Hemodynamic Response to Angiotensin-II When Used as the Second Vasopressor Agent for Septic Shock

An Open-label, Single-arm, Single-center Study Evaluating the Hemodynamic Response to Angiotensin-II When Used as the Second Vasopressor Agent for Septic Shock

Norepinephrine is a catecholamine that is the first-line vasopressor for septic shock. The addition of non-catecholamine vasopressors, including vasopressin and angiotensin-II may be used in adults with septic shock that have inadequate mean arterial pressure while on norepinephrine. Uncertainty exists regarding the timing of initiation of these agents and there is a lack of data comparing their safety and efficacy.

The current literature suggests that earlier initiation of angiotensin-II will have a more significant reduction on norepinephrine-equivalent dose compared to later initiation. In addition, approximately half of patients initiated on vasopressin do not have an early hemodynamic response 6 hours after initiation. The purpose of this study is to evaluate the efficacy of angiotensin-II when used as the second vasopressor agent for septic shock.

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis; Systemic Inflammatory Response Syndrome; Shock; Septic Shock
• Intervention / Treatment: Drug: Angiotensin II and hydrocortisone sodium succinate

Detailed Description

Objectives:

Primary Objective:

1. To evaluate the efficacy of ang-II when used as the second vasopressor agent for septic shock

Secondary Objectives:

1. To assess the duration of response to ang-II
2. To assess overall survival
3. To assess the amount of time spent in the ICU
4. To assess the need for renal replacement therapy
5. To assess the overall duration of vasoactive medication use
6. To assess toxicity and tolerability

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Tyson Dietrich, PharmD; Phone Number: 928-263-3933; Email: TDietrich@azkrmc.com
• Study Contact Backup: Name: Anthony Santarelli, PhD; Phone Number: 5143 928-757-0649; Email: anthony.santarelli@azkrmc.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients admitted to the ICU within 12 hours of presentation to the emergency department for septic shock requiring 15-25 mcg/min of norepinephrine. Septic shock will be defined as having a known or presumed infection with two or more criteria of systemic inflammatory response syndrome, a mean arterial pressure <65 mm Hg despite fluid resuscitation requiring vasopressor support, and a serum lactate >2 mmol/L. Criteria of systemic inflammatory response syndrome include a temperature >100.4°F or <96.8°F; heart rate >90/min; respiratory rate >20/min and a white blood cell count >12,000/mm3 or <4,000/mm3.

Exclusion Criteria:

• Age <18 years
• Pregnancy or lactation
• Known allergic reactions to angiotensin-II or hydrocortisone sodium succinate
• Requiring >25 mcg/min of norepinephrine or on any vasopressor other than norepinephrine at study enrollment
• Clinically significant bleeding precluding the use of chemical prophylaxis for venous thromboembolism
• Treatment with another investigational drug or other intervention during study timeframe

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Arm; Drug: Angiotensin II Other Names: Giapreza	Drug: Angiotensin II and hydrocortisone sodium succinate; Intravenous infusion angiotensin II (titrated for each individual patient by effect) and hydrocortisone 50 mg intravenous bolus every 6 hours.; Other Names: Giapreza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of hemodynamic response, defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 1 hour after initiation of angiotensin-II	Defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 1 hour after initiation of angiotensin-II.	1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of hemodynamic response at 3 hours after initiation of angiotensin-II	Defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 3 hours after initiation of angiotensin-II.	3 hours
The incidence of hemodynamic response at 6 hours after initiation of angiotensin-II	Defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 6 hours after initiation of angiotensin-II.	6 hours
28-day mortality	Defined as all cause mortality up to 28 days from study enrollment.	28 days
ICU length of stay	Defined as the time spent within the ICU until discharge to a step down unit.	1 year
Need for renal replacement therapy	Defined as patients started on either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD) during the study period.	1 year
Vasoactive medication duration overall	Defined as the duration (hours) of vasoactive medication use during the study period.	1 year
Incidence of adverse reactions	Define as an unexpected or unintended effect suspected to be caused by a medicine.	1 year

Collaborators and Investigators

• Sponsor: Kingman Regional Medical Center
• Collaborators: La Jolla Pharmaceutical Company
• Investigators: Principal Investigator: Tyson Dietrich, PharmD, Kingman Regional Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: November 3, 2023
• First Submitted That Met QC Criteria: November 3, 2023
• First Posted (Estimated): November 8, 2023

Study Record Updates

• Last Update Posted (Estimated): November 8, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Sepsis; Hydrocortisone; Angiotensin II
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Inflammation; Sepsis; Shock, Septic; Shock; Systemic Inflammatory Response Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Protease Inhibitors; Serine Proteinase Inhibitors; Vasoconstrictor Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Angiotensin II; Giapreza; Angiotensinogen
• Other Study ID Numbers: KRMC 0284

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes