Clinical trial NCT03462576
Conditions: Decompensated Cirrhosis
Sponsor: Meridian Bioscience, Inc.
Start date: 2017-06-28; Completion date: 2019-07-15
Enrollment: 199 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-17.The IDN-6556-17 study is a Phase 2, multicenter, double-blind, placebo-controlled trial of Emricasan in subjects with decompensated non-alcoholic steatohepatitis (NASH) cirrhosis.

Detailed description:
The protocol is intended to validate the ability of the MBT to predict deterioration by 48 weeks for all subjects, and at later time points for those followed longer, for subjects with decompensated NASH cirrhosis in the placebo treatment arm of Conatus' study IDN-6556-17.

As one of the Conatus' study secondary objectives, this companion protocol is designed to assess improvement in liver metabolic function as measured by Methacetin Breath Test (MBT) \[ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) \].

Arms: arm 1: The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. arm 2: The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. arm 3: The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48.
Interventions: intervention 1: Methacetin Breath Test intervention 2: Emricasan intervention 3: Placebo oral capsule
Intervention descriptions: intervention 1: A breath analyzer will be used to measure changes in carbon 12 to carbon13 ratio as a result of metabolism of the Methacetin substrate before and after treatment. intervention 2: Investigational drug for NASH treatment in Main Conatus protocol intervention 3: Placebo versus emricasan in Conatus NASH treatment trial

Protocol documents:
Prot_000.pdf: 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
Companion protocol for the ¹³C-Methacetin Breath Test 
using the BreathID® MCS System for Conatus phase 2 
study of Emricasan, an Oral Caspase Inhibitor, under 
Protocol IDN-6556-17 (IND111463) 
  
Protocol No. CON-EX-0217 
 
Document No: CSP000001 
Total pages: 28 
Version Level: 2.0 
Last update on: May 24, 2017 
 
 
Name 
Position 
Author / 
Owner 
Gil Guggenheim 
Clinical Research Development Manager 
Reviewed by 
Raffi Werner 
CEO  
Approved by 
Melina Arazy, MD 
VP of Clinical Affairs 
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 or computer language or distributed without the prior written consent of: 
Exalenz Bioscience Ltd. 4 Ha’Maayan St. Modi’in, Israel 7177872 
Versions Control: 
Version 
Date 
Responsible Person Description of Change 
1.0 
March 01, 2017 
Gil Guggenheim 
Initial Release 
2.0 
May 24, 2017 
Ora Msika 
Addition of Breath tests at 24-
week intervals 
 
 
 
 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 2 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
 
 
TABLE OF CONTENTS 
1 Abbreviations ........................................................................................................................ 5 
2 Protocol Synopsis ................................................................................................................. 6 
3 Background ......................................................................................................................... 12 
3.1 
Defining the need for a non-invasive test for the characterization of NASH severity ................. 13 
3.2 
Cirrhosis (compensated and de-compensated) and Portal Hypertension ..................................... 14 
3.3 
Rationale to use the MBT for assessment of Liver Disease Severity........................................... 14 
4 Intended Use / Indication for Use ..................................................................................... 15 
5 Study Design ....................................................................................................................... 15 
6 Study Objectives ................................................................................................................. 15 
6.1 
Primary Efficacy Objective .......................................................................................................... 16 
6.2 
Secondary Efficacy Objectives .................................................................................................... 16 
6.3 
MBT Safety Objective ................................................................................................................. 16 
6.4 
Primary Efficacy Endpoint ........................................................................................................... 16 
6.5 
Secondary Efficacy Endpoints ..................................................................................................... 16 
6.6 
Safety Endpoints .......................................................................................................................... 17 
7 Subject Selection ................................................................................................................. 17 
7.1 
Inclusion Criteria .......................................................................................................................... 17 
7.2 
Exclusion Criteria......................................................................................................................... 17 
7.3 
Exclusion Criteria On the day of the MBT .................................................................................. 17 
7.4 
Consenting ................................................................................................................................... 18 
8 Safety Termination and Early Withdrawal of Subjects or Study ................................. 18 
8.1 
Expected Study Duration ............................................................................................................. 18 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 3 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
9 Statistical Considerations .................................................................................................. 18 
9.1 
Study Design and Aim ................................................................................................................. 18 
9.2 
Endpoint Measures ....................................................................................................................... 19 
9.2.1 
Primary endpoint measure ............................................................................................................. 19 
9.2.2 
Secondary endpoint measures ........................................................................................................ 19 
9.2.3 
Safety endpoints measure .............................................................................................................. 20 
9.3 
Acceptance Criteria (Study Hypotheses) ..................................................................................... 20 
9.4 
Sample Size .................................................................................................................................. 20 
9.5 
Analysis sets ................................................................................................................................. 21 
9.6 
Statistical Analysis ....................................................................................................................... 21 
9.6.1 
General Considerations .................................................................................................................. 21 
9.6.2 
Demographic and other Baseline Characteristics .......................................................................... 21 
9.6.3 
Disposition of Subjects .................................................................................................................. 22 
9.6.4 
Safety Analysis .............................................................................................................................. 22 
9.6.5 
Primary Efficacy Analysis ............................................................................................................. 22 
9.6.6 
Secondary Efficacy Analyses ........................................................................................................ 22 
9.6.7 
Interim Analysis ............................................................................................................................ 23 
9.6.8 
Pooling ........................................................................................................................................... 23 
9.6.9 
Handling of Missing Data .............................................................................................................. 23 
10 Study Procedures ............................................................................................................... 23 
10.1 General ......................................................................................................................................... 23 
10.2 Breath Test Procedure .................................................................................................................. 23 
10.3 Investigational Product Handling ................................................................................................. 26 
10.4 Investigational Product Accountability ........................................................................................ 26 
11 Ethics & Regulatory Considerations ................................................................................ 26 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 4 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
12 Safety Considerations ........................................................................................................ 27 
13 Subject Confidentiality ...................................................................................................... 27 
14 Monitoring and Quality Assurance .................................................................................. 27 
15 Publication Policy and Finance ......................................................................................... 27 
16 Financial Aspects ................................................................................................................ 27 
17 Study termination ............................................................................................................... 27 
18 References ........................................................................................................................... 28 
 
 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 5 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
1 ABBREVIATIONS 
AE 
- Adverse Event 
AUC 
- Area under the Curve 
CDOB 
- Cumulative Delta over Baseline 
CI 
- Confidence Interval 
CL 
- Confidence Limits 
CO2 
- Carbon dioxide 
CPDRxx 
- Cumulative Percentage Dose Recovery at xx minutes from ingestion  
CRF 
- Case Report Form 
CSPH 
-  Clinically Significant Port Hypertension 
DOB 
- Delta over Baseline 
eCRF 
- Electronic Case Report Form 
GCP 
- Good Clinical Practice 
HVPG 
- Hepatic Venous Pressure Gradient 
IDE 
- Investigational Device Exemption 
KOL 
- Key Opinion Leader 
MBT 
- 
13C-Methacetin Breath Test 
MCS 
- Molecular Correlation Spectrometry  
MEGX 
- Monoethylglycinexylidide 
NAFLD 
- Nonalcoholic Fatty Liver Disease 
NASH 
- Nonalcoholic Steatohepatitis 
NPV 
- Negative Predictive Value 
PDR 
- Percent Dose Recovered (expressed as % per hour) 
PET 
 - Thermoplastic Polyester 
PH 
-  Portal Hypertension 
PO 
- Per Os (by mouth) 
PPV 
- Positive Predictive Value 
ROC 
- Receiver Operating Characteristic 
SAE 
- Serious Adverse Event 
SF 
- Screen Failures 
SUSAR 
- Suspected unexpected serious adverse reaction 
UADE 
- Unanticipated Adverse Device Effect  
US 
- United States (of America) 
USA 
- United States of America 
 
