Clinical Study of the BreathID® System to Train the Algorithm for the ¹³C-Octanoate Breath Test With or Without the ¹³C-Methacetin Breath Test (OBT and MBT Respectively) for Correlation With Histological Findings Associated With Non-Alcoholic Steatohepatitis (NASH) and Other Liver Diseases
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis
Sponsor: Meridian Bioscience, Inc.

Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
 
 
Clinical Study of the BreathID® System to train the 
algorithm for the ¹³C-Octanoate Breath Test with or 
without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
  
Protocol No. NASH-EX-1114 
 
Document No:CSD00080 
Total pages: 61 
Version Level: 1f 
Last update on: May 1, 2016 
 
 
Name 
Position 
Author / 
Owner 
Avraham Hershkowitz 
Clinical Trial Manager 
Supervisor / 
Revised by 
Gil Guggenheim 
Clinical Application Development 
Specialist and Database Manager 
Approved by 
Melina Arazy, M.D. 
VP of Clinical Affairs 
Electronic signatures and approvals, effective information and Lifecycle Status can be obtained by accessing 
the system generated approval page associated with this document.  The system generated approval page can 
be retrieved from the PDM system. 
This publication, in whole or in part, may not be reproduced, disclosed, translated into any language or 
computer language or distributed without the prior written consent of: 
Exalenz Bioscience Ltd. 4 Ha’Maayan St. Modiin, Israel 7177872  
Versions Control: 
Version 
Date 
Responsible Person 
Description of Change 
1 
22DEC2014 
Dan Peres 
Initial Release 
1a 
06 JAN2015 
Avraham Hershkowitz 
Minor revisions for clarity and defining 
monitoring plan 
1b 
28 JAN 2015 
Avraham Hershkowitz 
Changes due to FDA comments  
1c 
11 FEB 2015 
Avraham Hershkowitz 
Removal of LAR as option, 3 yr 
surveillance 
1d 
10 MAY 2015 
Avraham Hershkowitz 
Addition of paracetamol exclusion 
1e 
25 OCT 2015 
Avraham Hershkowitz 
Removal of contraceptive from exclusion 
criteria 
1f 
1 MAY 2016 
Avraham Hershkowitz 
Allowing biopsy after BT  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 2 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
 
1 TABLE OF CONTENTS 
 
1 Table of Contents ................................................................................................................. 2 
2 Abbreviations ........................................................................................................................ 6 
3 Protocol Synopsis ................................................................................................................. 9 
4 Visit Schedule Overview .................................................................................................... 15 
5 Background ......................................................................................................................... 16 
5.1 
Non-Alcoholic Fatty Liver Disease - NAFLD ............................................................................. 16 
5.1.1 
Pathogenesis of NAFLD ................................................................................................................ 17 
5.1.2 
The importance of diagnosing and characterizing NASH ............................................................. 17 
5.1.3 
Defining the need for a non-invasive test for the diagnosis and characterization of 
NASH and other liver conditions .................................................................................................................. 18 
5.2 
13C-Breath Tests ........................................................................................................................... 18 
5.2.1 
The BreathID System .................................................................................................................... 19 
5.2.2 
13C-Octanoate (Sodium Octanoate) Breath Test (OBT) ................................................................ 19 
5.2.3 
13C-Methacetin Breath Test (MBT) Overview .............................................................................. 21 
5.2.4 
Breath Test Components................................................................................................................ 24 
6 Intended Use / Indication for Use ..................................................................................... 24 
7 Proposed Clinical Algorithm using the OBT±MBT±Clinical / laboratory 
parameters .......................................................................................................................... 24 
8 Study Design ....................................................................................................................... 25 
9 Study Objectives ................................................................................................................. 25 
9.1 
Efficacy Objective ........................................................................................................................ 25 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 3 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
9.2 
Safety Objective ........................................................................................................................... 25 
9.3 
Secondary Objectives ................................................................................................................... 25 
9.4 
Efficacy Endpoints ....................................................................................................................... 26 
9.4.1 
Primary efficacy endpoint .............................................................................................................. 26 
9.4.2 
Secondary efficacy endpoint .......................................................................................................... 26 
9.5 
Safety Endpoints .......................................................................................................................... 26 
10 Subject Selection ................................................................................................................. 26 
10.1 Inclusion Criteria .......................................................................................................................... 27 
10.2 Exclusion Criteria: ....................................................................................................................... 27 
10.3 On the day of the OBT: ................................................................................................................ 29 
10.4 On the day of the MBT: ............................................................................................................... 29 
10.5 Consenting ................................................................................................................................... 29 
10.6 Safety Termination of Subjects or Study ..................................................................................... 30 
10.7 Early Withdrawal from the Study ................................................................................................ 30 
10.8 Expected Duration of Recruitment ............................................................................................... 30 
11 Statistical Considerations .................................................................................................. 31 
11.1 Study Design and Objectives ....................................................................................................... 31 
11.2 Primary endpoints ........................................................................................................................ 31 
11.3 Secondary efficacy endpoint ........................................................................................................ 31 
11.4 Safety Endpoints .......................................................................................................................... 31 
11.5 Sample Size estimation ................................................................................................................ 32 
11.6 Analysis sets ................................................................................................................................. 32 
11.7 Statistical Analysis ....................................................................................................................... 32 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 4 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
11.7.1 
General Considerations .................................................................................................................. 32 
11.7.2 
Demographic and Other Baseline Characteristics ......................................................................... 33 
11.7.3 
Disposition of Subjects .................................................................................................................. 33 
11.7.4 
Safety Analysis .............................................................................................................................. 33 
11.7.5 
Performance Analysis .................................................................................................................... 33 
11.7.6 
Interim Analysis ............................................................................................................................ 33 
11.7.7 
Pooling ........................................................................................................................................... 34 
11.7.8 
Handling of Missing Data .............................................................................................................. 34 
12 Study Procedures ............................................................................................................... 35 
12.1 General ......................................................................................................................................... 35 
12.2 Visit 1: Screening / enrollment..................................................................................................... 36 
12.3 Visit 2: 13C-Octanoate Breath Test (OBT) ................................................................................... 36 
12.4 Visit 3: 13C-Methacetin Breath Test (MBT) ................................................................................. 39 
12.5 Visit 4: 48 safety hours phone call ............................................................................................... 40 
12.6 Visit 5: Clinical Follow-Up 18 Months........................................................................................ 40 
12.7 Visit 6: Clinical Follow-Up 36 Months........................................................................................ 41 
13 Ethics & Regulatory Considerations ................................................................................ 41 
13.1 Ethics & Regulatory Approvals ................................................................................................... 41 
14 Investigator Responsibilities ............................................................................................. 42 
14.1 Investigational Product Handling ................................................................................................. 42 
14.2 Investigational Product Accountability ........................................................................................ 43 
15 Safety Considerations ........................................................................................................ 43 
15.1 Adverse Event Definitions ........................................................................................................... 43 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 5 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
15.2 Serious Adverse Event (SAE) and Suspected Unexpected Serious Adverse Reactions 
(SUSAR) ...................................................................................................................................... 43 
15.3 Relationship to Study medical device .......................................................................................... 44 
15.4 Adverse Event Severity ................................................................................................................ 45 
15.5 Adverse Event Reporting ............................................................................................................. 46 
15.6 Study-Specific Exceptions ........................................................................................................... 46 
16 Access to Source Data and Documents ............................................................................. 47 
16.1 Availability of Source Data and Documents ................................................................................ 47 
16.2 Patient Confidentiality ................................................................................................................. 47 
17 Monitoring and Quality Assurance .................................................................................. 47 
17.1 Data Collection and Monitoring ................................................................................................... 48 
18 Publication Policy and Finance ......................................................................................... 48 
19 Financial Aspects ................................................................................................................ 48 
20 Study termination ............................................................................................................... 48 
21 References ........................................................................................................................... 49 
Appendix I - Protocol Approval Signature Page ................................................................. 58 
Appendix II - Histopathological reading of Liver Biopsy Specimen .................................. 59 
 
