Rifaximin Improves Cognitive Functions and Health-Related Quality of Life in Patients With Minimal Hepatic Encephalopathy: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial (The RIME Trial)

e18

AGA

rectal bleeding subscore ⱖ1 point or absolute rectal bleeding subscore ⱕ1 point. Clinical remission was defined as Mayo score ⱕ2 points and no individual subscore ⬎1 point. The prespecified statistical analyses (SAP) defined patients as nonresponders if ⬍3 diary entries were present during the 7 days before assessment. More conventional analyses where any diary entry within a 3-day window before assessment contributed to the Mayo score were performed post hoc. RESULTS: In the SAP analyses at day 57, clinical response rates were 53% vs 35% in MDX vs placebo (Fisher exact P ⫽ .083). Clinical remission and mucosal healing rates were 18% vs 17% and 42% vs 35%, in MDX vs placebo. In the post hoc conventional Mayo score analyses, clinical response, remission, and mucosal healing rates were 60% vs 37% (P ⫽ .02), 24% vs 19%, and 42% vs 35%, in MDX vs placebo. When the response results were stratified according to MDX trough serum concentrations (SSCmin), there were increasing rates of response (53%, 63%, and 88%), remission (12%, 25%, and 44%), and mucosal healing (29%, 44%, and 69%) in the low, mid, and high tertile, of SSCmin. Logistic regression showed that increase in SSCmin led to increase in clinical response, remission, and mucosal healing with odds ratios of 3.77 (P ⫽ .017), 2.85 (P ⫽ .071), and 3.08 (P ⫽ .03), respectively. The proportions of patients with adverse events were low and comparable between the 2 groups. A greater proportion of patients had infection (12.7% vs 5.8%) and serious infection (5.5% vs 1.9%) in the MDX vs placebo. CONCLUSION: MDX-1100 was effective in inducing response with modest efficacy in patients with moderate to severe UC at the test dose of 10 mg/kg. Patients with higher MDX plasma levels had greater clinical benefits. There was a slightly higher rate of infections in the MDX group compared with placebo. MDX-1100 is a novel biologic agent focused on a new target in mucosal inflammation with evidence of clinical efficacy in UC.

Multimodality Endoscopic Therapy for Complete Eradication of Barrett’s Esophagus Neil Gupta, Julian A. Abrams, Dayna S. Early, Sachin B. Wani, Christine E. Hovis, Benjamin J. Vaccaro, Srinivas Gaddam, Ajay Bansal, Amit Rastogi, Steven A. Edmundowicz, Charles J. Lightdale, Prateek Sharma BACKGROUND & AIMS: Although the efficacy and safety of multimodality therapy (endoscopic mucosal resection [EMR] followed by mucosal ablation) for Barrett’s esophagus (BE) has been evaluated in European clinical trials, effectiveness data, especially from the United States, are lacking. In a multicenter cohort of BE patients receiving multimodality therapy, time to achieve complete eradication of intestinal metaplasia (CE-IM), number of endoscopic sessions needed, and overall complication rates were determined. METHODS: This is a multicenter outcomes project of a large cohort of BE patients being treated with endoscopic eradication therapy (EET). Patients who underwent EMR followed by endoscopic ablation with either radiofrequency ablation (RFA), argon plasma coagulation (APC), or both and achieved CE-IM were included in this analysis. Patients receiving any other EET before EMR and those who stopped EET and started surveillance before CE-IM were excluded. A stepwise, multivariate linear regression model was used to examine predictors for time needed to achieve CE-IM. RESULTS: Fifty-one BE patients (mean age, 64.8 [SD 10.9]; 88% male, 94% Caucasian, 92% hiatal hernia [mean length, 3.1 cm], mean BE length, 4.1 cm (SD 2.9; range, 1–13)] from 3 centers were included. Baseline histology was low-grade dysplasia (n ⫽ 1), high-grade dysplasia (HGD; n ⫽ 34), intramucosal cancer (n ⫽ 14), and submucosal cancer (n ⫽ 2). In addition to EMR, 23 were treated with RFA, 13 with APC, and 15 received both RFA and APC. The overall average number of endoscopic therapy sessions required to achieve CE-IM was 4.9 (range, 2–11). The average number of EMR, RFA, and APC sessions was 2.2, 1.9, and 1.1, respectively. The mean time to achieve CE-IM was 17.4 months (range, 2.6 – 48.1) with BE length as the only significant predictor (␤ coefficient 31.8; P ⫽ .025). All complications were successfully managed endoscopically: 6 (11.8%) bleeding, 3 (6%) symptomatic strictures, and 1 perforation. During a mean follow-up of 11.5 months (range, 0 – 66.1), 1 patient progressed to cancer, 2 had recurrent HGD, and 1 had recurrent IM. CONCLUSION: Results of this multicenter effectiveness trial show that multimodality therapy with EMR followed by RFA and/or APC can achieve complete eradication of BE; however, several sessions are required. For every 1 cm increase in BE length, there is an approximately 1-month increase in time needed to achieve CE-IM. Recurrence of or progression to dysplasia/cancer occurs in 6% of treated patients. Before initiating EET, patients should be counseled regarding the number of sessions, time needed to achieve CE-IM, and complications rates.

