Chronic Kidney DiseasePhase 2ZENITH-CKDNCT04724837

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

A Phase 2 study testing Zibotentan and Dapagliflozin in people with Chronic Kidney Disease, run by AstraZeneca at 164 sites in 19 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 18 to 130 years
Conditions the study is for: Chronic Kidney Disease
What is being tested?: Zibotentan and Dapagliflozin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 542 participants
Where: 164 sitesin 19 countries
Study dates: 28 Apr 2021to 1 Jun 2023
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 130 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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:
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.

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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.

Who cannot join

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

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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).
Cardiac surgery or non-elective percutaneous coronary interventions (PCI/TAVI) (within 3 months) or open chest coronary artery bypass grafting or valvular repair/replacement (within 3 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.
Kidney or any organ transplantation.
History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (eg, dapagliflozin, canagliflozin, empagliflozin) or drugs with a similar chemical structure to zibotentan.
Any clinically significant disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment), 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 [PAP] (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 (in the opinion of the investigator).
Positive hepatitis C antibody, or hepatitis B virus, surface antigen at screening.
Positive human immunodeficiency virus (HIV) test.
Participants treated with strong or moderate CYP3A4 inhibitor or inducer.
Any condition outside the renal and CV disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator's clinical judgment.
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.
Participation in another clinical study with an investigational product administered in the last 3 months prior to screening.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
Previous randomisation into the present study.
Plasma donation within 1 month of the visit at the clinic or any blood donation/blood loss > 500 mL during the 3 months prior to any visit at the clinic.
Male participant in a sexually active relation with pregnant or breastfeeding partner.
Participants can decline to participate in the genetic research and may still participate in the study. Exclusion from this optional genetic research may be for any of the exclusion criteria specified for the main study or any of the following:
Previous allogeneic bone marrow transplant.
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.

Trial locations and contacts

164 sites in 19 countries.

Country

City, postcode or hospital

164 sites in 19 countries

United States50 sites

Research Site
Arlington, Texas, 76002
Research Site
Augusta, Georgia, 30904
Research Site
Beverly Hills, California, 90211
Research Site
Boston, Massachusetts, 02215
Research Site
Chester, Pennsylvania, 19013
Research Site
Conroe, Texas, 77384
Research Site
Corpus Christi, Texas, 78414
Research Site
Downey, California, 90242
Research Site
El Paso, Texas, 79935
Research Site
Fayetteville, Georgia, 30214
Research Site
Flint, Michigan, 48504
Research Site
Flint, Michigan, 48532
Research Site
Forest, Virginia, 24551
Research Site
Fort Lauderdale, Florida, 33308
Research Site
Fountain Valley, California, 92708
Research Site
Greenville, North Carolina, 27834
Research Site
Hialeah, Florida, 33012
Research Site
Houston, Texas, 77004
Research Site
Houston, Texas, 77099
Research Site
Huntsville, Alabama, 35805
Research Site
Jacksonville, North Carolina, 28546
Research Site
Kinston, North Carolina, 28504
Research Site
Laguna Hills, California, 92653
Research Site
Las Vegas, Nevada, 89128
Research Site
Lincoln, Nebraska, 68510
Research Site
Los Angeles, California, 90057
Research Site
Marion, Ohio, 43302
Research Site
Memphis, Tennessee, 38104
Research Site
Memphis, Tennessee, 38119
Research Site
Metairie, Louisiana, 70006
Research Site
Morehead City, North Carolina, 28557
Research Site
New Bern, North Carolina, 28562
Research Site
New Port Richey, Florida, 34652
Research Site
Newport News, Virginia, 23606
Research Site
Northridge, California, 91324
Research Site
Odessa, Texas, 79761
Research Site
Ontario, California, 91762
Research Site
Orlando, Florida, 32806
Research Site
Owensboro, Kentucky, 42303
Research Site
Riverview, Florida, 33578
Research Site
San Antonio, Texas, 78212
Research Site
Shreveport, Louisiana, 71101
Research Site
South Gate, California, 90280
Research Site
Spokane, Washington, 99204
Research Site
Tampa, Florida, 33614
Research Site
Tarzana, California, 91356
Research Site
Vacaville, California, 95687
Research Site
Waxahachie, Texas, 75165
Research Site
Wichita, Kansas, 67214-2943
Research Site
Wilmington, North Carolina, 28401

Other trials in United States

Japan12 sites

Research Site
Chiba, 260-8712
Research Site
Chūōku, 103-0027
Research Site
Koshigaya-shi, 343-8577
Research Site
Nagoya, 455-8530
Research Site
Naka, 311-0113
Research Site
Osaka, 530-0001
Research Site
Osaka, 558-8558
Research Site
Osaka, 559-0012
Research Site
Takarazuka-shi, 665-0861
Research Site
Tsu, 514-1101
Research Site
Ueda-shi, 386-8610
Research Site
Yakushi, 581-0011

