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Mo1269 Enduring Effects Following a Course of Rifaximin Therapy in Patients With IBS-D: Incremental Benefit Upon Repeat Treatment
AGA Abstracts
duration (<24, 24-48, 48-120, ≥120 months). Results: In the overall population (n=636), the primary endpoint significantly favored RFX (33%) vs. PBO (25%, p=0.02). Regarding demographic characteristics, the RFX repeat treatment effect was evident in subjects < 65 years old (Δ=9%, p=0.0196) and ≥ 65 years old (Δ=18%, p=0.0410), in females (Δ=11%, p=0.0147) and males (Δ=7%, p=0.2515), and in subjects with BMI ≤ 30 kg/m2 (Δ=14%, p=0.0064) and BMI > 30 kg/m2 (Δ=5%, p=0.3035) (Figure). By race, the magnitude of the treatment effect was pronounced in white subjects (Δ=12%), but similar in non-white subjects (Δ=0.1%). A treatment by race interaction analysis yielded a p-value of 0.2440, an indication that race was not an effect modifier. Regarding baseline disease characteristics, the treatment effect was apparent in subjects with severe (Δ=10%, p=0.1564) and non-severe IBS (Δ= 10%, p=0.0185), and consistent across IBS symptom duration. Similar subpopulation results were observed for AP and SC when examined separately. Conclusions: Rifaximin response in subjects with IBS-D was significantly greater than placebo for the primary endpoint for all subgroups except non-white subjects where the sample size was quite small. These findings support the generalizability of the primary endpoint results. Figure. Study flow Mo1269 Enduring Effects Following a Course of Rifaximin Therapy in Patients With IBS-D: Incremental Benefit Upon Repeat Treatment Brian E. Lacy, Mark Pimentel, Lin Chang, Andrew C. Barrett, Jing Yu, Enoch Bortey, Craig Paterson, William P. Forbes Background: The efficacy of rifaximin (RFX) for the treatment of IBS-D has been demonstrated following a single course of therapy. To further evaluate RFX efficacy under conditions of repeat treatment, a study was designed that incorporated an open-label (OL) enrichment phase whereby only RFX responders were randomized to repeat treatment if they relapsed within 18 weeks. This analysis describes residual symptom improvements in subjects who met the definition of relapse, and incremental benefit upon repeat treatment with RFX. Methods: Patients with IBS-D (Rome III criteria) who presented with severity scores of ≥ 3 for IBS-related abdominal pain (AP, scale 0-10) and bloating (scale 0-6), and experienced ≥ 2 stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during a 7-day baseline were entered into the open-label (OL), enrichment phase. In the OL phase, patients were treated with RFX 550 mg TID for 2 weeks, followed by a 4-week treatment-free follow-up period. A responder was defined as meeting weekly response criteria for both AP (≥30% decrease from baseline in mean weekly pain score) and stool consistency (SC) (≥50% decrease from baseline in number of days/week with BSS Type 6 or 7) for ≥2 of 4 weeks. Responders were followed until relapse, which was defined as loss of response for AP OR SC for ≥3 out of a 4-week period during an 18-week maintenance phase. Patients with recurrence were randomized to receive up to 2 DB, placebo-controlled, repeat treatments (RFX 550 mg TID or placebo) separated by 10 weeks. The primary endpoint was the proportion of subjects who were responders during ≥2 of 4 weeks after the first repeat treatment. To assess response during the DB phase, baseline symptom severity at the time of randomization was used. Results: Overall, 636 patients were randomized to repeat treatment after responding to an initial OL course of RFX and then relapsing within 18 weeks. At the time of DB randomization, baseline scores for all IBS-related symptoms were significantly lower (p < 0.0001 for all symptoms, paired t-test) than observed at OL baseline (Figure 1). For example, weekly response for AP was defined as ≥ 30% improvement from baseline in weekly average score. However, symptom severity at time of recurrence indicated that randomized subjects were still experiencing an approximate 20% improvement in AP relative to their OL baseline. Similar carryover effects were observed for other IBS symptoms. Repeat treatment with RFX provided additional incremental benefit (primary endpoint responders: RFX 33% vs. PBO 25%, Δ=8%, p=0.02) to the enduring effects following initial treatment. Conclusions: Patients with IBS-D experienced persistent symptom improvement after a single, 2-week course of rifaximin therapy, and repeat treatment with rifaximin in patients meeting criteria for relapse provided additional incremental benefit.
