| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Kidney Disease |
| Malattia renale cronica |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Kidney Disease |
| Malattia renale cronica |
|
| 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 |
|
| 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 and dapagliflozin in combination and alone versus placebo on UACR. |
| Valutare l’effetto sul UACR di zibotentan e dapagliflozin in combinazione e in monoterapia rispetto a placebo. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine the change in UACR for doses of zibotentan combined with 10 mg dapagliflozin versus 10 mg dapagliflozin alone.
2. To determine the change in office systolic and diastolic BP for doses of zibotentan combined with 10 mg dapagliflozin and for zibotentan and 10 mg dapagliflozin alone versus placebo.
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 ranging doses of zibotentan and dapagliflozin in combination and alone on eGFR. |
1. Determinare la variazione del UACR ottenuta con dosi di zibotentan associate a dapagliflozin 10 mg rispetto a dapagliflozin 10 mg in monoterapia.
2. Determinare la variazione della PA sistolica e diastolica misurata presso lo studio del medico ottenuta con dosi di zibotentan associate a dapagliflozin 10 mg e con zibotentan e dapagliflozin 10 mg in monoterapia rispetto a placebo
3. Caratterizzare la relazione dose-risposta (relazione tra dosi differenti di zibotentan/una dose fissa di dapagliflozin e la riduzione del UACR).
4. Determinare l’effetto sulla eGFR di dosi diverse di zibotentan e dapagliflozin in combinazione e in monoterapia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of CKD, defined as:
(a) Part A: eGFR (CKD-EPI) >= 30 and <= 60 mL/min/1.73 m2
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 m2
2. Urine albumin to creatinine ratio (UACR) >= 200 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. On a stable dose of ACEi and/or ARB (>= 4 weeks before screening).
5. No current or prior treatment within 3 months prior to screening with cytotoxic therapy,
immunosuppressive therapy or other immunotherapy.
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.
PLEASE REFER TO THE PROTOCOL FOR FURTHER INCLUSION CRITERIA |
1. Diagnosi di malattia renale cronica (CKD), definita come:
(a) Parte A: eGFR (CKD-EPI) > = 30 e <=60 ml/min/1,73 m2
Parte B, se i dati di sicurezza della Parte A lo consentono (altrimenti come nella Parte A):
eGFR
(CKD-EPI) >=20 e <=60 ml/min/1,73 m2
2. Rapporto albumina/creatinina nelle urine (UACR) >=200 e <=5000 mg albumina/g creatinina, sulla base di un unico campione di urina estemporanea dalla prima minzione del mattino, allo screening del Trattamento Medico
3. Nessun trattamento medico in corso o precedente (entro 1 mese dallo screening) con un SGLT2i o qualsiasi combinazione a dose fissa (FDC) con SGLT2i (come SGLT2i + metformina).
4. In terapia con una dose stabile di ACE-inibitori e/o ARB (>= 4 settimane prima dello screening).
5. Nessun trattamento in corso o precedente nei 3 mesi prima dello screening con terapia citotossica, terapia immunosoppressiva o altra immunoterapia.
Peso
6 Indice di massa corporea (IMC) <= 40 kg/m2.
Sesso
7 Pazienti di sesso maschile o femminile non in età fertile.
Riproduzione
8 Le partecipanti di sesso femminile devono avere un test di gravidanza negativo allo screening, non devono allattare al seno e non in età fertile, confermato allo screening tramite il soddisfacimento di uno dei seguenti criteri:
(a) Essere in postmenopausa definita come amenorrea per almeno 12 mesi dopo la cessazione di tutti i trattamenti ormonali esogeni e presentare livelli di ormone follicolo-stimolante (FSH) e di ormone luteinizzante (LH) nell’intervallo post-menopausale.
(b) Documentazione di sterilizzazione chirurgica irreversibile mediante isterectomia, ovariectomia bilaterale o salpingectomia bilaterale, ma non legatura delle tube.
9 I partecipanti di sesso maschile devono essere chirurgicamente sterili, praticare l’astinenza o utilizzare, unitamente alla propria partner, un metodo contraccettivo altamente efficace per l’intera durata dello studio (dal momento della firma del consenso) e per 3 mesi dopo l’ultima dose del farmaco sperimentale, allo scopo di prevenire una gravidanza. I partecipanti allo studio di sesso maschile non devono donare o conservare sperma durante questo periodo di tempo.
