Renin and Renal Biomarker Response to Angiotensin II

Overview

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.

Full Title of Study: “Renin and Renal Biomarker Response to Angiotensin II Versus Controls in Septic Shock: An Open-Label Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: July 24, 2023

Interventions

  • Other: Standard of Care
    • These patients will receive standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured.
  • 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.

Arms, Groups and Cohorts

  • Active Comparator: Standard of Care Cohort
    • Patients in this group will receive standard of care treatment.
  • Experimental: Angiotensin II Cohort
    • Patients in this group will receive angiotensin II.

Clinical Trial Outcome Measures

Primary Measures

  • Change in Plasma Renin Levels
    • Time Frame: Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days)
    • 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.

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Alexander Flannery
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Alexander Flannery, Assistant Professor – University of Kentucky
  • Overall Official(s)
    • Alexander H Flannery, Pharm.D., Principal Investigator, University of Kentucky

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