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Mo1262 Effects of Baseline Abdominal Pain on Response to Lubiprostone in Patients With Constipation-Predominant Irritable Bowel Syndrome
Mo1262
Background: Compared with placebo (PBO), lubiprostone (LUB) 8 mcg twice daily, an activator of the ClC-2 chloride channel, significantly improved overall response rates (global 7-point scale; "significantly worse" to "significantly relieved") and symptoms in 2 pivotal trials in patients with constipation-predominant irritable bowel syndrome (IBS-C). Aims: To determine: 1) the efficacy of LUB in IBS-C according to the composite endpoint of improvements in abdominal pain and stool frequency compared with PBO, as recommended by the US Food and Drug Administration (FDA) and 2) the impact of baseline (BL) abdominal pain on its efficacy. Methods: Post hoc analyses of data from 2 phase 3, double-blind, randomized, PBO-controlled trials with LUB in patients with IBS-C were performed to determine response rates based on patients' BL abdominal pain ratings on a 5-point scale (0 [absent] to 4 [very severe]). Eligible patients reported BL pain scores of ≥1.36, which corresponds to the current FDA-recommended BL of ≥3 out of 10 on an 11-point scale (010). Responders were defined as those having a mean pain reduction ≥30% compared with BL and an increase from BL of ≥1 spontaneous bowel movement (SBM)/week for ≥6 of the 12 treatment weeks. In addition, the efficacy of LUB on the abdominal pain improvement alone was evaluated. The last observation carried forward method was used to impute missing data. Results: Composite response rates were 25.5% (39/153) and 13.0% (10/77) for patients who received LUB and PBO, respectively, in Study 1 (Table 1). In Study 2, the composite response rates were 27.2% (37/136) and 17.4% (15/86) with LUB and PBO, respectively. The composite response rates were significantly different in the pooled population for patients who received LUB and PBO (26.3% [76/289] vs 15.3% [25/163]; P=0.0079); response rates with LUB remained higher than with PBO at higher levels of BL pain, but not significantly so at the highest BL pain levels. With regard to abdominal pain relief alone, treatment response rates were 35.3% (54/153) and 24.7% (19/77) for patients who received LUB and PBO, respectively, in Study 1 (Table 1). In Study 2, the response rates were 38.2% (52/136) and 25.6% (22/86) with LUB and PBO, respectively. The response rates were significantly different in the pooled population for patients who received LUB and PBO (36.7% [106/289] vs 25.2% [41/163]); P=0.0046); response rates with LUB remained greater than with PBO with greater BL pain scores, but not significantly so at the greatest BL pain level. Conclusions: Lubiprostone significantly improved the composite endpoint of improvements in abdominal pain and stool frequency compared with PBO treatment in patients with IBS-C. This effect occurred in patients regardless of BL abdominal pain ratings, except in those with the highest pain scores, likely due to the small number of patients. Table 1: Responder Rates by Baseline Pain Severity According to 2 Response Definitions in Pivotal Studies of Lubiprostone for IBS-C
*p<0.05 for diagnosed patients vs. undiagnosed patients; † 7-point scale (1=mild to 7= severe); ‡ 7-point scale (1=not at all disruptive to 7=extremely disruptive) Mo1261 Characterizing the Effect of Rifaximin on Individual Symptoms of IBS-D: Findings From the Open-Label Phase of TARGET 3 Lin Chang, Mark Pimentel, Anthony Lembo, Andrew C. Barrett, Jing Yu, Enoch Bortey, Craig Paterson, William P. Forbes Background: IBS-D is characterized by a diverse group of core symptoms that include abdominal pain, altered stool consistency, bloating, and urgency. To assess the ability of rifaximin (RFX) to produce a common response to these multiple symptoms, the study design incorporated an open-label (OL) enrichment phase where RFX responders were identified for potential inclusion in a repeat treatment phase. This analysis describes the profile of symptom improvement from the OL enrichment phase. Methods: Subjects with IBS-D (Rome III criteria) with average symptom severity scores of ≥ 3 for abdominal pain (AP, scale 0-10) and bloating (scale 0-6), with ≥ 2 stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during the 7-day baseline were entered into the OL phase. In OL, all subjects received RFX 550 mg TID for 2 weeks, followed by a 4-week, treatment-free assessment period. A responder, as defined by the FDA composite endpoint, was required to achieve a ≥30% decrease from baseline in mean weekly AP score, and simultaneously respond for stool consistency (SC) with a ≥50% decrease from baseline in number of days/ week with BSS Type 6 or 7 stools, for ≥2 weeks of a 4-week period. In addition to the FDA composite endpoint, additional core symptoms of IBS-D were assessed, including bloating (6-point scale; 0=not at all, 6=a very great deal), urgency ("Yes/No" during the last 24 hours), and overall IBS symptoms ("How bothersome were your symptoms of IBS in the last 24 hours?"; 6-point scale; 0 = not at all, 6 = a very great deal). Results: A total 2579 subjects (mean age: 46.4; 68% female) received RFX treatment during the OL phase, of which 2331 were evaluable for efficacy. Based on the pre-specified FDA composite definition of response, which stipulates improvements in both AP and SC on the same weeks, 1074 (46%) subjects were deemed responders in the 4-week follow-up period. Another 14% of subjects responded only to the SC component, while a different 11% of subjects responded only to the AP component. Finally, 1% of subjects experienced improvements for AP and SC, but not on the same weeks of the 4-week assessment period. Collectively, 72% of evaluable subjects experienced improvement on at least one component of the FDA composite endpoint. When all symptoms were evaluated independently (AP, SC, urgency, bloating, and overall IBS symptoms), >50% of subjects were deemed to be responders following a 2-week course of OL RFX (Table). Conclusions: These findings suggest that over 70% of patients experience improvement in at least one of the two symptoms of the FDA composite endpoint. Improvements for bloating, urgency, and overall IBS symptoms, suggest that the benefit of rifaximin may extend beyond symptoms comprising the FDA composite endpoint. Proportion of Responders for IBS-D Symptoms During Open-label Phase
IBS-C=constipation-predominant irritable bowel syndrome; NC=not calculable; SBM=spontaneous bowel movement. *Scale from 0 (absent) to 4 (very severe). †Equivalent to 3 on a scale of 0 to 10. P values are based on Cochran-Mantel-Haenszel test stratifying by pooled site.
*Responder defined as ≥30% improvement from baseline in the weekly average abdominal pain score for ≥2 out of 4 weeks; † Responder defined as ≥50% reduction in the number of days in a week with stool consistency of type 6 or 7 compared with baseline, for ≥2 out of 4 weeks; ‡ Responder defined as ≥1-point decrease from baseline in their weekly average IBS-related bloating score for ≥2 out of 4 weeks; § Responder defined as ≥30% or greater improvement from baseline in the percentage of days with urgency for ≥2 out of 4 weeks; | Responder defined as ≥1-point decrease from baseline in weekly average IBS symptoms score for ≥2 out of 4 weeks
S-653
AGA Abstracts
AGA Abstracts
Effects of Baseline Abdominal Pain on Response to Lubiprostone in Patients With Constipation-Predominant Irritable Bowel Syndrome Lin Chang, William D. Chey, Douglas A. Drossman, Taryn R. Losch-Beridon, Martin Wang, Peter Lichtlen, Shadreck M. Mareya
Background: Compared with placebo (PBO), lubiprostone (LUB) 8 mcg twice daily, an activator of the ClC-2 chloride channel, significantly improved overall response rates (global 7-point scale; "significantly worse" to "significantly relieved") and symptoms in 2 pivotal trials in patients with constipation-predominant irritable bowel syndrome (IBS-C). Aims: To determine: 1) the efficacy of LUB in IBS-C according to the composite endpoint of improvements in abdominal pain and stool frequency compared with PBO, as recommended by the US Food and Drug Administration (FDA) and 2) the impact of baseline (BL) abdominal pain on its efficacy. Methods: Post hoc analyses of data from 2 phase 3, double-blind, randomized, PBO-controlled trials with LUB in patients with IBS-C were performed to determine response rates based on patients' BL abdominal pain ratings on a 5-point scale (0 [absent] to 4 [very severe]). Eligible patients reported BL pain scores of ≥1.36, which corresponds to the current FDA-recommended BL of ≥3 out of 10 on an 11-point scale (010). Responders were defined as those having a mean pain reduction ≥30% compared with BL and an increase from BL of ≥1 spontaneous bowel movement (SBM)/week for ≥6 of the 12 treatment weeks. In addition, the efficacy of LUB on the abdominal pain improvement alone was evaluated. The last observation carried forward method was used to impute missing data. Results: Composite response rates were 25.5% (39/153) and 13.0% (10/77) for patients who received LUB and PBO, respectively, in Study 1 (Table 1). In Study 2, the composite response rates were 27.2% (37/136) and 17.4% (15/86) with LUB and PBO, respectively. The composite response rates were significantly different in the pooled population for patients who received LUB and PBO (26.3% [76/289] vs 15.3% [25/163]; P=0.0079); response rates with LUB remained higher than with PBO at higher levels of BL pain, but not significantly so at the highest BL pain levels. With regard to abdominal pain relief alone, treatment response rates were 35.3% (54/153) and 24.7% (19/77) for patients who received LUB and PBO, respectively, in Study 1 (Table 1). In Study 2, the response rates were 38.2% (52/136) and 25.6% (22/86) with LUB and PBO, respectively. The response rates were significantly different in the pooled population for patients who received LUB and PBO (36.7% [106/289] vs 25.2% [41/163]); P=0.0046); response rates with LUB remained greater than with PBO with greater BL pain scores, but not significantly so at the greatest BL pain level. Conclusions: Lubiprostone significantly improved the composite endpoint of improvements in abdominal pain and stool frequency compared with PBO treatment in patients with IBS-C. This effect occurred in patients regardless of BL abdominal pain ratings, except in those with the highest pain scores, likely due to the small number of patients. Table 1: Responder Rates by Baseline Pain Severity According to 2 Response Definitions in Pivotal Studies of Lubiprostone for IBS-C