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Argentina11 sites

Research Site
Buenos Aires, C1425AGC
Research Site
CABA, C1120AAC
Research Site
CABA, C1440AAD
Research Site
Córdoba, 5003
Research Site
Corrientes, W3400AMZ
Research Site
Junín, 6000
Research Site
Mar del Plata, B7600FZN
Research Site
Mar del Plata, B7600
Research Site
San Luis, 5700
Research Site
San Miguel de Tucumán, 4000
Research Site
Santa Fe, S3000

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Spain11 sites

Research Site
A Coruña, 15006
Research Site
Barcelona, 08035
Research Site
Burela de Cabo, 27880
Research Site
Madrid, 28034
Research Site
Madrid, 28040
Research Site
Majadahonda, 28222
Research Site
Málaga, 29010
Research Site
Palma de Mallorca, 07010
Research Site
Seville, 41009
Research Site
Valencia, 46010
Research Site
Valencia, 46017

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Georgia10 sites

Research Site
Batumi, 6010
Research Site
Gori, 1400
Research Site
Gurjaani, 1500
Research Site
Kutaisi, 4600
Research Site
Marneuli, 3000
Research Site
Tbilisi, 0102
Research Site
Tbilisi, 0114
Research Site
Tbilisi, 0144
Research Site
Tbilisi, 0159
Research Site
Tbilisi, 112

Other trials in Georgia

Ukraine10 sites

Research Site
Chernivtsі, 58022
Research Site
Dnipro, 49102
Research Site
Kharkiv, 61103
Research Site
Kyiv, 03049
Research Site
Kyiv, 1004
Research Site
Ternopil, 46002
Research Site
Uzhhorod, 88018
Research Site
Vinnytsia, 21001
Research Site
Zaporizhia, 69001
Research Site
Zhytomyr, 10002

Other trials in Ukraine

Brazil9 sites

Research Site
Botucatu, 18618-687
Research Site
Campinas, 13010-001
Research Site
Curitiba, 80440-020
Research Site
Porto Alegre, 90020-090
Research Site
Santo André, 09090-790
Research Site
São José do Rio Preto, 15090-000
Research Site
São Paulo, 01228-200
Research Site
São Paulo, 04039-000
Research Site
São Paulo, 5403-000

Other trials in Brazil

Bulgaria8 sites

Research Site
Gabrovo, 5300
Research Site
Kozloduy, 3320
Research Site
Montana, 3400
Research Site
Plovdiv, 4023
Research Site
Sliven, 8800
Research Site
Sofia, 1407
Research Site
Sofia, 1510
Research Site
Stara Zagora, 6000

Other trials in Bulgaria

Italy8 sites

Research Site
Bari, 70124
Research Site
Genova, 16132
Research Site
Germaneto, 88100
Research Site
Naples, 80035
Research Site
Naples, 80131
Research Site
Naples, 80138
Research Site
Pavia, 27100
Research Site
San Giovanni Rotondo, 71013

Other trials in Italy

South Africa8 sites

Research Site
Bellville, 7530
Research Site
Bloemfontein, 9301
Research Site
Durban, 4001
Research Site
George, 6529
Research Site
Observatory, 7925
Research Site
Pretoria, 0157
Research Site
Pretoria, 0181
Research Site
Somerset West, 7130

Other trials in South Africa

Australia5 sites

Research Site
Adelaide, 5000
Research Site
Birtinya, 4575
Research Site
Elizabeth Vale, 5112
Research Site
Gosford, 2250
Research Site
Westmead, 2145

Other trials in Australia

Poland5 sites

Research Site
Bialystok, 15-375
Research Site
Krakow, 31-261
Research Site
Oświęcim, 32-600
Research Site
Poznan, 60-848
Research Site
Rzeszów, 35-055

Other trials in Poland

Canada4 sites

Research Site
London, Ontario, N6A-5A5
Research Site
St. John's, Newfoundland and Labrador, A1A 3R5
Research Site
Toronto, Ontario, M5N 1C1
Research Site
Waterloo, Ontario, N2T 0C1

Other trials in Canada

Denmark3 sites

Research Site
Århus N, 8200
Research Site
Gentofte Municipality, 2820
Research Site
Roskilde, 4000

Other trials in Denmark

Hungary3 sites

Research Site
Debrecen, 4032
Research Site
Hatvan, 3000
Research Site
Miskolc, 3530

Other trials in Hungary

Croatia2 sites

Research Site
Pula, 52000
Research Site
Vinkovci, 32100

Other trials in Croatia

Malaysia2 sites

Research Site
Kuala Lumpur, 59100
Research Site
Kuantan, 25200

Other trials in Malaysia

Netherlands2 sites

Research Site
Breda, 4800 RK
Research Site
Dordrecht, 3300 AK

Other trials in Netherlands

Slovakia1 site

Research Site
Rimavská Sobota, 979 01

Other trials in Slovakia

About this study

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

Read the detailed description

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.
Placebo + Dapagliflozin 10 mg once daily

Participants who were previously randomised cannot be re-randomised.

