Clinical trial NCT06942910: A Study to Investigate the Effects of Zibotentan/Dapagliflozin Combination Compared to Dapagliflozin Alone in Adult Participants With Chronic Kidney Disease and High Proteinuria
Official title: A Multicentre, Randomised, Double-blind, Active-Controlled, 2-arm Parallel-group Treatment, Phase II Study to Evaluate the Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin Alone in Adult Participants With Chronic Kidney Disease and High Proteinuria
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
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: 2025-04-24
Enrollment: 224
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A Study to Investigate the Effects of Zibotentan/Dapagliflozin Combination Compared to Dapagliflozin Alone in Adult Participants with Chronic Kidney Disease and High Proteinuria (ZODIAC)

Detailed description: This is a Phase II, multicentre, randomised, double-blind, active-controlled, 2-arm parallel group study to evaluate the efficacy, safety, and tolerability of zibotentan and dapagliflozin in FDC compared to dapagliflozin alone, given QD on top of SoC, in adult participants with CKD and high proteinuria, with or without T2DM.

Participants who are not already on SGLT2i at screening will receive a 28 day run in intervention with SGLT2i (dapagliflozin) QD. All participants will undergo a 12-week double-blind period. At the end of the treatment visit, participants will discontinue the blinded study intervention and begin open-label dapagliflozin monotherapy until the conclusion of the 4-week safety follow-up period.

The results of this study will provide clinical data on efficacy and safety of an innovation treatment in the new region (the Russian Federation), which will be an important additional data source for Zibotentan/Dapagliflozin FDC approval process in the Eurasian Economic Union.

Eligibility criteria: Inclusion Criteria:

* ≥ 18 years of age at the time of signing the informed consent.
* Diagnosis of CKD with eGFR ≥ 20 and \< 90 mL/min/1.73m2 AND UACR \> 700 mg/g (\> 79 mg/mmol) or UPCR \> 1000 mg/g (\> 113 mg/mmol).
* Body mass index (BMI) within the range ≤40 kg/m2.
* Female participants must be either - not of child-bearing potential or - women of childbearing potential (WOCBP) using at least one highly effective birth control method for at least 3 months prior to first dose of study intervention.
* All WOCBP must have a negative serum pregnancy test result at screening.
* 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:

* Clinically significant, unstable, or uncontrolled medical condition which in the Investigator's opinion makes it undesirable for the participant to participate in the study.
* Known hypersensitivity to dapagliflozin or zibotentan or any of the excipients of the investigational product. History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i therapy or ERAs.
* NYHA class III or class IV HF.
* Participants hospitalised for HF and/or who have not been stable on HF therapy during the last 6 months prior to screening.
* HF due to cardiomyopathies that would primarily require other specific treatment.
* High output HF (eg, due to hyperthyroidism or Paget's disease).
* HF due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
* Evidence of rales or jugular venous distention on physical examination.
* Type 1 diabetes mellitus.
* History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).
* Participants hospitalised for heart disease or cardiac procedures or for COVID-19 during the last 3 months prior to screening.
* History of solid organ transplantation or bone marrow transplant.
* Any condition with a life expectancy of less than 1 year based on investigator´s clinical judgment.
* Malignancy within the past 5 years. Exceptions to this criterion include non-melanoma skin cancer and curatively treated cervical carcinoma in situ.
* Significant liver disease as judged by the investigator.
* Renal replacement therapy or previous kidney transplant.
* Known history of significant drug or alcohol abuse within 12 months of screening.
* On treatment with strong or moderate CYP3A4 inducer.
* On systemic immunosuppression therapy other than prespecified stable maintenance therapy.
* Participants treated or expecting to be treated with tolvaptan (including as part of participation in a clinical trial), any other ERAs, or budesonide (where used to treat IBD or IgAN).
* Systolic blood pressure above 160 mmHg and/or below 90 mmHg.
* Significant impairment of liver function defined as AST or ALT \>3 x upper limit of normal (ULN) or Total serum bilirubin \>2 x ULN (an isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion).
* NT-proBNP ≥ 600 pg/mL (or NT-proBNP ≥ 1200 pg/mL, if associated with atrial fibrillation) measured by local laboratory at screening.
* Any of the following results of echocardiography at screening:

  * left ventricular ejection fraction (LVEF) \< 50%
  * significant ventricular wall motion abnormality or severe cardiac valve abnormalities
  * isolated pulmonary arterial hypertension (as defined by local clinical practice) or right ventricular failure; in the absence of left-sided HF
* Women who are pregnant, breast-feeding, or women with intent of getting pregnant.
* Women who are not willing to use adequate contraception or cannot, in the opinion of the Investigator, understand and/or comply with the study requirements regarding contraception.

Primary outcomes:
measure: Change in log-transformed Urinary Albumin to Creatinine Ratio (UACR) from baseline
timeFrame: At Week 12
Secondary outcomes:
measure: Change in log-transformed Urinary Protein to Creatinine Ratio (UPCR) from baseline
timeFrame: At Week 12
measure: Change in systolic and diastolic blood pressure (BP) from baseline
timeFrame: At Week 12
measure: Number of participants experiencing adverse events
timeFrame: From Week 1 (Day 1) until Follow-up visit (Week 18, Day 112)
Other outcomes:
measure: Change in estimated Glomerular Filtration Rate (eGFR) from baseline
timeFrame: At Week 12
measure: Proportion of participants achieving Urine Protein to Creatinine Ratio (UPCR) < 1000 mg/g and > 30% reduction from baseline
timeFrame: Across the visits from Week 2 (Day 14) up to Week 12 (Day 84)
measure: Proportion of participants achieving Urinary Albumin to Creatinine Ratio (UACR) < 300 mg/g
timeFrame: Across the visits from Week 2 (Day 14) up to Week 12 (Day 84)
Locations:
city: Aramil
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Perm
country: Russian Federation
facility: Research Site
city: Saratov
country: Russian Federation
facility: Research Site
city: Saratov
country: Russian Federation
facility: Research Site
city: St Petersburg
country: Russian Federation
facility: Research Site
city: Yaroslavl
country: Russian Federation
facility: Research Site
Study officials:
References: