A Phase 2a Study to Evaluate the Safety and Tolerability of OCR-002 (ornithine phenylacetate) in the Treatment of Patients with Acute Liver Failure due to Acetaminophen Overdose (STOP-ALF)

Summary

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. Patients will be stratified based upon normal renal function or comprised kidney function. Cohorts of 18 patients with normal renal function and approximately 6 with compromised kidney function will be assigned sequentially to 3 escalating dose levels of OCR-002 for assessment of pharmacokinetics. Escalation to the next dose level will be contingent upon the safety and tolerability of the preceding dose level as determinded by the safety charter committee. If all regimes are studied, a total of 24 patients will be enrolled across all study sites.

The study duration will be 30 days. OCR-002 will be administered to cohorts of 12 patients with normal renal function using the following schedule:

Subjects 1-12
Group 1 (normal kidney function):

* Dose Level 1 - The first 3 subjects enrolled in the study will receive 3.33 g/24 hours for a total of 5 days treatment

* Dose Level 2 – The next 3 subjects enrolled in the study will receive 3.33 g/24 hours for 12 hours then increase dose to 6.65 g/24 hours for the next 4 and a half days (total of 5 days treatment)

* Dose Level 3 – The next 6 subjects enrolled in the study will receive 3.33 g/24 hours for 12 hours, increase to 6.65 g/24 hours for 12 hours, then increase to 10 g/24 hours for 4 days (total of 5 days treatment).

If there are no safety concerns, cohorts of 6 patients with normal kidney function and 6 patients with comprised kidney function will receive OCR-002 dose at 3.33 g/24 hours for 12 hours, increase to 6.65 g/24 hours for 12 hours, then increase to 10 g/24 hours for 4 days (total of 5 days treatment). During the Post-Treatment Period, assessments of vital signs, laboratory measurements and safety monitoring will continue to be performed through Day 6 and evaluated at Day 30.

The 30 day study period is preceded by a 8 to 32 hour screening period. During this period, patients will be consent for participation, and then screened for elgibility. Inclusion into the study will require that the patients meets one of the protocol specified criteria for normal and comprised renal function (see Section 6.1). Thus patients must either be observed to have a protocol specified reduction in urine output for a required amount of time, or have reduced urine output in the presence of a fluid challenge.

Participant Eligibility

To be consided eligible to participate in this study, as subject must meet the following inclusion criteria:
1. Men and women, ages 18-65 (have not reached their 66th birthday).
2. Acute liver failure secondary to 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).
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 >75 µmol/L at baseline (within 8h prior to T0/initiation of infusion).
The conversion factor/units used for ammonia in recruiting sites is µmol/L to µg/dL. To obtain this conversion, divide the ammonia level in units of umol/L by 0.587 to convert the value to ug/dL units.

Example: (30 umol/L)/0.587 = 51 ug/dL (normal reference interval: 15-56 ug/dL)

6. Serum creatinine levels as follows:
a. Cohort 1: Creatinine < 1.0 mg/dL.
b. Cohort 2 only: Creatinine ≥ 1.0 mg/dL.
7. For Cohort 1, urine output defined as >300mL over 8h after 1500ml of normal saline. For Cohort 2, oliguria (defined as a < 300mL of urine output over 8 hr after 1500ml of normal saline).
8. Mean arterial pressure of >65 mmHg.
9. Patients enrolled in the Acute Liver Failure Study (IRB #062010-126)