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Study to Investigate Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin in Participants With Chronic Kidney Disease and High Proteinuria (ZENITH High Proteinuria)

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ClinicalTrials.gov Identifier: NCT06087835
Recruitment Status : Recruiting
First Posted : October 18, 2023
Last Update Posted : May 23, 2024
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This is a Phase III, randomised, multicentre, double-blinded study to evaluate efficacy, safety and tolerability of treatment with zibotentan/dapagliflozin and dapagliflozin alone in participants with chronic kidney disease (CKD) and high proteinuria.

Condition or disease Intervention/treatment Phase
Chronic Kidney Disease With High Proteinuria Drug: Zibotentan/Dapagliflozin Drug: Dapagliflozin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III, Randomised, Multicentre, Double-blind Study to Evaluate the Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin Alone in Participants With Chronic Kidney Disease and High Proteinuria
Actual Study Start Date : November 7, 2023
Estimated Primary Completion Date : June 30, 2027
Estimated Study Completion Date : June 30, 2027


Arm Intervention/treatment
Experimental: Zibotentan/Dapagliflozin dose A or Zibotentan/Dapagliflozin dose B
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.
Drug: Zibotentan/Dapagliflozin
Participants will receive zibotentan/dapagliflozin in fixed-dose combination as per the arms they are randomized to

Active Comparator: Dapagliflozin alone
Participants will receive daily oral dose of dapagliflozin.
Drug: Dapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized to




Primary Outcome Measures :
  1. Change in eGFR from baseline [ Time Frame: At month 24 ]
    To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone to slow decline in kidney function


Secondary Outcome Measures :
  1. Change in Urine Protein to Creatinine Ratio (UPCR) from baseline to each participant's mean level [ Time Frame: Across the visits from Day 15 up to Month 24 ]
    To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing proteinuria

  2. Change in UACR from baseline to each participant's mean level [ Time Frame: Across the visits from Day 15 up to Month 24 ]
    To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing albuminuria

  3. Time to the first occurrence of any of the components of the renal composite endpoint of 40% sustained decline in eGFR or ESKD or renal death [ Time Frame: Through study completion, approximately 43 months ]
    To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing the incidence of the renal composite endpoint of 40% sustained decline in eGFR or ESKD or renal death

  4. Change in systolic blood pressure from baseline to each participant's mean level [ Time Frame: Across the visits from Day 15 up to Month 24 ]
    To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing systolic blood pressure

  5. Proportion of participants achieving Urine Protein to Creatinine Ratio (UPCR) < 1000 mg/g and > 30% reduction from baseline for each participant's mean level [ Time Frame: Across the visits from Day 15 up to Month 24 ]
    To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone, in reducing proteinuria, as measured by the proportion of participants achieving Urine Protein to Creatinine Ratio (UPCR) < 1000 mg/g and > 30% reduction from baseline



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant must be ≥ 18 years of age and of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent.
  2. 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).
  3. All female participants must have a negative serum pregnancy test result at screening.
  4. Female participants must be either

    • not of child-bearing potential or
    • women of child bearing potential (WOCBP) using at least one highly effective birth control method for at least 3 months prior to first dose of study intervention
  5. Capable of giving signed informed consent
  6. Provision of signed informed consent prior to any study specific procedure.
  7. Provision of electronic informed consent prior to completion of the optional Study Participant Feedback Questionnaire (SPFQ).
  8. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics imitative research that supports the Genomic Initiative.
  9. Receiving RAASi therapy (ACEi or ARB), and for the patient maximum tolerated labelled daily dose, that has been stable for at least 4 weeks.

Exclusion Criteria:

  1. Participants with NYHA class III or class IV Congestive HF at the time of enrolment.
  2. Participants hospitalised for HF during the last 6 month prior to screening.
  3. Evidence of rales or jugular venous distention on physical examination.
  4. Participants with type 1 diabetes mellitus.
  5. History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).
  6. Blood pressure above 160 mmHg systolic.
  7. Blood pressure below 90 mmHg systolic.
  8. Participants hospitalised for heart disease or cardiac procedures or for COVID-19 during the last 3 months prior to screening.
  9. History of solid organ transplantation or bone marrow transplant.
  10. History or ongoing allergy/hypersensitivity, as judged by the Investigator, to SGLT2i therapy (eg, dapagliflozin, canagliflozin, empagliflozin or other SGLT2 inhibitors) or Endothelin Receptor Antagonists (eg, ambrisentan, atrasentan, bosentan, or other).
  11. Any condition with a life expectancy of less than 2 years based on investigator´s clinical judgment.
  12. Malignancy within the past 5 years. Exceptions to this criterion include non-melanoma skin cancer and curatively treated cervical carcinoma in situ.
  13. Significant liver disease as judged by the investigator or severe hepatic impairment with AST or ALT > 3 × ULN; or total bilirubin > 2 × ULN at time of screening. An isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion.
  14. Known blood-borne diseases.
  15. Clinically significant, unstable, or uncontrolled medical condition as assessed by the Investigator.
  16. Participants on renal replacement therapy or previous kidney transplant.
  17. Known history of drug or alcohol abuse within 12 months of screening.
  18. Participants on treatment with strong or moderate CYP3A4 inducer.
  19. Participants on systemic immunosuppression therapy other than stable maintenance therapy defined as prednisone 10 mg/day (or equivalent) or less, aziothioprine 100 mg/day or less; MMF 1000 mg/day or less for at least 3 months prior to Visit 1. Inhaled, nasal or dermatological steroids are also allowed.
  20. Participants treated or expecting to be treated with tolvaptan, any other ERAs, or budesonide (where used to treat IBD or IgAN).
  21. Participation in another clinical study with a study intervention administered in the last 3 months.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06087835


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT06087835    
Other Study ID Numbers: D4325C00010
First Posted: October 18, 2023    Key Record Dates
Last Update Posted: May 23, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame:

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Access Criteria:

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

URL: https://vivli.org/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Zibotentan
Nephrology
Dapagliflozin
Sodium-glucose co-transporter 2
sodium-glucose co-transporter 2 inhibitor
Kidney diseases
Endothelin antagonist
High Proteinuria
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Proteinuria
Urologic Diseases
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Male Urogenital Diseases
Renal Insufficiency
Chronic Disease
Disease Attributes
Pathologic Processes
Urination Disorders
Urological Manifestations
Dapagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs