{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:29Z","timestamp":1792790309662,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,14]]},"group-title":"Intensive Care and Critical Care Medicine","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Heart Lung and Blood Institute","award":["5R01HL177834-02"],"award-info":[{"award-number":["5R01HL177834-02"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Norepinephrine remains first-line vasopressor therapy for septic shock despite its association at high doses with undesirable cardiovascular, kidney, and immune effects. Angiotensin-II (Ang-II) is a non-catecholamine vasopressor of the renin-angiotensin-aldosterone system (RAAS) now approved to increase blood pressure in vasodilatory shock. RAAS dysregulation is common in septic shock and may represent a treatable trait. However, few prospective investigations evaluate the effect of early Ang-II use in septic shock on dysfunctional RAAS biology, host-response, or clinical outcomes. Therefore, we designed a mechanistic clinical trial to test the hypothesis that early Ang-II therapy in septic shock normalizes systemic RAAS abnormalities and modulates innate immune responses.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods and Analysis<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:bold>M<\/jats:bold>\n                    echanistic\n                    <jats:bold>A<\/jats:bold>\n                    ssessment of\n                    <jats:bold>N<\/jats:bold>\n                    orepinephrine\n                    <jats:bold>T<\/jats:bold>\n                    he\n                    <jats:bold>R<\/jats:bold>\n                    apy vs.\n                    <jats:bold>A<\/jats:bold>\n                    ngiotensin-II in Septic Shock (MANTRA) trial is an investigator-initiated, prospective, multicenter, open-label, randomized mechanistic clinical trial. Adults with septic shock by Sepsis-3 criteria receiving a norepinephrine-equivalent dose (NED) of 0.10-0.50 mcg\/kg\/min will be randomized 1:1 to primary Ang-II (to a maximum of 40 ng\/kg\/min) or norepinephrine (to a maximum 35 mcg\/min) treatment strategies over a 48-hour period. The primary outcome is the between-group difference in plasma renin trajectory from baseline to 24 hours, analyzed using a linear mixed-effects model with a treatment-by-time interaction term. With n=78, the trial has 90% power (at two-sided \u03b1=0.05) to detect a 25% between-group difference in 24-hour renin. Secondary clinical outcomes include longitudinal NED, hours alive and vasopressor-free at 72 hours, a 28-day composite outcome (days alive and free of vasopressors, renal replacement therapy, and mechanical ventilation), treatment failure requiring crossover or protocol discontinuation, and thrombotic and arrhythmia events through 28 days. Secondary mechanistic outcomes include serial RAAS biomarkers (prorenin, soluble prorenin receptor, angiotensinogen, ACE, ACE2, Ang-II, angiotensin-(1\u20137), aldosterone, and DPP3), immune measures (ex vivo monocyte function, monocyte gene expression, plasma cytokines), and organ injury biomarkers. Enrollment is planned from 5\/2026-7\/2030.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Strengths and limitations of this study<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>MANTRA is a randomized trial comparing angiotensin-II against an active standard-of-care norepinephrine strategy rather than placebo, enrolling patients earlier in septic shock than prior trials restricted to catecholamine-resistant shock.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Serial sampling profiles RAAS peptides, innate immune function, and organ-injury biomarkers, which will generate rich mechanistic data on how vasopressor strategy shapes the host response.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The sample size is adequate for the biomarker primary endpoints and will establish feasibility for a larger trial, but it does not provide sufficient power for hard clinical endpoints, which remain exploratory.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>MANTRA compares two open-label vasopressor strategies rather than monotherapies; clinician retain discretion over background and rescue vasopressors, steroids, and crossover, which may attenuate differences between-arms.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The 48-hour intervention window limit inference about clinician-assessed outcomes and the durability of treatment effect.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.12.26362906","type":"posted-content","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:05:18Z","timestamp":1789445118000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic Assessment of Norepinephrine Therapy versus Angiotensin-II in Septic Shock (MANTRA): Study Protocol for a multicenter randomized trial"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2588-7504","authenticated-orcid":false,"given":"Michael R.","family":"Filbin","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9670-9425","authenticated-orcid":false,"given":"Daniel E.","family":"Leisman","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Pachano-Bravo","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4266-9733","authenticated-orcid":false,"given":"Marcia B.