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Комбинация зиботентана и дапаглифлозина, оцененная при циррозе печени (исследование ZEAL) (ZEAL)

31 августа 2026 г. обновлено: AstraZeneca

Многоцентровое, рандомизированное, двойное слепое, плацебо-контролируемое, параллельное групповое исследование, состоящее из двух частей, для оценки эффективности, безопасности и переносимости комбинации зиботентана и дапаглифлозина и монотерапии дапаглифлозином по сравнению с плацебо у участников с циррозом печени. С признаками портальной гипертензии

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.

Обзор исследования

Статус

Прекращено

Условия

Вмешательство/лечение

Подробное описание

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.

Тип исследования

Интервенционный

Регистрация (Действительный)

205

Фаза

  • Фаза 2

Контакты и местонахождение

В этом разделе приведены контактные данные лиц, проводящих исследование, и информация о том, где проводится это исследование.

Места учебы

  • Австралия
      • Heidelberg, Австралия, 3084
        • Research Site
  • Австрия
      • Vienna, Австрия, 1090
        • Research Site
  • Бельгия
      • Edegem, Бельгия, 2650
        • Research Site
  • Германия
      • Dresden, Германия, 01307
        • Research Site
      • Landshut, Германия, 84034
        • Research Site
      • Mainz, Германия, 55131
        • Research Site
      • Münster, Германия, 48149
        • Research Site
      • Wiesbaden, Германия, 65189
        • Research Site
  • Дания
      • Aarhus N, Дания, 8200
        • Research Site
      • Esbjerg, Дания, 6700
        • Research Site
      • Hvidovre, Дания, 2650
        • Research Site
      • Køge, Дания, 4600
        • Research Site
  • Испания
      • Barcelona, Испания, 08035
        • Research Site
      • Barcelona, Испания, 08036
        • Research Site
      • Barcelona, Испания, 08041
        • Research Site
      • Madrid, Испания, 28034
        • Research Site
      • Madrid, Испания, 28007
        • Research Site
      • Majadahonda, Испания, 28222
        • Research Site
      • Santander, Испания, 39008
        • Research Site
  • Китай
      • Beijing, Китай, 100057
        • Research Site
      • Chengdu, Китай, 610000
        • Research Site
      • Guangzhou, Китай, 510515
        • Research Site
      • Hangzhou, Китай, 310015
        • Research Site
  • Нидерланды
      • Amsterdam, Нидерланды, 1081 HV
        • Research Site
  • Румыния
      • Cluj-Napoca, Румыния, 400162
        • Research Site
  • Соединенное Королевство
      • Birmingham, Соединенное Королевство, B9 5SS
        • Research Site
      • Cambridge, Соединенное Королевство, CB2 0XY
        • Research Site
      • London, Соединенное Королевство, SE5 9RS
        • Research Site
  • Соединенные Штаты
    • Alabama
      • Birmingham, Alabama, Соединенные Штаты, 35233
        • Research Site
    • California
      • Pasadena, California, Соединенные Штаты, 91105
        • Research Site
      • San Francisco, California, Соединенные Штаты, 94115
        • Research Site
      • West Hollywood, California, Соединенные Штаты, 90048
        • Research Site
    • Minnesota
      • Rochester, Minnesota, Соединенные Штаты, 55905
        • Research Site
    • New York
      • The Bronx, New York, Соединенные Штаты, 10467
        • Research Site
    • South Carolina
      • Charleston, South Carolina, Соединенные Штаты, 29425
        • Research Site
    • Texas
      • Dallas, Texas, Соединенные Штаты, 75246
        • Research Site
    • Virginia
      • Charlottesville, Virginia, Соединенные Штаты, 22903
        • Research Site
      • Richmond, Virginia, Соединенные Штаты, 23249
        • Research Site
    • Wisconsin
      • Milwaukee, Wisconsin, Соединенные Штаты, 53226
        • Research Site
  • Тайвань
      • Taipei, Тайвань, 10002
        • Research Site
      • Taipei, Тайвань, 112
        • Research Site
  • Франция
      • Angers, Франция, 49933
        • Research Site
      • Clichy, Франция, 92110
        • Research Site
      • Paris, Франция, 75651
        • Research Site
      • Toulouse, Франция, 31059
        • Research Site
  • Чехия
      • Prague, Чехия, 128 00
        • Research Site
      • Prague, Чехия, 169 02
        • Research Site
  • Швейцария
      • Bern, Швейцария, 3010
        • Research Site
      • Lucerne, Швейцария, 6000
        • Research Site
      • Lugano, Швейцария, 6900
        • Research Site

Критерии участия

Исследователи ищут людей, которые соответствуют определенному описанию, называемому критериям приемлемости. Некоторыми примерами этих критериев являются общее состояние здоровья человека или предшествующее лечение.

