13C-Methacetin Breath Test for the Prediction of Outcome in in ALI or ALF (ALFSG-MBT)
|ClinicalTrials.gov Identifier: NCT02786836|
Recruitment Status : Completed
First Posted : June 1, 2016
Last Update Posted : July 7, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Acute Liver Failure||Drug: 13C-Methacetin||Phase 2 Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||76 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||13C-Methacetin Breath Test for the Prediction of Outcome in in Acute Liver Injury or Acute Liver Failure|
|Actual Study Start Date :||June 10, 2016|
|Actual Primary Completion Date :||September 18, 2019|
|Actual Study Completion Date :||September 18, 2019|
Experimental: 13C-Methacetin Testing
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.
Other Name: N-(4)-13Cmethoxyphenyl acetamide
- Day 1 Percentage drug recovered Peak (PDRPeak) values and Day 21 spontaneous survival in patients with non-APAP ALI or ALF [ Time Frame: 21 Days ]This outcome requires only one measurement per subject and examines whether the distributions (means) of enrollment PDRPeak values vary between those that spontaneously survive at Day 21 and those that either die or get a transplant by Day 21.
- Comparison of Changes in Daily PDRPeak values with 21 day outcomes, day 1 vs. day 2 [ Time Frame: 21 Days ]Using changes in PDRPeak between day 1 and day 2, we will determine whether positive change in PDRpeak more effectively allows separation between those that do and do not spontaneously survive at Day 21.
- Comparison of Changes in Daily PDRPeak values with 21 day outcomes, day 1 vs. day 3 [ Time Frame: 21 Days ]Using changes in PDRPeak between day 1 and day 3, we will determine whether positive change in PDRpeak more effectively allows separation between those that do and do not spontaneously survive at Day 21.
- Comparison of Changes in Daily PDRPeak values with 21 day outcomes, day 1 vs day 5 [ Time Frame: 21 Days ]Using changes in PDRPeak between day 1 and day 5, we will determine whether positive change in PDRpeak more effectively allows separation between those that do and do not spontaneously survive at Day 21.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02786836
|United States, Alabama|
|University of Alabama, Birmingham|
|Birmingham, Alabama, United States, 35294|
|United States, California|
|University of California, San Francisco|
|San Francisco, California, United States, 94143|
|United States, Connecticut|
|Yale University School of Medicine|
|New Haven, Connecticut, United States, 06520|
|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|
|Ann Arbor, Michigan, United States, 48109|
|United States, Ohio|
|Ohio State University Medical Center|
|Columbus, Ohio, United States, 43210|
|United States, South Carolina|
|Medical University of South Carolina|
|Charleston, South Carolina, United States, 29425|
|United States, Texas|
|UT Southwestern Medical Center at Dallas|
|Dallas, Texas, United States, 75390-8887|
|United States, Virginia|
|VCU Medical Center|
|Richmond, Virginia, United States, 23298|
|United States, Washington|
|University of Washington Medical Center|
|Seattle, Washington, United States, 98195|
|Study Chair:||Robert J. Fontana, MD||University of Michigan|