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.
The primary objective of the study was to evaluate the safety and tolerability of ascending doses of OPA in patients with ALF and severe ALI with and without renal impairment. Secondary objectives included the evaluation of the PK and pharmacodynamic profile of OPA in patients with ALI/ALF. Exploratory objectives included the evaluation of the effects of OPA on serum ammonia.
Forty-seven patients with ALI/ALF were enrolled into the study, 36 of whom were predefined as evaluable (OPA infusion 72 hours) for measurement of ammonia-lowering efficacy (Table 1). The normal renal function cohort (serum creatinine level at screening of 1.5 mg/dL [n 5 30]) differed significantly from the impaired renal function cohort (creatinine level >1.5 mg/dL [n 5 17]) by percent female sex (80 versus 41%, respectively), the proportion with acetaminophen overdose as the etiology (83 versus 41%), and by definition, median serum creatinine (0.7 versus 2.5 mg/dL) and percent on continuous renal replacement therapy (CRRT; 3.3 versus 59%, respectively).
Liver Disease
Interventional
2012-06
2017-02
Acute Liver Failure
Pharmacokinetic/Pharmacodynamic, Phenylacetate, Hepatitis B, Autoimmune Hepatitis, Ornithine, Hepatic Encephalopathy, Renal Function Cohort, Acute Liver Failure, Acute Liver Injury, Acetaminophen Toxicity, Drug-Induced Liver Injury, Ammonia-Lowering Therapies
Division of Digestive Diseases and Nutrition
Document Name | Description | Document Type | File Format | Compliance | Download |
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Dataset Name | Description | # of Records | # of Variables | File Format(s) |
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End of Study Dataset | Captures end of study data including date and reason for ending the study | 47 | sas7bdat (128 KB); csv (1.56 KB) | |
Ammonia Collection Log Dataset | Captures data including date/time/type/location of blood draw and ammonia levels reported in the Ammonia Collection Log | 627 | sas7bdat (128 KB); csv (22.83 KB) | |
Study Drug Monitoring Log Dataset | Captures study drug monitoring data | 1316 | sas7bdat (128 KB); csv (26.77 KB) | |
West Haven Scale for Hepatic Encephalopathy Dataset | Captures data from the West Haven Scale for Hepatic Encephalopathy, including sedation status and scale grade | 412 | sas7bdat (128 KB); csv (15.71 KB) | |
Glasgow Coma Scale Dataset | Captures data from the Glasgow Coma Scale, including sedation status, coma grade, eye opening, verbal and motor response | 460 | sas7bdat (192 KB); csv (20.47 KB) | |
Day 30 Ammonia Dataset | Captures data at the Day 30 visit including date/time/type/location of blood draw and ammonia levels reported in the Ammonia Collection Log | 15 | sas7bdat (128 KB); csv (751 B) | |
Adverse Events Dataset | Captures adverse event data, including type, intubation status, relationship to study drug, severity, outcome, and date of resolution | 118 | sas7bdat (128 KB); csv (9.91 KB) | |
Electrocardiogram Dataset | Captures electrocardiogram data including date/time of scan, average QTc, and arrhythmia | 325 | sas7bdat (128 KB); csv (14.47 KB) | |
Pharmacokinetic Dataset | Pharmacokinetic data was read at a central laboratory and steady state values were calculated by a central reader | 46 | csv (3.14 KB); sas7bdat (128 KB) | |
End of Treatment Dataset | Captures end of treatment data, including status of treatment and reasons for premature study infusion termination | 47 | sas7bdat (128 KB); csv (1.53 KB) | |
Physical Exam Dataset | Captures physical exam data, including any abnormal findings | 460 | sas7bdat (192 KB); csv (18.55 KB) | |
Registry Dataset | Captures registry data, including etiology and indication of liver injury or liver failure, which are derived from the ALFSG registry database | 47 | sas7bdat (128 KB); csv (603 B) | |
Demographics Dataset | Captures demographic data | 47 | sas7bdat (128 KB); csv (1.76 KB) | |
Neurological Exam Dataset | Captures neurological data, including asterixis, pupillary, patellar, and biceps reflexes, babinski, and posturing | 408 | sas7bdat (192 KB); csv (18.07 KB) | |
Vital Signs Dataset | Captures vital signs data | 460 | sas7bdat (192 KB); csv (24.75 KB) | |
Urinalysis Dataset | Captures urinalysis results data | 207 | sas7bdat (128 KB); csv (9.74 KB) | |
The Orientation Log (O-Log) Dataset | Captures responses from the Orientation Log questions such as what city the participant is in and what year it is | 314 | sas7bdat (128 KB); csv (14.4 KB) | |
Medical History Dataset | Captures medical history data, including hospitalization and specific symptoms or signs | 47 | sas7bdat (128 KB); csv (4.88 KB) | |
Study Drug Infusion Log Dataset | Captures study drug infusion data including infusion site, start/stop time, highest MAP, lowest MAP, highest ICP, and lowest ICP | 109 | sas7bdat (128 KB); csv (3.94 KB) | |
Labs Dataset | Captures results from laboratory tests | 423 | sas7bdat (256 KB); csv (61.54 KB) | |
Eligibility Dataset | Captures eligibility data, including venous ammonia, creatinine, mean arterial pressure, medical history including chronic liver disease, and demographic information | 47 | sas7bdat (128 KB); csv (5.1 KB) |