Angiotensin II for Liver Transplant Complications

(AngLT-1 Trial)

Overseen By Michael P Bokoch, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of California, San Francisco

Must be taking: Norepinephrine

Must not be taking: Angiotensin blockers

Disqualifiers: Acute liver failure, Renal disease, others

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: Duration of surgery (approximately 8 hours)

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Angiotensin II, a drug that raises blood pressure, can safely assist during liver transplants. Researchers compare it to a placebo to determine its effectiveness in patients needing extra blood pressure support during surgery. Suitable candidates for this trial have received a liver from a deceased donor and require additional blood pressure support with norepinephrine during the transplant. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important medical advancements.

Do I need to stop my current medications for the trial?

The trial requires that you stop taking angiotensin II receptor blockers or angiotensin converting enzyme inhibitors at least 48 hours before participating. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Angiotensin II, the treatment under study, may improve blood flow to the kidneys during liver transplants, potentially reducing kidney problems. Studies have found that Angiotensin II is generally safe and has been tested in various situations, including liver and heart surgeries.

The findings suggest a low risk of serious side effects, such as blood clots, within 48 hours after use. However, because some studies were small, there might not be enough information to fully confirm this. Overall, Angiotensin II appears to be well-tolerated, with most people not experiencing adverse reactions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for liver transplant complications?

Researchers are excited about Angiotensin II for liver transplant complications because it offers a unique approach by directly targeting blood pressure management. Unlike typical treatments that rely on vasopressors such as norepinephrine or dopamine, Angiotensin II, known as Giapreza, mimics a natural hormone in the body to constrict blood vessels and improve blood flow. This targeted mechanism could provide faster and more efficient stabilization of blood pressure in patients experiencing complications after a liver transplant, potentially improving recovery outcomes.

What evidence suggests that Angiotensin II could be an effective treatment for liver transplant complications?

Research has shown that Angiotensin II, which participants in this trial may receive, effectively raises blood pressure during liver transplants. Studies have found that it reduces the need for norepinephrine, another drug used to stabilize blood pressure. Evidence also suggests that Angiotensin II may improve kidney blood flow, potentially lowering the risk of kidney problems during surgery. Additionally, it has saved lives during and after surgery compared to standard care alone. These findings suggest that Angiotensin II could be a promising option for managing blood pressure in liver transplant patients. ^{1 2 3 4 5}

Who Is on the Research Team?

Michael P Bokoch, M.D., Ph.D.

Principal Investigator

Department of Anesthesia and Perioperative Care, University of California, San Francisco

Are You a Good Fit for This Trial?

Adults over 18 needing a liver transplant from a deceased donor with severe liver disease (MELD-Na score >=25) can join. They must need certain blood pressure support during the transplant. Excluded are those with portal vein thrombosis, angiotensin II allergy, pre-transplant ventilation, other safety or data quality risks, active bronchospasm, specific types of transplants or re-transplants, recent certain heart or blood pressure meds use, portopulmonary hypertension, significant heart dysfunction, clotting disorders or anticoagulation therapy.

Inclusion Criteria

I need a specific medication at a certain rate during my lung treatment.

I received a liver transplant from a deceased donor.

Your MELD-Na score is 25 or higher at the time of transplant.

Exclusion Criteria

I have a history of blood clots or am on blood thinners.

I have a narrowing in my celiac artery.

I have taken blood pressure medication before surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Angiotensin II or placebo during liver transplantation to manage blood pressure

Duration of surgery (approximately 8 hours)

Follow-up

Participants are monitored for safety and effectiveness after liver transplantation

Up to 1 year

Hospital Stay

Participants remain in the hospital for recovery and monitoring post-transplantation

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Angiotensin II

Trial Overview This trial tests Angiotensin II as an additional medication to increase blood pressure in patients undergoing liver transplantation who aren't responding well enough to standard treatments. It compares its effectiveness and safety against saline (a placebo).

How Is the Trial Designed?

Group I: Angiotensin II (Giapreza) Experimental Treatment 1 Intervention

Giapreza (synthetic human angiotensin II), initiated at 5 ng/kg/min and titrated to between 1.25 ng/kg/min and 40 ng/kg/min, administered by continuous intravenous infusion.

Group II: Saline Placebo Group 1 Intervention

Sterile 0.9% saline, initiated and titrated at an equivalent volume infusion rate to the study drug, administered by continuous intravenous infusion.

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

La Jolla Pharmaceutical Company

Industry Sponsor

Trials

24

Recruited

2,700+

Published Research Related to This Trial

In a study of 80 patients with cirrhosis and portal hypertension, valsartan significantly increased portal blood flow and velocity without adversely affecting blood pressure or renal function, indicating its safety and potential efficacy in improving portal hemodynamics.

