Clinical trial NCT06087835: Study to Investigate Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin in Participants With Chronic Kidney Disease and High Proteinuria (ZENITH High Proteinuria)
Official title: A Phase III, Randomised, Multicentre, Double-blind Study to Evaluate the Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin Alone in Participants With Chronic Kidney Disease and High Proteinuria
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Kidney Disease With High Proteinuria
Keywords: Zibotentan
Nephrology
Dapagliflozin
Sodium-glucose co-transporter 2
sodium-glucose co-transporter 2 inhibitor
Kidney diseases
Endothelin antagonist
High Proteinuria
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-10-18
Enrollment: 1835
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase III, randomised, multicentre, double-blinded study to evaluate efficacy, safety and tolerability of treatment with zibotentan/dapagliflozin and dapagliflozin alone in participants with chronic kidney disease (CKD) and high proteinuria


Eligibility criteria: Inclusion Criteria:

1. Participant must be ≥ 18 years of age and of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent.
2. Diagnosis of CKD, defined as eGFR ≥ 20 and \< 90 mL/min/1.73 m2 and UACR \> 700 mg/g (\> 79 mg/mmol) or UPCR \> 1000 mg/g (\> 113 mg/mmoL).
3. All female participants must have a negative serum pregnancy test result at screening.
4. Female participants must be either

   * not of child-bearing potential or
   * women of child bearing potential (WOCBP) using at least one highly effective birth control method for at least 3 months prior to first dose of study intervention
5. Capable of giving signed informed consent
6. Provision of signed informed consent prior to any study specific procedure.
7. Provision of electronic informed consent prior to completion of the optional Study Participant Feedback Questionnaire (SPFQ).
8. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics imitative research that supports the Genomic Initiative.
9. Receiving RAASi therapy (ACEi or ARB), and for the patient maximum tolerated labelled daily dose, that has been stable for at least 4 weeks.

Exclusion Criteria:

1. Participants with NYHA class III or class IV Congestive HF at the time of enrolment.
2. Participants hospitalised for HF during the last 6 month prior to screening.
3. Evidence of rales or jugular venous distention on physical examination.
4. Participants with type 1 diabetes mellitus.
5. History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).
6. Blood pressure above 160 mmHg systolic.
7. Blood pressure below 90 mmHg systolic.
8. Participants hospitalised for heart disease or cardiac procedures or for COVID-19 during the last 3 months prior to screening.
9. History of solid organ transplantation or bone marrow transplant.
10. History or ongoing allergy/hypersensitivity, as judged by the Investigator, to SGLT2i therapy (eg, dapagliflozin, canagliflozin, empagliflozin or other SGLT2 inhibitors) or Endothelin Receptor Antagonists (eg, ambrisentan, atrasentan, bosentan, or other).
11. Any condition with a life expectancy of less than 2 years based on investigator´s clinical judgment.
12. Malignancy within the past 5 years. Exceptions to this criterion include non-melanoma skin cancer and curatively treated cervical carcinoma in situ.
13. Significant liver disease as judged by the investigator or severe hepatic impairment with AST or ALT \> 3 × ULN; or total bilirubin \> 2 × ULN at time of screening. An isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion.
14. Known blood-borne diseases.
15. Clinically significant, unstable, or uncontrolled medical condition as assessed by the Investigator.
16. Participants on renal replacement therapy or previous kidney transplant.
17. Known history of drug or alcohol abuse within 12 months of screening.
18. Participants on treatment with strong or moderate CYP3A4 inducer.
19. Participants on systemic immunosuppression therapy other than stable maintenance therapy defined as prednisone 10 mg/day (or equivalent) or less, aziothioprine 100 mg/day or less; MMF 1000 mg/day or less for at least 3 months prior to Visit 1. Inhaled, nasal or dermatological steroids are also allowed.
20. Participants treated or expecting to be treated with tolvaptan, any other ERAs, or budesonide (where used to treat IBD or IgAN).
21. Participation in another clinical study with a study intervention administered in the last 3 months.

