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NCT05824767·Phase 4·INTERVENTIONAL

Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock

Status

Completed

Phase

Phase 4

Enrollment

42

Locations

1

Results

Posted

Publications

12

Study summary

What the protocol is testing.

This trial will be a randomized controlled single-center pilot trial comparing the use of angiotensin II versus standard-of-care (SOC) vasopressor therapy in adult patients with persistent vasodilatory shock despite moderate-dose norepinephrine, with a primary outcome of the ability of novel biomarkers (renin and DPP3) to predict blood pressure response to angiotensin II. Given our angiotensin II will be compared to SOC, this will be an unblinded study.

Full detailed description

Sepsis affects \>1 million Americans yearly and, when septic shock ensues, it is associated with high morbidity and mortality. Though first-line norepinephrine is standard of care, there are limited prospective data to guide the choice of additional vasopressors in septic shock. While more studies are needed, preliminary data suggest that the vasopressor angiotensin II (AngII) may improve outcomes in septic shock, especially in certain subsets of patients, such as those with acute kidney injury (AKI) requiring renal replacement therapy (RRT), acute respiratory distress syndrome (ARDS), or high severity of illness. 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.

Interventions

Treatment arms and agents.

DRUG

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.

Timeline

From registration to results.

  1. First posted

    Apr 24, 2023

  2. Study start

    Apr 17, 2023

  3. Primary completion

    Mar 12, 2025

  4. Study completion

    Mar 12, 2025

  5. Results posted

    Jul 2, 2026

  6. Registry updated

    Jul 2, 2026

Outcomes

What the study measures.

Primary outcomes

Ability of Baseline Active Renin to Predict Norepinephrine Equivalent Dose (NED) at 3 Hours

Time frame · 3 hours post drug initiation or SOC equivalent

BP response will be assessed at 3 hours in both groups and measured using NED. The primary outcome will be ability of baseline renin (obtained at drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, stratified by treatment arm (AngII vs. SOC) and adjusted for baseline Sequential Organ Failure Assessment (SOFA) scores. Shown are beta-coefficients from linear regression analyses between baseline levels of each biomarker and change in NED at 3 hours, adjusted for baseline SOFA score. NED shown is as defined by Goradia et al. J Crit Care. 2021;61:233-240 and See et al. J Crit Care. 2024;79:154453.

Ability of Baseline DPP3 to Predict NED at 3 Hours

Time frame · 3 hours post drug initiation or SOC equivalent

BP response will be assessed at 3 hours in both groups and measured using NED. The primary outcome will be ability of baseline DPP3 (obtained at drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, stratified by treatment arm (AngII vs. SOC) and adjusted for baseline Sequential Organ Failure Assessment (SOFA) scores. Shown are beta-coefficients from linear regression analyses between baseline levels of each biomarker and change in NED at 3 hours, adjusted for baseline SOFA score. NED shown is as defined by Goradia et al. J Crit Care. 2021;61:233-240 and See et al. J Crit Care. 2024;79:154453.

Secondary outcomes

Hospital Mortality

Time frame · Until hospital discharge or 28 days post-randomization.

Death before hospital discharge. Specified as a key secondary outcome.

Eligibility

Who can take part.

Minimum age
18 Years
Maximum age
Not reported
Sex
ALL
Healthy volunteers
No

Inclusion Criteria: * Adult patients ≥18 years-old with persistent vasodilatory shock despite moderate-dose norepinephrine monotherapy, defined as those who require ≥0.1 mcg/kg/min for at least 30 minutes to maintain a MAP between 65-70 mmHg. * 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 who are \< 18 years of age. * 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.

Study locations

1 registered sites.

United States. Showing up to 24 locations stored in the fast local snapshot.

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, United States

Publications

Results and literature.

PMID 38475822Teixeira 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.PMID 28528561Khanna 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.PMID 29509568Tumlin 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.PMID 27483065Gordon 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.PMID 30653055Gleeson 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.PMID 32609011Bellomo 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.PMID 30407370Nguyen 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.PMID 33320784Kullmar 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.PMID 34391450Flannery 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.PMID 34166293Jeyaraju 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.PMID 35171852Meersch 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.PMID 32853284Deniau 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.

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