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)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT06087835
• Collaborator: (none)
• Enrollment: 1,500
• Locations: 100
• Arms: 2
• Anticipated Duration (Months): 43.8
• Patients Per Site: 15
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease With High Proteinuria	Drug: Zibotentan/Dapagliflozin; Drug: Dapagliflozin	Phase 3

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 1500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Anticipated Study Start Date: Nov 10, 2023
• Anticipated Primary Completion Date: Jul 5, 2027
• Anticipated Study Completion Date: Jul 5, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zibotentan/Dapagliflozin dose A or Zibotentan/Dapagliflozin dose B Drug dose (dose A or B) are determined based on eGFR values. Participants will receive daily oral dose of zibotentan/dapagliflozin in fixed dose combination.	Drug: Zibotentan/Dapagliflozin; Participants will receive zibotentan/dapagliflozin in fixed-dose combination as per the arms they are randomized to
Active Comparator: Dapagliflozin alone Participants will receive daily oral dose of dapagliflozin.	Drug: Dapagliflozin; Participants will receive dapagliflozin as per the arms they are randomized to

Outcome Measures

Primary Outcome Measures

1. Change in eGFR from baseline [At month 24]

   To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone to slow decline in kidney function

Secondary Outcome Measures

1. Change in Urine Protein to Creatinine Ratio (UPCR) from baseline to each participant's mean level [Across the visits from Day 15 up to Month 24]

   To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing proteinuria

2. Change in UACR from baseline to each participant's mean level [Across the visits from Day 15 up to Month 24]

   To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing albuminuria

3. 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 [Through study completion, approximately 43 months]

   To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing the incidence of the renal composite endpoint of 40% sustained decline in eGFR or ESKD or renal death

4. Change in systolic blood pressure from baseline to each participant's mean level [Across the visits from Day 15 up to Month 24]

   To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone in reducing systolic blood pressure

5. Proportion of participants achieving Urine Protein to Creatinine Ratio (UPCR) < 1000 mg/g and > 30% reduction from baseline for each participant's mean level [Across the visits from Day 15 up to Month 24]

   To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone, in reducing proteinuria, as measured by the proportion of participants achieving Urine Protein to Creatinine Ratio (UPCR) < 1000 mg/g and > 30% reduction from baseline

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 95 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Capable of giving signed informed consent

2. Provision of signed informed consent prior to any study specific procedure.

3. Provision of electronic informed consent prior to completion of the optional Study Participant Feedback Questionnaire (SPFQ).

4. 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 5.

5. 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 or 60 mmHg diastolic.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Bakersfield	California	United States	93309
2	Research Site	Chatsworth	California	United States	91311
3	Research Site	S. Gate	California	United States	90280
4	Research Site	Tarzana	California	United States	91356
5	Research Site	Victorville	California	United States	92395
6	Research Site	Miami	Florida	United States	33165
7	Research Site	Greenville	North Carolina	United States	27834
8	Research Site	Jacksonville	North Carolina	United States	28546
9	Research Site	Kinston	North Carolina	United States	28504
10	Research Site	New Bern	North Carolina	United States	28562
11	Research Site	Wilmington	North Carolina	United States	28401
12	Research Site	Winston-Salem	North Carolina	United States	27103
13	Research Site	Arlington	Texas	United States	76015
14	Research Site	San Antonio	Texas	United States	78204
15	Research Site	Buenos Aires		Argentina	C1425AGC
16	Research Site	Ciudad de Buenos Aires		Argentina	1280
17	Research Site	Mar del Plata		Argentina	7600
18	Research Site	Mar del Plata		Argentina	B7600
19	Research Site	Rosario		Argentina	S2000DSV
20	Research Site	Santa Fe		Argentina	S3000
21	Research Site	Gosford		Australia	2250
22	Research Site	Meadowbrook		Australia	4131
23	Research Site	Perth		Australia	6000
24	Research Site	Reservoir		Australia	3021
25	Research Site	Reservoir		Australia	3073
26	Research Site	Southport		Australia	4222
27	Research Site	Feldkirch		Austria	6800
28	Research Site	Wien		Austria	1130
29	Research Site	Dobrich		Bulgaria	9300
30	Research Site	Pleven		Bulgaria	5800
31	Research Site	Plovdiv		Bulgaria	4000
32	Research Site	Stara Zagora		Bulgaria	6000
33	Research Site	London	Ontario	Canada	N6A 5A5
34	Research Site	Waterloo	Ontario	Canada	N2J 3Z4
35	Research Site	Montreal	Quebec	Canada	H4J 1C5
36	Research Site	Baotou		China	014010
37	Research Site	Beijing		China	100035
38	Research Site	Linhai		China	318000
39	Research Site	Nanjing		China	210009
40	Research Site	XI 'an		China	710077
41	Research Site	Aalborg		Denmark	9100
42	Research Site	Aarhus		Denmark	8200
43	Research Site	Gentofte		Denmark	2820
44	Research Site	Herning		Denmark	7400
45	Research Site	Hvidovre		Denmark	2650
46	Research Site	Roskilde		Denmark	4000
47	Research Site	Aachen		Germany	52074
48	Research Site	Bad Oeynhausen		Germany	32545
49	Research Site	Berlin		Germany	13353
50	Research Site	Düsseldorf		Germany	40210
51	Research Site	Fulda		Germany	36043
52	Research Site	Hannover		Germany	30625
53	Research Site	Köln		Germany	01279
54	Research Site	Köln		Germany	50931
55	Research Site	Mainz		Germany	55131
56	Research Site	München		Germany	80336
57	Research Site	Bergamo		Italy	24127
58	Research Site	Bologna		Italy	40138
59	Research Site	Foggia		Italy	71100
60	Research Site	Genoa		Italy	16132
61	Research Site	Napoli		Italy	80138
62	Research Site	Pisa		Italy	56124
63	Research Site	Roma		Italy	161
64	Research Site	Torino		Italy	10126
65	Research Site	Viterbo		Italy	01100
66	Research Site	Cuautitlán		Mexico	91900
67	Research Site	Cuernavaca, MOR		Mexico	62448
68	Research Site	Mazatlán		Mexico	82110
69	Research Site	Mexico		Mexico	14080
70	Research Site	Monterrey		Mexico	64460
71	Research Site	Saltillo		Mexico	25230
72	Research Site	Veracruz		Mexico	91900
73	Research Site	Veracruz		Mexico	91910
74	Research Site	Breda		Netherlands	4818 CK
75	Research Site	Dordrecht		Netherlands	3318 AT
76	Research Site	Bodø		Norway	8073
77	Research Site	Lørenskog		Norway	1478
78	Research Site	Stavanger		Norway	4011
79	Research Site	Tromsø		Norway	9019
80	Research Site	Angeles City		Philippines	2009
81	Research Site	Benoni		South Africa	1501
82	Research Site	Cape Town		South Africa	7925
83	Research Site	Chatsworth		South Africa	4092
84	Research Site	Durban		South Africa	4450
85	Research Site	Lenasia		South Africa	1827
86	Research Site	Midrand		South Africa	1685
87	Research Site	Parow		South Africa	7505
88	Research Site	Soweto		South Africa	2013
89	Research Site	Rättvik		Sweden	79530
90	Research Site	Kaohsiung city		Taiwan	833
91	Research Site	Kaohsiung		Taiwan	807
92	Research Site	New Taipei		Taiwan	220
93	Research Site	Taichung		Taiwan	40705
94	Research Site	Taipei City		Taiwan	110
95	Research Site	Taipei		Taiwan	10002
96	Research Site	Taipei		Taiwan	11490
97	Research Site	Taoyuan		Taiwan	333
98	Research Site	Yong Kang City		Taiwan	710
99	Research Site	Ho Chi Minh City		Vietnam	70000
100	Research Site	Ho Chi Minh		Vietnam	700000

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT06087835
• Other Study ID Numbers: D4325C00010
• First Posted: Oct 18, 2023
• Last Update Posted: Oct 18, 2023
• Last Verified: Oct 1, 2023

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Zibotentan; Nephrology; Dapagliflozin; Sodium-glucose co-transporter 2; sodium-glucose co-transporter 2 inhibitor; Kidney diseases; Endothelin antagonist; High Proteinuria
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Proteinuria; Dapagliflozin

Study Results

No Results Posted as of Oct 18, 2023