OCR002-SP103 - Oral Immediate Release Study

Ocera Therapeutics, Inc.30 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Cirrhosis

Interventions

OCR-002 IR Oral TabletDRUG

OCR-002 3 gram immediate release (IR) tablet for oral administration

OCR-002 Oral SolutionDRUG

OCR-002 5 gram solution for oral administration

OCR-002 IV SolutionDRUG

OCR-002 5 gram solution for intravenous (IV ) administration

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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)

Locations (1)

Southern California Research Center

Coronado, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 6 months

Time to Cmax (Tmax) of PAA and PAGN