Overview
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
Inclusion Criteria:
- 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.
- 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).
- All female participants must have a negative serum pregnancy test result at screening.
- 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
- Capable of giving signed informed consent
- Provision of signed informed consent prior to any study specific procedure.
- Provision of electronic informed consent prior to completion of the optional Study Participant Feedback Questionnaire (SPFQ).
- 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.
- 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:
- Participants with NYHA class III or class IV Congestive HF at the time of enrolment.
- Participants hospitalised for HF during the last 6 month prior to screening.
- Evidence of rales or jugular venous distention on physical examination.
- Participants with type 1 diabetes mellitus.
- History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).
- Blood pressure above 160 mmHg systolic.
- Blood pressure below 90 mmHg systolic.
- 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.
- 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).
- Any condition with a life expectancy of less than 2 years 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 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.
- Known blood-borne diseases.
- Clinically significant, unstable, or uncontrolled medical condition as assessed by the Investigator.
- Participants on renal replacement therapy or previous kidney transplant.
- Known history of drug or alcohol abuse within 12 months of screening.
- Participants on treatment with strong or moderate CYP3A4 inducer.
- 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.
- Participants treated or expecting to be treated with tolvaptan, any other ERAs, or budesonide (where used to treat IBD or IgAN).
- Participation in another clinical study with a study intervention administered in the last 3 months.