Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock
NCT ID: NCT05824767
Last Updated: 2025-05-14
Study Results
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Basic Information
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COMPLETED
PHASE4
40 participants
INTERVENTIONAL
2023-04-17
2025-03-12
Brief Summary
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Detailed Description
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Furthermore, there are no validated biomarkers currently available to guide the choice of vasopressor therapy in septic shock. In this study the investigators will evaluate two potential biomarkers, renin and dipeptidyl peptidase 3 (DPP3). Renin has been shown in preliminary studies to accurately predict mortality in septic shock, outperforming lactate, and to predict beneficial response to AngII. A less well-known candidate biomarker is DPP3, which is an aminopeptidase that cleaves a variety of biologically active oligopeptides including angiotensin II. Similar to renin, preliminary observational data show that elevated DPP3 levels in patients with sepsis are associated with organ dysfunction and short-term mortality, outperforming lactate as a predictor of death.
This study is an unblinded pilot randomized controlled trial (RCT) comparing AngII (intervention) to standard-of-care (SOC) vasopressor therapy in adult patients with persistent vasodilatory shock requiring moderate dose norepinephrine. The primary outcome will be the ability of renin and DPP3 to predict blood pressure (BP) response to AngII. As both renin and DPP3 are associated with overall short-term prognosis in sepsis, the SOC arm will allow us to determine if the predictive value of renin and DPP3 is specific to AngII therapy. A variety of secondary clinical outcomes will also be tracked, but the primary purpose of this pilot study is to inform the future design of a large multicenter RCT evaluating the biomarker-guided use of angiotensin II as a second-line vasopressor in septic shock.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Angiotensin II
For patients randomized to the intervention group, once the dose of background norepinephrine reaches ≥0.10 mcg/kg/min for ≥30 minutes, angiotensin II will be started at a dose of 20 ng/kg/min (recommended starting dose in package insert).Thereafter, angiotensin II and norepinephrine will both be titrated to mean arterial pressure (MAP) goal of \>/= 65 mmHg according to the protocol titration scheme and in accordance with the University of New Mexico Hospital (UNMH) Nursing Department Titration Guideline. Angiotensin II treatment will be capped at 72 hours, at which point (if a second vasopressor is still needed) the patient will be started on an alternative agent.
Angiotensin II
Angiotensin II (Giapreza) is a pharmacologic version of a naturally occurring peptide hormone of the same name which is a component of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II (Giapreza) was FDA-approved in 2017 as a vasoconstrictive agent in the treatment of vasodilatory shock.
Standard of Care (SOC)
Vasopressor therapy be titrated by the clinical team per usual SOC and UNMH Nursing Department Titration Guideline. using other available vasopressor agents (e.g., higher-dose norepinephrine, vasopressin, epinephrine, phenylephrine, and/or dopamine). To provide a comparator arm, patients in the SOC will have renin and DPP3 levels obtained at equivalent timepoints.
No interventions assigned to this group
Interventions
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Angiotensin II
Angiotensin II (Giapreza) is a pharmacologic version of a naturally occurring peptide hormone of the same name which is a component of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II (Giapreza) was FDA-approved in 2017 as a vasoconstrictive agent in the treatment of vasodilatory shock.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Patients are required to have central venous and arterial catheters present, and they are expected to remain in place for at least the initial 72 hours of study.
* Patients are required to have an indwelling urinary catheter present, and it is expected to remain in place for at least the 72 hours of study.
* Patients must have received 20-30 mL/kg of crystalloid over the previous 24-hour period, as clinically appropriate, and no longer be fluid responsive as per UNMH protocol. By UNMH protocol, lack of fluid responsiveness is considered a failure to increase stroke volume, stroke volume index, cardiac output, or cardiac index (typically measured by non-calibrated pulse contour analysis using a FloTrac device) by at least 10% after a 500-mL crystalloid bolus or a passive leg raise. Patients for whom the treating physicians feel that 20 mL/kg of crystalloid may be clinically inappropriate can qualify for the study if the reason for withholding further IV fluids is documented.
* Patient or (in patients unable to consent) legal authorized representative (LAR) is willing and able to provide written informed consent and comply with all protocol requirements.
* Approval from the attending physician and clinical pharmacist conducting the study.
