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Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. The current aim was to evaluate rifaximin efficacy on individual and composite IBS-D symptoms using definitions not previously examined.
Methods
Phase III post hoc analyses of two randomized, double-blind, placebo-controlled trials and the open-label phase of a randomized, double-blind, placebo-controlled trial were conducted. Adults with IBS-D received a 2-week course of rifaximin 550 mg TID. Individual and composite responses for abdominal pain (mean weekly improvements from baseline of ≥30%, ≥40%, or ≥50%), bloating (mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%), stool consistency (mean weekly average stool consistency score <3 or <4), and urgency (improvement from baseline of ≥30% or ≥40% in percentage of days with urgency) for ≥2 of the first 4 weeks after treatment, and weekly for 12 weeks, were assessed.
Findings
Overall, 1258 patients from the double-blind trials (rifaximin [n = 624]; placebo [n = 634]) and 2438 from an open-label trial were analyzed. The percentage of bloating or urgency responders was significantly greater with double-blind rifaximin versus placebo (P ≤ 0.03). A significantly greater percentage of the double-blind group were composite abdominal pain and bloating responders versus placebo for all thresholds analyzed (P < 0.05). A significantly greater percentage of the double-blind group were tri-symptom composite end point responders (abdominal pain, bloating, and fecal urgency) versus placebo (P = 0.001). A significantly greater percentage of patients achieved response (≥30% composite tri-symptom threshold) with double-blind rifaximin versus placebo as early as 1 week posttreatment, with significance maintained through ≥5 weeks after treatment. Open-label results were consistent with those of the double-blind study.
Patients who have IBS with diarrhea (IBS-D) report that abdominal pain and bloating are 2 of the most common and troublesome symptoms, although patients with IBS frequently report multiple abdominal and bowel symptoms.
As such, efficacy end points in clinical trials of rifaximin reflect interest in understanding the impact of symptoms on patients and the impact of health care utilization due to these symptoms on payors (Figure 1, Table I).
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
Repeat treatment with rifaximin improves irritable bowel syndrome-related quality of life: a secondary analysis of a randomized, double-blind, placebo-controlled trial.
Reinterpretation of the results of previous rifaximin clinical trials based on the various IBS-D symptoms and symptom combinations and the magnitude of treatment effect may inform the use of this agent in clinical practice.
Figure 1Evolution of irritable bowel syndrome (IBS) diagnostic criteria and clinical trial efficacy end points.
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
Evaluated by patient response (yes/no) to the question “In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?”
for ≥2 of the first 4 weeks after treatment
Key secondary end point:
•
Percentage of patients with adequate relief of IBS-related bloating
Evaluated by patient response (yes/no) to the question “In regard to your symptoms of bloating, as compared with 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?”
Evaluated by patient's daily assessments of IBS symptoms. Relief rated using a 7-point scale (0 = “not at all”; 1 = “hardly”; 2 = “somewhat”; 3 = “moderately”; 4 = “a good deal”; 5 = “a great deal”; 6 = “a very great deal”) and defined as a score of 0 or 1 for ≥50% of the days in a given week or a score of 0, 1, or 2 for 100% of the days in a given week for ≥2 of the 4 weeks during a given month.
