A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants with Cirrhosis-ZEAL-UNLOCK

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

19 Apr 2024 → 12 Dec 2024

Decision date (initial)

2024-04-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

• To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on a composite endpoint of fluid retention.
• To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on a composite endpoint of fluid retention.
• To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body weight, body water volumes and body fat mass.
• To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body weight, body water volumes and body fat mass.
• To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on total loop-diuretic equivalents use.
• To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on total loop-diuretic equivalents use.
• To evaluate the effects of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on the composite of total body water and total dosage of loop-diuretic equivalents
• To evaluate the effects of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on the composite of total body water and total dosage of loop-diuretic equivalents
• To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on office-based systolic and diastolic blood pressure.
• To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on office-based systolic and diastolic blood pressure

Secondary objectives 1

1. To assess the safety and tolerability of zibotentan/dapagliflozin and zibotentan versus placebo.

Conditions and MedDRA coding

Cirrhosis of the liver is a condition in which the liver is scarred and damaged

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

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 14

1. Age: Participant must be aged ≥ 18 years and ≤ 80 years of age at the time of signing the informed consent.
2. Participants who have the following: a) Clinical and/or histological diagnosis of cirrhosis. Note: Either history of decompensation or compensated cirrhosis with signs of CSPH, including varices at endoscopy or collaterals at imaging (within 12 months prior to screening), and/or liver stiffness using vibration controlled elastography, liver stiffness > 25 kPa or > 21 kPa, and platelets < 150 × 109 (at time of screening).
3. Participants who have the following: b) Model for end stage liver disease score (MELD) < 15.
4. Participants who have the following: c) Child-Pugh score < 10.
5. Participants who have the following: d) No ascites or ascites up to grade 2 without change in diuretic treatment within the last month prior to first dose of study intervention and no paracentesis within the last month.
6. Participants who have the following: e) 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.
7. Medical Treatment: No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or endothelin receptor antagonist.
8. Medical Treatment: 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.
9. Sex and Contraceptive/Barrier Requirements: Males or females of non-childbearing potential.  Male participants must be surgically sterile, abstinent, or must use in conjunction with their female partner a highly effective method of contraception from the time they sign the informed consent document and for 3 months after the last dose of study intervention to prevent pregnancy in a partner. In addition, the male participant should use a condom for the duration of the study and for 3 months after the last dose of study intervention. Male participants must not donate or bank sperm during the same period See sections 5.3.5 and 8.4.9.2.
10. Sex and Contraceptive/Barrier Requirements: Males or females of non-childbearing potential.  Female participants must be of non-childbearing potential confirmed at screening by fulfilling one of the following criteria: o 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 (Note: The post-menopausal range must be checked against the specific FSH assay used). In the absence of 12 months of amenorrhoea, a single FSH measurement is insufficient to define post menopausal criteria. In case of perimenopause or infrequent periods with variable levels of FSH, women should be considered of childbearing potential and, therefore, not eligible for participation in this study. o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
11. Sex and Contraceptive/Barrier Requirements: Female participants must have a negative pregnancy test at screening and must not be lactating.
12. Informed Consent: Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
13. Informed Consent: Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
14. Informed Consent: Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports Genomic Initiative.

