Renin and Renal Biomarker Response to Angiotensin II

Study Overview
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Brief Summary
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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.

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

Conditions
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Septic Shock, Acute Kidney Injury

Intervention / Treatment
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* Other: Standard of Care
* Drug: Angiotensin II


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renin, Angiotensin II, vasopressor, sepsis