Proceedings of the Tenth Annual Beef Cattle Short Course.

91 p

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING Intercept Pharmaceuticals

Predicting ADR from PDR and individual adenoma-to-polyp-detection-rate ratio for screening and surveillance colonoscopies: A new approach to quality assessment

Background and aims: Adenoma detection rate (ADR) has been established as a quality indicator for screening colonoscopy. Because ADR is cumbersome to obtain in routine practice, polyp detection rate (PDR), polypectomy rate (PR) and adenoma-to-polyp-detection-rate-ratio (APDRR) have been proposed to estimate ADR. This study aimed to evaluate APDRR in order to estimate ADR (ADR(est)) in different settings. Methods: Average risk screening and surveillance colonoscopies from a community-based private practice and a tertiary academic hospital setting were retrospectively evaluated. APDRR was calculated as averaged group APDRR for all study procedures (APDRR) and for the first half of study procedures of each gastroenterologist (APDRR(ag)) or individually for each gastroenterologist on the basis of his or her first 25, 50 and 100 colonoscopies (APDRR(ind)). ADR(est) was determined from PDR by using APDRR, APDRR(ag), and APDRR(ind), respectively. Results: A total of 2717 individuals were analyzed. Using APDRR, significant correlations between ADR and ADR(est) were observed for the entire (0.944, p<0.001), proximal (0.854, p<0.001), and distal (0.977, p<0.001) colon. These correlations were lost when APDRR(ag) was used to estimate each gastroenterologist's ADR for the second half of his or her included colonoscopies. However, ADR and ADR(est) correlated significantly with a root-mean-square-error of 6.8% and 5.8% when APDRR(ind) on the basis of each gastroenterologist's first 50 and 100 colonoscopies was used for subsequent colonoscopies. Conclusions: ADR for subsequent colonoscopies of an individual endoscopist can be reliably estimated from PDR by using an individually calculated APDRR. Prospective studies are needed to verify this promising approach in different practice settings

Clinical management of chronic hepatitis B infection: results from a registry at a German tertiary referral center

We studied a cohort of adult patients with chronic hepatitis B (CHB) infection, followed at a tertiary referral liver center in Germany over 12.5 years to analyze the clinical features and impact of management on disease progression and survival of CHB patients in general and of those with CHB and HCC in particular. We retrospectively evaluated the medical records of 242 adult (age a parts per thousand yen 18 years) patients. CHB was defined as positive hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels > 10 IU/mL for at least 6 months. Patient demographics, HBV markers, antiviral treatment, laboratory parameters, liver imaging and histology were recorded for each visit. HCC patients were divided into two groups and separately analyzed (group 1: n = 24, HCC at first visit and group 2: n = 11, HCC during surveillance). The mean age was 44 years in CHB patients without HCC (63 % male) and about 59 years in patients with HCC (77 % male). Antiviral therapy was given to 59 % of patients without HCC compared to only 25 % in group 1 and 18 % in group 2 with comparable median HBV DNA levels of approximately 36,000 IU/mL. There was no statistically significant difference concerning the HCC stages (Milan, UCSF, BCLC) at first diagnosis. Five-year survival was 19 % in group 1 vs. 64 % in group 2 (p = 0.019), with LTx performed in 12 vs. 45 %, respectively. Surveillance of CHB patients did not result in early stage detection of HCC but in a higher likelihood to receive potentially curative treatments

Economic burden of Clostridium difficile associated diarrhoea: a cost-of-illness study from a German tertiary care hospital

Clostridium difficile associated diarrhoea (CDAD) is the most common cause of health-care-associated infectious diarrhoea. In the context of the German health-care system, direct and indirect costs of an initial episode of CDAD and of CDAD recurrence are currently unknown. We defined CDAD as presence of diarrhoea (a parts per thousand yen3 unformed stools/day) in association with detection of Clostridium difficile toxin in an unformed faecal sample. Patients treated with metronidazole (PO or IV) and/or vancomycin (PO) were included. Comprehensive data of patients were retrospectively documented into a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). Patients with CDAD were matched to control patients in a 1:1 ratio. Analysis was split in three groups: incidence group (CDAD patients without recurrence), recurrence group (CDAD patients with a parts per thousand yen1 recurrence) and control group (matched non-CDAD patients). Between 02/2010 and 12/2011, 150 patients with CDAD (114 patients in the incidence and 36 (24 %) in the recurrence group) and 150 controls were analysed. Mean length of stay was: 32 (95 %CI: 30-37), 94 (95 %CI: 76-112) and 24 days (95 %CI: 22-27; P = < 0.001), resulting in mean overall direct treatment costs per patient of a,not sign18,460 (95 %CI: a,not sign14,660-a,not sign22,270), a,not sign73,900 (95 %CI: a,not sign50,340-a,not sign97,460) and a,not sign14,530 (95 %CI: a,not sign11,730-a,not sign17,330; P = < 0.001). In the incidence and recurrence group, the mean cumulative number of antibiotic CDAD treatment days was 11 (95 %CI: 10-12) and 36 (95 %CI: 27-45; P = < 0.001). Especially CDAD recurrence was associated with excessive costs, which were mostly attributable to a significantly longer overall length of stay. Innovative treatment strategies are warranted to reduce treatment costs and prevent recurrence of CDAD

Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial

Alisporivir (ALV) is an oral, investigational host-targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double-blind, placebo-controlled, Phase II study explored the efficacy and safety of ALV with peginterferon-2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four-hundred-and-fifty-nine patients were randomized (1:1:1:1) to ALV 600mg once daily (QD), ALV 800mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received 31weeks of randomized treatment; patients completed 48weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P0.0131), with highest cEVR rate seen with ALV 400mg BID (74% vs 36% with PR alone; P40weeks of randomized treatment, the SVR12 rate was 89% for ALV 400mg BID vs 30% for PR alone (P=0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents