The Prediction Value of the BreathID 13C-Methacetin Breath Test for Hepatic Decompensation; a Retrospective Analysis
Conditions: Chronic Liver Disease
Sponsor: Meridian Bioscience, Inc.

Version 1b - April 1, 2015                                    Exalenz Bioscience LTD                CONFIDENTIAL 
The Prediction Value of the BreathID 13C-Methacetin 
Breath Test for Hepatic Decompensation; a 
Retrospective Analysis (#HIS-FU-EX-1213) 
 
 
  NCT02084160 
 
 

Version 1b – April 1, 2015                                     
 
Exalenz Bioscience Ltd                 
 
CONFIDENTIAL 
 
The Prediction Value of the BreathID 13C-Methacetin 
Breath Test for Hepatic Decompensation; a 
Retrospective Analysis (#HIS-FU-EX-1213) 
 
Document No.: CSD00074 
Total pages: 22 
Version Level: 1b 
Last update on: April 01, 2015 
 
 
 
Name 
Position 
Author / 
Owner 
Dan Peres, M.D. 
Director of Clinical Affairs 
Supervisor / 
Revised by 
Yaron Ilan, MD 
Medical Director 
Reviewed by 
 Gil Guggenheim 
Clinical Application Development 
Specialist & Database Manager  
Reviewed  by 
Avraham Hershkowitz Clinical Trial Manager 
Electronic signatures and approvals, effective information and Lifecycle Status can be 
obtained by accessing the system generated approval page associated with this document.  
The system generated approval page can be retrieved from the PDM system. 
 
This publication, in whole or in part, may not be reproduced, disclosed, translated into any language 
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Exalenz Bioscience Ltd.  4 Ha’Maayan St. Modiin, Israel 71700 
Versions Control: 
Version 
Date 
Responsible Person 
Description of Change 
1.0 
6-JAN-2014 
Avraham Hershkowitz Initial Document 
1a 
02-FEB-2014 Avraham Hershkowitz Minor change of anonymity  
1b 
1-APR-2015 
Avraham Hershkowitz Addition of PLT  study subjects to 
protocol. 

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Protocol: The predictive value of the BreathID, 13C-Methacetin 
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CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Number: 
HIS-FU-EX-1213 
 
Version: 
1.0 
 
Study Title: 
The prediction value of the BreathID, 13C-Methacetin breath test, of 
for Hepatic Decompensation; a retrospective analysis. 
 
Author:  
Dan Peres, M.D. 
 
Date of Protocol: 
April 01, 2015 
 
Contact Information: 
 
Applicant: 
Exalenz Bioscience Ltd 
 
4 Hama'ayan Street 
 
Modi'in, Israel 71700 
Tel:  +972-8-9737513 
 
Fax: +972-8-9737501 
 
Principal Investigator:  
Dr. Meir Mizrahi – Hadassah Medical Center 
 
Dr. Mohammed Siddqui– Virginia Commonwealth University 
 
Dr. Adrian Reuben – Medical University of South Carolina 
 
Dr. Stuart Gordon- Henry Ford Health System 
 
 
Clinical monitoring: 
Exalenz Bioscience Ltd. 
 
Medical Director: 
 
Prof. Yaron Ilan, MD 
 
 Tel:       +972-2-6777337 
 
 Mobile: +972-50-7874551 
 
  Email:yaroni@exalenz.com 
 
 Other Exalenz personnel who may be contacted by study site personnel for this study are listed in a separate 
document, Principal BMT Clinical Study Contacts, which will be updated on a regular basis when 
necessary and maintained by Exalenz Bioscience Ltd. 

