Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD Trial)
ZENITH-CKD
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
2 other identifiers
interventional
542
19 countries
164
Brief Summary
The purpose of the study is to assess efficacy, safety and tolerability of treatment with zibotentan and dapagliflozin in combination and dapagliflozin 10 mg as monotherapy in participants with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m\^2, and urinary albumin to creatinine ratio (UACR) ≥ 150 mg/g and ≤ 5000 mg/g.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Apr 2021
164 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
January 25, 2021
CompletedFirst Posted
Study publicly available on registry
January 26, 2021
CompletedStudy Start
First participant enrolled
April 28, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 1, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
June 1, 2023
CompletedResults Posted
Study results publicly available
July 30, 2024
CompletedJuly 30, 2024
July 1, 2024
2.1 years
January 25, 2021
May 16, 2024
July 5, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Change in Urinary Albumin to Creatinine Ratio (UACR) From Baseline to Week 12
The effect of zibotentan 1.5/dapagliflozin 10 mg versus dapagliflozin 10 mg on UACR was assessed.
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary Outcomes (7)
Change in UACR From Baseline to Week 12
From baseline (Week 0 [Day 1]) until Week 12
Change in Office Systolic Blood Pressure From Baseline to Week 12
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in Office Diastolic Blood Pressure From Baseline to Week 12
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in UACR From Baseline to Week 12
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in eGFR From Baseline to Week 1, Week 12, and Week 14
From baseline (Week 0 [Day 1]) until Week 1 (Day 8), Week 12 (Day 84), and Week 14 (Day 98)
- +2 more secondary outcomes
Study Arms (3)
Zibotentan Dose A + Dapagliflozin
EXPERIMENTALParticipants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks.
Zibotentan Dose B + Dapagliflozin
EXPERIMENTALParticipants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks.
Placebo + Dapagliflozin
EXPERIMENTALParticipants will receive once daily oral dose of dapagliflozin 10 mg and placebo for 12 weeks.
Interventions
Participants will receive zibotentan as per the arms they are randomized.
Participants will receive 10 mg dapagliflozin as per the arms they are randomized.
Participants will receive placebo as per the arms they are randomized to.
Eligibility Criteria
You may qualify if:
- Participants are eligible to be included in the study only if all of the following criteria apply:
- Diagnosis of Chronic kidney disease (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 Angiotensin-converting enzyme inhibitors (ACEi) and/or Angiotensin receptor blockers (ARB) and/or mineralocorticoid receptor agonist 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 ≤ 40 kg/m\^2.
- Male or female of non-childbearing potential.
- Female participants must have a negative pregnancy test at screening, must not be lactating, and must be of non-childbearing potential, confirmed at screening by fulfilling one of the following criteria:
- Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone and luteinizing hormone levels in the postmenopausal range.
- Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
- Male participants must be surgically sterile, abstinent, or in conjunction with a female sexual partner, using a highly effective method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the last dose of investigational product to prevent any pregnancies. Male study participants must not donate or bank sperm during this same time period.
- Capable of giving signed informed consent, as described in Appendix A, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
- Provision of signed and dated written Genetic informed consent prior to collection of samples (optional) for genetic analysis.
You may not qualify if:
- 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 (ie, chemotherapy, infective myocarditis, septic cardiomyopathy).
- High output HF (eg, due to hyperthyroidism or Paget's disease).
- 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%).
- Participants with Type 1 diabetes mellitus.
- Hyponatremia, defined as serum Na+ \< 135 mmol/L at the time of screening (Visit 1).
- 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.
- Prolonged QT interval (QTcF \> 470 ms) on ECG at screening (Visit 1) or randomisation visit (Visit 2), known congenital long QT syndrome or history of QT prolongation associated with other medications.
- History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter).
