Renin and Renal Biomarker Response to Angiotensin II

Renin and Renal Biomarker Response to Angiotensin II Versus Controls in Septic Shock: An Open-Label Study

Septic shock continues to exert a large economic burden around the world. Several developments have occurred that lead to the current study. First, angiotensin II is the newest FDA approved vasopressor agent indicated for use in vasodilatory shock. Several subgroups from the approval trial have indicated that angiotensin II may confer a survival benefit in certain conditions, including those patients requiring continuous renal replacement therapy, those with altered angiotensin I: angiotensin II ratios, and most recently, those with elevated renin levels (which may serve as a surrogate for dysfunctional angiotensin 1: angiotensin II ratios). This open-label, sequential period pilot study will evaluate angiotensin II and biomarker response (renin) in the treatment of septic shock.

Study Overview

• Status: Completed
• Conditions: Septic Shock; Acute Kidney Injury
• Intervention / Treatment: Other: Standard of Care; Drug: Angiotensin II

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alexander H Flannery, Pharm.D.; Phone Number: 859-562-2766; Email: alex.flannery@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky HealthCare Chandler Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Medical ICU admission
• Septic shock
• Norepinephrine requirement = 0.15 mcg/kg/min for = 30 minutes (if cirrhosis, norepinephrine requirement = 0.1 mcg/kg/min for = 30 minutes)
• Kidney Disease Improving Global Outcomes stage 1 or greater AKI

Exclusion Criteria:

• Prisoner
• Pregnancy
• Acute occlusive coronary syndrome requiring intervention or acute myocardial infarction of any degree
• Purely cardiogenic shock (no distributive component)
• Mesenteric ischemia
• Acute ischemic stroke
• Hemorrhagic shock
• Active treatment of hepatorenal syndrome targeting a MAP = 65 mm Hg
• Planned withdrawal of care within next 24 hours or no escalation of care
• Patient enrolled in an interventional study
• High likelihood of medical futility in using this drug:
• 3 or more vasopressors required to sustain MAP
• Sustained norepinephrine equivalents > 0.5 mcg/kg/min
• COVID-19 positive, or high suspicion of COVID-19

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care Cohort; Patients in this group will receive standard of care treatment.	Other: Standard of Care; These patients will receive standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured.
Experimental: Angiotensin II Cohort; Patients in this group will receive angiotensin II.	Drug: Angiotensin II; These patients will receive angiotensin II in addition to standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma Renin Levels	Plasma renin levels will be measured from blood collected at baseline, 24 hours, and at shock resolution. Additionally, a 3-hour measurement will be included in the angiotensin II arm.	Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Renal Biomarkers	Cystatin C, NGAL will be measured from blood collected at baseline, 24 hours, and at shock resolution.	Until shock resolution, up to 14 days (at baseline, 24 hours, and shock resolution, up to 14 days)
Time to discontinuation of catecholamines	Time from enrollment to discontinuation of catecholamines	Until shock resolution, up to 14 days
ICU Length of Stay	Number of days in the intensive care unit (ICU).	From enrollment to ICU discharge, up to 28 days following enrollment
In-hospital mortality	Assessment of all-cause mortality within hospital admission	Up to 3 months following enrollment
Renal replacement therapy-free days	Days free of renal replacement therapy from enrollment up to day 28	Within 28 days of enrollment
Safety outcomes	Incidence of venous thromboembolism, arrhythmia, extremity hypoperfusion, delirium, new ischemic event, new infection	Up to 72 hours following shock resolution, no longer than 17 days from enrollment

Collaborators and Investigators

• Sponsor: Alexander Flannery
• Investigators: Principal Investigator: Alexander H Flannery, Pharm.D., University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2020
• Primary Completion (Actual): July 24, 2023
• Study Completion (Actual): July 30, 2023

Study Registration Dates

• First Submitted: September 7, 2020
• First Submitted That Met QC Criteria: September 15, 2020
• First Posted (Actual): September 22, 2020

Study Record Updates

• Last Update Posted (Actual): August 9, 2023
• Last Update Submitted That Met QC Criteria: August 8, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: sepsis; Renin; Angiotensin II; vasopressor
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Kidney Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Renal Insufficiency; Shock; Sepsis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Shock, Septic; Acute Kidney Injury; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Vasoconstrictor Agents; Angiotensin II; Giapreza; Angiotensinogen
• Other Study ID Numbers: 57411

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