Methacetin Breath Test in Patients With Liver Disease Secondary to Heart Disease

Brief Title

Methacetin Breath Test in Patients With Liver Disease Secondary to Heart Disease

Official Title

Non-invasive Assessment of Liver Function in Patients Undergoing Heart and Liver Transplant Evaluation

Brief Summary

      The aim of this project is assess a non-invasive functional liver tests in patients with the
      Fontan circulation that may be used for prognostic purposes. Specifically, we aim to
      determine whether there are alterations in Methacetin Breath Test (MBT) in the Fontan patient
      and if so, whether it is related to conventional tests of liver and cardiac function. The
      hypothesis is that MBT CPDR 20 in the Fontan patient is abnormal as a result of alterations
      in liver perfusion, liver cell metabolic capability and transhepatic resistance secondary to
      hemodynamics unique to the Fontan as well as end-organ liver damage. Due to lack of robust
      biomarkers or other risk stratification schemes, we aim to determine whether there is
      prognostic value in hepatic MBT CPDR 20 in the Fontan patient.

      Aims - The aims of this study are three-fold:

        1. To measure MBT parameter in a cohort of patients with Congestive (Dilated)
           Cardiomyopathy and a group of Fontan patients and compare results to published normal
           controls.

        2. To explore any association between MBT parameter and clinical parameters already
           available, including Fontan hemodynamics as assessed by either of the following tests:
           cardiac catheterization, echocardiography, non-invasive imaging of the liver (CT or
           MRI), non-invasive assessment of liver stiffness (ARFI, MRE or Fibroscan), laboratory
           investigations, and clinical characteristics (i.e. age of patient, time since Fontan
           operation, type of Fontan etc.) within 12 months of the study.

        3. To determine whether MBT is predictive of clinical outcomes: heart failure, clinically
           significant ascites, and time to transplant or death.
    

Detailed Description

      Research Design and Methods Study Design: This is a prospective pilot cohort study in 20
      patients with Dilated Congestive Cardiomyopathy (10) and a group of adult Fontan (10)
      recruited from an adult congenital heart disease clinic in a tertiary care center. Patients
      enrolled in the study will be prospectively followed for 3-5 years.

      Study Timelines: We anticipate that it will take approximately 2 years to recruit patients
      who are to be included in this study. Patient will followed 3-5 years.

      Study Endpoints: The aim of this project is assess a non-invasive functional liver tests in
      patients with the Fontan circulation that may be used for prognostic purposes.

      PROCEDURES INVOLVED:

      Methods Screening and consent Eligible patients will be screened and recruited through the
      outpatient Hepatology Clinic, Heart Failure Clinic and the Adult congenital heart disease
      clinic. They will be approached the day of the scheduled outpatient appointment by the PI or
      a study coordinator in a private room.

      Informed consent will be obtained by the principal investigator, a sub-investigator or a
      member of the study team who is authorized to give consent. This will allow the potential
      subject sufficient opportunity to consider whether or not to participate and this will
      minimize the risk of influence or coercion. The subject will be informed of what the research
      entails. Any foreseeable risks or discomforts will be discussed with the subject. The
      protection of confidentiality will be discussed with subjects as well as the subject will be
      given the name(s)/number(s) of persons to contact should they have any further questions
      before signing the informed or consent or once they have enrolled in the study. It is
      reiterated to the subject that participation is voluntary and not participating will not
      affect present or future medical care. The subject will ask and have answered any and all
      questions before signing the informed consent. The subject is given a signed copy of the
      informed consents(s) and HIPAA authorization(s).

