Author information
1Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France.
2Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000 Nantes, France.
3Houston Research Institute, Houston Texas, USA.
4Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Belgium.
5Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
6Division of Gastroenterology and Hepatology, Duke University, Durham, NC, USA.
7Liver Unit, Digestive Disease Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
8Novo Nordisk A/S, Vandtårnsvej 108-110, 2860 Søborg Denmark.
9GENFIT, Parc Eurasanté 885, Avenue Eugène Avinée, 59120, Loos, France.
10Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C., USA.
11Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
12Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; INSERM UMRS 1138 CRC, Paris, France. Electronic address: vlad.ratziu@inserm.fr.
Abstract
The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.