Clinical trial NCT03439189
Conditions: NASH - Nonalcoholic Steatohepatitis Cirrhosis Portal Hypertension
Sponsor: Meridian Bioscience, Inc.
Start date: 2016-08-28; Completion date: 2019-05-13
Enrollment: 343 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To validate the ability of the Methacetin Breath Test (MBT) to detect clinically significant portal hypertension (CSPH)/severe portal hypertension (SPH) defined as hepatic venous pressure gradient (HVPG) ≥ 10 mmHg and HVPG ≥ 12 mmHg respectively, in patients with non-alcoholic steatohepatitis (NASH) during the course of treatment with Conatus's investigational product emricasan/placebo.

Detailed description:
This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-14 (NCT02960204).The IDN-6556-14 study is a Phase 2, multicenter, double-blind, randomized, placebo-controlled trial in subjects with non-alcoholic steatohepatitis (NASH) cirrhosis and severe portal hypertension.

As one of the Conatus' study exploratory objectives, this companion protocol is designed to assess whether emricasan compared to placebo improves liver metabolic function at Weeks 24 and 48 as assessed by the methacetin breath test (at select sites), if relevant.

Arms: arm 1: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day. The MBT will be performed at screening, at week 24/week 48/at early termination. arm 2: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day. The MBT will be performed at screening, at week 24/ week 48/ at early termination. arm 3: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day. The MBT will be performed at screening, at week 24/ week 48/ at early termination. arm 4: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day. The MBT will be performed at screening, at week 24/week 48/at early termination.
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 carbon-13 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_SAP_000.pdf: 
Exalenz Bioscience Ltd. 
 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
Validation Study for the BID-CSPH Test: Companion 
protocol for the ¹³C-Methacetin Breath Test using the 
BreathID® MCS System in Conatus phase 2 study of 
Emricasan, an Oral Caspase Inhibitor, under Protocol 
IDN-6556-14 
  
Protocol No. CON-EX-0616 
 
Document No: CSD00091 
Total pages: 50 
Version Level: 5.0 
Last update on: Oct. 17, 2018 
 
 
Name 
Position 
Author / 
Owner 
Gil Guggenheim 
 Clinical Research Development Manager 
Reviewed by 
Ofer Schlesinger 
VP R&D  
Reviewed by 
Lisa Deutsch, PhD 
Biostatistician (BioStats Ltd.) 
Approved by 
Michal Hershkovitz 
VP Regulatory Affairs & Quality 
Assurance 
Approved by 
Yaron Ilan, MD 
Medical Director 
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. Modiin, Israel 7177872 
 
 


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CONFIDENTIAL AND PROPRIETARY 
Versions Control: 
Version 
Date 
Responsible Person 
Description of Change 
1.0 
Jul. 18, 2016 
Gil Guggenheim 
Initial Release 
2.0 
May 08, 2017 
Ora Msika 
Addition of Breath test at week 48  
3.0 
Oct. 10, 2017 
Gil Guggenheim 
Increase sample size 
4.0 
Jul. 25, 2018 
Gil Guggenheim 
Implementing 
FDA 
comments 
from Pre-Sub Q180599 
5.0 
Oct. 17, 2018 
Gil Guggenheim 
Implementing 
FDA 
comments 
from 
Pre-Sub 
Q180599/S001, 
mainly: 
1. Intended use was updated to 
reflect clinically diagnosed NASH 
2. Modification of primary 
endpoint performance goals to be 
more clinically meaningful  
3. Addition of analyses for data 
pooling 
4. Addition of Sub-Group 
Analysis 
5. Revised Appendix A for more 
clarity 
 
 


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TABLE OF CONTENTS 
1 Abbreviations and Definitions ............................................................................................ 6 
1.1 
Abbreviations ................................................................................................................................. 6 
1.2 
Definitions ...................................................................................................................................... 7 
2 Protocol Synopsis ................................................................................................................. 8 
3 Background ......................................................................................................................... 16 
3.1 
Defining the need for a non-invasive test for the characterization of NASH severity ................. 17 
3.2 
Cirrhosis and Portal Hypertension ............................................................................................... 17 
3.3 
Hepatic Venous Pressure Gradient (HVPG) assessing Portal Hypertension ............................... 18 
3.4 
Limitations of HVPG ................................................................................................................... 18 
3.5 
Rationale to use the MBT for assessment of Portal Hypertension and BID-CSPH Test for 
Clinically Significant Portal Hypertension (CSPH) ..................................................................... 18 
4 Intended Use / Indication for Use ..................................................................................... 24 
5 Study Design ....................................................................................................................... 24 
6 Study Objectives and Endpoints ....................................................................................... 26 
6.1 
Study Objectives .......................................................................................................................... 26 
6.1.1 
Primary Performance Objective..................................................................................................... 26 
6.1.2 
Secondary Performance Objective ................................................................................................. 26 
6.1.3 
Exploratory Performance Objectives ............................................................................................. 26 
6.1.4 
MBT Safety Objective ................................................................................................................... 27 
6.2 
Study Endpoints ........................................................................................................................... 27 
6.2.1 
Primary Endpoint ........................................................................................................................... 27 
6.2.2 
Secondary Endpoints ..................................................................................................................... 27 
6.2.3 
Exploratory Endpoints ................................................................................................................... 27 
6.2.4 
Safety Endpoints ............................................................................................................................ 28 
7 Subject Selection ................................................................................................................. 28 
7.1 
Inclusion Criteria .......................................................................................................................... 28 


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7.2 
Exclusion Criteria......................................................................................................................... 29 
7.3 
Restriction on the day of the MBT ............................................................................................... 31 
7.4 
Consenting ................................................................................................................................... 31 
8 Safety Termination and Early Withdrawal of Subjects or Study ................................. 32 
8.1 
Expected Study Duration ............................................................................................................. 32 
9 Statistical Considerations .................................................................................................. 33 
9.1 
Study Design and Aim ................................................................................................................. 33 
9.2 
Endpoint Measures ....................................................................................................................... 33 
9.2.1 
Primary endpoints .......................................................................................................................... 33 
9.2.2 
Secondary endpoints ...................................................................................................................... 33 
9.2.3 
Exploratory endpoints .................................................................................................................... 33 
9.2.4 
Safety endpoints ............................................................................................................................ 34 
9.3 
Acceptance Criteria and Performance Goals................................................................................ 34 
9.4 
Sample Size .................................................................................................................................. 34 
9.5 
Randomization ............................................................................................................................. 35 
9.6 
Blinding ........................................................................................................................................ 35 
9.7 
Analysis sets ................................................................................................................................. 35 
9.7.1 
Safety Analysis Set ........................................................................................................................ 35 
9.7.2 
Performance Analysis Set .............................................................................................................. 35 
9.7.3 
Per-Protocol Analysis Set .............................................................................................................. 36 
9.7.4 
Statistical Analyses of Analysis Sets ............................................................................................. 36 
9.8 
Statistical Analysis ....................................................................................................................... 36 
9.8.1 
General Considerations .................................................................................................................. 36 
9.8.2 
Significance levels and handling of type I error ............................................................................ 36 
9.8.3 
Demographic and other Baseline Characteristics .......................................................................... 37 
9.8.4 
Disposition of Subjects .................................................................................................................. 37 
9.8.5 
Safety Analysis .............................................................................................................................. 37 


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9.8.6 
Primary Performance Analysis ...................................................................................................... 37 
9.8.7 
Secondary Performance Analysis .................................................................................................. 38 
9.8.8 
Exploratory Performance Analyses ............................................................................................... 38 
9.8.9 
Timing of Analyses ....................................................................................................................... 39 
9.8.10 
Pooling ........................................................................................................................................... 40 
9.8.11 
Sub-Group Analyses ...................................................................................................................... 40 
9.8.12 
Handling of Missing Data .............................................................................................................. 40 
10 Study Procedures ............................................................................................................... 41 
10.1 General ......................................................................................................................................... 41 
10.2 Breath Test Procedure .................................................................................................................. 41 
10.3 Investigational Product Handling ................................................................................................. 43 
10.4 Investigational Product Accountability ........................................................................................ 43 
11 Ethics & Regulatory Considerations ................................................................................ 44 
12 Safety Considerations ........................................................................................................ 44 
13 Subject Confidentiality ...................................................................................................... 44 
14 Monitoring and Quality Assurance .................................................................................. 44 
15 Publication Policy and Finance ......................................................................................... 44 
16 Financial Aspects ................................................................................................................ 44 
17 Study termination ............................................................................................................... 45 
18 References ........................................................................................................................... 46 
Appendix A – Methacetin Breath Test Parameters ............................................................. 47 
Appendix B – Conatus protocol IDN-6556-14 ...................................................................... 50 
 
 


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1 ABBREVIATIONS AND DEFINITIONS 
1.1 Abbreviations 
AE 
- Adverse Event 
AUC 
- Area under the Curve 
BID-CSPH Test 
- BreathID® CSPH 13C-Methacetin Breath Test 
BID-CSPH Algorithm - BID-CSPH MBT based algorithm used in the BID-CSPH Test 
cDOBx_min 
- Cumulative Delta over Baseline at x minutes from ingestion  
CI 
- Confidence Interval 
CL 
- Confidence Limits 
CO2 
- Carbon dioxide 
cPDRx_min 
- Cumulative Percentage Dose Recovery at x minutes from ingestion  
CRF 
- Case Report Form 
CSPH 
- Clinically Significant Portal Hypertension 
DOBx_min 
- Delta over Baseline at x minutes from ingestion 
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 
NSBB 
- Non-Selective Beta Blocker 
OUS 
- Out of US 
PDRx_min 
- Percent Dose Recovered (expressed as % per hour) at x minutes 
from ingestion 
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) 


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1.2 Definitions 
This companion protocol includes all randomized AND all screen failed subjects from the 
Conatus IDN-6556-14 study that performed an MBT. Only subjects that meet this 
companion study inclusion/exclusion criteria (sections 7.1, 7.2 and 7.3) will be considered 
for the performance analyses: 
• The study population for the primary and secondary as well as the first two 
exploratory endpoints will be screened subjects with valid MBT and HVPG results 
prior to any investigational treatment. This population is defined as the Validation 
Population. 
• Those subjects from the Validation Population that were randomized into the 
Conatus IDN-6556-14 study and have at least one MBT on treatment are defined as 
the Treated Sub-Population. 
 
