| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of zibotentan 1.5 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy on UACR. |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of zibotentan 0.25 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy on UACR.
2. To determine the change in office systolic and diastolic BP for doses ofzibotentan combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy.
3. To characterise the dose-response relationship (relationship between different doses of zibotentan/a fixed dose of dapagliflozin and UACR reduction).
4. To determine the effect of different doses of zibotentan and dapagliflozin 10 mg in combination versus dapagliflozin 10 mg monotherapy on eGFR. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Type of Participant and Disease Characteristics / Laboratory Parameters Diagnosis of CKD, defined as:
1. eGFR (CKD-EPI) ≥ 20 mL/min/1.73 m2
2. Urine albumin to creatinine ratio (UACR) ≥ 150 and ≤ 5000 mg albumin/g creatinine, based on a single first morning void spot urine sample at screening
Medical Treatment
3. No current or prior (within 1 month of screening) medical treatment with an SGLT2i or any FDC with SGLT2i (such as SGLT2i + metformin).
4. If ACEi and/or ARB and/or MRA 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.
5. 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.
Weight
6. Body mass index (BMI) ≤ 40 kg/m2.
Sex
7. Male or female of non-childbearing potential.
Reproduction
8. 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: (a) Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH and LH levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
9. 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. |
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| E.4 | Principal exclusion criteria |
1.Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease requiring significant immunosuppression, autosomal dominant or autosomal recessive polycystic kidney disease.
2.Participants with NYHA functional HF class III or IV. 3.Acute coronary syndrome events within 3 months prior to screening. 4.Participants with a BNP≥200pg/mL or NT proBNP≥600pg/mL (BNP≥400pg/mL or NT-proBNP≥1200pg/mL, respectively, if associated with atrial fibrillation) measured by local laboratory at screening (Visit 1). 5.Participants with unstable HF requiring hospitalisation for optimizationof HF treatment and/or who have not been stable on HF therapy within 6months prior to screening. 6.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. 7.High output HF (eg, due to hyperthyroidism or Paget's disease). 8.Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement. 9.Participants with uncontrolled diabetes mellitus (HbA1c>12%). 10.Participants with T1DM. 11.Hyponatremia, defined as serum Na+<135mmol/L at the time of screening (Visit 1). 12.Intermittent or persistent second or third degree AV block after sinusnode dysfunction, with clinically significant bradycardia or sinus pause when not treated with pacemaker. 13.Prolonged QT interval (QTcF>470ms) 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. 14.History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter). 15.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. 16.Heart transplantation or left ventricular assist device at any time. 17.Kidney or any organ transplantation. 18.History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (eg, dapagliflozin, canagliflozin, empagliflozin) ordrugs with a similar chemical structure to zibotentan. 19.Any clinically significant disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) which, as judged by the investigator, 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: (a)Isolated pulmonary arterial hypertension (defined as mean PAP≥ 25mmHg at rest) or right ventricular failure; in the absence of left-sided HF. (b)Anaemia defined as Hb level <100g/L or 10g/dL at screening (Visit 1). (c)Severe COPD or other lung disease including but not limited to pulmonary fibrosis requiring chronic O2 therapy, regular nebuliser use, or oral steroid therapy. 20.Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to screening. 21.Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas of the skin) and malignancies 5 years prior to screening. 22.Severe hepatic impairment (Child-Pugh class C Hepatic impairment), AST or ALT>2x the ULN; or total bilirubin >2xULN at time of screening. An isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion. 23.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). 24.Drug or alcohol abuse, either current or within 12 months before screening. 25.Positive hepatitis C antibody or hepatitis B virus surface antigen at screening. 26.Positive human immunodeficiency virus (HIV) test. 27.Participants treated with strong or moderate CYP3A4 inhibitor or inducer. 28.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. 29. (a)Participant has a positive test result for SARS-CoV-2 during screening. Participants who are not hospitalised for COVID-19 infections can be re-screened 4 weeks after they have recovered. (b)Participant has been previously hospitalised with COVID-19 infection.
30.Ejection fraction <50% measured by ECHO at screening. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in log-transformed UACR from baseline to Week 12 (zibotentan 1.5 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Change in log-transformed UACR from baseline to Week 12 (zibotentan 0.25 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg).
2. Change in BP from baseline (Visit 2) to Week 12
3. The least squares mean change of UACR at Week 12 from the zibotentan/dapagliflozin dose arms and the dapagliflozin monotherapy arm.
4.
● Change in eGFR from baseline to Week 1.
● Change in eGFR from baseline to Week 12.
● Change in eGFR from baseline to Week 14.
● Change in eGFR from Week 1 to Week 12. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline to week 12
2. Baseline to week 12
3. Baseline to week 12
4.
●Baseline to week 1
●Baseline to week12
●Baseline to week 14
●Week 1 to week 12 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 88 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Japan |
| Malaysia |
| South Africa |
| United States |
| Poland |
| Bulgaria |
| Netherlands |
| Spain |
| Italy |
| Croatia |
| Denmark |
| Georgia |
| Hungary |
| Serbia |
| Slovakia |
| Ukraine |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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