Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock

NCT05824767 | Completed Phase 4 FDA Drug

• 1 other identifier: 22-111
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Septic Shock; Vasodilatory Shock

Keywords

septic shock; vasopressor; angiotensin II; renin; dipeptidyl peptidase 3 (DPP3); randomized controlled trial

Outcome Measures

Primary Outcomes (2)

• Ability of baseline renin to predict norepinephrine equivalent dose (NED) at 3 hours

  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, using treatment arm (AngII vs. SOC) and baseline Sequential Organ Failure Assessment (SOFA) scores as covariables.

  3 hours post drug initiation or SOC equivalent

• Ability of baseline DPP3 to predict NED at 3 hours

  BP response will be assessed at 3 hours in both groups and measured using NED. The primary outcome will be ability of baseline DPP3 to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables.

  3 hours post drug initiation or SOC equivalent

Secondary Outcomes (21)

• Ability of pre-baseline renin to predict NED at 3 hours

  3 hours post drug initiation or SOC equivalent

• Ability of pre-baseline DPP3 to predict NED at 3 hours

  3 hours post drug initiation or SOC equivalent

• Ability of changes in renin level to predict NED at 3 hours

  3 hours post drug initiation or SOC equivalent

• Ability of changes in DPP3 level to predict NED at 3 hours

  3 hours post drug initiation or SOC equivalent

• Background NED at 1 hour

  1 hour post drug initiation or SOC equivalent

Other Outcomes (17)

• serum renin level at 1 hour

  1 hour post-drug initiation and SOC equivalent

• serum DPP3 level at 1 hour

  1 hour post-drug initiation and SOC equivalent

• serum renin level at 3 hours

  3 hours post-drug initiation and SOC equivalent

Study Arms (2)

Angiotensin II

EXPERIMENTAL

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.

Drug: Angiotensin II

Standard of Care (SOC)

NO INTERVENTION

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.

Interventions

Angiotensin II DRUG

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.

Also known as: Giapreza

Angiotensin II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• La Jolla Pharmaceutical Company: collaborator
• University of New Mexico: lead

Study Sites (1)

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, 87106, United States

Location

Related Publications (18)

• 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.

  PMID: 38475822 BACKGROUND

• 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.

  PMID: 28528561 BACKGROUND

• 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.

  PMID: 29509568 BACKGROUND

• 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.

  PMID: 27483065 BACKGROUND

• 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.

  PMID: 30653055 BACKGROUND

• 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.

  PMID: 32609011 BACKGROUND

• 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).

  BACKGROUND

• 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.

  PMID: 30407370 BACKGROUND

• 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.

  PMID: 33320784 BACKGROUND

• 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.

  PMID: 34391450 BACKGROUND

• 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.

  PMID: 34166293 BACKGROUND

• 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.

  PMID: 35171852 BACKGROUND

• 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.

  PMID: 32853284 BACKGROUND

• 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.

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• 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.

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  PMID: 33220576 BACKGROUND

MeSH Terms

Conditions

Shock, Septic

Interventions

Angiotensin II; Giapreza

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Angiotensins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Autacoids; Inflammation Mediators; Biological Factors

Study Officials

• Joao P Teixeira, MD

  University of New Mexico

  PRINCIPAL INVESTIGATOR

• Nathan D Nielsen, MD MSc

  University of New Mexico

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: March 5, 2023
• First Posted: April 24, 2023
• Study Start: April 17, 2023
• Primary Completion: March 12, 2025
• Study Completion: March 12, 2025
• Last Updated: February 5, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)