Search

Background & Aims Few treatments have demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). A phase 3, randomized, double-blind, placebo-controlled trial was performed to evaluate the safety and efficacy of repeat treatment with the nonsystemic antibiotic rifaximin. Methods The trial included adults with IBS-D, mean abdominal pain and bloating scores of 3 or more, and loose stool, located at 270 centers in the United States and Europe from February 2012 through June 2014. Those responding to a 2-week course of open-label rifaximin 550 mg 3 times daily, who then relapsed during an observation phase (up to 18 weeks), were randomly assigned to groups given repeat treatments of rifaximin 550 mg or placebo 3 times daily for 2 weeks. The primary end point was percentage of responders after first repeat treatment, defined as a decrease in abdominal pain of ≥30% from baseline and a decrease in frequency of loose stools of ≥50% from baseline, for 2 or more weeks during a 4-week post-treatment period. Results Of 1074 patients (44.1%) who responded to open-label rifaximin, 382 (35.6%) did not relapse and 692 (64.4%) did; of these, 636 were randomly assigned to receive repeat treatment with rifaximin (n = 328) or placebo (n = 308). The percentage of responders was significantly greater with rifaximin than placebo (38.1% vs 31.5%; P = .03). The percentage of responders for abdominal pain (50.6% vs 42.2%; P = .018) was significantly greater with rifaximin than placebo, but not stool consistency (51.8% vs 50.0%; P = .42). Significant improvements were also noted for prevention of recurrence, durable response, and bowel movement urgency. Adverse event rates were low and similar between groups. Conclusions In a phase 3 study of patients with relapsing symptoms of IBS-D, repeat rifaximin treatment was efficacious and well tolerated. ClinicalTrials.gov ID: NCT01543178.

Summary Background Mesalazine (mesalamine) granules (MG) were shown to be effective for the maintenance of remission of ulcerative colitis (UC) in two double-blind placebo-controlled trials. Aim To evaluate the efficacy of once-daily MG for maintenance of remission in patients with UC who switched from other 5-aminosalicylic acid (5-ASA) formulations. Methods Data from two independent multicenter, randomised, double-blind, placebo-controlled, 6-month trials evaluating patients with UC in remission were combined for analysis of a subpopulation of patients who switched from other 5-ASA formulations to MG 1.5 g or placebo upon randomisation. The primary endpoint was the percentage of patients who remained relapse-free at Month 6 or end of treatment. Relapse was defined as a Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, a UC flare or medication used to treat a UC flare. Results Of the 487 patients who received 5-ASA maintenance therapy at enrolment, 322 were in the MG group and 165 were in the placebo group. The percentage of patients who remained relapse-free (based on Sutherland Disease Activity Index scores) after 6 months was significantly higher with MG than placebo (78.3% vs. 58.8%, P

Aliment Pharmacol Ther 2011; 34: 853–861 Summary Background Hepatic encephalopathy (HE) is a brain disorder that often results from cirrhosis due to viral hepatitis, metabolic and alcohol-related liver disease, and is characterised by cognitive, psychiatric and motor impairments. Recurrent bouts of overt HE negatively impact daily functioning and quality of life. Aim To evaluate the effect of rifaximin on health-related quality of life (HRQL) in cirrhotic patients with HE. Methods Patients with cirrhosis in remission from HE (Conn score = 0 or 1) and a documented history of recurrent HE episodes (≥2 within 6 months of screening) were randomised to rifaximin 550 mg twice daily (N = 101) or placebo (N = 118) for 6 months. Concomitant lactulose was permitted during the study. The Chronic Liver Disease Questionnaire (CLDQ) was administered every 4 weeks, and time for occurrence of HE breakthrough was recorded. A longitudinal analysis using time-weighted averages of the CLDQ scores normalised by days on study therapy was used to evaluate the effect of treatment on HRQL, and between HE outcomes (HE recurrence, yes/no) irrespective of treatment. Results The time-weighted averages of the overall CLDQ score and each domain score were significantly higher in the rifaximin group vs. placebo (P-values ranged from 0.0087 to 0.0436); and were significantly lower in patients who experienced HE breakthrough compared to those who remained in remission (P-values were

Aliment Pharmacol Ther 2010; 32: 990–999 Summary Background Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder. Aim To evaluate once-daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC. Methods Randomized, double-blind, placebo-controlled trial of patients (n = 209 MG, n = 96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding = 0, mucosal appearance

Background Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. Aim The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. Methods Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. Results A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0 %, respectively). Adverse events occurred in 41.4 and 36.3 % of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic–pituitary–adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. Conclusions This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic–pituitary–adrenal axis.

