Paul Covington - Academia.edu (original) (raw)

Papers by Paul Covington

Research paper thumbnail of Effects of treatment with eluxadoline on abdominal pain in patients with IBS‐D: Additional post hoc analyses of Phase 3 trials

Neurogastroenterology & Motility

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Research paper thumbnail of Effect of Eluxadoline on Abdominal and Bowel Symptoms Over Time in Phase 3 Clinical Trials in Patients With Irritable Bowel Syndrome With Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Urgency as a Measure of Treatment Effect Due to Eluxadoline

American Journal of Gastroenterology

Research paper thumbnail of Adverse Event Profile of Eluxadoline Over Time in Patients With Irritable Bowel Syndrome With Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Eluxadoline Demonstrates Efficacy in IBS-D Loperamide Treatment Failures

American Journal of Gastroenterology

Research paper thumbnail of Using Radar Plots to Display Disparate Global Effects of Eluxadoline in Patients With Irritable Bowel Syndrome With Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Eluxadoline Demonstrates Efficacy for the Treatment of Irritable Bowel Syndrome (IBS) With Diarrhea (IBS-D) Among Multiple Clinically Relevant Patient Subgroups

American Journal of Gastroenterology

Research paper thumbnail of Efficacy and Safety of Eluxadoline in IBS-D Patients Who Report Prior Inadequate Symptom Control with Loperamide

American Journal of Gastroenterology

Research paper thumbnail of Impact of Baseline Pain Severity on the Efficacy of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Response to Lai

The American Journal of Gastroenterology

Research paper thumbnail of Impact of patient and disease characteristics on the efficacy and safety of eluxadoline for IBS-D: a subgroup analysis of phase III trials

Therapeutic Advances in Gastroenterology

Background: Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent gastrointestinal (GI) d... more Background: Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent gastrointestinal (GI) disorder with a varied presentation, often overlapping with other GI and non-GI disorders. Eluxadoline is a locally active mixed µ-and κ-opioid receptor agonist and δ-opioid receptor antagonist approved for the treatment of IBS-D in adults. As IBS-D is a heterogeneous disease, factors such as patient demographics, symptom severity, and symptom pattern history can potentially inform treatment selection. Methods: Here, we report additional prospectively planned analyses of two large doubleblind, placebo-controlled studies (IBS-3001 and IBS-3002) enrolling patients meeting Rome III criteria for IBS-D. Patients were randomized 1:1:1 to receive placebo or eluxadoline 75 mg or 100 mg twice daily. Efficacy (abdominal pain, stool consistency, and composite, simultaneous improvement in both) and safety were assessed for prospectively defined patient subgroups stratified by age, sex, race, presence of comorbidities, and baseline disease characteristics. Results: Across all age, sex, race, comorbidity, and disease characteristic subgroups, a greater proportion of patients were composite responders with both eluxadoline doses as compared with placebo, including patients with a history of depression or a history of gastroesophageal reflux disease. Among patients aged ⩾65 years, a greater proportion of patients receiving eluxadoline 75 mg were composite, abdominal pain, and stool consistency responders compared with those receiving 100 mg. The proportion of patients with at least one adverse event was slightly higher in patients aged ⩾65 years and also in female patients. Conclusions: This analysis suggests that eluxadoline is effective in treating IBS-D across a range of commonly encountered patient types. In contrast to the overall population, patients aged ⩾65 years demonstrated a greater proportion of responders at the lower approved 75 mg eluxadoline dose.

Research paper thumbnail of Safety of Eluxadoline in Patients With IBS-D Without a Gallbladder

The American journal of gastroenterology, 2017

Research paper thumbnail of Response to Croteau and Barkin

The American journal of gastroenterology, 2017

Research paper thumbnail of Evaluation of Eluxadoline Effect on Cardiac Repolarization

Clinical pharmacology in drug development, 2018

This study evaluated the effects of eluxadoline, a mixed μ-opioid receptor (OR) and κ-OR agonist ... more This study evaluated the effects of eluxadoline, a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, on cardiac repolarization. This evaluator-blinded, placebo- and positive-controlled, 4-period crossover study randomized healthy men and women to single oral doses of eluxadoline (therapeutic dose 100 mg or supratherapeutic dose 1000 mg), moxifloxacin 400 mg, or placebo. QT data were corrected using individual custom correction (QTcI). The primary endpoint was the change from baseline in QTcI intervals (ΔQTcI) between eluxadoline and placebo (ΔΔQTcI). An upper bound of the 95% confidence interval around ΔΔQTcI of 10 milliseconds was considered clinically significant. Concentration-QTc data were analyzed using a repeated-measures, mixed-effects linear model. Sixty-four volunteers were treated, and 58 completed the study. Assay sensitivity was demonstrated with moxifloxacin (noted by ΔΔQTcI of 11.94 milliseconds). The maximum ΔΔQTcI for eluxadoline 1000 mg was 4.10 mil...

