Renin and Renal Biomarker Response to Angiotensin II

• ClinicalTrials.gov Identifier: NCT04558359
• Recruitment Status: Recruiting
• First Posted: September 22, 2020
• Last Update Posted: December 1, 2020
• Sponsor: Alexander Flannery
• Information provided by (Responsible Party): Alexander Flannery, University of Kentucky

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Septic Shock; Acute Kidney Injury	Other: Standard of Care; Drug: Angiotensin II	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Renin and Renal Biomarker Response to Angiotensin II Versus Controls in Septic Shock: An Open-Label Study
• Actual Study Start Date: October 19, 2020
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 31, 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. 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.
2. Time to discontinuation of catecholamines [ Time Frame: Until shock resolution, up to 14 days ]
   Time from enrollment to discontinuation of catecholamines
3. 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).
4. In-hospital mortality [ Time Frame: Up to 3 months following enrollment ]
   Assessment of all-cause mortality within hospital admission
5. Renal replacement therapy-free days [ Time Frame: Within 28 days of enrollment ]
   Days free of renal replacement therapy from enrollment up to day 28
6. 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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Alexander H Flannery, Pharm.D.; 859-562-2766; alex.flannery@uky.edu

Locations

United States, Kentucky

University of Kentucky HealthCare Chandler Medical Center; Recruiting

Lexington, Kentucky, United States, 40536

Contact: Alexander H. Flannery, Pharm.D. 859-323-9078 alex.flannery@uky.edu

Sponsors and Collaborators

Alexander Flannery

Investigators

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

More Information

• Responsible Party: Alexander Flannery, Assistant Professor, University of Kentucky
• ClinicalTrials.gov Identifier: NCT04558359
• Other Study ID Numbers: 57411
• First Posted: September 22, 2020
• Last Update Posted: December 1, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Alexander Flannery, University of Kentucky:

Renin; Angiotensin II; vasopressor; sepsis

Additional relevant MeSH terms:

Angiotensin II; Giapreza; Shock, Septic; Acute Kidney Injury; Shock; Pathologic Processes; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Sepsis; Infection; Systemic Inflammatory Response Syndrome; Inflammation; Angiotensinogen; Vasoconstrictor Agents; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action