CirrhosisPhase 1NCT03846843
OCR002-SP103 - Oral Immediate Release Study
A Phase 1 study testing OCR-002 IR Oral Tablet, OCR-002 Oral Solution and OCR-002 IV Solution in people with Cirrhosis, run by Ocera Therapeutics, Inc. at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Cirrhosis
- What is being tested?
- OCR-002 IR Oral Tablet, OCR-002 Oral Solution and OCR-002 IV Solution
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Aug 2016to 31 Dec 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects eligible for enrollment must meet all of the following inclusion criteria:
- 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)
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- 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.
Who cannot join
- 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;
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- 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;
- 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;
- Current use of drugs whose renal excretion may be affected by OCR-002, such as quinidine, metformin, or cimetidine;
- Current use of molecular adsorbent recirculation system;
- Current use of AMMONUL (sodium benzoate with sodium phenylacetate), BUPHENYL (sodium phenylbutyrate), RAVICTI, or other medications that contain sodium benzoate or sodium phenylbutyrate.
- Current use of rifaximin or oral neomycin;
- Corrected QT interval (Fridericia's formula) >480 msec at Day -1;
- History or allergic reactions to ornithine, PAA, or their analogs;
- Currently hospitalized for any reason or clinically significant surgery within 4 weeks before the first dose of the study drug;
- Presence of transjugular intrahepatic portosystemic shunt;
- 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;
- Currently lactating;
- Positive screening result for drugs of abuse;
- Ingestion of grapefruit or grapefruit juice within 48 hours before study dose administration; or use of repaglinide throughout the study;
- 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;
- Prior diagnosis of cancer and receiving active therapy, or hepatic cancer or cancer with known brain metastasis;
- 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.
- Prior surgical shunt recipient (Part 2)
- Subject has a body weight <45 kg (Part 2).
- Current use of oral vancomycin or oral or parenteral antibiotic that could potentially alter gut flora (Part 2)
Trial locations and contacts
1 site in 1 country.
United States1 site
Southern California Research Center
Coronado, California, 92118
About this study
Official title: 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.
Read the 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).
- Conditions
- Cirrhosis
- Being tested
- OCR-002 IR Oral Tablet, OCR-002 Oral Solution, OCR-002 IV Solution
- Keywords
- Child-Pugh Class B
- Medical subject headings
- Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OCR-002 IR Oral TabletDrug
Also called Ornithine phenylacetate
OCR-002 3 gram immediate release (IR) tablet for oral administration
OCR-002 Oral SolutionDrug
Also called Ornithine phenylacetate
OCR-002 5 gram solution for oral administration
OCR-002 IV SolutionDrug
Also called Ornithine phenylacetate
OCR-002 5 gram solution for intravenous (IV ) administration
| Study group | Role | What they receive |
|---|---|---|
| OCR-002 - Treatment A | Experimental | A single 5 g oral dose of OCR-002 oral solution administered under fasting conditions Receives: 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 Receives: 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 Receives: 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 Receives: 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) Receives: 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) Receives: 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) Receives: Drug: OCR-002 IR Oral Tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 5 days
AUC of oral, immediate-release (IR) OCR 002 tablets
AUC of oral, immediate-release (IR) OCR 002 tablets will be determined.
Measured: 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.
Measured: 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.
Measured: 5 days
Elimination rate constant (kel) of OCR-002 immediate-release tablets
kel of OCR-002 immediate-release tablets will be determined.
Measured: 5 days
T1/2 of OCR-002 immediate-release tablets
T1/2 of OCR-002 immediate-release tablets will be determined.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 5 days
Secondary outcomes (20)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 5 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Feb 2019
- Study start15 Aug 2016
- Primary completion30 Nov 2017
- Study completion31 Dec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CirrhosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ocera Therapeutics, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Team Leader, Study director, Mallinckrodt
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03846843
- Sponsor's protocol ID
- OCR002-SP103
- Status last verified
- Sep 2021
- First submitted
- 2 Nov 2017
- Last updated
- 20 Sep 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03846843
- Acronym / sponsor ID
- OCR002-SP103
- Conditions
- Cirrhosis
- Keywords
- Child-Pugh Class B
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Ocera Therapeutics, Inc.Industry (pharma, biotech, devices)
- Study start
- 15 Aug 2016 (actual)
- Primary completion
- 30 Nov 2017 (actual)
- Study completion
- 31 Dec 2017 (actual)
- First posted
- 20 Feb 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| OCR-002 - Treatment A | Experimental | Drug: OCR-002 Oral SolutionA single 5 g oral dose of OCR-002 oral solution administered under fasting conditions |
| OCR-002 - Treatment B | Experimental | Drug: OCR-002 Oral SolutionA single 5 g oral dose of OCR-002 oral solution administered under fed conditions |
| OCR-002 - Treatment C | Experimental | Drug: OCR-002 IV SolutionA single 5 g intravenous dose of OCR-002 solution infused over 1 hour under fasting conditions |
| OCR-002 - Treatment D | Experimental | Drug: OCR-002 IV SolutionA single 5 g oral dose of OCR-002 oral solution administered under fasting conditions following discontinuation of lactulose |
| OCR-002 - Treatment E | Experimental | Drug: OCR-002 IR Oral Tablet6 g OCR-002 per day (2 tablets TID for 6 g total daily dose) |
| OCR-002 - Treatment F | Experimental | Drug: OCR-002 IR Oral Tablet12 g OCR-002 per day (4 tablets TID for 12 g total daily dose) |
| OCR-002 - Treatment G | Experimental | Drug: OCR-002 IR Oral Tablet21 g OCR-002 per day (7 tablets TID for 21 g total daily dose) |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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)
Key exclusion criteria (34 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OCR-002 IR Oral TabletAlso: Ornithine phenylacetateOCR-002 3 gram immediate release (IR) tablet for oral administration | Drug | OCR-002 - Treatment E, OCR-002 - Treatment F, OCR-002 - Treatment G |
| OCR-002 Oral SolutionAlso: Ornithine phenylacetateOCR-002 5 gram solution for oral administration | Drug | OCR-002 - Treatment A, OCR-002 - Treatment B |
| OCR-002 IV SolutionAlso: Ornithine phenylacetateOCR-002 5 gram solution for intravenous (IV ) administration | Drug | OCR-002 - Treatment C, OCR-002 - Treatment D |
Primary outcome
Maximum concentration (Cmax) of PAA and PAGN following described treatment
Time frame: 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.
