Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury
Condition: Acute Liver Failure; Acute Liver Injury
MeSH terms: Liver Failure; Hepatic Insufficiency; Liver Failure, Acute; Wounds and Injuries
Study type: Interventional
Phase: Phase 2

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 description: 
      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.
    

Intervention name(s): Ornithine Phenylacetate
Intervention type(s): Drug
Intervention description(s): Up to 36 patients will be enrolled into 2 groups [~18 with minimal renal dysfunction (Cohort 1) & ~18 w/ comprised renal function (Cohort 2)] and receive OCR-002 infusion for at least 72 hrs. OCR-002 will be administered in the vein and pharmacokinetics (pk) assessed for all subjects who receive the infusion.
The first 24 enrolled subjects received OCR-002 at 3 ascending dose levels (DLs 1-3) with a maximum target infusion rate equivalent to 10g/24h.
The remaining 12 patients (~6 Cohort 1 & ~6 Cohort 2) will be enrolled and receive identical quantities of OCR-002 at 20g/24hr continuously for 5 days (Dose Level 4).
Other intervention name(s): OCR-002
Intervention MeSH terms: Phenylacetic acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ornithine; phenylacetate; acetaminophen toxicity; acute liver failure; hepatitis B; autoimmune hepatitis; drug-induced liver injury