Angiotensin II for Septic Shock

(DARK-Sepsis Trial)

Overseen By Nathan D Nielsen, MD MSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of New Mexico

Must be taking: Norepinephrine

Must not be taking: Glucocorticoids

Disqualifiers: Coronary syndrome, Stroke, COPD, 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: Unknown

Duration: 72 hours

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called angiotensin II for people with septic shock, a severe condition where blood pressure drops dangerously low despite standard drug treatment. Researchers aim to determine if angiotensin II can improve blood pressure more effectively than current treatments. They will also assess whether certain blood markers can predict who will benefit from this new treatment. Individuals using norepinephrine (a common medication for low blood pressure) but still experiencing low blood pressure might be suitable candidates for this trial. As a Phase 4 trial, this research focuses on understanding how this already 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 is best to discuss this with the trial coordinators or your doctor.

What is the safety track record for angiotensin II?

Research has shown that angiotensin II is generally safe for patients with septic shock. In one study of 321 adults, 60.7% of those who received angiotensin II experienced serious side effects, which was lower than the 67.1% in the placebo group. This suggests that angiotensin II might be safer than not using it at all.

Although angiotensin II carries risks, the FDA has approved it for treating low blood pressure in shock, indicating it has passed safety checks for that use. However, as with any treatment, it's important to weigh the benefits and possible side effects before deciding to join a trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard of care for septic shock, which typically involves using vasopressors like norepinephrine, vasopressin, and epinephrine, Angiotensin II offers a novel mechanism of action. It specifically targets the angiotensin II receptors to raise blood pressure, which is a different pathway compared to traditional vasopressors that primarily act on adrenergic receptors. Researchers are excited about Angiotensin II because it could potentially stabilize blood pressure more effectively or rapidly in patients who don't respond well to conventional treatments. Additionally, by providing an alternative route to manage septic shock, it could help reduce the need for higher doses of other vasopressors, potentially minimizing side effects.

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, might help treat septic shock. One study found that 46% of patients who received angiotensin II died by day 28, compared to 54% of those who received a placebo, suggesting it might improve survival. Angiotensin II also raises blood pressure in patients with septic shock. Starting it earlier could enhance survival, especially when patients are on lower doses of other blood pressure medications. Overall, these findings support its potential effectiveness in managing septic shock. ^{2 3 4 5 6}

Who Is on the Research Team?

Joao P Teixeira, MD

Principal Investigator

University of New Mexico

Nathan D Nielsen, MD MSc

Principal Investigator

University of New Mexico

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Angiotensin II

Trial Overview The 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.

How Is the Trial Designed?

Group I: Angiotensin II Experimental Treatment 1 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 Control 1 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

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+

Published Research Related to This Trial

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]

Three cases of acute renal failure in preterm infants with congenital heart disease were linked to the use of ACE inhibitors (captopril or enalapril), highlighting a potential risk even at standard doses.

The renal failure was reversible after stopping the medication, suggesting that careful monitoring and conservative dosing of ACE inhibitors are essential in vulnerable populations like preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin Converting Enzyme Inhibitor (ACEI)-Induced Acute Renal Failure in Premature Newborns with Congenital Heart Disease. Lee, GJ., Cohen, R., Chang, AC., et al.[2021]

Quinapril hydrochloride, evaluated in 3,031 patients with hypertension and congestive heart failure, demonstrated a lower incidence of adverse effects and withdrawals compared to other ACE inhibitors like captopril and enalapril.

The drug showed minimal adverse effects on renal function and did not increase the risk of orthostatic hypotension, making it a safer option for patients, including older individuals without diuretic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety profile of quinapril: is there a difference among ACE inhibitors? Canter, D., Frank, GJ., Knapp, LE., 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]

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]

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]

A study involving 739 hypertensive patients (368 on captopril and 371 on enalapril) found no significant difference in mortality rates between the two medications, suggesting both are similarly safe for long-term use.

The relative risk of mortality for captopril compared to enalapril was 1.37, indicating no significant adverse effect on survival, as none of the deaths were due to renal failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mortality associated with captopril and enalapril: a report from the DHSS Hypertension Care Computing Project. Palmer, AJ., Beevers, DG., Bulpitt, CJ., et al.[2019]

ACE inhibitors like captopril are effective long-term treatments for congestive heart failure, improving symptoms and reducing mortality, with a typical starting dose of 6.25 mg to prevent first-dose hypotension.

In two reported cases, patients experienced symptomatic hypotension even at the test dose, but they were able to safely resume captopril therapy with much lower initial doses of 1 mg, suggesting that careful dose adjustments can help manage side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lower than conventional doses of captopril in the initiation of converting enzyme inhibition in patients with severe congestive heart failure. Scott, RA., Barnett, DB.[2019]

Exposure to angiotensin-converting enzyme inhibitors during late pregnancy has been linked to seven cases of neonatal renal failure, with two resulting in death and five requiring peritoneal dialysis for recovery.

Due to the potential risks of neonatal morbidity and mortality, healthcare providers should consider alternative treatments during the third trimester and be prepared to manage complications like renal failure and hypotension in newborns if these medications are used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal anuria with maternal angiotensin-converting enzyme inhibition. Rosa, FW., Bosco, LA., Graham, CF., et al.[2013]

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]

Citations

1. giapreza.com giapreza.com/efficacy

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

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

Angiotensin II, conventional vasopressor therapy, and ... Overall 30-day mortality was 56.4%. Groups statistically differed by all baseline variables. In multivariable logistic regression, Ang II ...

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

Angiotensin II for the Treatment of Vasodilatory Shock Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05193370

Angiotensin II vs. Vasopressin in Septic Shock While more studies are needed, preliminary data suggest that the vasopressor angiotensin II (AngII) may improve outcomes in septic shock. This study is a ...

5. 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.

6. giapreza.com giapreza.com/safety

Safety & Adverse Events The safety of GIAPREZA was evaluated in 321 adults with septic or other distributive shock in a randomized, double-blind, placebo-controlled study, ATHOS-3.