Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD Trial) (ZENITH-CKD)
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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. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04724837 |
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Recruitment Status :
Active, not recruiting
First Posted : January 26, 2021
Last Update Posted : March 9, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Chronic Kidney Disease | Drug: Zibotentan Drug: Dapagliflozin Drug: Placebo | Phase 2 |
The study will be conducted in approximately 220 sites in North America, South America, Africa, Asia/Pacific, and European countries.
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 or equal versus above 45 mL/min/1.73m^2).
A total of 495 participants will be randomised into this study, including participants randomised under the earlier study design. Four hundred and fifteen (415) participants will be randomised to have 166 participants in zibotentan Dose A/dapagliflozin 10 mg combination arm and dapagliflozin 10 mg monotherapy arm, and 83 participants in the zibotentan Dose B/dapagliflozin 10 mg combination arm.
- Zibotentan Dose A + Dapagliflozin 10 mg once daily.
- Zibotentan Dose B + Dapagliflozin 10 mg once daily.
- Dapagliflozin 10 mg + Placebo once daily.
Participants who were previously randomised cannot be re-randomised.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 542 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, Active-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) ≥ 20 mL/Min/1.73 m^2 |
| Actual Study Start Date : | April 28, 2021 |
| Estimated Primary Completion Date : | May 29, 2023 |
| Estimated Study Completion Date : | May 29, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Zibotentan Dose A + Dapagliflozin
Participants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks.
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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. |
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Experimental: Zibotentan Dose B + Dapagliflozin
Participants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks.
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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. |
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Experimental: Dapagliflozin + Placebo
Participants will receive once daily oral dose of dapagliflozin 10 mg and placebo for 12 weeks.
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Drug: Dapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized. Drug: Placebo Participants will receive placebo as per the arms they are randomized to. |
- 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) ]The effect of zibotentan Dose B/dapagliflozin 10 mg versus dapagliflozin 10 mg on UACR will be assessed.
- Change in Log-transformed UACR from baseline to Week 12 [ Time Frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84) ]The effect of zibotentan dose A/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy on UACR will be assessed.
- Change in Blood Pressure from baseline to Week 12 [ Time Frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84) ]The change in office systolic and diastolic blood pressure (BP) for doses of zibotentan combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy will be assessed.
- Least Squares Mean Change of UACR at Week 12 from the zibotentan/dapagliflozin dose arms and the dapagliflozin monotherapy arm [ Time Frame: From baseline until Week 12 (Day 84) ]The assessment of dose-response and relationship across different dose of zibotentan/dapagliflozin and dapagliflozin alone on UACR reduction.
- 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 ]The effect of different doses of zibotentan and dapagliflozin 10 mg in combination versus dapagliflozin 10 mg monotherapy on eGFR will be assessed.
- Change in eGFR from Week 1 to Week 12 [ Time Frame: From Week 1 (Day 8) until Week 12 (Day 84) ]The effect of different doses of zibotentan and dapagliflozin 10 mg in combination versus dapagliflozin 10 mg monotherapy on eGFR will be assessed.
- Number of Participants Experiencing Adverse events [ Time Frame: From Week 0 (Day 1) until Follow-up visit (Week 14 [Day 98]) ]The safety and tolerability of all doses of zibotentan combined with dapagliflozin 10 mg and dapagliflozin 10 mg monotherapy will be assessed.
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.
| Ages Eligible for Study: | 18 Years to 130 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
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Diagnosis of CKD, defined as:
(a) eGFR chronic kidney disease epidemiology collaboration (CKD-EPI) ≥ 20 mL/min/1.73 m^2, and (b) UACR ≥ 150 and ≤ 5000 mg albumin/g creatinine, based on a single first morning void spot urine sample at screening.
- 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
- If ACEi and/or ARB and/or mineralocorticoid receptor agonist (MRA) are prescribed, the dose must be stable ≥ 4 weeks before screening. Participants who have been deemed unable to tolerate ACEi or ARB therapy due to allergy or complications can be enrolled
- No current or prior treatment within 6 months prior to screening with cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary kidney disease
- Body mass index (BMI) ≤ 40 kg/m^2
- 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
- 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 B-type natriuretic peptide (BNP) ≥ 200 pg/mL or NT-proBNP ≥ 600 pg/mL (BNP ≥ 400 pg/mL or NT-proBNP ≥ 1200 pg/mL, respectively, if associated with atrial fibrillation) measured by local laboratory at screening (Visit 1)
- 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 other specific 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
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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 screening (Visit 1)
- 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, or hepatitis B virus, surface antigen at screening
- Participants treated with strong or moderate CYP3A4 inhibitor or inducer
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Confirmation of corona virus disease- 2019 (COVID-19) infection:
- Participant has a positive test result for severe acute respiratory syndrome coronavirus 2 during screening. Participants who are not hospitalised for COVID-19 infections can be re screened 4 weeks after they have recovered
- Participant has been previously hospitalised with COVID-19 infection
- Ejection fraction < 50% measured by echocardiogram at screening
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
Show 163 study locations
| 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 |
| 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: | March 9, 2023 |
| Last Verified: | March 2023 |
| 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 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Zibotentan Nephrology Dapagliflozin Sodium-glucose co-transporter 2 |
sodium-glucose co-transporter 2 inhibitor Kidney diseases Endothelin antagonist |
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Kidney Diseases Renal Insufficiency, Chronic Urologic Diseases Renal Insufficiency Dapagliflozin |
Sodium-Glucose Transporter 2 Inhibitors Molecular Mechanisms of Pharmacological Action Hypoglycemic Agents Physiological Effects of Drugs |