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A6 EFFECTS OF ELUXADOLINE TREATMENT ON ABDOMINAL AND BOWEL SYMPTOMS IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH DIARRHEA REPORTING INADEQUATE SYMPTOM CONTROL WITH LOPERAMIDE: AGGREGATED RESULTS FROM PHASE 3 AND 4 CLINICAL TRIALS

ABSTRACT: Abstract Background The heterogeneous nature of irritable bowel syndrome with diarrhea (IBS-D) presents a complex challenge in the management of a wide range of symptoms. Despite the need for more effective treatments that provide global IBS-D symptom relief, many therapies currently available in Canada only treat individual IBS-D symptoms. Eluxadoline (ELX) is a mixed µ- and ?-opioid receptor agonist and ?-opioid receptor antagonist approved by Health Canada for the treatment of IBS-D in adults. Aims To analyze the efficacy of ELX for managing a constellation of IBS-D symptoms among patients (pts) self-reporting inadequate responses to loperamide (LOP) from Phase 3 and 4 trials of ELX. Methods Adults with IBS-D were randomized to placebo (PBO) or ELX (75 or 100 mg) twice daily (BID) for 26 or 52 weeks in two Phase 3 trials (NCT01553591 and NCT01553747); the data from a subset reporting inadequate IBS-D symptom control with prior LOP use were pooled and prospectively analyzed. In the Phase 4 trial (RELIEF: NCT02959983), IBS-D pts with self-reported inadequate symptom control with LOP over the previous 12 months were randomized to PBO or ELX 100 mg BID for 12 weeks. In all trials, pts recorded their daily IBS-D symptoms including worst abdominal pain (0–10 scale), stool consistency (Bristol Stool Form Scale score 1–7), and daily urgency episodes. Results for ELX 100 mg vs. PBO were evaluated after 12 weeks of treatment, which included the generation of radar plots to visualize multiple efficacy endpoints. Results Of pts enrolled in the Phase 3 trials with prior LOP use, inadequate control of IBS-D symptoms was reported in 58.9% (n=166) and 58.8% (n=174) of pts in the PBO and ELX groups, respectively; in the Phase 4 trial, 174 and 172 pts were treated with PBO and ELX, respectively. ELX-treated pts had a greater proportion of responders compared to PBO-treated pts for all outcomes, including a significant increase in the proportion of pts achieving both ?50% and ?75% urgency-free days in the Phase 3 trials (Figure). Analysis of the global symptoms of pts enrolled in the Phase 4 trial further supported these results. Across Phase 3 and 4 trials, adverse events occurred in similar proportions regardless of treatment, with the most common being nausea. Conclusions In pts with inadequate responses to LOP, a greater proportion of ELX-treated pts were responders compared to PBO-treated pts in all Phase 3 and 4 trials for the respective primary composite endpoints, abdominal pain, stool consistency, and urgency after 12 weeks of treatment. These results validate the effectiveness of ELX in alleviating IBS-D symptoms in this population. aComposite endpoint of the Phase 4 trial defined as simultaneous daily improvement of ?40% in WAP score vs. baseline and BSFS score <5 (or no BM) on ?50% of treatment days; bComposite endpoint of the Phase 3 trials defined as simultaneous daily improvement of ?30% in WAP score vs. baseline and BSFS score <5 (or no BM) on ?50% of treatment days; cStool consistency response as per the composite endpoint; dUrgency-free response calculated using criteria of ?50% or ?75% of days with no urgency episodes. *p<0.05; **p<0.01; †p?0.001; the Phase 3 pooled data were analyzed based on a Cochran-Mantel-Haenszel test with study as a stratification factor, and the Phase 4 data were analyzed using a two-sided chi-square test and no adjustment was performed for multiplicity of endpoints. BID, twice daily; BM, bowel movement; BSFS, Bristol Stool Form Scale; WAP, worst abdominal pain Funding Agencies Writing assistance by Complete HealthVizion, funded by Allergan plc

