13C-Methacetin Breath Test for the Prediction of Outcome in in ALI or ALF

Overview

The ALFSG-MBT protocol is for a multicenter, open label, non-randomized study to determine the value of Breath Identification® (BreathID®) N-(4-Methoxy-13C-phenyl)acetamide (13C-Methacetin) Breath Test System in predicting the outcome of patients diagnosed with severe acute liver injury that is not related to acetaminophen overdose or acute liver failure who meet inclusion/exclusion criteria. Up to 200 evaluable patients will be enrolled. An evaluable patient is one who has completed one or more breath tests for at least 30 minutes after administration of the 13C-Methacetin solution (test substrate). The Breath Test will be performed up to five times during the study period on all enrolled patients. The first Breath Test will be performed upon admission into the study (Day 1) and repeated on Days 2, 3, 5 and 7 provided no contra-indications are present. Each test continuously measures changes in the metabolism of the 13C-Methacetin in order to assess the improvement or deterioration in liver metabolic function about improvement or deterioration in liver metabolic function. If an enrolled non-APAP ALI or ALF patient receives a liver transplant, is discharged /transferred from the hospital or dies prior to Day 7, additional Breath Tests will not be performed. Patients will be contacted for the Day 21 follow up (21 days after enrollment into the trial) to determine spontaneous survival, transplantation and occurrence of serious adverse events since the patient's last study treatment.

The importance of identifying the patient with with ALI or ALF who is likely to die without a liver transplant cannot be overstated and has remained a primary focus of clinical investigation for 25 years. A recent analysis also conducted by the Acute Liver Failure Study Group (ALFSG) found that poor outcomes in the ALI patients are less frequent than is observed in the ALF population. However, in cases where ALI was not related to an acetaminophen (APAP) overdose, progression to poor outcomes was similar. Traditional scoring systems and prognostic models, such as King's College Criteria (KCC), Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II), currently used to monitor patients with ALF lack individual sensitivity and specificity and do not provide direct information about the liver's metabolic function, which is a key variable in assessing liver status and potential disease progression versus recovery in ALF patients. Despite recent advances used by the ALFSG Prognostic Index (ALFSG-PI), ALI Prognostic Index (ALI-PI) and Model for End-Stage Liver Disease (MELD), better predictive modalities are still needed. The 13C-Methacetin breath test is a rapid, reproducible, point-of-care test of liver metabolic function. After oral or naso-enteric/orogastric tube administration, the 13C labeled Methacetin is O-demethylated by cytochrome P450 1A2 (liver enzyme name) in the liver and further biotransformed into carbon dioxide labeled with carbon 13 (13CO2), which is expired in breath. The BreathID® Molecular Correlation Spectroscopy (MCS) device captures and quantifies expired 13CO2 and standardizes recovery against expired normal carbon dioxide (12CO2) through a nasal cannula (in conscious patients) or an adaptor connected to the ventilator line (for intubated patients). The results obtained from the device are expressed as delta over baseline (DOB), which expresses the change in 13CO2/12CO2 ratio in comparison to the baseline measurement. It can be transformed into the percentage of 13C dose recovered over time (PDR) after the ingestion of Methacetin, and the cumulative PDR (CPDR), the rate at which 13C substrate is metabolized, derived from the breath 13C/12C ratio. This is a multicenter, open label, non-randomized study of the MBT to assess functional trends of liver metabolism in patients diagnosed with severe acute liver injury not related to acetaminophen overdose (non-APAP ALI) or acute liver failure (ALF). Up to 200 evaluable patients with non-APAP ALI or ALF present at the time of enrollment into the ALFSG Registry will be consecutively enrolled. An evaluable patient is one who has completed one or more Breath Tests measured for a minimum of 30 (and ideally 60) minutes after administration of the 13C-Methacetin solution. Study sites will include up to 11 of the clinical sites located in the United States that are involved in the ALFSG. The Breath Test will be performed up to five times during the study period on all enrolled subjects. The first Breath Test will be performed as close to the time of study enrollment as possible upon admission into the study (Day 1). The Breath Test will be repeated on Days 2, 3, 5 and 7 as close as possible to the same time of day as the first Breath Test. If a subject who is enrolled into the ALFSG-MBT Trial with non-APAP ALI converts to ALF, breath test collection will continue until a maximum of five Breath Tests have been performed. If an enrolled non-APAP ALI or ALF subject receives a liver transplant, is discharged/transferred from the hospital or dies prior to Day 7, no additional Breath Tests will be performed. Enrolled patients will be contacted for the Day 21 follow up (21 days after the subject's enrollment into the trial) to determine spontaneous survival, transplantation and occurrence of serious adverse events since the subject's last study treatment.