PHASE II, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, PROOF OF CONCEPT STUDY OF EFFICACY OF RIFAMYCIN SV-MMX® 600 MG ADMINISTERED THREE OR TWO TIMES DAILY TO PATIENTS WITH DIARRHEA-PREDOMINANT IRRITABLE BOWEL SYNDROME (IBS-D)

Introduction: Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction characterized by abdominal pain associated with bowel movements. Rifaximin -a non-resorbable antibiotic from the rifamycin group- has been shown to be effective in the treatment of non-constipated IBS patients. A novel targeted delivery formulation of rifamycin SV (rifamycin MMX® 600 mg tablets), based on Multimatrix® (MMX®) technology, was developed to provide a more precise delivery of the active substance in the distal small bowel and proximal colon, the region traditionally considered the origin of IBS symptoms.
Aim: To assess the efficacy and safety of rifamycin MMX® for improving symptoms in diarrhea predominant IBS (IBS-D) patients.
Methods: We conducted a randomized, double-blind, placebo-controlled study in 33 European centers. Patients fulfilling Rome IV criteria for IBS-D were randomized to receive either placebo or two different dosing regimens of rifamycin MMX® 600 mg (b.i.d = 1200mg/day or t.i.d =1800mg/day) for 2 weeks. Primary endpoint was the proportion of weekly responders in the first week of treatment assessed on the basis of patients’ daily reported symptoms and stool patterns. Response was defined as a reduction of ≥30% abdominal pain AND ≥50% reduction of weekly days with ≥1 Bristol stool types 6 or 7. Secondary endpoints included adequate relief regarding monthly global symptoms and bloating (adequate relief ≥2 weeks per month) based on weekly questions in the following three months.
Results: 279 patients were randomized to treatment groups that were comparable in terms of demographics and symptoms. A significantly higher percentage in the rifamycin b.i.d. group met the primary endpoint for response based on pain and stool pattern than in the t.i.d. and placebo group (25.0% vs. 12.4% and 9.5% respectively). Adjusted odds ratio for response of b.i.d. vs placebo was 3.26 ([95% CI: 1.39; 7.67], p=0.0066) and t.i.d. vs b.i.d. was 0.40 ([95% CI: 0.17; 0.92]; p=0.0314). There was no significant difference between t.i.d. and placebo (OR 1.30 [95% CI: 0.50; 3.42]; p=0.5892). Monthly global response rate was higher in the b.i.d. group than placebo for the first month and the first two months (66.7% vs 46.5%; OR= 2.36; p=0.0086 and 60.0% vs 42.4%; OR= 2.19; p= 0.0187; respectively). Monthly response for IBS-related bloating was higher in b.i.d. vs placebo (63.3% vs 40.0% 1^st month; OR=2.64; p=0.0031 and 59.3% vs 42.4% first 2 months; OR=2.03; p=0.0286 respectively). For the 3 months follow up, monthly global and bloating-related relief were numerically but not statistically higher in the b.i.d. group than in placebo.
Conclusion: In IBS-D, treatment with rifamycin SV-MMX® 600mg b.i.d. was more effective than placebo and t.i.d. dosing in the first week of treatment and provided more adequate relief over the first two months of follow up.