SI PREGA DI FARE RIFERIMENTO AL PROTOCOLLO PER ULTERIORI CRITERI DI INCLUSIONE |
|
| 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, or anatomical causes of CKD.
2 History of epilepsy syndrome.
3 Participants with NYHA functional HF class III or IV.
4 Acute coronary syndrome (ACS) events within 3 months prior to screening.
5 Participants with a confirmed BNP >= 200 pg/mL or BNP >= 400 pg/mL if with atrial fibrillation.
6 Participants with unstable HF requiring hospitalisation for optimization of HF treatment and/or who have not been stable on HF therapy within 6 months prior to screening.
7 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 (ie, chemotherapy, infective myocarditis, septic cardiomyopathy).
8 High output HF (eg, due to hyperthyroidism or Paget's disease).
9 Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
10 Participants with uncontrolled diabetes mellitus (HbA1c > 12%).
PLEASE REFER TO THE PROTOCOL FOR FURTHER EXCLUSION CRITERIA |
1 Malattia a cambiamento minimo, malattia renale instabile a rapida progressione e/o malattia renale che richiede immunosoppressione significativa, malattia renale policistica autosomica dominante o autosomica recessiva o cause anatomiche di CKD.
2 Anamnesi di sindrome epilettica.
3 Partecipanti con insufficienza cardiaca (IC) funzionale di classe III o IV secondo la NYHA.
4 Eventi di sindrome coronarica acuta (SCA) nei 3 mesi precedenti lo screening.
5 Partecipanti con valori confermati di peptide natriuretico di tipo B (BNP) >= 200 pg/ml o BNP >= 400 pg/ml se affetti da fibrillazione atriale.
6 Partecipanti con IC instabile che richiede ricovero per l’ottimizzazione del trattamento per IC e/o che non sono rimasti stabili in terapia per IC nei 6 mesi precedenti lo screening.
7 Insufficienza cardiaca dovuta a cardiomiopatie che richiederebbero principalmente altri trattamenti specifici: per es. cardiomiopatia dovuta a malattia pericardica, amiloidosi o altre malattie infiltrative, cardiomiopatia correlata a cardiopatia congenita, cardiomiopatia ipertrofica primaria, cardiomiopatia correlata a condizioni tossiche o infettive (ovvero chemioterapia, miocardite infettiva, cardiomiopatia settica).
8 IC ad alto rendimento (per es., dovuta a ipertiroidismo o malattia di Paget).
9 Insufficienza cardiaca dovuta a malattia/insufficienza valvolare cardiaca primaria, grave insufficienza funzionale della valvola mitrale o tricuspide o riparazione/sostituzione della valvola cardiaca programmata.
10 Partecipanti con diabete mellito non controllato (HbA1c >12%).
SI PREGA DI FARE RIFERIMENTO AL PROTOCOLLO PER ULTERIORI CRITERI DI ESCLUSIONE |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in log-transformed UACR from baseline to Week 12. |
| Variazione del UACR log-trasformato dal basale alla Settimana 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Change in log-transformed UACR from baseline to Week 12.
2. Change in BP from baseline (Visit 2) to Week 12
3. The least squares mean change of UACR at Week 12 from the 3 Zibo/Dapa dose groups and the dapagliflozin monotherapy group.
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. |
1. Variazione del UACR log-trasformato dal basale alla Settimana 12.
2. Variazione della PA dal basale (Visita 2) alla Settimana 12.
3. Variazione media dei minimi quadrati del UACR alla Settimana 12 osservata nei 3 gruppi in terapia combinata Zibo/Dapa e nel gruppo trattato con dapagliflozin in monoterapia.
4. Variazione della eGFR dal basale alla Settimana 1.
-Variazione della eGFR dal basale alla Settimana 12.
-Variazione della eGFR dal basale alla Settimana 14.
-Variazione della eGFR dalla Settimana 1 alla Settimana 12. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. week 12
2. week 12
3. week 12
4.
week 1
week 12
week 14
week 12 |
1. settimana 12
2. settimana 12
3. settimana 12
4.
settimana 1
settimana 12
settimana 14
settimana 12 |
|
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 10 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| Bosnia and Herzegovina |
| Brazil |
| Canada |
| Georgia |
| Japan |
| Korea, Republic of |
| Malaysia |
| Serbia |
| South Africa |
| Taiwan |
| Ukraine |
| United States |
| Belgium |
| Bulgaria |
| Denmark |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| Argentina |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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