of IBS symptoms, bloating, and abdominal pain/discomfort for ≥2 of 4 weeks during a given month
Other: improvement from baseline in daily symptom scores
•
Global IBS symptoms
•
IBS-related bloating
•
IBS-related abdominal pain/discomfort
•
Stool consistency
•
Percentage of days with fecal urgency
Trial 1, Trial 2, Trial 3:Assessment of individual and various composite responses (≥2 of the first 4 weeks after treatment and weekly for 12 weeks)
•
Abdominal pain
–
Mean weekly improvements from baseline of ≥30%, ≥40%, and ≥50%
•
Bloating
–
Mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%
•
Stool consistency
–
Mean weekly average stool consistency score <3 and <4
•
Fecal urgency
–
Improvement from baseline of ≥30% and ≥40% in the percentage of days with fecal urgency
•
Composite responses included:
–
Abdominal pain and bloating
–
Fecal urgency and stool consistency
–
Abdominal pain, bloating, and fecal urgency
Trial 3:Primary end point:
•
Percentage of patients achieving response for both abdominal pain (≥30% decrease from baseline in mean weekly pain score) and stool consistency (≥50% decrease from baseline in number of days with BSS type 6 or 7 stool) during the 4-week treatment-free follow-up period after the first repeat treatment course
Key secondary end point:
•
Percentage of patients with ≥1-point decrease from baseline in weekly average bloating score for ≥2 of the first 4 weeks after treatment
Additional end point:
•
Fecal urgency response (≥30% improvement from baseline in percentage of days with urgency for ≥2 weeks during the first 4 weeks after treatment)
Evaluated by patient response (yes/no) to the question “In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?”
† Evaluated by patient response (yes/no) to the question “In regard to your symptoms of bloating, as compared with 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?”
‡ Evaluated by patient's daily assessments of IBS symptoms. Relief rated using a 7-point scale (0 = “not at all”; 1 = “hardly”; 2 = “somewhat”; 3 = “moderately”; 4 = “a good deal”; 5 = “a great deal”; 6 = “a very great deal”) and defined as a score of 0 or 1 for ≥50% of the days in a given week or a score of 0, 1, or 2 for 100% of the days in a given week for ≥2 of the 4 weeks during a given month.
Rifaximin is approved in the United States and Canada for the treatment of adults with IBS-D. A 2011 publication of 2 randomized, double-blind, placebo-controlled clinical trials of patients with IBS-D (Trials 1 and 2) showed that rifaximin improved global IBS-D symptoms, including abdominal pain and stool consistency.
The efficacy end points of Trials 1 and 2 were established and evaluated before the introduction of the US Food and Drug Administration (FDA) Guidance for Industry regarding the evaluation of drugs for treatment of IBS in 2012 and the Rome IV guidelines in 2016.
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
A pooled post hoc analysis showed that the percentage of abdominal pain responders (≥30% improvement from baseline for ≥2 of the first 4 weeks after treatment [FDA end point]) was significantly greater with rifaximin 550 mg TID for 2 weeks versus placebo (51.9% vs 42.6%, respectively; P < 0.001).
A total of 56.8% of 2438 patients were abdominal pain responders (≥30% improvement from baseline for ≥2 of first 4 weeks after treatment) in the open-label (OL) phase; in the randomized, double-blind (DB), placebo-controlled phase, the percentage of abdominal pain responders was significantly greater with rifaximin compared with placebo (50.6% vs 42.2%; P = 0.02). The percentage of composite responders for both abdominal pain and stool consistency was significantly greater with DB rifaximin treatment compared with placebo (38.1% vs 31.5%; P = 0.03). Additional analyses of Trial 3 supported the benefits of rifaximin on abdominal pain, a key IBS-D symptom, based on a more stringent threshold to define abdominal pain response versus the threshold used in the clinical trial.
a greater understanding of the role of other symptoms in addition to abdominal pain and stool consistency has emerged. Bloating, the feeling of gassiness or pressure occurring in the abdomen, is a nonspecific symptom of IBS and is associated with other gastrointestinal conditions (eg, functional constipation, functional dyspepsia).
Indeed, survey data from 714 patients with IBS identified that 542 (76%) had bloating symptoms, in whom 15.5% reported it as their most problematic gastrointestinal symptom.
In Trials 1 and 2, a significantly greater percentage of patients receiving rifaximin compared with patients receiving placebo had adequate relief of bloating (patient-reported yes/no response) for ≥2 of the first 4 weeks after treatment (40.2% vs 30.3%, respectively; P < 0.001).
It should be noted that the FDA no longer considers “adequate relief” an appropriate efficacy outcome because it captures the direction of change but provides limited information on the effect of treatment on severity of a given symptom.
