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: 0

Duration: Duration of surgery (approximately 8 hours)

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing Angiotensin II, a drug that raises blood pressure, in liver transplant patients who need extra support to maintain their blood pressure. The drug works by tightening blood vessels to improve blood flow and increase blood pressure. Angiotensin II (ANG-2) is of increasing interest as an additional treatment to traditional therapy, both for improvement in blood pressure and for reducing the use of high-dose medications.

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.

What data supports the effectiveness of the drug Angiotensin II, Giapreza 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, drugs that block Angiotensin II have shown potential in reducing liver fibrosis in some studies, although results are mixed. ^{1 2 3 4 5}

Is Angiotensin II safe for use in humans?

Angiotensin II is approved for use in vasodilatory shock, indicating it has been evaluated for safety in humans. However, its safety specifically during liver transplantation is still being studied. ^{1 2 3 4 6}

How does the drug angiotensin II differ from other treatments for liver transplant complications?

Angiotensin II is unique because it is a peptide vasoconstrictor that may improve kidney function by enhancing blood flow to the kidneys, potentially reducing acute kidney injury during liver transplantation. Unlike standard catecholamine vasopressors, which can impair organ perfusion at high doses, angiotensin II is being evaluated as a second-line option to maintain blood pressure with potentially fewer side effects. ^{1 2 3 7 8}

Research Team

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

Principal Investigator

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

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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]

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 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]

References

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

Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial. [2023]

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

Angiotensin blockade does not affect fibrosis progression in recurrent hepatitis C after liver transplantation. [2013]

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

Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

New angiotensin II type 1 receptor blocker olmesartan improves portal hypertension in patients with cirrhosis. [2020]

6. Romania 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. [2015]

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

Intraoperative Use of Angiotensin II for Severe Vasodilatory Shock During Liver Transplantation: A Case Report. [2021]

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

Trauma- and sepsis-induced hepatic ischemia and reperfusion injury: role of angiotensin II. [2019]