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Protocol: The predictive value of the BreathID, 13C-Methacetin 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 2 
SYNOPSIS 
.............................................................................................................................
........................
......
4 
1. 
BACKGROUND INFORMATION .......................................................................... 7 
1.1. 
CLINICAL OUTCOME IN PATIENTS WITH CHRONIC LIVER DISEASE ............ 7 
1.2. 
IDENTIFYING PATIENTS WITH MARGINAL HEPATIC RESERVE AT RISK 
FOR COMPLICATIONS AND DECOMPENSATION: ........................................... 7 
1.4. 
BREATH TESTS .................................................................................................. 8 
1.5. 
BREATHID® SYSTEM: ......................................................................................... 9 
1.6. 
13C-LABELED SUBSTRATE - 13C-METHACETIN: ............................................... 9 
1.7. 
UTILITY AS FOLLOW-UP TOOL ......................................................................... 9 
1.7.1. 
Hepatic Impairment Score Using the BreathID MBT ............................................. 9 
1.7.2. 
Biopsy Scoring ................................................................................................... 10 
1.8. 
SAFETY AND EFFICACY OF THE INVESTIGATIONAL PRODUCT ................. 10 
1.9. 
RATIONALE FOR THE CURRENT STUDY ....................................................... 10 
1.10. 
SUMMARY OF OVERALL RISK AND BENEFITS .............................................. 10 
1.11. 
GUIDANCE FOR INVESTIGATOR .................................................................... 11 
2. 
OBJECTIVES ..................................................................................................... 11 
3. 
ENDPOINTS ...................................................................................................... 12 
3.1. 
PRIMARY EFFICACY ENDPOINTS ................................................................... 12 
3.2. 
SECONDARY EFFICACY ENDPOINTS ............................................................ 12 
3.3. 
SAFETY ENDPOINT .......................................................................................... 12 
4. 
STUDY DESIGN ................................................................................................ 13 
5. 
STUDY POPULATION ....................................................................................... 13 
5.1. 
ENTRY CRITERIA ............................................................................................. 13 
5.1.1. 
Inclusion Criteria (screening visit) ....................................................................... 13 
5.1.2. 
Exclusion Criteria (screening visit) ...................................................................... 13 
6. 
STUDY PROCEDURES AND ASSESSMENTS ................................................. 13 
6.1. 
GENERAL INSTRUCTIONS .............................................................................. 13 
6.2. 
OUTLINE OF STUDY PROCEDURES AND ASSESSMENTS ........................... 14 
6.2.1. 
Screening and baseline ...................................................................................... 14 
6.3. 
SAFETY OBSERVATIONS AND MEASUREMENTS ......................................... 14 
6.4. 
CONCOMITANT MEDICATIONS AND THERAPIES .......................................... 14 
6.5. 
SUBJECT COMPLETION AND WITHDRAWAL ................................................. 14 
7. 
INVESTIGATIONAL NEW DRUG USED IN THE STUDY .................................. 14 
7.1. 
TREATMENT OF OVERDOSE .......................................................................... 14 

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8. 
STATISTICAL CONSIDERATIONS .................................................................... 15 
8.1. 
STUDY DESIGN AND OBJECTIVES ................................................................. 15 
8.2. 
PRIMARY ENDPOINT ....................................................................................... 15 
8.3. 
SECONDARY ENDPOINT ................................................................................. 15 
8.4. 
SAFETY ENDPOINTS ....................................................................................... 15 
8.5. 
SAMPLE SIZE.................................................................................................... 15 
8.6. 
STATISTICAL ANALYSES ................................................................................. 16 
9. 
ADVERSE EVENTS ........................................................................................... 16 
10. 
STUDY ADMINISTRATION................................................................................ 16 
10.1. 
REGULATORY AND ETHICAL CONSIDERATIONS ......................................... 16 
10.1.1. 
Informed Consent ............................................................................................... 16 
10.1.2. 
Institutional Review Board .................................................................................. 16 
10.1.3. 
End of the study ................................................................................................. 17 
10.2. 
INVESTIGATOR RESPONSIBILITIES ............................................................... 17 
10.3. 
DATA MANAGEMENT ....................................................................................... 17 
10.4. 
STUDY MONITORING ....................................................................................... 17 
10.5. 
SUBJECT CONFIDENTIALITY .......................................................................... 17 
10.6. 
QUALITY ASSURANCE ..................................................................................... 18 
10.7. 
RETENTION OF ESSENTIAL STUDY DOCUMENTS ....................................... 18 
10.8. 
AGREEMENTS .................................................................................................. 18 
11. 
PUBLICATION ................................................................................................... 18 
12. 
REFERENCES................................................................................................... 18 
 

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Protocol: The predictive value of the BreathID, 13C-Methacetin 
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SYNOPSIS 
 
 
Investigational  
Product: 
 
0.05% 13C-Methacetin solution and the BreathID® Device 
 
Phase of Development: 
Retrospective clinical investigation  
 
Background: 
 
This study is a follow up study to be conducted in selected sites, that 
participated in Exalenz’ Pivotal HIS-EX-408 and/or PLT-BID-1108 
study using the MBT in chronic liver patients. The aim of the study 
was to compare the breath test to the liver biopsy to assess the 
capability to detect cirrhosis. 
 
Study Rationale:  
 
 
Previous studies have shown that the MBT can be used to predict liver 
decompensation. In the present study Exalenz wishes to evaluate the 
prognostic value of MBT and Biopsy in a long term retrospective 
surveillance of the described study population. 
 
Objectives: 
To evaluate the ability of the MBT to predict hepatic decompensation 
events, in patients with chronic liver disease. 
 
Primary outcome measures: MBT results and Hepatic decompensation measured with the time to 
each event, defined as the occurrence of at least one of the following 
events in the time frame between the last 13C-Methacetin Breath Test 
(MBT) to the time of data collection: 
1. Death (liver related) 
2. Transplantation (cadaveric and living donors) 
3. Ascites 
4. HE (Hepatic Encephalopathy) 
5. Newly diagnosed varices or variceal bleeding  
6. SBP (spontaneous bacterial peritonitis)/Sepsis 
7. HRS (Hepatorenal syndrome) 
8. HCC (hepatocellular carcinoma) 
9. Increase in CTP (Child Turcotte Pugh) Score by 3 points 
10. Increase in MELD score by 5 points 
 
Primary Endpoints: 
Time to the first occurrence of a hepatic decompensation event (as 
defined in the primary outcome measures).  
 