Критерии приемлемости

Возраст, подходящий для обучения

От 18 лет до 80 лет (Взрослый, Пожилой взрослый)

Принимает здоровых добровольцев

Нет

Полы, имеющие право на обучение

Все

Описание

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.

Учебный план

В этом разделе представлена ​​подробная информация о плане исследования, в том числе о том, как планируется исследование и что оно измеряет.

Как устроено исследование?

Детали дизайна

  • Основная цель: Скрининг
  • Распределение: Рандомизированный
  • Интервенционная модель: Параллельное назначение
  • Маскировка: Тройной

Оружие и интервенции

Группа участников / Армия
Вмешательство/лечение
Экспериментальный: Part A: Treatment Group 1

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

placebo capsule (matching zibotentan capsule)

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

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

zibotentan capsule

dapagliflozin tablet
Экспериментальный: Part B: Treatment Group 1

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

placebo capsule (matching zibotentan capsule)

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

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

placebo capsule (matching zibotentan capsule)

dapagliflozin tablet
Экспериментальный: Part B: Treatment Group 3

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

zibotentan capsule

dapagliflozin tablet
Экспериментальный: Part B: Treatment Group 4

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

zibotentan capsule

dapagliflozin tablet
Экспериментальный: Part B: Treatment Group 5

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

zibotentan capsule

dapagliflozin tablet

Что измеряет исследование?

Первичные показатели результатов

Мера результата
Мера Описание
Временное ограничение
Absolute Change in HVPG From Baseline to Week 6, Part A
Временное ограничение: 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
Временное ограничение: From Baseline to Week 6

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

Вторичные показатели результатов

Мера результата
Мера Описание
Временное ограничение
HVPG Percentage Change From Baseline to Week 6, Part A
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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

Соавторы и исследователи

Здесь вы найдете людей и организации, участвующие в этом исследовании.

Спонсор

AstraZeneca

Публикации и полезные ссылки

Лицо, ответственное за внесение сведений об исследовании, добровольно предоставляет эти публикации. Это может быть что угодно, связанное с исследованием.

Полезные ссылки

Даты записи исследования

Эти даты отслеживают ход отправки отчетов об исследованиях и сводных результатов на сайт ClinicalTrials.gov. Записи исследований и сообщаемые результаты проверяются Национальной медицинской библиотекой (NLM), чтобы убедиться, что они соответствуют определенным стандартам контроля качества, прежде чем публиковать их на общедоступном веб-сайте.

Изучение основных дат

Начало исследования (Действительный)

31 октября 2022 г.

Первичное завершение (Действительный)

22 мая 2025 г.

Завершение исследования (Действительный)

17 июля 2025 г.

Даты регистрации исследования

Первый отправленный

24 августа 2022 г.

Впервые представлено, что соответствует критериям контроля качества

24 августа 2022 г.

Первый опубликованный (Действительный)

25 августа 2022 г.

Обновления учебных записей

Последнее опубликованное обновление (Действительный)

25 сентября 2026 г.

Последнее отправленное обновление, отвечающее критериям контроля качества

31 августа 2026 г.

Последняя проверка

1 августа 2026 г.

Дополнительная информация

Термины, связанные с этим исследованием

Дополнительные соответствующие термины MeSH

Другие идентификационные номера исследования

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

Планирование данных отдельных участников (IPD)

Планируете делиться данными об отдельных участниках (IPD)?

ДА

Описание плана 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

Сроки обмена 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.

Критерии совместного доступа к 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

Совместное использование IPD Поддерживающий тип информации

  • STUDY_PROTOCOL
  • САП

Информация о лекарствах и устройствах, исследовательские документы

Изучает лекарственный продукт, регулируемый FDA США.

Да

Изучает продукт устройства, регулируемый Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США.

Нет

Эта информация была получена непосредственно с веб-сайта clinicaltrials.gov без каких-либо изменений. Если у вас есть запросы на изменение, удаление или обновление сведений об исследовании, обращайтесь по адресу register@clinicaltrials.gov. Как только изменение будет реализовано на clinicaltrials.gov, оно будет автоматически обновлено и на нашем веб-сайте. .

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