Valsartan treatment also led to a reduction in plasma aldosterone levels and increased urinary sodium excretion, suggesting a beneficial effect on sodium balance and potentially reducing portal resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of valsartan, an angiotensin II receptor antagonist, on portal and systemic hemodynamics and on renal function in liver cirrhosis. Fierbinteanu-Braticevici, C., Dragomir, P., Tribus, L., et al.[2015]

In a study involving 30 patients with severe and 15 with moderate portal hypertension, the angiotensin II receptor antagonist losartan significantly reduced portal pressure (HVPG) by approximately 46.8% in severe cases and 44.1% in moderate cases after one week of treatment.

Losartan was found to be safe, with only a slight decrease in blood pressure and no observed deterioration in liver or kidney function, indicating its potential as an effective treatment for portal hypertension in cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Schneider, AW., Kalk, JF., Klein, CP.[2022]

Angiotensin II (Ang-2) was successfully used for the first time during a liver transplant in a patient experiencing refractory hypotension due to liver failure and septic shock, suggesting its potential as a safe alternative vasopressor in this context.

This case highlights that Ang-2 may be a viable option when traditional therapies like catecholamines and vasopressin are ineffective, indicating its promise for improving outcomes in liver transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative Use of Angiotensin II for Severe Vasodilatory Shock During Liver Transplantation: A Case Report. Running, K., Weinberg, D., Trudo, W., et al.[2021]

In a study of 109 patients who underwent liver transplantation for hepatitis C, the use of angiotensin blockade (ACE-I/ARB) did not show a significant reduction in fibrosis progression compared to those not treated with these medications.

Despite previous suggestions that angiotensin blockade might inhibit fibrosis progression in recurrent hepatitis C post-transplant, this study found no difference in fibrosis rates or progression between the two groups over a median follow-up of 23 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin blockade does not affect fibrosis progression in recurrent hepatitis C after liver transplantation. Guillaud, O., Gurram, KC., Puglia, M., et al.[2013]

This clinical trial aims to evaluate the efficacy of angiotensin II as a second-line vasopressor during liver transplantation, potentially allowing for a reduction in the dose of norepinephrine needed to maintain adequate blood pressure in patients with severe liver disease.

The study will assess not only the primary outcome of norepinephrine dosage but also safety outcomes like thromboembolism and severe hypertension, ensuring a comprehensive evaluation of angiotensin II's impact on patient safety and organ perfusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial. Bokoch, MP., Tran, AT., Brinson, EL., et al.[2023]

In a study involving 18 female pigs, angiotensin II was found to significantly contribute to hepatic ischemia following burn and sepsis, as indicated by increased vascular resistance and decreased blood flow to the liver after burns.

Administering the angiotensin II antagonist DuP753 improved hepatic blood flow and oxygen delivery, suggesting that blocking this receptor can mitigate the harmful effects of burns and sepsis on liver function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trauma- and sepsis-induced hepatic ischemia and reperfusion injury: role of angiotensin II. Tadros, T., Traber, DL., Herndon, DN.[2019]

In a study of 18 cirrhosis patients, the oral angiotensin II type 1 receptor blocker olmesartan significantly reduced hepatic venous pressure gradient (HVPG) by an average of 16.8%, indicating its potential effectiveness in treating portal hypertension.

Olmesartan was well-tolerated with no reported complications, and 33.3% of patients experienced a reduction in HVPG of more than 20%, suggesting it may be a safe and effective option for managing portal hypertension in cirrhosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New angiotensin II type 1 receptor blocker olmesartan improves portal hypertension in patients with cirrhosis. Hidaka, H., Kokubu, S., Nakazawa, T., et al.[2020]

In a study of 128 liver transplant recipients with hepatitis C recurrence, those treated with angiotensin-blocking agents had a significantly lower incidence of cirrhosis in the graft compared to those who did not receive these medications (15% vs. 35%).

Patients on angiotensin-blocking agents also showed lower fibrosis stages and slower progression of fibrosis over time, suggesting these drugs may help protect against graft fibrosis after liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Rimola, A., Londoño, MC., Guevara, G., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10660907/

Angiotensin II in liver transplantation (AngLT-1): protocol of a ... This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04901169

NCT04901169 | Angiotensin II in Liver Transplantation The purpose of this study is to determine the efficacy and safety of Angiotensin II as a second-line vasopressor (drug that raises the blood pressure) during ...

3. withpower.com withpower.com/trial/phase-2-and-3-vasoplegia-8-2021-10b34

Angiotensin II for Liver Transplant Complications Research suggests that Angiotensin II can improve blood flow to the kidneys during liver transplantation, which might help reduce kidney injury. Additionally, ...

4. bmjopen.bmj.com bmjopen.bmj.com/content/13/11/e078713.reviewer-comments

Angiotensin II in liver transplantation (AngLT-1) However studies attempting to maintain MAP using this cutoff has failed to improve the outcomes. Cirrhotic patients generally have low systemic.

5. mdpi.com mdpi.com/2227-9059/12/8/1817

Angiotensin II as a Vasopressor for Perioperative ... The results of this analysis showed that the addition of AT2S saved 0.08 lives at day 28 compared to SOC alone, the cost per life saved was estimated to be USD ...