 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 6 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
2 ABBREVIATIONS 
 
AE 
- Adverse Event 
ALT 
- Alanine Aminotransferase 
APAP 
- n-acetyl-p-aminophenol (acetaminophen) 
AST 
- Aspartate Aminotransferase 
AUC 
- Area Under the Curve 
BMI 
- Body Mass Index 
BUN 
- Blood Urea Nitrogen 
CFR 
- Code of Federal Regulation 
CK18 
- Cytokeratin 18 
CO2 
- Carbon dioxide 
CoA 
- Coenzyme A 
CRF 
- Case Report Form 
CRP 
- C-Reactive Protein 
CT 
- Computed Tomography 
CTCAE 
- Common Terminology Criteria for Adverse Events 
EC 
- Ethics Committee 
eCRF 
- Electronic Case Report Form 
EDC 
- Electronic Data Capture 
EU 
- European Union 
FDA 
- Food and Drug Administration 
GCP 
- Good Clinical Practice 
GI 
- Gastrointestinal 
GGTP 
- Gamma-Glutamyl Transpeptidase 
GRAS 
- Generally Recognized As Safe 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 7 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
HbA1c 
- Hemoglobin A1c 
HCC 
- Hepatocellular Carcinoma 
HCO3 
- Bicarbonate 
HCV 
- Hepatitis C Virus 
HE 
- Hepatic Encephalopathy 
HVPG 
- Hepatic Venous Pressure Gradient 
IC 
- Informed Consent 
ICF 
- Informed Consent Form 
ICH 
-  International Conference of Harmonization 
IDE 
- Investigational Device Exemption 
IL6 
- Interleukin 6 
INR 
- International Normalized Ratio (for prothrombin time) 
IRB 
- Institutional Review Board 
K+ 
- Potassium 
MBT 
- 
13C-Methacetin Breath Test 
MCS 
- Molecular Correlation Spectrometry  
MELD 
- Model for End-stage Liver Disease 
MRI 
- Magnetic Resonance Imaging 
Na+ 
- Sodium 
NAFLD 
- Non-Alcoholic Fatty Liver Disease 
NAS 
- NASH Activity Score 
NASH  
- Non-Alcoholic Steato-Hepatitis 
NASH CRN 
- NIH NASH Clinical Research Network 
NIH 
- National Institute of Health 
NPV 
- Negative Predictive Value 
NSBB 
- Non-Selective Beta Blocker 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 8 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
OUS 
- Out of the United States 
O2 
- Oxygen 
OBT 
-  13C-Octanoate Breath Test 
PHT 
- Portal Hypertension 
PPV 
- Positive Predictive Value 
PT 
- Prothrombin Time 
PTT 
- Partial Thromboplastin Time 
ROC 
- Receiver Operating Characteristic 
SAE 
- Serious Adverse Event 
SUSAR 
- Suspected Unexpected Serious Adverse Reactions 
TNFα  
- Tumor Necrosis Factor Alpha 
TIPS 
- Transjugular Intrahepatic Portosystemic Shunt 
US 
- United States (of America) 
US 
- Ultrasound 
USA 
- United States of America 
WBC 
- White Blood Cells 
 
 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 9 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
3 PROTOCOL SYNOPSIS 
 
Protocol Title: 
Clinical Study of the BreathID® System to train the algorithm for 
the ¹³C-Octanoate Breath Test with or without the ¹³C-Methacetin 
Breath Test (OBT and MBT respectively) for correlation with 
histological findings of Non-Alcoholic Fatty Liver Disease 
(NAFLD) 
Protocol Number: 
NASH-EX-1114 
Version and Date: 
v 1f, May1, 2016 
 
Investigational subject: 
Biopsy characteristics of patients suspected of Non-Alcoholic 
Fatty Liver Disease (NAFLD) 
 
 
Investigational Product 
BreathID® System together with ¹³C-labeled Octanoate and ¹³C-
labeled Methacetin  
 
Primary Objective: 
The primary objective of the study is to develop an algorithm 
based on OBT with or without MBT with or without additional 
clinical and/or laboratory parameters, and its cut-off to correlate 
with histological findings of NAFLD. 
Primary Endpoint: 
Correlation of histological findings, as assessed by a central 
reader, of NAFLD compared to 13C-Octanoate Breath Test with 
or without 13C-Methactin Breath Test with or without additional 
clinical and/or laboratory parameters 
Secondary Endpoint: 
Correlation between OBT±MBT and clinical course (i.e. 
clinical outcome: liver decompensation events etc.) at 18 and 
36 months post the last breath test performed (visit / phone). 
NOTE: Patients undergoing intervention for NASH / NAFLD, 
including both approved and experimental approaches prior to 
the defined time points will be terminated hence will not be 
evaluated for this endpoint. 
Safety Endpoints: 
Safety will be assessed by reviewing all adverse and serious 
adverse events occurring in all subjects enrolled from the time of 
enrollment until the subject completes the protocol.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 10 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
Any AEs reported that are possibly or probably related to the use 
of the product or related to the procedure within 36 months post 
last breath test performed or until subject termination will be 
followed until resolution and if laboratory work is done 
secondary to AEs and found abnormal, these tests will be 
followed until normalization or stabilization. 
Study Design:  
A multicenter, non-randomized, open label, cross-sectional 
comparative exploratory study comparing OBT with or without 
MBT values to histology. 
This study will be used to train an algorithm using OBT with or 
without MBT with or without clinical and/or laboratory 
parameters correlating with histological findings of NAFLD. 
Study Population:  
At least 200 consecutive patients suspected of having NAFLD 
with a fresh liver biopsy (within 6 months before or 1 month 
after) indicated to rule-out / confirm NAFLD, meeting all 
inclusion/exclusion criteria will be enrolled.  
Inclusion Criteria:  
 
1. 
Adult men or women (≥18 years of age) 
2. 
Liver 
biopsy 
performed 
indicating 
NAFLD/NASH 
performed within 6 months prior to both breath-tests 
NOTE: The samples must meet pre-defined quality criteria. 
(See Appendix II for biopsy quality requirements)  
OR: 
Undergoing 
Liver 
biopsy 
to 
rule-out 
or 
confirm 
NAFLD/NASH. 
3. 
No other known co-existent liver disease, excluded by 
appropriate serologic / other testing 
4. 
Patient able and willing to sign an Informed Consent Form 
5. 
Can tolerate an overnight (8-hour) fast  
 
