Eluxadoline for Irritable Bowel Syndrome with Diarrhea

作者：Lembo, Anthony J.^*; Lacy, Brian E.; Zuckerman, Marc J.; Schey, Ron; Dove, Leonard S.; Andrae, David A.; Davenport, J. Michael; McIntyre, Gail; Lopez, Rocio; Turner, Lisa; Covington, Paul S.

来源：New England Journal of Medicine, 2016, 374(3): 242-253.

DOI：10.1056/NEJMoa1505180

• INDUCED ACUTE-PANCREATITIS
• ODDI MOTOR-ACTIVITY
• RECEPTOR ANTAGONIST
• CONTROLLED-TRIALS
• SPHINCTER
• ALOSETRON
• MORPHINE
• CONSTIPATION
• LOPERAMIDE
• WOMEN

BACKGROUND @@@ Effective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy and safety of eluxadoline, a new oral agent with mixed opioid effects (mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist), in patients with IBS with diarrhea. @@@ METHODS @@@ We randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point 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 the days from weeks 1 through 12 and from weeks 1 through 26. @@@ RESULTS @@@ For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P = 0.01 and P = 0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P = 0.11 and P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P = 0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666 patients in the safety population (0.3%). @@@ CONCLUSIONS @@@ Eluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea in men and women, with sustained efficacy over 6 months in patients who received the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and NCT01553747, respectively.)

• 出版日期2016-1-21