      MBT testing The ¹³C-Methacetin Breath Test (MBT) is a non-invasive test for assessing liver
      metabolic function. The BreathID® MCS System consists of the BreathID® MCS device and a test
      kit containing a breath collection cannula and a non-radioactive isotope 13C-Methacetin
      solution. It measures and computes the ratio between 13CO2 and 12CO2 in the patient's exhaled
      breath. The components of the MBT system include the (1MBT BreathID® MCS unit; (2
      13C-Methacetin solution. A dedicated flash memory stick for automatic raw data download will
      be provided to all participating investigative sites. All components of the MBT system will
      be provided by Exalenz Bioscience Ltd., The MBT BreathID® MCS Unit Exalenz Bioscience Ltd.
      has developed a molecular correlation spectrometer, based on specific optical-radiation
      emission and absorption by 13CO2 and 12CO2 gases. This device continuously senses exhaled
      breath and analyzes CO2 in real-time through a breath collection cannula connected to the
      patient. Based on Molecular Correlation Spectrometry (MCS), the BreathID® MCS device
      continuously measures 13CO2 and 12CO2 concentrations from the patient's breath and
      establishes the 13CO2/ 12CO2 ratio. The cannula continuously transports the breath sample
      from the patient to the BreathID® MCS device. Depending upon the status of the patient, the
      cannula may be nasal (for conscious patients) or an adaptor may be used for connection to the
      ALF-MBT Protocol Page 15 Version 2.0 (19Nov2015) Confidential respiratory line (for intubated
      patients). Results are displayed in real time on the device screen and are printed after the
      completion of the test. The BreathID® MCS device calculates the delta over baseline (DOB),
      which can be translated into the percent dose recovery (PDR) and the cumulative percent dose
      recovery (CPDR) for each time point derived from the ratio difference compared to baseline
      (normalized/adjusted to the patient's body weight and height as well as substrate dose)
      throughout the course of the test. The maximum value of the PDR is called the PDRPeak. The
      13C-Methacetin metabolism begins almost immediately since liquid passes through the stomach
      to the duodenum, where it is absorbed, without delay. The default breath collection test time
      is one hour after ingestion of 13C-Methacetin. The light sources are 13CO2 and 12CO2
      discharging lamps. By using 13CO2 and 12CO2 discharging lamps as light sources, light
      absorption will be solely due to the existence of 13CO2 and 12CO2 in the gas mixtures.
      Furthermore, by using 13CO2 and 12CO2 discharging lamps as light sources, background
      radiation will be substantially reduced, leading to highly sensitive absorption curves. These
      highly sensitive absorption curves enable detection of very small variations in 13CO2 and
      12CO2 concentrations and the 13CO2/ 12CO2 ratio. The BreathID® MCS System can detect
      variations of less than 1/1000 in the 13CO2/ 12CO2 ratio measurement. The actual breath
      collection is automatically done by the device and is not operator dependent. If the patient
      is not connected properly (e.g. the breath does not reach the device), the BreathID® MCS
      device will prompt the operator to adjust the nasal cannula. The cannula transports the
      breath sample from the patient to the BreathID® MCS device. The cannula test kit is a
      single-use kit and is comprised of a plastic sampling line with an in-line hydrophobic filter
      (used to reduce the amount of moisture present from the patient's breath) and a Luer-lock
      connector for connection to the BreathID® MCS device. The device is designed to accommodate
      an extended range of respiratory rates. 3.3.3 13C-Methacetin Exalenz Bioscience Ltd. will
      supply a ready to use, non-radioactive isotope ¹³C-Methacetin solution for single-use oral
      administration (75 mg in 150 ml purified water), dispensed in thermoplastic polyester (PTE)
      bottles sealed with a plastic child resistant stopper. The ¹³CMethacetin solution can be
      administered via typical oral. 13C-Methacetin meets all of the qualifications for a liver
      function test substrate: it is a nontoxic small molecule; is administered orally; is rapidly
      absorbed; and is exclusively metabolized by the liver. Furthermore, 13C can be easily
      synthesized into a key location within this molecule. No related adverse events have been
      reported when using this substance, including in vulnerable populations, and the compound
      remains stable over time. The 13C-Methacetin substrate is a well-known diagnostic reagent
      that has been described in the literature and used for over 30 years by researchers around
      the world. ¹³C-Methacetin is rapidly absorbed and metabolized by the hepatic mixed function
      oxidase, via O-demethylation. This process is carried out by hepatic cytochrome P450 enzymes
      that produce two products, acetaminophen and formaldehyde, which is transformed through two
      successive oxidative steps to 13CO2. Toxicology testing results in animals and other clinical
      information support the safe use of Methacetin in humans. Based on the acute toxicity studies
      in mice and rats where relatively high LD50 values of 1190mg/kg were administered, the
      Methacetin dose administered in human breath tests in adults of 75 mg, or approximately
      1mg/kg, has a safety ratio in excess of 1000- fold (10). There have been no reports of any
      complications with the use of this substance in over 2500 patients tested worldwide (see IDE
      filing). The main metabolite of Methacetin is acetaminophen which has wide routine clinical
      use at much higher doses than orally administered dose of 13C-Methacetin of 75mg used in this
      study

