Kunal Merchant

Rifaximin Treatment in Hepatic Encephalopathy

BACKGROUND Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy – a double-blind placebo-controlled study

Aliment Pharmacol Ther 2011; 34: 853–861

Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial.

Aliment Pharmacol Ther 2010; 32: 990–999

Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials

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.

Parents of children with periodic limb movement disorder versus sleep-disordered breathing report greater daytime mood and behavior difficulties in their child: the importance of using ICSD-2nd Edition criteria to define a PLMD study group.

Data from 249 children referred to a pediatric sleep clinic were analyzed. The first question of interest examined whether an International Classification of Sleep Disorders–Second Edition (ICSD–2)-based diagnosis of periodic limb movement disorder (PLMD) or sleep-disordered breathing (SDB) would more strongly associate with parental perceptions of daytime attention and behavior problems in their child. The second question was whether the outcome would differ based on PLMD diagnostic criteria—that is, previously used criteria to define PLMD (Periodic Limb Movement Index [PLMI] < 5 per hour vs. PLMI ≥ 5 per hour only) versus the ICSD–2 criteria. Parents of children with ICSD–2-defined PLMD perceived more problems with daytime behavior and attention, more symptoms of internalizing and externalizing, longer sleep latency, and more difficulty falling back to sleep than did parents of children with SDB. Most effects were lost when groups were defined by PLMI alone. The PLMI had acceptable sensitivity but low specificity in diagnosing PLMD.

T1202 Once-Daily Mesalamine Granules Effectively Maintain Remission from Ulcerative Colitis: Data from 2 Phase 3 Trials

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.

1041 Efficacy of Rifaximin for IBS Without Constipation in Men and Women

Background: Radiation proctitis (RAP) is defined as damage to the rectal mucosa resulting from radiotherapy to adjacent pelvic organs. More than 50 % of patients undergoing radiotherapy for prostate cancer (PC) will encounter symptoms such as diarrhea, blood and mucus in stool and tenesms that might alter qualitiy of life and might be dose limiting. The symptoms of radiation proctitis can be quantified by the acute EORTC/RTOG lower GI toxicity or the RAP score . Material and Methods: Patients undergoing radiotherapy (XRT) for PC were randomised to rectal budesonide (BUD) or placebo (PLB) treatment over 8 weeks. EORTC/RTOG lower GI toxicity score, RAP score and quality of life scores were taken at baseline and after 2, 4, 8 and 14 weeks as well as after 1 year. Flexible rectoscopy and assessment of the Vienna rectoscopy score (VRS) was done at baseline, after 8 weeks, 14 weeks and 1 year. 17 patients were included (n=8 budesonide, n=9 placebo) into the study. Results: 6/8 BUD patients and 6/9 PLB patients developed clinical signs of acute radiation proctitis, i.e. acute EORT/RTOG lower GI toxicity ≥ 1 for at least 2 consecutive days, during 8 weeks of treatment (p=0.8167). However, BUD ameliorated the severity of RAP by significantly reducing stool frequency at week 14 and after 1 year and numerically the number of tenesms at week 8. The endoscopic score for late radiation proctitis was diminished in the budesonide group compared to placebo. Conclusions: Rectal treatment with budesonide did not significantly prevent acute radiation proctitis in this pilot study. However, clinical symptoms of proctitis could be significantly reduced and the appearance of late radiation proctitis was diminished. Therefore BUD deserves further evaluation in the context of high dose XRT with curative intent to prevent or to ameliorate side effects that might be dose limiting.

Tu1406 Impact of Concurrent use of PPIs or Anti-Depressants on Efficacy of Rifaximin for IBS Without Constipation

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.

T1200 Long-Term Safety of Once-Daily 1.5-G Mesalamine Granules in Patients in Remission from Ulcerative Colitis

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.

T1204 Efficacy of Mesalamine Granules for Maintenance of Remission in Patients Recently Treated with Corticosteroids

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.