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Nitazoxanide Plus Peginterferon and Ribavirin in Naïve Patients With Chronic Hepatitis C Genotype 1 Infection: Final Report Bruce R. Bacon, Mitchell L. Shiffman, Joseph K. Lim, Arthur Berman, Vinod K. Rustgi, Emmet B. Keeffe BACKGROUND & AIMS: Treatment of chronic hepatitis C (CHC) with nitazoxanide (NTZ) and peginterferon (PegIFN) with or without ribavirin (RBV) improves sustained virologic response (SVR) rates in naïve genotype 4 patients (Gastroenterology 2009;136:856). The aim of this study was to determine the efficacy of NTZ plus PegIFN and RBV in naïve patients with CHC genotype 1 infection; the final sustained viral response (SVR) rates are reported. METHODS: One hundred twelve treatment-naïve patients with CHC genotype 1 underwent 2:1 randomization in 13 US centers in this double-blind, placebo-controlled study of

GASTROENTEROLOGY Vol. 139, No. 1

Table 1. Results Treatment group

RVR

cEVR

ETR

SVR

NTZ ⫹ PegIFN ⫹ RBV 9 (12%) 45 (62%) 46 (63%) 32 (44%) (n ⫽ 73) Placebo ⫹ PegIFN ⫹ RBV 7 (19%) 18 (49%) 17 (46%) 12 (32%) (n ⫽ 37)

NTZ (n ⫽ 75) vs placebo (n ⫽ 37) twice daily over a 4-week lead-in followed by continued NTZ or placebo plus PegIFN alfa-2a 180 ␮g weekly and weight-based RBV (1000 –1200 mg/d) for 48 weeks. Serum HCV RNA was measured using the Roche Cobas Taqman assay (LOQ ⫽ 50 IU/mL). RESULTS: Mean ages (⫾ SD) in the NTZ and placebo groups were 50 ⫾ 7 and 51 ⫾ 8 years, respectively, and 65% of patients were men in both groups. Mean baseline HCV RNA was 6.3 ⫾ 0.7 log10 IU/mL in the NTZ group and 6.4 ⫾ 0.7 log10 IU/mL in the placebo group. Analysis was by intention-to-treat for patients who received any dose of PegIFN. Results are shown in Table 1. In patients with HCV RNA levels ⬎800,000 IU/mL, SVR rates were also higher in the NTZ (n ⫽ 62) vs placebo (n ⫽ 31) group (42% vs 29%). In sites with customary standard of care response rates, SVR rates were higher in the NTZ group: 57% (n ⫽ 49) vs 42% (n ⫽ 24), and 55% vs 35% in patients with high viral load. There were no significant differences in adverse events, except for mild intermittent diarrhea in patients receiving NTZ; there were no significant differences in serious adverse events between the 2 treatment groups. CONCLUSION: Consistent with previously reported results in naïve genotype 4 patients, the addition of NTZ increased the SVR rate in genotype 1 naïve patients by more than one third. NTZ 675 mg tablets will be used in phase III studies with the goal of further improving SVR rates.

