Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure (STOP-ALF)
|ClinicalTrials.gov Identifier: NCT01548690|
Recruitment Status : Completed
First Posted : March 8, 2012
Last Update Posted : January 12, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Acute Liver Failure Acute Liver Injury||Drug: Ornithine phenylacetate||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||47 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||June 2012|
|Primary Completion Date :||February 23, 2017|
|Study Completion Date :||February 23, 2017|
Experimental: Ornithine Phenylacetate
Ornithine Phenylacetate is administered intravenously, through a peripheral venous catheter. Each infusion should will be administered over a period of 120 hours.
Drug: Ornithine phenylacetate
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 Name: OCR-002
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 30 Days ]To evaluate the safety and tolerability of OCR-002 in patients with acute liver failure/severe acute liver injury
- Measurement of OCR-002 Plasma Concentration [ Time Frame: 30 days ]To evaluate the steady state pharmacokinetic and pharmacodynamic profile of OCR-002 in patients with impaired and intact renal function using urinary PAGN as a surrogate marker
- Change in Ammonia [ Time Frame: 30 Days ]To evaluate the effect of OCR-002 on ammonia levels in patients with acute liver failure/severe acute liver injury
- Neurological Function measured by the Glasgow Coma Scale (GCS) [ Time Frame: 30 Days ]To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury
- Neurological Function measured by the West Haven Criteria (WHC) [ Time Frame: 30 Days ]To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury
- Neurological Function measured by the Orientation log (O-log) [ Time Frame: 30 Days ]To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01548690
|United States, California|
|University of California, San Francisco|
|San Francisco, California, United States, 94107|
|United States, Connecticut|
|Yale University School of Medicine|
|New Haven, Connecticut, United States, 06520|
|United States, Georgia|
|Atlanta, Georgia, United States, 30322|
|United States, Illinois|
|Chicago, Illinois, United States, 60611|
|United States, Kansas|
|University of Kansas Medical Center|
|Kansas City, Kansas, United States, 66160|
|United States, Michigan|
|University of Michigan Medical Center|
|Ann Arbor, Michigan, United States, 48109|
|United States, Ohio|
|The Ohio State University|
|Columbus, Ohio, United States, 43210|
|United States, South Carolina|
|Medical University of South Carolina|
|Charleston, South Carolina, United States, 29425|
|United States, Texas|
|University of Texas Southwestern Medical Center|
|Dallas, Texas, United States, 75390|
|United States, Virginia|
|Virginia Commonwealth University|
|Richmond, Virginia, United States, 23298|
|United States, Washington|
|University of Washington|
|Seattle, Washington, United States, 98195|
|Principal Investigator:||William M Lee, MD||UT Southwestern Medical Center|