Angiotensin II for Septic Shock

(ANGIO-ED Trial)

Overseen By Brett Faine, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Iowa

Must be taking: Norepinephrine, Antibiotics

Disqualifiers: Acute coronary syndrome, Cardiogenic shock, Mesenteric ischemia, Aortic dissection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Up to 6 hours

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are actively taking two vasoactive agents, you would not be eligible to participate.

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

Research shows that Angiotensin II can quickly increase blood pressure in patients with septic shock, which is crucial for survival. It has been approved to be used alongside other medications to reduce the need for high doses of other drugs that can have serious side effects. ^{1 2 3 4 5}

Is Angiotensin II (Giapreza) safe for use in humans?

Angiotensin II (Giapreza) was approved by the FDA in 2017 for increasing blood pressure in adults with septic or other vasodilatory shock. While it is used to reduce the need for other blood pressure medications, more research is needed to fully understand its long-term safety, especially regarding its effects on the lungs, brain, and risk of blood clots. ^{2 3 4 6 7}

How is the drug Angiotensin II (Giapreza) unique in treating septic shock?

Angiotensin II (Giapreza) is unique because it can quickly increase blood pressure in patients with septic shock, especially when other vasopressors (drugs that tighten blood vessels) are not effective. It works by mimicking a natural hormone in the body that helps regulate blood pressure, and it can reduce the need for high doses of other vasopressors, potentially lowering the risk of side effects. ^{1 2 3 4 7}

What is the purpose of this trial?

This pilot study will enroll 20 patients with septic shock and require emergent vasopressor support in the emergency department (ED). The primary objective of the study is to determine the feasibility of early peripheral administration of angiotensin II for treatment of septic shock in the ED

Eligibility Criteria

This trial is for a small group of 20 patients who arrive at the emergency department with septic shock and need immediate support to maintain blood pressure. Participants must be in a condition where they can receive angiotensin II within three hours after starting norepinephrine, a common drug used to treat low blood pressure.

Inclusion Criteria

I need norepinephrine to maintain my blood pressure after receiving enough fluids.

I am currently on IV antibiotics or will be starting them soon.

Can provide written informed consent (or legally authorized representative)

Exclusion Criteria

I have had a condition where my intestines did not get enough blood.

I have had a recent heart attack or related condition.

Expected lifespan of <12 hours

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Treatment

Participants receive intravenous angiotensin II infusion for blood pressure support in the emergency department

Up to 6 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 day

1 visit (in-person)

Treatment Details

Interventions

• Angiotensin II

Trial Overview The study is testing if giving angiotensin II early on can help treat septic shock in patients who have just arrived at the emergency department. It's a pilot study, which means it's an initial test before larger studies are done.

Participant Groups

Group I: Angiotensin II Infusion Experimental Treatment 1 Intervention

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

Approved in United States as Giapreza for:

• Septic shock
• Vasodilatory shock

Who Is Running the Clinical Trial?

University of Iowa

Lead Sponsor

Trials

486

Recruited

934,000+

Brett A Faine

Lead Sponsor

Trials

2

Recruited

60+

Findings from Research

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II in experimental hyperdynamic sepsis. Wan, L., Langenberg, C., Bellomo, R., et al.[2021]

Angiotensin II (AT-II) has been recently approved by the FDA as a vasopressor to be used alongside other medications for treating refractory septic shock, which is a severe condition characterized by persistent low blood pressure despite fluid resuscitation.

Current literature suggests that while AT-II can help reduce the need for high doses of catecholamines in septic shock, further large-scale studies are needed to fully understand its effects on various body systems and potential risks, such as venous thromboembolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II in septic shock. Jadhav, AP., Sadaka, FG.[2020]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Patient With Tricyclic Antidepressant Overdose With Catecholamine-Resistant Hypotension Rescued With Angiotensin II: A Case Report. Ferdowsali, J., Ferdowsali, K.[2021]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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 septic patients, lower levels of angiotensin II and AT-1 receptors are associated with septic shock and non-survivors, indicating their potential role as biomarkers for prognosis.

Angiotensin II and AT-2 levels show high sensitivity and specificity for identifying shock in septic patients, while the AT-1/AT-2 ratio may help predict mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II and angiotensin II receptor 2 levels can predict shock and mortality in septic patients. Ozer, AB., Bicakcioglu, M., Baykan, S., et al.[2022]

Angiotensin II (AT2) significantly improved mean arterial pressure (MAP) in patients with vasodilatory shock, achieving a response in 69.9% of those treated compared to only 23.4% in the placebo group, based on a Phase III trial with 321 participants.

While AT2 showed promise in increasing blood pressure, it did not significantly affect overall mortality rates, and its safety profile remains uncertain due to high rates of serious adverse events in both treatment and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of angiotensin II in treatment of refractory distributive shock. Rodriguez, R., Fernandez, EM.[2020]

Angiotensin II (AT-II) was approved by the FDA in December 2017 for increasing blood pressure in adults experiencing septic or distributive shock, showing a significant response rate compared to placebo in a phase 3 study.

While AT-II effectively raised mean arterial pressure in patients already on norepinephrine, it did not significantly reduce mortality by day 28, indicating the need for further research on its safety and optimal use in shock therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Blast From the Past: Revival of Angiotensin II for Vasodilatory Shock. Bissell, BD., Browder, K., McKenzie, M., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Angiotensin II in experimental hyperdynamic sepsis. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Angiotensin II in septic shock. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

A Patient With Tricyclic Antidepressant Overdose With Catecholamine-Resistant Hypotension Rescued With Angiotensin II: A Case Report. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

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]

5. Italy pubmed.ncbi.nlm.nih.gov

Angiotensin II and angiotensin II receptor 2 levels can predict shock and mortality in septic patients. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Role of angiotensin II in treatment of refractory distributive shock. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

A Blast From the Past: Revival of Angiotensin II for Vasodilatory Shock. [2019]