- +27 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- AstraZenecalead
Study Sites (164)
Research Site
Huntsville, Alabama, 35805, United States
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Beverly Hills, California, 90211, United States
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Downey, California, 90242, United States
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Fountain Valley, California, 92708, United States
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Laguna Hills, California, 92653, United States
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Los Angeles, California, 90057, United States
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Northridge, California, 91324, United States
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Ontario, California, 91762, United States
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South Gate, California, 90280, United States
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Tarzana, California, 91356, United States
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Vacaville, California, 95687, United States
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Fort Lauderdale, Florida, 33308, United States
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Hialeah, Florida, 33012, United States
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New Port Richey, Florida, 34652, United States
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Orlando, Florida, 32806, United States
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Riverview, Florida, 33578, United States
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Tampa, Florida, 33614, United States
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Augusta, Georgia, 30904, United States
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Fayetteville, Georgia, 30214, United States
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Wichita, Kansas, 67214-2943, United States
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Owensboro, Kentucky, 42303, United States
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Metairie, Louisiana, 70006, United States
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Shreveport, Louisiana, 71101, United States
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Boston, Massachusetts, 02215, United States
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Flint, Michigan, 48504, United States
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Flint, Michigan, 48532, United States
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Lincoln, Nebraska, 68510, United States
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Las Vegas, Nevada, 89128, United States
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Greenville, North Carolina, 27834, United States
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Jacksonville, North Carolina, 28546, United States
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Kinston, North Carolina, 28504, United States
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Morehead City, North Carolina, 28557, United States
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New Bern, North Carolina, 28562, United States
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Wilmington, North Carolina, 28401, United States
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Marion, Ohio, 43302, United States
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Chester, Pennsylvania, 19013, United States
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Memphis, Tennessee, 38104, United States
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Memphis, Tennessee, 38119, United States
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Arlington, Texas, 76002, United States
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Conroe, Texas, 77384, United States
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Corpus Christi, Texas, 78414, United States
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El Paso, Texas, 79935, United States
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Houston, Texas, 77004, United States
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Houston, Texas, 77099, United States
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Odessa, Texas, 79761, United States
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San Antonio, Texas, 78212, United States
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Waxahachie, Texas, 75165, United States
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Forest, Virginia, 24551, United States
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Newport News, Virginia, 23606, United States
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Spokane, Washington, 99204, United States
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Buenos Aires, C1425AGC, Argentina
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CABA, C1120AAC, Argentina
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CABA, C1440AAD, Argentina
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Corrientes, W3400AMZ, Argentina
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Córdoba, 5003, Argentina
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Junín, 6000, Argentina
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Mar del Plata, B7600FZN, Argentina
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Mar del Plata, B7600, Argentina
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San Luis, 5700, Argentina
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San Miguel de Tucumán, 4000, Argentina
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Santa Fe, S3000, Argentina
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Adelaide, 5000, Australia
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Birtinya, 4575, Australia
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Elizabeth Vale, 5112, Australia
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Gosford, 2250, Australia
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Westmead, 2145, Australia
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Botucatu, 18618-687, Brazil
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Campinas, 13010-001, Brazil
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Curitiba, 80440-020, Brazil
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Porto Alegre, 90020-090, Brazil
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Santo André, 09090-790, Brazil
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São José do Rio Preto, 15090-000, Brazil
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São Paulo, 01228-200, Brazil
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São Paulo, 04039-000, Brazil
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São Paulo, 5403-000, Brazil
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Gabrovo, 5300, Bulgaria
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Kozloduy, 3320, Bulgaria
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Montana, 3400, Bulgaria
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Plovdiv, 4023, Bulgaria
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Sliven, 8800, Bulgaria
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Sofia, 1407, Bulgaria
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Sofia, 1510, Bulgaria
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Stara Zagora, 6000, Bulgaria
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St. John's, Newfoundland and Labrador, A1A 3R5, Canada
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London, Ontario, N6A-5A5, Canada
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Toronto, Ontario, M5N 1C1, Canada
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Waterloo, Ontario, N2T 0C1, Canada
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Pula, 52000, Croatia
