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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.
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:
Multiple-dose, randomized, 3-period crossover study to evaluate OCR-002 oral tablets in subjects with cirrhosis (Child-Pugh class B). The purpose is to characterize the PK and pharmacodynamic (PD) of OCR-002 tablets after TID administration for 5 days in subjects with cirrhosis (Child-Pugh class B).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| OCR-002 - Treatment A | Experimental | A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions |
|
| OCR-002 - Treatment B | Experimental | A single 5 g oral dose of OCR-002 oral solution administered under fed conditions |
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| OCR-002 - Treatment C | Experimental | A single 5 g intravenous dose of OCR-002 solution infused over 1 hour under fasting conditions |
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| OCR-002 - Treatment D | Experimental | A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions following discontinuation of lactulose |
|
| OCR-002 - Treatment E | Experimental | 6 g OCR-002 per day (2 tablets TID for 6 g total daily dose) |
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| OCR-002 - Treatment F |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| OCR-002 IR Oral Tablet | Drug | OCR-002 3 gram immediate release (IR) tablet for oral administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum concentration (Cmax) of PAA and PAGN following described treatment | 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. | 6 months |
| Time to Cmax (Tmax) of PAA and PAGN | Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods. | 6 months |
| Area under the plasma concentration time curve over time (AUC0-t) of PAA and PAGN following described treatment | 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. | 6 months |
| 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) | Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods. | 6 months |
| 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) | Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods. |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse events of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C) | Adverse events data will be summarized. | 6 months |
| Adverse events of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets |
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Inclusion Criteria
Subjects eligible for enrollment must meet all of the following inclusion criteria:
Exclusion Criteria
Subjects meeting any of the following criteria will not be eligible for enrollment:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Team Leader | Mallinckrodt | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Southern California Research Center | Coronado | California | 92118 | United States |
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| ID | Term |
|---|---|
| D005355 | Fibrosis |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C572232 | ornithine phenylacetate |
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12 g OCR-002 per day (4 tablets TID for 12 g total daily dose) |
|
| OCR-002 - Treatment G | Experimental | 21 g OCR-002 per day (7 tablets TID for 21 g total daily dose) |
|
|
| OCR-002 Oral Solution | Drug | OCR-002 5 gram solution for oral administration |
|
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| OCR-002 IV Solution | Drug | OCR-002 5 gram solution for intravenous (IV ) administration |
|
|
| 6 months |
| 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) | Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods. | 6 months |
| 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) | Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods. | 6 months |
| 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) | 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. | 6 months |
| 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) | 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. | 6 months |
| 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) | 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. | 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) | 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. | 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) | 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. | 6 months |
| Urinary excretion of PAGN following a single dose of each treatment in participants with cirrhosis (Child-Pugh Classes A and C) | 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. | 6 months |
| Cmax of OCR-002 immediate-release tablets over the course of TID dosing for 5 days | Cmax of OCR-002 immediate-release tablets over the course of TID dosing for 5 days will be determined. | 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 | 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. | 5 days |
| Ammonia-lowering (Tmax) effect of OCR-002 over the course of TID dosing for 5 days | Ammonia-lowering (Tmax) effect of OCR-002 over the course of TID dosing for 5 days will be determined. | 5 days |
| AUC of oral, immediate-release (IR) OCR 002 tablets | AUC of oral, immediate-release (IR) OCR 002 tablets will be determined. | 5 days |
| AUC of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet administration for 5 days in participants with cirrhosis | AUC of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet will be determined. | 5 days |
| Degree of fluctuation (Day 5) of OCR-002 immediate-release tablets | Degree of fluctuation (Day 5) of OCR-002 immediate-release tablets will be determined. | 5 days |
| Elimination rate constant (kel) of OCR-002 immediate-release tablets | kel of OCR-002 immediate-release tablets will be determined. | 5 days |
| T1/2 of OCR-002 immediate-release tablets | T1/2 of OCR-002 immediate-release tablets will be determined. | 5 days |
| Drug elimination (Cmax) following discontinuation of OCR-002 oral tablets after TID administration for 5 days | Drug elimination (Cmax) following discontinuation of OCR-002 oral tablets will be determined. | 5 days |
