Zibotentan and Dapagliflozin combination, Evaluated in Liver cirrhosis (ZEAL study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

7 Oct 2022 → 18 Jul 2025

Decision date (initial)

2023-08-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-505405-17-00

EudraCT number

2021-006577-30

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacodynamic, Pharmacokinetic

Part A main objective:
To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo.
Part B main objective:
To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo

Secondary objectives 12

1. Part A: To evaluate the change from baseline in HVPG of zibotentan and dapagliflozin in combination versus placebo
2. Part A: To evaluate the proportion of participants achieving HVPG < 10 mmHg or a reduction in HVPG of ≥ 1.5 mmHg of zibotentan and dapagliflozin in combination versus placebo
3. Part A: To evaluate the effect on change in body weight of zibotentan and dapagliflozin in combination versus placebo
4. Part A: To evaluate the effect on total loop-diuretic equivalents use
5. Part A: To evaluate the effect on body water volumes and body fat mass of zibotentan and dapagliflozin in combination versus placebo
6. Part A: To evaluate the effect on changes in office-based systolic and diastolic blood pressure of zibotentan and dapagliflozin in combination versus placebo
7. Part B: To evaluate the change from baseline in HVPG of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
8. Part B: To evaluate the effect on change in body weight of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
9. Part B: To evaluate the effect on total loop-diuretic equivalents use
10. Part B: To evaluate the effect on body water volumes and body fat mass of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
11. Part B: To evaluate the effect on changes in office-based systolic and diastolic blood pressure of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo
12. Part B : To evaluate proportion of participants achieving at least 20% decrease in HVPG or a reduction to or below 12 mmHg in HVPG

Conditions and MedDRA coding

Liver cirrhosis with features of portal hypertension.

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age 18 to ≤80 years
2. Part A participants who have the following: Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness ≥ 21 kPa.
3. Part A: MELD score < 15
4. Part A: Child-Pugh score ≤ 6.
5. Part A:No clinically evident ascites
6. Part A: No evidence of worsening of hepatic function (eg, no clinically significant change insigns, symptoms, or laboratory parameters of hepatic disease status)within the last month prior to dosing, as determined by the investigator or usual practitioner.
7. Part A: HVPG recording of good enough quality as judged by a central reader
8. Part B participants who have the following: Clinical and/or histological diagnosis of cirrhosis with features of portal hypertension.
9. Part B: MELD score < 15.
10. Part B: Child-Pugh score < 10.
11. Part B: 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.
12. Part B: 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.
13. Part B: HVPG recording of good enough quality and HVPG > 10 mmHg, as judged by a central reader

Exclusion criteria 29

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.
10. Part A (only): INR > 1.5.
11. Part A (only): Serum/plasma levels of albumin ≤ 35 g/L.
12. Part A (only): Platelet count < 75 × 109/L.
13. Part A (only): History of ascites
14. Part A (only): History of hepatic hydrothorax
15. Part A (only): History of portopulmonary syndrome
16. Part A (only): History of hepatic encephalopathy
17. Part A (only): History of variceal haemorrhage
18. Part A (only): History of acute kidney injury
19. Part A (only): History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget's disease)
20. Part B (only): INR > 1.7.
21. Part B (only): Serum/plasma levels of albumin ≤ 28 g/L
22. Part B (only): Platelet count < 50 × /109L.
23. Part B (only): Acute kidney injury within 3 months of screening.
24. Part B (only): History of encephalopathy of West Haven grade 2 or higher.
25. Part B (only): History of variceal haemorrhage within 6 months prior to screening.
26. Part B (only): 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.
27. Part B (only): 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).
28. Part B (only): High output heart failure (eg, due to hyperthyroidism or Paget's disease).
29. Part B (only): Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A Primary End Point: Absolute change in HVPG from baseline to Week 6.
2. Part B Primary End Point: Absolute change in HVPG from baseline to Week 6

Secondary endpoints 12

1. Part A: Percent change in HVPG from baseline to Week 6.
2. Part A: HVPG response, where a responder is defined as HVPG < 10 mmHg or a reduction in HVPG of ≥ 1.5 mmHg from baseline to Week 6.
3. Part A: Evaluation of change in body weight (kg) over time course of study (Home-based balance) Percentage and absolute change from baseline in body weight at Week 6. (Office balance)
4. Part A: Percentage and Absolute change in total change dosage of loopdiuretic equivalents use from baseline to Week 6.
5. Part A: Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6. Change in total body fat mass from baseline to Week 6.
6. Part A: Change in systolic and diastolic blood pressure from baseline to Week 6
7. Part B: Percentage and change in HVPG from baseline to Week 6.
8. Part B: Evaluation of change in body weight (kg) over time course of study. (Home-based balance) Percentage and absolute change from baseline in body weight at Week 6 and Week 16. (Office balance)
9. Part B: Absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16
10. Part B: Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6 and Week 16. Change in total body fat mass from baseline to Week 6 and Week 16
11. Part B: Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16.
12. Part B : To evaluate Part B: HVPG response, where a responder is defined as at least 20% decrease or a reduction to or below 12 mmHg in HVPG from baseline to Week 6.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Locations

9 EU/EEA countries · 30 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 143 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

21 submissions — initial application plus substantial / non-substantial modifications