Hepatic Cirrhosis, Liver Fibrosis
Conditions
Keywords
Liver Fibrosis, Hepatic Cirrhosis
Brief summary
The purpose of this study is to measure the safety, tolerability, and the way the body absorbs, distributes, and metabolises AZD2389 as compared to placebo in participants with liver fibrosis and compensated cirrhosis. The study will also examine how the drug acts on the body
Detailed description
Study details include: The study duration will be up to 63 days (9 weeks). * 1 or 2 screening visits (up to 28 days before treatment) * 28 days of treatment including 5 clinic visits * Week 1: 24-hour in-clinic stay (Day 1) * Week 2: Outpatient clinic visit (Day 7) * Week 3: Outpatient clinic visit (Day 14) * Week 4: Telephone visit (Day 21) * Week 5: 24 to 48-hour in-clinic stay (Day 28) * Week 6: Follow-up visit (Day 35) Disclosure Statement: The study consists of two cohorts, each with a parallel-group design and two arms, with participants blinded to treatment allocation. Number of Participants: The study will randomise approximately 36 participants in total. Cohort A: Approximately 75 participants with presumed MASH/NASH with fibrosis will be screened such that approximately 18 participants will be randomised. Twelve participants will be randomised to receive AZD2389 and 6 participants will receive placebo. Cohort B: Approximately 75 participants with SLD with advanced fibrosis including compensated cirrhosis will be screened such that approximately 18 participants will be randomised. Twelve participants will be randomised to receive AZD2389 and 6 participants will receive placebo
Interventions
DRUGAZD2389
Doses of AZD2389 or placebo will be administered orally.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
This is a single-blind, randomized, placebo-controlled study with up to 2 study intervention cohorts that are participant and investigator-blinded.
Intervention model description
The total duration of study participation for each participant in Cohorts A and B will be approximately 63 days (9 weeks) and will include an up to 28-day screening period, a 28-day treatment period, and a follow-up visit seven days following completion of treatment. Assessments will be conducted as described in the SoA.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusions: * Males/females aged ≥ 18 years * Indications: Presumed MASH (cohort A) or other steatotic liver disease (cohort B) with fibrosis * No significant change in weight over the last 6 months * Barrier contraceptives use by males * Capable of informed consent * Judged to be suitable for study by investigator Key exclusions: * A condition that could put the participant at risk, influence the participant's ability to participate in the trial, interfere with evaluation of the study intervention or affect the interpretation of the results * Other causes of liver disease which are not the principal inclusion criteria for each cohort * Significant elevations in liver blood tests or platelets \<140 x10\^9/L * Decompensated liver disease, hepatobiliary cancer or listing for liver transplantation * Bleeding disorders or major bleeding risk * HIV infection or hepatitis B infection * Clinically significant cardiovascular (e.g. severe ischaemic heart disease, severe heart failure or cardiac dysrhythmia) or cerebrovascular disease within the past 3 months * Stage 2 hypertension * eGFR \<60ml/min/1.73m2 * Clinically significant gastrointestinal disease which can affect the interpretation of pharmacokinetic, safety, and tolerability data * Skin disorders or ongoing wound healing * Psychiatric disorders which may negatively affect participation in the trial. * Females of childbearing potential
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Notable Trends in Laboratory Assessments (Haematology, Coagulation, Clinical Chemistry, Fibrinolysis, and Urinalysis) | From screening up to and including Day 35 | The number of participants with notable trends in laboratory assessments (haematology, coagulation, clinical chemistry, fibrinolysis, and urinalysis) is presented. Notable trends were assessed based on evaluation of mean values over time, individual participant values, and clinically important abnormalities, including values outside predefined criteria. |
| Clinically Relevant Trends in Vital Signs (Blood Pressure, Pulse Rate, Oxygen Saturation, Body Temperature, and Respiration Rate), and 12-lead Electrocardiogram (ECG) | From Screening up to and including Day 35 | The number of participants with clinically relevant trends in vital signs (blood pressure, pulse rate, oxygen saturation, body temperature, and respiration rate), and12-lead ECGs is presented. Clinically relevant trends were assessed based on trends or group changes over time, changes in individual participants over time, and individual clinically important abnormalities. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Cmax | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. Cmax= Maximum Concentration |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Tmax | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. tmax = Time to Maximum Concentration |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: t1/2 Lambda z | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. t1/2 lambda z= Apparent Terminal Half-life |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: AUClast, AUCinf, and AUCtau | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. AUClast= Area Under the Concentration-time Curve to the Last Measurable Concentration AUCinf = Area Under the Concentration-time Curve Extrapolated to Infinity AUCtau = Area Under the Concentration-time Curve Over a Dosing Interval AUCtau presented as AUC(0-24h) in the table. In line with standard PK analysis methodologies, AUCinf was estimated only for Day 1. AUClast and AUCtau were estimated for both Day 1 and Day 28. |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Lambda z | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. lambda z = Terminal elimination rate constant |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Vz/F | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. Vz/F = Apparent Volume of Distribution |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: CL/F and CLR | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. CL/F = Apparent Clearance CLR = Renal Clearance |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: TCP AUC | Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. TCP is calculated as the ratio of steady-state AUCtau (AUC0-24h) to first-dose AUCinf TCP = Temporal Change Parameter AUC = Area Under the Concentration-time Curve |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Rac AUC and Rac Cmax | Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. Rac AUC = AUC Accumulation Ratio; ratio of steady state AUCtau (AUC0-24h)/First Dose AUCtau (AUC0-24h) Rac Cmax = Cmax Accumulation Ratio; ratio of steady state Cmax/First Dose Cmax |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Ae (0-24) | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. Ae (0-24) = Cumulative Amount of Drug Excreted Unchanged in Urine |
| Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Fe (0-24) | Day 1 and Day 28 | The PK of AZD2389 were evaluated following oral dosing in Cohort A and Cohort B and presented in table. Fe = Fraction of Dose Excreted Unchanged into Urine |
| Inhibition of FAP Activity Calculated as Percentage Change in FAP Activity Against Baseline Compared to Placebo. | Day 28 | Effect of AZD2389 on plasma FAP activity following oral administration of AZD2389 in participants with chronic Liver Disease and hepatic fibrosis was evaluated and presented as percentage change from baseline in FAP activity. Percentage change when comparing post-treatment visits to baseline for each group, calculated as (Geometric LS mean - 1) \*100. FAP=Fibroblast Activating Protein |
Countries
Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
A total of 95 participants were screened for the study at 9 centres (1 in the UK and 8 in the US).
Pre-assignment details
Of the 95 participants, 40 were eligible for the study: 22 with presumed MASH/NASH with fibrosis (Cohort A) and 18 with underlying SLDs of varying aetiologies (Cohort B).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 10.2 |
| Age, Customized 18 - < 65 | 30 Participants |
| Age, Customized >= 65 | 10 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 34 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized White | 8 Participants |
| Region of Enrollment USA | 8 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 8 | 0 / 12 | 0 / 6 |
| other Total, other adverse events | 6 / 14 | 3 / 8 | 1 / 12 | 1 / 6 |
| serious Total, serious adverse events | 0 / 14 | 0 / 8 | 0 / 12 | 0 / 6 |
Outcome results
None listed