Exclusion Criteria:  
1. 
Positive studies for any of the following within three years 
prior to biopsy 
a. Anti HCV positive 
b. HBsAg positive 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 11 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
c. Iron saturation > 60% + gene test for hereditary 
hemochromatosis or iron overload as defined by presence 
of 3+ or 4+ stainable iron on liver biopsy 
d. Antinuclear antibody at a titer > 1: 160 along with  
hypergammaglobulinemia  and 5 times ALT normal 
levels  
e. Alpha-1-antitrypsin level below lower limit of normal (< 
150 mg/dl) or no PAS diastase resistant globules on 
biopsy.  
f. Primary biliary cirrhosis as defined by elevation of 
alkaline phosphatase greater than upper limit of normal 
and anti-mitochondrial antibody (AMA) of greater than 
1:80 and consistent liver histology 
g. Low level of ceruloplasmin (< 10 ng/mL) 
h. Drug-induced liver disease as defined on the basis of 
typical exposure and history 
Note: These studies do not need to be performed if they 
are not available, as it is assumed that if they are not on 
file, the condition does not exist 
2. 
Patients known to have chronic liver disease other than 
NAFLD as routinely diagnosed by the investigator   
3. 
Concurrent acute hepatic condition other than NAFLD 
4. 
Alcohol consumption > 20 gm/day (0.71 oz./day) for women 
and > 30 gm/day (1.06 oz./day) for men 
5. 
Drugs that may interfere with octanoate metabolism or can 
also cause NAFLD independent of the metabolic syndrome, 
including: corticosteroids, amiodarone, tetracycline, valproic 
acid, methotrexate, stavudine, zidovudine  
6. 
When MBT is performed subject should not have taken any 
of the following at least 48 hours prior to the breath 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 
CYP 1A2 
7. 
Patients that have had more than 10% weight change 
between biopsy and enrollment. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 12 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
8. 
Hypersensitivity to any of the study substrates: Octanoate or 
Methacetin 
and 
their 
metabolites, 
i.e. 
paracetamol, 
acetaminophen. 
9. 
Known extra-hepatic diseases including but not limited to: 
severe congestive heart failure (NIHA>2), known severe 
pulmonary hypertension (>35 mmHg), history of chronic 
obstructive pulmonary disease or uncontrolled symptomatic 
bronchial 
asthma 
or 
uncontrolled 
diabetes 
mellitus 
(HA1c>9.5%) 
10. 
Previous surgical GI bypass surgery  
11. 
Extensive small bowel resection (>100 cm) 
12. 
Known uncontrolled malabsorption or diarrhea  
13. 
Concurrent total parenteral nutrition 
14. 
Any organ transplant 
15. 
Patients receiving any anti-viral treatment or any other liver 
directed therapy, procedure or surgery between the time of 
the biopsy and the breath test 
16. 
Pregnant or breast feeding 
17. 
Patients unable or refusing to sign informed consent 
18. 
Patients that, based on the opinion of the investigator, should 
not be enrolled into this study due to safety / adherence 
reasons. 
19. 
Patients participating in other clinical trials and already 
receiving experimental treatments or procedures  
20. 
Patients with suspected or documented hepatocellular 
carcinoma by ultra-sound or other imaging modality  
21. 
Patients diagnosed with partial / complete portal venous 
occlusion, hepatic venous occlusion, previous PHT surgery, 
or placement of a transjugular intrahepatic portosystemic 
shunt (TIPS) according to initial imaging studies. 
 
On the day of the OBT/MBT: 
1. 
8 hours fasting prior to OBT/MBT including all PO morning 
medications except for beta blockers. Diabetic patients that 
are driving should test their blood sugars to rule out 
hypoglycemia and respond accordingly.  
2. 
No Smoking on the day of the MBT 
3. 
No paracetamol (acetaminophen) based medications within 
24 hours prior to MBT 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 13 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
4. 
No general anesthesia or sedation within 24 hours prior to 
OBT/MBT 
5. 
No alcohol within 24 hours prior to OBT/MBT  
6. 
Patient should be symptom free of any prior intervention 
(e.g. biopsy) 
 
Listing of Study Procedures:  
1. 
Informed consenting and eligibility including fresh liver biopsy 
confirmed to meet quality standards (see Appendix II) 
2. 
Baseline and Physical Examination 
3. 
Blood drawing  for: 
a. 
Insulin and Glucose 
b. 
Complete Blood count (WBC, Hemoglobin, Platelets) 
and CRP 
c. 
Coagulation: PT (INR) 
d. 
Renal panel and electrolyte panel (BUN, creatinine, 
electrolytes (Na+ and K+),  
e. 
Collection of 4ml of blood for serum and freezing for 
storage (no preservative tube) where possible. 
f. 
Hepatic panel (AST, ALT, alkaline phosphatase, 
GGTP, total bilirubin, direct bilirubin, serum albumin 
and total protein) - if not available from within 3 
months 
g. 
Additional Coagulation Panel (PTT, fibrinogen) - if 
not available from within 3 months 
h. 
Total calcium, PO4 (phosphate corrected), magnesium 
- if not available from within 6 months 
i. 
Lipid profile and HbA1c - if not available within 6 
months 
j. 
Thyroid Panel - if not available within 12 months 
k. 
Other assays where routinely practiced; (optional): 
Adiponectin + Leptin + IL6 + CK18, TNFα, C-
peptide  
4. 
OBT - ¹³C-Octanoate Breath Test (within 6 months of liver biopsy or within 
1 month before liver biopsy) and ensuring MBT is feasible within 30 days 
but not less than 48 hours). If done on same day, OBT must be performed 
before the biopsy. 
5. 
MBT - ¹³C-Methacetin Breath Test (within 30 days post OBT but not less 
than 48 hours). If done on the same day as the liver biopsy, the MBT must be 
performed before the biopsy. 
6. 
Safety monitoring phone call 48 hours post last breath test. Any AEs reported 
that are possibly or probably related to the use of the product or related to the 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 14 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
procedure will be followed until resolution and if laboratory work is done 
secondary to AEs and found abnormal, these tests will be followed until 
normalization or stabilization. 
7. 
Follow-up Visit 18 months post last breath test performed: clinical evaluation 
(in person or telephone) 
8. 
Follow-up Visit 36 months post last breath test performed: clinical evaluation 
(in person or telephone) 
9. 
Any AEs reported that are possibly or probably related to the use of the 
product or related to the procedure within 36 months post last breath test 
performed or until subject termination will be followed until resolution  and 
if laboratory work is done secondary to AEs and found abnormal, these tests 
will be followed until normalization or stabilization. 
 
Rules of discontinuations (Subject and/or Study): 
1. 
Withdrawal of patients from the study if they have a CTCAE  
(Common Terminology Criteria for Adverse Events) Grade 
3 or higher regardless of whether the event is attributed to 
the drug unless it is caused by an accident that could not 
reasonably be attributable to the drug (CTCAE: Common 
Terminology Criteria for Adverse Events Version 4.0) 
2. 
Discontinuance 
of 
study, 
if 
≥ 
2 
patients 
on 
Octanoate/Methacetin develop the same CTCAE Grade 3 
event or 1 patient develops a CTCAE Grade 4 or higher 
event due to one of the breath tests 
 
Data Analysis / Statistics: 
An ROC analysis will be used to determine the optimal 
parameter and cut-offs for required performance measures 
sensitivity and specificity. 
 
