Angiotensin II for Septic Shock

Overseen By Lynnette Harris, RN

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Wake Forest University Health Sciences

Must be taking: Norepinephrine

Disqualifiers: Age <18, Pregnant, Surgery, 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

Compensation: Varies

Number of Visits: 28

Duration: 2 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates whether Angiotensin II, a medication, can be more effective than norepinephrine in treating septic shock, a severe condition with high mortality rates. Researchers aim to determine if Angiotensin II improves outcomes and aids in assessing the severity of septic shock. Participants must have septic shock, require norepinephrine to maintain blood pressure, and have or be suspected of having an infection. As a Phase 4 trial, this research seeks to understand how this FDA-approved and effective treatment can benefit more patients.

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's best to discuss this with the trial coordinators or your doctor.

What is the safety track record for these treatments?

Research has shown that Angiotensin II can be safe for patients with septic shock. One study found that 60.7% of patients receiving Angiotensin II experienced serious side effects, compared to 67.1% of those receiving a placebo. This indicates fewer serious events occurred in the Angiotensin II group than in the placebo group.

Angiotensin II is already used to treat certain types of low blood pressure, suggesting it is generally well-tolerated. However, every treatment carries risks. More studies are needed to fully understand its safety, but current results are promising for those with septic shock. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard treatments for septic shock, which typically involve vasopressors like norepinephrine, angiotensin II offers a unique approach by directly targeting the body's renin-angiotensin system. This mechanism can potentially lead to more effective blood pressure stabilization in patients who don't respond well to traditional therapies. Researchers are excited about angiotensin II because it could provide a faster and more efficient way to manage septic shock, especially in cases where other treatments fall short.

What evidence suggests that Angiotensin II could be an effective treatment for septic shock?

Research has shown that Angiotensin II, which participants in this trial may receive, can help raise blood pressure in people with vasodilatory shock, a condition where blood vessels widen and cause blood pressure to drop. One study found that adding Angiotensin II to standard treatment lowered death rates in patients with shock. It also improved survival rates by day 28, especially when used early in treatment. This treatment works by narrowing blood vessels, which helps increase blood pressure quickly, often within a few hours. Due to these benefits, Angiotensin II has been approved for use in septic and distributive shock. Meanwhile, another group in this trial will receive Norepinephrine, which also manages blood pressure in shock patients. ^{2 4 6 7 8}

Who Is on the Research Team?

Ashish Khanna, MD

Principal Investigator

Atrium Health Wake Forest Baptist

Are You a Good Fit for This Trial?

This trial is for patients with septic shock, a severe infection causing dangerously low blood pressure. Participants must have confirmed sepsis and require vasopressors to maintain blood pressure. Specific inclusion or exclusion criteria are not provided but typically would involve health status and prior treatments.

Inclusion Criteria

I am currently experiencing severe sepsis with low blood pressure.

I might have or have been diagnosed with an infection.

I need Norepinephrine to keep my blood pressure at 65 mmHg.

Exclusion Criteria

I am expected to undergo urgent surgery soon.

Prisoners

Leukocyte count <1,000 cells/μL

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive continuous infusion of Angiotensin II or Norepinephrine for up to 48 hours

2 days

Continuous monitoring during treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Regular assessments at Day 28

What Are the Treatments Tested in This Trial?

Interventions

• Angiotensin II
• Norepinephrine

Trial Overview The study is testing the effectiveness of Angiotensin II compared to norepinephrine in treating septic shock. It aims to find out if Angiotensin II can better predict the severity of septic shock and improve patient outcomes than the conventional treatment.

How Is the Trial Designed?

Group I: Angiotensin II Experimental Treatment 1 Intervention

Continuous infusion of Angiotensin II for up to 48 hours

Group II: Norepinephrine Active Control 1 Intervention

Continuous infusion of Norepinephrine for up to 48 hours

Who Is Running the Clinical Trial?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

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]

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 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]

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 (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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9830054/

How Effective is Angiotensin II in Decreasing Mortality of ... The average length of stay in non-shock patient is 3–7 days comparing with shock patient is 16.5 days. The use of Ang-2 showed the potential to ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1704154

Angiotensin II for the Treatment of Vasodilatory Shock Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors.

3. giapreza.com giapreza.com/efficacy

Efficacy and Trial Design | GIAPREZA® (angiotensin II) Survival Data · Increased patient survival at day 28 · Survival benefit was greatest when initiated with lower vasopressor doses · DON'T WAIT—start GIAPREZA sooner ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12286902/

Angiotensin II, conventional vasopressor therapy, and ... Ang II use, when added to conventional therapy, was independently associated with lower mortality in patients with shock, after controlling for ...

5. rtihs.org rtihs.org/sites/default/files/32465_Rockwood_2022_Effectiveness%20of%20angiotensin%20II%20for%20catecholamine%20refractory%20septic%20or%20distributive%20shock%20on%20mortality.pdf

32465_Rockwood_2022_Effectiv... IMPORTANCE: Angiotensin II (ATII) was approved for septic or other distribu- tive shock due to its property of increasing blood pressure within 3 hours.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10882873/

Angiotensin II therapy in refractory septic shock Promising results have been observed in treating refractory hypotension with angiotensin II, which has been shown to increase mean arterial pressure.

7. journals.lww.com journals.lww.com/ccmjournal/fulltext/2021/01001/851__safety_and_efficacy_outcomes_associated_with.819.aspx

851: Safety and Efficacy Outcomes Associated With... Conclusions: There is no survival difference for patients in shock who receive AT2 when compared to SOC agents. Large randomized studies are needed to assess ...

8. jmsma.scholasticahq.com jmsma.scholasticahq.com/article/131791-single-center-real-world-observational-analysis-of-angiotensin-ii-salvage-therapy-for-refractory-shock

Single-Center, Real-World Observational Analysis of ... This single-center observational cohort study was performed to assess the effectiveness of angiotensin-II use when implemented as salvage therapy.