Mechanistic Assessment of Norepinephrine Therapy vs. Angiotensin-II in Septic Shock (MANTRA)

Mechanistic Assessment of Norepinephrine TheRapy vs. Angiotensin-II in Septic Shock (MANTRA) Grant Submission- Dysfunctional Renin-Angiotensin System in Septic Shock

Despite best therapy efforts, sepsis and septic shock are associated with mortality rates of up to 40%. This clinical trial will determine the benefit of exogenous Angiotensin II versus norepinephrine (conventional care) treatment in septic shock patients. This trial will determine whether there are better predictors of septic shock severity. This approach may inform more appropriate treatment regimens and improve outcomes for these patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Angiotensin II; Drug: Norepinephrine

Detailed Description

This study will determine whether normalization of renin-angiotensin-aldosterone system (RAAS) signaling in sepsis occurs more rapidly with treatment with Angiotensin II compared with conventional vasopressors. Trial samples will be used to identify the best RAAS biomarker predictor of treatment response via in-depth longitudinal analysis of RAAS component and to determine the extent and mechanisms of Angiotensin II impact on innate immune function during sepsis. Successful accomplishment of our aims will provide the capability to improve endotyping of septic patients by establishing the most precise and robust measurement of renin (and RAAS dysfunction). This work will improve staging and clinical precision and will facilitate the criteria for therapeutic development of targets in septic shock.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ashish Khanna, MD; Phone Number: 513-658-5866; Email: ashish.khanna@wfusm.edu
• Study Contact Backup: Name: Lynnette Harris, RN; Phone Number: 336-716-8791; Email: lynnette.harris@advocatehealth.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital-Harvard
      • Contact: Michael R Filbin, MD, MS; Email: mfilbin@mgh.harvard.edu
      • Contact: Daniel E Leisman, MD; Email: dleisman@mgh.harvard.edu
      • Principal Investigator: Michael R Filbin, MD, MS
      • Principal Investigator: Daniel E Leisman, MD
      • Sub-Investigator: Marcia Goldberg, MD
      • Sub-Investigator: Kathryn Hibbert, MD
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Atrium Health Wake Forest Baptist
      • Contact: Lynnette C Harris, BSN; Phone Number: 336-716-8791; Email: lcharris@wakehealth.edu
      • Contact: Ashish Khanna, MD; Phone Number: 513-658-5866; Email: akhanna@wakehealth.edu
      • Principal Investigator: Ashish Khanna, MD
      • Sub-Investigator: Christopher Schaich, PhD
      • Sub-Investigator: Daniel C Files, MD
      • Principal Investigator: Mark Chappell, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

- The presence of septic shock, defined by sepsis-3 criteria: 1-adult patients (18 years or older) with septic shock, defined by SEPSIS-3 criteria: a) suspected or known infection, b) hypotension requiring vasopressors, and c) lactate >2mmol/L 2-receiving either norepinephrine or phenylephrine with or without additional vasopressor support 3- total norepinephrine equivalent dose (NED) ≥0.1 mcg/kg/min and ≤0.5 mcg/kg/min, to maintain a MAP of at least 65 mmHg, is required for randomization 4-ability to consent and randomize within 24 hrs of first reaching NED threshold and within 48 hrs of hospital arrival

Exclusion Criteria:

• Age <18 years
• Prisoners
• Pregnant women
• Patients for whom urgent surgery is anticipated
• Leukocyte count <1,000 cells/μL
• Absolute monocyte count <200 cells/μL
• Bone marrow transplant within the past 30 days
• Patients that will be withdrawing aggressive resuscitation, including withdraw of vasopressor support
• transfer from outside ICU
• history of liver cirrhosis with Child-Pugh score ≥6