 


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2 PROTOCOL SYNOPSIS 
Protocol Title: 
Validation Study for the BID-CSPH Test: Companion protocol for the 
¹³C-Methacetin Breath Test (MBT) using the BreathID® MCS System in 
Conatus phase 2 study of Emricasan, an Oral Caspase Inhibitor, under 
protocol IDN-6556-14 
Short Title: 
BID-CSPH Test validation: Companion protocol assessing MBT in subjects 
participating in the IDN-6556-14 study 
Protocol 
Reference 
Number: 
CON-EX-0616 
Version and 
Date: 
v 5.0, Oct. 17, 2018 
Phase of 
Development: 
Pivotal 
Sponsor: 
Exalenz Bioscience Ltd. 
4 Ha’Maayan Street 
Modi'in, Israel 7177872 
Tel: +972-8-9737500 
Fax: +972-8-9737501 
Investigated 
Disease: 
Subjects with advanced chronic liver disease (ACLD) due to Non-Alcoholic 
Steatohepatitis (NASH) 
Combination 
Product: 
The Exalenz ¹³C-labeled Methacetin and the BreathID® MCS System. 
Investigated 
breath Test 
Measure: 
The BID-CSPH Test with its MBT based BID-CSPH Algorithm and its 
predefined cut-off to identify clinically significant portal hypertension 
(defined by HVPG ≥ 10 mmHg), developed under the Exalenz study CSPH-
EX-0414, IDE# G140190 and Companion Protocol to Galectin's study GT26 
(GT-EX-0215), conducted in collaboration with Galectin Therapeutics Inc. 
under their IND 115459 and Exalenz' IDE G150125. 
Comparator: 
Hepatic Vein Portal Pressure Gradient (HVPG) 
Primary 
Performance 
Objective: 
To validate the ability of the BID-CSPH Test to identify clinically significant 
portal hypertension (CSPH) defined as HVPG ≥ 10mmHg in the Validation 
Population using the BID-CSPH Algorithm with a predefined cutoff in terms 
of PPV and NPV. 


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Secondary 
Performance 
Objective: 
1. To present additional performance measures for the ability of the BID-
CSPH Test to identify clinically significant portal hypertension (CSPH) 
defined as HVPG ≥ 10mmHg in the Validation Population using the 
BID-CSPH Algorithm with a predefined cut-off in terms of sensitivity 
and specificity. 
2. To assess the ability of the BID-CSPH Test to identify severe portal 
hypertension defined as HVPG ≥ 12 mmHg in the Validation Population 
using the BID-CSPH Algorithm with a second predefined cut-off.  
Exploratory 
Objectives: 
1. To assess the correlation between MBT result parameters (see Appendix 
A, item 7) and HVPG results in the Validation Population. 
2. To assess the effect of frequently used medications or other confounding 
factors on the correlation of MBT result parameters (see Appendix A, 
item 7) with HVPG readings in the Validation Population. 
3. To show the ability of the MBT to measure the effect of Emricasan on 
the metabolic capacity of the liver at treatment week 24 (versus pre-
treatment), as compared to placebo treated subjects in the Treated Sub-
Population. 
4. To show correlation of changes in the MBT results with changes in 
HVPG at treatment week 24 (versus pre-treatment), in subjects with and 
without treatment with Emricasan for nonalcoholic steatohepatitis 
(NASH) in the Treated Sub-Population. 
5. To show the ability of the MBT to measure the effect of Emricasan on 
the metabolic capacity of the liver at treatment week 48 (versus pre-
treatment), as compared to placebo treated subjects in the Treated Sub-
Population.  
Safety Objective: 
To evaluate safety events related to the BreathID MCS System or the 
MBT/BID-CSPH Test. 
Study 
Population: 
This companion protocol includes all randomized AND all screen failed 
subjects from the Conatus IDN-6556-14 study that performed an MBT. Only 
subjects that meet the companion study inclusion/exclusion criteria (sections 
7.1, 7.2 and 7.3) will be considered for the performance analyses. 
The study population for the primary and secondary as well as first two 
exploratory endpoints will be screened subjects with valid MBT and HVPG 
results prior to any investigational treatment. This population is referred to as 
the Validation Population. 
Those subjects from the Validation Population that were randomized into the 
Conatus IDN-6556-14 study and have at least one MBT on treatment are 
defined as the Treated Sub-Population. 


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Study Design: 
This companion protocol is a validation study for the BID-CSPH Test with its 
BID-CSPH 
Algorithm 
for 
identification 
of 
CSPH 
(defined 
as 
HVPG ≥  10 mmHg) that will analyze the data generated by Conatus' study of 
Emricasan under protocol IDN-6556-14. 
The IDN-6556-14 study is a Phase 2, multicenter, double-blind, randomized, 
placebo-controlled, dose-response study to evaluate the safety and efficacy of 
Emricasan in improving portal hypertension in subjects with NASH cirrhosis 
and severe portal hypertension. The Conatus study IDN-6556-14 randomizes 
subjects into 4 parallel treatment arms (5 mg, 25 mg, 50 mg Emricasan or 
placebo) (see Section 5). 
As part of the IDN-6556-14 study, the MBT will be performed during a 
screening visit.  
In addition, the MBT will be performed at treatment week 24 and at the end 
of treatment (at week 48), in randomized subjects who had MBT at screening. 
Inclusion 
Criteria: 
Subjects must meet all of the following criteria for this validation study:  
1. Male or female subjects 18 years or older, able to provide written 
informed consent and able to understand and willing to comply with the 
requirements of the study.  
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. 
chronic viral hepatitis, alcoholic liver disease, etc.)  
• 
Diagnosis of cirrhosis is based on:  
o Biopsy OR  
o Clinical evidence: platelet count <150,000, AST > ALT, and 
either nodular liver surface on imaging or splenomegaly  
• 
NASH is based on at least 1 of the following:  
o Prior or current biopsy showing steatohepatitis (fat, ballooning 
degeneration, inflammation) consistent with NASH  
o At least 2 metabolic risk factors for at least 5 years preceding 
the diagnosis of cirrhosis: diabetes mellitus, impaired fasting 
glucose, obesity (Body Mass Index (BMI) ≥30 kg/m2 or central 
obesity), hypertension, dyslipidemia (See Appendix IV of 
Conatus IDN-6556-14 protocol)  
o Prior or current biopsy showing some but not all diagnostic 
features of NASH (e.g. only fat or ballooning degeneration or 
inflammation) but with no evidence for viral hepatitis or other 
liver disease AND either fatty liver disease on prior imaging or 
at least 1 metabolic risk factor (as above) for at least 5 years 
preceding the diagnosis of cirrhosis  
Note: Previous viral hepatitis that was curatively treated (with sustained 
viral response) is not an exclusion as long as: 1) viral eradication 
was achieved at least 3 years prior to the diagnosis of cirrhosis 


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and 2) all other criteria are met for NASH as the etiology of 
cirrhosis  
3. Compensated cirrhosis (no history of or presence of clinically evident 
ascites, variceal hemorrhage, or encephalopathy, and on no medications 
to treat these complications)  
OR  
Decompensated cirrhosis with no more than 1 prior significant 
decompensating event:  
a) If a prior decompensating event was variceal hemorrhage, event 
must have occurred at least 3 months prior to MBT or HVPG 
b) If a prior decompensating event was ascites requiring chronic 
diuretics, ascites should be well controlled (not clinically evident, 
i.e. no ascites or ascites only detectable by ultrasound examination) 
on a stable dose of diuretics for at least 3 months prior to MBT and 
HVPG 
c) If a prior decompensating event was hepatic encephalopathy ≥ grade 
II or requiring hospitalization, encephalopathy should be well-
controlled (Stage 0 or 1) on stable medication for at least 3 months 
prior to MBT and HVPG 
Note: Previous transient ascites or hepatic encephalopathy in a subject 
who is currently stable without clinically evident ascites or 
encephalopathy and on no medications for these conditions does 
not count as a prior significant decompensating event  
4. Subjects who are on NSBB or statins must be on a stable dose for at least 
1 month prior to MBT and HVPG. 
5. Subjects must have an initial MBT test performed during screening. 
Exclusion 
Criteria: 
Subjects who meet any of the following criteria will be excluded from this 
validation study:  
1. Evidence of severe decompensation, defined as:  
• 
Presence or history of more than one type of significant 
decompensating event (clinically evident ascites requiring chronic 
diuretics, variceal hemorrhage, and/or overt encephalopathy)  
Note: Previous transient ascites or hepatic encephalopathy in a subject 
who is currently stable without clinically evident ascites or 
encephalopathy and on no medications for these conditions does 
not count towards this exclusion.  
• 
One type of decompensating event with the following characteristics:  
o More than 1 episode of variceal hemorrhage or bleeding from a 
portal 
hypertensive 
source 
(e.g. 
portal 
hypertensive 
gastropathy)  