 
 
All efficacy analysis will include the point estimates of 
sensitivity, specificity, PPV and NPV with respective exact 95% 
confidence intervals. The respective Positive and Negative 
Predictive Values (PPV and NPV) will be presented as a 
function of possible NAFLD prevalence and will include the 
prevalence of the enrolled population. 
This test will not replace biopsies to rule out other liver diseases such as autoimmune hepatitis, 
alcoholic hepatitis, alpha-1-antitrypsin deficiency, etc. 
 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 15 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
4 VISIT SCHEDULE OVERVIEW 
 
Screening
 
•Informed Consent 
•Inclusion/exclusion criteria; fresh biopsy sample available (within 6 months)  
•Biopsy evaluated for quality 
•Safety urine sample (pregnancy test) * 
•Medical/disease history 
•Concomitant medications 
visit 1  
Octanoate 
BT 
•Within 6 months after or within 1 month before liver biopsy and ensuring MBT is feasible 
within 30 days but not less than 48 hours (if done on same day as liver biopsy, OBT precedes) 
•Physical examination and vital signs 
•Blood sampling within 1 hour prior to OBT 
•Serum storage  
•13C- Octanoate breath test 
•Concomitant medications  
•Adverse event reporting 
visit 2 
Methacetin 
BT 
•Within 30 days but not less than 48 hours following OBT(if done on same day as liver biopsy, 
OBT precedes) 
•13C- Methacetin breath test 
•Concomitant medications  
•Adverse event reporting 
Safety Call
 
•48 hours post last breath test 
•Safety phone call 
NOTE: All subjects with AEs possibly or possibly related to the drug or procedure will be 
followed to resolution. If laboratory work is done secondary to AEs and found abnormal, these 
tests will be followed until normalization or stabilization. 
Follow Up
 
18 Months
 
•In person or by telephone 
•Clinical follow up (only subjects not treated up to time of study visit) 
Follow Up
 
36 Months
 
•In person or by telephone 
•Clinical follow up (only subjects not treated up to time of study visit) 
•Record review  
•All subjects with AEs within 36 months of OBTor until termination, possibly or possibly related to the 
drug or procedure will be recorded and followed to resolution. If laboratory work is done secondary to 
AEs and found abnormal, these tests will be followed until normalization or stabilization. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 16 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
5 BACKGROUND 
Liver diseases can be caused by a variety of etiologies such as viral infection, metabolic 
diseases, alcohol abuse and autoimmune disorders. Liver disease can be acute or develop 
into chronic conditions. The conditions may vary from subtle disease to life threatening 
episodes, and/or may appear as mild inflammation up to significant inflammation leading 
to fibrosis, resulting in cirrhosis.  Chronic liver disease and cirrhosis are currently the 
12th leading cause of death, accounting for approximately 27,000 deaths annually (in the 
United States), increasing in numbers due to HCV, obesity and metabolic syndrome 
epidemic(1). 
Standard biochemical and clinical tests are not capable of providing good correlation with 
disease staging and grading. 
The unmet clinical need for a non-invasive means to evaluate liver fibrosis can be clearly 
reflected from the recently published NIH action plan for improving liver disease 
management. It positions this challenge second to improving HCV eradication rates. 
The concept of a metabolic test, which 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, the compound is taken up by 
the liver and 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 pathway. Several compounds have been utilized to evaluate 
hepatic metabolic function in this manner, including indocyanine green, galactose, 
aminopyrine, caffeine, lidocaine, phenylalanine, Methacetin and Octanoate [N-(4-
Methoxy-phenyl) acetamide] and sodium-octanoate. For example, previous studies have 
demonstrated hepatic metabolism of lidocaine to monoethylglycinexylidide (MEGX) 
declines in association with liver fibrosis and cirrhosis and improves with successful 
treatment of the underlying liver disease. Furthermore, these studies showed the lidocaine 
test to accurately predict which patients with stable cirrhosis awaiting liver 
transplantation were at risk to develop future hepatic decompensation. Most of these 
methods have been abandoned due to impracticality or undesired side effects. 
5.1 Non-Alcoholic Fatty Liver Disease - NAFLD 
Nonalcoholic fatty liver disease (NAFLD) is defined by the presence of predominantly 
macrovesicular hepatic steatosis or steatohepatitis in individuals who either do not 
consume any alcohol or consume alcohol in quantities that are not generally considered 
to be harmful to the liver(1). The histologic spectrum of NAFLD includes: 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 17 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
(1) Isolated hepatic steatosis: characterized by a fatty liver and no other histologic 
abnormalities. It is also referred to as nonalcoholic fatty liver (NAFL). 
(2) Steatohepatitis: characterized by steatosis along with varying combinations of 
histologic findings, including: cytologic ballooning, Mallory’s hyaline, and 
inflammation and pericellular fibrosis. The minimal histologic criteria for the 
diagnosis of non-alcoholic steatohepatitis (NASH) is the presence of steatosis, 
inflammation and cytologic ballooning(2). Given the variable presence of these 
individual parameters, the presence of steatohepatitis is often made as an overall 
gestalt of these histologic findings. The NASH activity score (NAS) was developed 
by the NIH NASH Clinical Research Network (NASH CRN). It is based on 
individual scores for steatosis, inflammation and cytologic ballooning which have 
been validated(2). Steatohepatitis is diagnosed when the NAS is 5 or higher.  
5.1.1 Pathogenesis of NAFLD  
NAFLD is considered the hepatic manifestation of the metabolic syndrome. The 
major risk factors associated with NAFLD are obesity, diabetes, hypertension and 
hypertriglyceridemia. Hepatic steatosis results from insulin resistance, which is the 
main pathophysiologic abnormality in the metabolic syndrome. The development of 
steatohepatitis requires both accumulation of fat and additional injurious processes in 
the liver which produce the steatohepatitis. It is believed that oxidative stress plays an 
important role in this process. The probability of having NAFLD rises with increasing 
body mass index (BMI) with over 80% of subjects with a BMI > 35 having NAFLD.  
5.1.2 The importance of diagnosing and characterizing NASH  
The public health priority of any disease is based on three considerations: (1) 
prevalence, (2) impact of disease on the affected individuals and (3) availability of 
effective therapy. 
Since the gold-standard for diagnosis of NASH and other liver diseases is a liver 
biopsy, hospital-based studies with liver biopsies are subject to ascertainment bias. 
Population based studies have utilized imaging modalities such as ultrasound and 
MRI to diagnose NAFLD but are limited by the absence of histologic confirmation. 
Recently, specific changes on MRI have been correlated with hepatic lipid content 
and presence of NAFLD may be diagnosed with relative confidence. Based on MRI, 
it has been estimated that the overall prevalence of NAFLD in the United States is 
about 30%(3). MRI does not distinguish between NAFL and NASH(4). Approximately 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 18 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
4-5% of the US population is estimated to have NASH. NAFL is associated with a 
benign clinical course and the majority of cases of NAFL remain asymptomatic and 
free of fibrosis or development of steatohepatitis over a 5-10 year time frame from 
diagnosis(5). On the other hand, NASH can progress to cirrhosis in about 20% of the 
cases(6). 
About 15% of cases referred for liver transplant have either NASH or cryptogenic 
cirrhosis, which is believed to be the end result of NASH(7).  
5.1.3 Defining the need for a non-invasive test for the diagnosis and 
characterization of NASH and other liver conditions 
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(8). 
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%. However, there are no noninvasive ways to distinguish 
between NAFL and NASH. Moreover, NASH would progress to cirrhosis in 
approximately 20% of the cases(6) hence requires disease surveillance.. 
Currently, such patients are offered a liver biopsy as standard of care to diagnose 
NAFLD and assess the risk of potential cirrhosis.  This is the population to be 
studied using the 13C-Octanoate Breath Test with or without 13C-Methacetin Breath 
Test in an attempt to find a noninvasive tool to discriminate various histological 
findings of NAFLD, in order to distinguish between high versus low risk for 
deterioration and avoid unnecessary biopsies (rule-out) and eventually replacing the 
need for biopsy in the diagnosis of NASH. It is important to note that a liver biopsy 
is invasive, can be painful and carries a small but definite risk of hemorrhage and 
even death amongst other complications. Also, given the sheer numbers of subjects 
with NAFLD in the world, it is not logistically feasible to biopsy all subjects with 
NAFLD, thus there is a great need for a simple non-invasive method to diagnosis 
NASH in large populations. 
5.2 
13C-Breath Tests 
Breath testing using 13C-labeled substrates provides a safe, non-invasive means for 
evaluating organ function. The concept of 13C-breath testing is the administration of a 
specific 13C-labeled substrate known to undergo degradation through a specific metabolic 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 19 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
path through which 13CO2 is produced. The monitoring of the 13CO2 levels within the 
patient's exhaled breath is presumed to quantify the metabolic rate of the investigated 
metabolic path. When targeting a major metabolic path; e.g. the p450 cytochrome system 
within the liver, the test should supply a good estimate of the target organ function, and a 
decrease in function could be interpreted as impairment associated with disease. Other 
targeted metabolic pathways might be used for diagnosis when they are presumed to be 
defective in certain disease states (e.g. mitochondrial beta-oxidation in NASH). 13C is a 
stable, non-radioactive isotope, which can be incorporated into a specific location within 
a test substrate in order for it to be metabolized into 13CO2. Ideally, the 13C-compound 
should be administered orally and rapidly absorbed and exclusively metabolized by the 
targeted metabolic path.  
5.2.1 The BreathID System 
The BreathID® System consisting of the BreathID® device and a test kit containing a 
breath collection cannula and a non-radioactive isotope 13C-labeled substrate. It measures 
and computes the ratio between 13CO2 and 12CO2 in the patient’s exhaled breath. 
For more details please refer to the study's Investigator Brochure.  
The device is based on a CE marked and FDA cleared device (510k#: K130524) for 
assessment of H. pylori infection in the stomach utilizing 13C-Urea as a substrate to 
assess the bacterial urease activity. Performance and safety of the original BreathID 
(510k# K011668) device utilizing multiple 13C- substrates (including 13C-Methacetin and 
13C-Octanoate) for assessment of liver function, have been studied in thousands of 
patients worldwide, including in a large US pivotal study – under IDE G080107 – of over 
400 patients with chronic liver disease from 11 participating sites (including 141 patients 
with biopsy proven cirrhosis),(9) which validated the safety of the device using 13C-
labeled Methacetin. 
5.2.2 13C-Octanoate (Sodium Octanoate) Breath Test (OBT) 
The sodium octanoate is metabolized through mitochondrial (beta-oxidation) in the 
liver and in other organ / tissues.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 20 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
C8H15NaO2 
 
