This study has been transitioned to CTIS with ID 2023-505405-17-00 check the CTIS register for the current data. The main objective of this Phase IIa/b study is to demonstrate the effectof zibotentan on HVPG, and that dapagliflozin can mitigate…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PART A:
Obj: To evaluate the change from baseline in HVPG on zibotentan and
dapagliflozin in combination versus placebo.
endpoint: Absolute change in HVPG from baseline to Week 6.
PART B:
Obj: To evaluate the proportion of participants achieving at least 20% decrease
in HVPG or a reduction to or below 12mmHg in HVPG on zibotentan and
dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
endpoint: HVPG response, where a responder is defined as at least 20% decrease
or a reduction to or below 12 mmHgin HVPG from baseline to Week6.
Secondary outcome
PART A:
obj: To evaluate the change from baseline in HVPG on zibotentan and
dapagliflozin in combination versus placebo.
endpoint: Percent change in HVPG from baseline to Week6.
obj: To evaluate the proportion of participants achieving HVPG < 10 mmHg or a
reduction in HVPG of >= 1.5 mmHg on zibotentan and dapagliflozin versus placebo.
endpoint: 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.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination
versus placebo on change in body weight.
endpoint:
•Evaluation of change in body weight (kg) overtime course of studya.
•Percentage and absolute change from baseline inbody weight at Week6.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination
versus placebo on accumulated additional loop-diuretic equivalents use.
endpoint: Percentage and absolute change in accumulated dosage of loop-diuretic
equivalentscuse from baseline to Week 6.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination
versus placeboon body water volumes and body fat mass.
endpoint:
•Change in total body water, extracellular water,and intracellular water
volumes from baseline toWeek6.
•Change in total body fat mass from baseline toWeek6.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination
versus placebo on changes in office-based systolic and diastolic blood pressure.
endpoint: Change in systolic and diastolic blood pressure from baseline to
Week6.
PART B:
obj: To evaluate the change from baseline in HVPG on zibotentan and
dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
endpoint: Percentage and absolute change in HVPG from baseline to Week6.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination and
dapagliflozin monotherapy versus placebo on change in body weight.
endpoint: •Evaluation of change in body weight (kg) overtime course of
studya.•Percentage and absolute change from baseline inbody weight at Week6 and
Week16b.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination and
dapagliflozin monotherapy versus placebo on accumulated additional
loop-diuretic equivalents use.
endpointL Percentage and absolute change in accumulated dosage of loop-diuretic
equivalentscuse from baseline to Week6 and Week16.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination and
dapagliflozin monotherapy versus placebo on body water volumes and body fat
mass.
endpoint: •Change in total body water, extracellular waterand intracellular
water volumes from baseline toWeek6 and Week16.•Change in total body fat mass
from baseline toWeek6 and Week16.
obj: To evaluate the effect of zibotentan and dapagliflozin in combination and
dapagliflozin monotherapy versus placebo on changes in office-based systolic
and diastolic blood pressure.
endpoint: Change in systolic and diastolic blood pressure from baseline to
Week6 and Week16.
Background summary
Patients with cirrhosis with features of portal hypertension have limited
treatment options and
significant risk of decompensation and death with limited pharmacological
treatment options.
2.2.1 Cirrhosis with Features of Portal Hypertension
Cirrhosis is the end-stage result of chronic liver injury/disease and is
characterised by
advanced fibrosis and, ultimately, hepatic failure. Cirrhosis may be
compensated in which no
clinical complications that affect outcome (i.e., variceal haemorrhage,
ascites, hepatic
encephalopathy, hepatocellular cancer) have occurred, or decompensated, in
which patients
have had at least one clinical complication. In decompensated patients, the
liver is unable to
perform vital metabolic, synthetic and storage functions (Tsochatzis et al,
2014). The
aetiology of cirrhosis varies with viral hepatitis (hepatitis B and C),
alcoholic liver disease,
and non-alcoholic steatohepatitis (NASH) being the leading causes of cirrhosis
globally, with
less common causes including autoimmune hepatitis, primary sclerosing
cholangitis, primary
biliary cholangitis, haemochromatosis, and Wilson*s disease (Romanelli et al,
2016). Cirrhosis
is a serious condition which leads to significant morbidity, resource intensive
complications,
hepatocellular carcinoma, and, in the absence of liver transplantation, death.
