Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury (STOP-ALF)
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|ClinicalTrials.gov Identifier: NCT01548690|
Recruitment Status : Completed
First Posted : March 8, 2012
Results First Posted : September 20, 2018
Last Update Posted : October 30, 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/Severe Acute Liver Injury|
|Study Start Date :||June 2012|
|Actual Primary Completion Date :||February 23, 2017|
|Actual Study Completion Date :||February 23, 2017|
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 That do Not Tolerate the Administered Dose and Had Grade 3 or 4 Treatment Emergent 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: 24 Hours after last infusion ]To evaluate the steady state pharmacokinetic and pharmacodynamic profile of OCR-002 in patients with impaired and intact renal function using urinary phenylacetylglutamine (PAGN) as a surrogate marker
- Change in Ammonia [ Time Frame: Baseline and 72 Hours ]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 West Haven Criteria (WHC) for Hepatic Encephalopathy [ Time Frame: 120 hours from start of infusion ]The West Haven Criteria (WHC) for Hepatic Encephalopathy measures the severity of encephalopathy and patient's level of consciousness. The scale ranges from 0 to 4; a minimum score of 0 represents a better outcome, and a maximum total score of 4 represents a worse outcome. A score of 0 corresponds to normal consciousness and behavior and normal neurological examination. A score of 1 corresponds to mild lack of awareness, shortened attention span, and impaired addition or subtraction; mild asterixis or tremor. A score of 2 corresponds to lethargy, disorientated or inappropriate behavior, obvious asterixis; slurred speech. A score of 3 corresponds to somnolent but arousable, gross disorientation or bizarre behavior, muscle rigidity and clonus; hyperreflexia. A score of 4 corresponds to coma and decerebrate posturing.
- Neurological Function Measured by the Orientation Log (O-log) [ Time Frame: 30 Days ]The orientation log focuses on orientation to place, time, and circumstance. There are 10 items on the orientation log, which are scored 0-3. A spontaneous correct response is awarded 3 points. A spontaneous response that is lacking or incorrect, but a correct response is provided following a logical cue is awarded 2 points. A score of 1 is given if spontaneous and cued responses are lacking or incorrect, but a correct response is provided in a recognition format. A score of 0 is given if the spontaneous, cued, or recognition format does not generate a correct answer. Scores from the 10 items are summed and the final score ranges from 0 to 30.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
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|