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Kombination aus Zibotentan und Dapagliflozin, bewertet bei Leberzirrhose (ZEAL-Studie) (ZEAL)

31. August 2026 aktualisiert von: AstraZeneca

Eine zweiteilige multizentrische, randomisierte, doppelblinde, placebokontrollierte Parallelgruppen-Dosisfindungsstudie der Phase IIa/b zur Bewertung der Wirksamkeit, Sicherheit und Verträglichkeit der Kombination von Zibotentan und Dapagliflozin sowie Dapagliflozin-Monotherapie im Vergleich zu Placebo bei Teilnehmern mit Zirrhose Mit Funktionen von Portal Hypertension

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.

Studienübersicht

Status

Beendet

Bedingungen

Intervention / Behandlung

Detaillierte Beschreibung

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.

Studientyp

Interventionell

Einschreibung (Tatsächlich)

205

Phase

  • Phase 2

Kontakte und Standorte

Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.

Studienorte

  • Australien
      • Heidelberg, Australien, 3084
        • Research Site
  • Belgien
      • Edegem, Belgien, 2650
        • Research Site
  • China
      • Beijing, China, 100057
        • Research Site
      • Chengdu, China, 610000
        • Research Site
      • Guangzhou, China, 510515
        • Research Site
      • Hangzhou, China, 310015
        • Research Site
  • Deutschland
      • Dresden, Deutschland, 01307
        • Research Site
      • Landshut, Deutschland, 84034
        • Research Site
      • Mainz, Deutschland, 55131
        • Research Site
      • Münster, Deutschland, 48149
        • Research Site
      • Wiesbaden, Deutschland, 65189
        • Research Site
  • Dänemark
      • Aarhus N, Dänemark, 8200
        • Research Site
      • Esbjerg, Dänemark, 6700
        • Research Site
      • Hvidovre, Dänemark, 2650
        • Research Site
      • Køge, Dänemark, 4600
        • Research Site
  • Frankreich
      • Angers, Frankreich, 49933
        • Research Site
      • Clichy, Frankreich, 92110
        • Research Site
      • Paris, Frankreich, 75651
        • Research Site
      • Toulouse, Frankreich, 31059
        • Research Site
  • Niederlande
      • Amsterdam, Niederlande, 1081 HV
        • Research Site
  • Rumänien
      • Cluj-Napoca, Rumänien, 400162
        • Research Site
  • Schweiz
      • Bern, Schweiz, 3010
        • Research Site
      • Lucerne, Schweiz, 6000
        • Research Site
      • Lugano, Schweiz, 6900
        • Research Site
  • Spanien
      • Barcelona, Spanien, 08035
        • Research Site
      • Barcelona, Spanien, 08036
        • Research Site
      • Barcelona, Spanien, 08041
        • Research Site
      • Madrid, Spanien, 28034
        • Research Site
      • Madrid, Spanien, 28007
        • Research Site
      • Majadahonda, Spanien, 28222
        • Research Site
      • Santander, Spanien, 39008
        • Research Site
  • Taiwan
      • Taipei, Taiwan, 10002
        • Research Site
      • Taipei, Taiwan, 112
        • Research Site
  • Tschechien
      • Prague, Tschechien, 128 00
        • Research Site
      • Prague, Tschechien, 169 02
        • Research Site
  • Vereinigte Staaten
    • Alabama
      • Birmingham, Alabama, Vereinigte Staaten, 35233
        • Research Site
    • California
      • Pasadena, California, Vereinigte Staaten, 91105
        • Research Site
      • San Francisco, California, Vereinigte Staaten, 94115
        • Research Site
      • West Hollywood, California, Vereinigte Staaten, 90048
        • Research Site
    • Minnesota
      • Rochester, Minnesota, Vereinigte Staaten, 55905
        • Research Site
    • New York
      • The Bronx, New York, Vereinigte Staaten, 10467
        • Research Site
    • South Carolina
      • Charleston, South Carolina, Vereinigte Staaten, 29425
        • Research Site
    • Texas
      • Dallas, Texas, Vereinigte Staaten, 75246
        • Research Site
    • Virginia
      • Charlottesville, Virginia, Vereinigte Staaten, 22903
        • Research Site
      • Richmond, Virginia, Vereinigte Staaten, 23249
        • Research Site
    • Wisconsin
      • Milwaukee, Wisconsin, Vereinigte Staaten, 53226
        • Research Site
  • Vereinigtes Königreich
      • Birmingham, Vereinigtes Königreich, B9 5SS
        • Research Site
      • Cambridge, Vereinigtes Königreich, CB2 0XY
        • Research Site
      • London, Vereinigtes Königreich, SE5 9RS
        • Research Site
  • Österreich
      • Vienna, Österreich, 1090
        • Research Site