Conditions: Chronic Kidney Disease
Being tested: Zibotentan, Dapagliflozin, Placebo
Keywords: Zibotentan, Nephrology, Dapagliflozin, Sodium-glucose co-transporter 2, sodium-glucose co-transporter 2 inhibitor, Kidney diseases, Endothelin antagonist
Medical subject headings: Renal Insufficiency, Chronic, Kidney Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ZibotentanDrug
Participants will receive zibotentan as per the arms they are randomized.
DapagliflozinDrug
Participants will receive 10 mg dapagliflozin as per the arms they are randomized.
PlaceboDrug
Participants will receive placebo as per the arms they are randomized to.

Study groups in NCT04724837
Study group	Role	What they receive
Zibotentan Dose A + Dapagliflozin	Experimental	Participants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks. Receives: Drug: Zibotentan; Drug: Dapagliflozin
Zibotentan Dose B + Dapagliflozin	Experimental	Participants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks. Receives: Drug: Zibotentan; Drug: Dapagliflozin
Placebo + Dapagliflozin	Experimental	Participants will receive once daily oral dose of dapagliflozin 10 mg and placebo for 12 weeks. Receives: Drug: Dapagliflozin; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)

Secondary outcomes (7)

Change in UACR From Baseline to Week 12
The effect of zibotentan 0.25 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy on UACR was assessed.
Measured: From baseline (Week 0 [Day 1]) until Week 12
Change in Office Systolic Blood Pressure From Baseline to Week 12
The change in office systolic blood pressure for doses of zibotentan combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy was assessed.
Measured: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in Office Diastolic Blood Pressure From Baseline to Week 12
The change in office diastolic blood pressure for doses of zibotentan combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy was assessed.
Measured: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in UACR From Baseline to Week 12
The assessment of dose-response and relationship across different dose of zibotentan/dapagliflozin and dapagliflozin alone on UACR reduction.
Measured: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in eGFR From Baseline to 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 was assessed.
Measured: From baseline (Week 0 [Day 1]) until Week 1 (Day 8), Week 12 (Day 84), and Week 14 (Day 98)
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
The safety and tolerability of all doses of zibotentan combined with dapagliflozin 10 mg and dapagliflozin 10 mg monotherapy was assessed.
Measured: From Screening (Day -28) until Follow-up visit (Day 98), up to 126 days
Change in eGFR From Week 1 to Week 12
The effect of different doses of zibotentan and dapagliflozin 10 mg in combination versus dapagliflozin 10 mg monotherapy on eGFR was assessed.
Measured: From Week 1 (Day 8) to Week 12 (Day 84)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

28 Apr 20211 Jun 2023

First posted26 Jan 2021
Study start28 Apr 2021
Primary completion1 Jun 2023
Study completion1 Jun 2023

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (4)Papers the sponsor has linked to this study.
Other trials for Chronic Kidney DiseaseStudies of the same condition, open and under way.
More trials run by AstraZenecaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Care provider, Investigator
Enrolment: 542 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04724837
Sponsor's protocol ID: D4325C00001
Other IDs: 2020-004101-32
Acronym: ZENITH-CKD
Status last verified: Jul 2024
First submitted: 25 Jan 2021
Last updated: 30 Jul 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: 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.

Publications

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.
PubMed 39352861
Heerspink 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.
PubMed 37931629
Heerspink 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.
PubMed 37632201
Smeijer 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.
PubMed 33990507

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 30 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT04724837
Acronym / sponsor ID: ZENITH-CKD / D4325C00001
Conditions: Chronic Kidney Disease
Keywords: Zibotentan, Nephrology, Dapagliflozin, Sodium-glucose co-transporter 2, sodium-glucose co-transporter 2 inhibitor, Kidney diseases, Endothelin antagonist
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 542 participants (actual)
Lead sponsor: AstraZenecaIndustry (pharma, biotech, devices)
Study start: 28 Apr 2021 (actual)
Primary completion: 1 Jun 2023 (actual)
Study completion: 1 Jun 2023 (actual)
First posted: 26 Jan 2021 (actual)
Results: Posted 30 Jul 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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.