Time to Cmax (Tmax) of PAA and PAGN
Time frame: 6 months
Plasma concentrations of PAA, PAGN and ornithine will be analyzed by non-compartmental PK methods.
Area under the plasma concentration time curve over time (AUC0-t) of PAA and PAGN following described treatment
Time frame: 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.
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)
Time frame: 6 months
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)
Time frame: 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)
Time frame: 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)
Time frame: 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 Cmax of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh Classes A and C)
Time frame: 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 the AUC of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh Classes A and C)
Time frame: 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)
Time frame: 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 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)
Time frame: 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.
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)
Time frame: 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)
Time frame: 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.
Cmax of OCR-002 immediate-release tablets over the course of TID dosing for 5 days
Time frame: 5 days
Cmax of OCR-002 immediate-release tablets over the course of TID dosing for 5 days will be determined.
Cmax of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet administration for 5 days in participants with cirrhosis
Time frame: 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.
Ammonia-lowering (Tmax) effect of OCR-002 over the course of TID dosing for 5 days
Time frame: 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
Time frame: 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
Time frame: 5 days
AUC of PAA, PAGN, and ornithine following 3 times a day (TID) OCR 002 oral tablet will be determined.
Degree of fluctuation (Day 5) of OCR-002 immediate-release tablets
Time frame: 5 days
Degree of fluctuation (Day 5) of OCR-002 immediate-release tablets will be determined.
Elimination rate constant (kel) of OCR-002 immediate-release tablets
Time frame: 5 days
kel of OCR-002 immediate-release tablets will be determined.
T1/2 of OCR-002 immediate-release tablets
Time frame: 5 days
T1/2 of OCR-002 immediate-release tablets will be determined.
Drug elimination (Cmax) following discontinuation of OCR-002 oral tablets after TID administration for 5 days
Time frame: 5 days
Drug elimination (Cmax) following discontinuation of OCR-002 oral tablets will be determined.
Urinary excretion profile of urea following TID administration of OCR-002 oral tablets of each treatment in participants with cirrhosis
Time frame: 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
Time frame: 5 days
Urinary excretion of PAGN following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis will be determined
Urinary excretion of PAA following TID administration of OCR 002 oral tablets of each treatment in participants with cirrhosis
Time frame: 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
Time frame: 5 days
Change from Baseline in serum BUN over the course of TID dosing for 5 days will be calculated.
Change from Baseline in serum creatinine over the course of TID dosing for 5 days
Time frame: 5 days
Change from Baseline in serum creatinine over the course of TID dosing for 5 days will be calculated.
Change from Baseline in creatinine clearance over the course of TID dosing for 5 days
Time frame: 5 days
Change from Baseline in creatinine clearance over the course of TID dosing for 5 days will be calculated.
Urea clearance over the course of TID dosing for 5 days
Time frame: 5 days
Urea clearance 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
Time frame: 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.
20 secondary outcomes
Adverse events of 5 g OCR-002 oral solution in participants with cirrhosis (Child-Pugh class A and C)
Time frame: 6 months
Adverse events of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 6 months
Change from Baseline in sitting blood pressure of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets
Time frame: 6 months
Change from Baseline in heart rate of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets
Time frame: 6 months
Change from Baseline in body temperature of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 6 months
Proportion of participants with abnormal hematology values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets
Time frame: 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)
Time frame: 6 months
Proportion of participants with abnormal urinalysis values of OCR-002 in participants with cirrhosis following multiple TID doses of OCR-002 tablets
Time frame: 6 months
Cmax of ornithine over the course of TID administration of OCR-002 for 5 days
Time frame: 5 days
Tmax of ornithine over the course of TID administration of OCR-002 for 5 days
Time frame: 5 days
AUC0-24 of ornithine over the course of TID administration of OCR-002 for 5 days
Time frame: 5 days
Degree of fluctuation of ornithine over the course of TID administration of OCR-002 for 5 days
Time frame: 5 days
kel of ornithine over the course of TID administration of OCR-002 for 5 days
Time frame: 5 days
T1/2 of ornithine over the course of TID administration of OCR-002 for 5 days
Time frame: 5 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Team Leader study director
Mallinckrodt
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing OCR-002 IR Oral Tablet, OCR-002 Oral Solution and OCR-002 IV Solution in people with Cirrhosis, run by Ocera Therapeutics, Inc. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum concentration (Cmax) of PAA and PAGN following described treatment (time frame: 6 months). The study lists 30 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2021.