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o Ascites that has required more than 1 large-volume paracentesis 
(>5 L) for treatment or that has been complicated by 
spontaneous bacterial peritonitis, hyponatremia (serum Na 
<130), and/or hepatorenal syndrome  
o More than 1 episode of overt hepatic encephalopathy requiring 
hospitalization  
2. Estimated creatinine clearance <30 mL/min  
3. Prior transjugular intrahepatic portosystemic shunt or other porto-
systemic bypass procedure  
4. Known portal vein thrombosis  
5. Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the 
last 6 months, unless resolved following cholecystectomy, other 
definitive treatment (e.g., sphincterotomy), or medical management (e.g., 
ursodeoxycholic acid)  
6. Current use of medications that are considered inhibitors of OATP1B1 
and OATP1B3 transporters: atazanavir, cyclosporine, eltrombopag, 
gemfibrozil, indinavir, lopinavir, ritonavir, rifampin, saquinavir, 
simeprevir, telaprevir, tipranovir, or some combination of these 
medications  
7. Alpha-fetoprotein >50 ng/mL  
8. History or presence of clinically concerning cardiac arrhythmias, or 
prolongation of screening (pre-treatment) QT Interval Corrected by the 
Fridericia Correction Formula (QTcF) interval of >500 msec  
9.  History of or active malignancies, other than those successfully treated 
with curative intent and believed to be cured  
10. Significant systemic or major illness other than liver disease that in the 
opinion of the investigator would preclude the subject from participating 
in and completing the study, including but not limited to acute coronary 
syndrome or stroke within 6 months of screening or major surgery 
within 3 months of screening  
11. Prior liver transplant  
12. Previous restrictive bariatric surgery or bariatric device or prior 
malabsorptive bariatric surgery  
13. Known human immunodeficiency virus infection  
14. Use of controlled substances (including inhaled or injected drugs) or 
non-prescribed use of prescription drugs within 1 year of screening to 
the point of interfering with the subject’s ability to comply with study 
procedures and study drug administration in the investigator’s judgement  
15. History of significant alcohol consumption (>20 g/day for females and 
>30 g/day for males on average) within the past 5 years  
16. If female: planned or known pregnancy, positive urine or serum 
pregnancy test, or lactating/breastfeeding  
17. Previous treatment with Emricasan or active investigational medication 


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(except Methacetin) in a clinical trial within 3 months prior to MBT and 
HVPG 
18. Known allergy to acetaminophen (paracetamol) 
19. Known hypotension (systolic pressure < 100mmHg), 
20. Known pulmonary hypertension (right ventricular systolic pressure 
> 45mmHg) 
21. Uncontrolled malabsorption or diarrhea  
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 randomized 
subjects), 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 consume any alcohol or caffeine within 24 hours prior 
to the test  
7. Subject should not have general anesthesia or sedation within 24 hours 
prior to the test 
8. Subjects on beta-blockers or statins should be on stable dose at least 30 
days prior to the test 
Primary 
Endpoints 
The primary endpoints are the positive and negative predictive value (PPV 
and NPV, respectively) of the BID-CSPH Test binary response for clinically 
significant portal hypertension (CSPH) as determined by HVPG, defined as 
HVPG ≥ 10 mmHg in the Validation Population. 


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Secondary 
Endpoints: 
The secondary endpoints are: 
1. Sensitivity and specificity of the BID-CSPH Test binary response for 
clinically significant portal hypertension (CSPH) as determined by 
HVPG, defined as HVPG ≥ 10 mmHg in the Validation Population. 
2. Positive and negative predictive value (PPV and NPV, respectively) 
of the BID-CSPH Test binary response for severe portal hypertension 
as determined by HVPG, defined as HVPG ≥ 12 mmHg in the 
Validation Population. The cut-off value of the BID-CSPH 
Algorithm for identifying severe portal hypertension is different from 
the cut-off value used to identify CSPH. 
Exploratory 
Endpoints: 
1. Correlation between MBT result parameters (see Appendix A, item 7) 
and HVPG readings in the Validation Population. 
2. Comparison of correlation between MBT result parameters (see 
Appendix A, item 7) and HVPG readings between frequently used 
medications or other confounding factors in the Validation Population. 
3. Change in MBT result parameters (see Appendix A, item 7) at treatment 
week 24. Change is measured as the difference between pre-treatment 
and treatment week 24 MBT measurements in each of the four treatment 
arms. 
4. Correlation between changes in the MBT result parameters (see 
Appendix A, item 7) and changes in HVPG to treatment week 24, both 
measured as the difference between pre-treatment and treatment week 24 
values. 
5. Change in MBT result parameters (see Appendix A, item 7) at treatment 
week 48. Change is measured as the difference between pre-treatment 
and treatment week 48 MBT measurements in each of the four treatment 
arms. 
Sample Size 
The plan is to enroll a subset of subjects that will be screened under the 
Conatus IDN-6556-14 study. It is expected that up to 510 subjects will 
perform the MBT during the screening visit of the Conatus study. 
It should be noted that HVPG results (a primary endpoint in this companion 
protocol) may not be available for all subjects tested with MBT prior to the 
HVPG procedure (for screen failure subjects as part of the Conatus study). 
Thus, for the primary endpoint there will be fewer subjects with pairs of MBT 
and HVPG measurements. It is expected that approximately 250 subjects will 
have valid MBT and HVPG results during screening. 
Statistical 
Analysis: 
Statistical analyses will be performed using SAS® v9.4 or higher (SAS 
Institute, Cary NC, US). 
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%. 


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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. 
Primary performance analyses: 
A 2x2 table of the results comparing the positive /negative results obtained 
from the BID-CSPH Algorithm compared to HVPG ≥ 10mmHg / < 10mmHg 
at baseline (screening) will be presented. 
The primary performance analysis will present the estimation of the PPV and 
NPV of the diagnosis together with their respective Wilson’ score two-sided 
95% confidence intervals (CI).  
The study will be deemed successful if: 
• 
The lower limit of the Wilson’ score two-sided 95% CI for the PPV 
is 5% higher than the observed prevalence; and 
• 
the lower limit of the Wilson’ score two-sided 95% CI for the NPV is 
higher than 1 - the observed prevalence. 
PPV and NPV will be presented for the prevalence of 65%, 70%, 75% and 
80% in addition to the prevalence observed in the study. 
Secondary performance analyses: 
1. Secondary performance analysis will present the estimation of the 
sensitivity and specificity of the BID-CSPH Algorithm to identify CSPH, 
HVPG ≥ 10mmHg, together with their respective Wilson’ score two-sided 
95% confidence intervals (CI). 
2.  A 2x2 table of the results comparing the positive /negative results 
obtained from the BID-CSPH Algorithm (with a second cut-off for the 
detection of severe portal hypertension) compared to HVPG ≥ 12mmHg / 
< 12mmHg at baseline (screening) will be presented. 
This secondary performance analysis of the detection of severe portal 
hypertension will present the estimation of the PPV and NPV as well as of the 
sensitivity and specificity of the diagnosis together with their respective 
Wilson’ score two-sided 95% CI. 
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 (screening) variables. 


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3 BACKGROUND 
The background of non-alcoholic fatty liver disease (NAFLD) and its advanced stage of 
non-alcoholic Steatohepatitis (NASH) and its pathogenesis is described in the Conatus' 
IDN-6556-14 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 in exhaled breath 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 tests to assess 
disease severity and to monitor disease progression using 13C-Methacetin. 


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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 with 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 
potential 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 one such 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 the end of each test. 
Breath tests using  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. 
3.2 Cirrhosis and Portal Hypertension 
As described in the Conatus protocol IDN-6556-14 part 4.1 (included in Appendix B). 


