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

Study ID
ALFSG-OCR-002

Cancer Related
No

Healthy Volunteers
No

Study Sites

  • UT Southwestern-Clinical Translational Research Center (CTRC)
  • Clements University Hospital
  • Zale Lipshy University Hospital
  • Parkland Health & Hospital System

Contact
Angela Bowling
214/645-3971
angela.bowling@utsouthwestern.edu

Principal Investigator
William Lee

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 Overview


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 10g/24h (0.42g/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.

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) 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 escalation 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.

Participant Eligibility


Inclusion Criteria:

1. Men and women, ages 18-65 (have not reached their 66th birthday).

2. Acute liver failure secondary to presumed acetaminophen toxicity, 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 7 days of the inciting event and with 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 drug-induced liver injury, autoimmune hepatitis, viral hepatitis
A or B, or indeterminate cause.

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. Venous ammonia level >60 µmol/L at baseline (within 8h prior to T0/initiation of
infusion).

6. Serum creatinine levels as follows:

- Cohort 1: Creatinine < 1.5 mg/dL.

- Cohort 2 only: Creatinine ≥ 1.5 mg/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 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 or the use
of vasopressors to support blood pressure.

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. Use of
rifaximin/lactulose more than 8 hours prior to initial infusion will not be an
exclusion.

11. Any other health condition that would preclude participation in the study in the
judgment of the principal investigator.