What side effects are associated with this type of intervention?

Common treatments for liver cirrhosis include endothelin receptor antagonists and SGLT2 inhibitors. Endothelin receptor antagonists, such as bosentan, are associated with hepatotoxicity, including elevated liver enzymes and potential liver injury. SGLT2 inhibitors, like dapagliflozin, can cause side effects such as urinary tract infections, genital mycotic infections, and an initial decrease in eGFR, which typically recovers. Both classes of drugs require careful monitoring due to their potential adverse effects on liver and kidney function.

What prior FDA approvals exist?

As of now, there are no FDA-approved treatments specifically for liver cirrhosis that involve endothelin receptor antagonists or SGLT2 inhibitors. The ZEAL study is exploring the combination of Zibotentan (an endothelin receptor antagonist) and Dapagliflozin (an SGLT2 inhibitor) for their potential efficacy in treating cirrhosis with features of portal hypertension. Current treatments for liver cirrhosis primarily focus on managing symptoms and complications, such as using diuretics for edema, beta-blockers for portal hypertension, and antiviral therapies for viral hepatitis-related cirrhosis.

What other types of research exist?

Promising novel alternatives for liver cirrhosis treatment in 2024 include: 1) Anti-fibrotic agents like simtuzumab, which targets lysyl oxidase-like 2 (LOXL2) to reduce fibrosis. 2) FXR agonists such as obeticholic acid, which modulate bile acid pathways and have shown potential in reducing liver fibrosis. 3) Anti-inflammatory agents like emricasan, a caspase inhibitor that reduces inflammation and apoptosis in liver cells. 4) Gene therapy approaches targeting specific genetic mutations associated with liver disease. These alternatives are currently under investigation and may offer new hope for liver cirrhosis patients.

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SGLT2 Inhibitor

Zibotentan + Dapagliflozin for Liver Cirrhosis (ZEAL Trial)

Phase 2

Recruiting

Research Sponsored by AstraZeneca

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Be older than 18 years old

Timeline

Screening 3 weeks

Treatment Varies

Follow Up at week 6 and week 16

Summary

This trial is testing a combination of two drugs, zibotentan and dapagliflozin, and also dapagliflozin alone. It targets people with liver disease (cirrhosis) that causes high blood pressure in the liver's veins. The treatment aims to lower this high blood pressure and improve liver health. Dapagliflozin is a medication that has been shown to reduce cardiovascular death and heart failure.

Who is the study for?

The ZEAL Study is for adults with liver cirrhosis and portal hypertension who haven't used SGLT2 inhibitors or endothelin receptor antagonists recently. They should have stable liver function, no recent severe kidney injury, variceal hemorrhage, or significant heart failure. Women must be non-pregnant, not breastfeeding, and either post-menopausal or surgically sterile.

What is being tested?

This study tests the safety and effectiveness of combining zibotentan with dapagliflozin versus placebo in treating liver cirrhosis with portal hypertension. It's a double-blind trial meaning neither participants nor researchers know who gets the real treatment versus a placebo.

What are the potential side effects?

Potential side effects may include typical drug reactions like nausea, headaches, possible kidney function changes due to dapagliflozin (a diabetes medication), and risks associated with zibotentan which could affect blood pressure since it targets blood vessel constriction.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ at week 6 and week 16

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~at week 6 and week 16

This trial's timeline: 3 weeks for screening, Varies for treatment, and at week 6 and week 16 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Part A: Absolute change in HVPG from baseline to Week 6.

Part B: Absolute change in HVPG from baseline to Week 6.

Secondary study objectives

Part A: Change in systolic and diastolic blood pressure from baseline to Week 6.

Part A: Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6. Change in total body fat mass from baseline to Week 6.

Part A: Evaluation of change in body weight (kg) over time course of study. Percentage and absolute change from baseline in body weight at Week 6.

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Trial Design

7Treatment groups

Experimental Treatment

Group I: Part B: Treatment Group 5Experimental Treatment1 Intervention

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Group II: Part B: Treatment Group 4Experimental Treatment1 Intervention

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Group III: Part B: Treatment Group 3Experimental Treatment1 Intervention

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Group IV: Part B: Treatment Group 2Experimental Treatment1 Intervention

Participants will receive once daily dose of placebo matching zibotentan capsule + dapagliflozin tablet for 16 weeks.

Group V: Part B: Treatment Group 1Experimental Treatment1 Intervention

Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 16 weeks.

Group VI: Part A: Treatment Group 2Experimental Treatment1 Intervention

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 6 weeks.

Group VII: Part A: Treatment Group 1Experimental Treatment1 Intervention

Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks.

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Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Endothelin receptor antagonists, such as zibotentan, block the effects of endothelin-1, a molecule that causes blood vessels to constrict, thereby reducing intrahepatic resistance and portal hypertension in liver cirrhosis. SGLT2 inhibitors like dapagliflozin lower blood glucose levels and may also have anti-inflammatory and antifibrotic effects. These treatments are important for liver cirrhosis patients as they address key pathological processes, potentially improving liver function and reducing complications related to portal hypertension.

Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis.Novel treatment options for portal hypertension.[Hepatotoxicity in patients treated with endothelin receptor antagonists: systematic review and meta-analysis of randomized clinical trials].