 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 6 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
2 PROTOCOL SYNOPSIS 
Protocol Title: 
Companion protocol for the ¹³C-Methacetin Breath Test (MBT) using 
the BreathID® MCS System for Conatus phase 2 study of emricasan, 
an Oral Caspase Inhibitor, under protocol IDN-6556-17 (IND111463) 
Short Title: 
Companion protocol assessing MBT in subjects participating in the 
IDN-6556-17 study (IND111463) 
Protocol Reference 
Number: 
CON-EX-0217 
Version and Date: 
v 2.0, May24, 2017 
Phase of 
Development: 
Phase II/III 
Sponsor: 
Exalenz Bioscience Ltd. 
4 Ha’Maayan Street 
Modi'in, Israel 7177872 
Tel: +972-8-9737500 
Fax: +972-8-9737501 
Investigated 
Disease: 
Subjects with decompensated Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis 
Combination 
Product: 
¹³C-labeled Methacetin Breath Test Kit 
Comparators: 
Clinical Outcome  
Primary Efficacy 
Objective: 
To validate the ability of the MBT to predict deterioration by 48 
weeks for all subjects, and at later time points for those followed 
longer, for subjects with decompensated NASH cirrhosis in the 
placebo treatment arm of Conatus' study IDN-6556-17. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 7 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
Secondary Efficacy 
Objectives: 
1. To validate the ability of the MBT to predict deterioration at 6 
months for subjects with decompensated NASH cirrhosis in 
the placebo treatment arm of Conatus' study IDN-6556-17. 
2. To validate the ability of the MBT to predict deterioration at 6 
months and at least at 48 weeks and at final treatment visit for 
subjects with decompensated NASH cirrhosis in the 
emricasan treatment arms of Conatus' study IDN-6556-17. 
3. To show the ability of the MBT to measure the effect of 
emricasan on the metabolic capacity of the liver at 24-week 
intervals and at the final treatment visit, as compared to 
changes in placebo treated subjects. 
Safety Objective: 
Evaluation of safety related to BreathID MCS or MBT 
Study Population: 
Includes a subset of subjects that are being evaluated for the treatment 
phase of study IDN-6556-17, which is planned for approximately 210 
subjects in approximately 90 sites. Patients with decompensated 
NASH cirrhosis that meet the study criteria will be randomized for the 
study. A 45% screen failure (SF) rate is estimated.  
Not all participating sites are required to perform the MBT. 
Approximately 80 sites (enrolling approximately 90% of the subjects) 
will be performing the MBT. 
The total number of MBT’s expected is approximately 310 at 
screening and 200 at respective study visits with 24-week intervals 
and at the final treatment visit 
It is expected that the population performing the MBT at 24-week 
intervals and at the final treatment visit will approximately have an 
equal number of subjects from each of the 3 parallel treatment arms 
(5 mg, 25 mg or placebo). 
This data may be pooled with other parallel recruiting studies where 
MBT is performed and clinical follow up information is collected, in 
order to validate an algorithm being developed based on data collected 
from IDE# G080227 (primary study endpoint). 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 8 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
Study Design: 
This study is a companion protocol that will use the data generated by 
Conatus' 
study 
of 
emricasan 
under 
protocol 
IDN-6556-17 
(IND111463). The IDN-6556-17 study is a Phase 2, multicenter, 
double-blind, randomized, placebo-controlled, dose-response study to 
evaluate the safety and efficacy of emricasan in improving event-free 
survival based on a composite clinical endpoint (where all-cause 
mortality, new decompensation events, and MELD score progression 
are events) in subjects with decompensated NASH cirrhosis. 
The study treatment duration will be at least 48 weeks with study 
visits every 4 weeks up to week 48 and every 8 weeks after week 48. 
All subjects will continue treatment until the last subject in the study 
reaches 48 weeks in the study. This subject will undergo the 
assessments of the final treatment visit at week 48. For all other 
subjects, the final treatment visit should take place on their last study 
visit prior to or on the day of the final treatment visit of the last subject 
who has been in the study for 48 weeks. 
As part of the IDN-6556-17 study, the MBT will be performed during 
a screening visit, every 24 weeks and at the final treatment visit to 
assess whether emricasan compared to placebo improves liver 
metabolic function as determined by the Methacetin Breath Test. 
The data obtained in this study will be sequestered from Exalenz in 
order to allow pooling of the data received from Conatus' study as well 
as other parallel recruiting studies where both the MBT and clinical 
outcome will be available. Once sufficient data will be accrued, it will 
be used to validate the algorithm being developed using data from 
IDE# G080227. Additional analyses may be performed by Exalenz on 
the data to be received from this Conatus study after validation of the 
aforementioned algorithm. 
Inclusion Criteria: 
This protocol follows the inclusion criteria as defined in the main 
protocol, IDN-6556-17. This companion protocol assesses the data for 
all subjects that perform the breath test under the IDN-6556-17 
protocol, including their clinical follow up information. 
Exclusion Criteria: 
Exclusion criteria are defined in the main protocol, IDN-6556-17. 
Additionally, subjects designated to perform the MBT test that are 
known 
to 
be 
hypersensitive 
or 
allergic 
to 
acetaminophen 
(paracetamol) may not perform the MBT. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 9 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
Pre Breath Test 
Restrictions: 
1. Subject should be fasting, including all oral morning medications 
(except for beta-blockers and study drug [emricasan or placebo]), 
for at least 8 hours prior to the test  
2. Subject should not smoke on the day of the breath test prior to the 
breath test  
3. Subject should not take any of the following drugs within 48 hours 
prior to the test: acyclovir, allopurinol, carbamazepine, cimetidine, 
ciprofloxacin, daidzein (herbal), disulfiram, echinacea, enoxacin, 
famotidine, fluvoxamine, methoxsalen, mexiletine, montelukast, 
norfloxacin, 
phenylpropanolamine, 
phenytoin, 
propafenone, 
rifampin, terbinafine, ticlopidine, thiabendazole, verapamil, 
zileuton or any medication that might interfere with methacetin 
metabolism or might affect CYP1A2 (cytochrome P450 1A2) 
4. Subject should not take amiodarone within 30 days prior to the test  
5. Subject should not take paracetamol (acetaminophen) related 
medications within the 24 hours prior to the test  
6. Subject should not perform the test if allergic or hypersensitive to 
Methacetin or its metabolites (paracetamol, acetaminophen) 
7. Subject should not consume any alcohol or caffeine within 24 
hours prior to the test  
8. Subject should not have general anesthesia or sedation within 24 
hours prior to the test 
9. Subjects on beta-blockers or statins should be on a stable dose at 
least 30 days prior to the test 
Primary Efficacy 
Endpoint 
Clinical Outcome including all deterioration events at least at 48 
weeks and at final treatment visit captured under protocol IND-6556-
17 and the MBT derived algorithm developed using data from IDE# 
G080227 for the placebo treatment arm. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 10 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
Secondary Efficacy 
Endpoints: 
1. Clinical Outcome including all deterioration events at 6 months 
captured under protocol IND-6556-17 and the MBT derived 
algorithm developed using data from IDE# G080227 for the 
placebo treatment arm. 
2. Clinical Outcome including all deterioration events at 6 months 
and at least at 48 weeks and at final treatment visit captured under 
protocol IND-6556-17 and the MBT derived algorithm developed 
using data from IDE# G080227 for the emricasan treatment arms. 
3. MBT before, during and after treatment as well as changes in MBT 
results (CPDR30/PDR peak or other breath test parameters) in 
subjects with and without treatment (emricasan) for non-alcoholic 
steatohepatitis (NASH) at 24- week intervals and at the final 
treatment visit. 
Statistical Analysis: 
The data obtained in this study will be sequestered from Exalenz in 
order to allow pooling of the data received from Conatus' study as well 
as other parallel recruiting studies where MBT and clinical outcome 
measures will be available. Once sufficient data will be accrued, it will 
be used to validate the algorithm being developed on data collected as 
part of IDE# G080227.  
Additionally, all available breath test parameters (Delta Over Baseline 
[DOB] at the respective times) will be collected from the completed 
eCRFs. The DOBs will be transformed into percentage dose recovery 
(PDR) by normalizing the DOB using patient weight and height. The 
area under the DOB and PDR curves will be calculated for each 5 
minute time interval resulting in CDOB and CPDR at 5, 10, 15, 20, 25, 
30, 35, 40, 45, 50, 55 and 60 minutes. Additional breath test 
parameters will be extracted based on the features being developed 
under the Exalenz algorithm training study CSPH-EX-0414, IDE# 
G140190 as well as IDE# G080227. 
The primary endpoints of this study are clinical outcome measures and 
the MBT derived algorithm.  
The primary efficacy analysis as well as the first two secondary 
endpoints will include the point estimates of Hazard Ratio or Relative 
Risk with respective exact two-sided 95% confidence intervals.  
The Methacetin Breath Test will be assessed to measure the effect of 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 11 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
emricasan on the metabolic capacity of the liver at 24-week intervals, 
and at the final treatment visit as compared to placebo, by modelling 
the change from baseline MBT to each of the 24-week intervals visit 
using an analysis of covariance model. The change from baseline will 
also be derived.  
Treatment comparisons will be conducted using a linear mixed-effects 
model using treatment (3 levels), visit, treatment-by-visit interaction, 
presence of prior variceal hemorrhage, and presence of prior SBP as 
fixed effects. The unstructured covariance model will be used. These 
models will use all available information from all subjects randomized 
and assume that all missing data is missing at random. Least-square 
adjusted means (LSMeans) at each visit and the estimated difference 
and associated 95% CIs between each of the emricasan treatment 
groups and the placebo group will be reported. The LSMeans 
difference will be tested for each emricasan treatment group versus the 
placebo group at specified time points. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 12 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
3 BACKGROUND 
The background of cirrhosis especially in NAFLD/NASH and its pathogenesis is described 
in the Conatus' IDN-6556-17 study main protocol. 
Standard biochemical and clinical tests are not capable of providing good correlations with 
disease staging and grading. Furthermore, it is known that in a substantial percentage of the 
diseased population, standard liver function tests do not show abnormal results. 
Histological parameters have been shown to be correlated to liver disease severity(1) but 
biopsies have limitations such as sampling error and the risks involved in the biopsy 
procedure itself. Furthermore, biopsies are not a measure that can be repeated often enough 
in standard practice in order to monitor disease progression. 
The unmet clinical need for a non-invasive means to evaluate liver disease progression or 
response to therapy accurately is clearly a challenge that needs to be addressed as new 
NASH treatments are being developed. 
The concept of a metabolic test that could be utilized to assess the severity of liver disease 
was first explored several decades ago. Such tests are performed by administering a 
compound, either orally or intravenously, with the compound being taken up by the liver or 
metabolized; the end-products of the metabolic process can be measured in either blood, 
bile, urine, saliva or exhaled breath, supplying a measurable value to the level of liver 
metabolic activity. Several compounds have been utilized to evaluate hepatic metabolic 
function in this manner, including indocyanine green, galactose, aminopyrine, caffeine, 
lidocaine, phenylalanine, Methacetin (N-(4-Methoxy-phenyl) acetamide) and Octanoate 
(sodium-octanoate). For example, previous studies have demonstrated that hepatic 
metabolism of lidocaine to monoethylglycinexylidide (MEGX) decreases with liver 
fibrosis and cirrhosis and improves with successful treatment of the underlying liver 
disease. Furthermore, these studies showed the lidocaine test could accurately predict 
which subjects with stable cirrhosis awaiting liver transplantation were at risk of 
developing future hepatic decompensation. Most of these methods have been abandoned 
due to impracticality or undesired side effects. 
Exalenz Bioscience Ltd. has developed diagnostic breath test products consisting of a 
combination of a medical device and various 13C-labeled diagnostic substrates for 
gastrointestinal and liver applications. 
The rate and pattern of changes in the 13CO2/12CO2 ratio curve reflect substrate metabolism, 
i.e. the liver's metabolic capacity. 
The aim of the Company is to provide a non-invasive, point-of-care, breath test to assess 
disease severity and to monitor disease progression using 13C-Methacetin. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 13 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
3.1 Defining the need for a non-invasive test for the characterization of 
NASH severity 
About 7.9% of the US population has persistently elevated liver enzymes with negative 
findings for viral hepatitis and other common causes of liver diseases(2). Over 80% of such 
cases are estimated to be due to NAFLD (NAFL or NASH). In those who have 
concomitant features of the metabolic syndrome, the likelihood of NAFLD exceeds 90%. It 
is also known that in a substantial percentage of the diseased population, standard tests do 
not show abnormal results, especially in the NAFLD population. 
Furthermore, the standard biochemical and clinical tests do not provide good correlation 
with disease staging and grading. 
Currently, such subjects are offered a liver biopsy as standard of care to diagnose NASH 
and assess the risk of potential cirrhosis. Although histology results have been shown to be 
correlated to liver disease severity(1), biopsies have limitations such as sampling error and 
risks involved in the actual biopsy procedure. Additionally, given the sheer numbers of 
subjects with NASH in the world, it is not logistically feasible to biopsy all subjects with 
NASH. Furthermore, biopsies are not a measure that can be repeated often enough in 
standard practice in order to monitor disease progression. 
Based on all of the above, there is a great need for a simple non-invasive method to assess 
and monitor disease progression in the NAFLD/NASH group. 
Breath testing with 13C-labeled substrates provides a safe, non-invasive means for 
evaluating hepatic impairment as it pertains to liver metabolic function. 13C is a stable, non-
radioactive isotope, which can be incorporated into a specific location within a test 
substrate so it can be metabolized to 13CO2 by the liver. 13C-Methacetin has been identified 
as an appropriate substrate. 
The device being used is a molecular correlation based spectrometer, using a patented 
technology based on specific light source emissions and the different absorption of 13CO2 
and 12CO2 gases. This technology is already implemented in a similar device approved for 
marketing in Europe and cleared in the USA for other disease testing, namely H. pylori 
infection. 
The 13C-labeled substrates (in this case 13C-Methatecin) are metabolized by the target organ 
under investigation (in this case the liver), producing 13CO2 which in turn leads to changes 
