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Angiotensin II vs. Vasopressin in Septic Shock

Primary Purpose

Septic Shock

Status

Withdrawn

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Angiotensin II

Vasopressin

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring septic shock, vasopressor, angiotensin II, vasopressin, renin, randomized controlled trial

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Approval from the attending physician and clinical pharmacist conducting the study.

Exclusion Criteria:

1. Patients who are < 18 years of age.
2. Patients diagnosed with acute occlusive coronary syndrome requiring intervention and/or cardiogenic shock.
3. Patients with or suspected to have abdominal aortic aneurysm or aortic dissection.
4. Acute stroke.
5. Patients with acute mesenteric ischemia or those with a history of mesenteric ischemia.
6. Patients with known Raynaud's phenomenon, systemic sclerosis, or vasospastic disease.
7. Patients on veno-arterial (VA) ECMO.
8. Patients with liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥30.
9. Patients with burns covering >20% of total body surface area.
10. 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.
11. Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose.
12 Patients with an absolute neutrophil count (ANC) of < 1,000/mm3.
13. 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.
14. Patients with active bleeding AND hemoglobin < 7g/dL or any other condition that would contraindicate serial blood sampling.
15. Untreated venous thromboembolism (VTE) or inability to tolerate pharmacologic VTE prophylaxis.
16. Patients with a known allergy to mannitol.
17. Patients with an expected survival of <24 hours, SOFA score ≥ 16, or death deemed to be imminent or inevitable during the admission
18. Either the attending physician or patient and/or substitute decision-maker are not committed to all active treatment (e.g., DNR status).
19. 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.]
20. Prisoner status
21. Patients who are current participating in another interventional clinical trial.

Sites / Locations

University of New Mexico Health Sciences Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

angiotensin II (intervention)

vasopressin (standard of care)

Arm Description

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.

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

BP goal at other time points

The primary endpoint will be re-assessed at multiple additional time points (1 hour, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours)

Time to shock reversal

Time to sustained shock reversal (vasopressor independence).

Change in catecholamine dose

Change in catecholamine dose (as quantified in norepinephrine equivalents) at 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours.

SOFA score

Change in Sequential Organ Failure Assessment (SOFA) scores and/or organ-specific SOFA sub-scores at 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours. SOFA ranges from 0 to 24 with higher score indicating higher illness severity.

Acute Kidney Injury (AKI)

Frequency of AKI, as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria.

Freedom from Renal Replacement Therapy (RRT)

Days free from RRT (in first 28 days post study drug initiation)

Ventilator-free days

Days free from invasive mechanical ventilation (in first 28 days post drug initiation)

ICU LOS

ICU length of stay

Hospital LOS

Hospital length of stay

ICU mortality

ICU mortality (defined as binary yes/no, until ICU discharge or 28 days from drug initiation)

Hospital mortality

Hospital mortality (defined as binary yes/no, until hospital discharge or 28 days from drug initiation)

Renin levels

Renin levels will be obtained at 4 times points: at consent/pre-baseline; at baseline/time 0 (drug initiation); 1 hour post-initiation; and 3 hours post-initiation. The investigators will also perform exploratory analyses of differences in the primary and secondary outcomes as stratified by renin levels and/or changes in renin level.

Subgroup analyses

The investigators will perform exploratory analyses of the other primary and secondary outcomes as stratified by disease severity (as measured by SOFA scores). All the other primary and secondary outcomes will be also re-analyzed to assess for differences within the following subgroups: presence or absence of AKI presence or absence of ARDS

Prespecified Adverse Events

For these to be considered adverse events (AEs) they must be new hospital-acquired events which developed after randomization. The pre-defined AEs that will be tracked will include the rates of: New venous thromboembolism (VTE) or arterial thrombosis diagnosed during hospital stay. Atrial fibrillation Tachycardia Lactic acidosis Peripheral limb/digit ischemia Intestinal ischemia Thrombocytopenia Hyperglycemia Confirmed infection (with infecting organism confirmed by culture or other identification method; administration of appropriate antibiotic therapy; and clinical documentation of infection) Any other AE that is felt to be potentially related to study drug

Full Information

NCT ID

NCT05193370

First Posted

December 9, 2021

Last Updated

March 10, 2023

Sponsor

University of New Mexico

Collaborators

La Jolla Pharmaceutical Company, National Center for Advancing Translational Sciences (NCATS)

1. Study Identification

Unique Protocol Identification Number

NCT05193370

Brief Title

Angiotensin II vs. Vasopressin in Septic Shock

Official Title

A Randomized Controlled Pilot Trial of Angiotensin II Versus Vasopressin as Second-line Vasopressor in the Treatment of Septic Shock

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Withdrawn

Why Stopped

Funding and protocol changes. Replaced with new pilot trial.