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Angiotensin II; Continuous infusion of Angiotensin II for up to 48 hours	Drug: Angiotensin II; randomized to receive Angiotensin II continuous infusion for up to 48 hours
Active Comparator: Norepinephrine; Continuous infusion of Norepinephrine for up to 48 hours	Drug: Norepinephrine; randomized to receive Norepinephrine continuous infusion for up to 48 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Renin Level - Hour 24	Mean plasma renin level (PRA) as a measure of renin-angiotensin-aldosterone system restoration. Normal levels of active renin <1.1 pM (40 pg/mL). A level higher than normal can indicate level of shock.	Hour 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Days Without Renal Replacement Therapy	Number of days without renal replacement therapy	Day 28
Number of Days of Vasopressor Use	Number of days without vasopressor use	Day 28
Number of Days Without Mechanical Ventilation	Number of days without invasive mechanical ventilation	Day 28
Number of Hours Vasopressor Free	Number of hours without requiring vasopressors during first 72 hours after randomization	Hour 72
Number of Hours Alive	Number of hours alive during first 72 hours after randomization	Hour 72
Number of Days Alive	Number of days alive	Day 28
Sequential Organ Failure Assessment (SOFA) Score	SOFA score indicates the number and severity of failed organs and provides prognostic information on in-hospital survival in patients with severe sepsis and septic shock. Score above 0 indicates organ failure. The higher the score the more failed organs and degree of organ failure.	Baseline, Hour 24, Hour 48
APACHE-II Score	APACHE-II score assesses severity of illness in critically ill patients and indicates risk of mortality. Score range 0-10 low risk of mortality, 11-20 moderate risk, 21-30 high risk, 31 or above very high risk.	Baseline, Hour 24, Hour 48
Kidney Disease Improving Global Outcomes (KDIGO) Stage	Participant stage of acute kidney injury will be determined as follows Stage 1: Increase in serum creatinine ≥ 0.3 mg/dL in 48 hours or 1.5 to 1.9 multiplied by baseline (in 7 days); Stage 2: 2.0 to 2.9 multiplied by baseline serum creatinine; Stage 3: 3.0 or more multiplied by baseline; increase in serum creatinine ≥ 4.0 mg/dL; or beginning of renal replacement therapy regardless of a previous KDIGO stage. Higher stage indicates higher severity of renal failure.	Baseline, Hour 24, Hour 48
Creatinine Level	Creatinine level is an indicator of renal disease severity. Normal range for women 0.7-1.3 mg/dL, men 0.6-1.1 mg/dL. Levels higher than normal indicate renal disease. The higher the level the more severe.	Baseline, Hour 24, Hour 48
BUN Level	BUN level is an indicator of renal disease severity. Levels above 24 mg/dL indicate renal disease. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Bicarbonate Level	Bicarbonate level is an indicator of acid base disturbance severity. Normal range is 22-29 mEq/L. Levels above or below the normal range indicate acid base disturbance. The higher the score the more severe.	Baseline, Hour 24, Hour 48
Number of Participants with Acute Respiratory Distress Syndrome (ARDS)	Number of participants with ARDS	Baseline, Hour 24, Hour 48
SpO2/FiO2 Ratio Level	SpO2/FiO2 ratio level is an indicator of lung injury severity. Mild severity 315-235, moderate severity 148-235, severe <148.	Baseline, Hour 24, Hour 48
PaO2/FiO2 Ratio Level	PaO2/FiO2 ratio level is an indicator of lung injury severity. Mild severity 201-300 mmHg; moderate severity 101-200 mmHg, severe ≤ 100 mmHg.	Baseline, Hour 24, Hour 48
Serum Aspartate Aminotransferases Level	Serum aspartate aminotransferases level is an indicator of liver injury severity. Normal range 8-48 U/L. Levels above normal indicate livery injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Alanine Aminotransferases Level	Alanine aminotransferases level is indicator of liver injury severity. Normal range 7-55 U/L. Levels higher than normal indicate liver injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Alkaline Phosphatase Level	Alkaline phosphatase level is an indicator of liver injury severity. Normal range 40-129 U/L. Levels higher than normal indicate liver injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Bilirubin Level	Bilirubin level is an indicator of liver injury severity. Normal range 0.1-1.2 mg/dL. Levels higher than normal indicate liver injury. The higher the liver the more severe.	Baseline, Hour 24, Hour 48
Albumin Level	Albumin level is an indicator of liver injury severity. Normal range 3.5-5.0 g/dL. Levels higher than normal indicate liver injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Troponin I Level	Troponin I level is an indicator of cardiac myocyte injury. Normal range 0-0.04 ng/mL. Levels higher than normal indicate cardiac myocyte injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Troponin T Level	Troponin T level is an indicator of cardiac myocyte injury. Normal range 0-0.01 ng/mL. Levels higher than normal indicate cardiac myocyte injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Neutrophil Gelatinase-Associated Lipocalin Serum Level	Neutrophil gelatinase-associated lipocalin serum level indicates risk of kidney injury. Normal serum level is <10 mcg/L. Levels higher than normal indicate risk of kidney injury.	Baseline, Hour 24, Hour 48
Neutrophil Gelatinase-Associated Lipocalin Urine Level	Neutrophil gelatinase-associated lipocalin urine level indicates risk of kidney injury. Normal urine level is ≤50 ng/ml. Risk of kidney disease: Low risk 51-149 ng/ml, moderate risk 150-299 ng/ml, and high risk ≥300 ng/ml.	Baseline, Hour 24, Hour 48
Kidney Injury Molecule-I Urine Level	Kidney injury molecule-I urine level is used to detect kidney injury. Normal level is <1 ng/ml. Levels higher than normal indicate ischemic kidney injury.	Baseline, Hour 24, Hour 48
Kidney Injury Molecule-I Blood Level	Kidney injury molecule-I blood level is used to detect kidney injury. Normal levels 0.42-2.0 ng/ml. Levels higher than normal indicate kidney injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Soluble Receptor for Advanced Glycation End Product Level	Soluble receptor for advanced glycation end product level is a marker of aging, hypertension and diabetes. Normal range is 647-1248 pg/ml. Levels higher than normal indicate risk for hypertension and diabetes.	Baseline, Hour 24, Hour 48
Syndecan-1 Level	Syndecan-1 level is a marker of disease severity in critically ill patients. Levels >20ng/ml indicate severe disease. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Protein C Level	Protein C level is an indicator of inflammation and thrombotic state. Normal level is <8 mg/L. Levels higher than normal indicate inflammation and thrombotic state. The higher the level the more severe.	Baseline, Hour 24, Hour 48