in the 13CO2/12CO2 ratio in a subject's exhaled breath over time. These ratio changes are 
displayed in real time on the device's screen and printed at end of test. 
Breath tests using the 13C-Methacetin are being evaluated in this protocol in an attempt to 
find an effective tool to monitor liver disease progression/regression with and without 
treatment in NAFLD/NASH, and to assist in assessing disease severity and risk for 
decompensation. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 14 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
3.2 Cirrhosis (compensated and de-compensated) and Portal 
Hypertension 
As described in the Conatus protocol IDN-6556-17 part 4.1. 
3.3 Rationale to use the MBT for assessment of Liver Disease Severity 
Tests of true hepatic function that rely on the metabolism of administered exogenous 
compounds have not yet been widely adopted in clinical practice because they have been 
cumbersome to perform and the acquisition of results is slow. The recent development of 
the BreathID® MCS analyzer offers a unique opportunity to demonstrate a metabolism-
based test showing agreement with disease progression and HVPG measures. 
In advanced liver disorders, the liver has reduced 13C-Methacetin metabolic capacity, 
leading to low MBT values. Low values of Methacetin metabolism are suggestive of 
patients who are likely to have advanced liver disease and thus increased portal pressure. 
Several MBT output variables (percentage dose recovery rate and cumulative percentage 
dose recovered - PDR/CPDR values at different time points) could be used to assess 
disease progression. 
It has been shown in preliminary studies that MBT correlates with both CTP and MELD 
values. It may be even more sensitive and a better predictor of liver function because 
generally function deteriorates prior to the development of complications of cirrhosis and a 
decline in liver function as assessed by CTP and MELD(3).  
It is hypothesized that a decline in liver function as assessed by MBT measured serially 
over time will occur prior to the development of complications of cirrhosis (such as 
variceal bleeding, ascites and hepatic encephalopathy) and worsening in liver function as 
assessed by changes in CTP and MELD. 
The MBT could therefore produce immediate results to aid in decision making in patients 
with cirrhosis awaiting liver transplant. Such a test may in future help in decision-making 
regarding transplantation priority and provide point of care assessment of therapeutic 
interventions if relevant. 
This study’s aim is to show the ability of the 13C-methacetin breath test to identify patients 
at risk for decompensation and to determine the effect of Conatus’ study drug emricasan on 
the metabolic capacity of the liver at 24 week intervals of treatment and at final treatment 
visit at different treatment doses compared to placebo. 
 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 15 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
4 INTENDED USE / INDICATION FOR USE 
The ¹³C-Methacetin Breath Test is a non-invasive test intended as an aid in assessment of 
adult patients at risk for disease deterioration by measuring the ability of the liver to 
metabolize ¹³C-Methacetin and may be used to assess disease progression before and after 
treatment in adult subjects with decompensated NASH cirrhosis. 
5 STUDY DESIGN 
Please refer to protocol IDN-6556-17.  
This study is a companion protocol that will use the data generated by Conatus' study of 
emricasan under protocol IDN-6556-17. The IDN-6556-17 study is a Phase 2, multicenter, 
double-blind, randomized, placebo-controlled, dose-response study to evaluate the safety 
and efficacy of emricasan in improving event-free survival based on a composite clinical 
endpoint (where all-cause mortality, new decompensation events, and MELD score 
progression are events) in subjects with decompensated NASH cirrhosis. 
The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to 
week 48 and every 8 weeks after week 48. All subjects will continue treatment until the last 
subject in the study reaches 48 weeks in the study. This subject will undergo the 
assessments of the final treatment visit at week 48. For all other subjects, the final 
treatment visit should take place on their last study visit prior to or on the day of the final 
treatment visit of the last subject who has been in the study for 48 weeks. 
As part of the IDN-6556-17 study, the MBT will be performed during a screening visit, 
every 24 weeks and at the final treatment visit, to assess whether emricasan compared to 
placebo improves liver metabolic function as determined by the Methacetin Breath Test. 
The data obtained in this study will be sequestered from Exalenz in order to allow pooling 
of the data received from Conatus' study as well as other parallel recruiting studies where 
both the MBT and clinical outcome will be available. Once sufficient data will be accrued, 
it will be used to validate the algorithm being developed using data from IDE# G080227. 
Additional analyses may be performed by Exalenz on the data to be received from this 
Conatus study after validation of the aforementioned algorithm. 
6 STUDY OBJECTIVES  
The data generated in this study will be used to validate an algorithm being developed 
under parallel Exalenz studies. Additionally, the companion study aims to evaluate the 
capabilities of the MBT to assess the severity of NASH and monitor changes in subjects 
with and without NASH treatment compared to clinical outcome events. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 16 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
6.1 Primary Efficacy Objective 
To validate the ability of the MBT to predict deterioration at by 48 weeks for all 
subjects, and at later time points for those followed longer, for subjects with 
decompensated NASH cirrhosis in the placebo treatment arm of Conatus' study IDN-
6556-17. 
6.2 Secondary Efficacy Objectives 
1. To validate the ability of the MBT to predict deterioration at 6 months for 
subjects with decompensated NASH cirrhosis in the placebo treatment arm of 
Conatus' study IDN-6556-17. 
2. To validate the ability of the MBT to predict deterioration at 6 months and at 
least at 48 weeks and at final treatment visit for subjects with decompensated 
NASH cirrhosis in the emricasan treatment arms of Conatus' study IDN-6556-17. 
3. To show the ability of the MBT to measure the effect of emricasan on the 
metabolic capacity of the liver at 24 week- intervals and at the final treatment 
visit, as compared to changes in placebo treated subjects. 
6.3 MBT Safety Objective 
All adverse events, serious adverse events (SAE), suspected unexpected serious adverse 
reactions (SUSAR) and unanticipated adverse device effects (UADE) will be reported 
according to local regulations. The actual reporting is discussed in section 11. No breath-
test related adverse events are expected. For more information please refer to the 
Investigator's Brochure.  
6.4 Primary Efficacy Endpoint 
Clinical Outcome including all deterioration events at least at 48 weeks and at final 
treatment visit captured under protocol IND-6556-17 and the MBT derived algorithm 
developed using data from IDE# G080227 for the placebo treatment arm.  
6.5 Secondary Efficacy Endpoints 
1. Clinical Outcome including all deterioration events at 6 months captured under 
protocol IND-6556-17 and the MBT derived algorithm developed using data 
from IDE# G080227 for the placebo treatment arm.  
2. Clinical Outcome including all deterioration events captured at 6 months and at 
least at 48 weeks and at final treatment visit under protocol IND-6556-17 and the 
MBT derived algorithm developed using data from IDE# G080227 for the 
emricasan treatment arms. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 17 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
3. MBT before, during and after treatment as well as changes in MBT results 
(CPDR30/PDR peak or other breath test parameters) in subjects with and without 
treatment (emricasan) for nonalcoholic steatohepatitis (NASH) at 24 week 
intervals and at the final treatment visit.. 
4. Safety Endpoints 
All adverse events, serious adverse events (SAE), suspected unexpected serious adverse 
reactions (SUSAR) and unanticipated adverse device effects (UADE) possibly or probably 
related to the use of the BreathID MCS device and its substrates or related to the procedure 
will be reported according to local regulations. 
7 SUBJECT SELECTION 
This companion protocol assesses the data for all subjects being evaluated under IDN-
6556-17 at sites performing MBT. Subjects will be screened according to the 
inclusion/exclusion criteria of the IDN-6556-17 protocol, and will be randomly assigned to 
a study arm if they meet all the criteria. 
7.1 Inclusion Criteria  
Inclusion criteria are as those in the Conatus protocol number IDN-6556-17. This 
companion protocol assesses the data for all subjects that perform the breath test under the 
IDN-6556-17 protocol. 
7.2 Exclusion Criteria  
Exclusion criteria are as those in the Conatus protocol number IDN-6556-17. Additionally, 
subjects designated to perform the MBT test that are known to be hypersensitive or allergic 
to acetaminophen (paracetamol) may not perform the MBT. 
7.3 Exclusion Criteria On the day of the MBT 
1. 
Subject should be fasting, including all oral morning medications (except for 
beta-blockers and study drug [emricasan or placebo]), for at least 8 hours 
prior to the test  
2. 
Subject should not smoke on the day of the breath test prior to the breath test  
3. 
Subject should not take any of the following drugs within 48 hours prior to 
the test: acyclovir, allopurinol, carbamazepine, cimetidine, ciprofloxacin, 
daidzein (herbal), disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, 
methoxsalen, mexiletine, montelukast, norfloxacin, phenylpropanolamine, 
phenytoin, propafenone, rifampin, terbinafine, ticlopidine, thiabendazole, 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 18 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
verapamil, zileuton or any medication that might interfere with methacetin 
metabolism or might affect CYP1A2 (cytochrome P450 1A2) 
4. 
Subject should not take amiodarone within 30 days prior to the test  
5. 
Subject should not take paracetamol (acetaminophen) related medications 
within the 24 hours prior to the test  
6. 
Subject should not perform the test if allergic or hypersensitive to Methacetin 
or its metabolites (paracetamol, acetaminophen) 
7. 
Subject should not consume any alcohol or caffeine within 24 hours prior to 
the test  
8. 
Subject should not have general anesthesia or sedation within 24 hours prior 
to the test 
9. 
Subjects on beta-blockers or statins should be on a stable dose at least 30 
days prior to the test 
7.4 Consenting 
Subjects’ and/or their representative will be consented and sign the appropriate form as part 
of Conatus' IDN-6556-17 study prior to study participation. 
The consent will include willingness to share data with Exalenz and allow acquisition and 
collation of blood, clinical and imaging data taken on entry to the study, and incorporate all 
other data from the time of admission until the subject's termination from the study. 
8 SAFETY TERMINATION AND EARLY WITHDRAWAL OF 
SUBJECTS OR STUDY 
For safety termination and early withdrawal of subjects please refer to Conatus’ protocol 
IDN-6556-17. 
8.1 Expected Study Duration 
Conatus’ protocol IDN-6556-17 plans to have subjects remain on study therapy for a total 
of at least 48 weeks unless intolerable side effects develop, or the subject is withdrawn 
from study participation. In addition, subjects will have up to a 4 week screening period 
and a 2 week post-treatment follow-up visit for a total duration of at least 54 weeks. 
9 STATISTICAL CONSIDERATIONS 
9.1 Study Design and Aim 
This study is designed under a companion protocol that will use the data generated by 
Conatus’ study of emricasan under protocol IDN-6556-17 for which one of the secondary 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 19 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
goals is to assess whether emricasan compared to placebo improves liver metabolic 
function as assessed by the Methacetin Breath Test. The data obtained from this study will 
be sequestered from Exalenz in order to allow pooling of the data received from Conatus' 
study as well as other parallel recruiting studies where MBT and clinical outcome data will 
be available. The aim of the current study is to collect sufficient data to validate the 
algorithm being developed using data from IDE# G080227. Additional analyses may be 
performed by Exalenz on the data to be received from this Conatus study after validation of 
the aforementioned algorithm. 
9.2 Endpoint Measures 
9.2.1 Primary endpoint measure 
The primary endpoint measures will be point estimates of Hazard Ratio or Relative Risk at 
least at 48 weeks for classifying patients into risk groups for clinical deterioration with 
respective exact two-sided 95% confidence intervals in the placebo treatment arm, as 
determined in the training study using the algorithm developed based on data from IDE# 
G080227. 
9.2.2 Secondary endpoint measures 
1. The secondary endpoint measures will be point estimates of Hazard Ratio or 
Relative Risk at 6 months for classifying patients into risk groups for clinical 
deterioration with respective exact two-sided 95% confidence intervals in the 
placebo treatment arm, as determined in the training study using the algorithm 
developed based on data from IDE# G080227. 
2. The secondary endpoint measures will be point estimates of Hazard Ratio or 
Relative Risk at 6 months and at least at 48 weeks and at final treatment visit for 
classifying patients into risk groups for clinical deterioration with respective exact 
two-sided 95% confidence intervals in the emricasan treatment arms, as determined 
in the training study using the algorithm developed based on data from IDE# 
G080227. 
3. Repeat MBT results (CPDR30/PDR peak or other breath test parameters) and their 
changes in subjects with and without treatment (emricasan) for nonalcoholic 
steatohepatitis (NASH) at 24 week intervals and at the final treatment visit. Change 
is measured as the difference between baseline and each of the week 24 interval 
visits as well as at the final treatment visit MBT measurements in each of the three 
treatment groups. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 20 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
The metabolic capacity of the liver as determined by the MBT cumulative 
percentage dose recovery at 30 minutes (CPDR30) will be the main MBT parameter 
of interest. 
Nevertheless, available breath test parameters (Delta Over Baseline - DOB at the 
respective times) will be collected from the completed eCRFs. The DOBs will be 
transformed to percentage dose recovery – PDR, by normalizing the DOB using 
patient weight and height. The Area under the DOB and under the PDR curve will 
be calculated at 5-minute time intervals resulting in CDOB and CPDR at 5, 10, 15, 
20, 25, 30, 35, 40, 45, 50, 55 and 60 minutes respectively. Analyses may be done 
using all MBT derived parameters. 
9.2.3 Safety endpoints measure 
The cumulative incidence of adverse events, serious adverse events (SAE), suspected 
unexpected serious adverse reactions (SUSAR) and unanticipated adverse device effects 
(UADE) possibly or probably related to the use of the BreathID MCS device and its 
substrates or related to the procedure. 
9.3 Acceptance Criteria (Study Hypotheses) 
At least one cut-off, to be determined by the algorithm being developed under Exalenz 
study using data from IDE# G080227, will be validated in this study to classify patients 
into risk groups for deterioration events.  
Final success criteria will be defined and discussed with FDA as part of separate Pre-
submissions. 
9.4 Sample Size  
The plan is to enroll a subset of subjects that will be screened under Conatus' IDN-6556-17 
study. This Conatus study plans to enroll 210 subjects (70 subjects per treatment arm) to be 
randomly assigned to 1 of 2 treatment groups of emricasan or placebo (25 mg, 5 mg, or 
