Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock

Study Overview
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Brief Summary
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This trial will be a randomized controlled single-center pilot trial comparing the use of angiotensin II versus standard-of-care (SOC) vasopressor therapy in adult patients with persistent vasodilatory shock despite moderate-dose norepinephrine, with a primary outcome of the ability of novel biomarkers (renin and DPP3) to predict blood pressure response to angiotensin II. Given our angiotensin II will be compared to SOC, this will be an unblinded study.

Detailed Description
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Sepsis affects >1 million Americans yearly and, when septic shock ensues, it is associated with high morbidity and mortality. Though first-line norepinephrine is standard of care, there are limited prospective data to guide the choice of additional vasopressors in septic shock. While more studies are needed, preliminary data suggest that the vasopressor angiotensin II (AngII) may improve outcomes in septic shock, especially in certain subsets of patients, such as those with acute kidney injury (AKI) requiring renal replacement therapy (RRT), acute respiratory distress syndrome (ARDS), or high severity of illness. Furthermore, there are no validated biomarkers currently available to guide the choice of vasopressor therapy in septic shock. In this study the investigators will evaluate two potential biomarkers, renin and dipeptidyl peptidase 3 (DPP3). Renin has been shown in preliminary studies to accurately predict mortality in septic shock, outperforming lactate, and to predict beneficial response to AngII. A less well-known candidate biomarker is DPP3, which is an aminopeptidase that cleaves a variety of biologically active oligopeptides including angiotensin II. Similar to renin, preliminary observational data show that elevated DPP3 levels in patients with sepsis are associated with organ dysfunction and short-term mortality, outperforming lactate as a predictor of death. This study is an unblinded pilot randomized controlled trial (RCT) comparing AngII (intervention) to standard-of-care (SOC) vasopressor therapy in adult patients with persistent vasodilatory shock requiring moderate dose norepinephrine. The primary outcome will be the ability of renin and DPP3 to predict blood pressure (BP) response to AngII. As both renin and DPP3 are associated with overall short-term prognosis in sepsis, the SOC arm will allow us to determine if the predictive value of renin and DPP3 is specific to AngII therapy. A variety of secondary clinical outcomes will also be tracked, but the primary purpose of this pilot study is to inform the future design of a large multicenter RCT evaluating the biomarker-guided use of angiotensin II as a second-line vasopressor in septic shock.

Official Title
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DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) Pilot: Serum Biomarkers to Predict Response to Angiotensin II vs. Standard-of-care Vasopressor Therapy in the Treatment of Septic Shock, a Randomized Controlled Pilot Trial

Conditions
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Septic Shock, Vasodilatory Shock

Intervention / Treatment
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* Drug: Angiotensin II