Secondary endpoints: 

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 Histological liver biopsy results (obtained in the initial study) versus 
clinical outcome at time of current data collection 
 Time to each of the individual events as follows: 
1. Death (liver related) 
2. Transplantation (cadaveric and living donors) 
3. Ascites 
4. HE (Hepatic Encephalopathy) 
5. Newly diagnosed varices or variceal bleeding  
6. SBP (spontaneous bacterial peritonitis)/Sepsis 
7. HRS (Hepatorenal syndrome) 
8. HCC (hepatocellular carcinoma) 
9. Increase in CTP (Child Turcotte Pugh) Score by 3 points. 
10. Increase in MELD score by 5 points 
 
 
Study Design:  
Retrospective, multicenter clinical evaluation of patients' outcome 
initially enrolled (n=414+165=579) into the Exalenz pivotal studies 
(protocols  HIS-EX-408 and/or PLT-BID-1108 respectively). The 
information collected in this study will be anonymous. 
 
  
Study Population:  
A maximum of 579 adult male or female patients enrolled into the 
Exalenz studies (protocols HIS-EX-408 and/or PLT-BID-1108 ) 
who performed a 13C-Methacetin Breath Test.  
 
Main Inclusion Criteria:  
Patient has been tested with the MBT in the past Exalenz pivotal 
studies protocols HIS-EX-408 and/or PLT-BID-1108 (from August 
2008 to September 2012).  
 
Main Exclusion Criteria:  Patient had been enrolled into the pivotal study but not included in 
the final analysis due to conditions / factors interfering with the 
MBT (i.e. exclusion criteria within the HIS-EX-408 and/or PLT-
BID-1108 study). 
 
 
Statistical Analysis:  
Introduction:  
It is anticipated that 3-5% of patients with stable cirrhosis will develop 
hepatic decompensation and achieve an end-point within a year.  An 
additional 1-2% would be expected to die from these complications per year. 
This study is conducted 6 years post initial enrollment, accordingly the 
expected amount of complications are expected to be 6 times higher. 
Furthermore some of the patients that were not considered as cirrhotic at the 
time of enrollment may progress to cirrhosis and deteriorate.  

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All patients with valid breath test results from the HIS-EX-408 and/or PLT-
BID-1108 trials will be candidates for this follow up trial. 
Analyses: 
All statistical analyses and data presentations, including tabulations and 
listings, will be performed using the SAS version 9.3 (or higher) software. 
Statistical tests will be two-sided and the level of significance is 0.05. 
Nominal p-values will be presented. 
The ability of MBT to predict morbidity and mortality and other 
complications will be evaluated using survival analysis methods, mainly 
Kaplan-Meier curves and Cox regression analyses. 
 
 

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1. 
BACKGROUND INFORMATION 
1.1. 
Clinical outcome in patients with chronic liver disease 
Chronic liver disease is the 9th most common cause of death in the United States.  
Unfortunately, mortality secondary to chronic liver disease, cirrhosis and its complications 
is expected to increase in the future. This is primarily due to the maturation of the Hepatitis 
C Virus (HCV) epidemic, a rising rate of hepatocellular carcinoma (HCC) and an increasing 
prevalence of non-alcoholic steatohepatitis (NASH). 
Mortality in patients with chronic liver disease is typically confined to patients with 
cirrhosis; and the mortality risk in these patients has long been assessed by the Child-Pugh-
Turcotte (CTP) score. More recently, the Model of End-Stage Liver Disease (MELD) has 
been shown to more accurately predict 30 day survival in patients with cirrhosis. The 
MELD score is now utilized by the United Network for Organ Sharing (UNOS) to prioritize 
patients awaiting liver transplantation. Those factors which contribute to the CTP scoring 
systems are: Bilirubin, INR, albumin, ascites, encephalopathy and creatinine. The MELD 
score uses only blood tests and is thus less prone to subjective assessments such as ascites or 
encephalopathy. 
In general, declining liver function and an increase in the CTP and/or MELD scores appear 
prior to complications of cirrhosis; gastrointestinal bleeding from portal hypertension 
(varceal and non-variceal), ascites, spontaneous bacterial peritonitis (SBP), hepatic 
encephalopathy (HE), hepato-renal syndrome (types 1 and 2) and HCC. Patients are 
considered to have stable cirrhosis when they have normal or near-normal hepatic function 
and no prior complications of cirrhosis. Such patients have a CTP score of less than 7; 
reflective of Childs class A cirrhosis. Approximately 3-5% of patients with stable Child 
class A cirrhosis will develop worsening in hepatic function and/or complications of 
cirrhosis and decompensate on a yearly basis. In many patients the development of these 
complications, the deterioration in global liver function and the rise in MELD is a slow 
gradual process which allows sufficient time for successful transplantation. In contrast, 
approximately one-third of patients with cirrhosis develop rapid hepatic decompensation a 
precipitous rise in MELD and die from complications of cirrhosis before they can either be 
considered for or receive a liver transplant.  This observation explains why pre-transplant 
mortality for patients on the UNOS waiting list is actually greatest in patients with low 
MELD, not high MELD scores. It is currently believed that such patients have marginal 
hepatic metabolic capacity or hepatic reserve which both places them at risk for developing 
complications of cirrhosis and for rapid deterioration when complications occur. 
 