Primary outcomes:
measure: Change in eGFR from baseline
timeFrame: At month 24
Secondary outcomes:
measure: Change in Urine Protein to Creatinine Ratio (UPCR) from baseline to each participant's mean level
timeFrame: Across the visits from Day 15 up to Month 24
measure: Change in UACR from baseline to each participant's mean level
timeFrame: Across the visits from Day 15 up to Month 24
measure: Time to the first occurrence of any of the components of the renal composite endpoint of 40% sustained decline in eGFR or ESKD or renal death
timeFrame: Through study completion, approximately 43 months
measure: Change in systolic blood pressure from baseline to each participant's mean level
timeFrame: Across the visits from Day 15 up to Month 24
measure: Proportion of participants achieving Urine Protein to Creatinine Ratio (UPCR) < 1000 mg/g and > 30% reduction from baseline for each participant's mean level
timeFrame: Across the visits from Day 15 up to Month 24
Other outcomes:
Locations:
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state: Alabama
city: Sun City West
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facility: Research Site
state: Arizona
city: Bakersfield
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state: California
city: Huntington Park
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state: California
city: Los Alamitos
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state: California
city: Los Angeles
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state: California
city: Northridge
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city: Oxnard
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city: San Carlos
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city: San Dimas
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city: Victorville
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city: Arvada
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state: Colorado
city: Denver
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city: Boynton Beach
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city: Hialeah
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state: Florida
city: Hollywood
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city: Orlando
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city: Chicago
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city: Hinsdale
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city: Island Lake
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city: Flint
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country: Argentina
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country: Argentina
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country: Australia
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city: Reservoir
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city: Southport
country: Australia
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city: Feldkirch
country: Austria
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city: Wien
country: Austria
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city: Belem
country: Brazil
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city: Botucatu
country: Brazil
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city: Joinville
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city: Sao Jose Do Rio Preto
country: Brazil
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country: Brazil
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country: Brazil
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city: Dobrich
country: Bulgaria
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city: Pleven
country: Bulgaria
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country: Bulgaria
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city: London
country: Canada
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state: Ontario
city: Waterloo
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city: Greenfield Park
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state: Quebec
city: Montreal
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city: Baotou
country: China
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city: Beijing
country: China
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country: China
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city: Changsha
country: China
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country: China
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city: Guangzhou
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city: Hangzhou
country: China
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country: China
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city: Nanjing
country: China
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city: Nanjing
country: China
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city: Nanning
country: China
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city: Ningbo
country: China
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city: Pingxiang
country: China
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city: Shanghai
country: China
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country: China
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country: China
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city: Wenzhou
country: China
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city: Wuhan
country: China
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country: China
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city: XI 'an
country: China
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city: Xiamen
country: China
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country: China
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country: China
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country: China
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country: China
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country: China
facility: Research Site
city: Aalborg
country: Denmark
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city: Aarhus
country: Denmark
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city: Herlev
country: Denmark
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city: Herning
country: Denmark
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city: Roskilde
country: Denmark
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city: La Tronche
country: France
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country: France
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city: Nice
country: France
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city: Nimes
country: France
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country: France
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country: France
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country: France
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country: France
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city: Aachen
country: Germany
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country: Germany
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city: Berlin
country: Germany
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city: Dresden
country: Germany
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city: Hannover
country: Germany
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city: Mainz
country: Germany
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city: München
country: Germany
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city: Bangalore
country: India
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country: India
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city: Delhi
country: India
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country: India
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city: Ashkelon
country: Israel
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country: Israel
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city: Jerusalem
country: Israel
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country: Israel
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country: Israel
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country: Israel
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city: Ramat Gan
country: Israel
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city: Rehovot
country: Israel
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city: Bergamo