Research paper thumbnail of Effect of Hepatic Impairment on Eluxadoline Pharmacokinetics

The Journal of Clinical Pharmacology

Research paper thumbnail of Corrigendum: Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use

The American Journal of Gastroenterology

This corrects the article DOI: 10.1038/ajg.2017.72.

Research paper thumbnail of Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use

The American Journal of Gastroenterology

Irritable bowel syndrome (IBS) is the most common functional bowel disorder (1,2). Th e global pr... more Irritable bowel syndrome (IBS) is the most common functional bowel disorder (1,2). Th e global prevalence of IBS is estimated to be 11.2% (2,3). IBS can aff ect all members of society, irrespective of race, creed, color, or socioeconomic status, although women are more likely to be aff ected by IBS than men (3). IBS is associated with signifi cant impairment in quality of life and high rates of comorbid conditions (4) that imposes a signifi cant socioeconomic burden to society in terms of reduced work productivity and high health-care costs (5,6). As defi ned in the recent Rome criteria (1,7), IBS can be subcategorized into three major subtypes based on stool patterns: IBS with diarrhea (IBS-D), IBS with constipation, and IBS with mixed symptoms of constipation and diarrhea. IBS-D is the most common IBS subtype and comprises ∼ 40% of all cases (3). Despite intensive study, there is still no well-established treatment algorithm for IBS-D. Dietary and lifestyle modifi cations are commonly used for initial symptom management (2), although many patients continue to suff er from chronic symptoms. Clinicians oft en recommend the use of the over-the-counter antidiarrheal agent loperamide, a peripheral μ-opioid receptor (OR) agonist, to relieve diarrhea (8). Th e μ-OR activity of loperamide

Research paper thumbnail of Eluxadoline Demonstrates a Lack of Abuse Potential in Phase 2 and 3 Studies of Patients With Irritable Bowel Syndrome With Diarrhea

Clinical Gastroenterology and Hepatology

Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irri... more Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). Eluxadoline is a locally acting mixed μ-opiod and κ-opioid receptor agonist and δ-opioid receptor antagonist. The abuse potential of eluxadoline was evaluated as part of the Phase 2 and 3 clinical trials assessing the efficacy, safety, and tolerability of the drug. One Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) randomized controlled trials enrolled patients meeting Rome III criteria for IBS-D. Patients received oral twice-daily double-blind treatment with eluxadoline or placebo for 12, 26, or 52 weeks. The primary end point of these studies was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of days. Safety data were pooled, and specific adverse event terms potentially related to abuse were assessed descriptively. Adverse events reported during a 2-week post-treatment period (IBS-3001) and a 4-week single-blind washout period (IBS-3002) were assessed for signs of opioid withdrawal. Potential withdrawal effects were assessed by using the Subjective Opiate Withdrawal Scale. Overall, 807 and 1032 patients received 1 or more doses of eluxadoline (75 or 100 mg, respectively), and 975 patients received placebo. The overall incidence of adverse events potentially related to abuse did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (2.8%, 2.7%, and 4.3%, respectively). The most common adverse events potentially related to abuse were anxiety and somnolence, which occurred in less than 2% of patients in each group. Median overall Subjective Opiate Withdrawal Scale scores did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (3.0, 2.0, and 3.0, respectively). In an analysis of data from Phase 2 and Phase 3 trials of eluxadoline (75 or 100 mg) for patients with IBS-D, data revealed no signs of abuse potential for eluxadoline. ClinicalTrials.gov numbers: NCT01130272, NCT01553591, NCT01553747.

Research paper thumbnail of Sphincter of Oddi Function and Risk Factors for Dysfunction

Frontiers in Nutrition, 2017

The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic... more The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic secretions into the duodenum, initially described in 1887 by the Italian anatomist, Ruggero Oddi. SO dysfunction (SOD) is a broad term referring to numerous biliary, pancreatic, and hepatic disorders resulting from spasms, strictures, and relaxation of this valve at inappropriate times. This review brings attention to various factors that may increase the risk of SOD, including but not limited to: cholecystectomy, opiates, and alcohol. Lack of proper recognition and treatment of SOD may be associated with clinical events, including pancreatitis and biliary symptoms with hepatic enzyme elevation. Pharmacologic and non-pharmacologic approaches are discussed to help recognize, prevent, and treat SOD. Future studies are needed to assess the treatment benefit of agents such as calcium-channel blockers, glyceryl trinitrate, or tricyclic antidepressants in patients with SOD.

Research paper thumbnail of Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea

The American Journal of Gastroenterology, 2016

Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for ... more Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events. RESULTS: 2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were fi ve events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use. CONCLUSIONS: Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association.