1.2. 
Identifying patients with marginal hepatic reserve at risk for complications and 
decompensation: 
 
 
Tests to assess hepatic metabolic function are conducted by administering either 
intravenously or orally a compound with high hepatic extraction ratio and/or rapid hepatic 
metabolism.  The rate at which the parent compound is removed from the serum or a 
metabolic product of the parent compound appears in either the blood, urine, breath or saliva 
reflects hepatic metabolic function.  Some of the compounds which have been successfully 

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utilized for this purpose include choline, caffeine, galactose, aminopyrine, erythromycin, 
lidocaine and methionine and Methacetin [N-(4-Methoxy-phenyl) acetamide]. Previous 
studies utilizing a battery of liver function tests have demonstrated that these tests correlate 
with worsening fibrosis and cirrhosis. The hepatic metabolism of lidocaine to 
monoethylglycinexylodide (MEGX) has been shown to decline with increasing liver fibrosis 
and with worsening stages of cirrhosis, improve with successful treatment of the underlying 
liver disease, and to accurately predict which patients with stable cirrhosis awaiting liver 
transplantation were at risk to develop future hepatic decompensation. Unfortunately, 
administering lidocaine to perform this test is associated with parasthesias and could 
precipitate cardiac arrythmias. Thus, while promising as a potential liver function test the 
use of lidocaine for this purpose has been largely abandoned. 
 
 
1.3. 
Identifying patients with progression of liver disease and fibrosis at earlier stages (pre-
cirrhosis) of liver disease: 
 
Chronic liver patients that have varied levels of fibrosis based on biopsy need to be 
monitored for progression of disease as well. A significant percentage of these patients in 
earlier stages of liver disease have recurrent normal blood tests in the standard liver panel 
blood tests. Additionally, even patients where the blood tests do show irregular values, the 
values do not always correlate with disease progression and a non-invasive test that is both 
safe and accurate would be very beneficial to monitor their liver health. This is especially 
important in decision making regarding the decision to begin treatment when signs of 
disease progression are apparent to prevent deterioration to cirrhosis. Furthermore, a non- 
invasive test is necessary to monitor these patients once they begin treatment in order to 
assess the effectiveness of the treatment. 
 
1.4. 
Breath Tests 
Breath tests that are based on monitoring the 13CO2, which is a by-product of 13C labeled 
substrates metabolism by the liver, have been proposed as a tool for non-invasive evaluation 
of liver health and have been used for over 30 years.  
 
Methacetin may be utilized for the evaluation of liver functional capacity and/or the extent 
of liver impairment. The biochemical basis for the evaluation of functional capacity is that 
the compound is metabolized by the cytochrome P450 enzyme CYP1A2. Diseases of the 
liver that cause a loss in functional mass and/or impact the metabolic function of CYP1A2 in 
hepatic microsomes hepatocytes are associated with and may be correlated to a decrease in 
the liver capacity to metabolize Methacetin. 
 
One of the most common methods for determining the rate of metabolism of Methacetin is 
to analyze the rate of metabolism of the methoxy group (CH3O) of Methacetin to carbon 
dioxide, which is excreted in exhaled breath. To distinguish the carbon dioxide derived from 
Methacetin from all other sources of carbon dioxide, the methoxy group is labeled with 13C, 
a stable isotope of carbon. Thus all the CO2 derived from Methacetin will contain 13C 
(13CO2) in contrast to all other sources of CO2, which will contain approximately 99% 12C, 
and 1% 13C, the naturally abundant isotope. Thus, the rate of excretion of CO2 (normalized 

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to CO2) above background following the administration of Methacetin-methoxy-13C 
indicates its rate of metabolism, which relates to the hepatic cell "health" and to the 
functional mass of the liver. 
 
1.5. 
BreathID® System: 
Exalenz has developed the BreathID device to perform automatic breath tests based on a 
unique molecular correlation spectrometer (MCS). Based on specific optical-radiation 
emission and absorption by 13CO2 and 12CO2 gases, the portable BreathID MCS device 
continuously senses exhaled breath and analyzes CO2 in real-time through a nasal cannula 
worn by the patient The primary output of the BreathID is thePDR (percentage dose 
recovery) and CPDR (Cumulative PDR) which quantify the amount of 13C labeled substrate 
metabolized by the liver.. 
 
