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Cilofexor is a nonsteroidal farnesoid X receptor agonist that demonstrated significant improvements in liver biochemistry and markers of cholestasis in patients with PSC in a phase 2 study. We describe here the rationale, design, and implementation of the phase 3 PRIMIS trial, the largest placebo-controlled trial in PSC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Adults with large-duct PSC without cirrhosis are randomized 2:1 to receive oral cilofexor 100\u00a0mg once daily or placebo for up to 96\u00a0weeks during the blinded phase. Patients completing the blinded phase are eligible to receive open-label cilofexor 100\u00a0mg daily for up to 96\u00a0weeks. The primary objective is to evaluate whether cilofexor reduces the risk of fibrosis progression compared with placebo. Liver biopsy is performed at screening and Week 96 of the blinded phase for histologic assessment of fibrosis. The primary endpoint\u2014chosen in conjunction with guidance from the U.S. Food and Drug Administration\u2014is the proportion of patients with\u2009\u2265\u20091-stage increase in fibrosis according to Ludwig histologic classification at week 96. Secondary objectives include evaluation of changes in liver biochemistry, serum bile acids, liver fibrosis assessed by noninvasive methods, health-related quality of life, and safety of cilofexor.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The phase 3 PRIMIS study is the largest randomized, double-blind, placebo-controlled trial in PSC to date and will allow for robust evaluation of the efficacy and safety of cilofexor in noncirrhotic patients with large-duct PSC.<\/jats:p>\n                <jats:p><jats:italic>Trial Registration:<\/jats:italic> ClinicalTrials.gov NCT03890120; registered 26\/03\/2019.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12876-023-02653-2","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T11:17:58Z","timestamp":1678879078000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis"],"prefix":"10.1186","volume":"23","author":[{"given":"Michael","family":"Trauner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuhan","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Sterling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Tempany-Afdhal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary D.","family":"Goodman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martti","family":"F\u00e4rkkil\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palak","family":"Trivedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kris V.","family":"Kowdley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Bowlus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"2653_CR1","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1136\/gutjnl-2018-317993","volume":"68","author":"MH Chapman","year":"2019","unstructured":"Chapman MH, Thorburn D, Hirschfield GM, et al. 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The study protocol was reviewed and approved by the institutional review boards and independent ethics committees at all participating study sites. Ethics approval was obtained from the following institutional review boards and independent ethics committees: Bellberry Human Research Ethics Committee, Saint Vincent's Hospital Sydney, Sir Charles Gairdner Hospital, Westmead Hospital, Ethik-Kommission der Medizinischen Universit\u00e4t Wien, Ethikkommission des Landes Kaernten, H\u00f4pital Erasme, Advarra IRB Columbia\u2014Maryland Headquarters, Biomedical Research Ethics Board (BREB), Conjoint Health Research Ethics Board (CHREB), Hamilton Integrated Research Ethics Board, McGill University Health Centre, Research Ethics Board, North York General Hospital, Nova Scotia Health Authority, Research Ethics Board for Health Sciences Research Involving Human Subjects, University Health Network Research Ethics Board, University of British Columbia, Clinical Research Ethics Board, William Osler Health System Research Ethics Board, The Scientific Ethics Comities for Region Capital, TUKIJA National Committee on Medical Research Ethics, Comit\u00e9 de Protection des Personnes Ile de France III, Ethikkommission an der Medizinischen Fakult\u00e4t der Universit\u00e4t Leipzig, Ethikkommission der \u00c4rztekammer des Saarlandes, Ethikkommission der Christian-Albrechts-Universit\u00e4t zu Kiel, Ethikkommission der Friedrich-Schiller-Universit\u00e4t Jena, Ethik-Kommission der Landes\u00e4rztekammer Rheinland-Pfalz, Ethik-Kommission der Medizinischen Fakult\u00e4t Heidelberg, Ethikkommission der Medizinischen Hochschule Hannover, Ethikkommission der Medizinischen, Fakultat Essen Institut fur Pharmakologie Universitatsklinikum, Ethikkommission des Fachbereichs Medizin der Johann Wolfgang Goethe-Universit\u00e4t Frankfurt, Ethik-Kommission II der Medizinischen Fakult\u00e4t Mannheim der Universit\u00e4t Heidelberg, Landesamt f\u00fcr Gesundheit und Soziales Berlin, Gesch\u00e4ftsstelle der Ethik-Kommission des Landes Berl, Carmel Medical Center Helsinki Committee, Emek Medical Center, Hadassah University Hospital Ethics Helsinki Committee, Rabin Medical Center Ethics Helsinki Committee, Rambam Health Care Campus Ethics Helsinki Committee, Shaare Zedek Medical Center, Institutional Review Board, Tel Aviv Sourasky Medical Center Ethics Helsinki Committee, The Chaim Sheba Medical Center Ethics Helsinki Committee, A.O.U. Policlinico Paolo Giaccone, Azienda Ospedaliera Policlinico di Modena, Comitato Etico Provinciale di Modena, Comitato Etico