CAS# 1984-06-1, EC# 217-850-1, MW=166.2 amu 
Synonyms: Caprylic acid sodium salt, sodium caprylate, octanoic acid sodium, salt, 
sodium n-Octanoate. 
Octanoate is the salt form of octanoic (caprylic) acid (highly solubile in water: 50mg/ml), 
a medium chain fatty acid, possessing the physical and chemical properties making it a 
good candidate to assess hepatic mitochondrial beta-oxidation; Octanoate is absorbed 
promptly from the intestinal lumen and transported rapidly to the liver through the portal 
venous system, enters the hepatic mitochondria independently of the carnitine transport 
system and undergoes hepatic mitochondrial beta-oxidation which produces acetyl 
coenzyme A (CoA). Finally, acetyl CoA enters the Krebs cycle and is oxidized by carbon 
dioxide (CO2) which in-turn is exhaled. Non-Alcoholic Fatty Liver Disease (NAFLD) is 
associated with changes in beta-oxidation, hence targeting this metabolic pathway might 
reflect the extent of the disease.  
The current recommended dose (for an adult) used in the OBT, is 100mg(10).  
5.2.2.1 13C-Octanoate Safety 
During the past 20 years Octanoate has been used mainly to assess gastric motility and 
liver health function. No complications were reported by leading researchers throughout 
the globe (US, Europe and Japan) (11-16). 
Moreover, this material is used in vitamins and food supplements such as Caprylate, 
butter and malted barley1, all in higher doses than proposed under current protocol2. 
Furthermore, Octanoate (Caprylic Acid) is listed at the FDA as a Generally Recognized 
As Safe (GRAS) substance since 19743. 
For more information please refer to the investigator brochure.  
                                                     
1 http://www.opsi.gov.uk/SI/si1989/Uksi_19890945_en_3.htm  
2 http://www.vitaminshoppe.com/store/en/browse/sku_detail.jsp?id=AM-1098#prodInfo  
3 http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm261239.htm  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 21 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
5.2.2.2 Rationale for use: ¹³C-Octanaote Breath Test 
It has been previously suggested NAFLD is associated with changes in fatty acid β-
oxidation which might be demonstrated in 13CO2 production in NASH compared to 
NAFL or normal controls(17). It was therefore hypothesized that by evaluating the area 
under the curve, peak value and time to peak for 13CO2 after ingestion of labeled 13C-
Octanoate, a nontoxic medium chain fatty acid which is oxidized in the mitochondrial 
rather than the peroxisomes, can distinguish those with NAFL vs. NASH. The advantages 
of this test are that: (1) octanoate is nontoxic, (2) the small liquid dose is not affected 
substantially by gastric emptying, (3) 13C is a stable isotope and avoid radioactivity, (4) 
13CO2 can be measured easily and accurately and (5) this test can be performed in the 
office environment providing immediate results.  
This test will not replace biopsies to rule out other liver diseases such as autoimmune 
hepatitis, alcoholic hepatitis, alpha-1-antitrypsin deficiency, etc. 
For more details please refer to the study's Investigator Brochure.  
5.2.3  
13C-Methacetin Breath Test (MBT) Overview 
5.2.3.1 
13C-labelled Substrate: 13C-Methacetin 
13C-Methacetin is a white, crystalline powder bearing the chemical name [N-(4-Methoxy 
phenyl) acetamide]. 13C-Methacetin is rapidly absorbed and metabolized exclusively by 
hepatic microsomal function oxidase via O-demethylation, mainly by cytochrome p450 
1A2, into acetaminophen (also known as paracetamol, TylenolTM, and n-acetyl-p-
aminophenol or APAP) and formaldehyde(18-23). Formaldehyde is then transformed, 
through two successive oxidative steps, into ¹³CO2. The rate limiting factor in this process 
is the O-demethylation performed by the liver cytochrome p450(24). The general reaction 
is described in the following scheme: 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 22 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
 