1.6. 
13C-labeled substrate - 13C-Methacetin: 
The substrate used in the pivotal study breath test was 13C- Methacetin whose resultant 
¹³CO2 can be measured in the exhaled breath. The amount of metabolized Methacetin 
indicates the capability of the liver to accomplish one of its main physiological tasks and has 
been shown to correlate with liver fibrosis and cirrhosis.  13C-Methacetin meets all of the 
qualifications for an in-vivo diagnostic test. It is a non-toxic small molecule. No reports of 
any complications using this substance have been reported. The compound is considered to 
remain stable over an extended period of time.  
 
1.7. 
Utility as follow-up tool 
Biopsies, the gold standard of liver health are not repeated as routine patient care and blood 
test results are not always indicative or sensitive enough to foresee deterioration in liver 
function in a timely manner.  
A safe, non-invasive accurate test that assesses liver function and, when relevant, shows 
trends compared to previous breath tests, could highly improve patient management.  
Preliminary data utilizing the MBT has demonstrated that the results from this system 
correlated with hepatic fibrosis in patients with chronic HCV and with the clinical course in 
patients pre and post transplantation and with fulminate hepatitis. 
1.7.1. Hepatic Impairment Score Using the BreathID MBT 
Exalenz has developed an algorithm for the scoring of hepatic impairment in patients 
suffering from a wide range of chronic liver diseases. The algorithm developed was named 
the “Hepatic Impairment Score” (HIS). The HIS is a probability score based on breath test 
and other demographic parameters. It was developed using logistic regression methodology. 
The linear predictor of the model selected is transformed into a probability score of disease 
severity. The HIS is intended to be used as the device output. 
The use of the MBT test and its resultant continuous HIS for a particular patient enables the 
practitioner to assess the liver disease severity. This claim/label of the MBT is supported by 
several medical key opinion leaders (KOL). 
 
Assessing the severity of chronic liver disease is important for following reasons: 
 
To make a timely decision to perform liver biopsy 

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 
To aid in assessment of the risk of developing cirrhosis and its complications, 
including bleeding varices, infections, ascites, and hepatic encephalopathy.  
 
To decide when to initiate certain diagnostic investigations and therapeutic 
interventions including: Anti –viral treatment, upper endoscopy, use of beta 
blockers for varices and determination of frequency of monitoring of disease 
progression. 
 
To decide when to begin surveillance for liver cancer, such as blood tests (serum 
levels of alpha feto protein) and imaging (ultrasound).  
 
To decide when to prepare or list a patient for liver transplantation. 
1.7.2. Biopsy Scoring  
Repeat biopsy scoring, where available, will be collected according to the standard scoring 
procedure at each site. The study itself does not call for additional biopsies to be carried out. 
1.8. 
Safety and Efficacy of the Investigational Product  
Information on the Safety of the Investigational New Drug and safety and efficacy of the 
MBT and the BreathID device are provided in the Investigator Brochure, though no safety 
issues are expected since this is a retrospective non-interventional study. 
1.9. 
Rationale for the Current Study 
Timely assessment of disease progression associated morbidity and mortality is important 
for educated/proper management of cirrhotic patients. For example: 
 
Instrumental in determining the long-term prognosis of the patient  
 
Establishing the risk for hepatic complications in chronic liver patients regarding 
conditions that are common in these patients, such as portal hypertension and 
subsequent esophageal varices and cancer.  
 
Cirrhosis often is an indolent disease/condition; many of the patients remain 
asymptomatic until the occurrence of decompensation, characterized by ascites, 
spontaneous bacterial peritonitis, hepatic encephalopathy or variceal bleeding from 
portal hypertension. Thus, early diagnosis of patients at higher risk for such 
complications may lead to treatment that can prevent development of these 
complications and others such as hepatocellular carcinoma, overt encephalopathy 
and liver decompensation after surgery.  
1.10. Summary of Overall Risk and Benefits 
Since this proposed study is retrospective no adverse events and/or risk associated with the 
MBT are expected.  
The MBT BreathID system consists of the device and ¹³C-Methacetin. The same device but 
with a different substrate (¹³C-Urea) for the diagnosis of H. Pylori was cleared as a 510(K). 
The software of the cleared device was upgraded in order to allow the BreathID system to be 
used in the assessment  of liver disease severity. Therefore, the BreathID device does not 
pose any increased risk to patients participating in this study. 

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The 13C-methacetin substrate has been used for various breath tests in numerous patients 
including special populations such as neonatals and pregnant women. To the best of our 
knowledge no adverse events had ever been reported using 13C-Methacetin.  
Furthermore, Methacetin is a well known drug that has been available and described in 
literature for over 30 years and is currently used in medications (such as acetaminophen) for 
human therapeutic use. No risks have been reported in literature using much higher doses of 
Methacetin than currently used in the MBT. 
 
