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Zibotentan og Dapagliflozin-kombinasjon, evaluert i levercirrhose (ZEAL-studie) (ZEAL)

31. august 2026 oppdatert av: AstraZeneca

En todelt fase IIa/b multisenter, randomisert, dobbeltblind, placebokontrollert, parallell gruppedosestudie for å vurdere effektivitet, sikkerhet og tolerabilitet av kombinasjonen av Zibotentan og Dapagliflozin, og Dapagliflozin monoterapi versus placebo hos deltakere med cirrhosis Med funksjoner i 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.

Studieoversikt

Status

Avsluttet

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

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.

Studietype

Intervensjonell

Registrering (Faktiske)

205

Fase

  • Fase 2

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

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

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år til 80 år (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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.

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Screening
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Trippel

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: Part A: Treatment Group 1

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

placebo capsule (matching zibotentan capsule)

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

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

zibotentan capsule

dapagliflozin tablet
Eksperimentell: Part B: Treatment Group 1

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

placebo capsule (matching zibotentan capsule)

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

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

placebo capsule (matching zibotentan capsule)

dapagliflozin tablet
Eksperimentell: Part B: Treatment Group 3

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

zibotentan capsule

dapagliflozin tablet
Eksperimentell: Part B: Treatment Group 4

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

zibotentan capsule

dapagliflozin tablet
Eksperimentell: Part B: Treatment Group 5

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

zibotentan capsule

dapagliflozin tablet

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Absolute Change in HVPG From Baseline to Week 6, Part A
Tidsramme: 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
Tidsramme: From Baseline to Week 6

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

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
HVPG Percentage Change From Baseline to Week 6, Part A
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

AstraZeneca

Publikasjoner og nyttige lenker

Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.

Hjelpsomme linker

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Faktiske)

31. oktober 2022

Primær fullføring (Faktiske)

22. mai 2025

Studiet fullført (Faktiske)

17. juli 2025

Datoer for studieregistrering

Først innsendt

24. august 2022

Først innsendt som oppfylte QC-kriteriene

24. august 2022

Først lagt ut (Faktiske)

25. august 2022

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

25. september 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

31. august 2026

Sist bekreftet

1. august 2026

Mer informasjon

Begreper knyttet til denne studien

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

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

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

JA

IPD-planbeskrivelse

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-delingstidsramme

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.

Tilgangskriterier for IPD-deling

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

IPD-deling Støtteinformasjonstype

  • STUDY_PROTOCOL
  • SEVJE

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Ja

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

Denne informasjonen ble hentet direkte fra nettstedet clinicaltrials.gov uten noen endringer. Hvis du har noen forespørsler om å endre, fjerne eller oppdatere studiedetaljene dine, vennligst kontakt register@clinicaltrials.gov. Så snart en endring er implementert på clinicaltrials.gov, vil denne også bli oppdatert automatisk på nettstedet vårt. .

Abonnere