{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:23:53Z","timestamp":1792193033975,"version":"4.4.0"},"reference-count":50,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","award":["Not applicable"],"award-info":[{"award-number":["Not applicable"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2022,2,25]]},"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Small molecule inhibitors of the terminal step in intrahepatic triglyceride synthesis (diacylglycerol acyltransferase 2 inhibitor (DGAT2i, PF-06865571, ervogastat)) and upstream blockade of\n                      <jats:italic>de novo<\/jats:italic>\n                      lipogenesis via acetyl-coenzyme A carboxylase inhibitor (ACCi, PF-05221304, clesacostat) showed promise in reducing hepatic steatosis in early clinical trials. This study assesses efficacy and safety of these metabolic interventions to resolve non-alcoholic steatohepatitis (NASH) with fibrosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This phase II, randomised, dose-ranging, dose-finding study evaluates DGAT2i 25\u2013300\u2009mg two times per day (BID) or 150\u2013300\u2009mg once a day, DGAT2i 150\u2013300\u2009mg BID+ACCi 5\u201310\u2009mg BID coadministration or matching placebo in a planned 450 adults with biopsy-confirmed NASH and liver fibrosis stages 2\u20133 from approximately 220 sites in 11 countries across North America, Europe and Asia. A triage approach including double-confirmation via non-invasive markers is included prior to screening\/baseline liver biopsy. On confirmation of histological diagnosis, participants enter a \u22656-week run-in period, then a 48-week double-blind, double-dummy dosing period. The primary endpoint is the proportion of participants achieving histological NASH resolution without worsening fibrosis, \u22651 stage improvement in fibrosis without worsening NASH, or both, assessed by central pathologists. Other endpoints include assessment of hepatic steatosis (imaging substudy), overall safety and tolerability, and evaluation of blood-based biomarkers and quantitative ultrasound parameters over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>\n                      Metabolic Interventions to Resolve NASH with fibrosis (MIRNA) is conducted in accordance with the Declaration of Helsinki and Council for International Organisations of Medical Sciences (CIOMS) International Ethical Guidelines, International Council on Harmonisation Good Clinical Practice guidelines, applicable laws and regulations, including privacy laws. Local independent review board\/ethics committees (IRB\/ECs) review\/approve the protocol, any amendments, informed consent and other forms. Participants provide written informed consent. Details of all IRB\/ECs, as well as results, will be published in a peer-reviewed journal and publicly disclosed through ClinicalTrials.gov, EudraCT, and\/or\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"www.pfizer.com\">www.pfizer.com<\/jats:ext-link>\n                      and other public registries as per applicable local laws\/regulations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04321031\">NCT04321031<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-056159","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T12:57:32Z","timestamp":1648645052000},"page":"e056159","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":58,"title":["Efficacy and safety of an orally administered DGAT2 inhibitor alone or coadministered with a liver-targeted ACC inhibitor in adults with non-alcoholic steatohepatitis (NASH): rationale and design of the phase II, dose-ranging, dose-finding, randomised, placebo-controlled MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) study"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct04321031","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04321031","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04399538","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04399538","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04399538","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0727-4683","authenticated-orcid":false,"given":"Neeta B","family":"Amin","sequence":"first","affiliation":[{"name":"Pfizer Global Product Development, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Darekar","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development UK Ltd, Tadworth, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin M","family":"Anstee","sequence":"additional","affiliation":[{"name":"Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent Wai-Sun","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Charit\u00e9-Universit\u00e4tsmedizin Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoli","family":"Vourvahis","sequence":"additional","affiliation":[{"name":"Pfizer Global Product Development, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas S","family":"Lee","sequence":"additional","affiliation":[{"name":"Pfizer Global Product Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Charlton","sequence":"additional","affiliation":[{"name":"Transplant