A Phase III Study to assess efficacy, safety, and tolerability of Zibotentan combined with Dapagliflozin, compared to Dapagliflozin, in patients with Chronic Kidney Disease and High Proteinuria

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Metabolism [G03]

Trial duration

4 Apr 2024 → ongoing

Decision date (initial)

2024-03-25

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB Sweden

External identifiers

EU CT number

2023-504124-26-00

ClinicalTrials.gov

NCT06087835

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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

Secondary objectives 1

1. 1. To determine whether zibotentan and dapagliflozin in fixed-dose combination is superior to dapagliflozin alone in a)reducing albuminuria b)reducing the incidence of the renal composite endpoint of 40% sustained decline in eGFR or ESKD or renal death c) Reducing proteinuria in the biopsy-confirmed IgAN subgroup 2. To assess the safety and tolerability of treatment with zibotentan and dapagliflozin in fixed-dose combination compared to dapagliflozin alone.

Conditions and MedDRA coding

Chronic Kidney Disease and High Proteinuria

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. 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. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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. 2.Diagnosis of CKD, with eGFR ≥ 20 and < 90 mL/min/1.73 m2 and UACR > 700 mg/g (> 79 mg/mmol) or UPCR > 1000 mg/g (> 113mg/mmoL).
3. 3.All female participants must have a negative serum pregnancy test result at screening (unless participants meet inclusion criterion 4a for being of not childbearing potential.)
4. 4. Female participants must be either - not of child-bearing potential or - WOCBP using at least one highly effective birth control method for at least 3 months prior to first dose of study intervention
5. 5. Capable of giving signed informed consent
6. 6. Provision of signed informed consent prior to any study specific procedure.
7. 7. Provision of electronic informed consent prior to completion of the optional Study Participant Feedback Questionnaire (SPFQ).
8. 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 5.
9. 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 21

1. 1.Participants with NYHA class III or class IV Congestive HF at the time of enrolment.
2. 2. Participants hospitalised for HF during the last 6 month prior to screening.
3. 3. Evidence of rales or jugular venous distention on physical examination
4. 4. Participants with T1DM.
5. 5. History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).
6. 6. Blood pressure above 160 mmHg systolic.
7. 7. Blood pressure below 90 mmHg systolic
8. 8. Participants hospitalised for heart disease or cardiac procedures or for COVID-19 during the last 3 months prior to screening.
9. 9. History of solid organ transplantation or bone marrow transplant.
10. 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) or any of the excipients of the products.
11. 11. Any condition with a life expectancy of less than 2 years based on investigator´s clinical judgment
12. 12. Malignancy within the past 5 years. Exceptions to this criterion include non-melanoma skin cancer and curatively treated cervical carcinoma in situ
13. 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. 14. Known blood-borne diseases.
15. 15. Clinically significant, unstable, or uncontrolled medical condition as assessed by the Investigator.
16. 16. Participants on renal replacement therapy or previous kidney transplant.
17. 17. Known history of drug or alcohol abuse within 12 months of screening.
18. 18. Participants on treatment with strong or moderate CYP3A4 inducer.
19. 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. 20.Participants treated or expecting to be treated with tolvaptan, any other ERAs, or budesonide (where used to treat IBD or IgAN).
21. 21. Participation in another clinical study with a study intervention administered in the last 3 months.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in eGFR from baseline to Month 24

Secondary endpoints 3

1. 1. Change from baseline in UACR
2. 2. 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
3. 3. Change from baseline to UPCR

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

12 EU/EEA countries · 74 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 86 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

28 submissions — initial application plus substantial / non-substantial modifications