| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Liver cirrhosis with features of portal hypertension. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Liver cirrhosis with features of increased pressure in portal veins. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024667 |
| E.1.2 | Term | Liver cirrhosis |
| E.1.2 | System Organ Class | 100000004871 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 proportion of participants achieving at least 20% decrease in HVPG or a reduction to or below 12 mmHg in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo. |
|
| E.2.2 | Secondary objectives of the trial |
Part A secondary objectives- to evaluate:
• the change from baseline in HVPG
• the proportion of participants achieving HVPG < 10 mmHg or a reduction in HVPG of ≥ 1.5 mmHg
• the effect on change in body weight
• the effect on accumulated additional loop-diuretic equivalents use
• the effect on body water volumes and body fat mass
• the effect on changes in office-based systolic and diastolic blood pressure
Of zibotentan and dapagliflozin in combination versus placebo
Part B secondary objectives- to evaluate:
• the change from baseline in HVPG
• the effect on change in body weight
• the effect on accumulated additional loop-diuretic equivalents use
• the effect on body water volumes and body fat mass
• the effect on changes in office-based systolic and diastolic blood pressure
Of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Study principal inclusion criteria:
Participant must be aged 18 years and ≤ 80 years of age at the time of signing the
informed consent.
Part A participants who have the following:
(a) Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal
hypertension or (ii) liver stiffness ≥ 21 kPa.
(b) MELD score < 15.
(c) Child-Pugh score ≤ 6.
(d) No clinically evident ascites
(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.
(f) HVPG recording of good enough quality as judged by a central reader.
Part B participants who have the following:
(a) Clinical and/or histological diagnosis of cirrhosis with features of portal
hypertension.
(b) MELD score < 15.
(c) Child-Pugh score < 10.
(d) 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.
(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.
(f) HVPG recording of good enough quality as judged by a central reader. |
|
| E.4 | Principal exclusion criteria |
Study principal exclusion criteria:
a) Any evidence of a clinically significant disease which in the investigator’s opinion makes it undesirable for the participant to participate in the study.
b) Liver cirrhosis caused by chronic cholestatic liver disease
c) ALT or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN
d) Acute liver injury caused by drug toxicity or by an infection.
e) Any history of hepatocellular carcinoma.
f) Liver transplant or expected liver transplantation within 6 months of screening.
g) History of TIPS or a planned TIPS within 6 months from enrolment into the study.
h) Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year.
i) Participants with T1DM.
Medical Conditions (Part A only)
a) INR > 1.5.
b) Serum/plasma levels of albumin ≤ 35 g/L.
c) Platelet count < 75 × 109/L.
d) History of ascites
e) History of hepatic hydrothorax
f) History of portopulmonary syndrome
g) History of hepatic encephalopathy
h) History of variceal haemorrhage
i) History of acute kidney injury
j) History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget’s disease)
Medical Conditions (Part B only)
a) INR > 1.7.
b) Serum/plasma levels of albumin ≤ 28 g/L.
c) Platelet count < 50 × /109L.
d) Acute kidney injury within 3 months of screening.
e) History of encephalopathy of West Haven grade 2 or higher.
f) History of variceal haemorrhage within 6 months prior to screening.
g) 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.
h) 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).
i) High output heart failure (eg, due to hyperthyroidism or Paget’s disease).
j) Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A Primary End Point:
Absolute change in HVPG from baseline to Week 6.
Part B Primary End Point:
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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A Primary End Point Week 6
Part B Primary End Point: Week 6 |
|
| E.5.2 | Secondary end point(s) |
Part A Secondary End Points:
1 Percent change in HVPG from baseline to Week 6.
2 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 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 Percentage and absolute change in accumulated dosage of loop-diuretic equivalents use from baseline to Week 6.
5 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 Change in systolic and diastolic blood pressure from baseline to Week 6.
Part B Secondary End Points:
1 Percentage and absolute change in HVPG from baseline to Week 6.
2 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)
3 Percentage and absolute change in accumulated dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16.
4 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
5 Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A Secondary End Points:
1 Week 6
2 Week 6
3 Week 6
4 Week 6
5 Week 6
6 Week 6
Part B Secondary End Points:
1 Week 6
2 Week 6 and Week 16
3 Week 6 and Week 16
4 Week 6 and Week 16
5 Week 6 and Week 16 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Austria |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Belgium |
| Denmark |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of Part A is defined as the date of the last visit of the last participant in the Part A study.
The end of Part B is defined as the date of the last visit of the last participant in the Part B study.
All results will be presented by treatment group and overall (where specified) for Part A and Part B separately, with descriptive statistics appropriate to the nature of the variables. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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