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
A retrospective analysis (n = 368) reported that a significantly greater percentage of patients with urgency experienced abdominal pain and diarrhea compared with patients without urgency (abdominal pain, 79.2% vs 62.1%, respectively [P = 0.002]; diarrhea, 56.3% vs 24.2% [P < 0.001]).
Despite its importance to patients, FDA guidance for IBS clinical trials does not recommend that fecal urgency be a primary or co-primary efficacy end point but rather states that it could be considered an exploratory end point.
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
Furthermore, clinical trials of alosetron (a 5-HT3 antagonist) in women with IBS-D included fecal urgency as a primary or secondary efficacy outcome, underscoring the importance of this symptom to patients and clinicians.
Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint.
Effect of alosetron on bowel urgency and global symptoms in women with severe, diarrhea-predominant irritable bowel syndrome: analysis of two controlled trials.
The aim of the post hoc analyses presented here, of three Phase III clinical trials of rifaximin in patients with IBS-D, was to evaluate the response to rifaximin for individual or novel composite symptoms of IBS-D not addressed in prior publications and to use higher thresholds for symptom improvement.
Materials and Methods
The study designs and patient populations have been described previously.
The data presented here comprise a pooled post hoc analysis of two Phase III, identically designed, randomized, DB, placebo-controlled trials (Trials 1 and 2; ClinicalTrials.gov identifiers, NCT00731679 and NCT00724126) and a post hoc analysis of the OL phase of a Phase III, randomized, DB, placebo-controlled trial (Trial 3; ClinicalTrials.gov identifier, NCT01543178). The protocols were approved by all institutional review boards and ethics committees at participating sites, the trials were conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and all patients provided written informed consent before study-related procedures were initiated. In Trials 1 and 2, adults with IBS-D and mean daily abdominal pain and bloating scores, rated separately, of 2 to 4.5 on a 7-point Likert scale (scale range, 0 [“not at all”] to 6 [“a very great deal”]) received DB rifaximin 550 mg TID or matching placebo (identical except for active moiety) tablets for 2 weeks, followed by a 4-week, treatment-free period to evaluate response. Trial 3 included patients with IBS-D with mean abdominal pain ≥3 (scale range, 0 [“no pain”] to 10 [“worst possible pain”]) and bloating ≥3 (scale range, 0 [“not at all”] to 6 [“a very great deal”]) experiencing loose stools for ≥2 days in a week (Bristol Stool Scale type 6 or 7 [mushy/watery]); patients in this trial received OL rifaximin 550 mg TID for 2 weeks followed by a 4-week, treatment-free period to evaluate response. Patients with response to OL rifaximin who experienced a relapse in IBS-D symptoms during an 18-week treatment-free observation phase were eligible for random assignment to DB treatment.
Individual responses and various composite responses for abdominal pain (mean weekly improvements from baseline of ≥30%, ≥40%, and ≥50%), bloating (mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%), stool consistency (mean weekly average stool consistency score <3 and <4), and fecal urgency (improvement from baseline of ≥30% and ≥40% in the percentage of days with fecal urgency) for ≥2 of the first 4 weeks after treatment and weekly for 12 weeks were assessed. Data were analyzed by using last-observation-carried-forward methodology. P values were determined by using the Cochran-Mantel-Haenszel method, adjusting for center effect.
Results
Overall, 3696 adults with IBS-D were included in this set of analyses. A total of 1258 patients with IBS-D participated in Trials 1 and 2 (DB rifaximin [n = 624]; DB placebo [n = 634]) (Table II) .
Repeat treatment with rifaximin improves irritable bowel syndrome-related quality of life: a secondary analysis of a randomized, double-blind, placebo-controlled trial.
Trial did not report on the percentages of days with fecal urgency but evaluated mean (SD) number of days with bowel movement urgency; the finding was 5.9 (1.7) days. Some data from Pimentel et al7 or Cash et al.12
BMI = body mass index; DB = double-blind; OL = open-label.
