An Open-Label, Two-Part, Phase 1/2a, Crossover Study to Determine the Absolute Bioavailability and Pharmacokinetics of Oral Immediate-Release Doses of OCR-002 in Subjects With Varying Degrees of Cirrhosis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Area under the plasma concentration time curve over time (AUC0-t) of PAA and PAGN following described treatment
研究概览
简要总结
This is an open-label Phase 1, 2-part, crossover study in approximately 33 adult subjects (12 subjects in Part 1 and 21 subjects in Part 2), with varying degrees of cirrhosis with analysis of pharmacokinetic (PK) data after Part 1 to guide dose regimen selection and PK sampling time points for OCR-002 in Part 2.
详细描述
Part 1: Dosing Periods 1, 2, 3, and 4:
Single-dose, partially randomized, 4-period crossover study to evaluate 5 g OCR-002 oral solution administered under fed conditions, fasting conditions, or under fasting conditions following discontinuation of lactulose in 12 subjects with cirrhosis (Child-Pugh class A and C).
The purpose is to determine the pharmacokinetics of phenylacetic acid (PAA) and phenylacetylglutamine (PAGN) following a single 5 g dose of OCR-002 oral solution administered under fed conditions, fasting conditions, or under fasting conditions following discontinuation of lactulose as compared to a single 5 g intravenous dose of OCR-002 under fasting conditions in subjects with cirrhosis (Child-Pugh class A and C).
Analysis of pharmacokinetic data will be conducted after completion of Part 1 in order to determine the dose regimen of OCR-002 oral tablets to use in Part 2 of the study.
Part 2: Dosing Periods 1, 2 and 3:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
OCR-002 - Treatment A
A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions
干预措施: OCR-002 Oral Solution (Drug)
OCR-002 - Treatment B
A single 5 g oral dose of OCR-002 oral solution administered under fed conditions
干预措施: OCR-002 Oral Solution (Drug)
OCR-002 - Treatment C
A single 5 g intravenous dose of OCR-002 solution infused over 1 hour under fasting conditions
干预措施: OCR-002 IV Solution (Drug)
OCR-002 - Treatment D
A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions following discontinuation of lactulose
干预措施: OCR-002 IV Solution (Drug)
OCR-002 - Treatment E
6 g OCR-002 per day (2 tablets TID for 6 g total daily dose)
干预措施: OCR-002 IR Oral Tablet (Drug)
OCR-002 - Treatment F
12 g OCR-002 per day (4 tablets TID for 12 g total daily dose)
干预措施: OCR-002 IR Oral Tablet (Drug)
OCR-002 - Treatment G
21 g OCR-002 per day (7 tablets TID for 21 g total daily dose)
干预措施: OCR-002 IR Oral Tablet (Drug)
结局指标
主要结局
Area under the plasma concentration time curve over time (AUC0-t) of PAA and PAGN following described treatment
时间窗: 6 months
Area under the plasma concentration time curve over time (AUC0-t) of PAA and PAGN following a single 5 g dose of OCR-002 oral solution under fed or fasting conditions as compared to a single 5 g IV dose of OCR-002 under fasting conditions in participants with cirrhosis (Child-Pugh Classes A and C). Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
Maximum concentration (Cmax) of PAA and PAGN following described treatment
时间窗: 6 months
Maximum concentration (Cmax) of PAA and PAGN following a single 5 g dose of OCR-002 oral solution under fed or fasting conditions as compared to a single 5 g IV dose of OCR-002 under fasting conditions in participants with cirrhosis (Child-Pugh Classes A and C). Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
AUC0-36 of PAA and PAGN following a single 5 g dose of OCR-002 oral solution under fed or fasting conditions as compared to a single 5 g IV dose of OCR-002 under fasting conditions in participants with cirrhosis (Child-Pugh Classes A and C)
时间窗: 6 months
Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
Cmax of PAA and PAGN following a single dose of OCR-002 oral solution under fasting conditions in participants with cirrhosis who have discontinued lactulose (Child-Pugh Classes A and C)
时间窗: 6 months
Cmax of PAA and PAGN following a single dose of OCR-002 oral solution under fasting conditions in participants with cirrhosis who have discontinued lactulose (Child-Pugh Classes A and C) will be determined.
Ammonia-lowering (Tmax) effect of OCR-002 over the course of TID dosing for 5 days
时间窗: 5 days
Ammonia-lowering (Tmax) effect of OCR-002 over the course of TID dosing for 5 days will be determined.
AUC of oral, immediate-release (IR) OCR 002 tablets
时间窗: 5 days
AUC of oral, immediate-release (IR) OCR 002 tablets will be determined.
AUC of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet administration for 5 days in participants with cirrhosis
时间窗: 5 days
AUC of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet will be determined.
Drug elimination (Cmax) following discontinuation of OCR-002 oral tablets after TID administration for 5 days
时间窗: 5 days
Drug elimination (Cmax) following discontinuation of OCR-002 oral tablets will be determined.
Time to Cmax (Tmax) of PAA and PAGN
时间窗: 6 months
Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
Half-life (t1/2) of PAA and PAGN following a single 5 g dose of OCR-002 oral solution under fed or fasting conditions as compared to a single 5 g IV dose of OCR-002 under fasting conditions in participants with cirrhosis (Child-Pugh Classes A nd C)
时间窗: 6 months
Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
AUC0-inf of PAA and PAGN following a single 5 g dose of OCR-002 oral solution under fed or fasting conditions as compared to a single 5 g IV dose of OCR-002 under fasting conditions in participants with cirrhosis (Child-Pugh Classes A and C)
时间窗: 6 months
Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
AUC0-24 of PAA and PAGN following a single 5 g dose of OCR-002 oral solution under fed or fasting conditions as compared to a single 5 g IV dose of OCR-002 under fasting conditions in participants with cirrhosis (Child-Pugh Classes A and C)
时间窗: 6 months
Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
Evaluate the effect of a high-fat meal on the AUC of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh Classes A and C)
时间窗: 6 months
Participants will fast overnight for at least 8 hours prior to receiving the high fat (approximately 50% of total calorie content of the meal) and high-calorie (approximately 800 to 1000 calories) test meal, which will be entirely consumed within 30 minutes or less.