Figure. Subgroup Analysis of Primary Endpoint Mo1268 Characterization of Stool Microbiota in Subjects With IBS-D Receiving Repeat Treatments With Rifaximin in the TARGET 3 Study Mark Pimentel, Anthony A. Fodor, Pamela Golden, Enoch Bortey, William P. Forbes Background: Rifaximin (RFX) is a minimally absorbed antimicrobial agent that has shown promise in the treatment of IBS-D, although the precise mechanism of this beneficial effect is unknown. This analysis employed genomic characterization of stool bacteria using nextgeneration sequencing techniques to assess the effect of repeated treatments with RFX on stool microbiota. Methods: Subjects with IBS-D (Rome III criteria) were entered into the open-label (OL) phase in which they were treated with RFX 550 mg TID for 2 weeks, followed by a 4-week follow-up period. Responders based on a composite endpoint of abdominal pain AND stool consistency improvements during ≥2 of 4 weeks were followed until they relapsed (up to 18 additional weeks), at which time they were randomized to receive 2 double-blind (DB), repeat treatments (RFX 550 mg TID or placebo [PBO]) separated by 10 weeks. All subjects provided stool samples at the beginning and end of OL treatment, beginning and end of the first repeat treatment, and end of study (Figure). Subjects were randomly selected for inclusion in the stool microbiota sequencing substudy in a manner that incorporated responders and non-responders. Genomic characterization of microbiota was accomplished using 16S rRNA bacterial deep gene sequencing. Metrics to describe the data included the diversity index, composed of measures of richness (number of families in each sample corrected for different samples having different number of sequences), evenness (as calculated by Shannon equitability, with values ranging from 0 to 1, with 1 being complete evenness), and Shannon diversity (a measure of overall community complexity). Results: A total of 103 subjects (mean age: 47.9; 74% female) were randomly selected for inclusion in the substudy, of which 73 (37 in RFX group and 36 in PBO group, evenly matched according to demographics) participated in the DB phase. At baseline of the DB phase, Shannon diversity was 1.786 and 1.733 in the RFX and PBO groups, respectively; after the 2-week treatment period, Shannon diversity was 1.698 and 1.743 (p = 0.4335), and remained essentially unchanged in the follow-up period. No significant changes in the evenness of the microbiota were observed within or between the treatment groups in the DB phase. The richness of the microbiota in subjects treated with DB PBO remained unchanged, while richness decreased at Week 2 in RFX-treated subjects when compared to their DB baseline (p = 0.0331) and when compared to PBO (p = 0.0224); this change associated with RFX treatment appeared to be short-lived as it was not detected in the follow-up period. Conclusions: Overall, no sustained disturbance of the stool microbiota was observed in subjects during repeat treatment with rifaximin as compared to subjects taking a single course of open-label rifaximin followed by double-blind placebo.
Figure 1. Symptom Severity at Open-Label Baseline and Double-Blind Baseline
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AGA Abstracts
duration (<24, 24-48, 48-120, ≥120 months). Results: In the overall population (n=636), the primary endpoint significantly favored RFX (33%) vs. PBO (25%, p=0.02). Regarding demographic characteristics, the RFX repeat treatment effect was evident in subjects < 65 years old (Δ=9%, p=0.0196) and ≥ 65 years old (Δ=18%, p=0.0410), in females (Δ=11%, p=0.0147) and males (Δ=7%, p=0.2515), and in subjects with BMI ≤ 30 kg/m2 (Δ=14%, p=0.0064) and BMI > 30 kg/m2 (Δ=5%, p=0.3035) (Figure). By race, the magnitude of the treatment effect was pronounced in white subjects (Δ=12%), but similar in non-white subjects (Δ=0.1%). A treatment by race interaction analysis yielded a p-value of 0.2440, an indication that race was not an effect modifier. Regarding baseline disease characteristics, the treatment effect was apparent in subjects with severe (Δ=10%, p=0.1564) and non-severe IBS (Δ= 10%, p=0.0185), and consistent across IBS symptom duration. Similar subpopulation results were observed for AP and SC when examined separately. Conclusions: Rifaximin response in subjects with IBS-D was significantly greater than placebo for the primary endpoint for all subgroups except non-white subjects where the sample size was quite small. These findings support the generalizability of the primary endpoint results. Figure. Study flow Mo1269 Enduring Effects Following a Course of Rifaximin Therapy in Patients With IBS-D: Incremental Benefit Upon Repeat Treatment Brian E. Lacy, Mark Pimentel, Lin Chang, Andrew C. Barrett, Jing Yu, Enoch Bortey, Craig Paterson, William P. Forbes Background: The efficacy of rifaximin (RFX) for the treatment of IBS-D has been demonstrated following a single course of therapy. To further evaluate RFX efficacy under conditions of repeat treatment, a study was designed that incorporated an open-label (OL) enrichment phase whereby only RFX responders were randomized to repeat treatment if they relapsed within 18 weeks. This analysis describes residual symptom improvements in subjects who met the definition of relapse, and incremental benefit upon repeat treatment with RFX. Methods: Patients with IBS-D (Rome III criteria) who presented with severity scores of ≥ 3 for IBS-related abdominal pain (AP, scale 0-10) and bloating (scale 0-6), and experienced ≥ 2 stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during a 7-day baseline were entered into the open-label (OL), enrichment phase. In the OL phase, patients were treated with RFX 550 mg TID for 2 weeks, followed by a 4-week treatment-free follow-up period. A responder was defined as meeting weekly response criteria for both AP (≥30% decrease from baseline in mean weekly pain score) and stool consistency (SC) (≥50% decrease from baseline in number of days/week with BSS Type 6 or 7) for ≥2 of 4 weeks. Responders were followed until relapse, which was defined as loss of response for AP OR SC for ≥3 out of a 4-week period during an 18-week maintenance phase. Patients with recurrence were randomized to receive up to 2 DB, placebo-controlled, repeat treatments (RFX 550 mg TID or placebo) separated by 10 weeks. The primary endpoint was the proportion of subjects who were responders during ≥2 of 4 weeks after the first repeat treatment. To assess response during the DB phase, baseline symptom severity at the time of randomization was used. Results: Overall, 636 patients were randomized to repeat treatment after responding to an initial OL course of RFX and then relapsing within 18 weeks. At the time of DB randomization, baseline scores for all IBS-related symptoms were significantly lower (p < 0.0001 for all symptoms, paired t-test) than observed at OL baseline (Figure 1). For example, weekly response for AP was defined as ≥ 30% improvement from baseline in weekly average score. However, symptom severity at time of recurrence indicated that randomized subjects were still experiencing an approximate 20% improvement in AP relative to their OL baseline. Similar carryover effects were observed for other IBS symptoms. Repeat treatment with RFX provided additional incremental benefit (primary endpoint responders: RFX 33% vs. PBO 25%, Δ=8%, p=0.02) to the enduring effects following initial treatment. Conclusions: Patients with IBS-D experienced persistent symptom improvement after a single, 2-week course of rifaximin therapy, and repeat treatment with rifaximin in patients meeting criteria for relapse provided additional incremental benefit.
Figure. Subgroup Analysis of Primary Endpoint Mo1268 Characterization of Stool Microbiota in Subjects With IBS-D Receiving Repeat Treatments With Rifaximin in the TARGET 3 Study Mark Pimentel, Anthony A. Fodor, Pamela Golden, Enoch Bortey, William P. Forbes Background: Rifaximin (RFX) is a minimally absorbed antimicrobial agent that has shown promise in the treatment of IBS-D, although the precise mechanism of this beneficial effect is unknown. This analysis employed genomic characterization of stool bacteria using nextgeneration sequencing techniques to assess the effect of repeated treatments with RFX on stool microbiota. Methods: Subjects with IBS-D (Rome III criteria) were entered into the open-label (OL) phase in which they were treated with RFX 550 mg TID for 2 weeks, followed by a 4-week follow-up period. Responders based on a composite endpoint of abdominal pain AND stool consistency improvements during ≥2 of 4 weeks were followed until they relapsed (up to 18 additional weeks), at which time they were randomized to receive 2 double-blind (DB), repeat treatments (RFX 550 mg TID or placebo [PBO]) separated by 10 weeks. All subjects provided stool samples at the beginning and end of OL treatment, beginning and end of the first repeat treatment, and end of study (Figure). Subjects were randomly selected for inclusion in the stool microbiota sequencing substudy in a manner that incorporated responders and non-responders. Genomic characterization of microbiota was accomplished using 16S rRNA bacterial deep gene sequencing. Metrics to describe the data included the diversity index, composed of measures of richness (number of families in each sample corrected for different samples having different number of sequences), evenness (as calculated by Shannon equitability, with values ranging from 0 to 1, with 1 being complete evenness), and Shannon diversity (a measure of overall community complexity). Results: A total of 103 subjects (mean age: 47.9; 74% female) were randomly selected for inclusion in the substudy, of which 73 (37 in RFX group and 36 in PBO group, evenly matched according to demographics) participated in the DB phase. At baseline of the DB phase, Shannon diversity was 1.786 and 1.733 in the RFX and PBO groups, respectively; after the 2-week treatment period, Shannon diversity was 1.698 and 1.743 (p = 0.4335), and remained essentially unchanged in the follow-up period. No significant changes in the evenness of the microbiota were observed within or between the treatment groups in the DB phase. The richness of the microbiota in subjects treated with DB PBO remained unchanged, while richness decreased at Week 2 in RFX-treated subjects when compared to their DB baseline (p = 0.0331) and when compared to PBO (p = 0.0224); this change associated with RFX treatment appeared to be short-lived as it was not detected in the follow-up period. Conclusions: Overall, no sustained disturbance of the stool microbiota was observed in subjects during repeat treatment with rifaximin as compared to subjects taking a single course of open-label rifaximin followed by double-blind placebo.
Figure 1. Symptom Severity at Open-Label Baseline and Double-Blind Baseline
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AGA Abstracts