NAFLD and liver transplantation: current burden and expected challenges, Liver transplantation and nonalcoholic fatty liver disease, Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children, Pathogenesis of nonalcoholic steatohepatitis: interactions between liver parenchymal and nonparenchymal cells. Data were acquired using BD FACSDIVA software (BD Biosciences). Prolonged CVC therapy (14 weeks) yielded no significant differences in the total intrahepatic macrophage populations among treatment groups but increased the frequency of intrahepatic antiinflammatory macrophages in the highdose CVC group. In patients with fibrosis responses, we observed consistent reductions in levels of N-terminal type 3 collagen propeptide and enhanced liver fibrosis scores, while increases in aspartate aminotransferase-to-platelet ratio index and Fibrosis-4 scores were consistently observed in nonresponders. Fig.22A). The ePub format uses eBook readers, which have several "ease of reading" features Almeida Pereira T, Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Over 2 years, a similar proportion on CVC or placebo achieved 1-stage fibrosis improvement and no worsening of NASH (15% arm A versus 17% arm C). The trial is evaluating obeticholic acid, or Ocaliva, in non-cirrhotic NASH patients with advanced liver fibrosis. Dai K, Mrs. MelchorKhan is employed by Allergan. A randomized, placebocontrolled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis, GUID:D645020E-20DC-4042-979A-C74BCFD2E7B3. CVC was well tolerated, and year 2 data corroborate antifibrotic findings from year 1. Data represent four independent experiments in human pHSCs and six independent experiments in mouse pHSCs. Baseline Demographics and Disease Characteristics of Randomized Subjects per Treatment Group. Gassler N, et al. The CENTAUR study was sponsored by Tobira Therapeutics, a subsidiary of Allergan plc. Cryopreserved NPCs were rapidly thawed, washed with fluorescenceactivated cell sorting buffer (FACS) (phosphatebuffered saline with 2% heatinactivated FBS), and quantified with viability staining using Moxicyte and Moxiflow cytometry (Orflo, Ketchum, IN). Stepanova M, Z o.o. No notable differences in the individual components of NAS were observed. Janney CG, Adult subjects with histological evidence of NASH, a NAS 4 with 1 in each component, and LF (NASH Clinical Research Network [CRN] stages 13) were enrolled at 81 clinical sites in Australia, Belgium, France, Germany, Hong Kong, Italy, Poland, Spain, the UK, and the United States. He advises AbbVie, Janssen, and Perspectum. Cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months. Byron MM, Simulations in a NAFLD/NASH SimCohorts (n=73) consisting of individuals with stage 3 fibrosis scores predicted a -0.03 change in mean fibrosis stage with 150 mg QD CVC for 2 . Diehl AM, A person needs their liver to survive because the liver is responsible for filtering harmful substances in the blood and performing many other tasks that are important to the body. Additional Supporting Information may be found at http://onlinelibrary.wiley.com/doi/10.1002/hep4.1160/full. Overall, these data suggest that several chemokines are upregulated in response to CVC to compensate for CCR2/CCR5 blockade and may contribute to hepatocyte leukocyte infiltration by alternative pathways. Allergan, Plc, /PRNewswire/ -- Tobira Therapeutics, Inc., a clinical-stage biopharmaceutical company developing cenicriviroc (CVC) in liver disease and HIV, announced today. M1 and M2 macrophage subpopulations isolated from mouse livers in the 4 and 14week trials, analyzed by flow cytometry. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. Lefebvre E, This is called alcoholic liver, Jaundice is classified into one of three types depending on its cause. Cohen C, (2013). If a person has NAFLD, a doctor may recommend making dietary changes to lose weight and taking medications to promote better blood sugar control. Data represent median with IQR, min and max. Screening for liver fibrosis in the general population: a call for action. Efficacy and safety study of cenicriviroc for the treatment of nonalcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. He consults for Enanta and Verylx. In short, the progression of liver fibrosis involves multiple events, of which the activation of HSCs is publicly recognized as the central element. Hepatology 2017;65:1557-1565. Abbreviations: mITT, modified intenttotreat; PNPLA3, patainlike phospholipase domaincontaining protein 3. Dr. Abdelmalek advises and has received grants from Allergan. In a first phase 2b trial, cenicriviroc significantly improved fibrosis stage in patients