Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure (STOP-ALF)
This Phase 2a clinical study is designed to provide data on OCR-002 in patients with acute liver failure/acute liver injury (ALF/ALI) in regard to:
- safety and tolerability;
- metabolism of the compound to glutamine and phenylacetylglutamine (PAGN);
- its effect on circulating ammonia levels and neurological function in patients with and without impaired renal function after continuous infusion at different infusion rates.
Subjects will receive up to 120 hours (5 days) of drug infusion, followed by a 30 day follow-up visit post infusion. It is anticipated that this early safety and tolerability study, with appropriate PK/PD data, will lead to a development program for the use of OCR-002 in the treatment of hyperammonemia either due to ALF or possibly other liver conditions. The hypotheses are:
- Treatment with OCR-002 is safe and tolerable in patients with acute liver failure/acute liver injury due to acetaminophen overdose or drug-induced liver injury, autoimmune hepatitis, viral hepatitis or indeterminate etiologies.
- A dose of 20g/24h (0.84g/h) will achieve steady state plasma concentrations within 6-12h with little additional accumulation in the ALI/ALF setting.
- Treatment with OCR-002 will improve neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.
Acute Liver Failure
Acute Liver Injury
Drug: Ornithine phenylacetate
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 2a Study to Evaluate the Safety and Tolerability of OCR-002 (Ornithine Phenylacetate) in the Treatment of Patients With Acute Liver Failure|
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 30 Days ] [ Designated as safety issue: Yes ]To evaluate the safety and tolerability of OCR-002 in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose
- Measurement of OCR-002 Plasma Concentration [ Time Frame: 30 days ] [ Designated as safety issue: No ]To evaluate the steady state pharmacokinetic and pharmacodynamic profile of OCR-002 in patients with impaired and intact renal function using urinary PAGN as a surrogate marker
- Change in Venous Ammonia [ Time Frame: 30 Days ] [ Designated as safety issue: No ]To evaluate the effect of OCR-002 on venous ammonia levels in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose
- Neurological Function measured by the Glasgow Coma Scale (GCS) [ Time Frame: 30 Days ] [ Designated as safety issue: No ]To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.
- Neurological Function measured by the West Haven Criteria (WHC) [ Time Frame: 30 Days ] [ Designated as safety issue: No ]To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.
- Neurological Function measured by the Orientation log (O-log) [ Time Frame: 30 Days ] [ Designated as safety issue: No ]To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.
|Study Start Date:||June 2012|
|Estimated Study Completion Date:||June 2016|
|Estimated Primary Completion Date:||June 2016 (Final data collection date for primary outcome measure)|
Experimental: Ornithine Phenylacetate
Ornithine Phenylacetate is administered intravenously, through a peripheral venous catheter. Each infusion should will be administered over a period of 120 hours.
Drug: Ornithine phenylacetate
Subjects [~24 with minimal renal dysfunction (Cohort1) or ~24 with comprised renal function (Cohort 2)] will be enrolled to receive identical quantities of OCR-002 for assessment of pharmacokinetics (pk).
OCR-002 administered in the vein at:
•Dose Level 4 (DL4) -equal to 20 g/24 hours continuously for 5 days.
Other Name: OCR-002
There is strong experimental and clinical rationale for the use of ammonia-lowering therapies in ALF. Ammonia is normally produced in the gut and transformed by the liver into urea. As the liver fails, ammonia increases in the systemic circulation and enters into the brain. The result of a rapid rise in ammonia or related compounds in the cerebral circulation is hepatic encephalopathy (HE), a reversible neuropsychiatric condition that ranges in severity from mild impairment in attention, to delirium, the development of cerebral edema, coma and death. This is a Phase 2a, multi-center, open-label study, conducted in two cohorts in patients diagnosed with acute liver failure/acute liver injury (ALF/ALI) due to acetaminophen overdose who meet inclusion/exclusion criteria. This study is designed to provide data on OCR-002 with regards to
- the effect on circulating ammonia levels in patients with acute liver failure with and without impaired renal function at different doses after single and continuous infusion
- safety and dose tolerability as well as
- providing data on the metabolites, glutamine and phenylacetylglutamine in this patient population.
It is anticipated that this early efficacy, safety, tolerability, Pharmacokinetic/Pharmacodynamic (PK/PD) and dose-ranging study will lead to a Phase 3 development program for the use of OCR-002 in the treatment of hyperammonemia due to ALF. No clinical outcome measures will be formally studied because of the small sample size.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01548690
|Contact: William M. Lee, MDemail@example.com|
|United States, California|
|University of California, San Francisco||Recruiting|
|San Francisco, California, United States, 94107|
|Contact: Bilal Hameed, MD 415-476-6160 bilal.Hameed@ucsf.edu|
|Principal Investigator: Bilal Hameed, MD|
|United States, Georgia|
|Atlanta, Georgia, United States, 30322|
|Contact: Ram Subramanian, MD 404-712-3833 firstname.lastname@example.org|
|Principal Investigator: Ram Subramanian, MD|
|United States, Illinois|
|Chicago, Illinois, United States, 60611|
|Contact: Daniel R Ganger, MD 312-695-4496 DGanger@nmff.org|
|Principal Investigator: Daniel R Ganger, MD|
|United States, Kansas|
|University of Kansas Medical Center||Recruiting|
|Kansas City, Kansas, United States, 66160|
|Contact: Jody Olson, MD 913-588-1591 email@example.com|
|Principal Investigator: Jody Olson, MD|
|Sub-Investigator: Ryan Taylor, MD|
|United States, Michigan|
|University of Michigan Medical Center||Recruiting|
|Ann Arbor, Michigan, United States, 48109|
|Contact: Robert Fontana, M.D 734-936-4780 firstname.lastname@example.org|
|Principal Investigator: Robert Fontana, MD|
|United States, Ohio|
|The Ohio State University||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: James Hanje, MD 614-293-6255 email@example.com|
|Principal Investigator: James Hanje, MD|
|United States, South Carolina|
|Medical University of South Carolina||Recruiting|
|Charleston, South Carolina, United States, 29425|
|Contact: David Koch, MD 843-792-6901 firstname.lastname@example.org|
|Principal Investigator: David Koch, MD|
|United States, Texas|
|University of Texas Southwestern Medical Center||Recruiting|
|Dallas, Texas, United States, 75390|
|Contact: William M Lee, M.D. 214-645-6110 William.Lee@utsouthwestern.edu|
|Principal Investigator: William M Lee, MD|
|United States, Virginia|
|Virginia Commonwealth University||Recruiting|
|Richmond, Virginia, United States, 23298|
|Contact: Richard T Stravitz, M.D. 804-828-8514 email@example.com|
|Principal Investigator: Richard T Stravitz, MD|
|United States, Washington|
|University of Washington||Recruiting|
|Seattle, Washington, United States, 98195|
|Contact: Iris Liou, MD 206-598-4908 firstname.lastname@example.org|
|Principal Investigator: Iris Liou, MD|
|Principal Investigator:||William M Lee, MD||UT Southwestern Medical Center|