Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons

Open AccessPublished:October 07, 2022DOI:


      Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH.


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        • Younossi Z.
        • Tacke F.
        • Arrese M.
        • Chander Sharma B.
        • Mostafa I.
        • Bugianesi E.
        • et al.
        Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
        Hepatology. 2019; 69: 2672-2682
        • Liu W.
        • Baker R.D.
        • Bhatia T.
        • Zhu L.
        • Baker S.S.
        Pathogenesis of nonalcoholic steatohepatitis.
        Cell Mol Life Sci. 2016; 73: 1969-1987
        • Ratziu V.
        • Francque S.
        • Sanyal A.
        Breakthroughs in therapies for NASH and remaining challenges.
        J Hepatol. 2022; 76: 1263-1278
        • Vilar-Gomez E.
        • Martinez-Perez Y.
        • Calzadilla-Bertot L.
        • Torres-Gonzalez A.
        • Gra-Oramas B.
        • Gonzalez-Fabian L.
        • et al.
        Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
        Gastroenterology. 2015; 149: 367-378.e5
        • Promrat K.
        • Kleiner D.E.
        • Niemeier H.M.
        • Jackvony E.
        • Kearns M.
        • Wands J.R.
        • et al.
        Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
        Hepatology. 2010; : 121-129
        • Chalasani N.
        • Younossi Z.
        • Lavine J.E.
        • Charlton M.
        • Cusi K.
        • Rinella M.
        • et al.
        The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
        Hepatology. 2018; 67: 328-357
        • Oseini A.M.
        • Sanyal A.J.
        Therapies in non-alcoholic steatohepatitis (NASH).
        Liver Int. 2017; 37: 97-103
        • Attia S.L.
        • Softic S.
        • Mouzaki M.
        Evolving role for pharmacotherapy in NAFLD/NASH.
        Clin Transl Sci. 2021; 14: 11-19
        • Fraile J.M.
        • Palliyil S.
        • Barelle C.
        • Porter A.J.
        • Kovaleva M.
        Non-alcoholic steatohepatitis (NASH) – a review of a crowded clinical landscape, driven by a complex disease.
        Drug Des Devel Ther. 2021; 15: 3997-4009
        • Rinella M.E.
        • Tacke F.
        • Sanyal A.J.
        • Anstee QM.
        participants of the AASLD/EASL Workshop. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.
        J Hepatol. 2019; 71: 823-833
        • Ratziu V.
        • Friedman S.L.
        Why do so many NASH trials fail?.
        Gastroenterology. 2020 May 18; (S0016-5085(20)30680-30686)
        • Loomba R.
        • Wong R.
        • Fraysse J.
        • Shreay S.
        • Li S.
        • Harrison S.
        • et al.
        Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data.
        Aliment Pharmacol Ther. 2020; 51: 1149-1159
        • Brunt E.M.
        • Kleiner D.E.
        • Carpenter D.H.
        • Rinella M.
        • Harrison S.A.
        • Loomba R.
        • et al.
        NAFLD: reporting histologic findings in clinical practice.
        Hepatology. 2021; 73: 2028-2038
        • Masoodi M.
        • Gastaldelli A.
        • Hyötyläinen T.
        • Arretxe E.
        • Alonso C.
        • Gaggini M.
        • et al.
        Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests.
        Nat Rev Gastroenterol Hepatol. 2021; 18: 835-856
        • Selvaraj E.A.
        • Mózes F.E.
        • Jayaswal A.N.A.
        • Zafarmand M.H.
        • Vali Y.
        • Lee J.A.
        • et al.
        Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: a systematic review and meta-analysis.
        J Hepatol. 2021; 75: 770-785
        • Davison B.A.
        • Harrison S.A.
        • Cotter G.
        • Alkhouri N.
        • Sanyal A.
        • Edwards C.
        • et al.
        Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials.
        J Hepatol. 2020; 73: 1322-1332
        • Brunt E.M.
        • Clouston A.D.
        • Goodman Z.
        • Guy C.