matching placebo in a 1:1:1 ratio). A 45% screen failure (SF) rate is estimated. It is 
expected that approximately 90% of the patients enrolled will perform the MBT. The total 
number of MBT results expected is approximately 310 at screening and 200 at respective 
study visits with 24-week intervals and at the final treatment visit The data obtained in this 
study may not suffice to support the primary endpoint. It will therefore be sequestered from 
Exalenz in order to allow pooling of the data received from Conatus' study including data 
from screen failures as well as data from other parallel recruiting studies where MBT 
clinical outcome measures will be available. Once sufficient data will be accrued, it will be 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 21 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
used in order to validate an algorithm being developed based on data collected from IDE# 
G080227 (primary study endpoint). 
9.5 Analysis sets 
Safety Analysis Set: 
All subjects screened under Conatus' IDN-6556-17 study who have performed the MBT 
test. 
Efficacy Analysis Set: 
All subjects enrolled under Conatus' IDN-6556-17 study who have performed the MBT test 
and have met the inclusion exclusion criteria for the current study and have valid MBT 
measurements. 
Safety analyses will be performed on the safety analysis set and efficacy analyses on the 
efficacy analysis set. 
9.6 Statistical Analysis  
9.6.1 General Considerations 
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, 
USA). 
If any statistical tests are performed, they will be two-sided. The required significance level 
of findings will be equal to or lower than 5%. Where confidence limits are appropriate, the 
confidence level will be 95%. 
Baseline values are defined as the last valid value prior to investigational treatment start. 
Study data will be summarized by descriptive statistics. Continuous variables will be 
summarized by a mean, standard deviation, minimum, median and maximum, and 
categorical variables by a count and percentage. Confidence intervals will be provided 
where relevant. 
9.6.2 Demographic and other Baseline Characteristics 
Demographic, medical and clinical history variables will be tabulated. Continuous 
variables will be summarized by a mean, standard deviation, minimum, median and 
maximum, and categorical variables by a count and percentage. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 22 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
9.6.3 Disposition of Subjects 
The numbers of subjects who were enrolled will be provided, as well as the reasons for all 
enrollment discontinuations, grouped by major reason (e.g., lost to follow-up, adverse 
event, poor compliance). A list of discontinued subjects, protocol deviations, and subjects 
excluded from the efficacy analysis will be provided as well. 
9.6.4 Safety Analysis 
The adverse events possibly or probably related to Methacetin and/or the BreathID® MCS 
device will be presented along with a two sided 95% exact binomial confidence interval. 
The analysis of all adverse events will include incidence tables and will include analyses by 
severity, relationship to device or drug and baseline variables. 
9.6.5 Primary Efficacy Analysis 
1. The ability of the algorithm, developed under the Exalenz training study IDE# 
G080227), to identify patients at risk for decompensation at least at 48 weeks and at 
final treatment visit will be validated using data from Conatus' IND-6556-17 study 
for the placebo treatment arm. 
Final success criteria will be defined and discussed with FDA as part of separate 
Pre-submissions. 
9.6.6 Secondary Efficacy Analyses 
1. The ability of the algorithm, developed under the Exalenz training study IDE# 
G080227), to identify patients at risk for decompensation at 6 months will be 
validated using data from Conatus' IND-6556-17 study for the placebo treatment 
arm. 
2. Assessment of the ability of the MBT to predict Clinical Outcome (event free 
survival versus various deterioration events) at 6 months and at least at 48 weeks 
and at final treatment visit captured under protocol IND-6556-17 for the emricasan 
treatment arms. 
3. The ability of the 13C-methacetin breath test (MBT) to measure the effect of 
emricasan on the metabolic capacity of the liver at 24 week intervals of treatment 
and at the final treatment visit versus placebo treated subjects, will be assessed by 
comparing the differences between the MBT results at each of the 24 - week 
interval visitsand at the final treatment visit versus baseline in all subjects with and 
without treatment (emricasan) for nonalcoholic steatohepatitis (NASH). This will 
be done for each of the 3 treatment groups (5mg, 25mg and placebo) separately. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 23 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
Treatment comparisons will be conducted using a linear mixed-effects model using 
treatment (3 levels), visit, treatment-by-visit interaction, presence of prior variceal 
hemorrhage, and presence of prior SBP as fixed effects. The unstructured 
covariance model will be used. These models will use all available information 
from all subjects randomized and assume that all missing data is missing at random. 
Least-square adjusted means (LSMeans) at each visit and the estimated difference 
and associated 95% CIs between each of the emricasan treatment groups and the 
placebo group. The LSMeans difference will be tested for each emricasan treatment 
group versus the placebo group at specified time points. 
9.6.7 Interim Analysis 
9.6.8 No interim analysis is planned for this study.Pooling 
As there will be very few subjects enrolled at any given site, data from all sites will be 
pooled for analyses. Additionally, this data may be pooled with other parallel recruiting 
studies. The data obtained in these studies will be sequestered from Exalenz until sufficient 
data will be accrued to validate the algorithm being developed in a training study based on 
data from IDE# G080227. 
9.6.9 Handling of Missing Data 
The study variables cannot be evaluated for subjects for whom BreathID® MCS device 
MBT results are not available and therefore these subjects will be left out of the efficacy 
analysis. Subjects missing clinical outcome results will be excluded from the analyses.  
10 STUDY PROCEDURES 
10.1  General 
The schedule of the breath tests is based on the schedule of the IDN-6556-17 protocol. The 
first MBT will be performed during the screening period (Week -4 to Day 0). The 
subsequent MBTs will be performed at 24 -week interval visits and at the final treatment 
visit, respectively. 
10.2  Breath Test Procedure 
Preparation of the study subject 
Once consented, the patients will perform the breath test. In preparation for each breath test 
the patient will be asked to comply with the following precautions: 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 24 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
1. Subject should be fasting, including all oral morning medications (except for beta-
blockers and study drug [emricasan or placebo]), for at least 8 hours prior to the test  
2. Subject should not smoke on the day of the breath test prior to the breath test  
3. Subject should not take any of the following drugs within 48 hours prior to the test: 
acyclovir, allopurinol, carbamazepine, cimetidine, ciprofloxacin, daidzein (herbal), 
disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, 
montelukast, norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, 
terbinafine, ticlopidine, thiabendazole, verapamil, zileuton or any medication that 
might interfere with methacetin metabolism or might affect CYP1A2 (cytochrome 
P450 1A2) 
4. Subject should not take amiodarone within 30 days prior to the test  
5. Subject should not take paracetamol (acetaminophen) related medications within 
the 24 hours prior to the test  
6. Subject should not perform the test if allergic or hypersensitive to Methacetin or its 
metabolites (paracetamol, acetaminophen) 
7. Subject should not consume any alcohol or caffeine within 24 hours prior to the test  
8. Subject should not have general anesthesia or sedation within 24 hours prior to the 
test 
9. Subjects on beta-blockers or statins should be on a stable dose at least 30 days prior 
to the test 
Preparation of 13C-Methacetin 
Exalenz Bioscience Ltd. will provide 75 mg 13C-Methacetin doses in a 0.05% solution of 
¹³C-Methacetin in purified water, supplied, in amber thermoplastic polyester (PET) bottles 
with a child resistant plastic cap. No preparation is needed other than pouring the contents 
of the solution into a cup for ingestion. 
Performance of the breath test 
Only trained personnel will perform the breath test procedure. The actual breath collection 
is automatically performed by the device and is not operator dependent. If the IDcircuit (a 
nasal cannula manufactured specifically for Exalenz) is not connected properly to the 
subject (e.g. the breath does not reach the device), the BreathID® MCS device will prompt 
the operator to adjust the IDcircuit. 
1. Turn on device from switch in rear and allow up to 1 hour for warm-up to complete. 
To perform the test, ensure that the BreathID® MCS screen shows that the device is 
in ‘Ready’ state. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 25 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
2. The IDcircuit will be attached to the BreathID® MCS device and to the patient. 
Pressing the “Start” button on the device will begin the collection of the patient’s 
baseline exhaled breath. This will take approximately 5-10 minutes. 
3. The 13C-Methacetin solution is poured into a disposable cup and administrated to 
the patient when prompted by the device. The solution should be administered by a 
medical practitioner registered on the delegation log or a research nurse if specific 
training for administration has been given. Immediately after ingestion, the operator 
will press the "Continue" button, which activates the actual measurement. CO2 
production with 13C may be visible within a few minutes in cases with relatively 
functional livers. 
Note: In rare cases, the administration of fluids may cause vomiting. If this happens, the 
test should be aborted and repeated the next day. The expected adverse event should be 
reported in the appropriate CRF section.  
4. The patient should remain in a seated position breathing in a normal manner for up 
to 90 minutes, while data is collected. 
5. The BreathID® MCS device continuously measures and analyzes the patient’s 
exhaled breath in real time. As the 13C-Methacetin is metabolized, the value of the 
13CO2/12CO2 ratio in the exhaled breath will change and will be calculated in real 
time by the device. 
6. If at any time the device does not detect patient’s breath, or if there is any other 
deviation from the desired test requirements, the device will produce an appropriate 
warning on the screen. 
7. At the completion of the procedure, the IDcircuit is removed and the patient is 
disconnected from the BreathID® MCS device. 
The patient will be under the supervision of the physician or any other qualified medical 
staff during the entire test. 
The operators will be trained how to terminate the breath test early. In the following 
situations, the MBT will be terminated and a test termination form will be completed: 
1. The patient vomits after ingestion of the substrate. 
2. The BreathID® MCS device malfunctions (in this case, the operator will complete a 
technical complaint form in addition to the test termination form and contact 
Exalenz immediately for further instructions) after ingestion of the substrate. 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 26 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
In all these cases, MBT cannot be repeated the same day for that specific subject that has 
already ingested 13C-Methacetin. An entry will be made in the drug/kit accountability log 
and the 13C-Methacetin bottles will be kept for inspection by the study monitor. 
10.3  Investigational Product Handling 
The Investigator and Research Pharmacist (if relevant) will be provided with 
Investigational Product Handling Guidelines that will provide details regarding the 
packaging and labeling requirements, receipt of investigational product, dispensing and 
accountability procedures, preparation instructions, storage and stability of the 
Investigational product and disposition of the Investigational Product. 
10.4  Investigational Product Accountability 
The Investigator and Study Pharmacist (if relevant) are responsible for ensuring that all 
study supplies received at the site are inventoried and accounted for throughout the study. 
The dispensing of study substrate to the subject must be documented in the respective 
accountability form. The study Investigational Product must be stored in a limited access 
area or in a locked cabinet under appropriate environmental conditions. Unused study 
materials must be available for verification by the sponsor’s site monitor during on-site 
monitoring. The destruction of unused study materials (both, expired or unexpired) will be 
documented on the return/disposition form. The Sponsor will authorize destruction of 
excess supplies on site according to local policy. In this case, before proceeding, the site 
must seek authorization from the Sponsor using the return/destruction form and this must 
also be documented on the Study Supply Return Form. 
Study substrate should be dispensed under the supervision of the investigator, a qualified 
member of the investigational staff, or by hospital clinical pharmacist. 
11 ETHICS & REGULATORY CONSIDERATIONS 
The study will be conducted by Conatus as a Phase 2 study of emricasan in both the USA 
and in Europe. As such, regulatory requirements that are relevant for pharmaceutical 
investigations in all countries will be applicable during the study are to be conducted and 
overseen by Conatus. 
Conatus will obtain for the main study IND-6556-17 the applicable regulatory approvals 
for the use of clinical data from both regulatory authorities (if relevant) and ethics 
committees (IRBs). 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 27 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
12 SAFETY CONSIDERATIONS 
All adverse events (AE), serious adverse events (SAE), suspected unexpected serious 
adverse reactions (SUSAR) and unanticipated adverse device effects (UADE) possibly or 
probably related to the use of the MBT product or related to the MBT procedure will be 
collected and reported according to local regulations. 
Safety assessments of the Conatus study drug will be performed as described in Conatus 
protocol IDN-6556-17: Safety Assessments. 
13 SUBJECT CONFIDENTIALITY 
The subject’s name and personal data will remain confidential and will not be published in 
any way. All data will be coded and stored in locked offices or on password protected 
computers. 
14 MONITORING AND QUALITY ASSURANCE 
This study is a companion protocol that will use the data generated by the Conatus Phase 2 
study of emricasan under protocol IDN-6556-17. Conatus will ensure compliance with 
GCP, local regulations and scientific integrity and will manage and oversee the study 
conduct.  
15 PUBLICATION POLICY AND FINANCE 
It is intended that the results of the companion study will be reported and disseminated at 
international conferences and in peer-reviewed scientific journals. The policy regarding 
publications appears in the non-disclosure agreement signed by each study participant prior 
to signing of the contract. 
16 FINANCIAL ASPECTS  
The BreathID® MCS device and test kit including a nasal cannula and a solution containing 
13C-Methacetin will be provided by Exalenz Bioscience. Conatus will be responsible for 
the funding of regulatory approvals in regards to the main protocol and administration as 
well as for the funding for study support of staff at local sites. 
17 STUDY TERMINATION 
This study is a companion protocol that will use the data generated by Conatus from their 
Phase 2 study of emricasan under protocol IDN-6556-17. Conatus will be responsible for 
study termination procedures, when applicable. 
 
