NCT03846843

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
30

participants targeted

Target at P25-P50 for phase_1

Timeline
Completed

Started Aug 2016

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

August 15, 2016

Completed
1.2 years until next milestone

First Submitted

Initial submission to the registry

November 2, 2017

Completed
28 days until next milestone

Primary Completion

Last participant's last visit for primary outcome

November 30, 2017

Completed
1 month until next milestone

Study Completion

Last participant's last visit for all outcomes

December 31, 2017

Completed
1.1 years until next milestone

First Posted

Study publicly available on registry

February 20, 2019

Completed
Last Updated

September 20, 2021

Status Verified

September 1, 2021

Enrollment Period

1.3 years

First QC Date

November 2, 2017

Last Update Submit

September 16, 2021

Conditions

Cirrhosis

Keywords

Child-Pugh Class B

Outcome Measures

Primary Outcomes (30)

  • 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 Outcomes (20)

  • Adverse events of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)

    6 months

  • Adverse events 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

  • 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 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)

    6 months

  • +15 more secondary outcomes

Study Arms (7)

OCR-002 - Treatment A

EXPERIMENTAL

A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions

Drug: OCR-002 Oral Solution

OCR-002 - Treatment B

EXPERIMENTAL

A single 5 g oral dose of OCR-002 oral solution administered under fed conditions

Drug: OCR-002 Oral Solution

OCR-002 - Treatment C

EXPERIMENTAL

A single 5 g intravenous dose of OCR-002 solution infused over 1 hour under fasting conditions

Drug: OCR-002 IV Solution

OCR-002 - Treatment D

EXPERIMENTAL

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 - Treatment E

EXPERIMENTAL

6 g OCR-002 per day (2 tablets TID for 6 g total daily dose)

Drug: OCR-002 IR Oral Tablet

OCR-002 - Treatment F

EXPERIMENTAL

12 g OCR-002 per day (4 tablets TID for 12 g total daily dose)

Drug: OCR-002 IR Oral Tablet

OCR-002 - Treatment G

EXPERIMENTAL

21 g OCR-002 per day (7 tablets TID for 21 g total daily dose)

Drug: OCR-002 IR Oral Tablet

Interventions

OCR-002 IR Oral TabletDRUG

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

Also known as: Ornithine phenylacetate
OCR-002 - Treatment EOCR-002 - Treatment FOCR-002 - Treatment G
OCR-002 Oral SolutionDRUG

OCR-002 5 gram solution for oral administration

Also known as: Ornithine phenylacetate
OCR-002 - Treatment AOCR-002 - Treatment B
OCR-002 IV SolutionDRUG

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

Also known as: Ornithine phenylacetate
OCR-002 - Treatment COCR-002 - Treatment D

Eligibility Criteria

Age18 Years - 70 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Informed of the nature of the study and provided written informed voluntary consent;
  • 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;
  • Willing and able to abstain from tobacco products and alcohol during confinement at the research unit;
  • 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;
  • Currently using lactulose (minimum of 5 days prior to Day -1)
  • If using rifaximin at Screening Visit, it must be discontinued at least 7 days before the first dose of study drug;
  • Negative serum pregnancy test (females of childbearing potential only);
  • 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.

You may not qualify if:

  • Subjects meeting any of the following criteria will not be eligible for enrollment:
  • Not expected to survive for 2 months;
  • Presence of Type 1 hepatorenal syndrome;
  • Presence of hyponatremia (serum sodium \<125 mmol/L);
  • Presence of renal failure with serum creatinine \>3 mg/dL or need for hemodialysis, peritoneal dialysis, or continuous venovenous hemofiltration at Screening;
  • New York Heart Association Class 3 or 4 congestive heart failure or overt clinical signs of congestive heart failure;
  • Requirement for mechanical ventilation (continuous positive airway pressure is allowed);
  • Prior transplant recipient (solid organ, bone marrow, or stem cell);
  • Any prior stroke with cognitive sequelae;
  • Presence of acute alcoholic hepatitis;
  • Positive test for human immunodeficiency virus or hepatitis B surface antigen;
  • Presence of overt hepatic encephalopathy, other irreversible brain damage, aspiration pneumonia, or severe psychiatric disorder;
  • Known or suspected gastrointestinal bleeding within 7 days before Screening;
  • Hemodynamic instability, defined as mean arterial blood pressure \<60 mmHg and/or evidence of poor organ perfusion;
  • Current use of more than 1 vasopressor to support blood pressure;
  • +19 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Southern California Research Center

Coronado, California, 92118, United States

Location

MeSH Terms

Conditions

Fibrosis

Interventions

ornithine phenylacetate

Condition Hierarchy (Ancestors)

Pathologic ProcessesPathological Conditions, Signs and Symptoms

Study Officials

  • Clinical Team Leader

    Mallinckrodt

    STUDY DIRECTOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
NONE
Purpose
BASIC SCIENCE
Intervention Model
CROSSOVER
Sponsor Type
INDUSTRY
Responsible Party
SPONSOR

Study Record Dates

First Submitted

November 2, 2017

First Posted

February 20, 2019

Study Start

August 15, 2016

Primary Completion

November 30, 2017

Study Completion

December 31, 2017

Last Updated

September 20, 2021

Record last verified: 2021-09

Data Sharing

IPD Sharing
Will not share

Locations

US(1)