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Skojarzenie zibotentanu i dapagliflozyny, oceniane w marskości wątroby (badanie ZEAL) (ZEAL)

31 sierpnia 2026 zaktualizowane przez: AstraZeneca

Dwuczęściowe, wieloośrodkowe, randomizowane, podwójnie zaślepione, kontrolowane placebo badanie fazy IIa/b prowadzone w grupach równoległych z zastosowaniem różnych dawek w celu oceny skuteczności, bezpieczeństwa i tolerancji połączenia zybotentanu i dapagliflozyny oraz dapagliflozyny w monoterapii w porównaniu z placebo u uczestników z marskością wątroby Z cechami nadciśnienia wrotnego

This is a two part Phase IIa/b multicentre, randomised, double-blind, placebo-controlled, parallel group dose-ranging study to assess the efficacy, safety, and tolerability of the combination of zibotentan and dapagliflozin, and dapagliflozin monotherapy versus placebo in participants with cirrhosis with features of portal hypertension.

Przegląd badań

Status

Zakończony

Warunki

Interwencja / Leczenie

Szczegółowy opis

Part A will assess the efficacy, safety, and tolerability of the combination of B mg zibotentan and 10 mg dapagliflozin versus placebo in participants with Child-Pugh A cirrhosis with features of portal hypertension and with no history of decompensation events.

If the safety profile is determined to be acceptable at the conclusion of Part A, Part B will investigate efficacy, safety, and tolerability of A mg, B mg, or C mg zibotentan combined with 10 mg dapagliflozin and of 10 mg dapagliflozin monotherapy versus placebo in participants with cirrhosis with features of portal hypertension. Part B will include a broader range of Child- Pugh A and Child-Pugh B cirrhosis participants, including those with more severe disease, a history of decompensation events, or current ascites.

The study will be conducted in approximately 30 to 45 study centres in North America, Asia, and Europe.

Typ studiów

Interwencyjne

Zapisy (Rzeczywisty)

205

Faza

  • Faza 2

Kontakty i lokalizacje

Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.

Lokalizacje studiów

  • Australia
      • Heidelberg, Australia, 3084
        • Research Site
  • Austria
      • Vienna, Austria, 1090
        • Research Site
  • Belgia
      • Edegem, Belgia, 2650
        • Research Site
  • Chiny
      • Beijing, Chiny, 100057
        • Research Site
      • Chengdu, Chiny, 610000
        • Research Site
      • Guangzhou, Chiny, 510515
        • Research Site
      • Hangzhou, Chiny, 310015
        • Research Site
  • Czechy
      • Prague, Czechy, 128 00
        • Research Site
      • Prague, Czechy, 169 02
        • Research Site
  • Dania
      • Aarhus N, Dania, 8200
        • Research Site
      • Esbjerg, Dania, 6700
        • Research Site
      • Hvidovre, Dania, 2650
        • Research Site
      • Køge, Dania, 4600
        • Research Site
  • Francja
      • Angers, Francja, 49933
        • Research Site
      • Clichy, Francja, 92110
        • Research Site
      • Paris, Francja, 75651
        • Research Site
      • Toulouse, Francja, 31059
        • Research Site
  • Hiszpania
      • Barcelona, Hiszpania, 08035
        • Research Site
      • Barcelona, Hiszpania, 08036
        • Research Site
      • Barcelona, Hiszpania, 08041
        • Research Site
      • Madrid, Hiszpania, 28034
        • Research Site
      • Madrid, Hiszpania, 28007
        • Research Site
      • Majadahonda, Hiszpania, 28222
        • Research Site
      • Santander, Hiszpania, 39008
        • Research Site
  • Holandia
      • Amsterdam, Holandia, 1081 HV
        • Research Site
  • Niemcy
      • Dresden, Niemcy, 01307
        • Research Site
      • Landshut, Niemcy, 84034
        • Research Site
      • Mainz, Niemcy, 55131
        • Research Site
      • Münster, Niemcy, 48149
        • Research Site
      • Wiesbaden, Niemcy, 65189
        • Research Site
  • Rumunia
      • Cluj-Napoca, Rumunia, 400162
        • Research Site
  • Stany Zjednoczone
    • Alabama
      • Birmingham, Alabama, Stany Zjednoczone, 35233
        • Research Site
    • California
      • Pasadena, California, Stany Zjednoczone, 91105
        • Research Site
      • San Francisco, California, Stany Zjednoczone, 94115
        • Research Site
      • West Hollywood, California, Stany Zjednoczone, 90048
        • Research Site
    • Minnesota
      • Rochester, Minnesota, Stany Zjednoczone, 55905
        • Research Site
    • New York
      • The Bronx, New York, Stany Zjednoczone, 10467
        • Research Site
    • South Carolina
      • Charleston, South Carolina, Stany Zjednoczone, 29425
        • Research Site
    • Texas
      • Dallas, Texas, Stany Zjednoczone, 75246
        • Research Site
    • Virginia
      • Charlottesville, Virginia, Stany Zjednoczone, 22903
        • Research Site
      • Richmond, Virginia, Stany Zjednoczone, 23249
        • Research Site
    • Wisconsin
      • Milwaukee, Wisconsin, Stany Zjednoczone, 53226
        • Research Site
  • Szwajcaria
      • Bern, Szwajcaria, 3010
        • Research Site
      • Lucerne, Szwajcaria, 6000
        • Research Site
      • Lugano, Szwajcaria, 6900
        • Research Site
  • Tajwan
      • Taipei, Tajwan, 10002
        • Research Site
      • Taipei, Tajwan, 112
        • Research Site
  • Zjednoczone Królestwo
      • Birmingham, Zjednoczone Królestwo, B9 5SS
        • Research Site
      • Cambridge, Zjednoczone Królestwo, CB2 0XY
        • Research Site
      • London, Zjednoczone Królestwo, SE5 9RS
        • Research Site

Kryteria uczestnictwa

Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.

Kryteria kwalifikacji

Wiek uprawniający do nauki

18 lat do 80 lat (Dorosły, Starszy dorosły)

Akceptuje zdrowych ochotników

Nie

Płeć kwalifikująca się do nauki

Wszystko

Opis

Study principal inclusion criteria For both Part A and Part B

  1. No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or ERAs.

  2. On no or a stable dose of beta blockers, with no major dose changes within 1 month prior to the first dose of study intervention.

  3. Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.

  4. Female participants of non-childbearing potential confirmed at screening by fulfilling one of the following criteria:

    1. Post-menopausal: defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments; and also, FSH levels in the post-menopausal range by central laboratory.
    2. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

  5. Female participants must have a negative pregnancy test at screening and must not be lactating

Part A participants who have the following:

  1. Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness ≥ 21 kPa.
  2. MELD score < 15.
  3. Child-Pugh score ≤ 6.
  4. No clinically evident ascites.
  5. No evidence of worsening of hepatic function (eg, no clinically significant change in signs, symptoms, or laboratory parameters of hepatic disease status) within the last month prior to dosing, as determined by the investigator or usual practitioner.
  6. HVPG recording of good enough quality as judged by a central reader.

Part B participants who have the following:

  1. Clinical and/or histological diagnosis of cirrhosis and either history of decompensation or compensated cirrhosis with signs of clinically significant portal hypertension.
  2. HVPG recording of good enough quality and HVPG > 10 mmHg, as judged by a central reader.
  3. MELD score < 15.
  4. Child-Pugh score < 10.
  5. No ascites or ascites up to grade 2 without change in diuretic treatment within the last month prior to first dose and no paracentesis within the last month or planned paracentesis in the next 4 months at screening.
  6. No evidence of worsening of hepatic function (eg, no clinically significant change in signs, symptoms, or laboratory parameters of hepatic disease status) within the last month prior to dosing, as determined by the investigator or usual practitioner.

Study principal exclusion criteria:

  1. Any evidence of a clinically significant disease which in the investigator's opinion makes it undesirable for the participant to participate in the study.
  2. Liver cirrhosis caused by chronic cholestatic liver disease
  3. ALT or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN
  4. Acute liver injury caused by drug toxicity or by an infection.
  5. Any history of hepatocellular carcinoma.
  6. Liver transplant or expected liver transplantation within 6 months of screening.
  7. History of TIPS or a planned TIPS within 6 months from enrolment into the study.
  8. Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year.
  9. Participants with T1DM.

Medical Conditions (Part A only)

  1. INR > 1.5.
  2. Serum/plasma levels of albumin ≤ 35 g/L.
  3. Platelet count < 75 × 109/L.
  4. History of ascites
  5. History of hepatic hydrothorax
  6. History of portopulmonary syndrome
  7. History of hepatic encephalopathy
  8. History of variceal haemorrhage
  9. History of acute kidney injury
  10. History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget's disease)

Medical Conditions (Part B only)

  1. INR > 1.7.
  2. Serum/plasma levels of albumin ≤ 28 g/L.
  3. Platelet count < 50 × /109L.
  4. Acute kidney injury within 3 months of screening.
  5. History of encephalopathy of West Haven grade 2 or higher within 6 months prior to screening.
  6. History of variceal haemorrhage within 6 months prior to screening.
  7. NYHA functional heart failure class III or IV or with unstable heart failure requiring hospitalisation for optimisation of heart failure treatment and who are not yet stable on heart failure therapy within 6 months prior to screening.
  8. 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).
  9. High output heart failure (eg, due to hyperthyroidism or Paget's disease).
  10. Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.

Plan studiów

Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.

Jak projektuje się badanie?

Szczegóły projektu

  • Główny cel: Ekranizacja
  • Przydział: Randomizowane
  • Model interwencyjny: Przydział równoległy
  • Maskowanie: Potroić

Broń i interwencje

Grupa uczestników / Arm
Interwencja / Leczenie
Eksperymentalny: Part A: Treatment Group 1

Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks.
Lek: Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)

placebo capsule (matching zibotentan capsule)

placebo tablet (matching dapagliflozin tablet)
Eksperymentalny: Part A: Treatment Group 2

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 6 weeks.
Lek: Part A: zibotentan (dose B) + dapagliflozin

zibotentan capsule

dapagliflozin tablet
Eksperymentalny: Part B: Treatment Group 1

Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 16 weeks.
Lek: Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)

placebo capsule (matching zibotentan capsule)

placebo tablet (matching dapagliflozin tablet)
Eksperymentalny: Part B: Treatment Group 2

Participants will receive once daily dose of placebo matching zibotentan capsule + dapagliflozin tablet for 16 weeks.
Lek: Part B: placebo (matching zibotentan capsule) + dapagliflozin

placebo capsule (matching zibotentan capsule)

dapagliflozin tablet
Eksperymentalny: Part B: Treatment Group 3

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.
Lek: Part B: zibotentan (dose A) + dapagliflozin

zibotentan capsule

dapagliflozin tablet
Eksperymentalny: Part B: Treatment Group 4

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.
Lek: Part B: zibotentan (dose B) + dapagliflozin

zibotentan capsule

dapagliflozin tablet
Eksperymentalny: Part B: Treatment Group 5

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.
Lek: Part B: zibotentan (dose C) + dapagliflozin

zibotentan capsule

dapagliflozin tablet

Co mierzy badanie?

Podstawowe miary wyniku

Miara wyniku
Opis środka
Ramy czasowe
Absolute Change in HVPG From Baseline to Week 6, Part A
Ramy czasowe: From Baseline to Week 6

Absolute change in Hepatic venous pressure gradient from baseline to week 6.
From Baseline to Week 6
Absolute Change in HVPG From Baseline to Week 6, Part B
Ramy czasowe: From Baseline to Week 6

Absolute change in Hepatic venous pressure gradient from baseline to week 6.
From Baseline to Week 6

Miary wyników drugorzędnych

Miara wyniku
Opis środka
Ramy czasowe
HVPG Percentage Change From Baseline to Week 6, Part A
Ramy czasowe: From Baseline to Week 6

Hepatic venous pressure gradient percentage change from baseline to week 6, Part A.
From Baseline to Week 6
HVPG Percentage Change From Baseline to Week 6, Part B
Ramy czasowe: From baseline to week 6