      Risk Based Monitoring: To ensure compliance with GCP, local regulations and scientific
      integrity, monitoring of this trial will be managed and oversight retained by the Sponsor or
      designee.

      Requirements for Administration of Substrate: Fasting Subjects will perform the breath test
      once enrolled into the trial and when the following criteria have been met:

        -  Oral administration of substrate: The subject should be fasting from solid food for a
           minimum 6 hours and from oral medications for a minimum of 1 hour

        -  Subject has not ingested acetaminophen-related medications (e.g. Tylenol) within the
           past 24 hours (subjects with acetaminophen intoxication may be included 24 hours after
           ingestion).

        -  Subject has not had any products containing caffeine for 24 hours.

        -  Subject has not received general anesthesia in the last 24 hours. Performance of the
           Breath Collection will be performed after the substrate is administered to the subject;
           no waiting period is required once the substrate has been administered. Breath is
           collected automatically via a nasal cannula for a total of 75 minutes (up to 15 minutes
           for baseline measurement and 60 minutes following ingestion of Methacetin). All
           test-specific equipment will be supplied by Exalenz

      Study Feasibility: The Clinical Research Unit will provide essential resources for the
      conduct of the proposed research. Study coordinator already experienced form other studies
      with the Breath ID machine and protocol will be required for administration of the test.
      Subjects are expected to spend approximately 2 hours in the CRU for administration of MBT
      test.

      Study Limitations: One major limitation to this study is the unknown ability to correlate MBT
      with various clinical data, specifically variables derived from cardiac catheterization, if
      not available. Cardiac output, which is measured by cardiac catheterization, is a determinant
      of hepatic blood flow and likewise, Fontan pressure can influence hepatic perfusion. Cardiac
      catheterizations are not routinely performed in healthy Fontan patients and any analysis
      using this variable represents a selection bias towards a symptomatic and potentially sicker
      subgroup. There is merit in adding a non-invasive test like MBT when looking at FALD
      patients, given the difficulty to predict liver outcome in these patients.
    


Study Type

Interventional


Primary Outcome

Methacetin Breath Test Results in patients undergoing heart and liver transplant evaluation.


Condition

Dilated Cardiomyopathy

Intervention

Methacetin Breath Test (MBT)

Study Arms / Comparison Groups

 MBT in liver disease
Description:  Methacetin Breath test (MBT) intervention

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

20

Start Date

April 21, 2019

Completion Date

July 1, 2024

Primary Completion Date

February 28, 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent obtained prior to any study-specific assessments

          -  Adults patients ≥ 18 years of age

          -  Liver disease secondary to congenital heart disease or cardiomyopathy

        Exclusion Criteria:

          -  Inability to comprehend and/or give informed consent

          -  Male and female subjects < 18 years of age

          -  Females of child-bearing potential that are pregnant or breastfeeding

          -  Other exclusion criteria include those individuals who are prisoners.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Daniel R Ganger, MD, 3126959286, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04176458

Organization ID

STU00208318


Responsible Party

Principal Investigator

Study Sponsor

Northwestern University


Study Sponsor

Daniel R Ganger, MD, Principal Investigator, Northwestern University


Verification Date

December 2020