Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD Trial)

• Status: Recruiting
• Trial end date: 2022-06-06
• Target enrollment: 0
• Participant gender: All

Summary

The purpose of the study is to assess efficacy, safety and tolerability of treatment with zibotentan and dapagliflozin in combination and alone, compared with placebo in participants with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) between 20 and 60 mL/min/1.73^2.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: AstraZeneca
• Treatments: 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol; Dapagliflozin

Criteria

Inclusion Criteria:

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

• Diagnosis of CKD, defined as: Part A: eGFR chronic kidney disease epidemiology collaboration (CKD-EPI) ≥ 30 and ≤ 60 mL/min/1.73 m^2; Part B, if safety data from Part A allow (otherwise same as in Part A): eGFR (CKD-EPI) ≥ 20 and ≤ 60 mL/min/1.73 m^2; and UACR ≥ 200 and ≤ 5000 mg albumin/g creatinine

• 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

• All participants should follow protocol defined contraceptives procedures

Exclusion 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, or anatomical causes of CKD

• History of epilepsy syndrome

• 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 BNP ≥ 400 pg/mL if with atrial fibrillation

• 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 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 randomization visit (Visit 2)

• 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, hepatitis B virus surface antigen, or hepatitis B virus core antibody, at screening

• Participants treated with strong or moderate CYP3A4 inhibitor or inducer

• Any of the following signs or confirmation of corona virus disease- 2019 (COVID-19) infection:

• Participant has a positive test result for severe acute respiratory syndrome coronavirus 2 before randomisation (Visit 2)

• Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnoea, sore throat, fatigue) or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening (Visit 1) or at randomisation (Visit 2)

• Participant has been previously hospitalised with COVID-19 infection