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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04724837




Registration number
NCT04724837
Ethics application status
Date submitted
25/01/2021
Date registered
26/01/2021

Titles & IDs
Public title
Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD Trial)
Scientific title
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) = 20 mL/Min/1.73 m^2
Secondary ID [1] 0 0
2020-004101-32
Secondary ID [2] 0 0
D4325C00001
Universal Trial Number (UTN)
Trial acronym
ZENITH-CKD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Kidney Disease 0 0
Condition category
Condition code
Renal and Urogenital 0 0 0 0
Kidney disease
Renal and Urogenital 0 0 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Zibotentan
Treatment: Drugs - Dapagliflozin
Treatment: Drugs - Placebo

Experimental: Zibotentan Dose A + Dapagliflozin - Participants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks.

Experimental: Zibotentan Dose B + Dapagliflozin - Participants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks.

Experimental: Placebo + Dapagliflozin - Participants will receive once daily oral dose of dapagliflozin 10 mg and placebo for 12 weeks.


Treatment: Drugs: Zibotentan
Participants will receive zibotentan as per the arms they are randomized.

Treatment: Drugs: Dapagliflozin
Participants will receive 10 mg dapagliflozin as per the arms they are randomized.

Treatment: Drugs: Placebo
Participants will receive placebo as per the arms they are randomized to.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change in Urinary Albumin to Creatinine Ratio (UACR) From Baseline to Week 12
Timepoint [1] 0 0
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary outcome [1] 0 0
Change in UACR From Baseline to Week 12
Timepoint [1] 0 0
From baseline (Week 0 [Day 1]) until Week 12
Secondary outcome [2] 0 0
Change in Office Systolic Blood Pressure From Baseline to Week 12
Timepoint [2] 0 0
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary outcome [3] 0 0
Change in Office Diastolic Blood Pressure From Baseline to Week 12
Timepoint [3] 0 0
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary outcome [4] 0 0
Change in UACR From Baseline to Week 12
Timepoint [4] 0 0
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary outcome [5] 0 0
Change in eGFR From Baseline to Week 1, Week 12, and Week 14
Timepoint [5] 0 0
From baseline (Week 0 [Day 1]) until Week 1 (Day 8), Week 12 (Day 84), and Week 14 (Day 98)
Secondary outcome [6] 0 0
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Timepoint [6] 0 0
From Screening (Day -28) until Follow-up visit (Day 98), up to 126 days
Secondary outcome [7] 0 0
Change in eGFR From Week 1 to Week 12
Timepoint [7] 0 0
From Week 1 (Day 8) to Week 12 (Day 84)

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

* Diagnosis of Chronic kidney disease (CKD), defined as:

(a) eGFR chronic kidney disease epidemiology collaboration (CKD-EPI) = 20 mL/min/1.73 m^2, and (b) UACR = 150 and = 5000 mg 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 Angiotensin-converting enzyme inhibitors (ACEi) and/or Angiotensin receptor blockers (ARB) and/or mineralocorticoid receptor agonist are prescribed, the dose must be stable = 4 weeks 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 = 40 kg/m^2.
* Male or female of non-childbearing potential.
* 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:

* Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone and luteinizing hormone levels in the postmenopausal range.
* Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
* 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.
* Capable of giving signed informed consent, as described in Appendix A, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
* Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
* Provision of signed and dated written Genetic informed consent prior to collection of samples (optional) for genetic analysis.
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.
* 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 B-type natriuretic peptide (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).
* 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 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).
* High output HF (eg, due to hyperthyroidism or Paget's disease).
* 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%).
* Participants with Type 1 diabetes mellitus.
* Hyponatremia, defined as serum Na+ < 135 mmol/L at the time of screening (Visit 1).
* 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.
* Prolonged QT interval (QTcF > 470 ms) 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.
* History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter).
* 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.
* Heart transplantation or left ventricular assist device at any time.
* Kidney or any organ transplantation.
* 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.
* Any clinically significant disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment), 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 [PAP] (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 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 (in the opinion of the investigator).
* Positive hepatitis C antibody, or hepatitis B virus, surface antigen at screening.
* Positive human immunodeficiency virus (HIV) test.
* Participants treated with strong or moderate CYP3A4 inhibitor or inducer.
* Any condition outside the renal and CV disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator's clinical judgment.
* 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.
* Participation in another clinical study with an investigational product administered in the last 3 months prior to screening.
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
* Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
* Previous randomisation into the present study.
* Plasma donation within 1 month of the visit at the clinic or any blood donation/blood loss > 500 mL during the 3 months prior to any visit at the clinic.
* Male participant in a sexually active relation with pregnant or breastfeeding partner.
* Participants can decline to participate in the genetic research and may still participate in the study. Exclusion from this optional genetic research may be for any of the exclusion criteria specified for the main study or any of the following:

* Previous allogeneic bone marrow transplant.
* Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/04/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/06/2023
Sample size
Target
Accrual to date
Final
542
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Adelaide
Recruitment hospital [2] 0 0
Research Site - Birtinya
Recruitment hospital [3] 0 0
Research Site - Elizabeth Vale
Recruitment hospital [4] 0 0
Research Site - Gosford
Recruitment hospital [5] 0 0
Research Site - Westmead
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
4575 - Birtinya
Recruitment postcode(s) [3] 0 0
5112 - Elizabeth Vale
Recruitment postcode(s) [4] 0 0
2250 - Gosford
Recruitment postcode(s) [5] 0 0
2145 - Westmead
Recruitment outside Australia
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United States of America
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Alabama
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California
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Kansas
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Kentucky
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Louisiana
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Massachusetts
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Michigan
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Nagoya
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Naka
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Osaka-shi
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Rimavska Sobota
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Bellville
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Durban
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George
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Observatory
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Pretoria
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Somerset West
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A Coruna
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Barcelona
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Burela
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Madrid
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Malaga
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Sevilla
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Valencia
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Ukraine
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Chernivts?
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Ukraine
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Dnipro
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Ukraine
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Kharkiv
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Kyiv
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Ternopil
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Uzhhorod
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Vinnytsia
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Zaporizhia
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Ukraine
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Zhytomyr

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
David C Wheeler, MB ChB, MD, FRCP
Address 0 0
Centre for Nephrology Royal Free Campus University College London Rowland Hill Street London NW3 2PF United Kingdom
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP)
When will data be available (start and end dates)?
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Available to whom?
When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://astrazenecagroup-dt.pharmacm.com/DT/Home


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04724837