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3.3 Hepatic Venous Pressure Gradient (HVPG) assessing Portal 
Hypertension 
As described in the Conatus protocol IDN-6556-14 section 8.2.1(included in Appendix B). 
3.4 Limitations of HVPG 
HVPG is highly clinically valuable(3), and the method used to measure it is reasonably safe, 
accurate and reproducible when adhering to guidelines(4). However, there are limitations to 
the generalized use of HVPG such as the fact that it is an invasive procedure that uses 
contrast media injection and catheterization, has a need for expertise in execution to ensure 
reliable and reproducible measurements(5, 6). Hence HVPG is generally limited in use to 
large medical facilities due to requiring resources beyond those of the hepatology clinic 
and point of care physician, and presents added risk to the patients. Berzigotti et al. in their 
recent review(7) determined that HVPG is the best method to assess CSPH, but they also 
cite the limitations of the procedure, especially in the context of therapy monitoring: 
“HVPG measurements are not available in all centers, the technique is invasive 
and some patients are unwilling to be submitted to it. This is even more relevant 
when the repetition of the procedure is needed to monitor treatment response. 
These issues have raised interest to non-invasively determine when CSPH is 
present, so allowing defining a patient at risk of developing portal hypertension-
related complications.” (7) 
Hence, HVPG is a useful, but an impractical test for everyday clinical use. In fact, key 
opinion leaders (KOLs) have commented that many more HVPG measurements would be 
done since it is felt to be a good predictor of complications of cirrhosis(8), if it was not for 
the practical drawbacks and limitations. It is clearly desirable and necessary to have an 
equally reliable surrogate test that is non-invasive. 
Moreover, although HVPG is clinically highly valuable(3), even in experienced hands, 
complications can occur with large hematomas of the neck or groin being the most 
common (as reported by a leading Spanish center that regularly measures HVPG with a 
complication rate of 2.3%)(8). 
3.5 Rationale to use the MBT for assessment of Portal Hypertension and 
BID-CSPH Test for Clinically Significant Portal Hypertension (CSPH) 
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, 


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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 or presence of CSPH, as they were shown to be proportionally reduced in the 
presence of CSPH in two independent studies and in a meta-analysis described further 
below in this section. 
Exalenz completed a study in eight large US centers and three non-US centers entitled 
“Pivotal study to evaluate the efficacy and safety of the BreathID® MCS system for 
detection of cirrhosis using the ¹³C-Methacetin Breath Test MBT” (G080107) during which 
a subset of 21 patients with MBT data had undergone HVPG at the time of their liver 
biopsy. When comparing MBT variables and HVPG results, significant correlations were 
noted. For example, a statistically significant inverse relationship (r=-0.75) was found 
between the PDR values at 45 minutes (PDR45_min) and HVPG values as depicted in 
Figure 1 below. It can be concluded from the data of these 21 patients that the correlation 
does not seem to be affected by the use of non-selective beta-blockers or the presence of 
varices.  
 
Figure 1: Correlation between HVPG and MBT measure (PDR45_min) 
In addition, use of the Receiver Operating Characteristic (ROC) Area Under the Curve 
(AUC) to assess the ability of an MBT variable to identify CSPH, demonstrated that the 
Cumulative Percent Dose Recovered at 15 minutes (cPDR15_min) distinguished 


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HVPG ≥10mmHg (CSPH) from lower HVPG values (non-CSPH). The AUC of the MBT 
parameter (cPDR15_min) was 0.89 (95% CI [0.72-1.00], p < 0.0001)(9) (see Figure 2). The 
patient population tested included 5 non-CSPH subjects and 16 subjects with CSPH. 
 
Figure 2: ROC curve for the detection of CSPH as measured by cPDR15_min 
Based on these findings, an additional study was conducted in India to compare MBT to 
HVPG in 31 subjects clinically identified as cirrhotic. All subjects underwent both tests 
within 2 days of each other. The results showed a statistically significant correlation of 
approximately r= -0.6 for most MBT parameters compared to HVPG. The ROC AUC for 
the detection of CSPH remained at 0.90 for cPDR15_min (Cumulative PDR at 15 minutes) 
(see Figure 3). There were, however only two subjects with HVPG measures lower than 
10mmHg [Data on File].  


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Figure 3: ROC curve for the detection of CSPH as measured by cPDR15_min in Indian data 
The Company also conducted a meta-analysis of all accumulated data (in the US and in 
India) that included in addition six patients from another clinical study which enrolled 
cirrhotic patients conducted under IDE G080227, who had HVPG done as part of their 
clinical care. A total of 58 subjects were included in this meta-analysis to assess the 
correlation between MBT and HVPG as well as the ability of the MBT to identify CSPH 
(51 with CSPH and 7 without CSPH). The analysis demonstrated a statistically significant 
negative correlation between HVPG and MBT (r=-0.57) (cPDR15_min) as seen in Figure 4 
[Data on File].  


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Figure 4: Correlation between HVPG and MBT measure cPDR15_min on 58 patients 
The AUC for the detection of CSPH in this meta-analysis remained at 0.88 for 
cPDR15_min. The ability of cPDR15_min to assess CSPH can be seen in a boxplot in 
Figure 5. 
 
Figure 5: Boxplot showing the ability of cPDR15_min to assess CSPH in 58 patients 


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The results obtained for cPDR15_min were very similar to those when using cPDR30_min. The 
latter is believed to be more informative than cPDR15_min as it relies on more measurements 
throughout 30 minutes. 
Following these preliminary results, Exalenz conducted the CSPH-EX-0414 training study 
to develop the BID-CSPH Test algorithm at eight clinical sites; five in Europe and three in 
the United States (IDE# G140190). This study enrolled 247 patients with compensated 
advanced chronic liver disease. 
An additional training study (to develop the BID-CSPH Algorithm), the GT-EX-0215 
study, was conducted as a companion protocol to Galectin Therapeutics Inc. (Galectin’s) 
GT-026 study for evaluating the efficacy of their study drug GR-MD-02 (Galactoarabino-
rhamnogalacturonate) for treatment of NASH. This collaborative study was conducted 
under an IND and IDE; Galectin’s IND 115459 and Exalenz' IDE G150125. The MBT was 
performed during screening, after 26 weeks of treatment, as well as at the end of the study 
(between weeks 53-55). The HVPG procedure was performed during screening and at the 
end of the study. 
Beyond Galectin’s aim in this study, Exalenz' intent was to assess whether the MBT can 
serve as an aid in identifying changes in portal pressure by measuring performance of the 
liver before and after treatment with Galectin’s GR-MD-02 and to train MBT based 
algorithms (i.e., for the BID-CSPH Test) using data from screening visits to identify 
different risk levels of portal hypertension as defined by HVPG ≥ 6, 10, 12, 20 mmHg in 
adult patients with portal hypertension and cirrhosis due to NASH, without a history of 
clinical decompensation.  
Both training studies (CSPH-EX-0414 and GT-EX-0215) contributed data to the building 
of the algorithm of the BID-CSPH Test to identify CSPH (HVPG ≥ 10 mmHg) in NASH 
patients presenting with ACLD. 
The current validation and companion study’s primary aim is to validate the BID-CSPH 
Algorithm to identify CSPH (defined as HVPG ≥ 10mmHg) in screening/pre-treatment 
subjects (the Validation Population). Additionally it will help in the assessment in these 
subjects of the ability of the MBT to identify severe portal hypertension (defined as 
HVPG ≥ 12 mmHg), to assess the correlation of MBT results to HVPG and assess the 
effect of frequently used medications and confounding factors on the MBT results.  
Additionally, assessing the data of randomized subjects, this study will serve to determine 
the effect of Conatus’ study drug Emricasan on the metabolic capacity of the liver as 
determined by the MBT after 24 and 48 weeks of treatment (versus pre-treatment) at 
different treatment doses compared to placebo, and show correlation of changes in the 


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MBT results compared to changes in HVPG after 24 weeks of treatment (versus pre-
treatment) in patients with and without treatment for nonalcoholic steatohepatitis. 
4 INTENDED USE / INDICATION FOR USE 
The Exalenz ¹³C-Methacetin Breath Test (MBT) is intended to non-invasively measure 
changes in the 13CO2/12CO2 ratio of exhaled breath, which is indicative of the ability of the 
liver to metabolize a set dose of ¹³C-Methacetin over time. 
The Exalenz BID-CSPH Test is indicated for use as an aid in identifying clinically 
significant portal hypertension (CSPH) in adult patients with clinically diagnosis of Non-
alcoholic Steatohepatitis (NASH) who present with advanced chronic liver disease 
(ACLD).a The Test utilizes the ¹³C-Methacetin Solution, the BreathID® MCS System and 
the BID-CSPH Software Application. 
The MBT and its BID-CSPH Test are for use by trained health care professionals. To be 
administered under a physician’s supervision. 
5 STUDY DESIGN 
This companion protocol is a validation study for the BID-CSPH Test with its BID-CSPH 
Algorithm for identification of CSPH (defined as HVPG ≥ 10 mmHg) that will analyze the 
data generated by Conatus’ study of Emricasan under protocol IDN-6556-14. This data will 
be sequestered from Exalenz until the BID-CSPH Algorithm is fully developed and locked. 
The IDN-6556-14 study is a Phase 2, multicenter, double-blind, randomized, placebo-
controlled, dose-response study to evaluate the safety and efficacy of Emricasan in 
improving portal hypertension in subjects with NASH cirrhosis and severe portal 
hypertension. The Conatus study IDN-6556-14 randomizes subjects into 4 parallel 
treatment arms (5 mg, 25 mg, 50 mg Emricasan or placebo). 
As part of the IDN-6556-14 study, MBT will be performed during a screening visit. 
The screening data, including data from screen failed subjects, generated by the Conatus 
study IDN-6556-14 will be used to validate the BID-CSPH Test. 
In addition the MBT will be performed at treatment week 24 and at the end of treatment 
(week 48), in randomized subjects who had MBT at screening to assess whether Emricasan 
compared to placebo improves liver metabolic function as assessed by the MBT. It will be 
assessed once the data from treatment week 24 and treatment week 48, respectively, 
 
a - Although Conatus study IDN-6556-14 randomizes only  'NASH patients with cirrhosis and severe portal 
hypertension', this validation study, as part of the companion protocol to the Conatus IDN-6556-14 study, 
enrolls patients from the screening phase where the 13C-Methacetin Breath Test is performed, thereby also 
including screen failed patients without severe portal hypertension (HVPG <12 mmHg).  
 - Since in this study cirrhosis does not have to be biopsy proven, the terminology used is 'advanced chronic 
liver disease' - ACLD. 