During the test procedure, patient contact with the device is through a nasal cannula for 
collection and analysis of the breath samples. Nasal breathing cannulae are a well-known 
and proven medical tool having minimum side effects. No discomfort has been reported 
during prior feasibility studies conducted by Exalenz involving over 400 patients performed 
with the nasal cannula. 
 
The data analyzed in this study will be used to validate the hypothesis claiming a single 13C-
Methacetin breath test in chronic liver patients may correlate with liver related morbidity 
and mortality. This claim had been already been demonstrated in previous studies done by 
the company, showing a hazard ratio of up to 12 between a single MBT and complications 
and mortality in chronic patients within one year of the breath test. If such a claim is to be 
validated, it is expected to influence the clinical practice for such patients preventing the 
onset of complications and death.  
Furthermore, if the second endpoint shows that the predictive value of MBT is greater than 
that of liver biopsy, many patients would be able to avoid the invasive nature and 
economically burdensome liver biopsy.  
 
In consideration of the rationale and rating the benefits and risks, the conduct of this clinical 
trial is ethically justified.  
1.11. Guidance for Investigator 
The investigator is responsible for ensuring the study will be conducted according to GCP, 
ethical conduct as well as all applicable laws and regulations. 
 
We expect that the study would be granted a waiver from obtaining an informed consent 
since it is retrospective in nature.  
 
 
2. 
OBJECTIVES 
The objectives of this study are: 
 To evaluate the ability of the Methacetin Breath Test to detect hepatic decompensation 
events 
 To evaluate the relationship between liver Biopsy and clinical outcome and show that 
the MBT has a better predictive ability of clinical outcome than liver biopsy.  

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 To evaluate the ability of the MBT to predict each of the individual liver related 
complications.  
 
3. 
ENDPOINTS 
3.1. 
Primary Efficacy Endpoints 
The MBT results and the time to hepatic decompensation events: 
Hepatic decompensation is defined as the occurrence of at least one of the following events 
in the time frame between the last 13C-Methacetin Breath Test (MBT) to the time of data 
collection: 
1. 
Death (liver related) 
2. 
Transplantation (cadaveric and living donors) 
3. 
Ascites 
4. 
HE (Hepatic Encephalopathy) 
5. 
Newly diagnosed varices or variceal bleeding  
6. 
SBP (spontaneous bacterial peritonitis)/Sepsis 
7. 
HRS (Hepatorenal syndrome) 
8. 
HCC (hepatocellular carcinoma) 
9. 
Increase in CTP (Child Turcotte Pugh) Score by 3 points 
10. 
Increase in MELD score by 5 points 
 
3.2. 
Secondary Efficacy Endpoints 
 
 Histological liver biopsy results (obtained in the initial study) versus clinical outcome at 
time of current data collection 
 
 Time to each of the individual events as follows: 
1. Death (liver related) 
2. Transplantation (cadaveric and living donors) 
3. Ascites 
4. HE (Hepatic Encephalopathy) 
5. Newly diagnosed varices or variceal bleeding  
6. SBP (spontaneous bacterial peritonitis) 
7. HRS (Hepatorenal syndrome) 
8. HCC (hepatocellular carcinoma) 
9. Increase in CTP (Child Turcotte Pugh) Score by 3 points. 
10. Increase in MELD score by 5 points . 
 
3.3. 
Safety Endpoint 
No safety endpoint will be evaluated since this is a retrospective study. 

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4. 
STUDY DESIGN 
This is a retrospective, multi-center, non-randomized, open label study of the ¹³C-
Methacetin BreathID Test (MBT) that will include all patients previously enrolled into the 
BreathID pivotal study (HIS-EX-408)  and/or the PLT-BID-1108 study, that have performed 
a valid MBT. The information collected in this study will be anonymous. 
 
5. 
STUDY POPULATION 
All subjects previously enrolled into the BreathID pivotal study (HIS-EX-408)  and/or the 
PLT-BID-1108 study and had a valid 13C-Methacetin breath test result with or without a 
valid liver biopsy result at the time of MBT will be included in this retrospective 
investigation.  
5.1. 
Entry Criteria 
5.1.1. Inclusion Criteria (screening visit) 
To be eligible for inclusion into this study, the subjects must fulfill all of the following 
criteria: 
 Previously enrolled into a BreathID Methacetin study according to study protocol.  
 Has a valid Methacetin breath test result. 
 Patient file is available for review.  
5.1.2. Exclusion Criteria (screening visit) 
Subjects that meet any of the following criteria will not be included in this study:  
a. Patient was not enrolled into the pivotal or PLT studies according to study protocol.  
b. Patient file is not available for review.  
 
6. 
STUDY PROCEDURES AND ASSESSMENTS 
 
6.1. 
General Instructions 
This study is based on review of patients source file (patient's file) as well as the CRFs 
gathered from the BreathID Methacetin Breath Test studies (HIS-EX-408 and PLT-BID-
1108).  