with nonalcoholic steatohepatitis (NASH) already after 1 year of oral and well-tolerated therapy. Bedossa P, Ratziu V, Abbreviations: CK18, cytokeratin 18; PP, per protocol. First, we found that mice receiving highdose CVC had decreased frequencies of intrahepatic bone marrowderived Ly6Chigh macrophages at 4 weeks, a reduction that was still observed, albeit attenuated, after 14 weeks of highdose CVC therapy despite no change in total intrahepatic macrophage or leukocyte populations. Subjects were randomized to receive CVC 150mg or a matched placebo oncedaily. Role of hepatic stellate cells in liver ischemia-reperfusion injury. aOR and 95% CI not calculable. One possible explanation may be that the impact of CVC on the composition of immune cells in the inflamed lobule, as well as the noncellular components of inflammation (i.e., chemokines and soluble mediators), cannot be fully characterized by the hematoxylineosin stain alone (used to grade the degree of lobular inflammation). P = 0.06. Completed the AURORA study and who reached an adjudicated liver-related clinical outcome in Part 1 or Part 2 of the study of: o Histopathologic progression to cirrhosis; o MELD score 15; Females who are postmenopausal must have documentation of cessation of menses for 12 months and serum follicle-stimulating hormone (FSH) 30 milliunits (mU)/milliliter (mL) at Screening. Abdelmalek MF, Please remove one or more studies before adding more. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Potential conflict of interest: Dr. Friedman consults for, advises for, and received grants from Tobira and Allergan. 2022 Sep 6;18(15):5681-5697. doi: 10.7150/ijbs.65044. Gong Z. Hepatic CD206positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection. Yang L, Clin Transl Sci. Change from baseline to year 1 in collagen area by morphometry was analyzed as prespecified in the study protocol. Icahn School of Medicine at Mount Sinai, Studies a U.S. FDA-regulated Drug Product: Studies a U.S. FDA-regulated Device Product: Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Histology at Month 12 [TimeFrame:Month 12], Time to First Occurrence of Adjudicated Events in the Full Study Cohort [TimeFrame:From first dose of study drug to onset of first occurrence of the event (Up to approximately 42 months)], Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Histology at Month 12 [TimeFrame:Month 12], Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis at Month 12 [TimeFrame:Month 12], Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis at Month 12 [TimeFrame:Month 12], Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [TimeFrame:Month 12], Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [TimeFrame:Month 12], Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [TimeFrame:Month 12], Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [TimeFrame:Month 12], Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [TimeFrame:Month 60], Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [TimeFrame:Month 60], Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [TimeFrame:Month 60], Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [TimeFrame:Month 60], Male and female participants aged between 18-75 years, Ability to understand and sign a written informed consent form (ICF), Histological evidence of NASH based on central reading of the Screening biopsy. It. Longerich E, Krenkel O, Greater than 95% purity of isolated pHSCs was confirmed using autofluorescent ultraviolet analysis and bodipy staining for vitamin A droplets. Epub 2018 Feb 22. Smith P, He advises for Intercept, Conatus, Echosens, Galmed, Gilead, Pfizer, and Fibrogen. Background: Non-alcoholic steatohepatitis (NASH) is often accompanied by liver fibrosis, which can progress to cirrhosis; C-C chemokine receptors type 2 and 5 (CCR2/CCR5), which mediate . Liver weight, as a percentage of total body weight, in all CDAHFD mice was significantly higher than standard chow mice (http://onlinelibrary.wiley.com/doi/10.1002/hep4.1160/full), highlighting that the CDAHFD results in significant hepatic steatosis (http://onlinelibrary.wiley.com/doi/10.1002/hep4.1160/full). DOI: Lin Y-S. (2017). Liver histology. Methods and analysis: ClinicalTrials.gov number, NCT02217475 (CENTAUR). France, 3 In subjects with collagen morphometry of 2% at baseline, all subjects achieving at least one stage improvement in fibrosis (NASH CRN) had concordant reduction in collagen at year1. Serum chemokines unchanged at 4 weeks but increased after 14 weeks of CVC therapy. Participants received cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months. The study overenrolled by 15% but, because