Figure 1: 
Oxidative Cleavage of Methacetin to Acetaminophen and Formaldehyde 
The resultant ¹³CO2 can be measured in the exhaled breath. The amount of metabolized 
Methacetin indicates the capability of the liver to accomplish one of its main 
physiological tasks and has been shown to correlate with liver fibrosis and cirrhosis(25-28). 
5.2.3.2 
13C-Methacetin Safety 
Methacetin had been available and described in literature for over 100 years(29). Within 
the last 40 years its use for breath testing has been described as well(30). No risks have 
been reported in the literature using much higher doses of Methacetin than currently 
proposed to be used in this protocol. No adverse events have been reported in performing 
13C-Methacetin Breath Test (MBT) using the proposed device or substrate to date 
including in more vulnerable populations. Additional safety assessments will be made 
during this clinical study. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 23 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
Methacetin metabolism involves an initial O-demethylation process carried out 
exclusively by hepatic cytochrome p450 Iso-enzyme 1A2 producing two products: O-
demethylated 
Methacetin, 
similar 
to 
acetaminophen, 
and 
formaldehyde(18-23). 
Formaldehyde is then transformed into 13CO2, through additional fast enzymatic steps. 
The rate limiting factor in this process is the O-demethylation performed by the liver 
cytochrome p450(24). More details regarding the Methacetin metabolism are presented in 
section ‎5.2.3.1. 
In current literature regarding pre-clinical and clinical studies performed with Methacetin, 
results from a total of 2987 individuals (2021 chronic liver disease patients including 
critically ill patients and 966 controls) were reported in over 70 publications(25, 26, 30-98), 
including neonates,(55) infants,(53) healthy adults, adults with various forms of liver disease 
(including toxic injury), pregnant women(30) and the elderly - with no reports of adverse 
events. MBT has also been used in patients with Acute Liver Failure. Some of the data 
was recorded utilizing the Exalenz BreathID device and substrate, while the majority 
were performed with other similar systems. 
Regarding internal unpublished data using the BreathID device and Methacetin, 1466 
chronic liver patients (of these 278 cirrhotic - some before transplant) and 74 healthy 
controls/subjects without liver disease, have also been tested. No adverse events related to 
the substrate or the device were experienced by the subjects 
Toxicology testing results in animals and other information support the safe use of 
Methacetin in humans. Based on the acute toxicity studies in mice and rats where 
relatively high LD50 values of 1190mg/kg were administrated,(99) the Methacetin dose 
administered in human breath tests in adults of 75 mg, or approximately 1mg/kg, has a 
safety ratio in excess of 1000-fold. 
Many studies using 13C-Methacetin for liver function assessment have been published. 
Representative references supporting the conclusion 13C-Methacetin is a “safe” molecule 
have been cited including the use in high-risk population groups such as the elderly, 
neonates or pregnant women.(71, 73, 82, 100) This provides further assurance that the 
13C-Methacetin substrate is appropriate to use in breath tests intended for liver function 
assessment. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 24 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
5.2.4 Breath Test Components  
The following are the components of the BreathID® System: The BreathID® device, the 
13C-labelled substrate and the sampling kit containing breath collection cannulae. 
The BreathID® device will be provided by Exalenz Bioscience Ltd. The cannulae, 
accessories and the test substrate will be supplied in proper packaging and will bear all 
required labeling based on applicable regulatory requirements. 
For the MBT, the solution is administered orally to the patient is a 0.05% solution of ¹³C-
Methacetin in purified water, supplied in amber thermoplastic polyester (PET) bottles 
with a child resistant plastic stopper (75mg of ¹³C-Methacetin in 150mL purified water). 
All bottles are for single use only and must be used solely for per-protocol investigational 
product administration. 
For the OBT, 100 mg 13C-Octanoate, supplied in powder form, in amber glass vials will 
be used. Each vial contains a single test dose and must be used solely for per-protocol 
investigational product administration.  
All study test components must be stored in an environment according to the Investigator 
Brochure and product labeling guidance.  
For more details please refer to the study's Investigator Brochure. 
6 INTENDED USE / INDICATION FOR USE 
The BreathID® System together with 13C-Octanoate Breath Test (OBT) with or without 
13C-Methacetin Breath Test (MBT) with or without additional clinical and/or laboratory 
parameters are to be used for the characterization of the histological image of Non-
Alcoholic Fatty Liver Disease (NAFLD).  
7 PROPOSED CLINICAL ALGORITHM USING THE 
OBT±MBT±CLINICAL / LABORATORY PARAMETERS 
The Sponsor's goal is to develop a point-of-care device for the characterization of Non-
Alcoholic Fatty Liver Disease (NAFLD) compared to liver histology findings.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 25 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
The Sponsor proposes to train a selected OBT±MBT-based variable to reliably correlate 
with non-alcoholic Fatty Liver Disease (NAFLD) histological characteristics. This will 
enable the use of OBT±MBT to assess NAFLD by means of rule-in or rule-out or both. 
8 STUDY DESIGN  
This study is a multicenter, non-randomized, open-label, cross-sectional comparative 
exploratory study comparing OBT values with or without MBT values to histologic 
findings of liver biopsy. 
This study will be used to train an algorithm using OBT with or without MBT combined 
with other commercially available biomarkers and to select a cut-off to correlate with 
histological findings, as assessed by a central reader, of NALFD and determine clinical 
outcome at 18 and 36 months, if available. 
The modeled algorithm will be validated in a separate study. 
9 STUDY OBJECTIVES  
9.1 Efficacy Objective 
The primary objective of the study is to develop an algorithm based on OBT with or 
without MBT with or without additional clinical and/or laboratory parameters, and its 
cut-off to correlate with histological findings, as assessed by a central reader, of 
NAFLD. 
9.2 Safety Objective 
All adverse events, serious adverse events (SAE) and suspected unexpected serious 
adverse reactions (SUSAR) will be reported according to local regulations. The actual 
reporting is discussed in section ‎15 below. No breath-test related adverse events are 
expected. 
For more information please refer to the Investigator Brochure. 
9.3 Secondary Objectives 
To assess correlation between OBT with or without MBT with or without other 
available biomarkers and disease course, defined by clinical outcomes, at 18 and 36 
months. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 26 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
9.4 Efficacy Endpoints 
9.4.1 Primary efficacy endpoint 
Correlation of histological findings, as assessed by a central reader, of NAFLD compared 
to 13C-Octanoate Breath Test with or without 13C-Methactin Breath Test with or without 
additional clinical and/or laboratory parameters. 
9.4.2 Secondary efficacy endpoint 
Correlation between OBT with or without MBT and clinical course (i.e. clinical outcome: 
liver decompensation events etc.) at 18 and 36 months post the last breath test performed 
(visit / phone). 
NOTE: Patients undergoing intervention for NASH / NAFLD, including both approved 
and experimental approaches prior to the defined time points will be terminated hence 
will not be evaluated for this endpoint. 
9.5 Safety Endpoints 
Safety will be assessed by assessing all adverse and serious adverse events occurring in 
all subjects enrolled from the time of enrollment until the subject completes the protocol.  
Any AEs reported that are possibly or probably related  to the use of the product or 
related to the procedure within 36 months post last breath test performed or until subject 