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become available. All analyses using only screening data for the Validation Population 
may be performed prior to week 24. 
All sites in the US, Spain and France that will participate in the Conatus IDN-6556-14 
study will be offered the opportunity to perform the MBT for all of their subjects meeting 
the study criteria. Sites in Switzerland and Germany will not have the opportunity to 
perform the MBT as part of the study. 
Sites who elect to participate in the MBT measurements will perform the test at the 
specified visits for all subjects enrolled at their site. As described in the Conatus' study 
IDN-6556-14 protocol (Appendix B) section 8.2.6, the MBT will be performed at select 
sites at screening, treatment week 24, and treatment week 48. MBT should be performed 
within 1 week of HVPG but not within 24 hours after HVPG. If MBT is performed on the 
same day as the HVPG test, it should be performed before the HVPG test. For the 
treatment week 24 and treatment week 48 MBT, subjects should take their morning dose of 
study drug prior to the test.  
 
A graphical summary of the study schema is included in Figure 6, below. Further details 
can be found in the Conatus study protocol IDN-6556-14 included in Appendix B.  
 
 
Figure 6: Study Schema 


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6 STUDY OBJECTIVES AND ENDPOINTS 
The data generated in this study will primarily be used to validate the BID-CSPH Test, 
which uses an MBT based algorithm developed under the Exalenz study CSPH-EX-0414, 
IDE# G140190 and Companion Protocol to Galectin's study GT26 (GT-EX-0215), 
conducted in collaboration with Galectin Therapeutics Inc. under their IND 115459 and 
Exalenz' IDE G150125. 
6.1 Study Objectives 
6.1.1 Primary Performance Objective 
To validate the ability of the BID-CSPH Test to identify clinically significant portal 
hypertension (CSPH) defined as HVPG ≥ 10mmHg in the Validation Population using the 
BID-CSPH Algorithm with a predefined cutoff in terms of PPV and NPV. 
6.1.2 Secondary Performance Objective 
1. To assess additional performance measures for the ability of the BID-CSPH Test to 
identify 
clinically 
significant 
portal 
hypertension 
(CSPH) 
defined 
as 
HVPG ≥ 10mmHg in the Validation Population using the BID-CSPH Algorithm 
with a predefined cutoff in terms of sensitivity and specificity. 
2. To assess the ability of the BID-CSPH Test to identify severe portal hypertension 
defined as HVPG ≥ 12mmHg in the Validation Population using the BID-CSPH 
Algorithm with a second predefined cut-off. 
6.1.3 Exploratory Performance Objectives 
1. To assess the correlation between MBT result parameters (see Appendix A, item 
7) and HVPG results in the Validation Population. 
2. To assess the effect of frequently used medications or other confounding factors 
on the correlation of MBT result parameters (see Appendix A, item 7) with 
HVPG readings in the Validation Population. 
3. To show the ability of the MBT to measure the effect of Emricasan on the 
metabolic capacity of the liver at treatment week 24 of treatment (versus pre-
treatment), as compared to changes in placebo treated subjects in the Treated 
Sub-Population. 
4. To show correlation of changes in the MBT results with changes in HVPG at 
week 24 (versus pre-treatment), in subjects with and without treatment with 
Emricasan for nonalcoholic steatohepatitis (NASH) in the Treated Sub-
Population. 


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5. To show the ability of the MBT to measure the effect of Emricasan on the 
metabolic capacity of the liver at treatment week 48 of treatment (versus pre-
treatment), as compared to changes in placebo treated subjects in the Treated 
Sub-Population. 
6.1.4 MBT Safety Objective 
To evaluate safety events related to the BreathID MCS System or the MBT/BID-CSPH 
Test. 
6.2 Study Endpoints 
6.2.1 Primary Endpoint 
The primary endpoints are the positive and negative predictive value (PPV and NPV, 
respectively) of the binary response for clinically significant portal hypertension (CSPH) as 
determined by HVPG, defined as HVPG ≥ 10mmHg in the Validation Population. 
6.2.2 Secondary Endpoints 
The secondary endpoints are: 
1. Sensitivity and specificity of the BID-CSPH Test binary response for clinically 
significant portal hypertension (CSPH) as determined by HVPG, defined as 
HVPG ≥ 10 mmHg in the Validation Population. 
2. Positive and negative predictive value (PPV and NPV, respectively) of the BID-
CSPH Test binary response for severe portal hypertension as determined by HVPG, 
defined as HVPG ≥ 12mmHg in the Validation Population. 
The cut-off value of the BID-CSPH Algorithm for identifying severe portal 
hypertension is different from the one used to identify CSPH. 
6.2.3 Exploratory Endpoints 
1. Correlation between MBT result parameters (see Appendix A, item 7) and 
HVPG readings in the Validation Population. 
2. Comparison of correlation between MBT result parameters (see Appendix A, 
item 7) and HVPG readings between frequently used medications or other 
confounding factors in the Validation Population. 
3. Change in MBT result parameters (see Appendix A, item 7) at treatment week 
24. Change is measured as the difference between pre-treatment and treatment 
week 24 MBT measurements in each of the four treatment arms. 
4. Correlation between changes in the MBT result parameters (see Appendix A, 
item 7) and changes in HVPG to treatment week 24, both measured as the 
difference between pre-treatment and treatment week 24 values. 


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5. Change in MBT result parameters (see Appendix A, item 7) at treatment week 
48. Change is measured as the difference between pre-treatment and treatment 
week 48 MBT measurements in each of the four treatment arms. 
6.2.4 Safety Endpoints 
The cumulative incidence of 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 BreathID MCS System and its 
substrates or related to the procedure. 
7 SUBJECT SELECTION 
This companion protocol includes all randomized AND all screen failed subjects from the 
Conatus IDN-6556-14 study that performed an MBT. Only subjects that meet the 
companion study inclusion/exclusion criteria (sections 7.1, 7.2 and 7.3) will be considered 
for the performance analyses. 
7.1 Inclusion Criteria  
Subjects must meet all of the following criteria for this validation study:  
1. Male or female subjects 18 years or older, able to provide written informed consent 
and able to understand and willing to comply with the requirements of the study.  
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic 
viral hepatitis, alcoholic liver disease, etc.)  
• Diagnosis of cirrhosis is based on:  
o Biopsy OR  
o Clinical evidence: platelet count <150,000, AST > ALT, and either 
nodular liver surface on imaging or splenomegaly  
• NASH is based on at least 1 of the following:  
o Prior or current biopsy showing steatohepatitis (fat, ballooning 
degeneration, inflammation) consistent with NASH  
o At least 2 metabolic risk factors for at least 5 years preceding the 
diagnosis of cirrhosis: diabetes mellitus, impaired fasting glucose, 
obesity (Body Mass Index (BMI) ≥30 kg/m2 or central obesity), 
hypertension, dyslipidemia (See Appendix IV of Conatus IDN-6556-14 
protocol)  
o Prior or current biopsy showing some but not all diagnostic features of 
NASH (e.g. only fat or ballooning degeneration or inflammation) but 
with no evidence for viral hepatitis or other liver disease AND either 
fatty liver disease on prior imaging or at least 1 metabolic risk factor (as 
above) for at least 5 years preceding the diagnosis of cirrhosis  


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Note: Previous viral hepatitis that was curatively treated (with sustained viral 
response) is not an exclusion as long as: 1) viral eradication was achieved at 
least 3 years prior to the diagnosis of cirrhosis and 2) all other criteria are 
met for NASH as the etiology of cirrhosis  
3. Compensated cirrhosis (no history of or presence of clinically evident ascites, 
variceal hemorrhage, or encephalopathy, and on no medications to treat these 
complications)  
OR  
Decompensated cirrhosis with no more than 1 prior significant decompensating 
event:  
a) If a prior decompensating event was variceal hemorrhage, event must have 
occurred at least 3 months prior to MBT and HVPG 
b) If a prior decompensating event was ascites requiring chronic diuretics, ascites 
should be well controlled (not clinically evident, i.e. no ascites or ascites only 
detectable by ultrasound examination) on a stable dose of diuretics for at least 3 
months prior to MBT and HVPG 
c) If a prior decompensating event was hepatic encephalopathy ≥ grade II or 
requiring hospitalization, encephalopathy should be well-controlled (Stage 0 or 
1) on stable medication for at least 3 months prior to MBT and HVPG 
Note: Previous transient ascites or hepatic encephalopathy in a subject who is 
currently stable without clinically evident ascites or encephalopathy and on 
no medications for these conditions does not count as a prior significant 
decompensating event  
4. Subjects who are on NSBB or statins must be on a stable dose for at least 1 month 
prior to MBT and HVPG. 
5.  Subjects must have an initial MBT test performed during screening. 
7.2 Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from this validation study:  
1. Evidence of severe decompensation, defined as:  
• Presence or history of more than one type of significant decompensating event 
(clinically evident ascites requiring chronic diuretics, variceal hemorrhage, 
and/or overt encephalopathy)  
Note: Previous transient ascites or hepatic encephalopathy in a subject who is 
currently stable without clinically evident ascites or encephalopathy and on 
no medications for these conditions does not count towards this exclusion.  
• One type of decompensating event with the following characteristics:  