 


Exalenz Bioscience Ltd. 
Last update: May 24, 2017 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under protocol IDN-6556-17 
(IND111463) 
Protocol: CON-EX-0217 
Version: 2.0 
Document No: CSP000001 
Page 28 of 28 
 
Exalenz Bioscience Ltd.    2017 
 
CONFIDENTIAL AND PROPRIETARY 
18 REFERENCES 
1. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, 
Goodman Z. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol 
agreement and ability to predict liver-related mortality. Hepatology 2011;53:1874-
1882. 
2. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated 
aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960-967. 
3. Stravitz RT, Reuben A, Mizrahi M, Lalazar G, Brown K, Gordon SC, Ilan Y, et al. 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;63:1345-1351. 
 
 

SAP_001.pdf: 
Exalenz Bioscience Ltd.  
 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
Statistical Analysis Plan for the ¹³C-Methacetin Breath 
Test using the BreathID® MCS System for Conatus 
phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under Protocol IDN-6556-17 (IND111463) 
  
SAP for Protocol No. CON-EX-0217 
NCT03462576 
 
Document No: CSD00109 
Total pages: 21 
Version Level: 1.0 
Last update on: Aug 08, 2019 
Based On: CON-EX-0217 Companion Protocol Version 2.0 from May 24, 2017 
 
 
Name 
Position 
Author / 
Owner 
Gil Guggenheim 
Clinical Research Development Manager 
Reviewed by 
Yishai Friedlander 
Biostatistician from StatistX  
Reviewed by 
Susan Alpert, MD 
Executive VP Regulatory Affairs 
Approved by 
Ofer Schlesinger 
VP R&D and Clinical  
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 or computer language or distributed without the prior written consent of: 
Exalenz Bioscience Ltd. 4 Ha’Maayan St. Modi’in, Israel 7177872 
Versions Control: 
Version 
Date 
Responsible Person Description of Change 
1.0 
August 08, 2019 
Gil Guggenheim 
Initial Release 
 
 
 
 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 2 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
 