Prospective Clinical Validation of an Assay for Methylated SEPT9 DNA in Human Plasma as a Colorectal Cancer Screening Tool in Average Risk Men and Women >50 Years Timothy R. Church, Michael Wandell, Catherine Lofton–Day, Steve Mongin, Brent A. Blumenstein, John I. Allen, Thomas Roesch, Dale Snover, Robert Day, David F. Ransohoff BACKGROUND & AIMS: In screening for colorectal cancer (CRC), a blood-based screening test with appropriate sensitivity and specificity could provide increased convenience and safety compared with other screening modalities. Two previous case-control studies of clinically confirmed CRC suggested that detection of methylated SEPT9 DNA (mSEPT9) in human plasma can indicate the presence of CRC. The purpose of this study was to prospectively validate sensitivity and specificity of mSEPT9 in a screening setting. METHODS: With ethics board approvals, we recruited and consented subjects ⱖ50 years who were scheduled for screening colonoscopy in gastroenterology practices in the United States and Germany. Subjects provided blood samples before preparation for endoscopy. Results of endoscopy were obtained, including histopathology and postoperative reports for persons with polyps and CRC. A real-time polymerase chain reaction assay was used to detect the presence of mSEPT9 in 2 separate aliquots (“wells”) of plasma. Three independent laboratories blinded to clinical data performed the analysis for all cases of cancer and adenomas with high-grade dysplasia, and a stratified sample of other subjects. Test parameter estimates were adjusted to the US and German populations by age and gender, and nonparametric bootstrap confidence intervals were calculated. RESULTS: A total of 7938 men (45%) and women (55%) with an average age of 60 years (inter quartile range, 54 – 66) were recruited from 32 practices. Laboratory results for 53 cancers and for 1454 subjects with either advanced adenomas (313), nonadvanced adenomas (211), or no pathology (930) yielded a sensitivity for cancer of 50% (95% confidence interval [CI], 34%– 65%) and a specificity of 91% (95% CI, 90%–93%). Crude sensitivity ratios by stage were: I, 8/22; II, 8/14; III, 7/12; and IV, 4/5. CONCLUSION: These results demonstrate that CRC can be detected, in a screening setting, among persons of >50 years old by examination of serum for mSEPT9. Pending possible further improvement of test characteristics, the current test might be used to screen individuals unwilling or unable to undergo other screening examinations.

Rifaximin Improves Cognitive Functions and Health-Related Quality of Life in Patients With Minimal Hepatic Encephalopathy: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial (The RIME Trial) Sandeep Sidhu, Omesh Goyal, Bholeshwar P. Mishra, Ajit Sood, Rajoo S. Chhina, Ravinder K. Soni BACKGROUND & AIMS: Minimal hepatic encephalopathy (MHE) has a prevalence of 22%– 84% in cirrhotics. Patients with MHE have poor health-related quality of life (HRQOL). Treatment of MHE is under evolution. The aim of this pilot study was to assess the efficacy of rifaximin in improving neuropsychometric (NP) test performance and HRQOL in patients with MHE. METHODS: Patients with cirrhosis without prior history of encephalopathy were screened for

July 2010

AGA

e19

Table 1. Mean Change From Baseline to Week 12 in ITT Population Trial 01 (n ⫽ 630) Placebo Baselinea (n ⫽ 215) Overall (P value) Physical discomfort Psychosocial discomfort Worries/concerns Satisfaction aBaseline

Trial 303 (n ⫽ 642)

133 ␮g (n ⫽ 213)

266 ␮g (n ⫽ 202)

Placebo Baselinea (n ⫽ 209)

133 ␮g (n ⫽ 217)

266 ␮g (n ⫽ 216)

2.13 2.28

⫺0.6 ⫺0.63

⫺0.89 (⬍.0001) ⫺0.98 (⬍.0001) ⫺0.99 (⬍.0001) ⫺1.06 (⬍.0001)

2.04 2.28

⫺0.46 ⫺0.47

⫺0.94 (⬍.0001) ⫺0.87 (⬍.0001) ⫺1.07 (⬍.0001) ⫺.92 (⬍.0001)

