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Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock (DARK-Sepsis)

Primary Purpose

Septic Shock, Vasodilatory Shock

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Angiotensin II
Sponsored by
University of New Mexico
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring septic shock, vasopressor, angiotensin II, renin, dipeptidyl peptidase 3 (DPP3), randomized controlled trial

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of New Mexico Health Sciences CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Angiotensin II

Standard of Care (SOC)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
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.
Background NED at 1 hour
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Background NED at 6 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Background NED at 12 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Background NED at 24 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Background NED at 48 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Background NED at 72 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time to shock reversal
Time (in hours) to sustained vasopressor independence will be compared in two arms.
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.)
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.)
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.)
Acute Kidney Injury (AKI)
Rate of AKI during first 28 days as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria
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.
Days free from invasive mechanical ventilation (IMV)
Days alive and free from IMV. Specified as a key secondary outcome.
Intensive care unit (ICU) length of stay
Length of stay (in days)
Hospital length of stay
Length of stay (in days)
ICU mortality
Death before ICU discharge. Specified as a key secondary outcome.
Hospital mortality
Death before hospital discharge. Specified as a key secondary outcome.

Full Information

First Posted
March 5, 2023
Last Updated
October 4, 2023
Sponsor
University of New Mexico
Collaborators
La Jolla Pharmaceutical Company
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1. Study Identification

Unique Protocol Identification Number
NCT05824767
Brief Title
Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock
Acronym
DARK-Sepsis
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 17, 2023 (Actual)
Primary Completion Date
September 15, 2024 (Anticipated)
Study Completion Date
October 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of New Mexico
Collaborators
La Jolla Pharmaceutical Company

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Septic Shock, Vasodilatory Shock
Keywords
septic shock, vasopressor, angiotensin II, renin, dipeptidyl peptidase 3 (DPP3), randomized controlled trial