Background Patients with ulcerative colitis (UC) who achieve remission with corticosteroids often relapse after tapering or discontinuation; alternative treatments limiting steroid exposure and UC relapse would be beneficial. It remains uncertain whether patients with corticosteroid-induced remission experience benefit with mesalamine granules (MG), a locally acting aminosalicylate extended-release capsule formulation for maintenance of UC remission in adults. Aims Efficacy and safety of MG 1.5 g once daily was evaluated in patients with UC in corticosteroid-induced remission. Methods Data from patients with previous corticosteroid use to achieve baseline UC remission were analyzed from two 6-month randomized, double-blind, placebo-controlled trials and a 24-month open-label extension (OLE). Six-month relapse-free rates were assessed using the revised Sutherland Disease Activity Index. UC-related adverse events (AEs) were recorded during the 30 months. Results Included were 158 steroid-treated patients in UC remission (MG, n = 105; placebo, n = 53) and 74/105 MG-treated patients who continued MG in the OLE. A significantly larger percentage of patients remained relapse-free at 6 months with MG (77.1 %) versus placebo (54.7 %; P = 0.006), with a 55 % reduction in relapse risk (hazard ratio [HR] 0.45; 95 % CI 0.25–0.79). There was a similar (49.2 %) reduction in risk of UC-related AEs at 6 months (HR 0.51; 95 % CI 0.31–0.84; P = 0.009) that was sustained during the OLE. Conclusions MG 1.5 g once daily administered for maintenance of corticosteroid-induced remission was associated with low risk of relapse and UC-related AEs. ClinicalTrials.gov NCT00744016, NCT00767728, and NCT00326209.

SummaryBackground The Crohn's Disease Activity Index (CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes (PROs) should be the primary outcome in randomised controlled trials for Crohn's disease (CD). Aim As no validated PRO exists for CD, to investigate whether CDAI diary card items could be modified for this purpose. Methods Data from a trial of rifaximin-extended intestinal release were used to identify cut-points for stool frequency, pain and general well-being using receiver operating characteristic curves with CDAI

Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear.To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design.Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM.Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments.This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting.

the primary endpoint significantly favored RFX (33%) vs. PBO (25%, p=0.02). Regarding demographic characteristics, the RFX repeat treatment effect was evident in subjects 30 kg/m2 (Δ=5%, p=0.3035) (Figure). By race, the magnitude of the treatment effect was pronounced in white subjects (Δ=12%), but similar in non-white subjects (Δ=0.1%). A treatment by race interaction analysis yielded a p-value of 0.2440, an indication that race was not an effect modifier. Regarding baseline disease characteristics, the treatment effect was apparent in subjects with severe (Δ=10%, p=0.1564) and non-severe IBS (Δ= 10%, p=0.0185), and consistent across IBS symptom duration. Similar subpopulation results were observed for AP and SC when examined separately. Conclusions: Rifaximin response in subjects with IBS-D was significantly greater than placebo for the primary endpoint for all subgroups except non-white subjects where the sample size was quite small. These findings support the generalizability of the primary endpoint results.

the primary endpoint significantly favored RFX (33%) vs. PBO (25%, p=0.02). Regarding demographic characteristics, the RFX repeat treatment effect was evident in subjects 30 kg/m2 (Δ=5%, p=0.3035) (Figure). By race, the magnitude of the treatment effect was pronounced in white subjects (Δ=12%), but similar in non-white subjects (Δ=0.1%). A treatment by race interaction analysis yielded a p-value of 0.2440, an indication that race was not an effect modifier. Regarding baseline disease characteristics, the treatment effect was apparent in subjects with severe (Δ=10%, p=0.1564) and non-severe IBS (Δ= 10%, p=0.0185), and consistent across IBS symptom duration. Similar subpopulation results were observed for AP and SC when examined separately. Conclusions: Rifaximin response in subjects with IBS-D was significantly greater than placebo for the primary endpoint for all subgroups except non-white subjects where the sample size was quite small. These findings support the generalizability of the primary endpoint results.