        • Kleiner D.E.
        • Lackner C.
        • et al.
        Complexity of ballooned hepatocyte feature recognition: defining a training atlas for artificial intelligence-based imaging in NAFLD.
        J Hepatol. 2022; 76: 1030-1041
        • Roskilly A.
        • Shearer J.
        • Parker R.
        • Rowe I.A.
        vHigh rates of ineligibility for participation in trials of new therapies in non-alcoholic steatohepatitis: a systematic review.
        Eur J Gastroenterol Hepatol. 2020; 32: 1023-1029
        • Woodcock J.
        • LaVange L.M.
        Master protocols to study multiple therapies, multiple diseases, or both.
        N Engl J Med. 2017; 377: 62-70
        • Barker A.D.
        • Sigman C.C.
        • Kelloff G.J.
        • Hylton N.M.
        • Berry D.A.
        • Esserman L.J.
        I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy.
        Clin Pharmacol Ther Nat Publishing Group. 2009; 86: 97-100
        • Herbst R.S.
        • Gandara D.R.
        • Hirsch F.R.
        • Redman M.W.
        • LeBlanc M.
        • Mack P.C.
        • et al.
        Lung Master Protocol (Lung-MAP) - a biomarker-driven protocol for accelerating development of therapies for squamous cell lung cancer: SWOG S1400.
        Clin Cancer Res. 2015; 21: 1514-1524
        • Kaplan R.
        • Maughan T.
        • Crook A.
        • Fisher D.
        • Wilson R.
        • Brown L.
        • et al.
        Evaluating many treatments and biomarkers in oncology: a new design.
        J Clin Oncol. 2013; 31: 4562-4568
        • Sydes M.R.
        • Parmar M.K.B.
        • Mason M.D.
        • Clarke N.W.
        • Amos C.
        • Anderson J.
        • et al.
        Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial.
        Trials. 2012; 13: 1-14
        • Vanderbeek A.M.
        • Bliss J.M.
        • Yin Z.
        • Yap C.
        Implementation of platform trials in the COVID-19 pandemic: a rapid review.
        Contemp Clin Trials. 2022; 112106625
        • Meyer E.L.
        • Mesenbrink P.
        • Dunger-Baldauf C.
        • Fülle H.J.
        • Glimm E.
        • Li Y.
        • et al.
        The evolution of master protocol clinical trial designs: a systematic literature review.
        Clin Ther. 2020; 42: 1330-1360
        • Park J.J.H.
        • Siden E.
        • Zoratti M.J.
        • Dron L.
        • Harari O.
        • Singer J.
        • et al.
        Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.
        Trials. 2019; 20: 1-10
        • Loomba R.
        • Noureddin M.
        • Kowdley K.V.
        • Kohli A.
        • Sheikh A.
        • Neff G.
        • et al.
        Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH.
        Hepatology. 2021; 73: 625-643
        • Alkhouri N.
        • Herring R.
        • Kabler H.
        • Kayali Z.
        • Hassanein T.
        • Kohli A.
        • et al.
        Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: a randomised, open-label phase II trial.
        J Hepatol. 2022; 77 (S0168-8278(22)00235-5): 607-618
        • Saville B.R.
        • Connor J.T.
        • Ayers G.D.
        • Alvarez J.
        The utility of Bayesian predictive probabilities for interim monitoring of clinical trials.
        Clin Trials. 2014; 11: 485-493
        • Giovagnoli A.
        The bayesian design of adaptive clinical trials.
        Int J Environ Res Public Health. 2021; 18: 1-15
      1. Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) LITMUS Project ( Last accessed August 30, 2022.

      2. Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) | The Foundation for the National Institutes of Health ( Last accessed August 30, 2022.

        • Warner K.
        • See W.
        • Haerry D.
        • Klingmann I.
        • Hunter A.
        • May M.
        EUPATI guidance for patient involvement in Medicines research and development (R&D); guidance for pharmaceutical industry-led Medicines R&D.
        Front Med (Lausanne). 2018; 5: 270