not imply clinical efficacy. Additionally, there’s an increased systemic exposure in patients with severe (or Child-Pugh Class C) hepatic impairment. Caution should be exercised when administering XIFAXAN to these patients.

Christina: Now let’s discuss the clinical trials that looked at the efficacy and safety of XIFAXAN in adult patients with IBS-D. When I’m considering XIFAXAN for my adult IBS-D patients, I talk to them about the clinical trials, and many respond well to the information. Like we were saying earlier, they’ve tried so many things that I think it’s reassuring to hear the data that say, “this may work, it’s proven.” If you get too detailed, it has the potential to be overwhelming, but I do think it’s important to talk about both the TARGET 1 and TARGET 2 clinical studies of XIFAXAN for IBS-D treatment.

For those who might not be familiar, TARGET 1 and TARGET 2 were two identically designed phase 3 randomized, double-blind, placebo-controlled clinical trials conducted over a 3-month period that helped establish the efficacy and safety of XIFAXAN in IBS-D.

In these two trials, a total of 1258 adult patients with IBS-D (Rome II criteria) were enrolled and received either a 2-week course of XIFAXAN 550 mg dosed 3 times daily (n=624) or placebo (n=634). After the treatment period, patients were followed for an additional 10 weeks to assess for relief of IBS-D symptoms.

The primary endpoint for these trials was adequate relief of signs and symptoms of IBS for at least 2 weeks during the month following the treatment period. For context, patients were considered to have adequate relief if they answered “yes” to the following weekly question: “In regards to your IBS symptoms, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?”

In the two trials combined, 41% of patients (254 of 624) treated with XIFAXAN achieved adequate relief of their IBS signs and symptoms, compared with 31% of patients (98 of 314) taking placebo in TARGET 1, and 32% of patients (103 of 320) taking placebo in TARGET 2.

After the 2 weeks on treatment, more patients treated with XIFAXAN experienced significant relief from both abdominal pain and diarrhea compared with patients taking placebo. For context, in order to be considered a responder for both abdominal pain and diarrhea, you had to have at least a 30% decrease from baseline in abdominal pain plus a weekly mean stool consistency score of less than 4, and you had to meet both of these criteria for at least 2 weeks during the month following the treatment period.

In these two trials combined (pooled analysis), a total of 47% of patients (n=291/624) treated with XIFAXAN were considered abdominal pain and stool consistency responders compared with 37% of patients (n=237/634) who received placebo (P <0.001, represents pooled data).

[Secondary endpoint: In both studies, more patients in the XIFAXAN 550 mg group had adequate relief of global IBS-D symptoms (see primary endpoint for definition) within the first month compared with the placebo group. Relief continued during the first 2 months and throughout all 3 months in both studies. TARGET 1 odds ratio: 1.35 (95% CI, 1.00-1.82). TARGET 2 odds ratio: 1.52 (95% CI, 1.13-2.03).]

If you look at specific symptom response in the two trials combined (pooled analysis), 52% of patients (n=324/624) who received XIFAXAN were abdominal pain responders compared with 43% of patients (n=270/634) who received placebo. The proportion of stool consistency responders for the two trials combined was 76% (n=477/624) and 66% (n=418/634), respectively.

I’d also like to point out that XIFAXAN provided significant relief of bloating based on combined weekly response data from the first 4 weeks following treatment in TARGET 1 and 2: a total of 40% of patients (n=251/624) treated with XIFAXAN were considered bloating responders after the treatment period compared with a total of 30% of patients (n=192/634) who received placebo (P<0.001, represents pooled analysis). For context, patients who were considered responders for bloating answered “yes” to the following weekly question for at least 2 of 4 weeks during the month following 14 days of treatment: “In regards to your IBS symptom of bloating, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating?” In addition, pooling TARGET 1 and 2 together, patients treated with XIFAXAN were significantly more likely to have sustained relief from bloating across all 3 months of the study. This was based on patients who had adequate relief of bloating using a positive response to the same weekly question for at least 2 weeks per month.

[Key secondary endpoint: The proportion of subjects who achieved adequate relief of IBS-D–related bloating (ie, responders) for at least 2 of 4 weeks during the month following 14 days of treatment.]

A separate study—TARGET 3—included an open-label treatment phase that was 24 weeks—so basically 6 months—followed by a double-blind retreatment phase.

[TARGET 3 study design: This trial included an open-label phase followed by a randomized, placebo-controlled phase, with the aim of determining the efficacy and safety of repeat treatment with XIFAXAN in patients with IBS-D who had responded to a 2-week course of XIFAXAN and subsequently experienced IBS-D symptom recurrence.]

At the beginning of the study, a total of 2438 adult patients with IBS-D received XIFAXAN 550 mg 3 times a day for 2 weeks.

A total of 1074 of these patients, or 44%, responded to XIFAXAN, meaning that they had at least a 30% decrease from baseline in abdominal pain plus at least a 50% decrease from baseline in the number of days per week with diarrhea, and met both of these criteria for at least 2 weeks during the month following the treatment period.

By the end of the 6-month open-label phase, 36% of patients (n=382/1074) who initially responded—so over a third—had no recurrence of abdominal pain or diarrhea. (36% of open-label responders did not experience relapse during the 18-week observation phase before being withdrawn from the trial for any reason.)