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Angiotensin II
Arm Type
Experimental
Arm Description
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.
Arm Title
Standard of Care (SOC)
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Angiotensin II
Other Intervention Name(s)
Giapreza
Intervention Description
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.
Primary Outcome Measure Information:
Title
Ability of baseline renin to predict norepinephrine equivalent dose (NED) at 3 hours
Description
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.
Time Frame
3 hours post drug initiation or SOC equivalent
Title
Ability of baseline DPP3 to predict NED at 3 hours
Description
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.
Time Frame
3 hours post drug initiation or SOC equivalent
Secondary Outcome Measure Information:
Title
Ability of pre-baseline renin to predict NED at 3 hours
Description
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.
Time Frame
3 hours post drug initiation or SOC equivalent
Title
Ability of pre-baseline DPP3 to predict NED at 3 hours
Description
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.
Time Frame
3 hours post drug initiation or SOC equivalent
Title
Ability of changes in renin level to predict NED at 3 hours
Description
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.
Time Frame
3 hours post drug initiation or SOC equivalent
Title
Ability of changes in DPP3 level to predict NED at 3 hours
Description
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.
Time Frame
3 hours post drug initiation or SOC equivalent
Title
Background NED at 1 hour
Description
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time Frame
1 hour post drug initiation or SOC equivalent
Title
Background NED at 6 hours
Description
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time Frame
6 hours post drug initiation or SOC equivalent
Title
Background NED at 12 hours
Description
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time Frame
12 hours post drug initiation or SOC equivalent
Title
Background NED at 24 hours
Description
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time Frame
24 hours post drug initiation or SOC equivalent
Title
Background NED at 48 hours
Description
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time Frame
48 hours post drug initiation or SOC equivalent
Title
Background NED at 72 hours
Description
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time Frame
72 hours post drug initiation or SOC equivalent
Title
Time to shock reversal
Description
Time (in hours) to sustained vasopressor independence will be compared in two arms.
Time Frame
72 hours post drug initiation or SOC equivalent
Title
Change in Sequential Organ Failure Assessment (SOFA) score at 24 hours
Description
Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.)
Time Frame
24 hours post drug initiation or SOC equivalent
Title
Change in Sequential Organ Failure Assessment (SOFA) score at 48 hours
Description
Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.)
Time Frame
48 hours post drug initiation or SOC equivalent
Title
Change in Sequential Organ Failure Assessment (SOFA) score at 72 hours
Description
Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.)
Time Frame
72 hours post drug initiation or SOC equivalent
Title
Acute Kidney Injury (AKI)
Description
Rate of AKI during first 28 days as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria
Time Frame
28 days post randomization
Title
Days free from renal replacement therapy (RRT)
Description
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.
Time Frame
28 days post randomization
Title
Days free from invasive mechanical ventilation (IMV)
Description
Days alive and free from IMV. Specified as a key secondary outcome.
Time Frame
28 days post randomization
Title
Intensive care unit (ICU) length of stay
Description
Length of stay (in days)
Time Frame
Until ICU discharge or study termination, up to 26 weeks.
Title
Hospital length of stay
Description
Length of stay (in days)
Time Frame
Until hospital discharge or study termination, up to 26 weeks.
Title
ICU mortality
Description
Death before ICU discharge. Specified as a key secondary outcome.
Time Frame
Until ICU discharge or 28 days post-randomization.
Title
Hospital mortality
Description
Death before hospital discharge. Specified as a key secondary outcome.
Time Frame
Until hospital discharge or 28 days post-randomization.
Other Pre-specified Outcome Measures:
Title
serum renin level at 1 hour
Description
To generate a deeper understanding of renin kinetics, renin levels will be obtained at multiple equivalent timepoints in both arms, with approximately 2 hours between randomization and AngII initiation in the AngII arm.
Time Frame
1 hour post-drug initiation and SOC equivalent
Title
serum DPP3 level at 1 hour
Description
To generate a deeper understanding of DPP3 kinetics, DPP3 levels will be obtained at multiple equivalent timepoints in both arms, with approximately 2 hours between randomization and AngII initiation in the AngII arm.
Time Frame
1 hour post-drug initiation and SOC equivalent
Title
serum renin level at 3 hours
Description
To generate a deeper understanding of renin kinetics, renin levels will be obtained at multiple equivalent timepoints in both arms, with approximately 2 hours between randomization and AngII initiation in the AngII arm.
Time Frame
3 hours post-drug initiation and SOC equivalent
Title
serum DPP3 level at 3 hours
Description
To generate a deeper understanding of DPP3 kinetics, DPP3 levels will be obtained at multiple equivalent timepoints in both arms, with approximately 2 hours between randomization and AngII initiation in the AngII arm.
Time Frame
3 hours post-drug initiation and SOC equivalent
Title
serum renin level at 24 hours
Description
To generate a deeper understanding of renin kinetics, renin levels will be obtained at multiple equivalent timepoints in both arms, with approximately 2 hours between randomization and AngII initiation in the AngII arm.
Time Frame
24 hours post-drug initiation and SOC equivalent
Title
serum DPP3 level at 24 hours
Description
To generate a deeper understanding of DPP3 kinetics, DPP3 levels will be obtained at multiple equivalent timepoints in both arms, with approximately 2 hours between randomization and AngII initiation in the AngII arm.
Time Frame
24 hours post-drug initiation and SOC equivalent
Title
serum renin level 24 hours post drug discontinuation
Description
To evaluate for a rebound effect, final biomarker levels will be obtained in the AngII arm at approximately 24 hours after drug discontinuation.
Time Frame
24 hours post-drug discontinuation (AngII arm only)
Title
serum DPP3 level 24 hours post drug discontinuation
Description
To evaluate for a rebound effect, final biomarker levels will be obtained in the AngII arm at approximately 24 hours after drug discontinuation.
Time Frame
24 hours post-drug discontinuation (AngII arm only)
Title
Prespecified Adverse Events: new venous thromboembolism (VTE) or arterial thrombosis
Description
Requires radiographic documentation. For events to be considered adverse events (AEs) they must be new hospital-acquired events which developed after randomization.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: atrial fibrillation
Description
For events to be considered adverse events (AEs) they must be new hospital-acquired events which developed after randomization.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: tachycardia
Description
Tachycardia is defined as new rise in heart rate to >100/min sustained for at least 1 hour. For events to be considered adverse events (AEs) they must be new hospital-acquired events which developed after randomization.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: lactic acidosis
Description
Defined as rise in serum lactate level to above the upper limit of normal. For lactic acidosis to be considered an adverse event, lactate level must be higher than pre-randomization level.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: hyperglycemia
Description
Defined as rise in blood glucose level to above the upper limit of normal. For hyperglycemia to be considered an adverse event, glucose level must be higher than pre-randomization level.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: thrombocytopenia
Description
Defined as drop in platelet count to below the lower limit of normal. For thrombocytopenia to be considered an adverse event, the platelet level must be lower than pre-randomization level.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: peripheral limb/digit ischemia
Description
As diagnosed by clinical team. For events to be considered adverse events (AEs) they must be new hospital-acquired events which developed after randomization.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: intestinal ischemia
Description
As diagnosed by clinical team. For events to be considered adverse events (AEs) they must be new hospital-acquired events which developed after randomization.
Time Frame
Up to 28 days
Title
Prespecified Adverse Events: confirmed infection
Description
Requires the infecting organism to be confirmed by culture or other identification method; administration of appropriate antimicrobial therapy (if available); and clinical documentation of infection. For events to be considered adverse events (AEs) they must be new hospital-acquired events which developed after randomization.
Time Frame
Up to 28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joao P Teixeira, MD
Phone
505-272-0407
Email
jteixeira@salud.unm.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Nathan D Nielsen, MD MSc
Email
NDNielsen@salud.unm.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joao P Teixeira, MD
Organizational Affiliation
University of New Mexico
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nathan D Nielsen, MD MSc
Organizational Affiliation
University of New Mexico
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of New Mexico Health Sciences Center
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87106
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joao P Teixeira, MD
Phone
505-272-0407
Email
jteixiera@salud.unm.edu
First Name & Middle Initial & Last Name & Degree
Nathan D Nielsen, MD MSc
First Name & Middle Initial & Last Name & Degree
Joao P Teixeira, MD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Reasonable requests for data will be considered on a case-by-case basis and will require regulatory approval by both University of New Mexico and the study sponsor (La Jolla Pharmaceutical).
Citations:
PubMed Identifier
28528561
Citation
Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.
Results Reference
background
PubMed Identifier
29509568
Citation
Tumlin JA, Murugan R, Deane AM, Ostermann M, Busse LW, Ham KR, Kashani K, Szerlip HM, Prowle JR, Bihorac A, Finkel KW, Zarbock A, Forni LG, Lynch SJ, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Bellomo R; Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Investigators. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Crit Care Med. 2018 Jun;46(6):949-957. doi: 10.1097/CCM.0000000000003092. Erratum In: Crit Care Med. 2018 Aug;46(8):e824.
Results Reference
background
PubMed Identifier
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Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock

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