Research paper thumbnail of Effects of treatment with eluxadoline on abdominal pain in patients with IBS‐D: Additional post hoc analyses of Phase 3 trials

Neurogastroenterology & Motility

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Research paper thumbnail of Effect of Eluxadoline on Abdominal and Bowel Symptoms Over Time in Phase 3 Clinical Trials in Patients With Irritable Bowel Syndrome With Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Urgency as a Measure of Treatment Effect Due to Eluxadoline

American Journal of Gastroenterology

Research paper thumbnail of Adverse Event Profile of Eluxadoline Over Time in Patients With Irritable Bowel Syndrome With Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Eluxadoline Demonstrates Efficacy in IBS-D Loperamide Treatment Failures

American Journal of Gastroenterology

Research paper thumbnail of Using Radar Plots to Display Disparate Global Effects of Eluxadoline in Patients With Irritable Bowel Syndrome With Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Eluxadoline Demonstrates Efficacy for the Treatment of Irritable Bowel Syndrome (IBS) With Diarrhea (IBS-D) Among Multiple Clinically Relevant Patient Subgroups

American Journal of Gastroenterology

Research paper thumbnail of Efficacy and Safety of Eluxadoline in IBS-D Patients Who Report Prior Inadequate Symptom Control with Loperamide

American Journal of Gastroenterology

Research paper thumbnail of Impact of Baseline Pain Severity on the Efficacy of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea

American Journal of Gastroenterology

Research paper thumbnail of Response to Lai

The American Journal of Gastroenterology

Research paper thumbnail of Impact of patient and disease characteristics on the efficacy and safety of eluxadoline for IBS-D: a subgroup analysis of phase III trials

Therapeutic Advances in Gastroenterology

Background: Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent gastrointestinal (GI) d... more Background: Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent gastrointestinal (GI) disorder with a varied presentation, often overlapping with other GI and non-GI disorders. Eluxadoline is a locally active mixed µ-and κ-opioid receptor agonist and δ-opioid receptor antagonist approved for the treatment of IBS-D in adults. As IBS-D is a heterogeneous disease, factors such as patient demographics, symptom severity, and symptom pattern history can potentially inform treatment selection. Methods: Here, we report additional prospectively planned analyses of two large doubleblind, placebo-controlled studies (IBS-3001 and IBS-3002) enrolling patients meeting Rome III criteria for IBS-D. Patients were randomized 1:1:1 to receive placebo or eluxadoline 75 mg or 100 mg twice daily. Efficacy (abdominal pain, stool consistency, and composite, simultaneous improvement in both) and safety were assessed for prospectively defined patient subgroups stratified by age, sex, race, presence of comorbidities, and baseline disease characteristics. Results: Across all age, sex, race, comorbidity, and disease characteristic subgroups, a greater proportion of patients were composite responders with both eluxadoline doses as compared with placebo, including patients with a history of depression or a history of gastroesophageal reflux disease. Among patients aged ⩾65 years, a greater proportion of patients receiving eluxadoline 75 mg were composite, abdominal pain, and stool consistency responders compared with those receiving 100 mg. The proportion of patients with at least one adverse event was slightly higher in patients aged ⩾65 years and also in female patients. Conclusions: This analysis suggests that eluxadoline is effective in treating IBS-D across a range of commonly encountered patient types. In contrast to the overall population, patients aged ⩾65 years demonstrated a greater proportion of responders at the lower approved 75 mg eluxadoline dose.

Research paper thumbnail of Safety of Eluxadoline in Patients With IBS-D Without a Gallbladder

The American journal of gastroenterology, 2017

Research paper thumbnail of Response to Croteau and Barkin

The American journal of gastroenterology, 2017

Research paper thumbnail of Evaluation of Eluxadoline Effect on Cardiac Repolarization

Clinical pharmacology in drug development, 2018

This study evaluated the effects of eluxadoline, a mixed μ-opioid receptor (OR) and κ-OR agonist ... more This study evaluated the effects of eluxadoline, a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, on cardiac repolarization. This evaluator-blinded, placebo- and positive-controlled, 4-period crossover study randomized healthy men and women to single oral doses of eluxadoline (therapeutic dose 100 mg or supratherapeutic dose 1000 mg), moxifloxacin 400 mg, or placebo. QT data were corrected using individual custom correction (QTcI). The primary endpoint was the change from baseline in QTcI intervals (ΔQTcI) between eluxadoline and placebo (ΔΔQTcI). An upper bound of the 95% confidence interval around ΔΔQTcI of 10 milliseconds was considered clinically significant. Concentration-QTc data were analyzed using a repeated-measures, mixed-effects linear model. Sixty-four volunteers were treated, and 58 completed the study. Assay sensitivity was demonstrated with moxifloxacin (noted by ΔΔQTcI of 11.94 milliseconds). The maximum ΔΔQTcI for eluxadoline 1000 mg was 4.10 mil...