of these patients had fasting FGF19 measured. Alanine transaminase (ALT) and appearance of fatty liver on imaging (ultrasound, CT or MR) were retrospectively added to the database. Where multiple investigations had been performed, the test nearest to the date of the SeHCAT test was recorded. Patients with known chronic liver disease or alcohol abuse were excluded from the final analysis. Results: Of 578 SeHCAT values on the database, 303 (52%) were positive with a value 31IU/L (36% v 21%, p 31IU/L (21% v 7%, p 31IU/L (43% v 22%, p 31IU/L (23% v 7%, p 40 IU/L (40% vs 12%, p

of these patients had fasting FGF19 measured. Alanine transaminase (ALT) and appearance of fatty liver on imaging (ultrasound, CT or MR) were retrospectively added to the database. Where multiple investigations had been performed, the test nearest to the date of the SeHCAT test was recorded. Patients with known chronic liver disease or alcohol abuse were excluded from the final analysis. Results: Of 578 SeHCAT values on the database, 303 (52%) were positive with a value 31IU/L (36% v 21%, p 31IU/L (21% v 7%, p 31IU/L (43% v 22%, p 31IU/L (23% v 7%, p 40 IU/L (40% vs 12%, p

Background: Asimadoline, a peripherally-restricted highly selective kappa-opioid receptor (KOR) agonist, has been shown to be efficacious in relieving pain or discomfort, urgency, stool frequency and other symptoms in diarrhea-predominant-IBS (D-IBS) patients with at least moderate pain (Mangel et al 2008). The mechanism of action for this therapeutic effect is thought to involve activation of up-regulated KORs on visceral afferent terminals in the gut wall. KOR activation in the central nervous system (CNS) can lead to aquaresis, dysphoria, and sedation. Penetration of asimadoline into the CNS is poor due to its amphiphilic structure and because it is a substrate for P-glycoprotein (P-gp), thus, there is no evidence for CNS effects of asimadoline in the IBS dose range (1-2 mg/day). Aim: The potential for drug interaction-induced CNS effects with ketoconazole, an inhibitor of P-gp and cytochrome P450 3A4 (CYP3A4), which plays a role in the metabolism of asimadoline, was assessed in this study. Methods: This was a single center, double-blind, placebo-controlled, randomized, two-period, crossover drug interaction study. Twelve healthy male subjects (Caucasian, 1840 years) received ketoconazole 200 mg bid for 3 days followed by a combination of ketoconazole 200 mg and asimadoline 1.5 mg bid (3 fold higher than the 0.5 mg bid clinical dose for IBS) from Days 4 to 9 and a single morning dose on Day 10 in one period and the same treatments but with ketoconazole placebo in a second period, with a 14 day washout between treatments. Pharmacodynamic tests aimed at detecting activity of asimadoline in the CNS included plasma antidiuretic hormone concentrations, the Critical Flicker Fusion test, the Profile of Mood State and the Bond & Lader visual analogue scale of mood and alertness, performed on Days 1, 4, 7 and 10. Primary pharmacokinetic variables were plasma asimadoline Cmax and AUC0-τ after a single dose on Day 4 and after multiple doses on Day 10. Results: The Cmax of asimadoline was approximately doubled with ketoconazole compared to placebo co-administration (from 46.2 to 98.9 ng/mL on Day 4 and from 50.7 to 112.1 ng/mL on Day 10). Mean AUCτ values were 3-fold higher during ketoconazole compared to placebo treatment. Although co-administration of ketoconazole led to a 2to 3-fold increase in asimadoline Cmax and AUC, no effects were observed on any of the CNS pharmacodynamic endpoints. Conclusions: There were no CNS pharmacodynamic effects even at plasma asimadoline levels 8-fold higher than those achieved at the IBS dose. These data provide further evidence for the peripheral restriction of asimadoline and suggest that dose adjustment when co-administered with ketoconazole or other CYP3A4 / P-gp inhibitors is not required.