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients ≥18 years-old with persistent vasodilatory shock despite moderate-dose norepinephrine monotherapy, defined as those who require ≥0.1 mcg/kg/min for at least 30 minutes to maintain a MAP between 65-70 mmHg. Patients are required to have central venous and arterial catheters present, and they are expected to remain in place for at least the initial 72 hours of study. Patients are required to have an indwelling urinary catheter present, and it is expected to remain in place for at least the 72 hours of study. Patients must have received 20-30 mL/kg of crystalloid over the previous 24-hour period, as clinically appropriate, and no longer be fluid responsive as per UNMH protocol. By UNMH protocol, lack of fluid responsiveness is considered a failure to increase stroke volume, stroke volume index, cardiac output, or cardiac index (typically measured by non-calibrated pulse contour analysis using a FloTrac device) by at least 10% after a 500-mL crystalloid bolus or a passive leg raise. Patients for whom the treating physicians feel that 20 mL/kg of crystalloid may be clinically inappropriate can qualify for the study if the reason for withholding further IV fluids is documented. Patient or (in patients unable to consent) legal authorized representative (LAR) is willing and able to provide written informed consent and comply with all protocol requirements. Approval from the attending physician and clinical pharmacist conducting the study. Exclusion Criteria: Patients who are < 18 years of age. Patients diagnosed with acute occlusive coronary syndrome requiring intervention and/or cardiogenic shock. Patients with or suspected to have abdominal aortic aneurysm or aortic dissection. Acute stroke. Patients with acute mesenteric ischemia or those with a history of mesenteric ischemia. Patients with known Raynaud's phenomenon, systemic sclerosis, or vasospastic disease. Patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Patients with liver failure with a Model for End-Stage Liver Disease (MELD) score of =/>30. Patients with burns covering >20% of total body surface area. Patients with a history of asthma or chronic obstructive pulmonary disease (COPD) with active acute bronchospasm or (if not mechanically ventilated) with an acute exacerbation of their asthma/COPD requiring the use of inhaled bronchodilators. Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose. Patients with an absolute neutrophil count (ANC) of < 1,000/mm3 Patients with hemorrhagic shock OR active bleeding AND an anticipated need (within 48 hours of initiation of the study) for transfusion of >4 units of packed red blood cells. Patients with active bleeding AND hemoglobin < 7g/dL or any other condition that would contraindicate serial blood sampling. Untreated venous thromboembolism (VTE) or inability to tolerate pharmacologic VTE prophylaxis. Patients with a known allergy to mannitol. Patients with an expected survival of <24 hours, SOFA score ≥ 16, or death deemed to be imminent or inevitable during the admission. Either the attending physician or patient and/or substitute decisionmaker are not committed to all active treatment, e.g., do-not-resuscitate (DNR) status. Patients who are known to be pregnant at the time of screening. All women ≤50 years-old will need a negative serum pregnancy test (serum quantitative beta-hCG) to enroll. Prisoner status Patients who are currently participating in another interventional clinical trial.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Angiotensin II<br>For patients randomized to the intervention group, once the dose of background norepinephrine reaches ≥0.10 mcg/kg/min for ≥30 minutes, angiotensin II will be started at a dose of 20 ng/kg/min (recommended starting dose in package insert).Thereafter, angiotensin II and norepinephrine will both be titrated to mean arterial pressure (MAP) goal of >/= 65 mmHg according to the protocol titration scheme and in accordance with the University of New Mexico Hospital (UNMH) Nursing Department Titration Guideline. Angiotensin II treatment will be capped at 72 hours, at which point (if a second vasopressor is still needed) the patient will be started on an alternative agent. | Drug: Angiotensin II<br>* Angiotensin II (Giapreza) is a pharmacologic version of a naturally occurring peptide hormone of the same name which is a component of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II (Giapreza) was FDA-approved in 2017 as a vasoconstrictive agent in the treatment of vasodilatory shock.<br>* Other names: Giapreza;|
| No Intervention: Standard of Care (SOC)<br>Vasopressor therapy be titrated by the clinical team per usual SOC and UNMH Nursing Department Titration Guideline. using other available vasopressor agents (e.g., higher-dose norepinephrine, vasopressin, epinephrine, phenylephrine, and/or dopamine). To provide a comparator arm, patients in the SOC will have renin and DPP3 levels obtained at equivalent timepoints. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ability of baseline renin to predict norepinephrine equivalent dose (NED) at 3 hours | BP response will be assessed at 3 hours in both groups and measured using NED. The primary outcome will be ability of baseline renin (obtained at drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline Sequential Organ Failure Assessment (SOFA) scores as covariables. | 3 hours post drug initiation or SOC equivalent | 
| Ability of baseline DPP3 to predict NED at 3 hours | BP response will be assessed at 3 hours in both groups and measured using NED. The primary outcome will be ability of baseline DPP3 to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables. | 3 hours post drug initiation or SOC equivalent | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ability of pre-baseline renin to predict NED at 3 hours | The primary outcome analysis will be repeated, but instead using the ability of pre-baseline renin levels (obtained at randomization, approximately 2 hours before drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables. | 3 hours post drug initiation or SOC equivalent | 
| Ability of pre-baseline DPP3 to predict NED at 3 hours | The primary outcome analysis will be repeated, but instead using the ability of pre-baseline DPP3 levels (obtained at randomization, approximately 2 hours before drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables. | 3 hours post drug initiation or SOC equivalent | 
| Ability of changes in renin level to predict NED at 3 hours | The primary outcome analysis will be repeated, but instead evaluating the ability of changes in renin level (from pre-baseline to baseline) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables. | 3 hours post drug initiation or SOC equivalent | 
| Ability of changes in DPP3 level to predict NED at 3 hours | The primary outcome analysis will be repeated, but instead evaluating the ability of changes in DPP3 level (from pre-baseline to baseline) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables. | 3 hours post drug initiation or SOC equivalent | 
| Background NED at 1 hour | Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints. | 1 hour post drug initiation or SOC equivalent | 
| Background NED at 6 hours | Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints. | 6 hours post drug initiation or SOC equivalent | 
| Background NED at 12 hours | Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints. | 12 hours post drug initiation or SOC equivalent | 
| Background NED at 24 hours | Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints. | 24 hours post drug initiation or SOC equivalent | 
| Background NED at 48 hours | Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints. | 48 hours post drug initiation or SOC equivalent | 
| Background NED at 72 hours | Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints. | 72 hours post drug initiation or SOC equivalent | 
| Time to shock reversal | Time (in hours) to sustained vasopressor independence will be compared in two arms. | 72 hours post drug initiation or SOC equivalent | 
| Change in Sequential Organ Failure Assessment (SOFA) score at 24 hours | Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.) | 24 hours post drug initiation or SOC equivalent | 
| Change in Sequential Organ Failure Assessment (SOFA) score at 48 hours | Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.) | 48 hours post drug initiation or SOC equivalent | 
| Change in Sequential Organ Failure Assessment (SOFA) score at 72 hours | Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.) | 72 hours post drug initiation or SOC equivalent | 
| Acute Kidney Injury (AKI) | Rate of AKI during first 28 days as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria | 28 days post randomization | 
| Days free from renal replacement therapy (RRT) | Days alive and free from RRT. Freedom from RRT is considered a period without RRT of at least 72 hours. Specified as a key secondary outcome. | 28 days post randomization | 
| Days free from invasive mechanical ventilation (IMV) | Days alive and free from IMV. Specified as a key secondary outcome. | 28 days post randomization | 
| Intensive care unit (ICU) length of stay | Length of stay (in days) | Until ICU discharge or study termination, up to 26 weeks. | 
| Hospital length of stay | Length of stay (in days) | Until hospital discharge or study termination, up to 26 weeks. | 
| ICU mortality | Death before ICU discharge. Specified as a key secondary outcome. | Until ICU discharge or 28 days post-randomization. | 
| Hospital mortality | Death before hospital discharge. Specified as a key secondary outcome. | Until hospital discharge or 28 days post-randomization. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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septic shock, vasopressor, angiotensin II, renin, dipeptidyl peptidase 3 (DPP3), randomized controlled trial