Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol
Michael Pavlides, Ferenc E Mózes, Salma Akhtar, Kristy Wonders, Jeremy Cobbold, Elizabeth M Tunnicliffe, Michael Allison, Edmund M Godfrey, Guruprasad P Aithal, Susan Francis, Manuel Romero-Gomez, Javier Castell, Isabel Fernandez-Lizaranzu, Rocio Aller, Rebeca Sigüenza González, Salvador Agustin, Juan M Pericàs, Jerome Boursier, Christophe Aube, Vlad Ratziu, Mathilde Wagner, Salvatore Petta, Michela Antonucci, Elisabetta Bugianesi, Riccardo Faletti, Luca Miele, Andreas Geier, Jörn M Schattenberg, Emrich Tilman, Mattias Ekstedt, Peter Lundberg, Annalisa Berzigotti, Adrian T Huber, George Papatheodoridis, Hannele Yki-Järvinen, Kimmo Porthan, Moritz Jörg Schneider, Paul Hockings, Elizabeth Shumbayawonda, Rajarshi Banerjee, Kay Pepin, Mike Kalutkiewicz, Richard L Ehman, Aldo Trylesinksi, Harvey O Coxson, LITMUS Consortium Investigators, Miljen Martic, Carla Yunis, Theresa Tuthill, Patrick M Bossuyt, Quentin M Anstee, Stefan Neubauer, Stephen Harrison, Michael Pavlides, Ferenc E Mózes, Salma Akhtar, Kristy Wonders, Jeremy Cobbold, Elizabeth M Tunnicliffe, Michael Allison, Edmund M Godfrey, Guruprasad P Aithal, Susan Francis, Manuel Romero-Gomez, Javier Castell, Isabel Fernandez-Lizaranzu, Rocio Aller, Rebeca Sigüenza González, Salvador Agustin, Juan M Pericàs, Jerome Boursier, Christophe Aube, Vlad Ratziu, Mathilde Wagner, Salvatore Petta, Michela Antonucci, Elisabetta Bugianesi, Riccardo Faletti, Luca Miele, Andreas Geier, Jörn M Schattenberg, Emrich Tilman, Mattias Ekstedt, Peter Lundberg, Annalisa Berzigotti, Adrian T Huber, George Papatheodoridis, Hannele Yki-Järvinen, Kimmo Porthan, Moritz Jörg Schneider, Paul Hockings, Elizabeth Shumbayawonda, Rajarshi Banerjee, Kay Pepin, Mike Kalutkiewicz, Richard L Ehman, Aldo Trylesinksi, Harvey O Coxson, LITMUS Consortium Investigators, Miljen Martic, Carla Yunis, Theresa Tuthill, Patrick M Bossuyt, Quentin M Anstee, Stefan Neubauer, Stephen Harrison
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.
Keywords: 2D shear wave elastography; 2DSWE; DeMILI; Diffusion weighted imaging; Fibro-MRI; Iron corrected T1; Liver Multiscan; Magnetic resonance elastography; NASH-MRI; PDFF; Proton density fat fraction; R2*; T1 mapping; T2*; VCTE; liver stiffness; pSWE; point shear wave elastography; ultrasound elastography; vibration controlled transient elastography.
Conflict of interest statement
Declaration of Competing Interest FEM, SA, KW, JC, MA, EMG, SF, MRG, JC, IFL, RA, RSG, JMP, JB, VR, MW, SP, MA, RF, LM, ET, ME, PL, ATH, GP, HYJ, KP and PMB declare no conflicts of interest. MP is a shareholder in Perspectum Ltd. EMT is a shareholder in Perspectum Ltd. SA is currently employed by Boehringer Ingelheim (but was not during his participation in the project). GPA has served as a consultant and an advisory board member for Pfizer Inc., Inventiva Pharma, GlaxoSmithKline and KaNDy Therapeutics; he has been a consultant to BerGenBio ASA, Median Technologies, FRACTYL, Amryt Pharmaceuticals and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. CA declares the following potential conflicts of interest: Hologic: Support of study and expert; Guerbet: Member of board, PI of study; Siemens: Expert. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento; and a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer. She has also received a research grant from Gilead Sciences for fatty liver research. AG served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; received research funding from Intercept, Falk, Novartis. JMS reports consultancy for BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Pfizer, Roche, Sanofi; received research funding from Gilead Sciences and was on the speaker's bureau for Falk Foundation MSD Sharp & Dohme GmbH. MJS and PH are employed by Antaros Medical AB, Mölndal, Sweden. ES is employed by Perspectum Ltd., Oxford, UK. RB is a shareholder and employed (CEO) by Perspectum Ltd., Oxford, UK. KP and MK are employed by Resoundant Inc., Rochester, MN, USA. RLE and the Mayo Clinic have intellectual property rights and a financial interest in magnetic resonance elastography technology. AT is employed by ADVANZPHARMA, Capital House, 1st Floor, 85 King William Street, London, EC4N 7BL, United Kingdom. HC is employed by Boehringer Ingelheim Pharma GmbH & Co. MM is employed by Novartis AG, Basel, Switzerland. CY is employed by Pfizer Inc., Lake Mary, FL, USA. TT was employed by Pfizer at the time of her involvement with the project. QMA is coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. QMA has received research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals, Inc.; has served as a consultant on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept Pharmaceuticals, Inc., Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; has served as a speaker for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and receives royalties from Elsevier Ltd. SN is a shareholder in Perspectum Ltd. SAH has research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, Viking. He has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, HIghtide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking.
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Source: PubMed