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6.2. 
Outline of Study Procedures and Assessments  
6.2.1. Screening and baseline 
Subjects' existing CRFs will be reviewed to identify eligible subjects. The following data 
will be recorded: 
 Demographic data 
 Medical history  
 History of all prescription or non-prescription drugs, vitamins, and dietary supplements 
History of drug and alcohol use. 
 Disease history, including date of initial diagnosis, stage of disease , previous treatments 
and responses 
 Status of disease activity 
 Concomitant medication and procedures 
 MBT results  
 Most recent biopsy results if available.  
 
6.3. 
Safety Observations and Measurements 
Hepatic complication events occurring as described in the patient's file from the time of 
enrollment in the previous pivotal study and the time of this proposed investigation will be 
recorded.  
6.4. 
Concomitant Medications and Therapies 
All concomitant medications administered as described in the patient's file from the time of 
enrollment in the previous pivotal study and the time of this proposed investigation will be 
recorded. all medication prescribed from the time of enrollment to the time of this proposed 
investigation as described within the patient's file will all be recorded. 
 
6.5. 
Subject Completion and Withdrawal 
Not applicable. 
 
7. 
INVESTIGATIONAL NEW DRUG USED IN THE STUDY 
Not applicable. 
7.1. 
Treatment of Overdose 
Not applicable 

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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Study Design and Objectives 
This is a retrospective, multi-center, non-randomized, open label study of the ¹³C-Methacetin 
BreathID Test (MBT) that will include all patients previously enrolled into the BreathID 
pivotal study who have performed a valid MBT. 
The main objective of the study is to evaluate the ability of the MBT to predict time to 
hepatic decompensation events.  
The secondary objective of the study is show that MBT predictive ability is better than that 
of liver biopsy/MELD in predicting time to these events. 
 
8.2. 
Primary Endpoint 
The MBT results and the time to hepatic decompensation events: 
Hepatic decompensation event is defined as the occurrence of at least one of the following 
events in the time frame between the last 13C Methacetin Breath Test (MBT) to the time of 
data collection: 
1. 
Death (liver related) 
2. 
Transplantation (cadaveric and living donors) 
3. 
Ascites 
4. 
HE (Hepatic Encephalopathy) 
5. 
Newly diagnosed varices or variceal bleeding  
6. 
SBP (spontaneous bacterial peritonitis)/Sepsis 
7. 
HRS (Hepatorenal syndrome) 
8. 
HCC (Hepatocellular carcinoma) 
9. 
Increase in CTP (Child Turcotte Pugh) Score by 3 points 
10. 
Increase in MELD score by 5 points 
.  
8.3. 
Secondary Endpoint 
Histological liver biopsy results (obtained in the initial study) versus clinical outcome at 
time of current data collection. . 
8.4. 
Safety Endpoints 
There are no safety endpoints in this trial since it is retrospective and observational only. 
8.5. 
Sample size  
This protocol is looking back on retrospective data from Exalenz clinical studies  HIS-EX-
408 and/or PLT-BID-1108 . In the initial studies there were 414 and 165 subjects enrolled 
respectively, thus this retrospective study may include up to 579 subjects. 
 

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8.6. 
Statistical Analyses  
All statistical analyses and data presentations, including tabulations and listings, will be 
performed using the SAS version 9.3 (or higher) software. Statistical tests will be two-
sided and the level of significance is 0.05. Nominal p-values will be presented. 
Baseline demographics and medical characteristics will be presented in tabular format. The 
statistical evaluation of baseline characteristics will include all available data.  
For continuous variables, the following descriptive statistics will be given: N, Mean, 
Standard Deviation, Minimum, Median and Maximum values; for discrete variables, the 
Frequency and Percentage of patients or events will be provided.   
For comparison of means (continuous variables), the two-sample t-test or the Wilcoxon rank 
sum test will be used as appropriate. For comparison of proportions (categorical variables), 
the Chi-squared test or Fisher’s exact test will be used as appropriate. 
Kaplan-Meier curves of the time event data will be presented. For comparison of time to 
event data, the log rank test will be used. Cox regression will be used to estimate hazard 
ratios, their level of significance and 95% confidence limits. 
Risk stratification may be performed by categorizing the MBT into risk groups, for these 
groups Kaplan-Meier Curves of the time to clinical outcome will be presented for the MBT 
categories as well as the liver biopsy results to compare predictive value.  
 
9. 
ADVERSE EVENTS  
Not applicable in this retrospective observational study. 
10. 
STUDY ADMINISTRATION  
 
10.1. Regulatory and Ethical Considerations 
This study is to be performed in accordance with the protocol, the Declaration of Helsinki, 
the ICH Harmonized Tripartite Guideline for GCP, and all applicable regulatory 
requirements. 
 
10.1.1. Informed Consent 
• It is expected that no additional consenting will be required.  
 
10.1.2. Institutional Review Board  
Before initiation of the study at a given center, written approval of the protocol, and waiver 
for the Informed Consent Form must be approved from the appropriate IRB. If any 
amendments to any of these documents occur during the study, written approval must be 
obtained prior to their implementation.  
 