| Urinary excretion profile of urea following TID administration of OCR-002 oral tablets of each treatment in participants with cirrhosis | Urinary excretion profile of urea following TID administration of OCR-002 oral tablets of each treatment in participants with cirrhosis will be determined. | 5 days |
| Urinary excretion of PAGN following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis | Urinary excretion of PAGN following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis will be determined | 5 days |
| Urinary excretion of PAA following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis | Urinary excretion of PAA following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis will be determined. | 5 days |
| Change from Baseline in serum blood urea nitrogen (BUN) over the course of TID dosing for 5 days | Change from Baseline in serum BUN over the course of TID dosing for 5 days will be calculated. | 5 days |
| Change from Baseline in serum creatinine over the course of TID dosing for 5 days | Change from Baseline in serum creatinine over the course of TID dosing for 5 days will be calculated. | 5 days |
| Change from Baseline in creatinine clearance over the course of TID dosing for 5 days | Change from Baseline in creatinine clearance over the course of TID dosing for 5 days will be calculated. | 5 days |
| Urea clearance over the course of TID dosing for 5 days | Urea clearance over the course of TID dosing for 5 days will be calculated. | 5 days |
| Percent of PAA dose excreted in urine as PAGN and unchanged (as PAA) over each collection interval and the entire collection interval | 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. | 5 days |
Adverse events data will be summarized. |
| 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) | Sitting blood pressure will be measured after the participant has been in a sitting position for at least 3 minutes. | 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) | Heart rate will be measured after the participant has been in a sitting position for at least 3 minutes. | 6 months |
| Change from Baseline in body temperature of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C) | Body temperature will be measured after the participant has been in a sitting position for at least 3 minutes. | 6 months |
| Change from Baseline in sitting blood pressure of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets | Sitting blood pressure will be measured after the participant has been in a sitting position for at least 3 minutes. | 6 months |
| Change from Baseline in heart rate of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets | Heart rate will be measured after the participant has been in a sitting position for at least 3 minutes. | 6 months |
| Change from Baseline in body temperature of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets | Body temperature will be measured after the participant has been in a sitting position for at least 3 minutes. | 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) | Treatment-emergent abnormal laboratory tests are those in which the baseline value is normal (within the laboratory normal reference range) and post-baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer Institute Common Terminology Criteria. | 6 months |
| Proportion of participants with abnormal hematology values of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C) | Treatment-emergent abnormal laboratory tests are those in which the baseline value is normal (within the laboratory normal reference range) and post-baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer Institute Common Terminology Criteria. | 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 | Treatment-emergent abnormal laboratory tests are those in which the baseline value is normal (within the laboratory normal reference range) and post-baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer Institute Common Terminology Criteria. | 6 months |
| Proportion of participants with abnormal hematology values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets | Treatment-emergent abnormal laboratory tests are those in which the baseline value is normal (within the laboratory normal reference range) and post-baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer Institute Common Terminology Criteria. | 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) | Treatment-emergent abnormal laboratory tests are those in which the baseline value is normal (within the laboratory normal reference range) and post-baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer Institute Common Terminology Criteria. | 6 months |
| Proportion of participants with abnormal urinalysis values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets | Treatment-emergent abnormal laboratory tests are those in which the baseline value is normal (within the laboratory normal reference range) and post-baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer Institute Common Terminology Criteria. | 6 months |
| Cmax of ornithine over the course of TID administration of OCR-002 for 5 days | Cmax of ornithine over the course of TID administration of OCR-002 for 5 days will be reported. | 5 days |
| Tmax of ornithine over the course of TID administration of OCR-002 for 5 days | Tmax of ornithine over the course of TID administration of OCR-002 for 5 days will be reported. | 5 days |
| AUC0-24 of ornithine over the course of TID administration of OCR-002 for 5 days | AUC0-24 of ornithine over the course of TID administration of OCR-002 for 5 days will be reported. | 5 days |
| Degree of fluctuation of ornithine over the course of TID administration of OCR-002 for 5 days | Degree of fluctuation of ornithine over the course of TID administration of OCR-002 for 5 days will be reported. | 5 days |
| kel of ornithine over the course of TID administration of OCR-002 for 5 days | kel of ornithine over the course of TID administration of OCR-002 for 5 days will be reported. | 5 days |
| T1/2 of ornithine over the course of TID administration of OCR-002 for 5 days | T1/2 of ornithine over the course of TID administration of OCR-002 for 5 days will be reported. | 5 days |