The Global
Burden of Disease study in 2017 reported over 1.32 million cirrhosis-related
deaths globally,
which was approximately 2.4% of all deaths worldwide
(GBD 2017 Cirrhosis Collaborators, 2020).
Portal hypertension is a major complication of chronic liver disease. The
primary cause of
portal hypertension in cirrhosis is an increase in intrahepatic vascular
resistance due to
structural changes associated with fibrosis and increased vascular tone in the
hepatic
microcirculation (Iwakiri, 2014). As portal hypertension develops, the
formation of collateral
vessels and arterial vasodilation progress, which results in increased blood
flow to the portal
circulation (Iwakiri, 2014). Eventually, a hyperdynamic circulatory syndrome
develops,
leading to oesophageal varices and/or ascites (Poordad, 2015).
2.2.2 Current Treatment Options for Patients with Cirrhosis with Features of
Portal Hypertension
Standard treatment for patients with chronic liver disease centres upon
treatment of the
underlying cause of liver disease, e.g., abstinence from alcohol, anti-viral
agents for viral
hepatitis, and treatment of underlying metabolic disease in NASH. Although HCV
can now be
eradicated, given the continued emergence of fatty liver diseases, disease
modifying therapies
are in general expected to have marginal impact on the outcome in patients with
cirrhosis with
portal hypertension (Gunarathne et al, 2020). Accordingly, there is an enormous
unmet need
for new treatments in patients with cirrhosis with features of portal
hypertension. Current
guidelines support the use of non-selective beta blockers, diuretics and
vasoactive drugs
(Gunarathne et al, 2020). In patients developing variceal haemorrhage,
intervention with TIPS
may be used to reduce portal hypertension (García-Pagán et al, 2020).
Study objective
This study has been transitioned to CTIS with ID 2023-505405-17-00 check the CTIS register for the current data.
The main objective of this Phase IIa/b study is to demonstrate the effect
of zibotentan on HVPG, and that dapagliflozin can mitigate fluid retention
safety concerns
regarding its use in this population.
Study design
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.
Part A will assess the efficacy, safety, and tolerabilityof the combination of
2.5 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 1, 2.5, or 5 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 study centres in North America
and Europe.
Part A will include the following periods:
*Screening Period: up to 6weeks; to confirm participant eligibility and collect
baselinedata (Visits 1 and 2). Before randomisation, baseline HVPG recording
(Visit 2) must beof good enough quality as judged by central reader of HVPG, to
randomise theparticipant.
*Treatment Period: 6 weeks; at Visit 3 (Day1), participants will be randomised
and willtake the first dose of the study intervention. At each study visit
during the treatmentperiod (except at days of HVPG assessment and
VCTE/Fibroscan assessment),participants will take the once daily dose at the
study centre.
*Follow-up Period: 2 weeks; participants will return to the study centre for
follow-upassessments approximately 2 weeks after their last dose of study
intervention.
Disclosure Statement: This is a parallel group, 2-arm study that is blinded to
the participants, investigators, and sponsor.
Part B will include the following periods:
*Screening Period: up to 6weeks; to confirm participant eligibility and collect
baselinedata (Visits 1 and 2). Before randomisation, baseline HVPG recording
(Visit2) must be of good enough quality as judged by central reader of HVPG, to
randomise the participant.
*Treatment Period: 16 weeks; at Visit 3 (Day1), participants will be randomised
and willtake the first dose of the study intervention. At each study visit
during the treatmentperiod (except at days of HVPG assessment and
VCTE/Fibroscan assessment, if visitprocedures are separated on different days),
participants will take the once daily dose atthe study centre.
*Follow-up Period: 2 weeks; participants will return to the study centre for
follow-upassessments approximately 2 weeks after their last dose of study
intervention.
