OCR002-SP103 - Oral Immediate Release Study

Phase 1

Completed

• Conditions: Cirrhosis
• Interventions: Drug: OCR-002 IV Solution; Drug: OCR-002 IR Oral Tablet; Drug: OCR-002 Oral Solution

• Registration Number: NCT03846843
• Lead Sponsor: Ocera Therapeutics, Inc.

Brief Summary

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.

Detailed Description

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).

Study Timeline

• Study Start: 2016-08-15
• Study First Submitted: 2017-11-02
• Primary Completion: 2017-11-30
• Study Completion: 2017-12-31
• Study First Submitted QC: 2019-02-15
• Study First Posted: 2019-02-20
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-16
• Last Update Posted: 2021-09-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
OCR-002 - Treatment C	OCR-002 IV Solution	A single 5 g intravenous dose of OCR-002 solution infused over 1 hour under fasting conditions
OCR-002 - Treatment E	OCR-002 IR Oral Tablet	6 g OCR-002 per day (2 tablets TID for 6 g total daily dose)
OCR-002 - Treatment A	OCR-002 Oral Solution	A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions
OCR-002 - Treatment B	OCR-002 Oral Solution	A single 5 g oral dose of OCR-002 oral solution administered under fed conditions
OCR-002 - Treatment G	OCR-002 IR Oral Tablet	21 g OCR-002 per day (7 tablets TID for 21 g total daily dose)
OCR-002 - Treatment D	OCR-002 IV Solution	A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions following discontinuation of lactulose
OCR-002 - Treatment F	OCR-002 IR Oral Tablet	12 g OCR-002 per day (4 tablets TID for 12 g total daily dose)

Primary Outcome Measures

Name	Time	Method
Area under the plasma concentration time curve over time (AUC0-t) of PAA and PAGN following described treatment	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	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)	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)	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	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	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	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	5 days	Drug elimination (Cmax) following discontinuation of OCR-002 oral tablets will be determined.
Time to Cmax (Tmax) of PAA and PAGN	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)	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)	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)	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)	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	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	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)	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)	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	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	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	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	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)	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)	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	5 days	Degree of fluctuation (Day 5) of OCR-002 immediate-release tablets will be determined.
T1/2 of OCR-002 immediate-release tablets	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	5 days	Change from Baseline in creatinine 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	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	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	5 days	Change from Baseline in serum creatinine over the course of TID dosing for 5 days will be calculated.
Urea clearance over the course of TID dosing for 5 days	5 days	Urea clearance over the course of TID dosing for 5 days will be calculated.

Secondary Outcome Measures

Name	Time	Method
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	Body temperature will be measured after the participant has been in a sitting position for at least 3 minutes.
Change from Baseline in sitting blood pressure of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets	6 months	Sitting blood pressure will be measured after the participant has been in a sitting position for at least 3 minutes.
Change from Baseline in heart rate of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets	6 months	Heart rate will be measured after the participant has been in a sitting position for at least 3 minutes.
Proportion of participants with abnormal hematology values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets	6 months	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.
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	Sitting blood pressure will be measured after the participant has been in a sitting position for at least 3 minutes.
Proportion of participants with abnormal urinalysis values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets	6 months	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.
kel of ornithine over the course of TID administration of OCR-002 for 5 days	5 days	kel of ornithine over the course of TID administration of OCR-002 for 5 days will be reported.
Adverse events of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)	6 months	Adverse events data will be summarized.
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	Heart rate will be measured after the participant has been in a sitting position for at least 3 minutes.
Change from Baseline in body temperature of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets	6 months	Body temperature will be measured after the participant has been in a sitting position for at least 3 minutes.
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	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.
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	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.
Cmax of ornithine over the course of TID administration of OCR-002 for 5 days	5 days	Cmax of ornithine over the course of TID administration of OCR-002 for 5 days will be reported.
Adverse events of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets	6 months	Adverse events data will be summarized.
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	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.
Tmax of ornithine over the course of TID administration of OCR-002 for 5 days	5 days	Tmax of ornithine over the course of TID administration of OCR-002 for 5 days will be reported.
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	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.
Degree of fluctuation of ornithine over the course of TID administration of OCR-002 for 5 days	5 days	Degree of fluctuation of ornithine over the course of TID administration of OCR-002 for 5 days will be reported.
AUC0-24 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 will be reported.
T1/2 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 will be reported.

Trial Locations

Locations (1)

Southern California Research Center; 🇺🇸 Coronado, California, United States