Hepatic venous pressure gradient percentage change from baseline to week 6, Part B.
From baseline to week 6
Number of Participants With HVPG Response at Week 6, Part A
Ramy czasowe: From baseline to week 6

A HVPG responder is defined as a subject having <10 mmHg at week 6 if baseline HVPG >=10 or a reduction of >=1.5 mmHg from baseline to week 6. n: Number of subjects in analysis. N: Number of subjects per treatment group.
From baseline to week 6
Number of Participants With HVPG Response at Week 6, Part B
Ramy czasowe: From baseline to Week 6

A HVPG responder in Part B is defined as a subject having at least 20% decrease or a reduction to or below 12 mmHg if baseline HVPG > 12 mmHG from baseline to Week 6.
From baseline to Week 6
Change in Body Weight (kg) Over Time Course of Study, Part A
Ramy czasowe: From baseline to Week 6

The analysis is performed using MMRM. The model includes the continuous covariate of the Baseline measurements as the fixed effect covariate and fixed categorical effects of treatment group, visit, and treatmentby-visit interaction.
From baseline to Week 6
Change in Body Weight (kg) Over Time Course of Study, Part B
Ramy czasowe: From baseline to Week 6 and Week 16

The analysis is performed using MMRM. The model includes the continuous covariate of the Baseline measurements as the fixed effect covariate and fixed categorical effects of treatment group, visit, and treatmentby-visit interaction.
From baseline to Week 6 and Week 16
Change in Total Dosage of Loop-diuretic Equivalents Use From Baseline to Week 6, Part A
Ramy czasowe: From baseline to Week 6

Change in total dosage of loop-diuretic equivalents use from baseline to Week 6, Part A. A loop-diuretic equivalent is based on 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg ethacrynic acid.
From baseline to Week 6
Change in Total Dosage of Loop-diuretic Equivalents Use From Baseline to Week 6 and Week 16, Part B
Ramy czasowe: From Baseline to Week 6 and Week 16

Change in total dosage of loop-diuretic equivalents use from baseline to Week 6, Part B. A loop-diuretic equivalent is based on 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg ethacrynic acid.
From Baseline to Week 6 and Week 16
Change in Total Body Water From Baseline to Week 6, Part A
Ramy czasowe: From Baseline to Week 6

Change in total body water from baseline to Week 6, Part A. The analysis is performed using MMRM.
From Baseline to Week 6
Change in Total Body Water From Baseline to Week 6 and Week 16, Part B
Ramy czasowe: From Baseline to Week 6 and Week 16

Change in total body water from baseline to Week 6 and Week 16, Part B. The analysis is performed using MMRM.
From Baseline to Week 6 and Week 16
Change in Extracellular Water From Baseline to Week 6, Part A
Ramy czasowe: From baseline to Week 6

Change in extracellular water from baseline to Week 6, Part A. The analysis is performed using MMRM. Bioimpedance spectroscopy (BIS) was performed at the study centre to monitor body water volumes and body fat mass.
From baseline to Week 6
Change in Extracellular Water From Baseline to Week 6 and Week 16, Part B
Ramy czasowe: From Baseline to Week 6 and to Week 16

Change in extracellular water from baseline to Week 6 and Week 16, Part B. The analysis is performed using MMRM. Bioimpedance spectroscopy (BIS) was performed at the study centre to monitor body water volumes and body fat mass.
From Baseline to Week 6 and to Week 16
Change in Intracellular Water From Baseline to Week 6, Part A
Ramy czasowe: From Baseline to Week 6

Change in intracellular water from Baseline to Week 6, Part A. The analysis is performed using MMRM. Bioimpedance spectroscopy (BIS) was performed at the study centre to monitor body water volumes and body fat mass.
From Baseline to Week 6
Change in Intracellular Water From Baseline to Week 6 and Week 16, Part B
Ramy czasowe: From Baseline to Week 6 and Week 16