Institute, Center for Liver Diseases, University of Chicago Biological Sciences, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naim","family":"Alkhouri","sequence":"additional","affiliation":[{"name":"Arizona Liver Health, Phoenix, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6263-1436","authenticated-orcid":false,"given":"Atsushi","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Yunis","sequence":"additional","affiliation":[{"name":"Pfizer Global Product Development, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,3,30]]},"reference":[{"key":"2025120618342612000_12.3.e056159.1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28431"},{"key":"2025120618342612000_12.3.e056159.2","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/MCG.0000000000000116","article-title":"World gastroenterology organisation global guidelines: nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"48","author":"LaBrecque","year":"2014","journal-title":"J Clin Gastroenterol"},{"key":"2025120618342612000_12.3.e056159.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1503519"},{"key":"2025120618342612000_12.3.e056159.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.109"},{"key":"2025120618342612000_12.3.e056159.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0104-9"},{"key":"2025120618342612000_12.3.e056159.6","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.04.043"},{"key":"2025120618342612000_12.3.e056159.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.07.027"},{"key":"2025120618342612000_12.3.e056159.8","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.01.043"},{"key":"2025120618342612000_12.3.e056159.9","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29085"},{"key":"2025120618342612000_12.3.e056159.10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.11.049"},{"key":"2025120618342612000_12.3.e056159.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.07.009"},{"key":"2025120618342612000_12.3.e056159.12","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121689"},{"key":"2025120618342612000_12.3.e056159.13","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R800018-JLR200"},{"key":"2025120618342612000_12.3.e056159.14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI37007"},{"key":"2025120618342612000_12.3.e056159.15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200215593"},{"key":"2025120618342612000_12.3.e056159.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704213200"},{"key":"2025120618342612000_12.3.e056159.17","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav9701"},{"key":"2025120618342612000_12.3.e056159.18","article-title":"Diacylglycerol acyltransferase 2 (DGAT2) inhibitor PF-06865571 reduces liver fat by MRI-PDFF after 2 weeks in adults with NAFLD [abstract]","volume":"70(Suppl 1)","author":"Saxena","year":"2019","journal-title":"Hepatology"},{"key":"2025120618342612000_12.3.e056159.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.04.037"},{"key":"2025120618342612000_12.3.e056159.20","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.07.027"},{"key":"2025120618342612000_12.3.e056159.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2018.04.042"},{"key":"2025120618342612000_12.3.e056159.22","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1002\/cpdd.782","article-title":"Safety, tolerability, pharmacokinetics and pharmacodynamics of a liver-targeting ACC inhibitor (PF-05221304): a three-part randomized phase 1 study","volume":"9","author":"Bergman","year":"2020","journal-title":"Clin Pharmacol Drug Dev"},{"key":"2025120618342612000_12.3.e056159.23","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1038\/s41591-021-01489-1","article-title":"ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials","volume":"27","author":"Calle","year":"2021","journal-title":"Nat Med"},{"key":"2025120618342612000_12.3.e056159.24","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2020.1668374"},{"key":"2025120618342612000_12.3.e056159.25","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3803\/EnM.2017.32.1.6","article-title":"The SCAP\/SREBP pathway: a mediator of hepatic steatosis","volume":"32","author":"Moon","year":"2017","journal-title":"Endocrinol Metab"},{"key":"2025120618342612000_12.3.e056159.26","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30097"},{"key":"2025120618342612000_12.3.e056159.27","article-title":"Co-administration of the ACC inhibitor PF-05221304 and the DGAT2 inhibitor PF-06865571 produces greater efficacy and mitigates ACC inhibitor-mediated increases in circulating triglyceride NAFLD\/NASH models [abstract]","volume":"70(Suppl 1","author":"Ross","year":"2019","journal-title":"Hepatology"},{"key":"2025120618342612000_12.3.e056159.28","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2019.12565","article-title":"Association of histologic disease activity with progression of nonalcoholic fatty liver disease","volume":"2","author":"Kleiner","year":"2019","journal-title":"JAMA Netw