Zibotentan + Dapagliflozin for Liver Cirrhosis

(ZEAL Trial)

Recruiting at 43 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must not be taking: SGLT2 inhibitors, ERAs

Disqualifiers: Chronic cholestatic liver disease, Hepatocellular carcinoma, T1DM, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

195 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you have not used SGLT2 inhibitors or ERAs within one month before joining. You can continue taking beta blockers if your dose has been stable for at least a month before starting the study.

What data supports the effectiveness of the drug Dapagliflozin for liver cirrhosis?

Dapagliflozin is effective in managing type 2 diabetes and has benefits for heart failure and chronic kidney disease, but there is no direct evidence supporting its use for liver cirrhosis. ^{1 2 3 4 5}

Is the combination of Zibotentan and Dapagliflozin safe for humans?

Dapagliflozin, also known as Farxiga or Forxiga, has been studied for its safety in treating type 2 diabetes and reducing kidney disease risk. It is generally considered safe for these conditions, but specific safety data for the combination with Zibotentan is not available. ^{1 2 3 6 7}

How is the drug combination of Zibotentan and Dapagliflozin unique for treating liver cirrhosis?

The combination of Zibotentan and Dapagliflozin is unique because it targets both the metabolic and potential fibrotic aspects of liver cirrhosis, with Dapagliflozin being a sodium-glucose cotransporter-2 (SGLT-2) inhibitor that helps manage glucose levels, which is crucial since many patients with liver cirrhosis also have diabetes. This dual approach may offer a novel way to address the complex needs of patients with liver cirrhosis and diabetes, although safety concerns like potential liver injury with Dapagliflozin need to be considered. ^{8 9 10 11 12}

Eligibility Criteria

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.

Inclusion Criteria

Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses

I am not pregnant or breastfeeding.

I haven't taken SGLT2 inhibitors or ERAs in the last month.

Exclusion Criteria

My liver cirrhosis is due to long-term bile flow issues.

Any evidence of a clinically significant disease which in the investigator's opinion makes it undesirable for the participant to participate in the study

Participants with T1DM

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Participants receive a combination of zibotentan and dapagliflozin or placebo for 6 weeks

6 weeks

Weekly visits (in-person)

Treatment Part B

Participants receive varying doses of zibotentan combined with dapagliflozin, dapagliflozin monotherapy, or placebo for 16 weeks

16 weeks

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dapagliflozin
• Zibotentan

Trial Overview 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.

Participant Groups

Group I: Part B: Treatment Group 5 Experimental Treatment 1 Intervention

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

Group II: Part B: Treatment Group 4 Experimental Treatment 1 Intervention

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

Group III: Part B: Treatment Group 3 Experimental Treatment 1 Intervention

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

Group IV: Part B: Treatment Group 2 Experimental Treatment 1 Intervention

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

Group V: Part B: Treatment Group 1 Experimental Treatment 1 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 2 Experimental Treatment 1 Intervention

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

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

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

Dapagliflozin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Forxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in United States as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in Canada as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

Dapagliflozin is an effective treatment for type 2 diabetes, proven through multiple controlled clinical trials that assess its efficacy, safety, and tolerability.

It is approved by the FDA for use as a standalone therapy or in combination with other glucose-lowering medications, including insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. Davis, PN., Ndefo, UA., Oliver, A.[2021]

Dapagliflozin (Farxiga) is approved for reducing the risk of declining kidney function and kidney failure in adults with chronic kidney disease, regardless of whether they have type 2 diabetes.

It also helps lower the risk of cardiovascular death and hospitalization for heart failure, highlighting its efficacy in managing both kidney and heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidiabetic Drug Approved to Reduce Risk of Kidney Disease. Aschenbrenner, DS.[2023]

Dapagliflozin (DAPA) is an effective SGLT2 inhibitor for treating type 2 diabetes, showing favorable pharmacokinetics and pharmacodynamics that help lower blood sugar levels while having beneficial effects on other metabolic risk factors.

While DAPA is generally safe, it carries an increased risk of genital and urinary infections, and concerns about bladder cancer and cardiovascular safety remain, prompting the FDA to seek further data on these issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. Maranghi, M., Carnovale, A., Durante, C., et al.[2021]

Dapagliflozin, an SGLT2 inhibitor, effectively improves glycemic control in type 2 diabetes and is associated with benefits such as reduced blood pressure, weight loss, and improved lipid profiles.

The review highlights dapagliflozin's potential to lower cardiovascular risks and mitigate microangiopathic complications like kidney disease and retinopathy, emphasizing its underuse in clinical practice despite these benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond the Glycaemic Control of Dapagliflozin: Microangiopathy and Non-classical Complications. Bellido, V., Martínez, J., Calvo, F., et al.[2022]

Dapagliflozin is an effective SGLT2 inhibitor for managing type 2 diabetes, showing consistent reductions in blood glucose levels and body weight over long-term follow-up periods of 1-4 years across various clinical trials.

It has a low risk of causing hypoglycemia and is generally well tolerated, although it can lead to genital infections, particularly in women, and is not recommended for patients with moderate to severe renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: a review of its use in patients with type 2 diabetes. Plosker, GL.[2022]

Dapagliflozin (Forxiga) is no longer authorized for the treatment of type 1 diabetes mellitus, indicating a significant change in its regulatory status.

This decision reflects safety concerns or efficacy issues that may have arisen from clinical evaluations or post-marketing surveillance, emphasizing the importance of ongoing drug safety assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin no longer licensed for type 1 diabetes. [2022]

The fixed-dose combination of dapagliflozin and saxagliptin (QTERN) effectively reduces hemoglobin A1C levels in patients with uncontrolled type 2 diabetes when used alongside metformin, showing a significant difference in A1C reduction compared to other combinations.

QTERN is generally well tolerated, but its use may be limited by cost and modest efficacy in A1C reduction, highlighting the need for further research on its long-term effects on diabetes complications and cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for the Treatment of Type 2 Diabetes. Coppenrath, VA., Hydery, T.[2022]

In a study of patients with cirrhosis and type 2 diabetes, those treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) experienced significantly lower rates of decompensation events compared to those treated with dipeptidyl peptidase-4 (DPP-4) inhibitors and sulfonylureas, indicating better safety and efficacy of GLP-1RAs in this population.

The study found that GLP-1RAs reduced the risk of specific decompensation events, such as ascites and spontaneous bacterial peritonitis, with hazard ratios indicating a 32% to 36% lower risk compared to DPP-4 inhibitors and sulfonylureas, suggesting that GLP-1RAs may be a preferable treatment option for managing diabetes in patients with cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients With Cirrhosis and Diabetes. Simon, TG., Patorno, E., Schneeweiss, S.[2023]

About 80% of patients with liver cirrhosis experience glucose metabolism disorders, with 30% developing overt diabetes mellitus, which is linked to higher risks of liver complications and mortality.

There is a need for more research on the safety and effectiveness of antidiabetic medications in cirrhosis patients, particularly newer treatments like SGLT2 inhibitors and GLP-1 receptor agonists, as current therapies can pose risks like hypoglycemia and lactic acidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The treatment of diabetes mellitus of patients with chronic liver disease. García-Compeán, D., González-González, JA., Lavalle-González, FJ., et al.[2019]

A case study of a 48-year-old woman with type 2 diabetes and liver cirrhosis revealed acute cholestatic liver injury after starting dapagliflozin, highlighting potential safety concerns with this medication.

The liver biopsy indicated drug-induced liver injury, suggesting that dapagliflozin may pose hepatotoxic risks, especially in patients with pre-existing liver conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin-Induced Acute-on-Chronic Liver Injury. Levine, JA., Ann Lo, A., Wallia, A., et al.[2021]

Non-alcoholic steatohepatitis (NASH) is a serious liver condition with no approved therapies currently available, making it a significant focus for drug development, especially given its rising prevalence and impact on liver transplantation.

Combination therapies targeting multiple pathways involved in NASH show promise, with Phase 2 and Phase 3 studies indicating that these strategies may achieve better response rates than single-drug treatments, potentially leading to safer and more effective management of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination strategies for pharmacologic treatment of non-alcoholic steatohepatitis. Suri, J., Borja, S., Lim, JK.[2023]

Type 2 diabetes mellitus (T2DM) is closely linked to non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), which can lead to serious liver complications, highlighting the need for effective treatments.

While traditional medications like metformin are safe for T2DM, they are not effective for NAFLD/NASH, and newer antidiabetic drugs such as GLP-1 receptor agonists and SGLT2 inhibitors may offer better options for managing liver disease in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus. Sumida, Y., Seko, Y., Yoneda, M.[2020]

References

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

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. [2021]

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

Antidiabetic Drug Approved to Reduce Risk of Kidney Disease. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. [2021]

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

Beyond the Glycaemic Control of Dapagliflozin: Microangiopathy and Non-classical Complications. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Dapagliflozin: a review of its use in patients with type 2 diabetes. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Dapagliflozin no longer licensed for type 1 diabetes. [2022]

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

Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for the Treatment of Type 2 Diabetes. [2022]

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

Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients With Cirrhosis and Diabetes. [2023]

9. Mexico pubmed.ncbi.nlm.nih.gov

The treatment of diabetes mellitus of patients with chronic liver disease. [2019]

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

Dapagliflozin-Induced Acute-on-Chronic Liver Injury. [2021]

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

Combination strategies for pharmacologic treatment of non-alcoholic steatohepatitis. [2023]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus. [2020]