Chronic Kidney Disease Kidney Failure
Conditions
Interventions
Eligible participants will be randomised to either of the following treatments,
in addition to receiving background local SoC therapy:
• Zibotentan 0.25 mg + Dapagliflozin 10 mg once daily.
• Zibote
and one zibotentan
capsule containing zibotentan 1.5 mg, zibotentan 0.25 mg or placebo.
For each participant, the total duration of participation will be approximately
17 to 19 weeks. The screening
Sponsors
Astra Zeneca
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Age 1 Participant must be 18 years of age or older at the time of signing the informed consent. Type of Participant and Disease Characteristics / Laboratory Parameters 2 Diagnosis of CKD, defined as: (a) eGFR (CKD-EPI) >= 20 mL/min/1.73 m2 (by CKD-EPI formula, see Section 8.1.2.2) AND (b) Urine albumin to creatinine ratio (UACR) >= 150 and = 4 weeks before screening. Participants who have been deemed unable to tolerate ACEi or ARB therapy due to allergy or complications can be enrolled. 5 No current or prior treatment within 6 months prior to screening with cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary kidney disease. Weight 6 Body mass index (BMI) <= 40 kg/m2. Sex 7 Male or female of non-childbearing potential. Reproduction 8 Female participants must have a negative pregnancy test at screening, must not be lactating, and must be of non-childbearing potential, confirmed at screening by fulfilling one of the following criteria: (a) Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH and LH levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. 9 Male participants must be surgically sterile, abstinent, or in conjunction with a female sexual partner, using a highly effective method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the last dose of investigational product to prevent any pregnancies. Male study participants must not donate or bank sperm during this same time period (see Section 8.3.8.2). Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered highly effective birth control methods such as: • Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: * Oral. * Intravaginal. * Transdermal. • Progesterone-only hormonal contraception associated with inhibition of ovulation: * Oral. * Injectable. * Implantable. • Intrauterine device (IUD). • Intrauterine hormone-releasing system (IUS). • Bilateral tubal occlusion of female partner. • Male vasectomy. • True sexual abstinence. True abstinence refers to: when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (eg, calendar, ovulation, symptom-thermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. Informed Consent 10 Capable of giving signed informed consent, as described in Appendix A, which includes compliance with the requirements and restrictions liste
Exclusion criteria
Exclusion criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1 Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease requiring significant immunosuppression, autosomal dominant or autosomal recessive polycystic kidney disease. 2 Participants with NYHA functional HF class III or IV. 3 Acute coronary syndrome (ACS) events within 3 months prior to screening. 4 Participants with a BNP >= 200 pg/mL or NT-proBNP >= 600 pg/mL (BNP >= 400 pg/mL or NT-proBNP >= 1200 pg/mL, respectively, if associated with atrial fibrillation) measured by local laboratory at screening (Visit 1). 5 Participants with unstable HF requiring hospitalisation for optimisation of HF treatment and/or who have not been stable on HF therapy within 6 months prior to screening. 6 Heart failure due to cardiomyopathies that would primarily require other specific treatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or other infiltrative diseases, cardiomyopathy related to congenital heart disease, primary hypertrophic cardiomyopathy, cardiomyopathy related to toxic or infective conditions (ie, chemotherapy, infective myocarditis, septic cardiomyopathy). 7 High output HF (eg, due to hyperthyroidism or Paget*s disease). 8 Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement. 9 Participants with uncontrolled diabetes mellitus (HbA1c > 12%). 10 Participants with T1DM. 11 Hyponatremia, defined as serum Na+ 470ms) on ECG at screening (Visit 1) or randomisation visit (Visit 2), known congenital long QT syndrome or history of QT prolongation associated with other medications. 14 History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter). 15 Cardiac surgery or non-elective percutaneous coronary interventions (PCI/TAVI) (within 3 months) or open chest coronary artery bypass grafting or valvular repair/replacement (within 3 months) prior to screening or is planned to undergo any of these procedures after randomisation. 16 Heart transplantation or left ventricular assist device at any time. 17 Kidney or any organ transplantation. 18 History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (eg, dapagliflozin, canagliflozin, empagliflozin) or drugs with a similar chemical structure to zibotentan. 19 Any clinically significant disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) which, as judged by the investigator, might put the participant at risk because of participation in the study, or probable alternative primary reason for participant*s symptoms in judgment of investigator, including but not limited to: (a) Isolated pulmonary arterial hypertension (de
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| · Change in log-transformed UACR from baseline to Week 12. The primary estimand is a hypothetical estimand such that the treatment effect is quantified in the optimal situation where any potential confounder is avoided. The population of interest is the Full Analysis population. Participants will be included in the analysis if they have a non-missing baseline and at least one post-treatment visit UACR measurement. For the intercurrent events, if a participant is lost to follow up, prematurely discontinues study treatment or uses a prohibited medication, the UACR data are treated as missing after the event and no imputation is performed. The summary measure being evaluated is the geometric mean reduction of UACR from baseline to Week 12. | — |
Secondary
| Measure | Time frame |
|---|---|
| Change in log-transformed UACR from baseline to Week 12. Change in BP from baseline (Visit 2) to Week 12. The least squares mean change of UACR at Week 12 from the Zibo/Dapa dose arms and the dapagliflozin monotherapy arm. Change in eGFR from baseline to Week 1. Change in eGFR from baseline to Week 12. Change in eGFR from baseline to Week 14. Change in eGFR from Week 1 to Week 12. | — |
Countries
Netherlands
Outcome results
None listed