Exclusion Criteria
* Patients diagnosed with acute occlusive coronary syndrome requiring intervention and/or cardiogenic shock.
* Patients with or suspected to have abdominal aortic aneurysm or aortic dissection.
* Acute stroke.
* Patients with acute mesenteric ischemia or those with a history of mesenteric ischemia.
* Patients with known Raynaud's phenomenon, systemic sclerosis, or vasospastic disease.
* Patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO).
* Patients with liver failure with a Model for End-Stage Liver Disease (MELD) score of =/\>30.
* Patients with burns covering \>20% of total body surface area.
* Patients with a history of asthma or chronic obstructive pulmonary disease (COPD) with active acute bronchospasm or (if not mechanically ventilated) with an acute exacerbation of their asthma/COPD requiring the use of inhaled bronchodilators.
* Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose.
* Patients with an absolute neutrophil count (ANC) of \< 1,000/mm3
* Patients with hemorrhagic shock OR active bleeding AND an anticipated need (within 48 hours of initiation of the study) for transfusion of \>4 units of packed red blood cells.
* Patients with active bleeding AND hemoglobin \< 7g/dL or any other condition that would contraindicate serial blood sampling.
* Untreated venous thromboembolism (VTE) or inability to tolerate pharmacologic VTE prophylaxis.
* Patients with a known allergy to mannitol.
* Patients with an expected survival of \<24 hours, SOFA score ≥ 16, or death deemed to be imminent or inevitable during the admission.
* Either the attending physician or patient and/or substitute decisionmaker are not committed to all active treatment, e.g., do-not-resuscitate (DNR) status.
* Patients who are known to be pregnant at the time of screening. All women ≤50 years-old will need a negative serum pregnancy test (serum quantitative beta-hCG) to enroll.
* Prisoner status
* Patients who are currently participating in another interventional clinical trial.
18 Years
ALL
No
Sponsors
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La Jolla Pharmaceutical Company
INDUSTRY
University of New Mexico
OTHER
Responsible Party
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Joao P. Teixeira
Assistant Professor
Principal Investigators
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Joao P Teixeira, MD
Role: PRINCIPAL_INVESTIGATOR
University of New Mexico
Nathan D Nielsen, MD MSc
Role: PRINCIPAL_INVESTIGATOR
University of New Mexico
Locations
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University of New Mexico Health Sciences Center
Albuquerque, New Mexico, United States
Countries
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References
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Teixeira JP, Perez Ingles D, Barton JB, Dean JT, Garcia P, Kunkel SJ, Sarangarm P, Weiss NK, Schaich CL, Busse LW, Nielsen ND. The scientific rationale and study protocol for the DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) randomized controlled trial: serum biomarkers to predict response to angiotensin II versus standard-of-care vasopressor therapy in the treatment of septic shock. Trials. 2024 Mar 12;25(1):182. doi: 10.1186/s13063-024-07995-0.
Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.
Tumlin JA, Murugan R, Deane AM, Ostermann M, Busse LW, Ham KR, Kashani K, Szerlip HM, Prowle JR, Bihorac A, Finkel KW, Zarbock A, Forni LG, Lynch SJ, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Bellomo R; Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Investigators. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Crit Care Med. 2018 Jun;46(6):949-957. doi: 10.1097/CCM.0000000000003092.
Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485.
Gleeson PJ, Crippa IA, Mongkolpun W, Cavicchi FZ, Van Meerhaeghe T, Brimioulle S, Taccone FS, Vincent JL, Creteur J. Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients. Crit Care Med. 2019 Feb;47(2):152-158. doi: 10.1097/CCM.0000000000003544.
Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, Hastbacka J, Khanna AK, Albertson TE, Tumlin J, Storey K, Handisides D, Tidmarsh GF, Chawla LS, Ostermann M. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial. Am J Respir Crit Care Med. 2020 Nov 1;202(9):1253-1261. doi: 10.1164/rccm.201911-2172OC.
Busse L, Albertson T, Gong M. Outcomes in patients with acute respiratory distress syndrome receiving angiotensin II for vasodilatory shock [Abstract P125]. Crit Care.2018;22(Suppl 1):82 (50).
Nguyen M, Denimal D, Dargent A, Guinot PG, Duvillard L, Quenot JP, Bouhemad B. Plasma Renin Concentration is Associated With Hemodynamic Deficiency and Adverse Renal Outcome in Septic Shock. Shock. 2019 Oct;52(4):e22-e30. doi: 10.1097/SHK.0000000000001285.