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o More than 1 episode of variceal hemorrhage or bleeding from a portal 
hypertensive source (e.g. portal hypertensive gastropathy)  
o Ascites that has required more than 1 large-volume paracentesis (>5 L) 
for treatment or that has been complicated by spontaneous bacterial 
peritonitis, hyponatremia (serum Na <130), and/or hepatorenal 
syndrome  
o More than 1 episode of overt hepatic encephalopathy requiring 
hospitalization  
2. Estimated creatinine clearance <30 mL/min  
3. Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass 
procedure  
4. Known portal vein thrombosis  
5. Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 
months, unless resolved following cholecystectomy, other definitive treatment 
(e.g., sphincterotomy), or medical management (e.g., ursodeoxycholic acid)  
6. Current use of medications that are considered inhibitors of OATP1B1 and 
OATP1B3 transporters: atazanavir, cyclosporine, eltrombopag, gemfibrozil, 
indinavir, lopinavir, ritonavir, rifampin, saquinavir, simeprevir, telaprevir, 
tipranovir, or some combination of these medications  
7. Alpha-fetoprotein >50 ng/mL  
8. History or presence of clinically concerning cardiac arrhythmias, or prolongation 
of screening (pre-treatment) QT Interval Corrected by the Fridericia Correction 
Formula (QTcF) interval of >500 msec  
9.  History of or active malignancies, other than those successfully treated with 
curative intent and believed to be cured  
10.  Significant systemic or major illness other than liver disease that in the opinion of 
the investigator would preclude the subject from participating in and completing 
the study, including but not limited to acute coronary syndrome or stroke within 6 
months of screening or major surgery within 3 months of screening  
11. Prior liver transplant  
12. Previous restrictive bariatric surgery or bariatric device or prior malabsorptive 
bariatric surgery  
13. Known human immunodeficiency virus infection  
14. Use of controlled substances (including inhaled or injected drugs) or non-
prescribed use of prescription drugs within 1 year of screening to the point of 
interfering with the subject’s ability to comply with study procedures and study 
drug administration in the investigator’s judgement  
15. History of significant alcohol consumption (>20 g/day for females and >30 g/day 
for males on average) within the past 5 years  


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16. If female: planned or known pregnancy, positive urine or serum pregnancy test, or 
lactating/breastfeeding  
17. Previous treatment with Emricasan or active investigational medication (except 
Methacetin) in a clinical trial within 3 months prior to MBT and HVPG 
18. Known allergy to acetaminophen (paracetamol) 
19. Known hypotension (systolic pressure < 100mmHg), 
20. Known pulmonary hypertension (right ventricular systolic pressure > 45mmHg) 
21. Uncontrolled malabsorption or diarrhea 
7.3 Restriction 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 randomized subjects), 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 consume any alcohol or caffeine within 24 hours prior to the 
test  
7. Subject should not have general anesthesia or sedation within 24 hours prior to the 
test 
8. Subjects on beta-blockers or statins should be on 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-6556-14 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. 


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8 SAFETY TERMINATION AND EARLY WITHDRAWAL OF 
SUBJECTS OR STUDY 
For safety termination and early withdrawal of subjects please refer to Conatus’ protocol 
IDN-6556-14. 
8.1 Expected Study Duration 
Conatus’ protocol IDN-6556-14 is designed to have subjects remain on study therapy for a 
total of 48 weeks unless intolerable side effects develop, or the subject is withdrawn from 
study participation. In addition, subjects will have up to a 6 week screening period and a 2 
week post-treatment follow-up visit for a total duration of up to 56 weeks.  
 


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9 STATISTICAL CONSIDERATIONS 
9.1 Study Design and Aim 
This companion protocol is a validation study for the BID-CSPH Test with its MBT based 
algorithm for identification of CSPH (defined as HVPG ≥ 10 mmHg) that will analyze the 
data generated by Conatus’ study of Emricasan under protocol IDN-6556-14. The Conatus 
study IDN-6556-14 randomizes subjects into 4 parallel treatment arms (5 mg, 25 mg, 50 
mg Emricasan or placebo) (see Section 5). 
As part of the IDN-6556-14 study, MBT will be performed during a screening visit. 
The screening data, including data from screen failed subjects, generated by the Conatus 
study IDN-6556-14 will be used to validate the BID-CSPH Test. 
In addition the MBT will be performed at treatment week 24 and at the end of treatment 
(week 48), in randomized subjects who had MBT at screening to assess whether Emricasan 
compared to placebo improves liver metabolic function as assessed by the MBT. 
9.2 Endpoint Measures 
9.2.1 Primary endpoints 
The primary endpoints are the positive and negative predictive value (PPV and NPV, 
respectively) of the BID-CSPH Test binary response for clinically significant portal 
hypertension (CSPH) as determined by HVPG, defined as HVPG ≥ 10mmHg in the 
Validation Population. 
9.2.2 Secondary endpoints 
The secondary endpoints are: 
1. Sensitivity and specificity of the BID-CSPH Test binary response for clinically 
significant portal hypertension (CSPH) as determined by HVPG, defined as 
HVPG ≥ 10 mmHg in the Validation Population (prior to any investigational 
treatment). 
2. Positive and negative predictive value (PPV and NPV, respectively) of the BID-
CSPH Test binary response for severe portal hypertension (defined as HVPG ≥ 
12mmHg) in the Validation Population (prior to any investigational treatment). 
The cut-off value of the BID-CSPH Algorithm for identifying severe portal 
hypertension is different from the one used to identify CSPH. 
9.2.3 Exploratory endpoints 
1. Correlation between MBT result parameters (see Appendix A, item 7) and HVPG 
readings in the Validation Population. 


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2. Comparison of correlation between MBT result parameters (see Appendix A, item 
7) and HVPG readings between frequently used medications or other confounding 
factors in the Validation Population. 
3. Change in MBT result parameters (see Appendix A, item 7) at treatment week 24. 
Change is measured as the difference between pre-treatment and treatment week 
24 MBT measurements in each of the four treatment arms. 
4. Correlation between changes in the MBT result parameters (see Appendix A, item 
7) and changes in HVPG to treatment week 24, both measured as the difference 
between pre-treatment and treatment week 24 values. 
5. Change in MBT result parameters (see Appendix A, item 7) at treatment week 48. 
Change is measured as the difference between pre-treatment and treatment week 
48 MBT measurements in each of the four treatment arms. 
9.2.4 Safety endpoints 
The cumulative incidence of 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 BreathID MCS System and its 
substrates or related to the procedure. 
9.3 Acceptance Criteria and Performance Goals 
One predefined cut-off to identify CSPH, determined by the BID-CSPH Test with its BID-
CSPH Algorithm will be validated in this study.  
The study will be deemed successful if:  
- the PPV is statistically significantly higher than the observed prevalence + 5% in the 
Validation Population, in other words if the lower two-sided 95% confidence bound is 5% 
higher than the prevalence. 
and  
- the NPV is statistically significantly higher than one minus the observed prevalence 
(1-prevalence) in the Validation Population, in other words if the lower two-sided 95% 
confidence bound is higher than 1-prevalence. 
9.4 Sample Size 
The plan is to enroll a subset of subjects that will be screened under Conatus' IDN-6556-14 
study. It is expected that up to 510 subjects will perform the MBT during the screening 
visit of the Conatus study. 
It should be noted that HVPG results (a primary endpoint in this companion protocol) may 
not be available for all subjects tested with MBT prior to the HVPG procedure (for screen 
failure subjects as part of the Conatus study). Thus, for the primary endpoint there will be 


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fewer subjects with pairs of MBT and HVPG measurements. It is expected that 
approximately 250 subjects will have valid MBT and HVPG results during screening, prior 
to randomization and any treatment visit. 
A sample size of approximately 250 subjects will enable confirmation that the lower two-
sided 95% exact confidence limit of the PPV is 5% higher than the observed prevalence if 
the observed PPV is at least 11% higher than the prevalence (assuming a prevalence of 
70%-80%). 
A sample size of approximately 250 subjects will enable confirmation that the lower two-
sided 95% exact confidence limit of the NPV is higher than one minus the observed 
prevalence if the observed NPV is at least 7% higher than the 1-prevalence (assuming a 
prevalence of 70%-80%). 
9.5 Randomization 
Subjects enrolled into the Conatus' IDN-6556-14 study, were randomized to one of the four 
treatment arms (5 mg, 25 mg, 50 mg of Emricasan or placebo) for the CON-EX-0616 
validation study, this is not relevant for the primary and secondary study endpoints. 
9.6 Blinding 
The Sponsor, the investigators and study sites personnel and the study statistician are 
blinded to the BID-CSPH Test results. 
9.7 Analysis sets 
9.7.1 Safety Analysis Set 
All subjects screened under Conatus' IDN-6556-14 study and for whom the MBT test was 
initiated. 
9.7.2 Performance Analysis Set 
All subjects screened under Conatus' IDN-6556-14 study who have performed the MBT 
test and have met the inclusion and exclusion criteria for this companion protocol and have 
valid measurements of MBT and HVPG at the screening visit. Subjects not randomized in 
the Conatus study IDN-6556-14, or with missing valid MBT or HVPG results at the 
treatment weeks 24 or 48 visits will not be part of the corresponding analysis. 
The study population for the primary and secondary as well as first two exploratory 
endpoints will be screened subjects with valid MBT and HVPG results prior to any 
investigational treatment. This population is referred to as the Validation Population. 