Open"},{"key":"2025120618342612000_12.3.e056159.29","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29367"},{"key":"2025120618342612000_12.3.e056159.30","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.jhep.2021.05.025","article-title":"EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update","volume":"75","year":"2021","journal-title":"J Hepatol"},{"key":"2025120618342612000_12.3.e056159.31","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S2468-1253(19)30383-8","article-title":"FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study","volume":"5","author":"Newsome","year":"2020","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"2025120618342612000_12.3.e056159.32","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"2025120618342612000_12.3.e056159.33","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.12.036"},{"key":"2025120618342612000_12.3.e056159.34","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s11901-020-00505-1","article-title":"Accounting for the placebo effect and optimizing outcomes in clinical trials of nonalcoholic steatohepatitis (NASH)","volume":"19","author":"Noureddin","year":"2020","journal-title":"Curr Hepatol Rep"},{"key":"2025120618342612000_12.3.e056159.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.04.030"},{"key":"2025120618342612000_12.3.e056159.36","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/hep4.1079","article-title":"Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: facilitating development approaches for an emerging epidemic","volume":"1","author":"Filozof","year":"2017","journal-title":"Hepatol Commun"},{"key":"2025120618342612000_12.3.e056159.37","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) . Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment \u2013 guidance for industry, 2018. Available: https:\/\/www.fda.gov\/media\/119044\/download [Accessed 6 Apr 2021]."},{"key":"2025120618342612000_12.3.e056159.38","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1002\/hep.30672","article-title":"Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the liver forum","volume":"70","author":"Cheung","year":"2019","journal-title":"Hepatology"},{"key":"2025120618342612000_12.3.e056159.39","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.23928"},{"key":"2025120618342612000_12.3.e056159.40","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.jhep.2020.06.025","article-title":"Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials","volume":"73","author":"Davison","year":"2020","journal-title":"J Hepatol"},{"key":"2025120618342612000_12.3.e056159.41","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.jhep.2019.10.023","article-title":"Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study","volume":"72","author":"Harrison","year":"2020","journal-title":"J Hepatol"},{"key":"2025120618342612000_12.3.e056159.42","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21655"},{"key":"2025120618342612000_12.3.e056159.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.07.012"},{"key":"2025120618342612000_12.3.e056159.44","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31608"},{"key":"2025120618342612000_12.3.e056159.45","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1001\/jama.2015.16702","article-title":"Dose-finding trials: optimizing phase 2 data in the drug development process","volume":"314","author":"Viele","year":"2015","journal-title":"JAMA"},{"key":"2025120618342612000_12.3.e056159.46","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.jhep.2019.04.019","article-title":"Report on the AASLD\/EASL joint workshop on clinical trial endpoints in NAFLD","volume":"71","author":"Rinella","year":"2019","journal-title":"J Hepatol"},{"key":"2025120618342612000_12.3.e056159.47","unstructured":"Committee for Medicinal Products for Human Use (CHMP) . Reflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH): EMA, 2018. Available: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/reflection-paper-regulatory-requirements-development-medicinal-products-chronic-non-infectious-liver_en.pdf [Accessed 6 Apr 2021]."},{"key":"2025120618342612000_12.3.e056159.48","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/dom.12460","article-title":"Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin","volume":"17","author":"Amin","year":"2015","journal-title":"Diabetes Obes Metab"},{"key":"2025120618342612000_12.3.e056159.49","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1111\/dom.12474","article-title":"Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes","volume":"17","author":"Amin","year":"2015","journal-title":"Diabetes Obes Metab"},{"key":"2025120618342612000_12.3.e056159.50","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20783"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2021-056159","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T02:34:38Z","timestamp":1765074878000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2021-056159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3,30]]},"published-print":{"date-parts":[[2022,3]]}},"alternative-id":["10.1136\/bmjopen-2021-056159"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2021-056159","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3]]}}}