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10.1.3. End of the study 
For administrative reporting purposes the end of the study will be defined as the date of the 
final clinical database lock. This provides for a single and conservative definition across all 
study sites. 
10.2. Investigator Responsibilities 
Investigators are responsible for ensuring that the investigation is conducted according to the 
signed Investigator Agreement, the investigational plan (Protocol Approval Signature page–
Appendix A), applicable FDA regulations, local regulations, and any conditions of approval 
imposed by an IRB or FDA, in order to protect the rights, safety, and welfare of subjects 
under the investigator's care, and for the control of devices under investigation. 
 
Investigators are responsible for ensuring that informed consent is available from each 
subject, or re-obtained if applicable. 
10.3. Data Management 
The Investigator or designee will be responsible for recording study data in the paper CRF. 
It is the Investigator’s responsibility to ensure the accuracy of the data entered in the CRFs. 
A copy of the paper CRF will be kept at site and the original sent for data processing. 
 
The data will then be entered into a validated database. Database lock will occur once 
quality assurance procedures have been completed. 
10.4. Study Monitoring 
The Investigator must ensure that CRFs are completed in a timely manner and must allow a 
Sponsor representative (CRO) periodical access to CRFs, subject records and all study-
related materials. The frequency of monitoring visits will be determined by factors such as 
the design of the study. In order to verify that the study is conducted in accordance with ICH 
GCP, regulatory requirements, and the study protocol and that the data are authentic, 
accurate and complete, the CRA will review CRFs and other study documents and will 
conduct source data verification. 
 
Upon study completion, the CRA will visit the site to conduct a study termination visit. This 
will involve collection of any outstanding documentation. 
10.5. Subject Confidentiality 
The Investigator must ensure that the patients’ anonymity is maintained. On the CRFs or 
other documents, patients should not be identified by their names, but by their assigned 
identification number and initials. If subject names are included on copies of documents, the 
names (except for initials) must be obliterated and the assigned subject numbers added to the 
documents. 
The Investigator should keep a separate log of patients’ identification numbers, names, 
addresses, telephone numbers and hospital numbers (if applicable). Non anonymized 

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documents, such as signed Informed Consent Forms, should be maintained in strict 
confidence by the Investigator. 
10.6. Quality Assurance 
In compliance with GCP and regulatory requirements, agencies or IRB may conduct quality 
assurance audits at any time during or following a study. The Investigator must agree to 
allow auditors direct access to all study-related documents including source documents, and 
must agree to allocate his or her time and the time of his or her study staff to the auditors in 
order to discuss findings and issues. 
10.7. Retention of Essential Study Documents 
Essential documents as defined by ICH GCP include the signed protocol and any 
amendment(s), copies of the completed CRFs, signed Informed Consent Forms from all 
patients who consented, hospital records, diary cards and other source documents, IRB 
approvals and all related correspondence including approved documents, drug accountability 
records, study correspondence and a list of the patients’ names and addresses.  
 
The Investigator must retain copies of the essential documents for the period for at least 5 
years as specified by ICH GCP and longer if required by applicable regulatory requirements. 
 
10.8. Agreements  
A clinical trial letter of agreement (CTLA) between the Sponsor and Investigator will be 
used as a separate study related document.  
11. 
PUBLICATION 
Any manuscript, abstract or other publication or presentation of results or information 
arising from the study (including ancillary studies involving trial patients) must be prepared 
in conjunction with Exalenz. Such materials must be submitted to Exalenz for review and 
comment at least 30 days prior to submission for publication or presentation. 
 
 
12. 
REFERENCES  
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3.  J Fahl et al, Hepatology, Vol. 4, No.5, 1984 
4.  Braden B. et al, Alimentary Pharmacology & Therapeutics Volume 21 Issue 2 Page 
179  - January 2005 

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5.  Festi D, Capodicasa S, Sandri L, Colaiocco-Ferrante L, Staniscia T, Vitacolonna E, 
Vestito A, Simoni P, Mazzella G, Portincasa P, Roda E, Colecchia A. Measurement of 
hepatic functional mass by means of 13C-methacetin and 13C-phenylalanine breath 
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21. Ciccociopo R, Candelli M, Di Francesco D, Ciocca F, Taglieri G, Armuzzi A, 
Gasbarrini  G and Gasbarrini A, Aliment Parmacol Ther 2003; 17: 271-277. 
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Appendix A 
 
APPROVAL SIGNATURE 
 
 
Protocol No:  
HIS-FU-EX-1213 
Protocol Title: 
The predictive value of the BreathID, 13C-Methacetin breath test for Hepatic 
Decompensation; a retrospective analysis 
Version: 
 
1b 
Date of Protocol:  
01-APR-2014 
 
Site Name: 
 
 
Principal Investigator (Print name):  
 
I have read this protocol and agree to conduct the study as outlined herein and as per GCP 
 and local regulations. 
 
Principal Investigator____________________________ Date_____________________