An Open-label Study to Investigate the Pharmacokinetics, Safety, and Tolerability of Odalasvir and AL-335 Alone and in Combination With Simeprevir in Subjects With Moderately Impaired Hepatic Function
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of AL-335 and its Metabolites ALS-022399 and ALS-022227
研究概览
简要总结
The purpose of this study is to evaluate the pharmacokinetics (PK) of AL-335, odalasvir (ODV) and its metabolites ALS-022399 and ALS-022227, after a single oral dose of ODV and AL-335 respectively, in participants with moderately impaired hepatic function compared to participants with normal hepatic function. Also to evaluate the steady-state PK of AL-335 and its metabolites ALS-022399 and ALS-022227, ODV and simeprevir (SMV) after multiple oral doses of the combination of AL-335+ODV+SMV, in participants with moderately impaired hepatic function compared to participants with normal hepatic function.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participant must have a body mass index (BMI; weight in kilogram (kg) divided by the square of height in meters) of 18.0 to 35.0 kilogram per meter square (kg/m^2) extremes included, and a body weight not less than 50.0 kg
- •Participant must have a normal 12-lead electrocardiogram (ECG) (based on the mean value of triplicate ECG parameters) consistent with normal cardiac conduction and function at screening, as defined in the protocol
- •Absence of findings indicative of hepatocellular carcinoma in an ultrasonography determined within 90 days prior to screening (or between screening and Day -1 of Part 1 of the study)
- •Contraceptive use by women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies; a female participant with non childbearing potential must be; a) postmenopausal, or b) surgically sterile. Participant of childbearing potential must; a) have a negative highly sensitive serum (beta human chorionic gonadotropin [beta hCG]) pregnancy test at screening and a negative urine beta hCG pregnancy test at baseline (Day -1), and b) not get pregnant from screening until at least 60 days after the end of treatment by adhering to one of the acceptable methods of birth control to avoid pregnancy
- •Contraceptive use by men should be consistent with local regulations regarding the use of contraceptive methods for participant participating in clinical studies: A male participant: a) must either be surgically sterile, or b) must not be heterosexually active from baseline until at least 60 days after the end of treatment or c) must be practicing an acceptable method of birth control from baseline until at least 60 days after the end of treatment, if heterosexually active with a woman of childbearing potential
- •Participants with moderately impaired hepatic function (Cohort 1) must meet the following additional inclusion criteria:
- •Participants must have a stable hepatic function as confirmed by serum bilirubin, serum albumin, prothrombin, ascites, and hepatic encephalopathy status measured during screening and those measured within 24 hours prior to first study drug administration on Day 1 in Part 1
- •Participants must be hepatically impaired with a Class B classification as defined by the Child Pugh classification of severity of liver disease, that is, a total Child-Pugh score of 7 to 9, inclusive.
- •Participants with normal hepatic function (Cohort 2) must meet the additional inclusion criteria to be enrolled in the study: Participants must have a normal hepatic function as confirmed by serum bilirubin, serum albumin, prothrombin, ascites, and hepatic encephalopathy status measured during screening and those measured within 24 hours prior to first study drug administration on Day 1 in Part 1
排除标准
- •Participant has either: a history of renal insufficiency (estimated creatinine clearance lesser than (<) 90 milliliter per minute per 1.73 meter square (mL/min/1.73m^2) for estimated glomerular filtration rate [eGFR] according to the Chronic Kidney Disease Epidemiology Collaboration [CKD- EPI] equation) 18, or serum creatinine grade 1 or greater than (>) 1.1* upper limit of normal [ULN]) during screening
- •Participant has any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant (example, compromise the well-being), or that could prevent, limit, or confound the protocol-specified assessments
- •Participant with any history of clinically significant skin disease such as, but not limited to, dermatitis, eczema, drug rash, psoriasis, food allergy, or urticarial
- •Participant has known allergies, hypersensitivity, or intolerance to simeprevir (SMV), odalasvir (ODV), or AL 335, or their excipients
- •Participant who smokes more than 10 cigarettes or 2 cigars or 2 pipes per day from within 90 days before screening until the end of the study
研究组 & 干预措施
Cohort1:Participants With Moderately Impaired Hepatic Function
Participants With moderately impaired hepatic function will receive a single oral dose of AL-335 800 milligram (mg) (2 tablets of 400 mg AL-335) on Day 1 of Part 1 followed by a single oral dose of odalasvir (ODV) 25 mg (1 tablet of 25 mg ODV) on Day 8 of Part 1 and a combination of AL-335 800 mg (2 tablets of 400 mg AL-335) + ODV 25 mg (1 tablet of 25 mg ODV) + simeprevir (SMV) 75 mg (1 capsule of 75 mg SMV) once daily on Day 1 to 14 of Part 2. There will be a washout period between Part 1 and Part 2 of at least 14 days. Day 8 of Part 1 will be the start of the washout period. Prior to the start of study drug administration in Part 2, a safety review will be performed by the Sponsor.