Cmax of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet administration for 5 days in participants with cirrhosis
时间窗: 5 days
Cmax of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet administration for 5 days in participants with cirrhosis will be determined.
Elimination rate constant (kel) of OCR-002 immediate-release tablets
时间窗: 5 days
kel of OCR-002 immediate-release tablets will be determined.
Evaluate the effect of a high-fat meal on the Cmax of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh Classes A and C)
时间窗: 6 months
Participants will fast overnight for at least 8 hours prior to receiving the high fat (approximately 50% of total calorie content of the meal) and high-calorie (approximately 800 to 1000 calories) test meal, which will be entirely consumed within 30 minutes or less.
Evaluate the effect of a high-fat meal on oral bioavailability of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh Classes A and C)
时间窗: 6 months
Participants will fast overnight for at least 8 hours prior to receiving the high fat (approximately 50% of total calorie content of the meal) and high-calorie (approximately 800 to 1000 calories) test meal, which will be entirely consumed within 30 minutes or less.
Cmax of OCR-002 immediate-release tablets over the course of TID dosing for 5 days
时间窗: 5 days
Cmax of OCR-002 immediate-release tablets over the course of TID dosing for 5 days will be determined.
Urinary excretion of PAA following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis
时间窗: 5 days
Urinary excretion of PAA following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis will be determined.
Change from Baseline in serum blood urea nitrogen (BUN) over the course of TID dosing for 5 days
时间窗: 5 days
Change from Baseline in serum BUN over the course of TID dosing for 5 days will be calculated.
Percent of PAA dose excreted in urine as PAGN and unchanged (as PAA) over each collection interval and the entire collection interval
时间窗: 5 days
Percent of PAA dose excreted in urine as PAGN and unchanged (as PAA) over each collection interval and the entire collection interval will be calculated.
AUC of PAA and PAGN following a single dose of OCR-002 oral solution under fasting conditions in participants with cirrhosis who have discontinued lactulose (Child-Pugh Classes A and C)
时间窗: 6 months
AUC of PAA and PAGN following a single dose of OCR-002 oral solution under fasting conditions in participants with cirrhosis who have discontinued lactulose (Child-Pugh Classes A and C) will be determined.
Urinary excretion of PAGN following a single dose of each treatment in participants with cirrhosis (Child-Pugh Classes A and C)
时间窗: 6 months
Urinary excretion profile of PAGN following a single dose of each treatment in participants with cirrhosis (Child-Pugh Classes A and C) will be determined.
Degree of fluctuation (Day 5) of OCR-002 immediate-release tablets
时间窗: 5 days
Degree of fluctuation (Day 5) of OCR-002 immediate-release tablets will be determined.
T1/2 of OCR-002 immediate-release tablets
时间窗: 5 days
T1/2 of OCR-002 immediate-release tablets will be determined.
Change from Baseline in creatinine clearance over the course of TID dosing for 5 days
时间窗: 5 days
Change from Baseline in creatinine clearance over the course of TID dosing for 5 days will be calculated.
Urea clearance over the course of TID dosing for 5 days
时间窗: 5 days
Urea clearance over the course of TID dosing for 5 days will be calculated.
Urinary excretion profile of urea following TID administration of OCR-002 oral tablets of each treatment in participants with cirrhosis
时间窗: 5 days
Urinary excretion profile of urea following TID administration of OCR-002 oral tablets of each treatment in participants with cirrhosis will be determined.
Urinary excretion of PAGN following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis
时间窗: 5 days
Urinary excretion of PAGN following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis will be determined
Change from Baseline in serum creatinine over the course of TID dosing for 5 days
时间窗: 5 days
Change from Baseline in serum creatinine over the course of TID dosing for 5 days will be calculated.
次要结局
- Change from Baseline in body temperature of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)(6 months)
- Change from Baseline in sitting blood pressure of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets(6 months)
- Change from Baseline in heart rate of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets(6 months)
- Proportion of participants with abnormal hematology values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets(6 months)
- Change from Baseline in sitting blood pressure of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)(6 months)
- Proportion of participants with abnormal urinalysis values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets(6 months)
- kel of ornithine over the course of TID administration of OCR-002 for 5 days(5 days)
- Adverse events of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)(6 months)
- Change from Baseline in heart rate of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)(6 months)
- Change from Baseline in body temperature of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets(6 months)
- Proportion of participants with abnormal clinical chemistry values of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)(6 months)
- Proportion of participants with abnormal clinical chemistry values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets(6 months)
- Cmax of ornithine over the course of TID administration of OCR-002 for 5 days(5 days)
- Adverse events of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets(6 months)
- Proportion of participants with abnormal urinalysis values of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)(6 months)
- Tmax of ornithine over the course of TID administration of OCR-002 for 5 days(5 days)
- Proportion of participants with abnormal hematology values of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)(6 months)
- Degree of fluctuation of ornithine over the course of TID administration of OCR-002 for 5 days(5 days)
- AUC0-24 of ornithine over the course of TID administration of OCR-002 for 5 days(5 days)
- T1/2 of ornithine over the course of TID administration of OCR-002 for 5 days(5 days)