13C-Methacetin Breath Test for the Prediction of Outcome in in ALI or ALF
Condition: Acute Liver Failure
MeSH terms: Liver Failure; Hepatic Insufficiency; Liver Failure, Acute
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): 13C-Methacetin
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): N-(4)-13Cmethoxyphenyl acetamide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: acute liver failure; methacetin; breath test; severe acute liver injury; hepatic encephalopathy; ALFSG Registry; acetaminophen toxicity