{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:26:24Z","timestamp":1788459984107,"version":"build-2803163510"},"reference-count":27,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T00:00:00Z","timestamp":1586304000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:p>This thorough QT (TQT) study evaluated the effect of zanubrutinib on electrocardiogram (ECG) parameters by using concentration\u2010QTc (C\u2010QTc) analysis as the primary analysis for this study. Part A of the study determined the safety and tolerability of a single supratherapeutic dose of zanubrutinib (480\u00a0mg) in healthy volunteers. Part B was a randomized, blinded, placebo\u2010controlled and positive\u2010controlled, four\u2010way crossover, TQT study of single therapeutic (160\u00a0mg) and supratherapeutic (480\u00a0mg) doses of zanubrutinib, placebo, and open\u2010label moxifloxacin 400\u00a0mg. Thirty\u2010two participants received at least 1 dose of zanubrutinib, and 26 participants completed all 4 periods. Zanubrutinib did not have any effect on heart rate or cardiac conduction (pulse rate, QRS interval, or T\u2010wave morphology) and was generally well\u2010tolerated. Using C\u2010QTc analysis, the predicted placebo\u2010corrected change\u2010from\u2010baseline QT interval using Fridericia\u2019s formula (\u0394\u0394QTcF) was \u22123.4\u00a0msec (90% confidence interval: \u22124.9 to \u22121.9\u00a0msec) at peak concentrations of the 480\u00a0mg dose. A QT effect (\u0394\u0394QTcF) exceeding 10\u00a0msec could be excluded within the observed concentration range at 160 and 480\u00a0mg doses. Assay sensitivity was established by moxifloxacin with 90% lower bound exceeding 5\u00a0msec. Implementing a C\u2010QTc analysis prospectively in this TQT study resulted in a substantially smaller sample size to maintain a similar study power as shown in the traditional time\u2010point analysis. A single 160\u2010mg or 480\u2010mg zanubrutinib dose did not prolong the QTc interval or have any other clinically relevant effects on ECG parameters.<\/jats:p>","DOI":"10.1111\/cts.12779","type":"journal-article","created":{"date-parts":[[2020,3,7]],"date-time":"2020-03-07T10:30:00Z","timestamp":1583577000000},"page":"923-931","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["No QTc Prolongation With Zanubrutinib: Results of Concentration\u2010QTc Analysis From a Thorough QT Study in Healthy Subjects"],"prefix":"10.1111","volume":"13","author":[{"given":"Song","family":"Mu","sequence":"first","affiliation":[{"name":"BeiGene, Inc. San Mateo California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borje","family":"Darpo","sequence":"additional","affiliation":[{"name":"eResearchTechnology, Inc. 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Poster presented at: 24th Annual Congress of the European Hematology Association (EHA). June 13\u201316 2019;Amsterdam Netherlands.","DOI":"10.1002\/j.2572-9241.2019.tb00086.x"},{"key":"e_1_2_12_8_1","unstructured":"Song Y.et al.Zanubrutinib in patients with relapsed or refractory mantle cell lymphoma: a single\u2010arm multicenter pivotal phase 2 study. Presented at: 15th International Conference on Malignant Lymphoma. June 18\u201322 2019;Lugano Switzerland."},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001160"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-015-0325-5"},{"key":"e_1_2_12_11_1","unstructured":"ICH E14 Implementation Working Group ICH E14 guideline: the clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs. Questions and answers (R3). <https:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Efficacy\/E14\/E14_Q_As_R3__Step4.pdf> (2015). Accessed June 7 2019."},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-017-3471-x"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.60"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/anec.12227"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543406.2018.1535498"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-019-04015-w"},{"key":"e_1_2_12_18_1","unstructured":"U.S. Department of Health and Human Services.Guidance for industry: E14 clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs.<https:\/\/www.fda.gov\/media\/71372\/download> (2005). 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