A Phase 2a Study to Evaluate the Safety and Tolerability of OCR-002 (ornithine phenylacetate) in the Treatment of Patients with Acute Liver Failure/Severe Acute Liver Injury due to Acetaminophen Overdose (STOP-ALF)
This is a Phase 2a, multi-center, open-label study, conducted in two cohorts in patients diagnosed with acute liver failure/severe acute liver injury (aLF/aLi) due to presumed acetaminophen overdose. Patients will be stratified based upon minimal renal dysfunction or comprised renal function. Cohorts of 12 patients with minimal renal dysfunction and approximately 12 with compromised renal 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 determined 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 minimal renal dysfunction (Cohort 1) and 12 patients with compromised renal function (Cohort 1) using the following schedule:
* Dose Level 1 - Subjects assigned to Dose Level 1will receive 3.33 g/24 hours for a total of 5 days of treatment
* Dose Level 2 x Subjects assigned to Dose Level 2 will receive 3.33 g/24 hours for 12 hours; if that dose is
well tolerated, the dose is increased to 6.65 g/24 hours for the next 4 and a half days (total of 5 days
* Dose Level 3 xSubjects assigned to Dose Level 3 will receive 3.33 g/24 hours for 12 hours;
if that dose is well tolerated, the dose is increased to 6.65 g/24 hours for 12 hours; if that
dose is well tolerated, the dose is increased to 10 g/24 hours for 4 days (total of 5 days
if there are no safety concerns, the schedule will be as follows:
Cohort 1, Dose Level 1 (3 evaluable subjects)
Cohort 1, Dose Level 2 (3 evauluable subjects)
enrollment paused for Safety Review Committee (SRC) review of safety and pK data (6 evaluable subjects)
Cohort 1, Dose Level 3 (~6 evaluable subjects)
Cohort 2, Dose Level 1 (3 evaluable subjects)
Cohort 2, Dose Level 2 (3 evaluable subjects)
enrollment paused for SRC Review of safety and pK data (~12 evaluable subjects)
Cohort 2, Dose Level 3 (~6 evaluable subjects)
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 up to 32 hour screening period. During this period, patients will be consent for participation, and then screened for eligibility. inclusion into the study will require that the patients meets one of the protocol specified criteria for minimal rendal dysfunction and comprised renal function.
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 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).
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[Single Quote]s legally authorized representative or family member if he/she is considered encephalopathic (ALF).
5. Venous ammonia level >60 [MICRO-SYMBOL]mol/L at baseline (within 8h prior to T0/initiation of infusion).
The conversion factor/units used for ammonia in recruiting sites is [MICRO-SYMBOL]mol/L to [MICRO-SYMBOL]g/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 < 1.5 mg/dL.
b. Cohort 2 only: Creatinine >= 1.5 mg/dL and 10 mg/dL.
7. Mean arterial pressure of >65 mmHg with no use of vasopressors and in Cohort 2 patients, after correction of hypovolemia.
8. Patients enrolled in the Acute Liver Failure Study (IRB #062010-126)