 
TABLE OF CONTENTS 
1 Abbreviations ................................................................................................................... 4 
2 INTRODUCTION ........................................................................................................... 5 
3 STUDY OBJECTIVES AND ENDPOINTs .................................................................. 5 
3.1 
Study Objectives ....................................................................................................................... 5 
3.1.1 
Primary Objective ............................................................................................................... 6 
3.1.2 
Secondary Objective ........................................................................................................... 6 
3.1.3 
Exploratory Objective ......................................................................................................... 6 
3.1.4 
Safety Objective ................................................................................................................. 7 
3.2 
Study Endpoints ........................................................................................................................ 7 
3.2.1 
Primary Endpoint ................................................................................................................ 7 
3.2.2 
Secondary Endpoints .......................................................................................................... 7 
3.2.3 
Exploratory Endpoints ........................................................................................................ 7 
3.2.4 
Safety Endpoint Measure .................................................................................................... 8 
4 STUDY DESIGN ............................................................................................................. 8 
4.1 
Sample Size Considerations ...................................................................................................... 9 
5 GENERAL CONSIDERATIONS FOR HANDLING OF MISSING DATA ............ 9 
5.1 
Premature Withdrawal and Missing Data ................................................................................. 9 
6 SIGNIFICANCE LEVELS AND HANDLING OF TYPE I ERROR........................ 9 
6.1 
Type I Error ............................................................................................................................... 9 
6.2 
Hierarchy Approach for Secondary Endpoint Analysis .......................................................... 10 
7 ANALYSIS SETS .......................................................................................................... 10 
7.1 
Safety Analysis Set ................................................................................................................. 10 
7.2 
Intent To Diagnose (ITD) Analysis Set ................................................................................... 10 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
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CONFIDENTIAL AND PROPRIETARY 
7.3 
Per Protocol (PP) Analysis Set ................................................................................................ 10 
7.4 
Statistical Analysis of Analysis Sets ....................................................................................... 11 
8 STATISTICAL ANALYSES ........................................................................................ 11 
8.1 
General Considerations for Data Analyses ............................................................................. 11 
8.2 
Baseline Definitions ................................................................................................................ 11 
8.3 
Disposition of Patients ............................................................................................................ 12 
8.4 
Efficacy Analyses .................................................................................................................... 12 
8.4.1 
Primary Endpoint .............................................................................................................. 12 
8.4.2 
Secondary Endpoints ........................................................................................................ 14 
8.4.3 
Exploratory Endpoints ...................................................................................................... 16 
8.5 
Treatment by Site Interaction .................................................................................................. 18 
8.6 
Safety Analyses ....................................................................................................................... 18 
Appendix A - MBT parameter & Algorithm Calculation .............................................. 19 
Appendix B – MELD Score Formula from US OPTN Policy (2016) ............................ 21 
 
 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 4 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
1 ABBREVIATIONS 
AE 
- Adverse Event 
CDOB 
- Cumulative Delta over Baseline 
CI 
- Confidence Interval 
CL 
- Confidence Limits 
CO2 
- Carbon dioxide 
cPDRxx 
- Cumulative Percentage Dose Recovery at xx minutes from ingestion  
CRF 
- Case Report Form 
CSR 
- Clinical Study Report 
CTP 
- Child-Turcotte-Pugh (score) 
DOB 
- Delta over Baseline 
eCRF 
- Electronic Case Report Form 
EGD 
- Esophagogastroduodenoscopy 
GCP 
- Good Clinical Practice 
HCC 
- Hepatocellular Carcinoma 
HE 
- Hepatic Encephalopathy 
HR 
- Hazard Ratio 
IDE 
- Investigational Device Exemption 
ITT 
- Intent to treat (population) 
MBT 
- 
13C-Methacetin Breath Test 
MCS 
- Molecular Correlation Spectrometry  
MELD 
- Model for Endstage Liver Disease 
NAFLD 
- Nonalcoholic Fatty Liver Disease 
NASH 
- Nonalcoholic Steatohepatitis 
OPTN 
- Organ Procurement and Transplantation Network 
PDR 
- Percent Dose Recovered (expressed as % per hour) 
PP 
- Per Protocol (population) 
SAE 
- Serious Adverse Event 
SAP 
- Statistical Analysis Plan 
SBP 
- Spontaneous Bacterial Peritonitis 
SD 
- Standard Deviation 
SF 
- Screen Failures 
SUSAR 
- Suspected unexpected serious adverse reaction 
TIPS 
- Transjugular Intrahepatic Shunt 
UADE 
- Unanticipated Adverse Device Effect  
US 
- United States (of America) 
USA 
- United States of America 
 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 5 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
2 INTRODUCTION 
This Statistical Analysis Plan (SAP) (for Exalenz’ companion study protocol: CON-EX-
0217) was developed based on the original study protocol version 2.0, dated 24 May 2017 
and is a more detailed companion to the “Statistical Methods” section of the study protocol. 
 
The companion protocol and this SAP describe how Exalenz intends to use the clinical data 
being obtained during the study conducted by Conatus Pharmaceuticals Inc. (Conatus) for 
study IDN-6556-17 (Emricasan) being conducted under IND 111463. 
 
When differences exist in methods, descriptions or explanations provided in the protocol and 
this SAP, the SAP prevails.  
 
Since this study is a companion to a pharmaceutical company’s study, the data management 
for the main study can independently determine as to when a data freeze or a data lock shall 
be performed. Therefore, for the Exalenz companion protocol purposes, any amendments to 
the SAP will be made prior to Exalenz independently accessing the data from the database 
freeze or lock. In case additional analyses not described in the final SAP or deviations from 
the final SAP are required, they will be documented in the clinical study report (CSR). 
 
3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 Study Objectives 
The data generated in this companion study will be used to validate an algorithm developed 
under parallel Exalenz studies. Additionally, the companion study aims to evaluate the 
capabilities of the MBT to assess the severity of Nonalcoholic Steatohepatitis (NASH), 
predict clinical outcome (hepatic decompensation) events and monitor changes of MBT 
results in subjects with and without NASH treatment. 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 6 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
3.1.1 Primary Objective 
• To validate the ability of the MBT to predict any hepatic decompensation event 
(considering all hepatic decompensation events as defined in section 8.4.1) 
using a predefined cut-off of PDRpeak ≤ 5.5%/h (see Appendix A for detailed 
description of parameter calculation). 
3.1.2 Secondary Objective 
• To validate the ability of the MBT to predict any hepatic decompensation event 
(considering all hepatic decompensation events as defined in section 8.4.1) 
using a second predefined cut-off of PDRpeak ≤ 7.5%/h. 
• To validate the ability of the MBT to predict hepatic decompensation events 
within one year (for each of the two predefined cut-offs independently). 
• To validate the ability of the MBT to predict hepatic decompensation events 
when using all the repetitions of the MBT measurements (time dependent 
parameter) (for each of the two predefined cut-offs independently). 
• To validate the ability of the MBT to predict hepatic decompensation events 
within six months (for each of the two predefined cut-offs independently). 
• To validate the ability of the MBT to predict new hepatic decompensation 
events (considering only reported hepatic decompensation events, as defined 
in section 8.4.2.5 as per Conatus protocol IDN-6556-17) as observed 
throughout the study (for each of the two predefined cut-offs independently). 
3.1.3 Exploratory Objective 
• To validate the ability of the MBT to predict specific types of hepatic 
decompensation events (for each of the two predefined cut-offs independently). 
• To describe the change in MBT between the emricasan treatment arms and the 
placebo arm, thus assessing the response to treatment. 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 7 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
3.1.4 Safety Objective 
All adverse events, serious adverse events (SAE), suspected unexpected serious 
adverse reactions (SUSAR) and unanticipated adverse device effects (UADE) will be 
reported according to local regulations. No breath-test related adverse events are 
expected. For more information please refer to the Investigator's Brochure.  
3.2 Study Endpoints  
3.2.1 Primary Endpoint  
The primary efficacy endpoint is the event-free survival (considering all hepatic 
decompensation events including events based on the reported AEs or SAEs, as 
defined in section 8.4.1). 
3.2.2 Secondary Endpoints  
The secondary efficacy endpoints for this study include: 
• The event-free survival (considering all hepatic decompensation events including 
events based on the reported AEs or SAEs, as defined in section 8.4.1) 
• The one-year event-free survival 
• The event free survival when using all the repetitions of the MBT measurements 
(time dependent parameter). 
• The six-month event-free survival 
• The event-free survival (considering only reported hepatic decompensation 
events, as defined in section 8.4.2.5 as per Conatus protocol IDN-6556-17) 
3.2.3 Exploratory Endpoints  
• The specific type of hepatic decompensation event-free survival 
• Absolute mean and percent mean change in MBT parameters between MBT visits 
(for each treatment arm) 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 8 of 21 
 
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CONFIDENTIAL AND PROPRIETARY 
3.2.4 Safety Endpoint Measure 
Safety endpoints includes all AE’s in general and by seriousness, severity related to the 
MBT. No breath-test related adverse events are expected. 
 
4 STUDY DESIGN 
Please refer to Conatus’ protocol IDN-6556-17.  
This study is a companion protocol that will use the data generated by Conatus' study of 
emricasan under protocol IDN-6556-17. The IDN-6556-17 study is a Phase 2, multicenter, 
double-blind, randomized, placebo-controlled, dose-response study to evaluate the safety 
and efficacy of emricasan in improving event-free survival based on a composite clinical 
endpoint (where all-cause mortality, new decompensation events, and Model for Endstage 
Liver Disease (MELD) score progression are counted as events as defined in section 8.4.2.5) 
in subjects with decompensated NASH cirrhosis. 
The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to 
week 48 and every 8 weeks after week 48. All subjects will continue treatment until the last 
subject in the study reaches 48 weeks in the study. This subject will undergo the assessments 
of the final treatment visit at week 48. For all other subjects, the final treatment visit should 
take place on their last study visit prior to or on the day of the final treatment visit of the last 
subject who has been in the study for 48 weeks. 
As part of the IDN-6556-17 study, the MBT will be performed during a screening visit, every 
24 weeks and at the final treatment visit, to assess whether emricasan compared to placebo 
improves liver metabolic function as determined by the Methacetin Breath Test. 
The data obtained in this study will be sequestered from Exalenz in order to allow potential 
pooling of the data received from Conatus' study as well as other parallel recruiting studies, 
if applicable, where both the MBT and clinical outcome (e.g. hepatic decompensation events) 
will be available. Once sufficient data will be accrued, it will be used to validate the algorithm 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 9 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
developed using data from IDE# G080227 and other clinical data accumulated by Exalenz 
to date. Additional analyses may be performed by Exalenz on the data to be received from 
this Conatus study after validation of the aforementioned algorithm. 
4.1 Sample Size Considerations 
The plan is to enroll a subset of subjects that will be screened under Conatus' IDN-6556-17 
study. This Conatus study plans to enroll 210 subjects (70 subjects per treatment arm) to be 
randomly assigned to 1 of 3 treatment groups, 2 doses of emricasan (25 mg or 5 mg) or 
placebo in a 1:1:1 ratio. A 45% screen failure (SF) rate is estimated. It is expected that 
approximately 90% of the patients enrolled will perform the MBT. The total number of MBT 
results expected ranges between 120 and 310 at screening and up to 200 at respective study 
visits with 24-week intervals and at the final treatment visit.  
 