Neuron-Specific Enolase Level	Neuron-specific enolase level is an indicator of brain injury. Normal range is 16-17 ug/L. Levels higher than normal indicate brain injury. The higher the level the more severe.	Baseline, Hour 24, Hour 48
S-100β Level	S-100β level is indicator of brain injury. Normal range is 0.02-0.05 μg/dL. Levels higher than normal indicate brain injury. The higher the number the more severe.	Baseline, Hour 24, Hour 48
TNFα Level	TNFα level is an indicator of systemic inflammation. Normal levels are 75 +/- 15 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
sTNFR1 Level	sTNFR1 level is an indicator of systemic inflammation. Normal levels are <2.4 ng/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL-6 Level	IL-6 level is an indicator of systemic inflammation. Normal range is 0-43.5 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
sIL-6R Level	sIL-6R level is an indicator of systemic inflammation. Normal range is 14-46 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL-8 Level	IL-8 level is an indicator of systemic inflammation. Normal range is 0-66.1 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL-1β Level	IL-1β level is an indicator of systemic inflammation. Normal range is 0.5-12 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Interferon Gamma Level	IFN-ɣ level is an indicator of systemic inflammation. Normal range is 0-8.6 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL12p70 Level	IL12p70 level is an indicator of systemic inflammation. Normal range is 0-1.9 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL-17 Level	IL-17 level is an indicator of systemic inflammation. Normal range is 0-1.4 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
MIP1-alpha Level	MIP1-αlpha level is an indicator of systemic inflammation. Normal range is 0-208 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
MIP1-beta Level	MIP1-beta level is an indicator of systemic inflammation. Normal range is 59-647 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IP-10 Level	IP-10 level is an indicator of systemic inflammation. Normal range is 4.8-9.8 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL-10 Level	IL-10 level is an indicator of systemic inflammation. Normal range is 4.8-9.8 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL-1RA Level	IL-1RA level is an indicator of systemic inflammation. Normal range is 100-300 ng/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
IL-12p40 Level	IL-12p40 level is an indicator of systemic inflammation. Normal range is 0.064-1000 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
C reactive protein (CRP) Level	CRP level is an indicator of systemic inflammation. Normal range is 0-10 mg/dl. Levels higher than normal indicate inflammation. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Procalcitonin Level	Procalcitonin level is an indicator of systemic inflammation. Levels >0.25 mg/ml indicate inflammation and infection. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Platelet Level	Platelet level is an indicator of systemic inflammation and thrombocytosis. Normal range is 150000-450000 platelets per microliter. Levels higher than normal indicate inflammation and thrombocytosis. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Absolute Neutrophil Count Level	Absolute neutrophil count level is an indicator of inflammation and infection/sepsis. Normal range is 2500-7000 neutrophils per microliter. Levels higher than normal indicate inflammation, infection/sepsis. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Absolute Granulocyte Count Level	Absolute granulocyte count level is an indicator of inflammation and infection/sepsis. Normal range is 1500-8500 granulocytes per microliter. Levels higher than normal indicate inflammation, infection/sepsis. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Absolute Lymphocytes Count Level	Absolute lymphocyte count level is an indicator of inflammation and infection/sepsis. Normal range is 1000-4800 granulocytes per microliter. Levels higher than normal indicate inflammation, infection/sepsis. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Neutrophil-Lymphocyte Ratio Level	Neutrophil-lymphocyte ratio level is an indicator of inflammation and infection/sepsis or marrow malignancy. Normal range is 1-2. Levels higher than normal indicate inflammation, infection/sepsis, marrow malignancy. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48
Norepinephrine Equivalent Dose Requirement (NEE)	NEE indicates severity of shock and need for vasopressors to support blood pressure. Normal range is 0.0-1.0 mcg/kg/min. Levels above normal indicate shock and need for vasopressors. The higher the level the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72
Mean Renin Level	Mean renin level as a measure of renin-angiotensin-aldosterone system restoration. Normal levels of active renin <1.1 pM (40 pg/mL). A level higher than normal can indicate level of shock.	Baseline, Hour 3, Hour 12, Hour 48, Hour 72
Angiopoietin-2 Level	Angiopoietin-2 level is a marker of inflammation. Normal range is 1434-4141 pg/mL. Levels higher than normal indicate inflammation.	Baseline, Hour 24, Hour 48, Hour 72
Lactate Level	Lactate is an indicator of sepsis severity. Levels 2.3-20 mmol/L indicate sepsis. The higher the score the more severe.	Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72
Angiotensin (1-7)	Angiotensin (1-7) level as a measure of the renin-angiotensin-aldosterone system	Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72
Plasma renin activity	levels at indicated timepoints	baseline, hour 3, hour 12, hour 24, hour 48
Prorenin	levels at indicated timepoints	baseline, hour 3, hour 12, hour 24, hour 48
Soluble prorenin receptor (sPRR)	levels at indicated timepoints	baseline, hour 24, hour 48
Aldosterone	levels at indicated timepoints	baseline, hour 3, hour 12, hour 24, hour 48
Intact Aogen	levels at indicated timepoints	baseline, hour 24, hour 48
ANG II	levels at indicated timepoints	baseline, hour 3, hour 12, hour 24, hour 48, hour 72
Angiotensin-converting enzyme (ACE)	levels at indicated timepoints	baseline, hour 24, hour 48
Angiotensin-converting enzyme-2 (ACE2)	levels at indicated timepoints	baseline, hour 24, hour 48
Dipeptidyl peptidase 3 (DPP3)	levels at indicated timepoints	baseline, hour 24, hour 48
RNA Paxgene Bulk (Bulk RNA sequencing)	levels at indicated timepoints	baseline, hour 24, hour 48
Whole blood cryopreserved (scRNAsesq)	levels at indicated timepoints	baseline, hour 24, hour 48

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients with New Deep Venous Thrombosis	Number of patients with development of new deep venous thrombosis	Day 7, Day 28
Patients with New Pulmonary Embolism	Number of patients with development of new pulmonary embolism	Day 7, Day 28
Patients with New-Onset Atrial Fibrillation	Number of patients with new-onset atrial fibrillation	Hour 72, day 28
Patients with New-Onset Ventricular Arrhythmias	Number of patients with new-onset ventricular arrhythmias	Hour 72, Day 7, Day 28

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Ashish Khanna, MD, Atrium Health Wake Forest Baptist

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): October 7, 2028

Study Registration Dates

• First Submitted: December 18, 2024
• First Submitted That Met QC Criteria: December 18, 2024
• First Posted (Actual): December 24, 2024

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: kidney disease; intensive care; sepsis
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Sepsis; Kidney Diseases; Shock, Septic; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Hydrocarbons, Aromatic; Amines; Catechols; Phenols; Benzene Derivatives; Alcohols; Amino Alcohols; Ethanolamines; Autacoids; Inflammation Mediators; Biogenic Monoamines; Biogenic Amines; Catecholamines; Angiotensins; Norepinephrine; Angiotensin II
• Other Study ID Numbers: IRB00115287; R01HL177834 (U.S. NIH Grant/Contract)

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.: No