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Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD Trial) (ZENITH-CKD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04724837
Recruitment Status : Recruiting
First Posted : January 26, 2021
Last Update Posted : July 6, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
The purpose of the study is to assess efficacy, safety and tolerability of treatment with zibotentan and dapagliflozin in combination and alone, compared with placebo in participants with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) between 20 and 60 mL/min/1.73^2.

Condition or disease Intervention/treatment Phase
Chronic Kidney Disease Drug: Zibotentan Drug: Dapagliflozin Drug: Placebo Phase 2

Detailed Description:

The study will be conducted in approximately 200 sites in North America, South America, Africa, Asia/Pacific, and European countries.

The study will be conducted in 2 parts, Part A and Part B. In both study parts, participants will be randomized to 12 weeks of treatment plus 2 weeks follow-up.

After screening, eligible participants will be stratified by diabetes (diabetic kidney disease [DKD] versus non-diabetes mellitus [non-DM] CKD) and baseline eGFR (below versus above 45 mL/min/1.73m^2).

Participants will be randomized to treatments with 4 arms in Part A and 6 arms in Part B, in addition to receiving background local standard of care (SoC) therapy as follows:

Part A:

  1. Zibotentan Dose A + Dapagliflozin 10 mg once daily.
  2. Zibotentan Dose A once daily.
  3. Dapagliflozin 10 mg once daily.
  4. Placebo once daily.

Part B:

  1. Zibotentan Dose A + Dapagliflozin 10 mg once daily.
  2. Zibotentan Dose A once daily.
  3. Dapagliflozin 10 mg once daily.
  4. Placebo once daily.
  5. Zibotentan Dose B + Dapagliflozin 10 mg once daily.
  6. Zibotentan Dose C+ Dapagliflozin 10 mg once daily.

Participants randomized in Part A cannot be randomized in Part B.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 660 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2b Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Dose-Ranging Study to Assess the Efficacy, Safety and Tolerability of Zibotentan and Dapagliflozin in Patients With Chronic Kidney Disease With Estimated Glomerular Filtration Rate (eGFR) Between 20 and 60 mL/Min/1.73 m^2
Actual Study Start Date : April 28, 2021
Estimated Primary Completion Date : July 4, 2022
Estimated Study Completion Date : July 4, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: Part A and Part B: Zibotentan Dose A + Dapagliflozin
Participants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks.
Drug: Zibotentan
Participants will receive zibotentan as per the arms they are randomized.

Drug: Dapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized.

Experimental: Part A and Part B: Zibotentan Dose A
Participants will receive once daily oral dose A of zibotentan alone for 12 weeks.
Drug: Zibotentan
Participants will receive zibotentan as per the arms they are randomized.

Experimental: Part A and Part B: Dapagliflozin
Participants will receive once daily oral dose of dapagliflozin 10 mg alone for 12 weeks.
Drug: Dapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized.

Placebo Comparator: Part A and Part B: Placebo
Participants will receive once daily oral dose of placebo matched to zibotentan or dapagliflozin for 12 weeks.
Drug: Placebo
Participants will receive placebo matched to zibotentan or dapagliflozin.

Experimental: Part B Only: Zibotentan Dose B + Dapagliflozin
Participants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks.
Drug: Zibotentan
Participants will receive zibotentan as per the arms they are randomized.

Drug: Dapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized.

Experimental: Part B Only: Zibotentan Dose C + Dapagliflozin
Participants will receive once daily oral dose C of zibotentan and 10 mg dapagliflozin for 12 weeks.
Drug: Zibotentan
Participants will receive zibotentan as per the arms they are randomized.

Drug: Dapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized.




Primary Outcome Measures :
  1. Change in Log-transformed Urinary Albumin to Creatinine Ratio (UACR) from baseline to Week 12 [ Time Frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84) ]
    Integrated data from Part A and B will be used for assessment of effect of zibotentan and dapagliflozin in combination and alone versus placebo on UACR.


Secondary Outcome Measures :
  1. Change in Log-transformed UACR from baseline to Week 12 [ Time Frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84) ]
    Integrated data from Part A and B will be used for assessment of the change in UACR for doses of zibotentan combined with 10 mg dapagliflozin versus 10 mg dapagliflozin alone.

  2. Change in Blood Pressure from baseline to Week 12 [ Time Frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84) ]
    Integrated data from Part A and B will be used for assessment of the change in office systolic and diastolic blood pressure (BP) for doses of zibotentan combined with 10 mg dapagliflozin and for zibotentan and 10 mg dapagliflozin alone versus placebo. Integrated data from Part A and B

  3. Least Squares Mean Change of UACR at Week 12 for Zibotentan and Dapagliflozin in Combination and Dapagliflozin alone [ Time Frame: At Week 12 (Day 84) ]
    Integrated data from Part A and B will be used for assessment of dose-response significance and relationship across different dose of zibotentan/dapagliflozin and dapagliflozin alone on UACR reduction. Integrated data from Part A and B.

  4. Change in eGFR from Baseline to Week 1, Week 12 and Week 14 [ Time Frame: From baseline (Week 0 [Day 1]) until Week 1, Week 12, and Week 14 ]
    Integrated data from Part A and B will be used for assessment of the effect of ranging doses of zibotentan and dapagliflozin in combination and alone on eGFR.