5 GENERAL CONSIDERATIONS FOR HANDLING OF MISSING 
DATA 
5.1 Premature Withdrawal and Missing Data 
For patients who are withdrawn from the study prior to study completion, all data compiled 
up to the point of discontinuation will be used for analysis. All withdrawals will be included 
in all analyses up to the time of withdrawal. 
There will be no imputation for missing data. 
 
6 SIGNIFICANCE LEVELS AND HANDLING OF TYPE I ERROR 
6.1 Type I Error 
The overall significance level for this study is 5% using two-tailed tests, except for treatment 
by site interaction that will be tested at a significance level of 10%. 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 10 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
6.2 Hierarchy Approach for Secondary Endpoint Analysis 
The hierarchy approach will be adopted for the primary and secondary endpoints to control 
type I error due to multiple endpoint testing. Thus the primary endpoint will first be analyzed 
and only if p<0.05, will the secondary endpoint be analyzed. This approach will maintain the 
overall study type I error by continuing to analyze the next end-point in the hierarchy only if 
the previous endpoint analysis was found significant. The hierarchy approach is extended for 
the secondary endpoints as well, according to the order that they appear in section 3.2.2 
above. 
 
 
7 ANALYSIS SETS 
7.1 Safety Analysis Set 
The Safety analysis set will include all subjects (randomized and non-randomized into the 
Conatus emricasan study under protocol IDN-6556-17) that initiated at least one MBT (had 
taken Methacetin), even if the MBT was not completed or the result was not valid. 
7.2 Intent To Diagnose (ITD) Analysis Set 
The intent to diagnose (ITD) analysis set will include all subjects that were randomized into 
the Conatus emricasan study under protocol IDN-6556-17 and that had at least one valid 
MBT result.  
7.3 Per Protocol (PP) Analysis Set 
The per protocol (PP) analysis set will include all subjects from the ITD analysis set who did 
not have any major protocol deviations and exclude any subject that had a previous 
transjugular intrahepatic shunt (TIPS) or bariatric surgery that may affect the efficacy of the 
breath test. 


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 11 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
7.4 Statistical Analysis of Analysis Sets 
The safety analysis set will serve as the principal data analysis set for the safety. 
The PP analysis set will serve as the principal analysis set for the efficacy analyses. 
The primary and secondary efficacy assessments will also be performed on the ITD analysis 
set. 
8 STATISTICAL ANALYSES 
8.1 General Considerations for Data Analyses 
All analyses will be performed using either SAS® v9.4 or higher (SAS Institute, Cary NC, 
US) or the R software version 3.6 or higher (R Development Core Team. Vienna, Austria).  
The standard summary statistics for continuous variables are: N, mean, standard deviation, 
median, minimum and maximum. The standard summary statistics for categorical variables 
are: count and proportion. 
Any statistical tests performed, will be two-sided. The required significance level of findings 
will be equal to or lower than 5%. Where confidence limits are appropriate, the confidence 
level will be 95%. Nominal p-values and unadjusted confidence intervals will be presented. 
8.2 Baseline Definitions 
The study baseline will be defined as the last available, non-missing observation prior to first 
study drug (emricasan or placebo) administration, unless specifically mentioned otherwise. 
For survival models: The first valid MBT test will be defined as the baseline and day 0 of 
follow up. For MELD scores, the first value measured on or after the day of the first valid 
MBT will serve as baseline value, even if there are later MELD results available prior to first 
study drug (emricasan or placebo) administration. The MELD progression outcome, 4 point 
increase in MELD, will thus be calculated by comparing each MELD score to the first 
available MELD score on or after the first valid MBT date.  


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 12 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
8.3 Disposition of Patients 
Subject dispositions will be summarized based on all subjects screened into the study, and 
for each treatment group.  
The following subject disposition information will be presented: 
• The number and percentage of subjects who had valid MBT for each visit. 
• The number and percentage of reasons for not having a valid MBT for each visit.  
• The number and percentages of subjects that were excluded from the PP analysis set, 
by reason for exclusion. 
8.4 Efficacy Analyses 
All hepatic decompensation events will be summarized descriptively in summary tables for 
each event type described in the following sections. 
8.4.1 Primary Endpoint 
The MBT parameter used to predict hepatic decompensation event is PDRpeak. Any PDRpeak 
value of less or equal to 5.5 %/h (see Appendix A for detailed description of parameter 
calculation) will be considered as ‘high risk’ and any value above that threshold will be 
considered as ‘lesser risk’. The dichotomic MBT result will be tested for significance using 
the Cox proportional hazards regression model with site and Conatus protocol IDN-6556-17 
randomized arm as covariates. If the Conatus protocol IDN-6556-17 randomized arm factor 
is found non-significant (i.e. p-value > 0.05), then this factor will not be a covariate for the 
main analysis to be performed. If the Conatus protocol IDN-6556-17 randomized arm factor 
is found statistically significant (i.e. p-value ≤ 0.05), then the main analysis will be performed 
keeping this factor as a covariate (to ‘adjust’ the analysis for treatment).  
The following list defines the hepatic decompensation events for the primary endpoint: 
• Liver-specific mortality 
• Liver transplant  
• New and/or recurrent hepatic decompensation events  


Exalenz Bioscience Ltd. 
Last update: August 8, 2019 
SAP for Protocol CON-EX-0217: Companion protocol for the 
¹³C-Methacetin Breath Test using the BreathID® MCS System for 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
Document Version: 1.0 
 
Document No: CSD00109 
Page 13 of 21 
 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
o Variceal hemorrhage that required ‘non-drug therapy’ (e.g. variceal 
ligation, sclerotherapy) based on the AE log or requiring hospitalization 
o Portal hypertensive gastropathy hemorrhage requiring hospitalization 
o Occurrence of large gastroesophageal varices or any varices with red wale 
sign (classified as severe in the AE log) and that required ‘non-drug 
therapy’ (e.g. variceal ligation or sclerotherapy)  based on the AE log to 
avoid hemorrhage 
o Ascites requiring diuretics (in a subject without prior history of ascites 
requiring diuretics) or refractory ascites requiring ‘non-drug therapy’ (e.g. 
paracentesis) based on the AE log (in a subject with history of ascites 
requiring diuretics). 
o Any onset of hepatic encephalopathy (HE) requiring hospitalization 
(classified as SAE) in the absence of known co-morbidities or alternative 
causes.  
o Hepatorenal syndrome requiring hospitalization  
o Spontaneous bacterial peritonitis (SBP) requiring hospitalization  
• MELD score progression defined as any increase ≥4 points from baseline  
 
These hepatic decompensation events are identified using the study’s ‘new decompensation 
event’ dataset as well as events listed in the AE and SAE logs, the reason for (early) 
termination, the comment and the lab results (incl. MELD scores) datasets. All potential 
hepatic decompensation events will be adjudicated through a medical review prior to the 
primary efficacy analysis and blinded to the breath test results. Once defined and adjudicated, 
the first of the hepatic decompensation events after the first valid MBT will be used for the 
respective event-free survival analysis. 
All MELD scores will be calculated using the formula from the US Organ Procurement and 
Transplantation Network (OPTN) Policy from 2016 (Appendix B). MELD score 
progression will not include subjects who are started on anticoagulants after the first valid 


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MBT (and prior to the identified MELD progression event) that can affect the PT or INR at 
the time of MELD assessment. 
 
The time-to-first event will be derived as the number of days between the day of the screening 
MBT test and the date when the first hepatic decompensation event occurs or when a subject 
is censored (i.e., event/censored date minus screening MBT date plus 1). Subjects will be 
censored at their last study visit for the following reasons:  
• If a subject discontinues the study prior to the end of the study without experiencing a 
hepatic decompensation event 
• If a subject reaches the Final Treatment visit without experiencing a hepatic 
decompensation event  
• If a subject developes hepatocellular carcinoma (HCC) 
 
Survival analysis will be conducted using the Cox proportional hazard model. The model 
summary will include the number of subjects in the model, and a table with each covariate 
in a separate line specifying the coefficient's value, Hazard Ratio, Hazard Ratio 95% 
Confidence Interval and p-value. In addition, a Kaplan-Meier plot for event-free survival 
will be presented, stratified by MBT parameter along with the MBT parameter log-rank p-
value. Additionally a crosstab table of MBT parameter and events will be presented. 
8.4.2 Secondary Endpoints 
8.4.2.1 The overall event-free survival with a second predefined cut-off 
The event free survival will be analyzed in the same manner as the primary endpoint analysis 
with the exception that the dichotomic MBT result will be based on a second predefined cut-
off: Any PDRpeak value of less or equal to 7.5 %/h (see Appendix A for detailed description 
of parameter calculation) will be considered as ‘high risk’ and any value above that threshold 
will be considered as ‘lesser risk’.  


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8.4.2.2 The one-year event-free survival 
The one-year event free survival will be analyzed in the same manner as the primary endpoint 
analysis with the exception of censoring all subjects after 1 year (365 days) from baseline 
MBT date.  
This analysis will be repeated while using the second pre-defined cut-off described in the 
first secondary endpoint (section 8.4.2.1).  
8.4.2.3 The event free survival when using all the repetitions of the MBT measurements 
(time dependent parameter) 
The event free survival will be analyzed in the same manner as the primary endpoint analysis 
with the exception of using all repetitions of the MBT measurements while dividing the 
prediction times to the intervals between tests by applying the Time dependent covariate 
method.  
This analysis will be repeated while using the second pre-defined cut-off described in the 
first secondary endpoint (section 8.4.2.1). 
8.4.2.4 The six-month event-free survival  
The six-month event free survival will be analyzed in the same manner as the primary 
endpoint analysis with the exception of censoring all subjects after six months (180 days) 
from baseline MBT date.  
This analysis will be repeated while using the second pre-defined cut-off described in the 
first secondary endpoint (section 8.4.2.1). 
8.4.2.5 The event-free survival considering only new hepatic decompensation events as 
defined in Conatus study protocol IDN-6556-17 
The event free survival will be analyzed in the same manner as the primary and secondary 
endpoint analyses (sections 8.4.1, 8.4.2.1, 8.4.2.3 and 8.4.2.4) taking only hepatic 
decompensation events into consideration as defined and adjudicated in the Conatus study 
protocol IDN-6556-17: 
1. All-cause mortality 
2. New decompensation events 


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Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
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a. Variceal hemorrhage (including recurrent variceal hemorrhage) documented 
by endoscopy and requiring hospitalization 
b. New onset ascites requiring diuretics (in a subject without prior history of 
ascites requiring diuretics) 
c. New onset HE ≥ grade II requiring hospitalization in the absence of other co-
morbidities or alternative causes (in a subject without prior history of HE ≥ 
grade II) 
d. Hepatorenal syndrome requiring hospitalization (either type 1 or 2) 
e. SBP requiring hospitalization 
3.  MELD score progression defined as any increase ≥4 points from baseline 
 
This analysis will be repeated while using the second pre-defined cut-off described in the 
first secondary endpoint (section 8.4.2.1). 
8.4.3 Exploratory Endpoints 
8.4.3.1 The specific hepatic decompensation type event free survival 
The specific types of hepatic decompensation events or combinations of them for event free 
survival will be analyzed in a similar manner as the primary endpoint analysis. The following 
list contains all the separate analyses that will be performed:  
1. All-cause mortality 
2. Liver-specific mortality 
3. Liver-specific mortality or liver transplant 
4. Liver transplant 
5. Variceal hemorrhage that required ‘non-drug therapy’ (e.g. variceal ligation, 
sclerotherapy) based on the AE log or requiring hospitalization or portal hypertensive 
gastropathy hemorrhage requiring hospitalization 
6. Variceal hemorrhage that required ‘non-drug therapy’ (e.g. variceal ligation, 
sclerotherapy)  based on the AE log or requiring hospitalization or portal 
hypertensive gastropathy hemorrhage requiring hospitalization or occurrence of 


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Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
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CONFIDENTIAL AND PROPRIETARY 
large varices or varices with red wale signs (classified as severe in the AE log) and 
that required ‘non-drug therapy’ (e.g. variceal band ligation or sclerotherapy) based 
on the AE log to avoid hemorrhage 
7. New onset ascites requiring diuretics (in a subject without prior history of ascites 
requiring diuretics) 
8. SBP requiring hospitalization 
9. New onset ascites requiring diuretics (in a subject without prior history of ascites 
requiring diuretics) or any occurrence of refractory ascites requiring ‘non-drug 
therapy’ (e.g. paracentesis) based on the AE log (in a subject with history of ascites 
requiring diuretics) or SBP requiring hospitalization 
10. New onset HE ≥ grade II requiring hospitalization (classified as SAE) in the absence 
of other co-morbidities or alternative causes (in a subject without prior history of HE 
≥ grade II) 
11. Any onset of HE requiring hospitalization (classified as SAE) in the absence of 
known co-morbidities or alternative causes  
12. Hepatorenal syndrome requiring hospitalization  
13. MELD score progression defined as any increase ≥4 points from baseline  
14. All hepatic decompensation events defined in section 8.4.1, except for MELD score 
progression. 
This analysis will be repeated while using the second pre-defined cut-off described in the 
first secondary endpoint (section 8.4.2.1). 
8.4.3.2 Absolute mean and percent mean change in MBT parameters 
The absolute and percent change in MBT parameters will be summarized descriptively by 
summarizing the PDRPeak and cPDR30min (see Appendix A) changes and percent changes for 
each treatment group. Due to the small sample expected in this analysis (missing values were 
not related to outcome), no statistical tests will be applied on that endpoint. 


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Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
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8.5 Treatment by Site Interaction 
Site by MBT dichotomy interaction will be added to the primary efficacy model as a 
covariate to test for site effect on the endpoints.  
For sites with less than 10 subjects, the following pooling of sites method will be applied: 
Sites will be sorted from smallest to largest based on the number of randomized subjects with 
valid baseline MBT results. The smallest site will be pooled with the second smallest, and if 
necessary with the next sites in line until the site group reaches 10 subjects or more. The site 
value for those sites will be assigned "Site Group 1". Then the next site in line, if lower than 
10 subjects, will be pooled with the sites after it until the site group reaches 10, and so forth 
until all sites or site groups have at least 10 subjects. 
8.6 Safety Analyses 
All safety analyses will be conducted on the safety analysis set. 
All safety data will be presented by patient in listings (including assessments of abnormality 
and clinical significance, where applicable) and summarized appropriately,  
No inferential statistical testing will be performed for safety variables. 
 
 


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Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, 
under protocol IDN-6556-17 (IND111463) 
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APPENDIX A - MBT PARAMETER & ALGORITHM CALCULATION 
1. MBT PARAMETER OF INTEREST 
- 
The MBT parameter of interest for the primary and all the secondary endpoints to be 
calculated is the PDRpeak measured in %/h, which is the maximum rate of metabolized 
13C-Methacetin observed within a breath test. When applying a predefined test cut-
off on the PDRpeak, the dichotomic test result is obtained. 
- An additional parameter to be used for the assessment of treatment response as part 
of an exploratory endpoint is the cPDR30min, which is the cumulative percentage dose 
recovery of the metabolized 13C-Methacetin 30 minutes after ingestion of the test 
substrate. 
2. MBT PREDICTIVE TEST ALGORITHM CALCULATION 
The following steps shall be followed to calculate the parameter of interest and the resulting 
dichotomized test result.  
1. Subjects visit height and weight as well as all delta over baseline (DOB) measures 
with corresponding time point (T) shall be retrieved from the database.  
2. DOB values must be sorted by time from lowest to highest time before any 
calculation, while a first pair of data points should always be added with time T0=0 
min and DOB0 =0. 
3. In order for a test to be valid, the following conditions should be met: 
a. Height should be within acceptable range: 120 cm – 240 cm. 
b. Weight should be within acceptable range: 35 kg – 200 kg. 
c. The last time point (T) should be after 30 minutes. 
4. PDR: The DOBs shall be transformed into percentage dose recovery rates (PDRs) 
by normalizing the DOB using patient body weight and height at each observed 
time point (i) by using the following formula: 
 
𝑃𝐷𝑅𝑖= 0.01817853 ∙𝐷𝑂𝐵𝑖∙𝑊𝑒𝑖𝑔ℎ𝑡0.5378 ∙𝐻𝑒𝑖𝑔ℎ𝑡0.3963 
 
 
 
 
While Weight is in kg, and Height is in cm 
 
5. PDRpeak: PDRpeak is defined as the maximum PDR. 
 
𝑃𝐷𝑅𝑝𝑒𝑎𝑘= max⁡(𝑃𝐷𝑅0, 𝑃𝐷𝑅1, 𝑃𝐷𝑅2, … , 𝑃𝐷𝑅24) 


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6. Cut-off: The cut-off to be applied for the predictive MBT test for assessment of 
event-free survival is 5.5 %/h.  
• Any PDRpeak value below, or equal to 5.5%/h is considered as high risk 
for development of hepatic decompensation events.  
• Any PDRpeak value greater than 5.5%/h is considered as lesser risk for 
development of hepatic decompensation events. 
 
7. Second Cut-off: A second cut-off to be applied for the predictive MBT test for 
assessment of event-free survival is 7.5 %/h.  
• Any PDRpeak value below, or equal to 7.5%/h is considered as high risk 
for development of hepatic decompensation events.  
• Any PDRpeak value greater than 7.5%/h is considered as lesser risk for 
development of hepatic decompensation events. 
 
An additional parameter will be used for the exploratory endpoint analysis of treatment 
response: cPDR30min 
8. cPDR30min: The following formula will be used to obtain cPDR30min: 
 
• 
Find 'a', the index for which: 
𝑇𝑎−1 < 30 ≤𝑇𝑎 
• 
Calculate PDR30min: 
𝑃𝐷𝑅30𝑚𝑖𝑛= 𝑃𝐷𝑅𝑎−1 + 𝑃𝐷𝑅𝑎−𝑃𝐷𝑅𝑎−1
𝑇𝑎−𝑇𝑎−1
∙(30 −𝑇𝑎−1) 
 
• 
Finally, calculate cPDR30min: 
𝑐𝑃𝐷𝑅30𝑚𝑖𝑛= ∑(
𝑇𝑖−𝑇𝑖−1
60
∙(𝑃𝐷𝑅𝑖+ 𝑃𝐷𝑅𝑖−1)
2
)
𝑎−1
𝑖=1
+
30 −𝑇𝑎−1
60
∙(𝑃𝐷𝑅30𝑚𝑖𝑛+ 𝑃𝐷𝑅𝑎−1)
2
 
No cut-offs are being applied on this parameter for the planned analyses. 
 
 


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APPENDIX B – MELD SCORE FORMULA FROM US OPTN POLICY 
(2016) 
Subjects receive an initial MELD(i) score equal to:  
initial MELD(i) = 0.957 x Loge(creatinine mg/dL) + 0. 378 x Loge(bilirubin mg/dL) + 
1.120 x Loge (INR) + 0.643  
Laboratory values less than 1.0 will be set to 1.0 when calculating a subject’s MELD score.  
The following subjects will receive a creatinine value of 4.0 mg/dL:  
• Subjects with a creatinine value greater than 4.0 mg/dL  
• Subjects who received two or more dialysis treatments within the prior 7 days  
• Subjects who received 24 hours of continuous veno-venous hemodialysis 
(CVVHD) within the prior 7 days  
The MELD score derived from this calculation will be rounded to the tenth decimal place 
and then multiplied by 10. The maximum MELD score is 40. 
For candidates with an initial MELD score greater than 11, the MELD score is then re-
calculated as follows:  
MELD = MELD(i) + 1.32*(137-Na) – [0.033*MELD(i)*(137-Na)]  
Sodium values less than 125 mmol/L will be set to 125, and values greater than 137 
mmol/L will be set to 137. 
 
Resources: 
https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf   Section 9.1.D on Page 169