Zibotentan + Dapagliflozin for Liver Cirrhosis

(ZEAL Trial)

No longer recruiting at 53 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two drugs, zibotentan and dapagliflozin (a medication for type 2 diabetes), in treating liver cirrhosis, particularly with portal hypertension (increased blood pressure in the liver's veins). Researchers compare different combinations of these drugs to determine the most effective and safe option. Individuals with cirrhosis who have noticeable symptoms like swelling or a history of liver issues might be suitable candidates. The study seeks participants who haven't recently used similar medications and whose liver condition remains stable. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking liver cirrhosis therapies.

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.

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

Research has shown that the combination of zibotentan and dapagliflozin is safe, particularly for individuals with chronic kidney disease. These studies found the treatment to be generally well-tolerated. However, higher doses of zibotentan were associated with increased fluid retention, which may cause swelling from extra fluid in the body. Despite this, the combination with dapagliflozin remains safe overall, with no serious liver problems reported in previous studies. This suggests the treatment could be safe for potential trial participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of zibotentan and dapagliflozin for liver cirrhosis because it offers a fresh approach compared to standard treatments, which usually focus on managing symptoms rather than targeting the underlying disease mechanisms. Zibotentan works as an endothelin receptor antagonist, potentially reducing fibrosis and improving liver function, while dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, may provide additional benefits by improving metabolic conditions associated with liver damage. This dual-action approach is promising because it targets both vascular and metabolic pathways, which could lead to more comprehensive management of liver cirrhosis and potentially slow disease progression.

What evidence suggests that this trial's treatments could be effective for liver cirrhosis?

Research shows that combining zibotentan and dapagliflozin may help treat chronic kidney disease (CKD). Studies have found that this combination can significantly reduce albuminuria, a common sign of kidney problems characterized by excess protein in the urine. The treatment is considered safe, although high doses of zibotentan alone might cause fluid buildup, which dapagliflozin can help control. Importantly, this combination works well for patients with or without type 2 diabetes. In this trial, participants will receive different combinations of zibotentan and dapagliflozin to evaluate their potential benefits for people with liver cirrhosis, particularly those with increased blood pressure in the liver's veins. ^{2 3 5 6 7}

Are You a Good Fit for This Trial?

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

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

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

Participants with T1DM

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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, 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 (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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12232351/

Effects of combined treatment with zibotentan and ... Combination therapy with zibotentan and dapagliflozin demonstrated consistent efficacy and safety across CKD patients with and without type 2 diabetes.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0140673623022304

Zibotentan in combination with dapagliflozin compared ... The results showed a robust and clinically meaningful reduction in albuminuria and an acceptable safety profile.

3. journals.lww.com journals.lww.com/jasn/fulltext/2024/10000/effects_of_zibotentan_alone_and_in_combination.10.aspx

Effects of Zibotentan Alone and in Combination with... High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04724837

Zibotentan and Dapagliflozin for the Treatment of CKD ... The purpose of the study is to assess efficacy, safety and tolerability of treatment with zibotentan and dapagliflozin in combination and dapagliflozin 10 mg ...

5. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D4326C00003

Zibotentan and Dapagliflozin combination, EvAluated in ... Part A will assess the efficacy, safety, and tolerability of the combination of B mg zibotentan and 10 mg dapagliflozin versus placebo in participants with ...

6. tandfonline.com tandfonline.com/doi/full/10.1080/14740338.2024.2328816

A comprehensive analysis of liver safety across zibotentan ... We used data from previous oncology clinical trials to determine the liver safety profile of zibotentan, which is currently in clinical development (in ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06269484

NCT06269484 | A Phase IIb Study to Evaluate the Safety of ... The study is designed to evaluate the safety of zibotentan/dapagliflozin in combination as compared to zibotentan monotherapy as well as zibotentan/ ...