  5. Change in eGFR from Week 1 to Week 12 [ Time Frame: From Week 1 (Day 8) until Week 12 (Day 84) ]
    Integrated data from Part A and B will be used for assessment of the effect of ranging doses of zibotentan and dapagliflozin in combination and alone on eGFR.

  6. Number of Participants Experiencing Adverse events [ Time Frame: From Week 0 (Day 1) until Follow-up visit (Week 14 [Day 98]) ]
    Integrated data from Part A and B will be used for assessment of the safety and tolerability of ranging doses of zibotentan and dapagliflozin in combination and alone versus placebo.



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 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

• Diagnosis of CKD, defined as: Part A: eGFR chronic kidney disease epidemiology collaboration (CKD-EPI) ≥ 30 and ≤ 60 mL/min/1.73 m^2; Part B, if safety data from Part A allow (otherwise same as in Part A): eGFR (CKD-EPI) ≥ 20 and ≤ 60 mL/min/1.73 m^2; and UACR ≥ 200 and ≤ 5000 mg albumin/g creatinine

  • No current or prior (within 1 month of screening) medical treatment with an SGLT2i (sodium-glucose co-transporter 2 inhibitor) or any fixed dose combination with SGLT2i
  • All participants should follow protocol defined contraceptives procedures

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

  • Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease requiring significant immunosuppression, autosomal dominant or autosomal recessive polycystic kidney disease, or anatomical causes of CKD
  • History of epilepsy syndrome
  • Participants with New York Heart Association classification functional heart failure (HF) class III or IV
  • Acute coronary syndrome events within 3 months prior to screening
  • Participants with a confirmed B-type natriuretic peptide (BNP) ≥ 200 pg/mL or BNP ≥ 400 pg/mL if with atrial fibrillation
  • Participants with unstable HF requiring hospitalisation for optimisation of HF treatment and/or who have not been stable on HF therapy within 6 months prior to screening
  • Heart failure due to cardiomyopathies that would primarily require specific other treatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or other infiltrative diseases, cardiomyopathy related to congenital heart disease, primary hypertrophic cardiomyopathy, cardiomyopathy related to toxic or infective conditions
  • High output HF
  • Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement
  • Participants with uncontrolled diabetes mellitus (HbA1c > 12%), and with T1DM
  • Intermittent or persistent second or third degree atrioventricular block after sinus node dysfunction, with clinically significant bradycardia or sinus pause when not treated with pacemaker
  • History of any life-threatening cardiac dysrhythmia
  • Cardiac surgery or non-elective percutaneous coronary interventions (within 3 months) or open chest coronary artery bypass grafting or valvular repair/replacement (within 12 months) prior to screening or is planned to undergo any of these procedures after randomisation
  • Heart transplantation or left ventricular assist device at any time
  • History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i or drugs with a similar chemical structure to zibotentan
  • Any clinically significant disease or disorder, which might put the participant at risk because of participation in the study, or probable alternative primary reason for participant's symptoms in judgment of investigator, including but not limited to:

    • Isolated pulmonary arterial hypertension (defined as mean PAP ≥ 25 mmHg at rest) or right ventricular failure; in the absence of left-sided HF
    • Anaemia defined as haemoglobin (Hb) level < 100 g/L or 10 g/dL at randomization visit (Visit 2)
    • Severe chronic obstructive pulmonary disease or other lung disease including but not limited to pulmonary fibrosis requiring chronic oxygen therapy, regular nebuliser use, or oral steroid therapy
  • Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to screening Severe hepatic impairment (Child-Pugh class C Hepatic impairment), aspartate transaminase or alanine transaminase > 2x the upper limit of normal [ULN]; or total bilirubin > 2x ULN at time of screening
  • Participants with newly detected pathological laboratory values or an ongoing disease condition requiring investigation and/or initiation or adjustment of current treatment
  • Positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core antibody, at screening
  • Participants treated with strong or moderate CYP3A4 inhibitor or inducer
  • Any of the following signs or confirmation of corona virus disease- 2019 (COVID-19) infection:

    • Participant has a positive test result for severe acute respiratory syndrome coronavirus 2 before randomisation (Visit 2)
    • Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnoea, sore throat, fatigue) or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening (Visit 1) or at randomisation (Visit 2)
    • Participant has been previously hospitalised with COVID-19 infection

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): NCT04724837


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

Locations
Show Show 173 study locations
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: David C Wheeler, MB ChB, MD, FRCP Centre for Nephrology Royal Free Campus University College London Rowland Hill Street London NW3 2PF United Kingdom
Principal Investigator: Jamie P. Dwyer, M.D. Nephrology Clinical Trials Center Nephrology and Hypertension Vanderbilt University Medical Center Nashville TN United States of America
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04724837    
Other Study ID Numbers: D4325C00001
2020-004101-32 ( EudraCT Number )
First Posted: January 26, 2021    Key Record Dates
Last Update Posted: July 6, 2021
Last Verified: June 2021
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://astrazenecagroup-dt.pharmacm.com/DT/Home

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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
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Urologic Diseases
Renal Insufficiency
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs