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

NCT02786836 | Completed Phase 2 Results DMC

• 2 other identifiers: STU 122015-008U01DK058369
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 11

Brief 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.

Conditions

Acute Liver Failure

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Peak Percent Dose Recovery (PDR) Value

  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.

  Days 1 and 21

Secondary Outcomes (2)

• Peak Percent Dose Recovery (PDR) Value

  The first MBT reading either on Day 1 or Day 2 and Day 21

• Cumulative Percent Dose Recovery 20 (cPDR20) Value

  The first MBT reading either on Day 1 or Day 2 and Day 21

Study Arms (1)

13C-Methacetin Testing

EXPERIMENTAL

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.

Drug: 13C-Methacetin

Interventions

13C-Methacetin DRUG

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.

Also known as: N-(4)-13Cmethoxyphenyl acetamide

13C-Methacetin Testing

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Medical University of South Carolina: collaborator
• University of Michigan: collaborator
• Meridian Bioscience, Inc.: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (11)

University of Alabama, Birmingham

Birmingham, Alabama, 35294, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06520, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

UT Southwestern Medical Center at Dallas

Dallas, Texas, 75390-8887, United States

Location

VCU Medical Center

Richmond, Virginia, 23298, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Related Publications (17)

• O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439-45. doi: 10.1016/0016-5085(89)90081-4.

  PMID: 2490426 BACKGROUND

• Cholongitas E, Senzolo M, Patch D, Kwong K, Nikolopoulou V, Leandro G, Shaw S, Burroughs AK. Risk factors, sequential organ failure assessment and model for end-stage liver disease scores for predicting short term mortality in cirrhotic patients admitted to intensive care unit. Aliment Pharmacol Ther. 2006 Apr 1;23(7):883-93. doi: 10.1111/j.1365-2036.2006.02842.x.

  PMID: 16573791 BACKGROUND

• Craig DG, Ford AC, Hayes PC, Simpson KJ. Systematic review: prognostic tests of paracetamol-induced acute liver failure. Aliment Pharmacol Ther. 2010 May;31(10):1064-76. doi: 10.1111/j.1365-2036.2010.04279.x. Epub 2010 Feb 24.

  PMID: 20180786 BACKGROUND

• Stravitz RT, Reuben A, Mizrahi M, Lalazar G, Brown K, Gordon SC, Ilan Y, Sanyal A. Use of the methacetin breath test to classify the risk of cirrhotic complications and mortality in patients evaluated/listed for liver transplantation. J Hepatol. 2015 Dec;63(6):1345-51. doi: 10.1016/j.jhep.2015.07.021. Epub 2015 Jul 26.

  PMID: 26220750 BACKGROUND

• Lalazar G, Adar T, Ilan Y. Point-of-care continuous (13)C-methacetin breath test improves decision making in acute liver disease: results of a pilot clinical trial. World J Gastroenterol. 2009 Feb 28;15(8):966-72. doi: 10.3748/wjg.15.966.

  PMID: 19248196 BACKGROUND

• Goetze O, Selzner N, Fruehauf H, Fried M, Gerlach T, Mullhaupt B. 13C-methacetin breath test as a quantitative liver function test in patients with chronic hepatitis C infection: continuous automatic molecular correlation spectroscopy compared to isotopic ratio mass spectrometry. Aliment Pharmacol Ther. 2007 Jul 15;26(2):305-11. doi: 10.1111/j.1365-2036.2007.03360.x.

  PMID: 17593076 BACKGROUND

• Nista EC, Fini L, Armuzzi A, Candelli M, Zocco MA, Cazzato IA, Merra G, Finizio R, Miele L, Grieco A, Gasbarrini G, Gasbarrini A. 13C-breath tests in the study of microsomal liver function. Eur Rev Med Pharmacol Sci. 2004 Jan-Feb;8(1):33-46.

  PMID: 15209153 BACKGROUND

• Starmer GA, McLean S, Thomas J. Analgesic potency and acute toxicity of substituted anilides and benzamides. Toxicol Appl Pharmacol. 1971 May;19(1):20-8. doi: 10.1016/0041-008x(71)90185-2. No abstract available.

  PMID: 5570565 BACKGROUND

• de Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol. 2000 Nov;33(5):846-52. doi: 10.1016/s0168-8278(00)80320-7. No abstract available.

  PMID: 11097497 BACKGROUND

• Lalazar G, Pappo O, Hershcovici T, Hadjaj T, Shubi M, Ohana H, Hemed N, Ilan Y. A continuous 13C methacetin breath test for noninvasive assessment of intrahepatic inflammation and fibrosis in patients with chronic HCV infection and normal ALT. J Viral Hepat. 2008 Oct;15(10):716-28. doi: 10.1111/j.1365-2893.2008.01007.x. Epub 2008 Jul 11.

  PMID: 18638013 BACKGROUND

• Lalazar G, Mullhaupt, B., Margalit M. Point of care non-invasive 13C methacetin breath testing accurately identifies significant liver inflammation and fibrosis: a novel method for assessing liver damage. Gastroenterology; 2007 abstract

  BACKGROUND

• Allman K, Wilson I. Oxford Handbook of Anaesthesia. 2nd ed. New York: Oxford University Press 2006;xxiv:1203.

  BACKGROUND

• Lee WM, James L, Wendon J, Stravitz RT, Pop OT, Audimoolam VK. Does Methacetin breath testing increase acetaminophen hepatotoxicity in the setting of acute liver failure? Hepatology 2015: Accepted for poster presentation at the AASLD Liver Meeting held in San Francisco from November 13-17, 2015.

  BACKGROUND

• Audimoolam VK, Patel VC, Bernal W, Meir M, Lalazar G, Ilan Y, Wendon J. Use of an on-line at the point of care 13C-methacetin breath test as an adjunct tool for decision making in patients with acute liver failure. Hepatology 56;4Suppl:970A.

  BACKGROUND

• Koch DG, Battenhouse H, Durkalski V, Lee WM, Reuben A. Clinical predictors of spontaneous survival in acute liver failure (ALF) patients with advanced coma. Hepatology 56;4Suppl:964A.

  BACKGROUND

• Koch DG, Speiser JL, Durkalski V, Fontana RJ, Davern T, McGuire B, Stravitz RT, Larson AM, Liou I, Fix O, Schilsky ML, McCashland T, Hay JE, Murray N, Shaikh OS, Ganger D, Zaman A, Han SB, Chung RT, Brown RS, Munoz S, Reddy KR, Rossaro L, Satyanarayana R, Hanje AJ, Olson J, Subramanian RM, Karvellas C, Hameed B, Sherker AH, Lee WM, Reuben A. The Natural History of Severe Acute Liver Injury. Am J Gastroenterol. 2017 Sep;112(9):1389-1396. doi: 10.1038/ajg.2017.98. Epub 2017 Apr 25.

  PMID: 28440304 BACKGROUND

• Stravitz RT, Fontana RJ, Karvellas C, Durkalski V, McGuire B, Rule JA, Tujios S, Lee WM; Acute Liver Failure Study Group. Future directions in acute liver failure. Hepatology. 2023 Oct 1;78(4):1266-1289. doi: 10.1097/HEP.0000000000000458. Epub 2023 May 16.

  PMID: 37183883 DERIVED

Related Links

• Acute Liver Failure Study Website

MeSH Terms

Conditions

Liver Failure, Acute; Hepatic Encephalopathy

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

Recruitment goal of 200 patients not met due to challenges including multiple concomitant contraindicated meds, fasting requirement, establishing rapport with patients' family members due to sudden nature of illness and concerns for liver transplant

Results Point of Contact

• Title: William M. Lee, MD
• Organization: UT Southwestern Medical Center at Dallas

William.Lee@UTSouthwestern.edu

(214) 645-6110

Study Officials

• Robert J. Fontana, MD

  University of Michigan

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 6, 2016
• First Posted: June 1, 2016
• Study Start: June 10, 2016
• Primary Completion: September 18, 2019
• Study Completion: September 18, 2019
• Last Updated: December 22, 2020
• Results First Posted: December 22, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share

Locations

US (11)