Five-point scale (1 = very hard; 2 = hard; 3 = formed; 4 = loose; 5 = watery).†Seven-point scale (0 = “not at all”; 6 = “a very great deal”). “Discomfort” part of description (ie, abdominal pain/discomfort) for Trials 1 and 2 only.
‡ Calculated using the following formula: 100 × (number of days with a sense of urgency with any bowel movement ÷ number of days with bowel movement).
§ Trial did not report on the percentages of days with fecal urgency but evaluated mean (SD) number of days with bowel movement urgency; the finding was 5.9 (1.7) days. Some data from Pimentel et al
Repeat treatment with rifaximin improves irritable bowel syndrome-related quality of life: a secondary analysis of a randomized, double-blind, placebo-controlled trial.
For the pooled population of Trials 1 and 2, a significantly higher percentage of patients treated with DB rifaximin were bloating responders versus DB placebo for the various thresholds analyzed (ie, ≥30% [P < 0.001], ≥40% [P = 0.003], ≥50% [P = 0.006], ≥1-point [P < 0.001], or ≥2-point [P = 0.03] improvement from baseline threshold) (Figure 2). In addition, data from Trial 3 showed a generally similar percentage for OL rifaximin–treated patients with improvement for the various thresholds.
Figure 2Bloating response defined by using various thresholds. *Various thresholds met for ≥2 of the first 4 weeks after treatment. DB = double-blind; OL = open-label.
For the composite end point of abdominal pain and bloating response, a significantly greater percentage of patients treated with DB rifaximin were responders using abdominal pain component thresholds of ≥30%, ≥40%, or ≥50% improvement from baseline and bloating component thresholds of ≥1- or ≥2-point improvement from baseline versus DB placebo for ≥2 of the first 4 weeks after treatment (for all comparisons, P < 0.05) (Figure 3A). Similarly, a significantly greater percentage of patients treated with DB rifaximin were composite responders for abdominal pain and bloating versus DB placebo when the thresholds for the abdominal pain component were defined as ≥30%, ≥40%, and ≥50%, and the bloating components were defined as ≥30%, ≥40%, or ≥50% improvement from baseline for ≥2 of the first 4 weeks after treatment (P ≤ 0.02 for all comparisons) (Figure 3B). For OL rifaximin treatment, composite response for abdominal pain and bloating defined by using various thresholds showed outcomes generally similar to those for DB rifaximin (Figure 3C).
Figure 3Composite abdominal pain and bloating response defined by using various thresholds for Trials 1 and 2 pooled (A and B) and Trial 3 (C). *Various thresholds met for ≥2 of the first 4 weeks after treatment. DB = double-blind.
A significantly greater percentage of patients treated with DB rifaximin were responders using the thresholds of ≥30% and ≥40% improvement from baseline in the percentage of days with urgency versus DB placebo for ≥2 of the first 4 weeks after treatment (for both comparisons, P ≤ 0.005) (Figure 4A). With OL rifaximin treatment, approximately one half of patients were urgency responders for each threshold. In addition, the percentage of urgency responders to DB rifaximin at the ≥30% threshold was significantly greater than DB placebo during the 2-week treatment phase and the posttreatment follow-up (Weeks 3–6) and maintenance phases (Weeks 7–12) (Figure 4B); at the ≥40% threshold, significance was achieved during weeks 2 to 11 (Figure 4C). The percentage of fecal urgency responders to OL rifaximin treatment was highest at Week 3 and was generally similar through the end of follow-up for both threshold definitions of response (Figure 4D).
Figure 4Fecal urgency responders for ≥2 of the first 4 weeks after treatment (A) and by week for double-blind (DB) treatment (B and C) or open-label (OL) treatment (D), defined by using various thresholds.
Patients who received DB rifaximin were significantly more likely to achieve a weekly average stool consistency score <4 (1 = very hard; 2 = hard; 3 = formed; 4 = loose) for ≥2 of the first 4 weeks after treatment compared with DB placebo (82.7% [516 of 624] vs 77.8% [493 of 634]; P = 0.03); with OL rifaximin, 71.9% (1752 of 2438) of patients had a weekly average Bristol Stool Scale stool consistency score <4 for ≥2 of the first 4 weeks after treatment.
