Efficacy and Safety of Eluxadoline in IBS-D Patients Who Report Inadequate Symptom Control With Prior Loperamide Use: A Phase 4, Multicenter, Multinational, Randomized, Placebo-controlled, Double-blinded Study (RELIEF): Presidential Poster Award

Introduction: Irritable bowel syndrome with diarrhea (IBS-D) is a functional gastrointestinal disorder with limited treatment options. We evaluated the efficacy and safety of eluxadoline, an FDA-approved mixed μ-opioid receptor (OR) and ?-OR agonist and d-OR antagonist compared to placebo in IBS-D patients who reported inadequate symptom control with prior use of loperamide, an over-the-counter μ-OR agonist. Methods: Adults with IBS-D (Rome III criteria) who reported inadequate symptom control subsequent to loperamide use within the preceding 12 months were randomized 1:1 to placebo or eluxadoline 100 mg twice daily taken with food for 12 weeks. Patients recorded daily IBS-D symptoms, including worst abdominal pain (WAP) on a 0 to 10-point scale and stool consistency (evaluated by Bristol Stool Score [BSS]). The primary efficacy endpoint was the proportion of composite responders, defined as patients who met daily composite response criteria (WAP improvement by ≥40% AND BSS score <5 or absence of bowel movement accompanied by ≥40% WAP improvement compared to baseline) for at least 50% of treatment days, and had ≥60 days of diary entries over the 12-week treatment period. Results: 346 patients were enrolled. The majority (70%) were female, and mean age was 44 years. A significantly greater proportion of patients receiving eluxadoline achieved the primary composite responder endpoint compared to placebo (22.7% [39/172] vs. 10.3% [18/174]; p=0.0022). Additionally, a higher proportion of patients achieved the secondary endpoints of improvements in stool consistency (27.9% [48/172] vs. 16.7% [29/174]; p=0.0119) and WAP (43.6% [75/172] vs. 31.0% [54/174]; p=0.0174) with eluxadoline than placebo, respectively. Throughout the 12-week study, a greater proportion of eluxadoline patients met the monthly composite responder endpoint compared with placebo (Weeks 1-4:14.0% vs. 6.9%, p=0.0330; Weeks 5-8: 26.7% vs. 14.9%, p=0.0063; Weeks 9-12: 30.8% vs. 16.7%, p=0.0018). A comparable number of patients reported treatment-emergent adverse events (TEAEs) with eluxadoline (124 events; 37.4% [64/171]) and placebo (112 events, 35.3% [61/173]). More patients discontinued treatment due to TEAEs with eluxadoline compared with placebo (10 vs. 3). No treatment-related serious AE was reported. Conclusion: Eluxadoline appears safe, effective, and well tolerated for treating IBS-D symptoms in patients who report inadequate symptom control with prior loperamide use.