Zibotentan + Dapagliflozin for Chronic Kidney Disease

Not currently recruiting at 281 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with chronic kidney disease (CKD) who have high levels of protein in their urine, often indicating worsening kidney function. The study tests dapagliflozin (a medication for type 2 diabetes and heart failure) alone and with zibotentan to determine which approach is more effective, safe, and tolerable. Participants with CKD who are on specific kidney-related medications and have high protein levels in their urine might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment for CKD.

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.

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

Research shows that both the combination of zibotentan and dapagliflozin, and dapagliflozin alone, are safe for people with chronic kidney disease (CKD).

Studies have found that the combination of zibotentan and dapagliflozin is well-tolerated by CKD patients, including those with type 2 diabetes. This combination reduced protein in the urine and maintained a good safety record, with few serious side effects.

Dapagliflozin alone has also been tested for safety in CKD patients. Research indicates it has a good safety profile, with no cases of diabetic ketoacidosis, a serious diabetes complication. It has been shown to lower the risk of kidney failure and related deaths in CKD patients, highlighting its effectiveness and safety.

In summary, previous research has shown the treatments under study to be safe, making them promising options for those with chronic kidney disease. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for chronic kidney disease, which often include drugs like ACE inhibitors or ARBs, the combination of zibotentan and dapagliflozin offers a unique approach. Zibotentan is an endothelin receptor antagonist, which means it helps relax blood vessels and reduce pressure, potentially protecting kidney function. Meanwhile, dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, helps lower blood sugar, which is beneficial for kidney health. Researchers are excited about this combination because it could address kidney disease from multiple angles, potentially offering better protection and improved outcomes for patients.

What evidence suggests that this trial's treatments could be effective for chronic kidney disease?

Research has shown that combining zibotentan with dapagliflozin may benefit people with chronic kidney disease (CKD). In this trial, some participants will receive this combination, which studies have found can significantly reduce protein in the urine, an important indicator of kidney health. This treatment is also safe and well-tolerated, making it a promising option for people with CKD. Other participants will receive dapagliflozin alone, which has been proven to slow CKD progression, lower the risk of kidney failure, and improve kidney function. Both treatments offer hope for those dealing with CKD. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 (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]

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]

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 (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. nejm.org nejm.org/doi/full/10.1056/NEJMoa2024816

Dapagliflozin in Patients with Chronic Kidney Disease The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38730538/

The long-term effects of dapagliflozin in chronic kidney ... Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years [dapagliflozin: 25.2, 95% confidence interval (CI) ...

3. farxiga-hcp.com farxiga-hcp.com/chronic-kidney-disease

Chronic Kidney Disease | FARXIGA® (dapagliflozin) 5 mg ... The primary efficacy endpoint was a composite of sustained ≥50% eGFR decline, ESKD, or CV or renal death. 97% of patients received a stable dose of ACEi/ARB ...

4. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2021/farxiga-approved-in-the-us-for-ckd.html

Farxiga approved in the US for the treatment of chronic ... In August 2020, results from the DAPA-CKD Phase III trial demonstrated that Farxiga achieved unprecedented reduction in the composite risk of ...

5. academic.oup.com academic.oup.com/ndt/article/39/12/2040/7668437

The long-term effects of dapagliflozin in chronic kidney disease Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years [dapagliflozin: 25.2, 95% confidence interval (CI) ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39834621/

Efficacy and safety of dapagliflozin in patients with CKD We provide evidence of the anti-proteinuric efficacy of short-term dapagliflozin in the presence of good safety profile in patients with CKD ...

7. hfsa.org hfsa.org/farxiga-demonstrated-unprecedented-reduction-risk-kidney-failure-and-cardiovascular-or-renal-death

Farxiga demonstrated unprecedented reduction in the risk ... Farxiga is the first medicine to significantly prolong survival in a renal outcomes trial in patients with chronic kidney disease with and without type-2 ...