1.25

⫺0.49

⫺0.52 (.0185)

1.10

⫺0.44

⫺0.53 (.0497)

2.1 3.47

⫺0.62 ⫺0.71

⫺0.94 (⬍.0001) ⫺1.02 (⬍.0001) ⫺1.26 (⬍.0001) ⫺1.36 (⬍.0001)

2.02 3.41

⫺0.51 ⫺0.36

⫺0.64 (.0010)

⫺0.55 (.1472)

0.51–1.01 (⬍.0001) ⫺0.96 (⬍.0001) ⫺1.34 (⬍.0001) ⫺1.13 (⬍.0001)

mean for all patients; range ⫽ 0 (best) to 4 (worse).

presence of MHE by 5 NP tests (number and figure connection, picture completion, digit symbol, and block design tests). MHE was diagnosed if any 2 NP tests were deranged beyond 2 standard deviations (SD) of normal. The NP test results were expressed as Z-scores, indicating the differences (in SD) between observed and expected scores. HRQOL was assessed by the Sickness Impact Profile. Informed consent was taken and it conformed to the principles of the Declaration of Helsinki. RESULTS: A total of 486 patients with cirrhosis were screened; 284 were eligible. Of these, 115 (40.9%) patients were diagnosed with MHE. Twenty-one patients refused consent. Thus, 94 patients were randomized to receive placebo (n ⫽ 45) and rifaximin (n ⫽ 49; 1200 mg/d) for 8 weeks. Fourteen percent of the patients were lost to follow-up. Intention-to-treat analysis showed that rifaximin group had significant improvement both at 2 weeks (57.1% [28/49] vs 17.8% [8/45] in the placebo group; P ⬍ .0001) and 8 weeks (75.5% [37/49]) vs 20% [9/45] in the placebo group; P ⬍ .0001). The rifaximin group showed significant reduction in mean number of abnormal NP tests (baseline, 2.35 [95% CI, 2.17–2.53]; 2 weeks, 1.29 [95% CI, 1.02–1.56; P ⫽ .002]; 8 weeks, 0.81 [95% CI, 0.61–1.02; P ⫽ .000]), compared with the placebo group (baseline, 2.31 [95% CI, 2.03–2.59]; 2 weeks, 2.03 [95% CI, 1.74 –2.31]; 8 weeks, 1.97 [95% CI, 1.69 –2.25; P ⬎ .05]). The rifaximin group also showed a significant reduction in mean Z-score (baseline, ⫺2.54 [95% CI, ⫺2.81 to ⫺2.27]; 8 weeks, ⫺1.44 [95% CI, ⫺1.84 to ⫺1.03; P ⫽ .000]), compared with the placebo group (baseline, ⫺2.61 [95% CI, ⫺2.89 to ⫺2.33]; 8 weeks, ⫺2.26 [95% CI, ⫺2.55 to ⫺1.98; P ⬎.05]). The mean total Sickness Impact Profile score also improved significantly in rifaximin group (baseline, 11.67 [95% CI, 10.31–13.03]; 8 weeks, 6.45 [95% CI, 5.59 –7.30; P ⫽ .000]) compared with the placebo group (baseline, 9.86 [95% CI, 8.66 –11.06]; 8 weeks, 8.51 [95% CI, 7.35–9.67; P ⫽ .82]). Improvements in HRQOL correlated with improvement in NP tests (r ⫽ 0.376; P ⫽ .002). Two patients in the rifaximin group had minor GI symptoms. CONCLUSION: Rifaximin at a dose of 1200 mg/d significantly improves both cognitive functions and HRQOL in patients with MHE. It is safe and well tolerated.