country: Italy
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city: Bologna
country: Italy
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city: Foggia
country: Italy
facility: Research Site
city: Genoa
country: Italy
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city: Napoli
country: Italy
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city: Pisa
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Fujisawa-shi
country: Japan
facility: Research Site
city: Fukui-shi
country: Japan
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city: Fukuoka-shi
country: Japan
facility: Research Site
city: Fukuoka-shi
country: Japan
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city: Fukuoka-shi
country: Japan
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city: Hashima-gun
country: Japan
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city: Kamakura-shi
country: Japan
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city: Kasuga-shi
country: Japan
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city: Kawaguchi-shi
country: Japan
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city: Kitakyushu-shi
country: Japan
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city: Kitakyusyu-shi
country: Japan
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city: Kofu-shi
country: Japan
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city: Kurume-shi
country: Japan
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city: Kurume-shi
country: Japan
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city: Kusatsu-shi
country: Japan
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city: Kyoto-shi
country: Japan
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city: Matsumoto-shi
country: Japan
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city: Meguro-ku
country: Japan
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city: Minato-ku
country: Japan
facility: Research Site
city: Minokamo shi
country: Japan
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city: Nishinomiya-Shi
country: Japan
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city: Nishinomiya-shi
country: Japan
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city: Okawa-shi
country: Japan
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city: Osaka-shi
country: Japan
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country: Japan
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city: Oyama-shi
country: Japan
facility: Research Site
city: Saku-shi
country: Japan
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city: Sapporo-shi
country: Japan
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country: Japan
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city: Sendai-shi
country: Japan
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city: Soka-shi
country: Japan
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city: Takamatsu-shi
country: Japan
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country: Japan
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city: Tondabayashi-shi
country: Japan
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country: Japan
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city: Urayasu
country: Japan
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city: Utsunomiya-shi
country: Japan
facility: Research Site
city: Ansan-si
country: Korea, Republic of
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Cheonan-si
country: Korea, Republic of
facility: Research Site
city: Daegu
country: Korea, Republic of
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: Research Site
city: Alor Setar
country: Malaysia
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country: Malaysia
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country: Malaysia
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country: Malaysia
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country: Malaysia
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country: Mexico
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country: Netherlands
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country: Netherlands
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city: Dordrecht
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country: Norway
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country: Norway
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city: Chrzanów
country: Poland
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country: Slovakia
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country: South Africa
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country: South Africa
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country: South Africa
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country: South Africa
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country: South Africa
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country: South Africa
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country: Spain
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country: Spain
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country: Spain
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country: Spain
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country: Spain
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country: Spain
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country: Spain
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city: Göteborg
country: Sweden
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country: Sweden
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country: Sweden
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country: Sweden
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city: Uppsala
country: Sweden
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city: Kaohsiung city
country: Taiwan
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country: Taiwan
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country: Taiwan
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city: Taichung
country: Taiwan
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country: Taiwan
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city: Taipei City
country: Taiwan
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city: Taipei
country: Taiwan
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country: Taiwan
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country: Taiwan
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city: Bangkok
country: Thailand
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city: Bangkok
country: Thailand
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city: Chaingmai
country: Thailand
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city: Hat Yai
country: Thailand
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city: Khon Kaen
country: Thailand
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city: Ratchathewi
country: Thailand
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city: Adapazarı
country: Turkey
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city: Ankara
country: Turkey
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city: Bursa
country: Turkey
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city: Dinar
country: Turkey
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city: Kahramanmaras
country: Turkey
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city: Kayseri
country: Turkey
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city: Kocaeli
country: Turkey
facility: Research Site
city: Cardiff
country: United Kingdom
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city: Dundee
country: United Kingdom
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city: Glasgow
country: United Kingdom
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city: London
country: United Kingdom
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city: London
country: United Kingdom
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city: London
country: United Kingdom
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city: York
country: United Kingdom
facility: Research Site
city: Hai Phong
country: Vietnam
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city: Hanoi
country: Vietnam
facility: Research Site
city: Ho Chi Minh City
country: Vietnam
facility: Research Site
city: Ho Chi Minh City
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
Study officials:
References: