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

Chronic Kidney Disease Clinical Trial

— ZENITH-CKD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04724837
• Other study ID #: D4325C00001
• Secondary ID: 2020-004101-32
• Status: Completed
• Phase: Phase 2
• Start date: April 28, 2021
• Est. completion date: June 1, 2023

Study information

• Verified date: August 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 creatinine ratio (UACR) ≥ 150 mg/g and ≤ 5000 mg/g.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 542
• Est. completion date: June 1, 2023
• Est. primary completion date: June 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion Criteria:

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.

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 (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.

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Zibotentan
Participants will receive zibotentan as per the arms they are randomized.
• Dapagliflozin
Participants will receive 10 mg dapagliflozin as per the arms they are randomized.
• Placebo
Participants will receive placebo as per the arms they are randomized to.

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	Caba
Argentina	Research Site	Cordoba
Argentina	Research Site	Corrientes
Argentina	Research Site	Junín
Argentina	Research Site	Mar del Plata
Argentina	Research Site	San Luis
Argentina	Research Site	San Miguel de Tucuman
Argentina	Research Site	Santa Fe
Australia	Research Site	Adelaide
Australia	Research Site	Birtinya
Australia	Research Site	Elizabeth Vale
Australia	Research Site	Gosford
Australia	Research Site	Westmead
Brazil	Research Site	Botucatu
Brazil	Research Site	Campinas
Brazil	Research Site	Curitiba
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Santo Andre
Brazil	Research Site	São José do Rio Preto
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Brazil	Research Site	São Paulo
Bulgaria	Research Site	Gabrovo
Bulgaria	Research Site	Kozloduy
Bulgaria	Research Site	Montana
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sliven
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Stara Zagora
Canada	Research Site	London	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Waterloo	Ontario
Croatia	Research Site	Pula
Croatia	Research Site	Vinkovci
Denmark	Research Site	Århus N
Denmark	Research Site	Gentofte
Denmark	Research Site	Roskilde
Georgia	Research Site	Batumi
Georgia	Research Site	Gori
Georgia	Research Site	Gurjaani
Georgia	Research Site	Kutaisi
Georgia	Research Site	Marneuli
Georgia	Research Site	Tbilisi
Georgia	Research Site	Tbilisi
Georgia	Research Site	Tbilisi
Georgia	Research Site	Tbilisi
Georgia	Research Site	Tbilisi
Hungary	Research Site	Debrecen
Hungary	Research Site	Hatvan
Hungary	Research Site	Miskolc
Italy	Research Site	Bari
Italy	Research Site	Genova
Italy	Research Site	Germaneto
Italy	Research Site	Napoli
Italy	Research Site	Napoli
Italy	Research Site	Napoli
Italy	Research Site	Pavia
Italy	Research Site	San Giovanni Rotondo
Japan	Research Site	Chiba-shi
Japan	Research Site	Chuo-ku
Japan	Research Site	Koshigaya-shi
Japan	Research Site	Nagoya
Japan	Research Site	Naka
Japan	Research Site	Osaka-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Takarazuka-shi
Japan	Research Site	Tsu-shi
Japan	Research Site	Ueda-shi
Japan	Research Site	Yao-shi
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Kuantan
Netherlands	Research Site	Breda
Netherlands	Research Site	Dordrecht
Poland	Research Site	Bialystok
Poland	Research Site	Krakow
Poland	Research Site	Oswiecim
Poland	Research Site	Poznan
Poland	Research Site	Rzeszow
Slovakia	Research Site	Rimavska Sobota
South Africa	Research Site	Bellville
South Africa	Research Site	Bloemfontein
South Africa	Research Site	Durban
South Africa	Research Site	George
South Africa	Research Site	Observatory
South Africa	Research Site	Pretoria
South Africa	Research Site	Pretoria
South Africa	Research Site	Somerset West
Spain	Research Site	A Coruna
Spain	Research Site	Barcelona
Spain	Research Site	Burela
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda
Spain	Research Site	Malaga
Spain	Research Site	Palma de Mallorca
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Spain	Research Site	Valencia
Ukraine	Research Site	Chernivts?
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Ternopil
Ukraine	Research Site	Uzhhorod
Ukraine	Research Site	Vinnytsia
Ukraine	Research Site	Zaporizhia
Ukraine	Research Site	Zhytomyr
United States	Research Site	Arlington	Texas
United States	Research Site	Augusta	Georgia
United States	Research Site	Beverly Hills	California
United States	Research Site	Boston	Massachusetts
United States	Research Site	Chester	Pennsylvania
United States	Research Site	Conroe	Texas
United States	Research Site	Corpus Christi	Texas
United States	Research Site	Downey	California
United States	Research Site	El Paso	Texas
United States	Research Site	Fayetteville	Georgia
United States	Research Site	Flint	Michigan
United States	Research Site	Flint	Michigan
United States	Research Site	Forest	Virginia
United States	Research Site	Fort Lauderdale	Florida
United States	Research Site	Fountain Valley	California
United States	Research Site	Greenville	North Carolina
United States	Research Site	Hialeah	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Huntsville	Alabama
United States	Research Site	Jacksonville	North Carolina
United States	Research Site	Kinston	North Carolina
United States	Research Site	Laguna Hills	California
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Lincoln	Nebraska
United States	Research Site	Los Angeles	California
United States	Research Site	Marion	Ohio
United States	Research Site	Memphis	Tennessee
United States	Research Site	Memphis	Tennessee
United States	Research Site	Metairie	Louisiana
United States	Research Site	Morehead City	North Carolina
United States	Research Site	New Bern	North Carolina
United States	Research Site	New Port Richey	Florida
United States	Research Site	Newport News	Virginia
United States	Research Site	Northridge	California
United States	Research Site	Odessa	Texas
United States	Research Site	Ontario	California
United States	Research Site	Orlando	Florida
United States	Research Site	Owensboro	Kentucky
United States	Research Site	Riverview	Florida
United States	Research Site	S. Gate	California
United States	Research Site	San Antonio	Texas
United States	Research Site	Shreveport	Louisiana
United States	Research Site	Spokane	Washington
United States	Research Site	Tampa	Florida
United States	Research Site	Tarzana	California
United States	Research Site	Vacaville	California
United States	Research Site	Waxahachie	Texas
United States	Research Site	Wichita	Kansas
United States	Research Site	Wilmington	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Bulgaria,  Canada,  Croatia,  Denmark,  Georgia,  Hungary,  Italy,  Japan,  Malaysia,  Netherlands,  Poland,  Slovakia,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Log-transformed Urinary Albumin to Creatinine Ratio (UACR) from baseline to Week 12	The effect of zibotentan Dose B/dapagliflozin 10 mg versus dapagliflozin 10 mg on UACR will be assessed.	From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary	Change in Log-transformed UACR from baseline to Week 12	The effect of zibotentan dose A/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy on UACR will be assessed.	From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary	Change in Blood Pressure from baseline to Week 12	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.	From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary	Change in log-transformed 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.	From baseline until Week 12 (Day 84)
Secondary	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 will be assessed.	From baseline (Week 0 [Day 1]) until Week 1, Week 12, and Week 14
Secondary	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 will be assessed.	From Week 1 (Day 8) until Week 12 (Day 84)
Secondary	Number of Participants Experiencing Adverse events	The safety and tolerability of all doses of zibotentan combined with dapagliflozin 10 mg and dapagliflozin 10 mg monotherapy will be assessed.	From Week 0 (Day 1) until Follow-up visit (Week 14 [Day 98])