Composite Fecal Urgency and Stool Consistency
A significantly larger percentage of patients treated with DB rifaximin achieved the composite response for fecal urgency and stool consistency (either ≥30% or ≥40% improvement from baseline in percentage of days with fecal urgency, with a weekly average stool consistency score <4) for ≥2 of the first 4 weeks after treatment compared with DB placebo (Figure 5A). Results favoring DB rifaximin versus DB placebo were also observed when assessed weekly (Figures 5B and 5C). For OL rifaximin treatment, composite response for urgency and stool consistency using the same threshold of response showed outcomes similar to those for DB rifaximin (Figures 5A and 5D).
Figure 5Composite fecal urgency and stool consistency response for ≥2 of the first 4 weeks after treatment (A) and by week for double-blind (DB) treatment (B and C) or open-label (OL) treatment (D), defined using various thresholds.
), patients treated with rifaximin were significantly more likely to be composite end point responders than patients receiving placebo when analyzed using either the ≥30% or ≥40% threshold for the 3 symptoms. Importantly, OL rifaximin treatment results were similar to those observed with DB rifaximin (Figure 6A). A significantly greater percentage of patients achieved response (≥30% composite tri-symptom threshold) with DB rifaximin compared with DB placebo as early as 1 week posttreatment (Week 3) (Figure 6B), with significance maintained through ≥5 weeks after treatment. Significant differences between DB rifaximin and DB placebo were achieved with a ≥40% composite tri-symptom threshold at 2 through 4 weeks after treatment (Weeks 4–6) (Figure 6C). With OL rifaximin treatment, tri-symptom composite response (≥30% or ≥40% threshold) improved from baseline after Week 1 of treatment (Figure 6D).
Figure 6Tri-symptom composite (abdominal pain, bloating, and fecal urgency) response for ≥2 of the first 4 weeks after treatment (A) and by week for double-blind (DB) treatment (B and C) or open-label (OL) treatment (D), defined by using various thresholds.
show that a 2-week course of rifaximin is efficacious for simultaneously and significantly improving multiple symptoms of IBS-D, using current, clinically relevant definitions of treatment response. A 2-week course of DB rifaximin significantly improved individual and multiple symptoms, under various scenarios that may be experienced by patients with IBS-D, for up to 10 weeks after treatment compared with DB placebo. OL rifaximin efficacy outcomes were similar (albeit without a placebo comparator) to those observed with DB rifaximin, further supporting the potential benefits of a 2-week course of rifaximin for the treatment of IBS-D.
Guidance from the FDA recommends defining clinically relevant abdominal pain response as ≥30% improvement from baseline in the mean weekly abdominal pain score,
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
and the analyses reported in this study examined response thresholds exceeding this minimum standard. Although guidance from the FDA does not mention bloating and only recommends fecal urgency as a potential exploratory end point in clinical trials in IBS,
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
bloating and fecal urgency are recognized to be very bothersome to patients, to frequently overlap with other IBS symptoms, and to be independent predictors of IBS severity.
Both 2-week DB and OL rifaximin treatments improved bloating at thresholds of ≥30%, ≥40%, and ≥50%, with comparable percentages of patients achieving response with DB or OL treatment, thus validating the OL trial. Similarly, a comparable percentage of patients were fecal urgency responders after DB and OL rifaximin treatment. The reduction in the percentage of urgency responders with increasing threshold stringency is consistent with trends observed with alosetron.
Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint.
Thus, rifaximin not only met current standard thresholds used for adjudication of responders in clinical trials but also achieved higher thresholds for many of these symptoms, suggesting potential for even more robust clinical improvements.