SUBMITTER: Brenner D

PROVIDER: S-EPMC7043685 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Irritable bowel syndrome with diarrhea (IBS-D) is a chronic disorder of gut-brain interaction that negatively affects work productivity and health-related quality of life (HRQOL). IBS-D therapeutic options are limited and include loperamide, an over-the-counter μ-opioid receptor agonist commonly used as an antidiarrheal agent, and eluxadoline, a mixed μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved in the United States for the treatment of IBS-D in adults. OBJECTIVE: To characterize the effect of eluxadoline on work productivity and HRQOL in patients with IBS-D with previous inadequate response to loperamide. METHODS: The Work Productivity and Activity Impairment Questionnaire for IBS-D (WPAI:IBS-D), Centers for Disease Control and Prevention Healthy Days Core Module (CDC HRQOL-4), and EuroQoL-5 Dimension (EQ-5D) instruments were administered at baseline and week 12 of a phase 4 clinical trial (RELIEF), assessing the efficacy and safety of eluxadoline treatment in adults with IBS-D reporting previous inadequate response to loperamide. Changes from baseline to week 12 for each assessment were evaluated using an analysis of covariance model. Indirect costs were calculated by converting overall work productivity losses into monetary values. RESULTS: A total of 346 patients were randomized to either eluxadoline (n = 172) or placebo (n = 174). From baseline to week 12, compared with placebo, twice-daily treatment with eluxadoline resulted in significantly greater reductions in absenteeism (2.6%; P = 0.046). Numerically greater decreases in presenteeism, overall work productivity loss, and daily activity impairment were also observed in patients receiving eluxadoline compared with those receiving placebo (P = not significant for each). Numerical reductions in overall work productivity loss from baseline to week 12 translate to approximately 2.4 hours per patient per week (123 hours annually) and correspond to an avoided overall work loss of $4,503 annually for an employee with IBS-D treated with eluxadoline. In addition, from baseline to week 12, treatment with eluxadoline led to a significantly greater reduction in the number of unhealthy days experienced (-1.7 days; P = 0.042), as well as numerical improvements in EQ-5D measures in comparison with placebo (P = not significant for each). CONCLUSIONS: In patients with IBS-D reporting inadequate response to loperamide, eluxadoline treatment was associated with significant reductions in absenteeism and the number of unhealthy days experienced. Eluxadoline treatment of IBS-D may lead to significant cost savings via mitigation of losses in work productivity. DISCLOSURES: This study was sponsored by Allergan plc (before acquisition by AbbVie, Inc.). Allergan plc and/or AbbVie, Inc., was involved in the study design, collection, analysis, interpretation of the data, writing of the report, and the decision to submit the report for publication. Abel and Burslem are employees of AbbVie, Inc., and own stock/stock options. Brenner has served as a consultant, speaker, and/or advisor for Allergan plc (before acquisition by AbbVie, Inc.), Alnylam, Alpha Sigma, Arena, Bayer, Ironwood Pharmaceuticals, Salix Pharmaceuticals, Shire, Synergy, and Takeda Pharmaceuticals. He is also supported in research by an unrestricted gift from the Irene D. Pritzker Foundation. Sayuk has served as a consultant and speaker for Allergan plc (before acquisition by AbbVie, Inc.), Gi Health Foundation, Ironwood Pharmaceuticals, Salix Pharmaceuticals, and Synergy. Portions of the current work were presented at AMCP Nexus; October 22-25, 2018; Orlando, FL.

Project description:ObjectivesEluxadoline 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.MethodsAdults 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.Results2,776 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 five events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use.ConclusionsEluxadoline 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.

