40 Participants Needed

Angiotensin II for Septic Shock

(DARK-Sepsis Trial)

JP
ND
Overseen ByNathan D Nielsen, MD MSc
Age: 18+
Sex: Any
Trial Phase: Phase 4
Sponsor: University of New Mexico
Must be taking: Norepinephrine
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)
Prior Safety DataThis treatment has passed at least one previous human trial
Approved in 1 JurisdictionThis treatment is already approved in other countries

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It is best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Angiotensin II (Giapreza) for treating septic shock?

Angiotensin II has been shown to increase blood pressure within 3 hours in patients with septic shock, and it can reduce the need for other blood pressure-raising drugs. It has been approved for use in septic shock due to its ability to improve blood flow and potentially change outcomes for patients.12345

Is Angiotensin II (Giapreza) generally safe for humans?

The provided research articles do not contain specific safety data for Angiotensin II (Giapreza) in humans, as they focus on different medications and conditions.678910

How is the drug Angiotensin II (Giapreza) different from other treatments for septic shock?

Angiotensin II (Giapreza) is unique because it works by increasing blood pressure quickly, within 3 hours, and can reduce the need for other blood pressure-raising drugs (catecholamines) in septic shock. It is a newer option approved for use when other treatments are not effective, offering a different mechanism by targeting the body's renin-angiotensin-aldosterone system.123411

Research Team

JP

Joao P Teixeira, MD

Principal Investigator

University of New Mexico

ND

Nathan D Nielsen, MD MSc

Principal Investigator

University of New Mexico

Eligibility Criteria

Adults over 18 with persistent vasodilatory shock despite certain treatments, who have specific catheters in place and are not fluid responsive. They must be able to consent or have a representative do so, and not fall under exclusion criteria like acute stroke, severe liver failure, high-dose steroid use, extensive burns, very low neutrophils count, active bleeding with low hemoglobin levels or conditions contraindicating blood sampling.

Inclusion Criteria

I've been given fluids as per protocol and no longer respond to them.
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.
See 3 more

Exclusion Criteria

I have recently had a stroke.
Patients with an absolute neutrophil count (ANC) of < 1,000/mm3
I have been diagnosed with a severe heart blockage or shock.
See 18 more

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either Angiotensin II or standard-of-care vasopressor therapy for septic shock

72 hours
Continuous monitoring in ICU

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 days
Regular assessments and biomarker measurements

Long-term follow-up

Participants are monitored for long-term outcomes such as ICU and hospital mortality, and adverse events

Up to 26 weeks

Treatment Details

Interventions

  • Angiotensin II
Trial OverviewThe trial is testing if angiotensin II can better manage blood pressure in adults with septic shock compared to standard vasopressor therapy. It's also looking at whether two biomarkers can predict the response to this treatment. This unblinded study randomly assigns participants to either receive angiotensin II or stick with the usual care.
Participant Groups
2Treatment groups
Experimental Treatment
Active Control
Group I: Angiotensin IIExperimental Treatment1 Intervention
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.
Group II: Standard of Care (SOC)Active Control1 Intervention
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.

Angiotensin II is already approved in United States for the following indications:

🇺🇸
Approved in United States as Giapreza for:
  • Septic shock
  • Vasodilatory shock

Find a Clinic Near You

Who Is Running the Clinical Trial?

University of New Mexico

Lead Sponsor

Trials
393
Recruited
3,526,000+

La Jolla Pharmaceutical Company

Industry Sponsor

Trials
24
Recruited
2,700+

Findings from Research

In a study of 147 adult patients in the ICU requiring multiple vasopressors for septic shock, those treated with angiotensin II (ATII) had higher mortality rates compared to those receiving other vasopressors, although the difference was not statistically significant after adjusting for other factors.
Despite ATII's approval for increasing blood pressure in shock, the study found no significant improvement in hemodynamic response or mortality when used as a third-line treatment, with only 37.5% of ATII patients responding positively compared to 45.1% in the non-ATII group.
Effectiveness of Angiotensin II for Catecholamine Refractory Septic or Distributive Shock on Mortality: A Propensity Score Weighted Analysis of Real-World Experience in the Medical ICU.Quan, M., Cho, N., Bushell, T., et al.[2022]
In an animal study involving conscious ewes with induced hyperdynamic sepsis, angiotensin II infusion successfully restored arterial pressure but reduced renal blood flow significantly.
Despite the decrease in renal blood flow, angiotensin II infusion led to a remarkable increase in urine output (7-fold) and improved creatinine clearance by 70%, indicating its potential efficacy in managing renal function during hypotensive hyperdynamic sepsis.
Angiotensin II in experimental hyperdynamic sepsis.Wan, L., Langenberg, C., Bellomo, R., et al.[2021]
Angiotensin II (Giapreza) was successfully used to treat vasodilation caused by a tricyclic overdose, improving hemodynamic parameters in the patient.
This novel application of angiotensin II may allow for lower doses of other vasopressors, potentially enhancing patient outcomes in cases of vasodilatory shock.
A Patient With Tricyclic Antidepressant Overdose With Catecholamine-Resistant Hypotension Rescued With Angiotensin II: A Case Report.Ferdowsali, J., Ferdowsali, K.[2021]

References

Effectiveness of Angiotensin II for Catecholamine Refractory Septic or Distributive Shock on Mortality: A Propensity Score Weighted Analysis of Real-World Experience in the Medical ICU. [2022]
Angiotensin II in experimental hyperdynamic sepsis. [2021]
A Patient With Tricyclic Antidepressant Overdose With Catecholamine-Resistant Hypotension Rescued With Angiotensin II: A Case Report. [2021]
Angiotensin II in septic shock. [2020]
Angiotensin II and angiotensin II receptor 2 levels can predict shock and mortality in septic patients. [2022]
Angiotensin Converting Enzyme Inhibitor (ACEI)-Induced Acute Renal Failure in Premature Newborns with Congenital Heart Disease. [2021]
Lower than conventional doses of captopril in the initiation of converting enzyme inhibition in patients with severe congestive heart failure. [2019]
Mortality associated with captopril and enalapril: a report from the DHSS Hypertension Care Computing Project. [2019]
The safety profile of quinapril: is there a difference among ACE inhibitors? [2019]
10.United Statespubmed.ncbi.nlm.nih.gov
Neonatal anuria with maternal angiotensin-converting enzyme inhibition. [2013]
11.United Statespubmed.ncbi.nlm.nih.gov
A Blast From the Past: Revival of Angiotensin II for Vasodilatory Shock. [2019]