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 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 <150 as criterion. The operating properties of 2‐ and 3‐item PRO were evaluated using data from a trial of methotrexate in CD. Regression analysis determined PRO2 and PRO3 scores that correspond to CDAI‐defined thresholds of 150, 220 and 450 and changes of 50, 70 and 100 points. Results Optimum cut‐points for CDAI remission were mean daily stool frequency ≤1.5, abdominal pain ≤1, and general well‐being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, respectively). The effect estimates were similar using 2‐ and 3‐item PROs or CDAI. PRO2 and PRO3 values corresponding to CDAI scores of 150, 220 and 450 points were 8, 14, 34 and 13, 22, 53. The corresponding values for CDAI changes of 50, 70 and 100, were 2, 5, 8 and 5, 9, 14. Responsiveness to change was similar for both PROs. Conclusion Patient reported outcomes derived from CDAI diary items may be appropriate for use in clinical trials for CD.

Background: Subcutaneous methylnaltrexone (MNTX), dosed based on body weight, is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); however, fixed-dose administration of MNTX may improve ease of administration.Objective: The study objective was to assess safety and efficacy of fixed-dose MNTX in two phase 4 trials.Methods: In a double-blind, randomized, placebo-controlled trial (RCT), patients with advanced illness and OIC received MNTX (8 mg or 12 mg by body weight [38 kg to <62 kg or ≥62 kg, respectively]) or placebo every other day (QOD) for two weeks. Patients completing the RCT could enroll in an open-label extension (OLE) study with MNTX administered as needed (PRN). The primary endpoint was percentage of patients with a rescue-free bowel movement (RFBM) within four hours after ≥2 of the first 4 doses in the first week.Results: In the RCT, 116 and 114 patients received MNTX and placebo, respectively, and 149 patients continued to the OLE study. The percentage of patients achieving primary endpoint was 62.9% and 9.6% for MNTX and placebo groups, respectively (p<0.0001). Median time to RFBM after the first dose was 0.8 hour and 23.6 hours in MNTX and placebo groups, respectively (p<0.0001). Efficacy results during the OLE study were consistent with the RCT. MNTX demonstrated a favorable safety profile in the RCT and OLE study.Conclusion: Fixed-dose MNTX administered QOD in the RCT and PRN in the OLE study demonstrated robust efficacy and was well tolerated in treating OIC in patients with advanced illness.

Budesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. ClinicalTrials.gov ID: NCT01008410 and NCT01008423.

With functional evidence emerging that interstitial cells of Cajal (ICC) play a role in smooth muscle innervation, detailed knowledge is needed about the structural aspects of enteric innervation of the human gut. Conventional electronmicroscopy (EM), immunohistochemistry and immuno-EM were performed on the musculature of the distal human ileum focusing on ICC associated with the deep muscular plexus (ICC-DMP) and intramuscular ICC (ICC-IM). ICC-DMP could be identified by EM but not by c-Kit immunohistochemistry. Immuno-EM revealed that ICC-DMP were innervated by both cholinergic and nitrergic nerves, and were the only cells to possess specialized synapse-like junctions with nerve varicosities and gap junction contacts with smooth muscle cells. c-Kit positive ICC near the deep muscular plexus were not ICC-DMP, but ICC-IM located in septa. ICC-IM were innervated by both cholinergic and nitrergic nerves but without specialized contacts. Varicosities of both nerve types were also found scattered throughout the musculature without specialized contact with any ICC. No ICC showed immunoreactivity for neuronal nitric oxide synthase. As ICC-DMP form synapse-like junctions with cholinergic and nitrergic nerves and gap junction contacts with muscle cells, it is hypothesized that ICC-DMP hold a specialized function related to innervation of smooth muscle of the human intestine.

We conclude that the diagnosis and presentation of atypical smoldering diverticular disease is an uncommon and poorly defined entity. However, sigmoid resection in this subgroup of patients is safe and is associated with resolution of symptoms in the majority of cases.

SummaryBackgroundThe efficacy of rifaximin, a nonsystemic, gut‐targeted antibiotic for reducing non–constipation‐predominant irritable bowel syndrome (non‐C IBS) symptoms, has been demonstrated in one phase 2b and two phase 3 randomised, double‐blind, placebo‐controlled trials, but detailed data about rifaximin safety and tolerability during treatment and subsequent follow‐up periods are lacking.AimTo assess and determine the frequency of rifaximin and placebo adverse events (AEs) in phase 2b and phase 3 non‐C IBS trials.MethodsA post hoc pooled safety analysis of the phase 2b (rifaximin 275, 550, and 1100 mg twice daily for 2 weeks; 550 mg twice daily for 4 weeks) and phase 3 (rifaximin 550 mg three times daily for 2 weeks) studies was performed. Data on treatment and post‐treatment AEs were collected. Patients were followed up for 12 weeks and 10 weeks post‐treatment in the phase 2b and phase 3 trials, respectively.ResultsPatients receiving rifaximin (n = 1103) and placebo (n = 829) had a similar incidence of drug‐related AEs (12.1% vs. 10.7%), serious AEs (1.5% vs. 2.2%), drug‐related AEs resulting in study discontinuation (0.8% vs. 0.8%), gastrointestinal‐associated AEs (12.2% vs. 12.2%) and infection‐associated AEs (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis or deaths.ConclusionsThe safety and tolerability profile of rifaximin during treatment and post‐treatment was comparable to placebo. Future research should define the safety and tolerability profile, including risk of C. difficile colitis and microbial antibiotic resistance, with repeated courses of rifaximin in patients with non—constipation‐predominant irritable bowel syndrome (ClinicalTrials.gov: NCT00269412, NCT00731679, and NCT00724126).

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