Angiotensin II vs. Vasopressin in Septic Shock

NCT05193370 | Withdrawn Phase 4 FDA Drug

• 2 other identifiers: 21-040UL1TR001449
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a randomized controlled unblinded pragmatic single-center pilot trial of the use of vasopressin vs. angiotensin II as a second-line vasopressor in patients with septic shock and persistent hypotension despite moderate-to-high doses of norepinephrine.

Conditions

Septic Shock

Keywords

septic shock; vasopressor; angiotensin II; vasopressin; renin; randomized controlled trial

Outcome Measures

Primary Outcomes (1)

• Percentage of patients who achieve blood pressure (BP) goal (MAP ≥65 mmHg) at 3 hours post-drug initiation

  The primary endpoint will be the percentage of patients who achieve BP goal, specifically mean arterial pressure (MAP) of ≥65 mmHg, at the 3-hour time point. The primary endpoint will be binary (yes/no achievement of BP goal). Failure to respond to study drug will defined as any of the following: (1) MAP \<65 mmHg at 3 hours, (2) Need for increase in background norepinephrine to \>0.2 mcg/kg/min despite the addition of the study drug, or (3) Need for a third vasopressor.

  3 hours

Secondary Outcomes (14)

• BP goal at other time points

  Up to 72 hours

• Time to shock reversal

  Up to 72 hours

• Change in catecholamine dose

  Up to 72 hours

• SOFA score

  Up to 72 hours

• Acute Kidney Injury (AKI)

  Up to 28 days

Study Arms (2)

angiotensin II (intervention)

EXPERIMENTAL

For patients randomized to the intervention group, once the dose of background norepinephrine reaches ≥0.2 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 according to the schema in UNM Hospitals Nursing Department Titration Guideline. Angiotensin II treatment will be capped at 72h, at which point (if a second vasopressor is still needed) the patient will be started on an alternative agent.

Drug: Angiotensin II

vasopressin (standard of care)

ACTIVE COMPARATOR

In patients randomized to the control group, once the dose of background norepinephrine reaches ≥0.2 mcg/kg/min for ≥30 minutes, vasopressin will be used at a fixed dose of 0.04 units/min and norepinephrine will be titrated per usual standard of care (as also outlined in the UNM Hospitals Nursing Department Titration Guideline).

Drug: Vasopressin

Interventions

Angiotensin II DRUG

Angiotensin II (Giapreza) is a pharmacologic version of a naturally occurring hormone of the same name, peptide hormone of the renin-angiotensin-aldosterone system (RAAS), that was FDA-approved in 2017 as a vasoconstrictive agent in the treatment of vasodilatory shock.

Also known as: Giapreza

angiotensin II (intervention)

Vasopressin DRUG

Vasopressin (Vasostrict) is a pharmacologic version of a naturally occurring peptide hormone that serves as a vasoconstrictive agent in the treatment of vasodilatory shock.

Also known as: Vasostrict

vasopressin (standard of care)

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 vasodilatory shock refractory to norepinephrine monotherapy, defined as those who require ≥0.2 mcg/kg/min to maintain a MAP between 65-70 mmHg. Patients will be screened once they require ≥0.1 mcg/kg/min of norepinephrine and, if eligible, may be consented at this point. Study drug (angiotensin II or vasopressin) will be initiated once norepinephrine dose reaches ≥0.2 mcg/kg/min for at least 30 minutes.
• \. 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 veno-arterial (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 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

• University of New Mexico: lead
• La Jolla Pharmaceutical Company: collaborator
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (1)

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, 87106, United States

Location

Related Publications (6)

• 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

• Busse L, Albertson T, Gong M. Outcomes in patients with acute respiratory distress syndrome receiving angiotensin II for vasodilatory shock. Crit Care. 2018;22(Suppl 1):82.

  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

MeSH Terms

Conditions

Shock, Septic; Diabetes Insipidus

Interventions

Angiotensin II; Giapreza; Vasopressins; Arginine Vasopressin

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pituitary Diseases; Endocrine System Diseases

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; Pituitary Hormones, Posterior; Pituitary Hormones

Study Officials

• Joao P Teixeira, MD

  University of New Mexico School of Medicine

  PRINCIPAL INVESTIGATOR

• Nathan D Nielsen, MD MSc

  University of New Mexico School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: single-center, open-label pragmatic randomized controlled pilot trial using block randomization

Study Record Dates

• First Submitted: December 9, 2021
• First Posted: January 14, 2022
• Study Start: January 3, 2022
• Primary Completion: November 30, 2022
• Study Completion: November 30, 2022
• Last Updated: March 15, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)