干预措施: AL-335 800 mg (Drug)
Cohort1:Participants With Moderately Impaired Hepatic Function
Participants With moderately impaired hepatic function will receive a single oral dose of AL-335 800 milligram (mg) (2 tablets of 400 mg AL-335) on Day 1 of Part 1 followed by a single oral dose of odalasvir (ODV) 25 mg (1 tablet of 25 mg ODV) on Day 8 of Part 1 and a combination of AL-335 800 mg (2 tablets of 400 mg AL-335) + ODV 25 mg (1 tablet of 25 mg ODV) + simeprevir (SMV) 75 mg (1 capsule of 75 mg SMV) once daily on Day 1 to 14 of Part 2. There will be a washout period between Part 1 and Part 2 of at least 14 days. Day 8 of Part 1 will be the start of the washout period. Prior to the start of study drug administration in Part 2, a safety review will be performed by the Sponsor.
干预措施: ODV 25 mg (Drug)
Cohort1:Participants With Moderately Impaired Hepatic Function
Participants With moderately impaired hepatic function will receive a single oral dose of AL-335 800 milligram (mg) (2 tablets of 400 mg AL-335) on Day 1 of Part 1 followed by a single oral dose of odalasvir (ODV) 25 mg (1 tablet of 25 mg ODV) on Day 8 of Part 1 and a combination of AL-335 800 mg (2 tablets of 400 mg AL-335) + ODV 25 mg (1 tablet of 25 mg ODV) + simeprevir (SMV) 75 mg (1 capsule of 75 mg SMV) once daily on Day 1 to 14 of Part 2. There will be a washout period between Part 1 and Part 2 of at least 14 days. Day 8 of Part 1 will be the start of the washout period. Prior to the start of study drug administration in Part 2, a safety review will be performed by the Sponsor.
干预措施: SMV 75 mg (Drug)
Cohort 2: Participants With Normal Hepatic Function
Participants with normal hepatic function will receive a single oral dose of AL-335 800 mg (2 tablets of 400 mg AL-335) on Day 1 of Part 1 followed by a single oral dose of ODV 25 mg (1 tablet of 25 mg ODV) on Day 8 of Part 1 and a combination of AL-335 800 mg (2 tablets of 400 mg AL-335) + ODV 25 mg (1 tablet of 25 mg ODV) + SMV 75 mg (1 capsule of 75 mg SMV) once daily on Day 1 to 14 of Part 2. There will be a washout period between Part 1 and Part 2 of at least 14 days. Day 8 of Part 1 will be the start of the washout period. Prior to the start of study drug administration in Part 2, a safety review will be performed by the Sponsor.
干预措施: AL-335 800 mg (Drug)
Cohort 2: Participants With Normal Hepatic Function
Participants with normal hepatic function will receive a single oral dose of AL-335 800 mg (2 tablets of 400 mg AL-335) on Day 1 of Part 1 followed by a single oral dose of ODV 25 mg (1 tablet of 25 mg ODV) on Day 8 of Part 1 and a combination of AL-335 800 mg (2 tablets of 400 mg AL-335) + ODV 25 mg (1 tablet of 25 mg ODV) + SMV 75 mg (1 capsule of 75 mg SMV) once daily on Day 1 to 14 of Part 2. There will be a washout period between Part 1 and Part 2 of at least 14 days. Day 8 of Part 1 will be the start of the washout period. Prior to the start of study drug administration in Part 2, a safety review will be performed by the Sponsor.