[64% (n=692/1074) had symptom recurrence.]

The median time to symptom recurrence was 10 weeks, with a range of 6 to 24 weeks.

For context, recurring symptoms in this trial meant either a return of abdominal pain or lack of stool consistency for at least 3 weeks of a rolling 4-week period.

The 636 patients who did experience symptom recurrence then went on to the double-blind portion of the trial. The primary endpoint was the proportion of patients in the double-blind phase who were responders to a repeat treatment for both IBS-related abdominal pain and diarrhea. A total of 38% of patients (n=125/328, P<0.05) who were retreated with XIFAXAN were considered responders compared with 31% (n=97/308) in the placebo group.

[Primary endpoint: The proportion of patients who were responders to repeat treatment in both IBS-D–related abdominal pain and stool consistency during the 4 weeks following the first repeat treatment course.]

Patients in these three trials experienced side effects at rates similar to placebo. In TARGET 1 and 2, nausea was the only adverse reaction to occur in greater than or equal to 2% of IBS-D patients receiving XIFAXAN and at a higher rate than placebo, occurring in 3% of XIFAXAN-treated patients and 2% of patients who received placebo. In TARGET 3, adverse events occurring in greater than or equal to 2% of IBS-D patients receiving XIFAXAN and at a higher rate than placebo were nausea and increased levels of alanine transaminase, or ALT, which both occurred in 2% of XIFAXAN-treated patients and 1% of patients treated with placebo. (Most of the events of increased ALT were transient and resolved over time.)

[Constipation was observed in 0.3%-0.6% of patients treated with XIFAXAN.]

So, Kim, what’s your approach with XIFAXAN?

Kim: A benefit of XIFAXAN for treating adult patients with IBS-D that sticks out in my mind, is that it’s a short, 2-week treatment that provided relief from diarrhea and abdominal pain. So, I’ll tell patients that the amount of time this relief can last can vary, but I’ve seen patients go many months with improvement in these symptoms with only 2 weeks of treatment with a therapy that has a well-established safety profile.

This is supported by the results of TARGET 3, the study you mentioned earlier. In patients who saw a recurrence of symptoms after an initial response to XIFAXAN, the median time to symptom recurrence during the open-label phase was 10 weeks (with a range of 6 to 24 weeks).

And, I like the fact that you can retreat up to two times, and in the TARGET 3 clinical trial, side effects were at rates similar to placebo as was also observed in TARGET 1 and 2.

Christina: You bring up a good point, Kim. We talked earlier about how IBS-D is a chronic relapsing disorder and that symptoms can vary over time. So, you will likely have patients who experience symptom recurrence after taking a course of XIFAXAN. That doesn’t mean that XIFAXAN quote-unquote “didn’t work.”

Kim: Exactly. After initial relief, some patients may need to be retreated, but you’re right, that doesn’t mean that XIFAXAN didn't work for them. And, like I mentioned, patients who experience a return of symptoms can be retreated up to two times. That always gives me a lot of reassurance when I use XIFAXAN.

Christina: I agree, I feel the same way.

Kim: I’m thinking of this one patient I have, she’s in her early 30s.

She at first wanted to take a holistic, natural approach, including modifying her diet. She saw chiropractors and various holistic specialists. Her physician had tried multiple ways to manage her IBS-D, and she still had this persistent abdominal pain, bloating, and loose stools. She was eliminating so much from her diet—like gluten and dairy, for example. We had come to terms with the fact that this “natural” approach wasn’t helping to relieve her IBS-D symptoms.

I prescribed her a course of XIFAXAN—one 550-mg tablet by mouth three times a day for 2 weeks—and it was great to see the improvement she had in terms of relief of her abdominal pain and diarrhea. She did get retreated once so far because she started to feel like her symptoms were coming back again and we retreated. Like what we saw in the TARGET 3 clinical trial that we talked about earlier, she responded similarly to the second course as she did to the initial treatment, and she’s still doing well after my recent follow-up with her. At this point, she finally has relief of her symptoms. (Based on clinical trials in patients with IBS-D, individual response to treatment with XIFAXAN may vary.)

Christina: We should remember, though, that response to treatment with XIFAXAN may vary.

It's also important to point out that Clostridium difficile-associated diarrhea has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. If Clostridium difficile-associated diarrhea is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

But back to the story of your patient, Kim, that’s a great example of why it’s so important to schedule follow-ups, even if the patient has success with the first treatment.

Kim: Right—I mean, patients remember feeling bad and how that’s different from when they feel better. So they recognize when they’re starting to feel bad again and often reach out for some sort of support. But I do reach out to them proactively to make sure I know if they are starting to experience a recurrence of symptoms, because we do have that option to retreat up to two times.

Christina: Well, Kim, it’s been so great to talk to you about all of this.

Kim: My pleasure, Christina.

Christina: And thank you for sharing some of your insights around managing abdominal pain and diarrhea in IBS-D and your experience with XIFAXAN for IBS-D treatment. Now let’s provide an overview of the indication and full important safety information for XIFAXAN for those tuning in.