Clinical Trial: Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

Brief Summary:

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 10-20g/24h (0.42-.83g/h) will achieve steady state plasma concentrations within 6-12h with little additional accumulation in the ALI/ALF setting.
• Treatment with OCR-002 will reduce ammonia and improve neurological function in patients with acute liver failure/severe acute liver injury.

Detailed Summary:

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) 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.

Sponsor: William Lee

Current Primary Outcome: Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 30 Days ]

Original Primary Outcome: Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 30 Days ]

Current Secondary Outcome:

• Measurement of OCR-002 Plasma Concentration [ Time Frame: 30 days ]
  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 Ammonia [ Time Frame: 30 Days ]
  To evaluate the effect of OCR-002 on ammonia levels in patients with acute liver failure/severe acute liver injury
• Neurological Function measured by the Glasgow Coma Scale (GCS) [ Time Frame: 30 Days ]
  To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury
• Neurological Function measured by the West Haven Criteria (WHC) [ Time Frame: 30 Days ]
  To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury
• Neurological Function measured by the Orientation log (O-log) [ Time Frame: 30 Days ]
  To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury

Original Secondary Outcome:

• Measurement of OCR-002 Plasma Concentration [ Time Frame: 30 days ]
  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 ]
  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: 6 Days ]
  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: 6 Days ]
  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: 6 Days ]
  To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.

Information By: University of Texas Southwestern Medical Center

Dates:
Date Received: February 24, 2012
Date Started: June 2012
Date Completion: September 2017
Last Updated: February 4, 2016
Last Verified: February 2016