*p<0.05 for diagnosed patients vs. undiagnosed patients; † 7-point scale (1=mild to 7= severe); ‡ 7-point scale (1=not at all disruptive to 7=extremely disruptive) Mo1261 Characterizing the Effect of Rifaximin on Individual Symptoms of IBS-D: Findings From the Open-Label Phase of TARGET 3 Lin Chang, Mark Pimentel, Anthony Lembo, Andrew C. Barrett, Jing Yu, Enoch Bortey, Craig Paterson, William P. Forbes Background: IBS-D is characterized by a diverse group of core symptoms that include abdominal pain, altered stool consistency, bloating, and urgency. To assess the ability of rifaximin (RFX) to produce a common response to these multiple symptoms, the study design incorporated an open-label (OL) enrichment phase where RFX responders were identified for potential inclusion in a repeat treatment phase. This analysis describes the profile of symptom improvement from the OL enrichment phase. Methods: Subjects with IBS-D (Rome III criteria) with average symptom severity scores of ≥ 3 for abdominal pain (AP, scale 0-10) and bloating (scale 0-6), with ≥ 2 stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during the 7-day baseline were entered into the OL phase. In OL, all subjects received RFX 550 mg TID for 2 weeks, followed by a 4-week, treatment-free assessment period. A responder, as defined by the FDA composite endpoint, was required to achieve a ≥30% decrease from baseline in mean weekly AP score, and simultaneously respond for stool consistency (SC) with a ≥50% decrease from baseline in number of days/ week with BSS Type 6 or 7 stools, for ≥2 weeks of a 4-week period. In addition to the FDA composite endpoint, additional core symptoms of IBS-D were assessed, including bloating (6-point scale; 0=not at all, 6=a very great deal), urgency ("Yes/No" during the last 24 hours), and overall IBS symptoms ("How bothersome were your symptoms of IBS in the last 24 hours?"; 6-point scale; 0 = not at all, 6 = a very great deal). Results: A total 2579 subjects (mean age: 46.4; 68% female) received RFX treatment during the OL phase, of which 2331 were evaluable for efficacy. Based on the pre-specified FDA composite definition of response, which stipulates improvements in both AP and SC on the same weeks, 1074 (46%) subjects were deemed responders in the 4-week follow-up period. Another 14% of subjects responded only to the SC component, while a different 11% of subjects responded only to the AP component. Finally, 1% of subjects experienced improvements for AP and SC, but not on the same weeks of the 4-week assessment period. Collectively, 72% of evaluable subjects experienced improvement on at least one component of the FDA composite endpoint. When all symptoms were evaluated independently (AP, SC, urgency, bloating, and overall IBS symptoms), >50% of subjects were deemed to be responders following a 2-week course of OL RFX (Table). Conclusions: These findings suggest that over 70% of patients experience improvement in at least one of the two symptoms of the FDA composite endpoint. Improvements for bloating, urgency, and overall IBS symptoms, suggest that the benefit of rifaximin may extend beyond symptoms comprising the FDA composite endpoint. Proportion of Responders for IBS-D Symptoms During Open-label Phase
IBS-C=constipation-predominant irritable bowel syndrome; NC=not calculable; SBM=spontaneous bowel movement. *Scale from 0 (absent) to 4 (very severe). †Equivalent to 3 on a scale of 0 to 10. P values are based on Cochran-Mantel-Haenszel test stratifying by pooled site.
*Responder defined as ≥30% improvement from baseline in the weekly average abdominal pain score for ≥2 out of 4 weeks; † Responder defined as ≥50% reduction in the number of days in a week with stool consistency of type 6 or 7 compared with baseline, for ≥2 out of 4 weeks; ‡ Responder defined as ≥1-point decrease from baseline in their weekly average IBS-related bloating score for ≥2 out of 4 weeks; § Responder defined as ≥30% or greater improvement from baseline in the percentage of days with urgency for ≥2 out of 4 weeks; | Responder defined as ≥1-point decrease from baseline in weekly average IBS symptoms score for ≥2 out of 4 weeks
S-653
AGA Abstracts
AGA Abstracts
Effects of Baseline Abdominal Pain on Response to Lubiprostone in Patients With Constipation-Predominant Irritable Bowel Syndrome Lin Chang, William D. Chey, Douglas A. Drossman, Taryn R. Losch-Beridon, Martin Wang, Peter Lichtlen, Shadreck M. Mareya