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

  • STATUS
    Recruiting
  • End date
    Jun 6, 2022
  • participants needed
    660
  • sponsor
    AstraZeneca
Updated on 15 September 2021

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.

Description

The study will be conducted in approximately 200 sites in North America, South America, Africa, Asia/Pacific, and European countries.

The study will be conducted in 2 parts, Part A and Part B. In both study parts, participants will be randomized to 12 weeks of treatment plus 2 weeks follow-up.

After screening, eligible participants will be stratified by diabetes (diabetic kidney disease [DKD] versus non-diabetes mellitus [non-DM] CKD) and baseline eGFR (below versus above 45 mL/min/1.73m^2).

Participants will be randomized to treatments with 4 arms in Part A and 6 arms in Part B, in addition to receiving background local standard of care (SoC) therapy as follows:

Part A:

  1. Zibotentan Dose A + Dapagliflozin 10 mg once daily.
  2. Zibotentan Dose A once daily.
  3. Dapagliflozin 10 mg once daily.
  4. Placebo once daily.

Part B:

  1. Zibotentan Dose A + Dapagliflozin 10 mg once daily.
  2. Zibotentan Dose A once daily.
  3. Dapagliflozin 10 mg once daily.
  4. Placebo once daily.
  5. Zibotentan Dose B + Dapagliflozin 10 mg once daily.
  6. Zibotentan Dose C+ Dapagliflozin 10 mg once daily.

Participants randomized in Part A cannot be randomized in Part B.

Details
Condition chronic renal insufficiency, Chronic renal failure, chronic kidney disease, chronic kidney disease (ckd)
Treatment Placebo, Dapagliflozin, Zibotentan
Clinical Study IdentifierNCT04724837
SponsorAstraZeneca
Last Modified on15 September 2021

Eligibility

Yes No Not Sure

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
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