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NCT Number: NCT06746753

Mechanistic Assessment of Norepinephrine Therapy vs. Angiotensin-II 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.

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Key information

Conditions

Septic Shock Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Infections Inflammation Kidney Diseases Male Urogenital Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Sepsis Shock Shock, Septic Systemic Inflammatory Response Syndrome Urogenital Diseases Urologic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Massachusetts General Hospital-Harvard, Boston, Massachusetts, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Angiotensin II

Drug

randomized to receive Angiotensin II continuous infusion for up to 48 hours

norepinephrine

Drug

randomized to receive Norepinephrine continuous infusion for up to 48 hours

Primary outcomes

  1. Mean Renin Level - Hour 24

    Time frame: 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.

Secondary outcomes

  1. Norepinephrine Equivalent Dose Requirement (NEE)

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72

    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.

  2. Number of Days Without Renal Replacement Therapy

    Time frame: Day 28

    Number of days without renal replacement therapy

  3. Number of Days of Vasopressor Use

    Time frame: Day 28

    Number of days without vasopressor use

  4. Number of Days Without Mechanical Ventilation

    Time frame: Day 28

    Number of days without invasive mechanical ventilation

  5. Number of Hours Vasopressor Free

    Time frame: Hour 72

    Number of hours without requiring vasopressors during first 72 hours after randomization

  6. Number of Hours Alive

    Time frame: Hour 72

    Number of hours alive during first 72 hours after randomization

  7. Number of Days Alive

    Time frame: Day 28

    Number of days alive

  8. Mean Renin Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 48, Hour 72

    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.

  9. Sequential Organ Failure Assessment (SOFA) Score

    Time frame: Baseline, Hour 24, Hour 48

    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.

  10. APACHE-II Score

    Time frame: Baseline, Hour 24, Hour 48

    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.

  11. Lactate Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72

    Lactate is an indicator of sepsis severity. Levels 2.3-20 mmol/L indicate sepsis. The higher the score the more severe.

  12. Kidney Disease Improving Global Outcomes (KDIGO) Stage

    Time frame: Baseline, Hour 24, Hour 48

    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.

  13. Creatinine Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  14. BUN Level

    Time frame: Baseline, Hour 24, Hour 48

    BUN level is an indicator of renal disease severity. Levels above 24 mg/dL indicate renal disease. The higher the level the more severe.

  15. Bicarbonate Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  16. Number of Participants with Acute Respiratory Distress Syndrome (ARDS)

    Time frame: Baseline, Hour 24, Hour 48

    Number of participants with ARDS

  17. SpO2/FiO2 Ratio Level

    Time frame: Baseline, Hour 24, Hour 48

    SpO2/FiO2 ratio level is an indicator of lung injury severity. Mild severity 315-235, moderate severity 148-235, severe <148.

  18. PaO2/FiO2 Ratio Level

    Time frame: Baseline, Hour 24, Hour 48

    PaO2/FiO2 ratio level is an indicator of lung injury severity. Mild severity 201-300 mmHg; moderate severity 101-200 mmHg, severe ≤ 100 mmHg.

  19. Serum Aspartate Aminotransferases Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  20. Alanine Aminotransferases Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  21. Alkaline Phosphatase Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  22. Bilirubin Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  23. Albumin Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  24. Troponin I Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  25. Troponin T Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  26. Neutrophil Gelatinase-Associated Lipocalin Serum Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  27. Neutrophil Gelatinase-Associated Lipocalin Urine Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  28. Kidney Injury Molecule-I Urine Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  29. Kidney Injury Molecule-I Blood Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  30. Soluble Receptor for Advanced Glycation End Product Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  31. Angiopoietin-2 Level

    Time frame: Baseline, Hour 24, Hour 48, Hour 72

    Angiopoietin-2 level is a marker of inflammation. Normal range is 1434-4141 pg/mL. Levels higher than normal indicate inflammation.

  32. Syndecan-1 Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  33. Protein C Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  34. Neuron-Specific Enolase Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  35. S-100β Level

    Time frame: Baseline, Hour 24, Hour 48

    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.

  36. TNFα Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  37. sTNFR1 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  38. IL-6 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  39. sIL-6R Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  40. IL-8 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  41. IL-1β Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  42. Interferon Gamma Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  43. IL12p70 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  44. IL-17 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  45. MIP1-alpha Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  46. MIP1-beta Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  47. IP-10 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  48. IL-10 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  49. IL-1RA Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  50. IL-12p40 Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  51. C reactive protein (CRP) Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  52. Procalcitonin Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    Procalcitonin level is an indicator of systemic inflammation. Levels >0.25 mg/ml indicate inflammation and infection. The higher the score the more severe.

  53. Platelet Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  54. Absolute Neutrophil Count Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  55. Absolute Granulocyte Count Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  56. Absolute Lymphocytes Count Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  57. Neutrophil-Lymphocyte Ratio Level

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48

    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.

  58. Angiotensin (1-7)

    Time frame: Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72

    Angiotensin (1-7) level as a measure of the renin-angiotensin-aldosterone system

  59. Plasma renin activity

    Time frame: baseline, hour 3, hour 12, hour 24, hour 48

    levels at indicated timepoints

  60. Prorenin

    Time frame: baseline, hour 3, hour 12, hour 24, hour 48

    levels at indicated timepoints

  61. Soluble prorenin receptor (sPRR)

    Time frame: baseline, hour 24, hour 48

    levels at indicated timepoints

  62. Aldosterone

    Time frame: baseline, hour 3, hour 12, hour 24, hour 48

    levels at indicated timepoints

  63. Intact Aogen

    Time frame: baseline, hour 24, hour 48

    levels at indicated timepoints

  64. ANG II

    Time frame: baseline, hour 3, hour 12, hour 24, hour 48, hour 72

    levels at indicated timepoints

  65. Angiotensin-converting enzyme (ACE)

    Time frame: baseline, hour 24, hour 48

    levels at indicated timepoints

  66. Angiotensin-converting enzyme-2 (ACE2)

    Time frame: baseline, hour 24, hour 48

    levels at indicated timepoints

  67. Dipeptidyl peptidase 3 (DPP3)

    Time frame: baseline, hour 24, hour 48

    levels at indicated timepoints

  68. RNA Paxgene Bulk (Bulk RNA sequencing)

    Time frame: baseline, hour 24, hour 48

    levels at indicated timepoints

  69. Whole blood cryopreserved (scRNAsesq)

    Time frame: baseline, hour 24, hour 48

    levels at indicated timepoints

Other outcomes

  1. Patients with New Deep Venous Thrombosis

    Time frame: Day 7, Day 28

    Number of patients with development of new deep venous thrombosis

  2. Patients with New Pulmonary Embolism

    Time frame: Day 7, Day 28

    Number of patients with development of new pulmonary embolism

  3. Patients with New-Onset Atrial Fibrillation

    Time frame: Hour 72, day 28

    Number of patients with new-onset atrial fibrillation

  4. Patients with New-Onset Ventricular Arrhythmias

    Time frame: Hour 72, Day 7, Day 28

    Number of patients with new-onset ventricular arrhythmias

Study contacts

Contact information is provided by the study sponsor or research team.

Ashish Khanna, MD

CONTACT

[email protected]

513-658-5866

Lynnette Harris, RN

CONTACT

[email protected]

336-716-8791

Sponsors and collaborators

Lead sponsor

Wake Forest University Health Sciences

Other

Collaborators

  • National Heart, Lung, and Blood Institute (NHLBI)

Registry information

Official study title

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

Acronym: MANTRA

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Dec 24, 2024
Registry last updated
Jul 24, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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