Exclusion criteria 38

1. Medical Condition: 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. Medical Condition: Alanine aminotransferase/transaminase or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN.
3. Medical Condition: International normalised ratio > 1.7.
4. Medical Condition: Serum/plasma levels of albumin ≤ 28 g/L.
5. Medical Condition: Platelet count < 50 × 109L.
6. Medical Condition: Acute kidney injury (AKI) within 3 months of screening.
7. Medical Condition: History of encephalopathy of West Haven Grade 2 or higher.
8. Medical Condition: History of variceal haemorrhage within 6 months prior to screening.
9. Medical Condition: Any history of hepatocellular carcinoma.
10. Medical Condition: Any history of portal venous thrombosis.
11. Medical Condition: Liver transplant or expected liver transplantation within 6 months of screening.
12. Medical Condition: History of TIPS or a planned TIPS within 6 months from enrolment into the study.
13. Medical Condition: Positive alcohol breath test or screen for drugs of abuse (excluding drugs prescribed by the participants’ usual physician) at screening.
14. Medical Condition: Ongoing or history of significant use of alcohol expected to preclude correct adherence to study procedures (For details, refer to Section 5.3.2).
15. Medical Condition: Active treatment for HCV within the last 1 year or HBV anti-viral therapy for less than 1 year.
16. Medical Condition: Active urinary tract infection or genital infection.
17. Medical Condition: Uncontrolled diabetes mellitus (HbA1c > 8.5% or > 69 mmol/mol within the last month).
18. Medical Condition: Participants with T1DM.
19. Medical Condition: Renal transplant or chronic renal replacement therapy or short-term dialysis within the previous 6 months.
20. Medical Condition: eGFR < 60 mL/min/1.73m2 (eGFRcr[AS]).
21. Medical Condition: Acute coronary syndrome events within 3 months prior to screening.
22. Medical Condition: Orthostatic hypotension or hypotension (systolic blood pressure < 95 mmHg or diastolic blood pressure < 60 mmHg).
23. Medical Condition: New York Heart Association functional heart failure Class III or IV or patients 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.
24. Medical Condition: Heart failure due to cardiomyopathies that would primarily require specific other treatment.
25. Medical Condition: High output heart failure (eg, due to hyperthyroidism or Paget’s disease).
26. Medical Condition: Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
27. Medical Condition: Participants treated with strong CYP3A4 inhibitor or strong or moderate CYP3A4 inducer within 14 days (St. John’s Wort: 21 days) of study intervention administration; this includes grapefruit and grapefruit juice, if consumed more often than occasionally, or, in larger quantities.
28. Medical Condition: History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin), zibotentan, or drugs with a similar chemical structure to zibotentan.
29. Medical Condition: Any clinically significant chronic disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) which, as judged by the investigator, might put the participant at risk because of participation in the study, or probable alternative primary reason for participant’s symptoms in judgment of investigator.
30. Medical Condition: Acute liver injury caused by drug toxicity or by an infection.
31. Prior/Concurrent Clinical Study Experience: Participation in another clinical study with a study intervention administered in the last 3 months prior to randomisation.
32. Other Exclusions: Implanted electronic device such as pacemaker.
33. Other Exclusions: Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study centre).
34. Other Exclusions: Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
35. Other Exclusions: Male participant in a sexually active relation with pregnant or breastfeeding partner.
36. Other Exclusions: Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
37. Exclusion Criteria for Participants Consenting to Optional Genetic Sampling. The following participants are not eligible to consent to the optional genetic sampling: Previous allogeneic bone marrow transplant.
38. Exclusion Criteria for Participants Consenting to Optional Genetic Sampling. The following participants are not eligible to consent to the optional genetic sampling: Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 14

1. Occurrence of any of the following components of this composite endpoint from baseline to Week 6: > 2 kg increase in body weight (office-based)
2. Occurrence of any of the following components of this composite endpoint from baseline to Week 6: > 2 L increase in total body water
3. Occurrence of any of the following components of this composite endpoint from baseline to Week 6: Increase in 2 or more loop-diuretic equivalents
4. Occurrence of any of the following components of this composite endpoint from baseline to Week 6:Fluid retention adverse event (AE)
5. Occurrence of any of the following components of this composite endpoint from baseline to Week 6: > 2 kg increase in body weight (office-based)
6. Occurrence of any of the following components of this composite endpoint from baseline to Week 6: > 2 L increase in total body water
7. Occurrence of any of the following components of this composite endpoint from baseline to Week 6: Increase in 2 or more loop-diuretic equivalents
8. Occurrence of any of the following components of this composite endpoint from baseline to Week 6:Fluid retention adverse event (AE)
9. Change in body weight (kg) over time course of study (home-based monitoring).
10. Change from baseline in body weight, total body water, extracellular and intracellular water volumes, and body fat mass at Week 6 (office-based monitoring).
11. Change in total dosage of loop-diuretic equivalents use from baseline to Week 6.
12. Occurrence of either of the two components of this composite: > 3 L increase in total body water volume from baseline to Week 6.
13. Occurrence of either of the two components of this composite: Increase in 3 or more loop-diuretic equivalents use from baseline to Week 6.
14. Absolute change in systolic and diastolic blood pressure from baseline to Week 6.

Secondary endpoints 5

1. AEs, SAEs, and DAEs
2. AESIs (new or worsening HF; other signs of fluid retention; orthostatic hypotension; UTI; GI; AKI)
3. Vital signs
4. Safety laboratory tests
5. ECG assessments

Investigational products

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

Test 2

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 Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

6 EU/EEA countries · 22 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 91 files

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

Application history

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