Teilnahmekriterien

Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.

Zulassungskriterien

Studienberechtigtes Alter

18 Jahre bis 80 Jahre (Erwachsene, Älterer Erwachsener)

Akzeptiert gesunde Freiwillige

Nein

Studienberechtigte Geschlechter

Alle

Beschreibung

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.

Studienplan

Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.

Wie ist die Studie aufgebaut?

Designdetails

  • Hauptzweck: Screening
  • Zuteilung: Zufällig
  • Interventionsmodell: Parallele Zuordnung
  • Maskierung: Verdreifachen

Waffen und Interventionen

Teilnehmergruppe / Arm
Intervention / Behandlung
Experimental: Part A: Treatment Group 1

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

placebo capsule (matching zibotentan capsule)

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

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

zibotentan capsule

dapagliflozin tablet
Experimental: Part B: Treatment Group 1

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

placebo capsule (matching zibotentan capsule)

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

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

placebo capsule (matching zibotentan capsule)

dapagliflozin tablet
Experimental: Part B: Treatment Group 3

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

zibotentan capsule

dapagliflozin tablet
Experimental: Part B: Treatment Group 4

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

zibotentan capsule

dapagliflozin tablet
Experimental: Part B: Treatment Group 5

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

zibotentan capsule

dapagliflozin tablet

Was misst die Studie?

Primäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Absolute Change in HVPG From Baseline to Week 6, Part A
Zeitfenster: 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
Zeitfenster: From Baseline to Week 6

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

Sekundäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
HVPG Percentage Change From Baseline to Week 6, Part A
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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

Mitarbeiter und Ermittler

Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.

Sponsor

AstraZeneca

Publikationen und hilfreiche Links

Die Bereitstellung dieser Publikationen erfolgt freiwillig durch die für die Eingabe von Informationen über die Studie verantwortliche Person. Diese können sich auf alles beziehen, was mit dem Studium zu tun hat.

Nützliche Links

Studienaufzeichnungsdaten

Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.

Haupttermine studieren

Studienbeginn (Tatsächlich)

31. Oktober 2022

Primärer Abschluss (Tatsächlich)

22. Mai 2025

Studienabschluss (Tatsächlich)

17. Juli 2025

Studienanmeldedaten

Zuerst eingereicht

24. August 2022

Zuerst eingereicht, das die QC-Kriterien erfüllt hat

24. August 2022

Zuerst gepostet (Tatsächlich)

25. August 2022

Studienaufzeichnungsaktualisierungen

Letztes Update gepostet (Tatsächlich)

25. September 2026

Letztes eingereichtes Update, das die QC-Kriterien erfüllt

31. August 2026

Zuletzt verifiziert

1. August 2026

Mehr Informationen

Begriffe im Zusammenhang mit dieser Studie

Zusätzliche relevante MeSH-Bedingungen

Andere Studien-ID-Nummern

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

Plan für individuelle Teilnehmerdaten (IPD)

Planen Sie, individuelle Teilnehmerdaten (IPD) zu teilen?

JA

Beschreibung des IPD-Plans

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

IPD-Sharing-Zeitrahmen

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.

IPD-Sharing-Zugriffskriterien

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

Art der unterstützenden IPD-Freigabeinformationen

  • STUDIENPROTOKOLL
  • SAFT

Arzneimittel- und Geräteinformationen, Studienunterlagen

Studiert ein von der US-amerikanischen FDA reguliertes Arzneimittelprodukt

Ja

Studiert ein von der US-amerikanischen FDA reguliertes Geräteprodukt

Nein

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