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Center for Bacterial Pathogenesis, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Hibbert","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Rappaport","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon A.","family":"Mahler","sequence":"additional","affiliation":[{"name":"Departments of Emergency Medicine, Epidemiology and Prevention, and Implementation Science, Wake Forest University School of Medicine, Winston Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynnette","family":"Harris","sequence":"additional","affiliation":[{"name":"Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6252-6173","authenticated-orcid":false,"given":"Estelle B.","family":"Besong","sequence":"additional","affiliation":[{"name":"Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Reeves","sequence":"additional","affiliation":[{"name":"Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6234-6160","authenticated-orcid":false,"given":"Ryan C.","family":"Maves","sequence":"additional","affiliation":[{"name":"Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA"},{"name":"Section on Infectious Diseases, Departments of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Petrilli","sequence":"additional","affiliation":[{"name":"Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA"},{"name":"Section on Infectious Diseases, Departments of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5302-0828","authenticated-orcid":false,"given":"Christopher L.","family":"Schaich","sequence":"additional","affiliation":[{"name":"Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1595-4080","authenticated-orcid":false,"given":"D. Clark","family":"Files","sequence":"additional","affiliation":[{"name":"Section on Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5272-2289","authenticated-orcid":false,"given":"Kevin","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Section on Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Chappell","sequence":"additional","affiliation":[{"name":"Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9083-891X","authenticated-orcid":false,"given":"Ashish K.","family":"Khanna","sequence":"additional","affiliation":[{"name":"Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA"},{"name":"Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA"},{"name":"Outcomes Research Consortium, Houston, TX, USA"},{"name":"Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091721551136000_2026.09.12.26362906v1.1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287"},{"key":"2026091721551136000_2026.09.12.26362906v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0752-4"},{"key":"2026091721551136000_2026.09.12.26362906v1.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201911-2172OC"},{"key":"2026091721551136000_2026.09.12.26362906v1.4","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000000742"},{"key":"2026091721551136000_2026.09.12.26362906v1.5","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-021-03725-z"},{"key":"2026091721551136000_2026.09.12.26362906v1.6","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000003544"},{"key":"2026091721551136000_2026.09.12.26362906v1.7","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000005143"},{"key":"2026091721551136000_2026.09.12.26362906v1.8","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202106-1514OC"},{"key":"2026091721551136000_2026.09.12.26362906v1.9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.9.5577"},{"key":"2026091721551136000_2026.09.12.26362906v1.10","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000148824.93600.F3"},{"key":"2026091721551136000_2026.09.12.26362906v1.11","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00700.2002"},{"key":"2026091721551136000_2026.09.12.26362906v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.regpep.2006.01.007"},{"key":"2026091721551136000_2026.09.12.26362906v1.13","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.4049\/jimmunol.160.3.1436","article-title":"Angiotensin II generation at the cell surface of activated neutrophils: novel cathepsin G-mediated catalytic activity that is resistant to inhibition","volume":"160","year":"1998","journal-title":"J Immunol"},{"key":"2026091721551136000_2026.09.12.26362906v1.14","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006070707"},{"key":"2026091721551136000_2026.09.12.26362906v1.15","doi-asserted-by":"publisher","DOI":"10.1042\/CS20242168"},{"key":"2026091721551136000_2026.09.12.26362906v1.16","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202002-0339OC"},{"key":"2026091721551136000_2026.09.12.26362906v1.17","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201604-0862CP"},{"key":"2026091721551136000_2026.09.12.26362906v1.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1704154"},{"key":"2026091721551136000_2026.09.12.26362906v1.19","doi-asserted-by":"publisher","DOI":"10.1186\/s13613-023-01227-5"},{"key":"2026091721551136000_2026.09.12.26362906v1.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2211370119"},{"key":"2026091721551136000_2026.09.12.26362906v1.21","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000006095"},{"key":"2026091721551136000_2026.09.12.26362906v1.22","unstructured":"U.S. Food and Drug Administration. Norepinephrine in sodium chloride injection prescribing information. NDA 214628; revised 2024."},{"key":"2026091721551136000_2026.09.12.26362906v1.23","unstructured":"U.S. Food and Drug Administration. Angiotensin II injection prescribing information. NDA 209360; 2017."},{"key":"2026091721551136000_2026.09.12.26362906v1.24","doi-asserted-by":"crossref","unstructured":"Ashbeck EL , Bell ML . Single time point comparisons in longitudinal randomized controlled trials: power and bias in the presence of missing data. BMC Med Res Methodol 2016;16:43. PMCID: PMC4828848.","DOI":"10.1186\/s12874-016-0144-0"},{"key":"2026091721551136000_2026.09.12.26362906v1.25","unstructured":"U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) v6.0 (MedDRA 28.0) [Internet]. Published July 22, 2025. Available from: CTCAE and AE Reporting \u2013 NCI."}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.12.26362906","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:55:23Z","timestamp":1789707323000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.12.26362906"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":25,"URL":"https:\/\/doi.org\/10.64898\/2026.09.12.26362906","relation":{},"subject":[],"published":{"date-parts":[[2026,9,14]]},"subtype":"preprint"}}