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The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

ABSTRACT: Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups.These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2017).

SUBMITTER: Loomba R

PROVIDER: S-EPMC5814892 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

Loomba Rohit R Lawitz Eric E Mantry Parvez S PS Jayakumar Saumya S Caldwell Stephen H SH Arnold Hays H Diehl Anna Mae AM Djedjos C Stephen CS Han Ling L Myers Robert P RP Subramanian G Mani GM McHutchison John G JG Goodman Zachary D ZD Afdhal Nezam H NH Charlton Michael R MR

Hepatology (Baltimore, Md.) 20171226 2

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of ...[more]

PMID: 28892558

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Project description:BackgroundRecently factors in the relationship between gut microbiota, obesity, diabetes and the metabolic syndrome have been suggested in the development and progression of nonalcoholic steatohepatitis (NASH). In this sense, this work aims to evaluate the effects of probiotic supplementation on intestinal microbiota modulation, degree of hepatic steatosis and fibrosis, inflammation, gut permeability, and body composition.MethodsThis double-blind, randomized clinical trial will include adult outpatients with a diagnosis of NASH confirmed by biopsy with or without transient elastography. All patients will undergo a complete anamnesis to investigate their alcohol consumption, previous history, medications, nutritional assessment (dietary intake and body composition), sarcopenia, physical activity level and physical and functional capacity, cardiovascular risk, biochemical parameters for assessment of inflammatory status, lipid profile, hepatic function, gut permeability, and assessment of microbiota. These procedures will be performed at baseline and repeated after 24 weeks (at the end of the study). Through the process of randomization, patients will be allocated to receive treatment A or treatment B. Both patients and researchers involved will be blinded (double-blind study). The intervention consists of treatment with a probiotic mix (Lactobacillus acidophillus + Bifidobacterium lactis + Lactobacillus rhamnosus + Lactobacillus paracasei, 1 x 109 CFU for each) and the placebo which is identical in all its characteristics and packaging. Patients will be instructed to consume two sachets/day during 24 weeks and to report any symptoms or side effects related to the use of the sachets. Adherence control will be carried out through the patient's notes on a form provided, and also by checking the number of sachets used.DiscussionThe final results of study will be analyzed and disseminated in 2020.Trial registrationClinicalTrials.gov, ID: NCT03467282 . Registered on 15 March 2018.

Project description:High-Intensity Interval Training (HIIT) involves bursts of high-intensity exercise interspersed with lower-intensity exercise recovery. HIIT may benefit cardiometabolic health in people with nonalcoholic steatohepatitis (NASH). We aimed to examine the safety, feasibility, and efficacy of 12-weeks of supervised HIIT compared with a sham-exercise control (CON) for improving aerobic fitness and peripheral insulin sensitivity in biopsy-proven NASH. Participants based in the community [(n = 14, 56 ± 10 years, BMI 39.2 ± 6.7 kg/m2, 64% male), NAFLD Activity Score 5 (range 3-7)] were randomized to 12-weeks of supervised HIIT (n = 8, 4 × 4 min at 85-95% maximal heart rate, interspersed with 3 min active recovery; 3 days/week) or CON (n = 6, stretching; 3 days/week). Safety (adverse events) and feasibility determined as ≥ 70% program completion and ≥ 70% global adherence (including session attendance, interval intensity adherence, and duration adherence) were assessed. Changes in cardiorespiratory fitness (V̇O2peak), exercise capacity (time-on-test) and peripheral insulin sensitivity (euglycemic hyperinsulinemic clamp) were assessed. Data were analysed using ANCOVA with baseline value as the covariate. There were no HIIT-related adverse events and HIIT was globally feasible [program completion 75%, global adherence 100% (including adherence to session 95.4 ± 7.3%, interval intensity 95.3 ± 6.0% and duration 96.8 ± 2.4%)]. A large between-group effect was observed for exercise capacity [mean difference 134.2 s (95% CI 19.8, 248.6 s), ƞ2 0.44, p = 0.03], improving in HIIT (106.2 ± 97.5 s) but not CON (- 33.4 ± 43.3 s), and for peripheral insulin sensitivity [mean difference 3.4 mg/KgLegFFM/min (95% CI 0.9,6.8 mg/KgLegFFM/min), ƞ2 0.32, p = 0.046], improving in HIIT (1.0 ± 0.8 mg/KgLegFFM/min) but not CON (- 3.1 ± 1.2 mg/KgLegFFM/min). HIIT is safe, feasible and efficacious for improving exercise capacity and peripheral insulin sensitivity in people with NASH. Australian New Zealand Clinical Trial Registry (anzctr.org.au) identifier ACTRN12616000305426 (09/03/2016).

Dataset Information

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

Publications

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

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