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

Overview

A Study to Investigate the Effects of Zibotentan/Dapagliflozin Combination Compared to Dapagliflozin Alone in Adult Participants with Chronic Kidney Disease and High Proteinuria

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.

Interventions

• Drug Zibotentan/Dapagliflozin
  Participants will receive zibotentan/dapagliflozin in fixed-dose combination as per the arms they are randomized to
• Drug Dapagliflozin
  Participants will receive monotherapy dapagliflozin as per the arms they are randomized to

Primary outcome measures

• Change in log-transformed Urinary Albumin to Creatinine Ratio (UACR) from baseline [Time frame: At Week 12]

Secondary outcome measures (3)

• Change in log-transformed Urinary Protein to Creatinine Ratio (UPCR) from baseline [Time frame: At Week 12]
• Change in systolic and diastolic blood pressure (BP) from baseline [Time frame: At Week 12]
• Number of participants experiencing adverse events [Time frame: From Week 1 (Day 1) until Follow-up visit (Week 18, Day 112)]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Russia · 15 centers

• Research Site — Aramil
• Research Site — Izhevsk
• Research Site — Krasnoyarsk
• Research Site — Moscow
• Research Site — Moscow
• Research Site — Moscow
• Research Site — Moscow
• Research Site — Omsk
• … and 7 more centers

Identifiers

NCT: NCT06942910 · AZ-RU-00010

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