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Vinkovci, 32100, Croatia
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Århus N, 8200, Denmark
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Gentofte Municipality, 2820, Denmark
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Roskilde, 4000, Denmark
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Batumi, 6010, Georgia
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Gori, 1400, Georgia
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Gurjaani, 1500, Georgia
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Kutaisi, 4600, Georgia
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Marneuli, 3000, Georgia
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Tbilisi, 0102, Georgia
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Tbilisi, 0114, Georgia
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Tbilisi, 0144, Georgia
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Tbilisi, 0159, Georgia
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Tbilisi, 112, Georgia
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Debrecen, 4032, Hungary
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Hatvan, 3000, Hungary
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Miskolc, 3530, Hungary
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Bari, 70124, Italy
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Genova, 16132, Italy
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Germaneto, 88100, Italy
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Napoli, 80035, Italy
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Napoli, 80131, Italy
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Napoli, 80138, Italy
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Pavia, 27100, Italy
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San Giovanni Rotondo, 71013, Italy
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Chiba, 260-8712, Japan
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Chūōku, 103-0027, Japan
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Koshigaya-shi, 343-8577, Japan
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Nagoya, 455-8530, Japan
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Naka, 311-0113, Japan
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Osaka, 530-0001, Japan
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Osaka, 558-8558, Japan
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Osaka, 559-0012, Japan
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Takarazuka-shi, 665-0861, Japan
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Tsu, 514-1101, Japan
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Ueda-shi, 386-8610, Japan
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Yakushi, 581-0011, Japan
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Kuala Lumpur, 59100, Malaysia
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Kuantan, 25200, Malaysia
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Breda, 4800 RK, Netherlands
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Dordrecht, 3300 AK, Netherlands
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Bialystok, 15-375, Poland
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Krakow, 31-261, Poland
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Oświęcim, 32-600, Poland
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Poznan, 60-848, Poland
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Rzeszów, 35-055, Poland
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Rimavská Sobota, 979 01, Slovakia
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Bellville, 7530, South Africa
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Bloemfontein, 9301, South Africa
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Durban, 4001, South Africa
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George, 6529, South Africa
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Observatory, 7925, South Africa
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Pretoria, 0157, South Africa
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Pretoria, 0181, South Africa
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Somerset West, 7130, South Africa
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A Coruña, 15006, Spain
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Barcelona, 08035, Spain
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Burela de Cabo, 27880, Spain
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Madrid, 28034, Spain
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Madrid, 28040, Spain
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Majadahonda, 28222, Spain
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Málaga, 29010, Spain
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Palma de Mallorca, 07010, Spain
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Seville, 41009, Spain
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Valencia, 46010, Spain
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Valencia, 46017, Spain
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Chernivtsі, 58022, Ukraine
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Dnipro, 49102, Ukraine
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Kharkiv, 61103, Ukraine
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Kyiv, 03049, Ukraine
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Kyiv, 1004, Ukraine
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Ternopil, 46002, Ukraine
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Uzhhorod, 88018, Ukraine
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Vinnytsia, 21001, Ukraine
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Zaporizhia, 69001, Ukraine
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Zhytomyr, 10002, Ukraine
Related Publications (4)
Smeijer JD, Wasehuus VS, Dhaun N, Gorriz JL, Soler MJ, Astrand M, Mercier AK, Greasley PJ, Ambery P, Heerspink HJL. Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD. J Am Soc Nephrol. 2024 Oct 1;35(10):1381-1390. doi: 10.1681/ASN.0000000000000436. Epub 2024 Jul 12.
PMID: 39352861DERIVEDHeerspink HJL, Kiyosue A, Wheeler DC, Lin M, Wijkmark E, Carlson G, Mercier AK, Astrand M, Ueckert S, Greasley PJ, Ambery P. Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial. Lancet. 2023 Nov 25;402(10416):2004-2017. doi: 10.1016/S0140-6736(23)02230-4. Epub 2023 Nov 3.
PMID: 37931629DERIVEDHeerspink HJL, Greasley PJ, Ahlstrom C, Althage M, Dwyer JP, Law G, Wijkmark E, Lin M, Mercier AK, Sunnaker M, Turton M, Wheeler DC, Ambery P. Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial. Nephrol Dial Transplant. 2024 Feb 28;39(3):414-425. doi: 10.1093/ndt/gfad183.
PMID: 37632201DERIVEDSmeijer JD, Kohan DE, Webb DJ, Dhaun N, Heerspink HJL. Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease. Curr Opin Nephrol Hypertens. 2021 Jul 1;30(4):456-465. doi: 10.1097/MNH.0000000000000716.
PMID: 33990507DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Limitations and Caveats
No multiple testing correction was considered in this early phase study.
Results Point of Contact
- Title
- Global Clinical Lead
- Organization
- AstraZeneca Clinical study Information Center
Study Officials
- 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
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- TRIPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 25, 2021
First Posted
January 26, 2021
Study Start
April 28, 2021
Primary Completion
June 1, 2023
Study Completion
June 1, 2023
Last Updated
July 30, 2024
Results First Posted
July 30, 2024
Record last verified: 2024-07
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, 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.
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.