Project description:Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by chronic abdominal pain associated with changes in bowel habits. It is the most common GI problem seen by gastroenterologists. IBS is a heterogenous disorder encompassing a spectrum of underlying mechanisms and clinical presentations. The pathophysiology of diarrhea-predominant form of IBS (IBS-D) remains poorly understood, and current available therapeutic options for IBS-D are limited. Eluxadoline is a novel, locally acting mixed ?- and ?-opioid receptor agonist and ?-receptor antagonist approved by the Food and Drug Administration (FDA) for treatment of adults with IBS-D. Data from two phase III clinical trials showed that approximately 25-30% of the eluxadoline-treated patients achieved composite clinical response, defined by a reduction of abdominal pain and improvement in stool consistency. Patients who achieve composite response during the first month of therapy were significantly more likely to demonstrate sustained clinical response. The most common adverse events reported with eluxadoline use were constipation, nausea and abdominal pain. The risk of abuse, dependence, or withdrawal is low. Serious adverse events associated with eluxadoline include sphincter of Oddi spasm (SOS) and pancreatitis particularly in patients without a gallbladder. Development of pancreatitis is likely secondary to SOS, but it remains unclear why pancreatitis occurs so quickly after initial doses. This adverse event profile helps guide proper selection of IBS-D patients for eluxadoline use, with important contraindications including absence of a gallbladder, biliary duct obstruction or sphincter of Oddi dysfunction, alcoholism, history of pancreatitis, or structural diseases of the pancreas. With the recent clinical trials demonstrating its efficacy, eluxadoline provides an additional option to the few existing pharmacologic interventions available for IBS-D. In this review, we discuss the drug development, efficacy and safety of eluxadoline, as well as selection criteria for identifying appropriate candidates for this medication.

Project description:OBJECTIVES: Despite a documented clinical need, no patient reported outcome (PRO) symptom measure meeting current regulatory requirements for clinically relevant end points is available for the evaluation of treatment benefit in diarrhea-predominant IBS (IBS-D). METHODS: Patients (N=113) with IBS-D participated in five study phases: (1) eight concept elicitation focus groups (N=34), from which a 17-item IBS-D Daily Symptom Diary and four-item IBS-D Symptom Event Log (Diary and Event Log) were developed; (2) one-on-one cognitive interviews (N=11) to assess the instrument's comprehensiveness, understandability, appropriateness, and readability; (3) four data triangulation focus groups (N=32) to confirm the concepts elicited; (4) two hybrid (concept elicitation and cognitive interview) focus groups (N=16); and (5) two iterative sets of one-on-one cognitive interviews (N=20) to further clarify the symptoms of IBS-D and debrief a revised seven-item Diary and four-item Event Log. RESULTS: Of thirty-six concepts initially identified, 22 were excluded because they were not saturated, not clinically relevant, not critical symptoms of IBS-D, considered upper GI symptoms, or too broad or vaguely defined. The remaining concepts were diarrhea, immediate need (urgency), bloating/pressure, frequency of bowel movements, cramps, abdominal/stomach pain, gas, completely emptied bowels/incomplete evacuation, accidents, bubbling in intestines (bowel sounds), rectal burning, stool consistency, rectal spasm, and pain while wiping. The final instrument included a daily diary with separate items for abdominal and stomach pain and an event log with four items completed after each bowel movement as follows: (1) a record of the bowel movement/event and an assessment of (2) severity of immediacy of need/bowel urgency, (3) incomplete evacuation, and (4) stool consistency (evaluated using the newly developed Astellas Stool Form Scale). Based on rounds of interviews and clinical input, items considered secondary or nonspecific to IBS-D (rectal burning, bubbling in intestines, spasms, and pain while wiping) were excluded. CONCLUSIONS: The IBS-D Symptom Diary and Event Log represent a rigorously developed PRO instrument for the measurement of the IBS-D symptom experience from the perspective of the patient. Its content validity has been supported, and future work should evaluate the instrument's psychometric properties.

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A6 EFFECTS OF ELUXADOLINE TREATMENT ON ABDOMINAL AND BOWEL SYMPTOMS IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH DIARRHEA REPORTING INADEQUATE SYMPTOM CONTROL WITH LOPERAMIDE: AGGREGATED RESULTS FROM PHASE 3 AND 4 CLINICAL TRIALS

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