A Phase 2b Multicentre, Randomised, Double-Blind, Active-Controlled, Parallel Group Dose-Ranging Study to Assess the Efficacy, Safety and Tolerability of Zibotentan and Dapagliflozin in Patients With Chronic Kidney Disease With Estimated Glomerular Filtration Rate (eGFR) Between 20 mL/Min/1.73 m^2 or more

JRCT ID: jRCT2041200106

Registered date:08/03/2021

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Chronic Kidney Disease
• Date of first enrollment: 28/04/2021
• Target sample size: 660
• Countries of recruitment: Argentina,Japan,Australia,Japan,Bulgaria,Japan,Brazil,Japan,Canada,Japan,Denmark,Japan,Georgia,Japan,Hungary,Japan,Italy,Japan,Malaysia,Japan,Netherlands,Japan,Poland,Japan,Serbia,Japan,South Africa,Japan,Spain,Japan,Ukraine,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

Eligible participants will be randomised to either of the following treatments:

- Zibotentan 0.25 mg + Dapagliflozin 10 mg once daily.
- Zibotentan 1.5 mg + Dapagliflozin 10 mg once daily.
- Dapagliflozin 10 mg once daily.

Outcome(s)

Primary Outcome

Change in Log-transformed Urinary Albumin to Creatinine Ratio (UACR) from baseline to Week 12 [ Time Frame: From baseline (Week 0 [Day 1]) until Week 12 (Day 84) ]
The effect of zibotentan Dose 1.5 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg on UACR will be assessed.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

Diagnosis of CKD, defined as:

(a) eGFR chronic kidney disease epidemiology collaboration (CKD-EPI) 20 mL/min/1.73 m^2 or more, and

(b) UACR 150 or more and 5000 mg or less albumin/g creatinine, based on a single first morning void spot urine sample at screening.

- No current or prior (within 1 month of screening) medical treatment with an SGLT2i (sodium-glucose co-transporter 2 inhibitor) or any fixed dose combination with SGLT2i

- If ACEi and/or ARB and/or mineralocorticoid receptor agonist (MRA) are prescribed, the dose must be stable 4 weeks or more before screening. Participants who have been deemed unable to tolerate ACEi or ARB therapy due to allergy or complications can be enrolled

- 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

- Body mass index (BMI) 40 kg/m^2 or less

- All participants should follow protocol defined contraceptives procedures

Exclude criteria

Participants are excluded from the study if any of the following criteria apply:

- Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease requiring significant immunosuppression, autosomal dominant or autosomal recessive polycystic kidney disease.

- Participants with New York Heart Association classification functional heart failure (HF) class III or IV

- Acute coronary syndrome events within 3 months prior to screening

- Participants with a confirmed B-type natriuretic peptide (BNP) 200 pg/mL or more, or NT-proBNP 600 pg/mL or more (or BNP 400 pg/mL or more or NT-proBNP 1200 pg/mL or more, respectively, if associated with atrial fibrillation measured by local laboratory at screening (Visit 1)

- 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

- Heart failure due to cardiomyopathies that would primarily require specific other 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

- High output HF

- Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement

- Participants with uncontrolled diabetes mellitus (HbA1c > 12%), and with T1DM

- Intermittent or persistent second or third degree atrioventricular block after sinus node dysfunction, with clinically significant bradycardia or sinus pause when not treated with pacemaker

- History of any life-threatening cardiac dysrhythmia

- Cardiac surgery or non-elective percutaneous coronary interventions (within 3 months) or open chest coronary artery bypass grafting or valvular repair/replacement (within 12 months) prior to screening or is planned to undergo any of these procedures after randomisation

- Heart transplantation or left ventricular assist device at any time

- History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i or drugs with a similar chemical structure to zibotentan

- Any clinically significant disease or disorder, which 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:

_ Isolated pulmonary arterial hypertension (defined as mean PAP 25 mmHg or more at rest) or right ventricular failure; in the absence of left-sided HF

_ Anaemia defined as haemoglobin (Hb) level < 100 g/L or 10 g/dL at screening (Visit 1)

_ Severe chronic obstructive pulmonary disease or other lung disease including but not limited to pulmonary fibrosis requiring chronic oxygen therapy, regular nebuliser use, or oral steroid therapy

- Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to screening Severe hepatic impairment (Child-Pugh class C Hepatic impairment), aspartate transaminase or alanine transaminase > 2x the upper limit of normal [ULN]; or total bilirubin > 2x ULN at time of screening

- Participants with newly detected pathological laboratory values or an ongoing disease condition requiring investigation and/or initiation or adjustment of current treatment

- Positive hepatitis C antibody, or hepatitis B virus surface antigen at screening

- Participants treated with strong or moderate CYP3A4 inhibitor or inducer

- Confirmation of corona virus disease- 2019 (COVID-19) infection:

_ Participant has a positive test result for severe acute respiratory syndrome coronavirus 2 during screening. Participants who are not hospitalised for COVID-19 infections can be re screened 4 weeks after they have recovered

_ Participant has been previously hospitalised with COVID-19 infection

Ejection fraction < 50% measured by echocardiogram at screening

Related Information

• Primary Sponsor: Ageishi Yuji
• Secondary ID(s): NCT04724837