Angiotensin II for Septic Shock
(DARK-Sepsis Trial)
Recruiting in Palo Alto (17 mi)
Overseen byJoao P Teixeira, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 4
Recruiting
Sponsor: University of New Mexico
Must be taking: Norepinephrine
Must not be taking: Glucocorticoids
Disqualifiers: Coronary syndrome, Stroke, COPD, others
No Placebo Group
Prior Safety Data
Approved in 1 Jurisdiction
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.
12345Is 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.
678910How 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.
123411Eligibility 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.
+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.
+18 more
Trial 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
Participant Groups
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.
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
Research Locations NearbySelect from list below to view details:
University of New Mexico Health Sciences CenterAlbuquerque, NM
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Who Is Running the Clinical Trial?
University of New MexicoLead Sponsor
La Jolla Pharmaceutical CompanyIndustry Sponsor
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 (ATII) was approved for septic or other distributive shock due to its property of increasing blood pressure within 3 hours. Limited data exist regarding its effectiveness when used in real-world clinical practice.
Angiotensin II in experimental hyperdynamic sepsis. [2021]Angiotensin II (Ang II) is a potential vasopressor treatment for hypotensive hyperdynamic sepsis. However, unlike other vasopressors, its systemic, regional blood flow and renal functional effects in hypotensive hyperdynamic sepsis have not been investigated.
A Patient With Tricyclic Antidepressant Overdose With Catecholamine-Resistant Hypotension Rescued With Angiotensin II: A Case Report. [2021]This case report explores the novel use of angiotensin II (Giapreza) for the treatment of vasodilation in the setting of a tricyclic overdose. The purpose of this case is to describe how the use of angiotensin II can improve hemodynamic parameters and result in a dose reduction of other catecholamine vasopressors in vasodilatory shock. The use of angiotensin II is new to clinical practice and has the potential to change outcomes for patients.
Angiotensin II in septic shock. [2020]Septic shock is a life threatening condition and a medical emergency. It is associated with organ dysfunction and hypotension despite optimal volume resuscitation. Refractory septic shock carries a very high rate of mortality and is associated with ischemic and arrhythmogenic complications from high dose vasopressors. Angiotensin II (AT-II) is a product of the renin-angiotensin-aldosterone system. It is a vasopressor agent that has been recently approved by FDA to be used in conjunction with other vasopressors (catecholamines) in refractory shock and to reduce catecholamine requirements. We have reviewed the physiology and current literature on AT-II in refractory septic/vasodilatory shock. Larger trials with longer duration of follow-up are warranted to address the questions which are unanswered by the ATHOS-3 trial, especially pertaining to its effects on lungs, brain, microcirculation, inflammation, and venous thromboembolism risk.
Angiotensin II and angiotensin II receptor 2 levels can predict shock and mortality in septic patients. [2022]The aim of this study was to evaluate the place of angiotensin II and its receptors in the prognosis of septic patients.
Angiotensin Converting Enzyme Inhibitor (ACEI)-Induced Acute Renal Failure in Premature Newborns with Congenital Heart Disease. [2021]We report three cases of angiotensin converting enzyme inhibitor (ACEI) induced nephrotoxicity in preterm infants with congenital heart disease. Patients developed acute renal failure after starting captopril or enalapril at doses commonly prescribed for term neonates. There was no underlying renal disease found in these infants and the acute renal failure was reversible upon discontinuation of the ACEI. Conservative starting doses of ACEI should be used in patients with multiple risk factors for nephrotoxicity. A summary of previously reported ACEI induced renal failure in premature infants and congenital heart disease is included.
Lower than conventional doses of captopril in the initiation of converting enzyme inhibition in patients with severe congestive heart failure. [2019]Angiotensin converting enzyme (ACE) inhibitors are effective long-term therapy for congestive heart failure, improving symptoms, exercise tolerance, biochemical anomalies, and mortality. Captopril, in doses of up to 150 mg daily is relatively free of serious adverse effects. A test dose of 6.25 mg normally precedes regular therapy in an attempt to avoid first-dose hypotension, which may also be prevented by reduction in diuretic dosage and by the avoidance of over-diuresis leading to volume depletion. We report two patients who, despite the above precautions developed symptomatic first-dose hypotension with 6.25 mg, but were subsequently able to recommence captopril therapy by the initial oral administration of doses as low as 1 mg.
Mortality associated with captopril and enalapril: a report from the DHSS Hypertension Care Computing Project. [2019]In 1986, the Committee on Safety of Medicines published a report suggesting that enalapril may have an adverse effect on renal function. The prescription event monitoring scheme subsequently published figures on adverse drug reactions and mortality for patients treated with enalapril. They concluded that enalapril did not have an adverse effect on renal function and survival. Similar data were not available for captopril, as the drug was marketed before prescription event monitoring had been developed. In the Department of Health and Social Security (DHSS) Hypertension Care Computing Project (DHCCP), 368 hypertensive patients treated with captopril and 371 treated with enalapril were followed for an average of 3.1 and 1.6 years, respectively. Thirty-two patients died; none had renal failure as an underlying cause of death. The death rate was similar in both drug groups, at 17.5 (enalapril) and 24.0 (captopril) per 1000 patient-years. The present report shows that, for patients treated for high blood pressure, the relative risk of mortality with captopril compared with enalapril was 1.37, an insignificant difference (95% confidence interval 0.63, 2.98).
The safety profile of quinapril: is there a difference among ACE inhibitors? [2019]The safety of quinapril hydrochloride, a new nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor with an intermediate duration of action, has been evaluated in 3,031 patients with hypertension and congestive heart failure (CHF) and has been compared with other ACE inhibitors. A comparison of double-blind studies showed quinapril to have a lower incidence of adverse effects and withdrawals than reported for captopril or enalapril. Analysis of onset of adverse events or withdrawals did not show either a time-dependent or dose-dependent relationship with quinapril. The proportion of patients who experienced orthostatic hypotension was less than that of patients on captopril or enalapril. Double-blind, long-term, and open-label studies with quinapril showed no increase in the incidence of events reported in patients with CHF compared with hypertensive patients. Quinapril produced minimal adverse effects on renal function in both patients with normal renal function and in those with pre-existing renal impairment. Age analysis of data from all studies showed no increase in total reporting of adverse events in older patients who did not take concomitant diuretics.
Neonatal anuria with maternal angiotensin-converting enzyme inhibition. [2013]The use of angiotensin-converting enzyme inhibitors as antihypertensives has increased rapidly since the introduction of captopril in 1981. Seven cases of neonatal renal failure have been reported in patients with exposure to angiotensin-converting enzyme inhibitors that continued to the time of delivery. Two cases resulted in death of the newborn; the other five patients recovered after peritoneal dialysis. Because the relative frequency of normal outcomes is unknown, these data are insufficient for incidence-rate estimates or risk/benefit analyses. However, given the potential neonatal morbidity and mortality associated with late-pregnancy exposure to angiotensin-converting enzyme inhibitors, alternative therapies in the third trimester should be given consideration. If these drugs must be used in this context, the clinician should be prepared to deal with renal failure and hypotension in the newborn. The Food and Drug Administration invites reports of adverse pregnancy outcomes associated with such exposure.
A Blast From the Past: Revival of Angiotensin II for Vasodilatory Shock. [2019]To review and summarize data on angiotensin II (AT-II), approved by the Food and Drug Administration (FDA) in December 2017 to increase blood pressure in adults with septic or other distributive shock.