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
Intervention: Ornithine Phenylacetate
Intervention description: 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).
Intervention MeSH terms: Phenylacetic acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 47.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: ornithine; phenylacetate; acetaminophen toxicity; acute liver failure; hepatitis B; autoimmune hepatitis; drug-induced liver injury

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Men and women, ages 18-65 (have not reached their 66th birthday).

          2. Acute liver failure, defined as the development of coagulopathy (International
             normalized ratio [INR] ≥1.5) with encephalopathy in a patient with no prior history of
             liver disease, with onset of symptoms within 28 days of the inciting event. Patients
             may have either a history of acetaminophen overdose (defined as >4 g/day within 7 days
             of presentation) and/or detectable acetaminophen levels in the serum, with a pattern
             of liver function tests typical for acetaminophen toxicity (bilirubin < 10 mg/dL and
             alanine aminotransferase (ALT) ≥1000 IU/L), or a diagnosis of hepatitis A, hepatitis
             B, drug-induced liver injury, autoimmune hepatitis or indeterminate cause based on
             standard criteria.

          3. ALI patients may also be enrolled (those meeting the above criteria plus coagulopathy
             (INR ≥ 2.0) and no evidence of encephalopathy)

          4. Written informed consent from the patient (ALI) or patient's legally authorized
             representative or family member if he/she is considered encephalopathic (ALF).

          5. Ammonia level ≥60 μmol/L at baseline (within 8h prior to T0/initiation of infusion).

          6. Serum creatinine levels as follows:

               1. Cohort 1: Creatinine ≤1.5 mg/dL; and

               2. Cohort 2: Creatinine >1.5 mg/dL and <10mg/dL.

          7. Mean arterial pressure of >65 mmHg.

        Exclusion Criteria:

          1. History of chronic liver disease.

          2. Signs of overt cerebral herniation, or uncontrolled intracranial hypertension by
             intracranial pressure (ICP) monitoring (if applicable).

          3. Evidence of Wilson's disease, alcoholic hepatitis, biliary obstruction, ischemic
             hepatitis, severe acute renal tubular necrosis (ATN) due to shock, or any patient with
             ongoing hypotension.

          4. Significant gastrointestinal bleeding (coffee grounds per nasogastric tube and/or
             melena).

          5. Hemodynamic instability, defined by a mean arterial pressure of <65 mmHg.

          6. Cardiopulmonary complications such as pulmonary edema, aspiration pneumonia, heart
             failure.

          7. QT interval of >500msec at baseline EKG.

          8. Pregnancy.

          9. History of malignancy that has not been cured or any cancer in remission for less than
             1 within the past 5 year. Non-melanoma skin cancers do not preclude participation in
             the trial.

         10. Concomitant administration of drugs known to interfere with renal excretion of
             phenylacetylglutamine or those medications that may induce hyperammonemia such as
             haloperidol, valproic acid and systemic corticosteroids (prohibited during the study).
             Alternative ammonia modifying agents such as lactulose and rifaximin are not
             considered standard of care and are prohibited during the study period.

         11. Any other health condition that would preclude participation in the study in the
             judgment of the principal investigator.