What side effects are associated with this type of intervention?

Common treatments for Chronic Kidney Disease (CKD) like Endothelin Receptor Antagonists (ERAs) and Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors have specific side effects. ERAs can cause fluid retention, liver enzyme elevations, and anemia. SGLT2 inhibitors, such as dapagliflozin, may lead to an initial acute decrease in eGFR, urinary tract infections, genital infections, and a potential risk of diabetic ketoacidosis. Both classes of drugs are generally well-tolerated but require careful monitoring for these adverse effects.

What prior FDA approvals exist?

For the treatment of Chronic Kidney Disease (CKD), the FDA has approved several Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors, including dapagliflozin and empagliflozin. These drugs have shown significant benefits in reducing renal and cardiovascular events in patients with CKD. Dapagliflozin, for instance, was highlighted in the DAPA-CKD trial for its efficacy in lowering the frequency of a combined renal endpoint. While Endothelin Receptor Antagonists (ERAs) like zibotentan are being studied for their potential benefits in CKD, they have not yet received FDA approval specifically for this indication.

What other types of research exist?

Promising novel alternatives for CKD treatment in 2024 include: 1) Finerenone, a non-steroidal mineralocorticoid receptor antagonist, which has shown efficacy in reducing the risk of CKD progression and cardiovascular events in patients with CKD and type 2 diabetes. 2) Bardoxolone methyl, an activator of the Nrf2 pathway, which has demonstrated potential in improving eGFR in patients with CKD. 3) Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, which is being investigated for its ability to treat anemia in CKD patients and may have renal protective effects. These alternatives are in various stages of clinical trials and have shown promising results in recent studies.

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Zibotentan + Dapagliflozin for Chronic Kidney Disease

Verified Trial

Phase 3

Recruiting

Research Sponsored by AstraZeneca

Eligibility Criteria Checklist

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

Must have

Diagnosis of CKD, defined as eGFR ≥ 20 and < 90 mL/min/1.73 m2 and UACR > 700 mg/g (> 79 mg/mmol) or UPCR > 1000 mg/g (> 113 mg/mmoL).

All female participants must have a negative serum pregnancy test result at screening.

Must not have

Participants hospitalised for HF during the last 6 month prior to screening.

Participants with NYHA class III or class IV Congestive HF at the time of enrolment.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up through study completion, approximately 43 months

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial is testing two treatments for people with chronic kidney disease who have high levels of protein in their urine. One treatment combines two drugs, zibotentan and dapagliflozin, while the other uses only dapagliflozin. Zibotentan helps relax blood vessels to reduce kidney damage, and dapagliflozin lowers blood sugar and protects the kidneys.

Who is the study for?

Adults with chronic kidney disease and high protein in urine, on stable RAASi therapy for at least 4 weeks. They must not have severe heart conditions, recent hospitalizations for heart issues or COVID-19, organ transplants, certain cancers within the last 5 years, drug/alcohol abuse history within a year, or be on specific other treatments.

What is being tested?

The trial is testing the effectiveness of Zibotentan combined with Dapagliflozin versus Dapagliflozin alone in patients with chronic kidney disease to see which is better at managing their condition. It's a Phase III study where participants are randomly assigned to one of these two options.

What are the potential side effects?

Possible side effects include blood pressure changes, symptoms related to heart failure (like swelling), liver issues (elevated enzymes), sensitivity reactions to medication components and potential risks associated with diabetes medications such as dehydration.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have chronic kidney disease with specific kidney function and protein levels.

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I am not pregnant, as confirmed by a blood test.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I was hospitalized for heart failure in the last 6 months.

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I have severe heart failure.

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I have type 1 diabetes.

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I am on dialysis or have had a kidney transplant.

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I have signs of fluid in my lungs or swollen neck veins.

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I have had dangerous irregular heartbeats.

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I have been hospitalized for heart issues or COVID-19 in the last 3 months.

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I have had a solid organ or bone marrow transplant.

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I am currently taking medication that strongly affects liver enzymes.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ through study completion, approximately 43 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~through study completion, approximately 43 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and through study completion, approximately 43 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Change in eGFR from baseline

Secondary study objectives

Change in UACR from baseline to each participant's mean level

Change in Urine Protein to Creatinine Ratio (UPCR) from baseline to each participant's mean level

Change in systolic blood pressure from baseline to each participant's mean level

+2 more

Side effects data

From 2018 Phase 4 trial • 30 Patients • NCT03006471

20%

Cervicovaginal infection

13%

Urinary tract infections

100%

80%

60%

40%

20%

Study treatment Arm

Dapagliflozin

Placebo

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Zibotentan/Dapagliflozin dose A or Zibotentan/Dapagliflozin dose BExperimental Treatment1 Intervention

Drug dose (dose A or B) are determined based on eGFR values. Participants will receive daily oral dose of zibotentan/dapagliflozin in fixed dose combination.

Group II: Dapagliflozin aloneActive Control1 Intervention

Participants will receive daily oral dose of dapagliflozin.

0 / 11Eligibility criteria met

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 (ERAs) like Zibotentan work by blocking the endothelin-1 receptor, which reduces vasoconstriction and inflammation, thereby lowering blood pressure and proteinuria, key factors in CKD progression. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors like Dapagliflozin reduce glucose reabsorption in the kidneys, leading to glycosuria and improved glycemic control. They also have beneficial effects on blood pressure and reduce the risk of heart failure. These mechanisms are crucial for CKD patients as they help slow disease progression, reduce cardiovascular risks, and improve overall kidney function.

Correlates and Consequences of an Acute Change in eGFR in Response to the SGLT2 Inhibitor Dapagliflozin in Patients with CKD.Effects of sacubitril/valsartan versus valsartan on renal function in patients with and without diabetes and heart failure with preserved ejection fraction: insights from PARAGON-HF.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.