dell\u2019Universit\u00e0 Cattolica del Sacro Cuore Policlinico Universitario Agostino Gemel, Comitato Etico della Provincia Monza Brianza, Comitato Etico dell'Azienda Ospedaliera Ospedali Riuniti di Foggia, Comitato Etico dell'IRCCS Istituto Clinico Humanitas, Comitato Etico Interaziendale Novara, Comitato Etico Milano Area 2, Comitato Etico per la Sperimentazione Clinica della Provincia di Padova, Comitato Etico Regionale delle Marche, Chiba University Hospital, Ehime University Hospital Institutional Review Board, Hiroshima University hospital IRB, Juntendo University Hospital, Nagasaki Medical Center, Okayama University Hospital, Osaka University Hospital, Teikyo University Hospital, Tohoku University Hospital Institutional Review Board, Yamagata University Hospital, Health and Disability Committees, Hospital General Universitario Gregorio Mara\u00f1on, Research Ethics Committee\u2014South Central\u2014Hampshire A, Advarra IRB Columbia\u2014Maryland Headquarters, Baylor Institutional Review Board, Baylor Scott and White Research Institute, Brany-IRB, Cedars-Sinai Medical Center, Institutional Review Board, Cleveland Clinic Foundation, Institutional Review Board, Columbia University Medical Center Institutional Review Board, Committee on Clinical Investigation Beth Israel Deaconess Medical Center, Duke University Health System Institutional Review Board, Georgetown University Institutional Review Board, Henry Ford Health System Institutional Review Board, Human Research Protection Program\u2014Health Science Committee, Icahn School of Medicine at Mount Sinai Program for the Protection of Human Subjects, Intermountain Healthcare\u2014Institutional Review Board, IRBMED, Kansas University Medical Center, Human Subjects Committee, Mayo Clinic, Institutional Review Board, Medical University of South Carolina, Institutional Review Board for Human Subjects, Mercy Medical Center, Institutional Review Board, NYU IRB, Ochsner Institutional Review Board, Penn State College of Medicine Institutional Review Board, Reading Hospital Occupational Health Services\u2014West Reading, Regional Health Command-Central Institutional Review Board, Rush University Medical Center Institutional Review Board, Office of Research Affairs, UCLA Office of the Human Research Protection Program, University of California at Davis, Office of Human Research Protection, University of Chicago Biological Sciences Division IRB, University of Tennessee Health Science Center IRB, University of Utah IRB, University of Vermont, Research Protections Office, Committees on Human Research, University of Virginia Institutional Review Board for Health Sciences Research, Walter Reed National Military Medical Center IRB, Weill Cornell Medical College\u2014Sandra and Edward Meyer Cancer Center, Western Institutional Review Board, and Western IRB, Yale\u2014New Haven Hospital. Informed consent is obtained from all individual participants. The study was designed and conducted by the sponsor (Gilead Sciences, Inc., Foster City, CA, USA) in collaboration with the principal investigators according to the protocol.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable, this manuscript does not contain individual person data.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MT consults, is on the speakers\u2019 bureau, and has received grants from Gilead, Falk, Intercept, and MSD; consults and has received grants from Albireo; consults for BiomX, Boehringer Ingelheim, Genfit, Janssen, Novartis, Phenex, Pliant, Regulus, and Shire; is on the speakers\u2019 bureau for BMS and Roche; and has received grants from Alnylam, CymaBay, Takeda, and UltraGenyx. CC, KS, X Liu, X Lu, and JX are employed by and own stock in Gilead. CT-A receives funding from Gilead; serves as a medical advisor to Profound Medical and Promaxo; and is an independent contractor for Medscape. ZDG has no personal conflicts of interest with respect to this work; his institution currently receives funding to support his research from Gilead, BMS, CymaBay, Eiger, Inventiva, MSD, NGM, and Novartis. MF has received grant support from Gilead; and is participating in a clinical trial of norUDCA in a study sponsored by Falk. AT consults for Gilead, EA Pharma, and GSK; and has received grants from AbbVie and Chugai. PT is on the speakers\u2019 bureau of Falk and Intercept; consults and has received grants from Gilead, BMS, Falk, Intercept, LifeArc, Medical Research Foundation, National Institute of Health Research, Perspectum, and Wellcome Trust; and is an advisor for CymaBay, Falk, Intercept, and Pliant. KVK has received grant support from Gilead, 89bio, BMS, Celgene, Corcept, CymaBay, Enanta, Genfit, GSK, Hanmi, HighTide, Intercept, Madrigal, Metacrine, Mirum, NGM, Pfizer, Pliant, Protagonist, Terns, and Viking; serves as a consultant and on advisory boards for Gilead, 89bio, CymaBay, Enanta; Genfit, HighTide, Inipharm, Intercept, Madrigal, Mirum, NGM, and Pfizer, and Enanta; and is on speakers\u2019 bureaus for Gilead, AbbVie, and Intercept. CLB advises and has received grants from Gilead, CymaBay, Eli Lilly, and Intercept; advises BiomX, Parvus, Patara, and Pliant; and has received grants from Arena, BMS, Genkyotex, GSK, and Takeda. CL advises and has received grants from Gilead, Cara, CymaBay, Genfit, Genkyotex, GSK, Intercept, Mirum, Pliant, and Target RWE; advises Escient and Teva; and has received grants from Alnylam, Mitsubishi, NGM, Novartis, and Zydus. RPM was formerly employed by Gilead.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"75"}}