Study Start Date

January 3, 2022 (Anticipated)

Primary Completion Date

November 30, 2022 (Anticipated)

Study Completion Date

November 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of New Mexico

Collaborators

La Jolla Pharmaceutical Company, National Center for Advancing Translational Sciences (NCATS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

Detailed Description

Sepsis affects >1 million Americans yearly and, when septic shock ensues, 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. This study is a pilot randomized controlled trial (RCT) comparing AngII (intervention) and vasopressin (standard of care) as second-line vasopressors in septic shock. The goal is to demonstrate feasibility of a large multicenter RCT and eventually to demonstrate that AngII use improves important endpoints (e.g., mortality, need for organ support) in all or certain subsets of patients with septic shock. Furthermore, there are no biomarkers currently available and validated to guide the choice of vasopressor therapy in septic shock. In this study the investigators will investigate serum renin as such a biomarker. Renin has been shown in preliminary studies to accurately predict mortality in septic shock, outperforming lactate, and to predict beneficial response to AngII. The investigators aim to validate the use of renin as a biomarker in septic shock and prove its utility in guiding vasopressor selection, with the goal of incorporating renin levels at specified time points and/or change in renin levels into an algorithm used to select patients for AngII therapy in the subsequent large multicenter RCT.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Septic Shock

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

angiotensin II (intervention)

Arm Type

Experimental

Arm Description

Arm Title

vasopressin (standard of care)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Angiotensin II

Other Intervention Name(s)

Giapreza

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Vasopressin

Other Intervention Name(s)

Vasostrict

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

Time Frame

3 hours

Secondary Outcome Measure Information:

Title

BP goal at other time points

Description

The primary endpoint will be re-assessed at multiple additional time points (1 hour, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours)

Time Frame

Up to 72 hours

Title

Time to shock reversal

Description

Time to sustained shock reversal (vasopressor independence).

Time Frame

Up to 72 hours

Title

Change in catecholamine dose

Description

Change in catecholamine dose (as quantified in norepinephrine equivalents) at 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours.

Time Frame

Up to 72 hours

Title

SOFA score

Description

Time Frame

Up to 72 hours

Title

Acute Kidney Injury (AKI)

Description

Frequency of AKI, as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria.

Time Frame

Up to 28 days

Title

Freedom from Renal Replacement Therapy (RRT)

Description

Days free from RRT (in first 28 days post study drug initiation)

Time Frame

Up to 28 days

Title

Ventilator-free days

Description

Days free from invasive mechanical ventilation (in first 28 days post drug initiation)

Time Frame

Up to 28 days

Title

ICU LOS

Description

ICU length of stay

Time Frame

Though study completion, up to 1 year

Title

Hospital LOS

Description

Hospital length of stay

Time Frame

Though study completion, up to 1 year

Title

ICU mortality

Description

ICU mortality (defined as binary yes/no, until ICU discharge or 28 days from drug initiation)

Time Frame

Up to 28 days

Title

Hospital mortality

Description

Hospital mortality (defined as binary yes/no, until hospital discharge or 28 days from drug initiation)

Time Frame

Up to 28 days

Title

Renin levels

Description

Time Frame

Up to 3 hours

Title

Subgroup analyses

Description

Time Frame

Though study completion, up to 1 year

Title

Prespecified Adverse Events

Description

Time Frame

Up to 28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. Approval from the attending physician and clinical pharmacist conducting the study. Exclusion Criteria: 1. Patients who are < 18 years of age. 2. Patients diagnosed with acute occlusive coronary syndrome requiring intervention and/or cardiogenic shock. 3. Patients with or suspected to have abdominal aortic aneurysm or aortic dissection. 4. Acute stroke. 5. Patients with acute mesenteric ischemia or those with a history of mesenteric ischemia. 6. Patients with known Raynaud's phenomenon, systemic sclerosis, or vasospastic disease. 7. Patients on veno-arterial (VA) ECMO. 8. Patients with liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥30. 9. Patients with burns covering >20% of total body surface area. 10. 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. 11. Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose. 12 Patients with an absolute neutrophil count (ANC) of < 1,000/mm3. 13. 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. 14. Patients with active bleeding AND hemoglobin < 7g/dL or any other condition that would contraindicate serial blood sampling. 15. Untreated venous thromboembolism (VTE) or inability to tolerate pharmacologic VTE prophylaxis. 16. Patients with a known allergy to mannitol. 17. Patients with an expected survival of <24 hours, SOFA score ≥ 16, or death deemed to be imminent or inevitable during the admission 18. Either the attending physician or patient and/or substitute decision-maker are not committed to all active treatment (e.g., DNR status). 19. 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.] 20. Prisoner status 21. Patients who are current participating in another interventional clinical trial.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joao P Teixeira, MD

Organizational Affiliation

University of New Mexico School of Medicine

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Nathan D Nielsen, MD MSc

Organizational Affiliation

University of New Mexico School of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of New Mexico Health Sciences Center

City

Albuquerque

State/Province

New Mexico

ZIP/Postal Code

87106

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

28528561

Citation

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.

Results Reference

background

PubMed Identifier

29509568

Citation

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. Erratum In: Crit Care Med. 2018 Aug;46(8):e824.

Results Reference

background

PubMed Identifier

27483065

Citation

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.

Results Reference

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Citation

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.

Results Reference

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PubMed Identifier

30653055

Citation

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.

Results Reference

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PubMed Identifier

32609011

Citation

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.

Results Reference

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Angiotensin II vs. Vasopressin in Septic Shock

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