of an anticipated dropout rate of 15%, this sample size was still expected to provide at least an 80% power to demonstrate superiority (for a twosided type 1 error rate of 0.05) of CVC versus placebo. already built in. placebo-controlled study on cenicriviroc for the treatment of liver fibrosis for those with NASH. A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) 4, and LF (stages 1-3, NASH Clinical Research Network . In contrast, intrahepatic CCR5+ macrophage frequency was not different between groups at either 4 or 14 weeks, reflecting the less potent receptor antagonistic effect of CVC on CCR5 or host compensatory mechanisms over time. Nonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Reversal of liver fibrosis. In conclusion, we evaluated CVC in the CDAHFD mouse model where CVC demonstrated a potent antifibrotic effect after 14 weeks, consistent with human phase 2b NASH studies. (DGD). Cell viability is represented as percentage of ATP in the treatment group divided by ATP in mock cells. Division of Gastroenterology & Hepatology, Department of Medicine, No significant differences were observed in other biochemical parameters during either the 4 or 14week trials. The remaining liver was manually dispersed in a sterile petri dish over a mesh gauze (Seward stomacher strainer; FermionX, Worthing, United Kingdom), digested with collagenase B (0.5 mg/mL with approximately 0.180 units/mg; Roche Diagnostics, Indianapolis, IN) and deoxyribonuclease 1 (20 units/mL, Roche Diagnostics) at 37oC for 20 minutes with gentle agitation, followed by collagenase neutralization with R10 media (Roswell Park Memorial Institute with 10% 4(2hydroxyethyl)1piperazine ethanesulfonic acid, 10% heat inactivated fetal bovine serum [FBS], 1% penicillin 5,000 units/mL, and streptomycin 5,000 g/mL), and then centrifuged at 50g for 3 minutes to pellet hepatocytes. After 1 year, half of the subjects receiving placebo crossed over to CVC, based on preplanned randomization, for a second year of treatment. Beljaars L, Lasseter K, A placebocontrolled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. Fibrosis stage was evaluated using the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. CDAHFD mice were simultaneously initiated on diet and treatment (diet alone, vehicle control, CVC 10 mg/kg/day intraperitoneally, or CVC 30 mg/kg/day intraperitoneally for 4 weeks; http://onlinelibrary.wiley.com/doi/10.1002/hep4.1160/full), dosages previously evaluated in animal models. The study was conducted in two parts: part . The majority of subjects had NAS 5 (74% [214 of 289]) and 67% (193 of 289) had fibrosis stage2 or 3 at screening. Missing biopsies were counted as treatment failure. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. (Hepatology Communications 2018;2:529545). Bruckbauer A, Although chemokine antagonism is an attractive therapeutic target, it is also a highly redundant system, raising concerns that a singular CCR/CCL blockade may be easily surmounted, mitigating any antirecruitment effects. Flow cytometric analyses of the liver NPC fraction in each of the five groups at 4 weeks revealed that the intrahepatic immune cell population, as represented by the frequency of live CD45+ cells (a common leukocyte antigen), was significantly lower in the highdose CVC group (30 mg/kg/day) compared with CDAHFDuntreated mice or vehicletreated controls (Fig. For accelerated conditional approval on. Lebray P, et al. MA, 3 Adequate liver biopsy sample for evaluation by Central Reader. If statistical significance was achieved at =0.05, twosided for the primary endpoint, a composite analysis on the sum of the two key secondary endpoints was to be performed with an ordinal logistic regression model. Liver fibrosis, but no other histologic features, is associated with longterm outcomes of patients with nonalcoholic fatty liver disease. Abdelmalek MF, et al. Pellicoro A, Fig.33 because the vehicle control is the most relevant group for comparison to assess the effect of CVC. To date, this therapeutic approach has helped identify a potential disconnect between steatosis reduction and disease . NY, 2 Giral P, Dr. Wiens is employed by Allergan. Mouse pHSCs were derived from livers of 5weekold male C57BL/6N mice fed CDAHFD for 4 weeks. Figs.2,2, ,3,3, ,44 by treatment group are detailed in http://onlinelibrary.wiley.com/doi/10.1002/hep4.1160/full. Other secondary outcomes included: change in fibrosis stage (NASH CRN and Ishak systems); change in histological scores for steatosis, lobular inflammation, and hepatocellular ballooning; change in collagen morphometry on liver biopsy; safety and tolerability of CVC; and change