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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04724837




Registration number
NCT04724837
Ethics application status
Date submitted
25/01/2021
Date registered
26/01/2021
Date last updated
1/09/2023

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 Log-transformed 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 Log-transformed UACR from baseline to Week 12
Timepoint [1] 0 0
From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
Secondary outcome [2] 0 0
Change in 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 log-transformed UACR from baseline to Week 12
Timepoint [3] 0 0
From baseline until Week 12 (Day 84)
Secondary outcome [4] 0 0
Change in eGFR from Baseline to Week 1, Week 12 and Week 14
Timepoint [4] 0 0
From baseline (Week 0 [Day 1]) until Week 1, Week 12, and Week 14
Secondary outcome [5] 0 0
Change in eGFR from Week 1 to Week 12
Timepoint [5] 0 0
From Week 1 (Day 8) until Week 12 (Day 84)
Secondary outcome [6] 0 0
Number of Participants Experiencing Adverse events
Timepoint [6] 0 0
From Week 0 (Day 1) until Follow-up visit (Week 14 [Day 98])

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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Dnipro
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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
The purpose of the study is to assess efficacy, safety and tolerability of treatment with
zibotentan and dapagliflozin in combination and dapagliflozin 10 mg as monotherapy in
participants with chronic kidney disease (CKD) with estimated glomerular filtration rate
(eGFR) = 20 mL/min/1.73 m^2, and urinary albumin to creatinine ratio (UACR) = 150 mg/g and =
5000 mg/g.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04724837
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04724837