A Phase 2a, Randomised, Single-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics and Explore the Pharmacodynamic Effects of AZD2389 in Participants With Liver Fibrosis and Compensated Cirrhosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 40
- 试验地点
- 10
- 主要终点
- Reported quantity and severity of adverse events (AEs) following oral administration of AZD2389
研究概览
简要总结
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
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
This is a single-blind, randomized, placebo-controlled study with up to 2 study intervention cohorts that are participant and investigator-blinded.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- 未提供
研究组 & 干预措施
Cohort A
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.
干预措施: AZD2389 (Drug)
Cohort B
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.
干预措施: AZD2389 (Drug)
结局指标
主要结局
Reported quantity and severity of adverse events (AEs) following oral administration of AZD2389
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Reporting frequency and severity of AEs based on qualifying symptoms, signs, abnormalities in measured values, or other diagnoses as identified by investigator
Number of participants with observed changes in blood pressure against baseline mmHg value
时间窗: Up to and including Day 35 (from pre-screening to follow-up visit)
Assess blood pressure level (with systolic and diastolic pressure) in mmHg
Number of participants with observed changes in heart rate (BPM) against baseline value
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Pulse rate measured in beats per minute (BPM)
Number of participants with observed changes in Sp02 oxygen values against baseline measurement
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Sp02 oxygen saturations measured by percentage
Number of participants with observed changes in body temperature against baseline value
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Body temperature measured in degrees Celsius
Number of participants with observed changes in respiratory rate against baseline value
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Respiratory rate measured in respirations per minute
Number of participants with identified abnormalities in results of 12-lead safety electrocardiograms (ECG)
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
12-lead safety ECG (PR interval, QRS complex, ST interval, T wave)
Number of participants with changes in physical baseline values identified during physical examinations
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Physical examinations will include assessment of general appearance, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities) and neurological symptoms (examination of the participants' feet to observe skin integrity, circulation, and presence of any neuropathy).
Number of participants with abnormal laboratory test results detected in blood samples
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Hematology - Platelets (x10\^9/L) Clinical Chemistry - ALT (U/L), AST (U/L), ALP (U/L) Coagulation - INR Fibrinolysis - D-dimer (ng/mL fibrinogen-equivalent units)
Number of participants with abnormal laboratory results detected in urine samples
时间窗: Up to and including day 35 (from pre-screening to follow-up visit)
Urinalysis - Paper chromatography
Number of participants with visible changes (against baseline observations) to the condition of abdominal organs as identified by FibroScan imaging
时间窗: Up to and including Day 35 (from pre-screening to follow-up visit)
FibroScan (VCTE) ultrasound imaging will measure a participant's level of LSM (liver stiffness), CAP (amount of fat in the liver), and/or SSM (spleen stiffness).
Notable Trends in Laboratory Assessments (Haematology, Coagulation, Clinical Chemistry, Fibrinolysis, and Urinalysis)
时间窗: 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)
时间窗: 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.
次要结局
- To evaluate the effect of AZD2389 on plasma FAP activity following oral administration of AZD2389 in participants with CLD and hepatic fibrosis(From Day 1 to Day 35)
- Maximum Plasma Concentration (Cmax) detected in blood sample(From Day 1 to Day 35)
- Time to Maximum Concentration (Tmax) as detected in blood sample(From Day 1 to Day 35)
- Area Under the Concentration-time Curve to the Last Measurable Concentration (AUClasta) as detected in blood sample(From Day 1 to Day 35)
- Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) as detected in blood sample(From Day 1 to Day 35)
- Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) as detected in blood sample(From Day 1 to Day 35)
- Terminal Half-life (t1/2λz) as detected in blood sample(From Day 1 to Day 35)
- Apparent Volume of Distribution (Vz/F) as detected in blood sample(From Day 1 to Day 35)
- Apparent Clearance (CL/F) as detected in blood sample(From Day 1 to Day 35)
- Temporal Change Parameter (TCP) as detected in blood sample(From Day 1 to Day 35)
- Cmax Accumulation Ratio (Rac Cmax) as detected in blood sample(From Day 1 to Day 35)
- AUC Accumulation Ratio (Rac AUC) as detected in blood sample(From Day 1 to Day 35)
- Renal Clearance (CLR) as detected in blood sample(From Day 1 to Day 35)
- Amount of Drug Excreted in Urine (Ae) as detected in urine sample(From Day 1 to Day 35)
- Fraction of Drug Excreted in Urine (Fe) as detected in urine sample(From Day 1 to Day 35)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Cmax(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Tmax(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: t1/2 Lambda z(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: AUClast, AUCinf, and AUCtau(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Lambda z(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Vz/F(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: CL/F and CLR(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: TCP AUC(Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Rac AUC and Rac Cmax(Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Ae (0-24)(Day 1 and Day 28)
- Plasma and Urine Pharmacokinetic (PK) Parameters of AZD2389: Fe (0-24)(Day 1 and Day 28)
- Inhibition of FAP Activity Calculated as Percentage Change in FAP Activity Against Baseline Compared to Placebo.(Day 28)