Research paper thumbnail of Effect of Hepatic Impairment on Eluxadoline Pharmacokinetics

The Journal of Clinical Pharmacology

Research paper thumbnail of Corrigendum: Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use

The American Journal of Gastroenterology

This corrects the article DOI: 10.1038/ajg.2017.72.

Research paper thumbnail of Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use

The American Journal of Gastroenterology

Irritable bowel syndrome (IBS) is the most common functional bowel disorder (1,2). Th e global pr... more Irritable bowel syndrome (IBS) is the most common functional bowel disorder (1,2). Th e global prevalence of IBS is estimated to be 11.2% (2,3). IBS can aff ect all members of society, irrespective of race, creed, color, or socioeconomic status, although women are more likely to be aff ected by IBS than men (3). IBS is associated with signifi cant impairment in quality of life and high rates of comorbid conditions (4) that imposes a signifi cant socioeconomic burden to society in terms of reduced work productivity and high health-care costs (5,6). As defi ned in the recent Rome criteria (1,7), IBS can be subcategorized into three major subtypes based on stool patterns: IBS with diarrhea (IBS-D), IBS with constipation, and IBS with mixed symptoms of constipation and diarrhea. IBS-D is the most common IBS subtype and comprises ∼ 40% of all cases (3). Despite intensive study, there is still no well-established treatment algorithm for IBS-D. Dietary and lifestyle modifi cations are commonly used for initial symptom management (2), although many patients continue to suff er from chronic symptoms. Clinicians oft en recommend the use of the over-the-counter antidiarrheal agent loperamide, a peripheral μ-opioid receptor (OR) agonist, to relieve diarrhea (8). Th e μ-OR activity of loperamide

Research paper thumbnail of Eluxadoline Demonstrates a Lack of Abuse Potential in Phase 2 and 3 Studies of Patients With Irritable Bowel Syndrome With Diarrhea

Clinical Gastroenterology and Hepatology

Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irri... more Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). Eluxadoline is a locally acting mixed μ-opiod and κ-opioid receptor agonist and δ-opioid receptor antagonist. The abuse potential of eluxadoline was evaluated as part of the Phase 2 and 3 clinical trials assessing the efficacy, safety, and tolerability of the drug. One Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) randomized controlled trials enrolled patients meeting Rome III criteria for IBS-D. Patients received oral twice-daily double-blind treatment with eluxadoline or placebo for 12, 26, or 52 weeks. The primary end point of these studies was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of days. Safety data were pooled, and specific adverse event terms potentially related to abuse were assessed descriptively. Adverse events reported during a 2-week post-treatment period (IBS-3001) and a 4-week single-blind washout period (IBS-3002) were assessed for signs of opioid withdrawal. Potential withdrawal effects were assessed by using the Subjective Opiate Withdrawal Scale. Overall, 807 and 1032 patients received 1 or more doses of eluxadoline (75 or 100 mg, respectively), and 975 patients received placebo. The overall incidence of adverse events potentially related to abuse did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (2.8%, 2.7%, and 4.3%, respectively). The most common adverse events potentially related to abuse were anxiety and somnolence, which occurred in less than 2% of patients in each group. Median overall Subjective Opiate Withdrawal Scale scores did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (3.0, 2.0, and 3.0, respectively). In an analysis of data from Phase 2 and Phase 3 trials of eluxadoline (75 or 100 mg) for patients with IBS-D, data revealed no signs of abuse potential for eluxadoline. ClinicalTrials.gov numbers: NCT01130272, NCT01553591, NCT01553747.

Research paper thumbnail of Sphincter of Oddi Function and Risk Factors for Dysfunction

Frontiers in Nutrition, 2017

The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic... more The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic secretions into the duodenum, initially described in 1887 by the Italian anatomist, Ruggero Oddi. SO dysfunction (SOD) is a broad term referring to numerous biliary, pancreatic, and hepatic disorders resulting from spasms, strictures, and relaxation of this valve at inappropriate times. This review brings attention to various factors that may increase the risk of SOD, including but not limited to: cholecystectomy, opiates, and alcohol. Lack of proper recognition and treatment of SOD may be associated with clinical events, including pancreatitis and biliary symptoms with hepatic enzyme elevation. Pharmacologic and non-pharmacologic approaches are discussed to help recognize, prevent, and treat SOD. Future studies are needed to assess the treatment benefit of agents such as calcium-channel blockers, glyceryl trinitrate, or tricyclic antidepressants in patients with SOD.

Research paper thumbnail of Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea

The American Journal of Gastroenterology, 2016

Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for ... more Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events. RESULTS: 2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were fi ve events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use. CONCLUSIONS: Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association.