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Those subjects from the Validation Population that were randomized into the Conatus 
IDN-6556-14 study and have at least one MBT on treatment are defined as the Treated 
Sub-Population. 
9.7.3 Per-Protocol Analysis Set 
All subjects from the performance analysis set without any major protocol violation. 
9.7.4 Statistical Analyses of Analysis Sets 
Safety analyses will be performed on the safety analysis set. 
The per-protocol analysis set will be the main analysis set for the performance analyses. 
Performance analyses will also be presented for the performance analysis set. 
9.8 Statistical Analysis  
9.8.1 General Considerations 
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, 
US). 
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. 
9.8.2 Significance levels and handling of type I error 
9.8.2.1 Type I Error 
The overall significance level for this study is 5% using two-tailed tests, except for the 
treatment by site interaction that will be tested at a significance level of 10%. 
9.8.2.2 Hierarchy Approach for Endpoints Analysis 
There are two primary endpoints. The study will be deemed successful only if both 
acceptance criteria are met. 
The hierarchy approach will be adopted for the primary and secondary endpoints to control 
the type I error due to multiple endpoint testing. Thus, the primary endpoints will first be 
analyzed and only if both primary endpoints will be found significant, will the secondary 
endpoints be analyzed. The first set of secondary endpoints will be presented descriptively 


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with confidence intervals. The second set of secondary endpoints of identification of severe 
portal hypertension will be analyzed together and will be considered met only if both PPV 
and NPV are found significant. This approach will maintain the overall study type I error. 
9.8.3 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. 
Demographic information and disease characteristics for subjects that were screened for the 
Conatus study, but not enrolled into the MBT validation study will be compared to those 
enrolled into the MBT validation study. 
9.8.4 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 performance analysis will be provided as well. Any subject with missing 
primary endpoint data will be accounted for, including the reason for missing data. 
Demographic and other baseline characteristics of the subjects with and without HVPG 
results will be presented in tabular format. 
9.8.5 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, which will be coded according to MedDRA, will include 
incidence tables and will include analyses by severity, relationship to device or drug and 
baseline (pre-treatment) variables. 
9.8.6 Primary Performance Analysis 
A 2x2 table of the results comparing the positive /negative results obtained from the BID-
CSPH Algorithm compared to HVPG ≥ 10mmHg / < 10mmHg at baseline (screening) will 
be presented. 
The primary performance analysis will present the estimation of the PPV and NPV of the 
diagnosis together with their respective Wilson’ score two-sided 95% confidence intervals 
(CI).  


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The study will be deemed successful if: 
• The lower limit of the Wilson’ score two-sided 95% CI for the PPV is 5% higher 
than the observed prevalence; and 
• The lower limit of the Wilson’ score two-sided 95% CI for the NPV is higher than 
1 - the observed prevalence. 
PPV and NPV will be presented for the prevalence of 65%, 70%, 75% and 80% in addition 
to the prevalence observed in the study. 
9.8.7 Secondary Performance Analysis 
1. Secondary performance analysis will present the estimation of the sensitivity and 
specificity of the BID-CSPH Algorithm to identify CSPH, HVPG ≥ 10mmHg, 
together with their respective Wilson’ score two-sided 95% confidence intervals 
(CI). 
2. A 2x2 table of the results comparing the positive /negative results obtained from the 
BID-CSPH Algorithm (with a second cut-off for the detection of severe portal 
hypertension) compared to HVPG ≥ 12mmHg / < 12mmHg at baseline (screening) 
will be presented. 
This secondary performance analysis of the detection of severe portal hypertension 
will present the estimation of the PPV and NPV as well as of the sensitivity and 
specificity of the diagnosis together with their respective Wilson’ score two-sided 
95% confidence intervals (CI). 
The secondary endpoints will be deemed successful if: 
• The lower limit of the Wilson’ score two-sided 95% CI for the PPV is higher than 
the observed prevalence; and 
• The lower limit of the Wilson’ score two-sided 95% CI for the NPV is higher than 
1 - the observed prevalence. 
9.8.8 Exploratory Performance Analyses 
The Spearman's and Pearson’s correlation coefficient of the MBT result parameters 
(Appendix A, item 7) with the HVPG (as a continuous variable) at baseline (screening) will 
be presented in a tabular form along with their respective two-sided 95% CI’s. 
The Spearman's and Pearson’s correlation coefficient of the MBT result parameters 
(Appendix A, item 7) with the HVPG (as a continuous variable) at baseline (screening) by 
subgroups of frequently used medications and other confounding factors, will be presented 
in a tabular form along with their respective two-sided 95% CI’s as well. 


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The changes from baseline (screening) to treatment week 24 of the MBT result parameters 
(Appendix A, item 7) will be presented by descriptive statistic by Conatus' IDN-6556-14 
study arm for randomized subjects. 
The change from baseline (screening) to treatment week 24 visit in selected MBT result 
parameters (PDRpeak, cPDR30_min, PDR45_min) will be modeled and compared between the 
Conatus' IDN-6556-14 study arms with regression models. The models will include 
treatment arm and screening HVPG (as a continuous value). Adjusted means of the change 
in MBT parameters for each treatment arm will be extracted from the regression model and 
compared between the treatments arms. 
The Spearman's and Pearson’s correlation coefficient of the change from baseline 
(screening) to week 24 in MBT result parameters (Appendix A, item 7) with the change 
from baseline (screening) to treatment week 24 in HVPG (as a continuous variable) at 
baseline (screening) will be presented in a tabular form by Conatus' IDN-6556-14 study 
arm for randomized subjects along with their respective two-sided 95% CI’s. 
The changes from baseline (screening) to treatment week 48 of the MBT result parameters 
will be presented by descriptive statistic by Conatus' IDN-6556-14 study arm for 
randomized subjects. 
The change from baseline (screening) to treatment week 48 visit in selected MBT result 
parameters (PDRpeak, cPDR30_min, PDR45_min) will be modeled and compared between the 
Conatus' IDN-6556-14 study arms with regression models. The models will include 
treatment arm and baseline HVPG (as a continuous value). Adjusted means of the change 
in MBT parameters for each treatment arm will be extracted from the regression model and 
compared between the treatments arms. 
9.8.9 Timing of Analyses  
After the last subject has completed the screening visits and the BID-CSPH Algorithm has 
been locked including its respective cut-off, all data for all subjects across all screening 
visits will be cleaned, locked, and considered as the main analysis set for this validation 
study. This validation analysis will include all primary, secondary, and exploratory 
endpoint analyses that require only screening data (Validation Population). This analysis 
may be performed prior to or together with the assessment from treatment week 24. 
For the Conatus phase 2 study, after the last randomized subject has completed its 
treatment week 24 visit, all data for all subjects across all visits will be cleaned, locked, and 
considered as the main analysis for this study to assess treatment efficacy. This treatment 
week 24 analysis will include all primary, secondary, and exploratory endpoint analyses 
that require treatment week 24 data. Although Conatus will be unblinded for the treatment 


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week 24 analysis, the investigative sites will remain blinded throughout the study. The 
purpose of the treatment week 24 analysis is for Conatus’ internal decision making.  
The final analysis of the study (i.e., treatment week 48 analysis) will be conducted after all 
randomized subjects have completed all study visits up to and including the follow-up visit. 
All study data across all subjects and visits will be cleaned and locked for this final 
analysis. 
9.8.10 Pooling 
Poolability will be tested in the primary analysis at a significance level of 10%. 
Poolability across centers, for the two primary endpoints, will be assessed using Fisher’s 
exact test. The Cochran-Mantel-Haenszel odds ratio estimator or logistic regression will be 
used to adjust for site effects, as appropriate. Forest plots will be presented for further 
visual assessment.  
Centers with less than 10 subjects will be grouped together by geographical area (In US: 
West, Mid-West, North-East, South, and OUS: Spain and France together), a table of the 
sites and their location within the USA will be attached to the statistical report to justify the 
grouping. If found significant, the reason for the significance will be further explored and 
rationalized. This evaluation may include demographic features, symptoms at presentation, 
clinical and treatment history, and site comparability in the features found to be associated 
with the primary performance variables. In addition, detailed information about each site, 
including patient enrollment and performance data will be presented. 
Pooling analysis will be repeated with US centers combined, and Out of US (OUS) centers 
combined. 
9.8.11 Sub-Group Analyses 
Primary and secondary performance analyses will be performed on the following subsets: 
1. Subjects with biopsy proven NASH 
2. Subjects classified as compensated ACLD 
9.8.12 Handling of Missing Data 
The study variables cannot be evaluated for subjects for whom BreathID® MCS System 
MBT results are not available and therefore these subjects will be left out of the 
performance analysis. Subjects missing HVPG results will be excluded from the relevant 
analyses.  


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Measurements with unknown values or unavailable estimates will be treated as missing 
values and excluded from the analysis. No imputation for missing data is planned for the 
primary, secondary and exploratory endpoints. 
Missing data will be reported as such in the data listings. 
10 STUDY PROCEDURES 
10.1  General 
The schedule of the breath tests is based on the schedule of the IDN-6556-14 protocol. The 
first MBT will be performed during the screening period (week -6 to Day 0), usually before 
the HVPG. The second MBT will be performed at treatment week 24 and the third MBT at 
treatment week 48 (end of treatment).  
10.2 Breath Test Procedure 
Preparation of the study subject 
In preparation for each breath test the patient will be asked to comply with the following 
restrictions: 
1. Subject should be fasting, including all oral morning medications (except for 
betablockers and study drug [Emricasan or placebo] for randomized subjects), 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 consume any alcohol or caffeine within 24 hours prior to the test  
7. Subject should not have general anesthesia or sedation within 24 hours prior to the 
test 
8. Subjects on beta-blockers or statins should be on stable dose at least 30 days prior 
to the test 


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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. 
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. 