Effect of Linaclotide on Quality of Life in Adults With Chronic Constipation: Results From 2 Randomized, Double-Blind, Placebo-Controlled Phase III Trials Robyn T. Carson, Stavros Tourkodimitris, James E. MacDougall, Barbara E. Lewis, Steven J. Shiff, Bernard J. Lavins, Caroline B. Kurtz, Anthony Lembo, Jeffrey M. Johnston BACKGROUND & AIMS: Linaclotide is a first-in-class, minimally absorbed guanylate cyclase type C receptor agonist that significantly improved bowel and abdominal symptoms and constipation severity in 2 phase III chronic constipation (CC) trials. CC is a common functional GI disorder that significantly affects patients’ quality of life. METHODS: Patients meeting modified Rome II criteria for CC were randomized to oral once-daily 133 ␮g or 266 ␮g linaclotide or placebo for 12 weeks in 2 phase III trials (trials 01 and 303). The Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire, consisting of 28 items, was completed at baseline and end of treatment. The PAC-QOL consists of an overall and 4 subscale scores (physical discomfort, satisfaction, worries/concern, and psychosocial discomfort). The change from baseline to week 12 was analyzed using an analysis of covariance model with fixed effect terms for treatment group and geographical region and the corresponding baseline PAC-QOL score as a covariate. The percentage of responders (ie,

patients with ⱖ1 point decrease) was calculated by treatment group. RESULTS: In both trials, the change from baseline in the PAC-QOL overall and physical discomfort, worries/concern, and satisfaction subscale scores was significant for both linaclotide dosage groups vs placebo. The psychosocial discomfort score was significant for both linaclotide dosage groups vs placebo in trial 01. A greater percentage of patients treated with linaclotide were responders at week 12 for the PAC-QOL overall score (42.2% and 44.9% at 133 ␮g; 46.8% and 35.5% at 266 ␮g; 27.8% and 18.7% with placebo in trials 01 and 303, respectively). CONCLUSION: Compared with placebo, once-daily linaclotide treatment significantly improved overall QOL and important QOL domains of physical discomfort, worries/concern, and satisfaction, as measured by the PAC-QOL, in adults with CC in 2 phase III trials. Table 1.

International Inflammatory Bowel Disease Genetics Consortium Identifies >50 Genetic Risk Factors for Ulcerative Colitis John D. Rioux, the International IBD Genetics Consortium Genome-wide association studies (GWAS) have proven to be very powerful at identifying genetic risk factors for common diseases. This has been especially true for Crohn’s disease (CD) where early GWAS implicated the involvement of TNFRSF15, IL23R, PTGER4, ATG16L1, IRGM, and NKX2-3 in disease pathogenesis. Although such individual studies have been very successful, the statistical power for gene discovery is limited by sample size. The International IBD Genetics Consortium thus performed 1 of the first studies to combine GWAS results and identified ⬎30 genetic risk factors for CD (Nat Genet 40:955–962). At that time, much less was known about the genetics of ulcerative colitis (UC), with only the MHC and the IL23R genes having confirmed associations. In the last year, multiple GWAS of UC have been performed and have produced 18 independent new associations. The regions identified include loci encoding IFNg/IL26, IL10, and HNF4␣, among others. These studies have thus provided a unique opportunity to identify a much more complete catalogue of genetic risk factors for UC. In the current study, results from 6 GWA studies of UC were combined using a meta-analysis approach. Specifically, the data from 6433 patients with UC and 20,099 population controls, collected from across North America and Europe, were combined; all samples having been directly genotyped at a minimum of 300,000 single nucleotide polymorphisms genome-wide (and ⬎1.2 million with genotype imputation). This combined dataset identified 75 independent genomic regions with association P values ⬍5⫺05. These 75 loci include all of the previously confirmed UC associations. Interestingly, ⬃50% of the 75 loci have previously been associated with CD, and of the ⬃45 putative novel loci, 25 have previously been associated with other chronic inflammatory diseases such as CD, psoriasis, celiac disease, multiple sclerosis, systemic lupus erythematosus, and type 1 diabetes. Therefore, these results strongly support the hypothesis that certain biological pathways are shared between inflammatory diseases. The other 20 novel loci seem to be UC specific. We are currently testing all novel loci in an independent set of ⬃10,000 UC patients and a similar number of population controls to confirm these findings, but even the preliminary results provide convincing evidence of association to genes of biological significance to disease pathogenesis (eg, TNFRSF14, JAK2, CARD9). CONCLUSION: This work has dramatically increased the number of known UC loci and is expected to significantly increase our understanding of disease pathogenesis relating to both shared and UC-specific inflammatory pathways.