Disclosure Statement: This is a parallel group, 5-arm study that is blinded to
the participants, investigators, and sponsor.
Intervention
Part A: Participants who meet the eligibility criteria and agree to participate
will be randomised to one of the following 2 treatment groups (15participants
per group).
*Treatment Group 1: placebo matching zibotentan capsule + placebo
matchingdapagliflozin tablet.
*Treatment Group 2: zibotentan capsule 2.5 mg + dapagliflozin tablet 10mg
The study intervention will be a once daily dose of the assigned study
intervention (oralcapsules and tablets) for 6weeks, in addition to their
standard of care therapy. Total study duration for participants in Part A will
be approximately 14weeks (including the screening and follow- up period).
Part B: Participants who meet the eligibility criteria and agree to participate
will be randomised to one of the following 5treatment groups (22participants
per group).
*Treatment Group 1: placebo matching zibotentan capsule + placebo
matchingdapagliflozin tablet.
*Treatment Group 2: placebo matching zibotentan capsule + dapagliflozin tablet
10 mg.
*Treatment Group 3: zibotentan capsule 1 mg + dapagliflozin tablet 10mg.
*Treatment Group 4: zibotentan capsule 2.5 mg + dapagliflozin tablet 10mg.
*Treatment Group 5: zibotentan capsule 5 mg + dapagliflozin tablet 10 mg.
Study burden and risks
Dapagliflozin administration is generally safe and well tolerated. The
potential and identified
risks of dapagliflozin treatment have been well characterised through the
dapagliflozin clinical
development program and from post marketing data. In clinical studies, commonly
reported AEs include UTIs, genital infections, polyuria, and hypoglycaemia when
combined with insulin or a sulfonylurea. In addition, diabetic ketoacidosis was
commonly seen in T1DM
patients treated with dapagliflozin but was rare in clinical trials with T2DM
patients.
The adverse clinical effects of zibotentan observed in healthy volunteers and
oncology
populations were largely due to its pharmacologically-mediated effects on ET
receptor
antagonism resulting in vasodilation: headache, hypotension, nasal congestion,
peripheral
oedema, conjunctival reddening, dizziness, flushing, minor decreases in
systemic vascular
resistance, minor increases in cardiac output, and effects due to haemodilution
which leads to
a reduction in the concentration of the cellular elements of blood: reduction
in Hb, anaemia.
Reduction in Hb tends to develop within a month of commencing the drug and in
most
patients is mild (CTC Grade 1/2), non-progressive and tends to reverse on
stopping drug.
However, some patients in oncology studies have developed clinical anaemia. The
adverse
clinical effect of heart failure has been observed, being more commonly
reported in
Castration-resistant Prostate Cancer (CRPC) patients receiving zibotentan than
in those
receiving placebo. The frequency of reports in patients receiving zibotentan
has been less than
10% and most cases have responded to standard heart failure treatment.
More detailed information about the known and expected benefits and potential
risks of
zibotentan and dapagliflozin may be found in the respective Investigator*s
Brochures
(Zibotentan Investigator*s Brochure and Dapagliflozin Investigator*s Brochure).
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
Participant must be aged 18 years and <= 80 years of age at the time of signing
theinformed consent.
Part A participants who have the following:
(a) Clinical and/or histological diagnosis of cirrhosis with either (i)
features of portalhypertension 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 insigns, symptoms, or laboratory parameters of hepatic disease status)
within the lastmonth 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
portalhypertension.
(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 lastmonth prior to first dose and no paracentesis within the last
month or plannedparacentesis in the next 4 months at screening.
(e) No evidence of worsening of hepatic function (eg, no clinically significant
change insigns, symptoms, or laboratory parameters of hepatic disease status)
within the lastmonth prior to dosing, as determined by the investigator or
usual practitioner.
(f) HVPG recording of good enough quality as judged by a central reader.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-505405-17-00 |
| EudraCT | EUCTR2021-006577-30-NL |
| ClinicalTrials.gov | NCT05516498 |
| CCMO | NL82798.056.22 |