Zibotentan + Dapagliflozin for Chronic Kidney Disease

Recruiting at 228 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must be taking: RAASi therapy

Must not be taking: SGLT2 inhibitors, ERAs

Disqualifiers: Heart failure, Type 1 diabetes, Transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 15

Duration: 24 months

1835 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be on a stable dose of RAASi therapy (like ACE inhibitors or ARBs) for at least 4 weeks before joining. Some medications, like strong CYP3A4 inducers or certain immunosuppressants, are not allowed.

What data supports the effectiveness of the drug Zibotentan + Dapagliflozin for chronic kidney disease?

Dapagliflozin is approved to reduce the risk of worsening kidney function and kidney failure in people with chronic kidney disease, and it is part of the standard care for this condition. Combining it with zibotentan, which works differently, may enhance its effectiveness in slowing kidney disease progression. ^{1 2 3 4 5}

Is the combination of Zibotentan and Dapagliflozin safe for humans?

Dapagliflozin, also known as Farxiga or Forxiga, is generally considered safe for treating type 2 diabetes and reducing kidney disease risk, but there have been safety studies to monitor its effects on kidney function. It is no longer approved for type 1 diabetes due to safety concerns. ^{1 4 6 7 8}

How is the drug combination of zibotentan and dapagliflozin unique for treating chronic kidney disease?

The combination of zibotentan and dapagliflozin is unique because it combines two different mechanisms: dapagliflozin, which helps the kidneys by reducing fluid retention and improving heart and kidney outcomes, and zibotentan, which slows kidney disease progression but can cause fluid retention. Together, they may enhance treatment effectiveness while reducing the risk of fluid retention. ^{1 2 3 5 9}

What is the purpose of this trial?

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.

Eligibility Criteria

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.

Inclusion Criteria

Provision of electronic informed consent prior to completion of the optional Study Participant Feedback Questionnaire (SPFQ).

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

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

Exclusion Criteria

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

I have severe heart failure.

Your doctor believes you have less than 2 years to live due to a health condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily oral doses of zibotentan/dapagliflozin or dapagliflozin alone

24 months

Regular visits from Day 15 up to Month 24

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 19 months

Treatment Details

Interventions

• Dapagliflozin
• Zibotentan/Dapagliflozin

Trial Overview 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.

Participant Groups

Group I: Zibotentan/Dapagliflozin dose A or Zibotentan/Dapagliflozin dose B Experimental Treatment 1 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 alone Active Control 1 Intervention

Participants will receive daily oral dose of dapagliflozin.

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 (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 has been shown to be effective in improving outcomes for patients with chronic kidney disease, as highlighted in the commentary on a study involving diverse patient populations.

The commentary emphasizes the importance of dapagliflozin's mechanism of action, which includes reducing the risk of kidney disease progression and cardiovascular events, making it a valuable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin in people with chronic kidney disease. Sylvester, RD., Khong, TK.[2023]

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 has been shown to significantly improve kidney outcomes in patients with chronic kidney disease, demonstrating its efficacy in reducing the risk of kidney disease progression.

The study involved a large cohort of patients, providing robust evidence for the safety and effectiveness of dapagliflozin in managing chronic kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In CKD, dapagliflozin reduced a composite of eGFR decline, end-stage kidney disease, or CV or renal mortality. Molony, DA., LeMaistre, FI.[2021]

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 (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]

In a study involving over 34,000 person-years of real-world exposure, dapagliflozin was associated with a significantly lower incidence of hospitalization for acute kidney injury (hAKI) compared to other glucose-lowering drugs, indicating a safer profile for kidney function.

The adjusted incidence rate ratios showed that dapagliflozin users had a 30% reduced risk of hAKI, supporting its safety and efficacy in treating type 2 diabetes mellitus without compromising kidney health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Authorization Safety Study of Hospitalization for Acute Kidney Injury in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting. Johannes, CB., Beachler, DC., Layton, JB., et al.[2023]

References

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

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

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

Dapagliflozin in people with chronic kidney disease. [2023]

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

Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial. [2023]

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

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

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

In CKD, dapagliflozin reduced a composite of eGFR decline, end-stage kidney disease, or CV or renal mortality. [2021]

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

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

7. England pubmed.ncbi.nlm.nih.gov

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

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

Post-Authorization Safety Study of Hospitalization for Acute Kidney Injury in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting. [2023]

9. England pubmed.ncbi.nlm.nih.gov

The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan. [2023]