Kullmar M, Saadat-Gilani K, Weiss R, Massoth C, Lagan A, Cortes MN, Gerss J, Chawla LS, Fliser D, Meersch M, Zarbock A. Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients. Am J Respir Crit Care Med. 2021 May 1;203(9):1119-1126. doi: 10.1164/rccm.202005-2050OC.
Flannery AH, Ortiz-Soriano V, Li X, Gianella FG, Toto RD, Moe OW, Devarajan P, Goldstein SL, Neyra JA. Serum renin and major adverse kidney events in critically ill patients: a multicenter prospective study. Crit Care. 2021 Aug 14;25(1):294. doi: 10.1186/s13054-021-03725-z.
Jeyaraju M, McCurdy MT, Levine AR, Devarajan P, Mazzeffi MA, Mullins KE, Reif M, Yim DN, Parrino C, Lankford AS, Chow JH. Renin Kinetics Are Superior to Lactate Kinetics for Predicting In-Hospital Mortality in Hypotensive Critically Ill Patients. Crit Care Med. 2022 Jan 1;50(1):50-60. doi: 10.1097/CCM.0000000000005143.
Meersch M, Weiss R, Massoth C, Kullmar M, Saadat-Gilani K, Busen M, Chawla L, Landoni G, Bellomo R, Gerss J, Zarbock A. The Association Between Angiotensin II and Renin Kinetics in Patients After Cardiac Surgery. Anesth Analg. 2022 May 1;134(5):1002-1009. doi: 10.1213/ANE.0000000000005953.
Deniau B, Blet A, Santos K, Vaittinada Ayar P, Genest M, Kastorf M, Sadoune M, de Sousa Jorge A, Samuel JL, Vodovar N, Bergmann A, Mebazaa A, Azibani F. Inhibition of circulating dipeptidyl-peptidase 3 restores cardiac function in a sepsis-induced model in rats: A proof of concept study. PLoS One. 2020 Aug 27;15(8):e0238039. doi: 10.1371/journal.pone.0238039. eCollection 2020.
Rehfeld L, Funk E, Jha S, Macheroux P, Melander O, Bergmann A. Novel Methods for the Quantification of Dipeptidyl Peptidase 3 (DPP3) Concentration and Activity in Human Blood Samples. J Appl Lab Med. 2019 May;3(6):943-953. doi: 10.1373/jalm.2018.027995. Epub 2018 Nov 30.
Blet A, Deniau B, Santos K, van Lier DPT, Azibani F, Wittebole X, Chousterman BG, Gayat E, Hartmann O, Struck J, Bergmann A, Antonelli M, Beishuizen A, Constantin JM, Damoisel C, Deye N, Di Somma S, Dugernier T, Francois B, Gaudry S, Huberlant V, Lascarrou JB, Marx G, Mercier E, Oueslati H, Pickkers P, Sonneville R, Legrand M, Laterre PF, Mebazaa A; AdrenOSS-1 Study Investigators. Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study. Crit Care. 2021 Feb 15;25(1):61. doi: 10.1186/s13054-021-03471-2.
Picod A, Deniau B, Vaittinada Ayar P, Genest M, Julian N, Azibani F, Mebazaa A. Alteration of the Renin-Angiotensin-Aldosterone System in Shock: Role of the Dipeptidyl Peptidase 3. Am J Respir Crit Care Med. 2021 Feb 15;203(4):526-527. doi: 10.1164/rccm.202010-3873LE. No abstract available.
Jentzer JC, Vallabhajosyula S, Khanna AK, Chawla LS, Busse LW, Kashani KB. Management of Refractory Vasodilatory Shock. Chest. 2018 Aug;154(2):416-426. doi: 10.1016/j.chest.2017.12.021. Epub 2018 Jan 9.
Goradia S, Sardaneh AA, Narayan SW, Penm J, Patanwala AE. Vasopressor dose equivalence: A scoping review and suggested formula. J Crit Care. 2021 Feb;61:233-240. doi: 10.1016/j.jcrc.2020.11.002. Epub 2020 Nov 14.
Other Identifiers
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22-111
Identifier Type: -
Identifier Source: org_study_id
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