Clinical trial NCT05824767: Serum Biomarkers to Predict Response to Angiotensin II in Septic Shock
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Septic Shock
Vasodilatory Shock
Keywords: septic shock
vasopressor
angiotensin II
renin
dipeptidyl peptidase 3 (DPP3)
randomized controlled trial
Lead sponsor: University of New Mexico
Sponsor class: OTHER
Collaborators: name: La Jolla Pharmaceutical Company
First posted: 2023-04-24
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Ability of baseline renin to predict norepinephrine equivalent dose (NED) at 3 hours
timeFrame: 3 hours post drug initiation or SOC equivalent
measure: Ability of baseline DPP3 to predict NED at 3 hours
timeFrame: 3 hours post drug initiation or SOC equivalent
Secondary outcomes:
measure: Ability of pre-baseline renin to predict NED at 3 hours
timeFrame: 3 hours post drug initiation or SOC equivalent
measure: Ability of pre-baseline DPP3 to predict NED at 3 hours
timeFrame: 3 hours post drug initiation or SOC equivalent
measure: Ability of changes in renin level to predict NED at 3 hours
timeFrame: 3 hours post drug initiation or SOC equivalent
measure: Ability of changes in DPP3 level to predict NED at 3 hours
timeFrame: 3 hours post drug initiation or SOC equivalent
measure: Background NED at 1 hour
timeFrame: 1 hour post drug initiation or SOC equivalent
measure: Background NED at 6 hours
timeFrame: 6 hours post drug initiation or SOC equivalent
measure: Background NED at 12 hours
timeFrame: 12 hours post drug initiation or SOC equivalent
measure: Background NED at 24 hours
timeFrame: 24 hours post drug initiation or SOC equivalent
measure: Background NED at 48 hours
timeFrame: 48 hours post drug initiation or SOC equivalent
measure: Background NED at 72 hours
timeFrame: 72 hours post drug initiation or SOC equivalent
measure: Time to shock reversal
timeFrame: 72 hours post drug initiation or SOC equivalent
measure: Change in Sequential Organ Failure Assessment (SOFA) score at 24 hours
timeFrame: 24 hours post drug initiation or SOC equivalent
measure: Change in Sequential Organ Failure Assessment (SOFA) score at 48 hours
timeFrame: 48 hours post drug initiation or SOC equivalent
measure: Change in Sequential Organ Failure Assessment (SOFA) score at 72 hours
timeFrame: 72 hours post drug initiation or SOC equivalent
measure: Acute Kidney Injury (AKI)
timeFrame: 28 days post randomization
measure: Days free from renal replacement therapy (RRT)
timeFrame: 28 days post randomization
measure: Days free from invasive mechanical ventilation (IMV)
timeFrame: 28 days post randomization
measure: Intensive care unit (ICU) length of stay
timeFrame: Until ICU discharge or study termination, up to 26 weeks.
measure: Hospital length of stay
timeFrame: Until hospital discharge or study termination, up to 26 weeks.
measure: ICU mortality
timeFrame: Until ICU discharge or 28 days post-randomization.
measure: Hospital mortality
timeFrame: Until hospital discharge or 28 days post-randomization.
Other outcomes:
measure: serum renin level at 1 hour
timeFrame: 1 hour post-drug initiation and SOC equivalent
measure: serum DPP3 level at 1 hour
timeFrame: 1 hour post-drug initiation and SOC equivalent
measure: serum renin level at 3 hours
timeFrame: 3 hours post-drug initiation and SOC equivalent
measure: serum DPP3 level at 3 hours
timeFrame: 3 hours post-drug initiation and SOC equivalent
measure: serum renin level at 24 hours
timeFrame: 24 hours post-drug initiation and SOC equivalent
measure: serum DPP3 level at 24 hours
timeFrame: 24 hours post-drug initiation and SOC equivalent
measure: serum renin level 24 hours post drug discontinuation
timeFrame: 24 hours post-drug discontinuation (AngII arm only)
measure: serum DPP3 level 24 hours post drug discontinuation
timeFrame: 24 hours post-drug discontinuation (AngII arm only)
measure: Prespecified Adverse Events: new venous thromboembolism (VTE) or arterial thrombosis
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: atrial fibrillation
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: tachycardia
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: lactic acidosis
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: hyperglycemia
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: thrombocytopenia
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: peripheral limb/digit ischemia
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: intestinal ischemia
timeFrame: Up to 28 days
measure: Prespecified Adverse Events: confirmed infection
timeFrame: Up to 28 days
Locations:
city: Albuquerque
country: United States
facility: University of New Mexico Health Sciences Center
state: New Mexico
Study officials:
affiliation: University of New Mexico
name: Joao P Teixeira, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Nathan D Nielsen, MD MSc
role: PRINCIPAL_INVESTIGATOR
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