OCR002-SP103 - Oral Immediate Release Study

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

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.

Study Overview

• Status: Completed
• Conditions: Cirrhosis
• Intervention / Treatment: Drug: OCR-002 Oral Solution; Drug: OCR-002 IV Solution; Drug: OCR-002 IR Oral Tablet

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 Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Subjects eligible for enrollment must meet all of the following inclusion criteria:

1. Informed of the nature of the study and provided written informed voluntary consent;
2. Male or female ≥18 years of age or the legal age of consent (whichever is greater) and ≤70 years of age at the time of Screening;
3. Willing and able to abstain from tobacco products and alcohol during confinement at the research unit;
4. Evidence of/known cirrhosis (Child-Pugh class A and C in Part 1, Child-Pugh class B in Part 2). Diagnosis of liver cirrhosis will be based on clinical, radiological, or histological criteria;
5. Currently using lactulose (minimum of 5 days prior to Day -1)
6. If using rifaximin at Screening Visit, it must be discontinued at least 7 days before the first dose of study drug;
7. Negative serum pregnancy test (females of childbearing potential only);
8. Agree to utilize an effective barrier method (mechanical barrier, intrauterine device, or condom with spermicide) of contraception from Screening through to at least 4 weeks after the last dose of study drug for sexually active female who is not surgically sterile or post-menopausal. Sexually active males must use contraception and also refrain from donating sperm while on study drug from admission to at least 4 weeks after the last dose of study drug; Able to communicate effectively with the Investigator/designee and other study center personnel and agree to comply with the study procedures and restrictions.

Exclusion Criteria

Subjects meeting any of the following criteria will not be eligible for enrollment:

1. Not expected to survive for 2 months;
2. Presence of Type 1 hepatorenal syndrome;
3. Presence of hyponatremia (serum sodium <125 mmol/L);
4. Presence of renal failure with serum creatinine >3 mg/dL or need for hemodialysis, peritoneal dialysis, or continuous venovenous hemofiltration at Screening;
5. New York Heart Association Class 3 or 4 congestive heart failure or overt clinical signs of congestive heart failure;
6. Requirement for mechanical ventilation (continuous positive airway pressure is allowed);
7. Prior transplant recipient (solid organ, bone marrow, or stem cell);
8. Any prior stroke with cognitive sequelae;
9. Presence of acute alcoholic hepatitis;
10. Positive test for human immunodeficiency virus or hepatitis B surface antigen;
11. Presence of overt hepatic encephalopathy, other irreversible brain damage, aspiration pneumonia, or severe psychiatric disorder;
12. Known or suspected gastrointestinal bleeding within 7 days before Screening;
13. Hemodynamic instability, defined as mean arterial blood pressure <60 mmHg and/or evidence of poor organ perfusion;
14. Current use of more than 1 vasopressor to support blood pressure;
15. Current use of drugs that could potentially interfere with renal excretion of PAGN, such as probenecid, estrone sulfate, ibuprofen, cimetidine, or diclofenac. Use of L-ornithine L-aspartate is prohibited;
16. Current use of drugs whose renal excretion may be affected by OCR-002, such as quinidine, metformin, or cimetidine;
17. Current use of molecular adsorbent recirculation system;
18. Current use of AMMONUL (sodium benzoate with sodium phenylacetate), BUPHENYL (sodium phenylbutyrate), RAVICTI, or other medications that contain sodium benzoate or sodium phenylbutyrate.
19. Current use of rifaximin or oral neomycin;
20. Corrected QT interval (Fridericia's formula) >480 msec at Day -1;
21. History or allergic reactions to ornithine, PAA, or their analogs;
22. Currently hospitalized for any reason or clinically significant surgery within 4 weeks before the first dose of the study drug;
23. Presence of transjugular intrahepatic portosystemic shunt;
24. Blood loss or blood donation of >500 mL within 30 days or plasma donation >500 mL within 14 days before administration of the first dose of study drug;
25. Currently lactating;
26. Positive screening result for drugs of abuse;
27. Ingestion of grapefruit or grapefruit juice within 48 hours before study dose administration; or use of repaglinide throughout the study;
28. Receipt of an investigational product or device, or participation in a drug research study within a period of 30 days (or 5 half-lives of the drug, whichever is longer) before the first dose of study drug;
29. Prior diagnosis of cancer and receiving active therapy, or hepatic cancer or cancer with known brain metastasis;
30. Any condition or set of circumstances which, in the judgment of the Investigator or Sponsor, could interfere with their ability to comply with the dosing schedule and completion of the study evaluations.
31. Prior surgical shunt recipient (Part 2)
32. Subject has a body weight <45 kg (Part 2).
33. Current use of oral vancomycin or oral or parenteral antibiotic that could potentially alter gut flora (Part 2)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OCR-002 - Treatment A; A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions	Drug: OCR-002 Oral Solution; OCR-002 5 gram solution for oral administration; Other Names: Ornithine phenylacetate
Experimental: OCR-002 - Treatment B; A single 5 g oral dose of OCR-002 oral solution administered under fed conditions	Drug: OCR-002 Oral Solution; OCR-002 5 gram solution for oral administration; Other Names: Ornithine phenylacetate
Experimental: OCR-002 - Treatment C; A single 5 g intravenous dose of OCR-002 solution infused over 1 hour under fasting conditions	Drug: OCR-002 IV Solution; OCR-002 5 gram solution for intravenous (IV ) administration; Other Names: Ornithine phenylacetate
Experimental: OCR-002 - Treatment D; A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions following discontinuation of lactulose	Drug: OCR-002 IV Solution; OCR-002 5 gram solution for intravenous (IV ) administration; Other Names: Ornithine phenylacetate
Experimental: OCR-002 - Treatment E; 6 g OCR-002 per day (2 tablets TID for 6 g total daily dose)	Drug: OCR-002 IR Oral Tablet; OCR-002 3 gram immediate release (IR) tablet for oral administration; Other Names: Ornithine phenylacetate
Experimental: OCR-002 - Treatment F; 12 g OCR-002 per day (4 tablets TID for 12 g total daily dose)	Drug: OCR-002 IR Oral Tablet; OCR-002 3 gram immediate release (IR) tablet for oral administration; Other Names: Ornithine phenylacetate
Experimental: OCR-002 - Treatment G; 21 g OCR-002 per day (7 tablets TID for 21 g total daily dose)	Drug: OCR-002 IR Oral Tablet; OCR-002 3 gram immediate release (IR) tablet for oral administration; Other Names: Ornithine phenylacetate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.	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

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Ocera Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2016
• Primary Completion (Actual): November 30, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: November 2, 2017
• First Submitted That Met QC Criteria: February 15, 2019
• First Posted (Actual): February 20, 2019

Study Record Updates

• Last Update Posted (Actual): September 20, 2021
• Last Update Submitted That Met QC Criteria: September 16, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Child-Pugh Class B
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Pharmaceutical Solutions; Phenylacetic acid
• Other Study ID Numbers: OCR002-SP103

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No