干预措施: ODV 25 mg (Drug)
Cohort 2: Participants With Normal Hepatic Function
Participants with normal hepatic function will receive a single oral dose of AL-335 800 mg (2 tablets of 400 mg AL-335) on Day 1 of Part 1 followed by a single oral dose of ODV 25 mg (1 tablet of 25 mg ODV) on Day 8 of Part 1 and a combination of AL-335 800 mg (2 tablets of 400 mg AL-335) + ODV 25 mg (1 tablet of 25 mg ODV) + SMV 75 mg (1 capsule of 75 mg SMV) once daily on Day 1 to 14 of Part 2. There will be a washout period between Part 1 and Part 2 of at least 14 days. Day 8 of Part 1 will be the start of the washout period. Prior to the start of study drug administration in Part 2, a safety review will be performed by the Sponsor.
干预措施: SMV 75 mg (Drug)
结局指标
主要结局
Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of AL-335 and its Metabolites ALS-022399 and ALS-022227
时间窗: Day 1: Predose, at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, 60, and 72 hours postdose
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C (last)/ lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of ODV
时间窗: Day 8: Predose, at 1, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC (last) and C (last)/lambda(z); wherein AUC (last) is area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Part 1: Maximum Observed Plasma Concentration (Cmax) of AL-335 and its Metabolites ALS-022399 and ALS-022227
时间窗: Day 1: Predose, at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, 60, and 72 hours postdose
Cmax is defined as maximum observed plasma concentration of AL-335 and its metabolites ALS-022399 and ALS-022227.
Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC [0-last]) of AL-335 and its Metabolites ALS-022399 and ALS-022227
时间窗: Day 1: Predose, at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, 60, and 72 hours postdose
The AUC (0-last) is the area under the plasma concentration-time curve from time zero to the time of the last measurable (non-below quantification limit \[non-BQL\]) concentration, calculated by linear-linear trapezoidal summation.
Part 1: Maximum Observed Plasma Concentration (Cmax) of Odalasvir (ODV)
时间窗: Day 8: Predose, at 1, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose
Cmax is defined as maximum observed plasma concentration of ODV.
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC [0-last]) of ODV
时间窗: Day 8: Predose, at 1, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose
The AUC (0-last) is the area under the plasma concentration-time curve from time zero to the time of the last measurable (non-below quantification limit \[non-BQL\]) concentration, calculated by linear-linear trapezoidal summation.
Part 2: Maximum Observed Plasma Concentration (Cmax) of Simeprevir (SMV)
时间窗: Day 14: Predose, 1, 2, 4, 6, 8, 10, 12, 16 and 24 hours postdose
Cmax is defined as maximum observed plasma concentration of SMV.
Part 2: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC[0-24]) of SMV
时间窗: Day 14: Predose, 1, 2, 4, 6, 8, 10, 12, 16 and 24 hours postdose
The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours postdose, calculated by linear-linear trapezoidal summation.
Part 2: Maximum Observed Plasma Concentration (Cmax) of ODV
时间窗: Day 14: Predose, 1, 3, 4, 5, 6, 7, 8, 12, 16 and 24 postdose
Cmax is defined as maximum observed plasma concentration of ODV.
Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours Postdose (AUC[0-24]) of ODV
时间窗: Day 14: Predose, 1, 3, 4, 5, 6, 7, 8, 12, 16 and 24 postdose
The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours postdose, calculated by linear-linear trapezoidal summation.
Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of ODV
时间窗: Day 14: Predose, 1, 3, 4, 5, 6, 7, 8, 12, 16 and 24 postdose
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C (last)/ lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Part 2: Maximum Observed Plasma Concentration (Cmax) of AL-335 and its Metabolites ALS-022399 and ALS-022227
时间窗: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours postdose
Cmax is defined as maximum observed plasma concentration of AL-335 and its metabolites ALS-022399 and ALS-022227.
Part 2: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) Postdose of AL-335 and its metabolites ALS-022399 and ALS-022227
时间窗: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours postdose
The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours postdose, calculated by linear-linear trapezoidal summation.
次要结局
- Part 1 and 2: Number of Participants With Adverse Events (AE) as a Measure of Safety and Tolerability(Up to 30-35 days after last drug intake (approximately up to 102 days))