A limitation of the present study is inclusion of patients with less severe IBS-D symptoms and those who failed to respond to other IBS-D therapies; thus, it is unclear whether response to rifaximin treatment may differ in patients with mild to moderate IBS symptoms compared with those with more severe symptoms. Furthermore, patients were not subgrouped based on rifaximin being a primary or secondary pharmacologic treatment (ie, treatment-naive). It is also unknown to what extent the criteria used to define the patient populations may have affected the results, as inclusion criteria at the time of the trials preceded Rome IV symptom-based diagnostic criteria (Rome II [Trials 1 and 2] or Rome III [Trial 3] criteria).
For example, patients with IBS diagnosed by using Rome III criteria tend to have less severe symptoms than patients diagnosed by using Rome IV criteria,
Epidemiological, clinical, and psychological characteristics of individuals with self-reported irritable bowel syndrome based on the Rome IV vs Rome III criteria.
thus possibly limiting the generalizability of findings to patients with IBS diagnosed using Rome IV criteria. Furthermore, Rome IV diagnostic criteria include only “abdominal pain,” rather than combining “abdominal pain/discomfort” as a single term; indeed, “abdominal discomfort” encompasses a broad range of symptoms (eg, bloating, urgency) and may be perceived differently because of divergent cultural perspectives.
However, patients with IBS-D who were enrolled in clinical treatment trials using Rome III criteria were typically required to have a symptom burden that would likely have met Rome IV criteria.
Limitations aside, the results of these analyses are clinically meaningful in daily practice, given that patients with IBS-D often seek treatment for multiple symptoms, and a single potentially effective treatment targeting these symptoms provides a useful option to providers and patients.
Conclusions
A 2-week course of rifaximin improved multiple symptoms, assessed individually and simultaneously as composite outcomes, based on higher thresholds for symptom improvement in adults with IBS-D.
Declaration of Interest
The study sponsor was involved in the study design and data collection.
Dr Lacy reports serving as a scientific advisory board member for Allakos Inc, AlphaSigma USA, Inc, Arena Pharmaceuticals, Ironwood Pharmaceuticals, Inc, and Salix Pharmaceuticals. Dr Chang reports serving as an advisory board member or consultant for Ardelyx, Arena Pharmaceuticals, Bausch Health, Immunic, Ironwood Pharmaceuticals, Inc, Mauna Kea Technologies, and Trellus; and receiving grant support from AnX Robotica, Arena Pharmaceuticals, and Ironwood Pharmaceuticals. Dr Rao reports receiving research funding from Salix Pharmaceuticals. Dr Heimanson is an employee of Salix Pharmaceuticals. Dr Sayuk reports serving as a consultant for AbbVie and Ironwood Pharmaceuticals, Inc; and serving on the speakers’ bureau for AbbVie, Ironwood Pharmaceuticals, Inc, and Salix Pharmaceuticals.
Acknowledgments
The clinical trials and current analyses were supported by Salix Pharmaceuticals. Technical editorial and medical writing assistance were provided under direction of the authors by Mary Beth Moncrief, PhD, and Sophie Bolick, PhD, Synchrony Medical Communications, LLC. Funding for this assistance was provided by Salix Pharmaceuticals.
Dr Lacy contributed as follows: conceptualization (lead), methodology–(lead), writing–original draft (lead), and review and editing (equal). Drs Chang, Rao, Heimanson, and Sayuk contributed as follows: methodology (equal) and writing–review and editing (equal). All authors have read and approved the final version of the manuscript.
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome—Clinical Evaluation of Drugs for Treatment. Silver Spring, MD: Center for Drug Evaluation and Research (CDER); 2012.
Repeat treatment with rifaximin improves irritable bowel syndrome-related quality of life: a secondary analysis of a randomized, double-blind, placebo-controlled trial.
Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint.
Effect of alosetron on bowel urgency and global symptoms in women with severe, diarrhea-predominant irritable bowel syndrome: analysis of two controlled trials.
Epidemiological, clinical, and psychological characteristics of individuals with self-reported irritable bowel syndrome based on the Rome IV vs Rome III criteria.
Evaluated by patient response (yes/no) to the question “In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?”
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