13C-Methacetin Breath Test for the Prediction of Outcome in in ALI or ALF (ALFSG-MBT)

13C-Methacetin Breath Test for the Prediction of Outcome in in Acute Liver Injury or Acute Liver Failure

Medical University of South Carolina, University of Michigan, Meridian Bioscience, Inc., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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.

acute liver failure, methacetin, breath test, severe acute liver injury, hepatic encephalopathy, ALFSG Registry, acetaminophen toxicity

All patients enrolled into the ALFSG Registry with the duration of illness <26 weeks with (1) severe acute liver injury; International Normalized Ratio (INR) ≥2.0) and not related to acetaminophen overdose, with no evidence of hepatic encephalopathy (HE); and (2) acute liver failure; INR ≥1.5 with presence of any degree of HE will perform the Breath Test.

The test substrate in this study, ¹³C-methacetin solution for single-use oral administration (75 mg in 150 ml purified water), is administered orally or via feeding tube, rapidly absorbed, exclusively metabolized by hepatic mixed function oxidase via O-demethylation, mainly by cytochrome P450 enzyme, subtype 1A2, into acetaminophen and formaldehyde. The formaldehyde is then transformed through two successive oxidative steps to ¹³carbon dioxide, the quantity of which is measured in exhaled breath as a ratio of 13C to 12C. The nasal or intubated breath sampling investigational device (ID) circuit continuously transports the breath sample from the patient to the BreathID® MCS device before and following administration of the 13C-methylacetanilide test substrate.

Peak PDR is the maximal percent dose recovery (PDR) rate which reflects the maximum rate of metabolism of 13C-methacetin measured as the change in 13CO2 / 12CO2 (normal carbon dioxide) ratio after ingestion of 13C-methacetin normalized using the patient's height and weight. The distributions of mean PDR Peak values were compared between TFS (transplant free survival) and non-TFS (death/transplant) at Day 21.

This outcome is similar to the peak PDR defined in the primary outcome but as a secondary we are looking at Day 1 or Day 2 peak PDR values. Peak PDR is the maximal percent dose recovery (PDR) rate which reflects the maximum rate of metabolism of 13C-methacetin measured as the change in 13CO2 / 12CO2 ratio after ingestion of 13C-methacetin normalized using the patient's height and weight. The distributions of mean PDR Peak values were compared between TFS and non-TFS (death/transplant) at Day 21.

The relationship between the cPDR (cumulative PDR of metabolized 13C-Methacetin 20 minutes after ingestion) in single time points of MBT measurements and TFS and non-TFS (death/transplant) at Day 21.

Inclusion Criteria: Adult men or women (18-80 years of age) Severe acute liver injury not related to acetaminophen overdose: INR ≥2.0; no evidence of HE Acute liver failure: INR ≥1.5; presence of any degree of HE Duration of illness <26 weeks Enrolled into the ALFSG Registry. Written informed consent from the patient or patient's legally authorized representative or family member as defined in the Federal Register Number 21 Congressional Federal Register (CFR)50.3(m) Exclusion Criteria: Evidence of pre-existing chronic liver disease Pre-existing New York Heart Association stage III/IV heart failure Evidence of pre-existing chronic renal failure Chronic hemodialysis prior to hospital admission Evidence of cirrhosis (unless clinically acute Wilson disease or autoimmune non-APAP ALI or ALF) Severe obstructive lung disease (FEV1 <50% of predicted on previous spirometry) Severe shock, defined as mean arterial pressure (MAP) <70 mmHg despite >15 µg/kg/min dopamine, >0.1 µg/kg/min epinephrine, or >0.1 norepinephrine µg/kg/min Extensive small bowel resection (>50 cm) Any evidence of upper GI bleeding at enrollment requiring intervention (endoscopy or red blood cell (RBC) transfusion specifically for upper GI bleeding) Liver transplantation (LT) prior to enrollment. (Note: Listing for LT does not preclude participation in the trial.) Pregnancy or breastfeeding women (Note: Pregnancy related non-APAP ALI or ALF may be considered for entry following the delivery of the baby and assuming the mother does not wish to breastfeed or collect breast milk during the study period.) Allergic to acetaminophen (such as Tylenol® or any other acetaminophen-containing medications) Participation in other clinical studies evaluating other experimental treatments or procedures. (Note: Participation in observatory studies is not an exclusion.) Patients in whom enteral drugs or fluids are contra-indicated or the patient either does not have an appropriately placed naso-enteric/orogastric tube in situ or cannot tolerate taking the drug preparation orally (200 ml) Budd-Chiari Syndrome Non-APAP ALI or ALF caused by malignancy Moderate and severe adult respiratory distress syndrome (ARDS), as defined by Berlin Criteria. Subjects who have received amiodarone in the 30 days prior to study enrollment Consumption of any food or beverage that contains caffeine in the 24 hours prior to enrollment Consumption of any of the following drugs that may interfere with the metabolism of 13C-Methacetin in the 48 hours prior to study enrollment including: allopurinol, carbamazepine, cimetidine, ciprofloxacin, daidzein, disulfiram, Echinacea, enoxacin, fluvoxamine, methoxsalen, mexiletine, montelukast, norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, terbinafine, ticlopidine, thiabendazole, verapamil, zileuton or oral contraceptives Consumption of alcohol in the 24 hours prior to enrollment Smoking cigarettes in the 8 hours prior to enrollment.

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