Change in intracellular water from Baseline to Week 6 and Week 16, Part B. The analysis is performed using MMRM. Bioimpedance spectroscopy (BIS) was performed at the study centre to monitor body water volumes and body fat mass.
From Baseline to Week 6 and Week 16
Change in Total Body Fat Mass From Baseline to Week 6, Part A
Ramy czasowe: From baseline to Week 6

Change in total body fat mass from Baseline to Week 6, Part A. The analysis is performed using MMRM. Bioimpedance spectroscopy (BIS) was performed at the study centre to monitor body water volumes and body fat mass.
From baseline to Week 6
Change in Total Body Fat Mass From Baseline to Week 6 and Week 16, Part B
Ramy czasowe: From Baseline to Week 6 and Week 16

Change in total body fat mass from Baseline to Week 6 and Week 16, Part B. The analysis is performed using MMRM. Bioimpedance spectroscopy (BIS) was performed at the study centre to monitor body water volumes and body fat mass.
From Baseline to Week 6 and Week 16
Change in Systolic Blood Pressure From Baseline to Week 6, Part A
Ramy czasowe: From Baseline to Week 6

Change in systolic blood pressure from baseline to Week 6, Part A. The analysis is performed using MMRM.
From Baseline to Week 6
Change in Systolic Blood Pressure From Baseline to Week 6 and Week 16, Part B
Ramy czasowe: From baseline to Week 6 and Week 16

Change in systolic blood pressure from baseline to Week 6 and Week 16, Part B. The analysis is performed using MMRM.
From baseline to Week 6 and Week 16
Change in Diastolic Blood Pressure From Baseline to Week 6, Part A
Ramy czasowe: From Baseline to Week 6

Change in diastolic blood pressure from baseline to Week 6, Part A. The analysis is performed using MMRM.
From Baseline to Week 6
Change in Diastolic Blood Pressure From Baseline to Week 6 and Week 16, Part B
Ramy czasowe: From baseline to Week 6 and Week 16

Change in diastolic blood pressure from baseline to Week 6 and Week 16, Part B. The analysis is performed using MMRM.
From baseline to Week 6 and Week 16

Współpracownicy i badacze

Tutaj znajdziesz osoby i organizacje zaangażowane w to badanie.

Sponsor

AstraZeneca

Publikacje i pomocne linki

Osoba odpowiedzialna za wprowadzenie informacji o badaniu dobrowolnie udostępnia te publikacje. Mogą one dotyczyć wszystkiego, co jest związane z badaniem.

Przydatne linki

Daty zapisu na studia

Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.

Główne daty studiów

Rozpoczęcie studiów (Rzeczywisty)

31 października 2022

Zakończenie podstawowe (Rzeczywisty)

22 maja 2025

Ukończenie studiów (Rzeczywisty)

17 lipca 2025

Daty rejestracji na studia

Pierwszy przesłany

24 sierpnia 2022

Pierwszy przesłany, który spełnia kryteria kontroli jakości

24 sierpnia 2022

Pierwszy wysłany (Rzeczywisty)

25 sierpnia 2022

Aktualizacje rekordów badań

Ostatnia wysłana aktualizacja (Rzeczywisty)

25 września 2026

Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości

31 sierpnia 2026

Ostatnia weryfikacja

1 sierpnia 2026

Więcej informacji

Terminy związane z tym badaniem

Dodatkowe istotne warunki MeSH

Inne numery identyfikacyjne badania

  • D4326C00003
  • 2021-006577-30 (Numer EudraCT)

Plan dla danych uczestnika indywidualnego (IPD)

Planujesz udostępniać dane poszczególnych uczestników (IPD)?

TAK

Opis planu IPD

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Ramy czasowe udostępniania IPD

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.

Kryteria dostępu do udostępniania IPD

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

Typ informacji pomocniczych dotyczących udostępniania IPD

  • PROTOKÓŁ BADANIA
  • SOK ROŚLINNY

Informacje o lekach i urządzeniach, dokumenty badawcze

Bada produkt leczniczy regulowany przez amerykańską FDA

Tak

Bada produkt urządzenia regulowany przez amerykańską FDA

Nie

Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .

Subskrybuj