in liver biochemistry and fasting metabolic parameters. The https:// ensures that you are connecting to the Twentysix treatmentemergent serious adverse events were reported (CVC, n=16; placebo, n = 10). Data represent mean and SD for (A) and (B): (A) Total hepatic hydroxyproline levels quantified from formalinfixed paraffinembedded liver tissue at 14 weeks. Advancements in MAFLD Modeling with Human Cell and Organoid Models. Google has not performed a legal analysis and makes no representation . At 4 weeks of CVC therapy, plasma CVC levels at 4 and 24 hours after IP injection were within the expected therapeutic range (http://onlinelibrary.wiley.com/doi/10.1002/hep4.1160/full). Chang W, (A) Eotaxin; (B) macrophagederived chemokine; (C) macrophage inflammatory protein1; (D) monocyte induced by, Serum chemokines increased at both 4 and 14 weeks of CVC therapy. Fibrosis is the first stage of liver scarring. (A) Monocyte chemotactic protein 1/chemokine ligand 2. 2018 Mar;27(3):301-311. doi: 10.1080/13543784.2018.1442436. Later, if more of the liver becomes scarred, its known as liver cirrhosis. Nonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Analysis of the key secondary endpoints was conducted as prespecified and is presented for full disclosure of data, although the primary endpoint was not met. Yang L, Gottwald M, No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. Hepatitis B surface antigen (HBsAg) positive, Human immunodeficiency virus (HIV)-1 or HIV-2 infection, Other known causes of chronic liver disease, History or presence of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding, Alcohol consumption greater than 21 units/week for males or 14 units/week for females, Aspartate transaminase (AST) >200 International units (IU)/liter (L) in males and females at Screening, Alanine transaminase (ALT) >250 IU/L in males and >200 IU/L in females at Screening, Serum albumin <3.5 gram (g)/deciliter (dL) at Screening, Estimated glomerular filtration rate (eGFR) < 50 mL/minute (min)/1.73 meter (m)^2 according to the Modification of Diet in Renal Disease (MDRD) equation, Platelet count <100,000/millimeter (mm)^3, International normalized ratio (INR) >1.3, Model of end stage liver disease (MELD) score >12, Weight reduction, defined as 7% of body weight, through bariatric surgery in the past 5 years or bariatric surgery planned during the conduct of the study (including gastric banding and sleeve surgery), History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous cell carcinoma, Active, serious infections that require parenteral antibiotic or antifungal therapy within 30 days prior to Screening Visit, Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, Females who are pregnant or breastfeeding, Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (eg, interleukins, interferons, cyclosporine, tacrolimus) except for vaccines or short-term corticosteroids. Priority date (The priority date is an assumption and is not a legal conclusion. TGF stimulation of plateactivated pHSCs increased the expression of SMA and COL1A1 from human pHSCs and ACTA2 and COL1A1 from mouse pHSCs, but this increase could be inhibited with concomitant CVC treatment in a dosedependent manner (Fig. Peng Y, Yin Q, Yuan M, Chen L, Shen X, Xie W, Liu J. Our study is also the longest trial of CVC in a mouse model to date. Its ability to alter intrahepatic macrophage populations and inhibit profibrogenic genes in hepatic stellate cells in NASH livers may contribute to its observed antifibrotic effect. (Fig.6).6). Innate immunity and inflammation in NAFLD/NASH. Harrison S, Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect. Based on its mechanism of action, the lack of effect of CVC on lobular inflammation was unexpected and will need to be further explored. Cenicriviroc (CVC), a dual antagonist of these chemokines' receptors, CCR2 and CCR5, has been tested in clinical trials in patients with NASH-associated liver fibrosis. Kechagias S, et al. (A) Monocyte chemotactic protein 1/chemokine ligand 2. Poulin D, Talk with your doctor and family members or friends about deciding to join a study. MELD is a scoring system for assessing the severity of chronic liver disease and uses the participant's values for total bilirubin, serum creatinine, and the international normalized ratio for prothrombin time to predict survival. Unable to load your collection due to an error, Unable to load your delegates due to an error. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage. A decrease in the frequency of CD169+ cells in the highdose CVC group at 14 weeks may have contributed to decreasing intrahepatic CD8+ Tcell activity (e.g., invariant NKT cell activity).24 Together, these data suggest that the composition of the inflammatory infiltrate is more important than total hepatic inflammation in determining the fate of liver injury and fibrogenesis. Australian Capital Territory, CVC provided antifibrotic benefits in both fibrosis strata (stages 2 and >2; Figs. Cenicriviroc (CVC), is a novel, orally administered, potent, small molecule agonist that acts to block chemokine 2 and 5 receptors (CCR2/CCR5), both with well-known roles in liver inflammation and fibrosis (Figure 2).18 CVC has been developed by Allergan Inc (an AbbVie Inc company) and has received a Fast Track designation by the FDA for the . Puengel T, Scatton O, When the two key secondary endpoints were analyzed separately, a similar proportion of subjects achieved complete resolution of SH and no worsening of fibrosis stage (8% vs. 6%; OR, 1.40 [95% CI, 0.543.63]; P=0.49), whereas twice as many subjects on CVC achieved improvement in fibrosis stage by 1 stage and no worsening of SH compared to those on placebo (20% vs. 10%; OR, 2.20 [95% CI, 1.114.35]; P=0.02; Fig. UK, 6 Ramachandran P, Therefore, the observation that some placebo subjects improved in the CENTAUR study is neither unexpected nor out of line with other reported results. Cenicriviroc (CVC), a CCR2/5 antagonist, was simulated in NAFLDsym. Eight and 3 subjects in the CVC and placebo groups, respectively, improved by two fibrosis stages on the NASH CRN system; 10 and 4 subjects, respectively, improved by two stages on the Ishak system. Abbreviations: GAPDH, glyceraldehyde 3phosphate dehydrogenase; mRNA, messenger RNA **P 0.05. 2021 Jan;14(1):11-19. doi: 10.1111/cts.12839. Advanced Clinical Research - Center for Digestive Health, Salt Lake City, Utah, United States, 84132, Gastroenterology Associates of Northern Virginia, Falls Church, Virginia, United States, 22042, Newport News, Virginia, United States, 23602, Gastroenterology Consultants of Southwest Virginia Research, Seattle, Washington, United States, 98104, Seattle, Washington, United States, 98105, Seattle, Washington, United States, 98195, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, United States, 25701, Camperdown, New South Wales, Australia, 2050, Kogarah, New South Wales, Australia, 2217, Adelaide, South Australia, Australia, 5000, Adelaide, South Australia, Australia, 5042, Perth, Western Australia, Australia, 6000, Hospital das Clnicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil, 30130-100, Faculdade de Medicina de So Jos do Rio Preto Hospital de Base, So Jos do Rio Preto, Sao Paulo, Brazil, 15090-000, Hospital Universitrio Clementino Fraga Filho, Hospital das Clnicas da Faculdade de Medicina da Universidade de So Paulo, Vancouver, British Columbia, Canada, V5Z 1M9, William Osler Health Centre, Brampton Memorial Hospital Campus, Centro de Investigaciones Clnicas Via del Mar, CHU De Bordeaux - Hpital Hat-Lvque CMC Magellan Unita de Recherche Clinique, Clermont-Ferrand, Aubergne, France, 63003, Centre Hospitalier Universitaire de Rennes- Hpital Pontchaillou, Centre Hospitalier Regional et Universitaire de Besancon - L'Hopital Jean Minjoz, Besanon cedex, Franche-Comte, France, 25030, Paris Cedex 12, Ile-de-France, France, 75571, Montpellier cedex 5, Languedoc-Roussillon, France, 34295, Centre Hospitalier Universitaire de Rouen CHU de Rouen Hopital Charles-Nicolle, Center Hospitalier Universitaire d'Angers, Hapital Sud Service d'Hepato- Gastroentarologie, Centre Hospitalier Universitaire de Nice Hpital l'Archet, Nice Cedex 3, Provence Alpes Cote D'Azur, France, 06202, Centre Hospitalier Universitaire Grenoble, Grenoble Cedex 09, Rhone-Alpes, France, 38700, Synexus Clinical Research GmbH, Prfzentrum Frankfurt, Philipps-Universitt und Universittsklinikum Gieen und Marburg GmbH, Herne, Nordhein-Westfalen, Germany, 44623, Aachen, Nordrhein-Westfalen, Germany, 52074, Kln, Nordrhein-westfalen, Germany, 50937, Universittsmedizin der Johannes Gutenberg Universitt Mainz, Synexus Clinical Research GmbH, Prfzentrum Berlin, Shatin, New Territories, Hong Kong, 00852, Synexus Magyarorszag Egeszsegugyi Szolgaltato Kft, Rambam Health Care Campus - Rambam Medical Center, Hadassah Medical Center, Institute of Gastroenterology and Liver Diseases, San Giovanni Rotondo, Foggia, Italy, 71013, ASST Grande Ospedale Metropolitano Niguarda, Azienda Ospedaliera Universitaria Careggi SOD Medicina Interna ed Epatologia, Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone, Fondazione Policlinico Universitario Agostino Gemelli, Pauls Stradins Clinical University Hospital, Consultorio Mdico Dr. Alma Laura Ladron de Guevara, Consultorio Dra.