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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 another qualified medical staff 
member 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. 
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. In these 
cases, attempts will be made to reschedule a MBT at the earliest convenience and at least 
24 hours later. 
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. 


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11 ETHICS & REGULATORY CONSIDERATIONS 
The study will be conducted by Conatus as a Phase 2 study of Emricasan in both the US 
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. 
This companion protocol will obtain the applicable regulatory approvals for the use of 
clinical data from both regulatory authorities (if relevant) and ethics committees (IRBs). 
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, assessed and reported according to local regulations. 
Safety assessments of the Conatus study drug will be performed as described in Conatus 
protocol IDN-6556-14 (Appendix B) section 8.1 - 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-6556-14. 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 investigator 
prior to signing of the conduct. 
16 FINANCIAL ASPECTS  
The BreathID® MCS device and test kits 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. 


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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-6556-14. Conatus will be responsible for 
study termination procedures, when applicable. 
 
 


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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. Gluud C, Brok J, Gong Y, Koretz RL. Hepatology may have problems with putative 
surrogate outcome measures. J Hepatol 2007;46:734-742. 
4. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. 
Portal pressure, presence of gastroesophageal varices and variceal bleeding. 
Hepatology 1985;5:419-424. 
5. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything 
worth doing should be done right. Hepatology 2004;39:280-282. 
6. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of 
gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 
2007;46:922-938. 
7. Berzigotti A, Ashkenazi E, Reverter E, Abraldes JG, Bosch J. Non-invasive diagnostic 
and prognostic evaluation of liver cirrhosis and portal hypertension. Dis Markers 
2011;31:129-138. 
8. Garcia-Tsao G, Bosch J, Groszmann RJ. Portal hypertension and variceal bleeding--
unresolved issues. Summary of an American Association for the study of liver diseases 
and European Association for the study of the liver single-topic conference. Hepatology 
2008;47:1764-1772. 
9. Reuben A, Guggenheim G, Hershkowitz A, Ben Oren I, Ilan Y. Hepatic 13C-
Methacetin Metabolism, Measured Using Exalenz BreathID, Correlates Well with the 
Hepatic Venous Pressure Gradient (HVPG) in Patients with Cirrhosis. AASLD 
Abstract 1560. Hepatology 2012;56:922A. 
 
 
 


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CONFIDENTIAL AND PROPRIETARY 
APPENDIX A – METHACETIN BREATH TEST PARAMETERS 
 
The BreathID MCS System measures the change of the 13CO2/12CO2 ratio in exhaled breath 
following ingestion of 13C-Methacetin compared to the 13CO2/12CO2 ratio before ingestion. 
This measure is called 'Delta Over Baseline' (DOB) and is automatically measured every 
2-3 minutes, resulting in approximately 23 DOB's and corresponding time points over one 
hour.  Subjects visit height and weight as well as all available DOB measures with 
corresponding time point (T) will be retrieved from the completed eCRFs. 
1. DOB values must be sorted by time before any calculation, while a first pair of data 
points should always be added with time T0=0 min and DOB0 =0. 
2. The DOBs will 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 
The units of PDR is %/hour 
3. The maximum rate at which metabolism occurs results in a peak value of the breath 
test called DOBPeak and PDRPeak, respectively. Both occur at the same time, which 
is called the Peak time. 
a. DOBpeak: DOBpeak is defined as the maximum DOB. 
 
𝐷𝑂𝐵𝑝𝑒𝑎𝑘= max⁡(𝐷𝑂𝐵0, 𝐷𝑂𝐵1, 𝐷𝑂𝐵2, … , 𝐷𝑂𝐵24) 
b. PDRpeak: PDRpeak is defined as the maximum PDR. 
 
𝑃𝐷𝑅𝑝𝑒𝑎𝑘= max⁡(𝑃𝐷𝑅0, 𝑃𝐷𝑅1, 𝑃𝐷𝑅2, … , 𝑃𝐷𝑅24) 
4. The area under the DOB curve will be calculated for each time point. This area 
represents the cumulative DOB (cDOB) at any given time point.  
a. DOBx_min and cDOBx_min: The following steps will be followed to obtain 
the DOB and cDOB at 5 minutes intervals (e.g. 5, 10, 15,…,60 min), where 
'x' is 05, 10, 15, …, 60 respectively. For each 'x' the following steps shall be 
followed: 
 
b. Find 'a', the index for which: 
𝑇𝑎−1 < 𝑥⁡ ≤𝑇𝑎 


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c. Calculate DOBx_min using the following formula: 
𝐷𝑂𝐵𝑥_𝑚𝑖𝑛= 𝐷𝑂𝐵𝑎−1 + 𝐷𝑂𝐵𝑎−𝐷𝑂𝐵𝑎−1
𝑇𝑎−𝑇𝑎−1
∙(𝑥−𝑇𝑎−1) 
d. Calculate cDOBx_min using the following formula: 
𝑐𝐷𝑂𝐵𝑥_𝑚𝑖𝑛= ∑(
𝑇𝑖−𝑇𝑖−1
60
∙(𝐷𝑂𝐵𝑖+ 𝐷𝑂𝐵𝑖−1)
2
)
𝑎−1
𝑖=1
+
𝑥−𝑇𝑎−1
60
∙(𝐷𝑂𝐵𝑥_𝑚𝑖𝑛+ 𝐷𝑂𝐵𝑎−1)
2
 
MBT parameters results that do not have data points for at least 'x' 
minutes cannot be calculated 
5. The PDR as well as the area under the PDR curve will be calculated for each time 
point. This area represents the cumulative PDR (cPDR) at any given time point in 
units of %.  
a. PDRx_min and cPDRx_min: The following steps will be followed to obtain 
the PDR and cPDR at 5 minutes intervals (e.g. 5, 10, 15,…,60 min), where 
'x' is 05, 10, 15, …, 60 respectively. For each 'x' the following steps shall be 
followed: 
 
b. Find 'a', the index for which: 
𝑇𝑎−1 < 𝑥⁡ ≤𝑇𝑎 
c. Calculate PDRx_min using the following formula: 
𝑃𝐷𝑅𝑥_𝑚𝑖𝑛= 𝑃𝐷𝑅𝑎−1 + 𝑃𝐷𝑅𝑎−𝑃𝐷𝑅𝑎−1
𝑇𝑎−𝑇𝑎−1
∙(𝑥−𝑇𝑎−1) 
d. Calculate cPDRx_min using the following formula: 
𝑐𝑃𝐷𝑅𝑥_𝑚𝑖𝑛= ∑(
𝑇𝑖−𝑇𝑖−1
60
∙(𝑃𝐷𝑅𝑖+ 𝑃𝐷𝑅𝑖−1)
2
)
𝑎−1
𝑖=1
+
30 −𝑇𝑎−1
60
∙(𝑃𝐷𝑅𝑥_𝑚𝑖𝑛+ 𝑃𝐷𝑅𝑎−1)
2
 
MBT parameters results that do not have data points for at least 'n' 
minutes cannot be calculated 
6. The cDOB and cPDR at the peak time are called cDOBpeak and cPDRpeak, 
respectively. They are calculated as described in steps 4 and 5, respectively, while 
'x' is the actual time 'T' of the observed peak value. The cPDRpeak divided by Peak 
time is named cPDRpeak_div_Peaktime. 
7. The following list of MBT result parameters will thus be used in the statistical 
analysis: DOBpeak, cDOBpeak, PDRpeak, cPDRpeak, cPDRpeak_div_Peaktime, Time to 
Peak, DOB5_min, DOB10_min, DOB15_min, DOB20_min, DOB25_min, DOB30_min, 


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DOB35_min, DOB40_min, DOB45_min, DOB50_min, DOB55_min, DOB60_min, cDOB5_min, 
cDOB10_min, cDOB15_min, cDOB20_min, cDOB25_min, cDOB30_min, cDOB35_min, 
cDOB40_min, cDOB45_min, cDOB50_min, cDOB55_min, cDOB60_min, PDR5_min, 
PDR10_min, PDR15_min, PDR20_min, PDR25_min, PDR30_min, PDR35_min, PDR40_min, 
PDR45_min, PDR50_min, PDR55_min, PDR60_min, cPDR5_min, cPDR10_min, cPDR15_min, 
cPDR20_min, cPDR25_min, cPDR30_min, cPDR35_min, cPDR40_min, cPDR45_min, 
cPDR50_min, cPDR55_min, cPDR60_min. 
8. Additional breath test result parameters will be extracted based on the features 
developed under the Exalenz algorithm training study CSPH-EX-0414, IDE# 
G140190 and Companion Protocol to Galectin's study GT26 (GT-EX-0215), 
conducted in collaboration with Galectin Therapeutics Inc. under their IND 115459 
and Exalenz' IDE G150125. 
 
 


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APPENDIX B – CONATUS PROTOCOL IDN-6556-14 
 
Protocol Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of 
Emricasan, an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis 
(NASH) Cirrhosis and Severe Portal Hypertension 
 
Protocol Number: IDN-6556-14 
 
Protocol Version: Version 9.0 (14 March 2018)