Zibotentan Dose A + Dapagliflozin 10 mg once daily.
Zibotentan Dose B + Dapagliflozin 10 mg once daily.
Placebo + Dapagliflozin 10 mg once daily

Participants who were previously randomised cannot be re-randomised.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, care provider, investigator)
Number of arms: 3

Arm	Type	Receives
Zibotentan Dose A + Dapagliflozin	Experimental	Drug: Zibotentan, Drug: DapagliflozinParticipants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks.
Zibotentan Dose B + Dapagliflozin	Experimental	Drug: Zibotentan, Drug: DapagliflozinParticipants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks.
Placebo + Dapagliflozin	Experimental	Drug: Dapagliflozin, Drug: PlaceboParticipants will receive once daily oral dose of dapagliflozin 10 mg and placebo for 12 weeks.

Who may qualify

Ages: 18 to 130 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (15 listed)

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:
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.

Key exclusion criteria (43 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
ZibotentanParticipants will receive zibotentan as per the arms they are randomized.	Drug	Zibotentan Dose A + Dapagliflozin, Zibotentan Dose B + Dapagliflozin
DapagliflozinParticipants will receive 10 mg dapagliflozin as per the arms they are randomized.	Drug	Placebo + Dapagliflozin, Zibotentan Dose A + Dapagliflozin, Zibotentan Dose B + Dapagliflozin
PlaceboParticipants will receive placebo as per the arms they are randomized to.	Drug	Placebo + Dapagliflozin

Primary outcome

Change in 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 1.5/dapagliflozin 10 mg versus dapagliflozin 10 mg on UACR was assessed.

7 secondary outcomes

Change in UACR From Baseline to Week 12
Time frame: From baseline (Week 0 [Day 1]) until Week 12
Change in Office Systolic Blood Pressure From Baseline to Week 12
Time frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in Office Diastolic Blood Pressure From Baseline to Week 12
Time frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in UACR From Baseline to Week 12
Time frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Change in eGFR From Baseline to Week 1, Week 12, and Week 14
Time frame: From baseline (Week 0 [Day 1]) until Week 1 (Day 8), Week 12 (Day 84), and Week 14 (Day 98)
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Time frame: From Screening (Day -28) until Follow-up visit (Day 98), up to 126 days
Change in eGFR From Week 1 to Week 12
Time frame: From Week 1 (Day 8) to Week 12 (Day 84)

Results and safety

Results posted to the registry on 30 Jul 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Zibotentan 0.25 mg + Dapagliflozin	91	82
Zibotentan 1.5 mg + Dapagliflozin	179	142
Placebo + Dapagliflozin	177	157

Primary outcome: Change in Urinary Albumin to Creatinine Ratio (UACR) From Baseline to Week 12

Time frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84). Geometric mean (Standard Error). Unit: milligram/gram (mg/g)

Measure	Zibotentan 1.5 mg + Dapagliflozin n = 105	Placebo + Dapagliflozin n = 132
Value	0.48 (1.094)	0.72 (1.090)

Zibotentan 1.5 mg + Dapagliflozin vs Placebo + Dapagliflozin: Adjusted % mean change from baseline: -33.7 (90% CI -42.5 to -23.5), p <0.001, Mixed Models Analysis

Population analysed: The full analysis set included all participants who were randomised and received any study intervention. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.

7 secondary outcomes are reported in the full results.

Adverse events

Time frame: From screening (Day -28) to Final Follow-up (Day 98), up to 126 days. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Zibotentan 0.25 mg + Dapagliflozin	2 of 91 (2.2%)	14 of 91 (15.4%)	0 of 91
Zibotentan 1.5 mg + Dapagliflozin	10 of 179 (5.6%)	24 of 179 (13.4%)	0 of 179
Placebo + Dapagliflozin	4 of 177 (2.3%)	6 of 177 (3.4%)	1 of 177

Limitations and caveats (from the sponsor): No multiple testing correction was considered in this early phase study.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 30 Jul 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 39352861Smeijer 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.
Derived from this study: PubMed 37931629Heerspink 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.
Derived from this study: PubMed 37632201Heerspink 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.
Derived from this study: PubMed 33990507Smeijer 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.
redacted CSPLink provided by the sponsor.
redacted SAPLink provided by the sponsor.
redacted CSR SynopsisLink provided by the sponsor.
Individual participant dataSharing planned: Yes. 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.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

David C Wheeler, MB ChB, MD, FRCP principal investigator

Centre for Nephrology Royal Free Campus University College London Rowland Hill Street London NW3 2PF United Kingdom

Jamie P. Dwyer, M.D. principal investigator

Nephrology Clinical Trials Center Nephrology and Hypertension Vanderbilt University Medical Center Nashville TN United States of America

164 sites in 19 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Zibotentan and Dapagliflozin in people with Chronic Kidney Disease, run by AstraZeneca at 164 sites in 19 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 43 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 164 sites in United States, Japan, Argentina, Spain, Georgia and 14 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Urinary Albumin to Creatinine Ratio (UACR) From Baseline to Week 12 (time frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04724837, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jul 2024.