termination will be followed until resolution and if laboratory work is done secondary to 
AEs and found abnormal, these tests will be followed until normalization or stabilization. 
10 SUBJECT SELECTION 
The study population will be enrolled on a consecutive basis of able and willing subjects 
with a fresh up-to-standard liver biopsy (i.e. tissue sample biopsied within 6 months prior 
to the OBT and MBT and evaluated for quality prior to enrollment), indicated to rule-out 
/ confirm NAFLD, meeting all inclusion/exclusion criteria. 
Patients to be enrolled in the proposed study will be from centers in Europe and the US. It 
is presumed patients on both continents have similar disease phenotypes and prognosis 
and the produced data can be used interchangeably in this multicenter clinical trial 
investigating NAFLD populations.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 27 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
10.1 Inclusion Criteria  
1. 
Adult men or women (≥18 years of age) 
2. 
Liver biopsy indicating NAFLD/NASH performed within 6 months prior to both 
breath-tests 
NOTE: The samples must meet pre-defined quality criteria. (See Appendix II for 
biopsy quality requirements)  
OR: 
Undergoing Liver biopsy to rule-out or confirm NAFLD/NASH. 
3. 
No other known co-existent liver disease, excluded by appropriate serologic / 
other testing 
4. 
Patient able and willing to sign an Informed Consent Form 
5. 
Can tolerate an overnight (8-hour) fast  
10.2  Exclusion Criteria:  
1. 
Positive studies for any of the following within three years prior to biopsy  
a. Anti HCV positive 
b. HBsAg positive 
c. Iron saturation > 60% + gene test for hereditary hemochromatosis or 
iron overload as defined by presence of 3+ or 4+ stainable iron on 
liver biopsy 
d. Antinuclear 
antibody 
at 
a 
titer 
> 
1: 
160 
along 
with  
hypergammaglobulinemia  and 5 times ALT normal levels  
e. Alpha-1-antitrypsin level below lower limit of normal (< 150 mg/dl) 
or no PAS diastase resistant globules on biopsy.  
f. Primary biliary cirrhosis as defined by elevation of alkaline 
phosphatase greater than upper limit of normal and anti-
mitochondrial antibody (AMA) of greater than 1:80 and consistent 
liver histology 
g. Low level of ceruloplasmin (< 10 ng/mL) 
h. Drug-induced liver disease as defined on the basis of typical 
exposure and history 
Note: these studies do not need to be performed if they are not available, 
as it is assumed that if they are not on file, the condition does not exist. 
2. 
Patients known to have chronic liver disease other than NAFLD as 
routinely diagnosed by the investigator   
3. 
Concurrent acute hepatic condition other than NAFLD 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 28 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
4. 
Alcohol consumption > 20 gm/day (0.71 oz./day) for women and > 30 
gm/day (1.06 oz./day) for men 
5. 
Drugs that may interfere with octanoate metabolism or that can also cause 
NAFLD independent of the metabolic syndrome, including: corticosteroids, 
amiodarone, 
tetracycline, 
valproic 
acid, 
methotrexate, 
stavudine, 
zidovudine  
6. 
When MBT is performed, subject should not have taken any of the 
following at least 48 hours prior to the breath 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 
CYP 1A2  
7. 
Patients that have had more than 10% weight change between biopsy and 
enrollment. 
8. 
Hypersensitivity to any of the study substrates: Octanoate or Methacetin 
and their metabolites, i.e. paracetamol, acetaminophen 
9. 
Known extra-hepatic diseases including but not limited to: severe 
congestive heart failure (NIHA>2), known severe pulmonary hypertension 
(>35 mmHg), history of chronic obstructive pulmonary disease or 
uncontrolled symptomatic bronchial asthma or uncontrolled diabetes 
mellitus (HA1c>9.5%) 
10. 
Previous surgical GI bypass surgery  
11. 
Extensive small bowel resection (>100 cm) 
12. 
Known uncontrolled malabsorption or diarrhea  
13. 
Concurrent total parenteral nutrition 
14. 
Any organ transplant 
15. 
Patients receiving any anti-viral treatment or any other liver directed 
therapy, procedure or surgery between the time of the biopsy and the breath 
test 
16. 
Pregnant or breast feeding 
17. 
Patients unable or refusing to sign informed consent 
18. 
Patients that, based on the opinion of the investigator, should not be 
enrolled into this study due to safety / adherence reasons 
19. 
Patients participating in other clinical trials and already receiving 
experimental treatments or procedures 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 29 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
20. 
Patients with suspected or documented hepatocellular carcinoma by ultra-
sound or other imaging modality 
21. 
Patients diagnosed with partial / complete portal venous occlusion, hepatic 
venous occlusion, previous PHT surgery, or placement of a trans-jugular 
intrahepatic porto-systemic shunt (TIPS) according to initial imaging 
studies 
10.3 On the day of the OBT: 
1. 
Eight (8) hours fasting prior to OBT including all PO morning medications 
except for beta blockers. Diabetic patients that are driving should test their 
blood sugars to rule out hypoglycemia and respond accordingly. 
2. 
No general anesthesia or sedation within 24 hours prior to OBT 
3. 
No alcohol within 24 hours prior to OBT  
4. 
Patient should be symptom free of any prior intervention (e.g. biopsy) 
10.4 On the day of the MBT: 
1. 
Eight (8) hours fasting prior to MBT including all PO morning medications 
except for beta blockers. Diabetic patients that are driving should test their 
blood sugars to rule out hypoglycemia and respond accordingly. 
2. 
No smoking on the day of the MBT 
3. 
No paracetamol (acetaminophen) based medications within 24 hours prior 
to MBT 
4. 
No general anesthesia or sedation within 24 hours prior to MBT 
5. 
No alcohol within 24 hours prior to MBT  
6. 
Patient should be symptom free of any prior intervention (e.g. biopsy) 
10.5 Consenting 
Patients will sign a consent form prior to study participation. 
The consent will include willingness to allow acquisition and collation of blood, clinical 
and imaging data obtained on entry to the study and incorporate all other data from time 
of enrollment until the patient's completion/termination of the study including consent to 
future surveillance for long term (up to 3 years) clinical outcomes. 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 30 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
10.6 Safety Termination of Subjects or Study 
1. 
Withdrawal of patients from the study if they have a CTCAE Grade 3 or 
higher regardless of whether the event is attributed to the drug unless it is 
caused by an accident that could not reasonably be attributable to the drug 
(CTCAE: Common Terminology Criteria for Adverse Events Version 
4.0). 
2. 
Discontinuance of study, if ≥ 2 patients administered Octanoate / 
Methacetin develop the same CTCAE Grade 3 event or 1 patient develops 
a CTCAE Grade 4 or higher event due to one of the breath tests. 
10.7 Early Withdrawal from the Study 
Patients, their relatives, their representatives or the patients’ physician may withdraw the 
patient from the study at any time if they feel the study is not in the patients’ best interest, 
or they may be withdrawn by the investigator or sponsor for safety, behavioral, or 
administrative reasons. All withdrawals must be fully documented. 
If the patient withdraws from the study and also withdraws consent for the disclosure of 
future information, no further evaluations should be performed and no additional data 
should be collected. Previously acquired data will be analyzed. This will not have any 
effect on the treatment that the patient receives. 
10.8 Expected Duration of Recruitment 
The enrollment to the study is planned for a duration of approximately 6-12 months.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 31 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
11 STATISTICAL CONSIDERATIONS 
11.1 Study Design and Objectives 
This is a multicenter, non-randomized, open-label, cross-sectional comparative 
exploratory study comparing OBT with or without MBT values to histologic 
findings from liver biopsy associated with NAFLD.  
This study will be used to train an algorithm using OBT with or without MBT 
with or without other commercially available biomarkers and to select a cut-off to 
determine correlation with histological findings of NALFD and determine clinical 
outcome at 18 and 36 months, if available.  
The modeled algorithm will be validated in a separate study.  
11.2 Primary endpoints 
Correlation of histological findings of NAFLD compared to 13C-Octanoate Breath 
Test with or without 13C-Methacetin Breath Test with or without additional 
clinical and/or laboratory parameters. 
11.3 Secondary efficacy endpoint 
Correlation between OBT with or without MBT and clinical course (i.e. clinical 
outcome: liver decompensation events etc.) at 18 and 36 months post the last 
breath test performed (visit / phone). NOTE: Patients undergoing intervention for 
NASH / NAFLD, including both approved and experimental approaches prior to 
the defined time points will be terminated hence will not be evaluated for this 
endpoint. 
11.4 Safety Endpoints 
All Adverse Events recorded from the time of enrollment until the subject completes the 
protocol.  
Any AEs reported that are possibly or probably related to the use of the product or related 
to the procedure within 36 months post last breath test performed or until subject 
termination will be followed until resolution and if laboratory work is done secondary to 
AEs and found abnormal, these tests will be followed until normalization or stabilization. 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 32 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
11.5 Sample Size estimation 
It is estimated that a total of 200 subjects with a fresh and evaluable liver biopsy 
undergoing OBT and MBT of which at least 50 will be positive for NASH and at 
least 50 will be positive for NAFLD will enable the estimation of a conservative 
AUC of 0.75 with a half width of the 95% confidence interval of 0.1. 
During the study the correlation between OBT with or without MBT and 
histological findings of NAFLD will be assessed periodically in order to see if 
there is any confounding factor(s) affecting the correlation. In the case that such a 
factor(s) is identified showing a significant difference in correlation, the study 
population may be increased up to 400 patients. 
11.6 Analysis sets 
1. Primary analysis set (per protocol): All subjects enrolled in the study with a valid 
biopsy and valid OBT and MBT results together with the proposed additional 
biomarkers.  
2. Secondary analysis set – ITT: all subjects performing at least one breath test.  
3. Safety analysis set: all patients performing at least one breath test 
11.7 Statistical Analysis  
11.7.1 General Considerations 
Statistical analyses will be performed using SAS® v9.3 or higher (SAS Institute, Cary 
NC, USA). 
If any statistical tests are performed, they will be two-sided. The required significance 
level of findings will be equal to or lower than 5%. Where confidence limits are 
appropriate, the confidence level will be 95%. 
Baseline values are defined as the last valid value prior to study treatment start. 
All statistical analyses of safety and performance measures will be descriptive in nature. 
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.  
If multiple measurements are taken in a single patient, statistics described below will be 
appropriately modified to accommodate the within patient correlation.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 33 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
11.7.2 Demographic and Other Baseline Characteristics 
Demographic, medical and clinical history variables will be tabulated. Continuous 
variables will be summarized by a mean, standard deviation, minimum, median and 
maximum, and categorical variables by a count and percentage. 
11.7.3 Disposition of Subjects 
The numbers of patients 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 patients, protocol deviations, and patients 
excluded from the efficacy analysis will be provided as well 
11.7.4 Safety Analysis 
The events related to study drug and/or device AEs rate will be presented along with a 
95% exact binomial two sided 95% confidence interval. The analysis of all adverse 
events will include incidence tables and will include analyses by severity, relationship to 
device or drug and baseline variables. 
11.7.5 Performance Analysis 
A model/algorithm will be developed for the correlation between histological findings of 
NAFLD and OBT with or without MBT. It will be developed using either logistic 
regression or neural network or any other known methodology. Using a cut-point on the 
score a binary diagnosis of NASH (Yes/No) or NAFL (Yes/No) will be obtained. The 
minimal criterion for sufficient efficacy is an Area under the Receiver Operating 
Characteristics (ROC) Curve (AUC) ≥0.75 in this patient population. A potential clinical 
utility was designated for the algorithm/model output; where this algorithm could aid the 
clinician in ruling-in or out NASH or NAFL. This will be translated into finding a model 
prediction cut-point that provides a high sensitivity (true positive rate) and at least 
moderate specificity (true negative rate), which in turn achieves a high negative 
predictive value (NPV). High NPV is considered to be near 90% (i.e. 88%) thus 
sensitivity should be at least 90% and specificity should be at least 50%. Cross validation 
methods will be used to test algorithm stability. 
11.7.6 Interim Analysis 
This study is an open label study for training purposes. The data may be assessed prior to 
achieving the full sample size. This will be done specifically in order to assess the effect 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 34 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
of confounding factors on the correlation between OBT with or without MBT and binary 
diagnosis of biopsy proven NASH or NAFL. If any confounding factor shows 
significantly different correlation than the rest of the population, the study population 
may be increased to up to 400 patients. 
11.7.7 Pooling 
Subgroup analysis of the primary performance endpoint by center via a regression model 
will be used to evaluate the poolability of the results. If the variable by center analysis is 
found significant, the reason for this will be further explored and rationalized. This 
evaluation may include demographic features, symptoms at presentation, clinical and 
treatment history, and center comparability in the features found to be associated with the 
primary efficacy variable 
11.7.8 Handling of Missing Data 
The study variables cannot be evaluated for patients for whom OBT or MBT results or 
liver biopsy results are not available and therefore these subjects will be left out of the 
primary efficacy analysis. Demographic clinical characteristics and safety data of patients 
with missing data will be compared to patients with complete data. 
11.7.8.1 Procedure 
After all the relevant data is entered into the database, a soft lock to the database will be 
performed. The study statistician will perform the assessment of the primary and safety 
endpoints. 
11.7.8.2 Decision Rules 
Stop the study in case of severe safety concern. 
 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 35 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
12 STUDY PROCEDURES  
12.1  General 
1. The study will be conducted in compliance with this protocol, in 
concordance with GCP standards, and applicable regulatory 
requirements. 
2. The study design is: cross-sectional, enrolling patients in a 
consecutive manner per site, so as to prevent any bias.  
3. Patients will sign a consent/assent form prior to study participation 
4. An eCRF will be completed for each subject.  
5. The raw data will be saved on the BreathID® device.  
6. All patients undergoing liver biopsy to rule-out or confirm 
NAFLD, within 6 months prior to breath tests and within 1 month 
after first breath test, should be considered for enrollment. If the 
biopsy is done on the day of one of the breath tests, the breath test 
must precede the biopsy. 
7. Biopsy slides of enrolled patients may undergo high-resolution 
scanning to simplify central reading and filing.  
8. All tissue slides or their respective scans if relevant, will be read 
twice; once by the local (study site) pathologist and once by the 
central reading laboratory. In case of discrepancy the central 
reading results prevail. The characteristics to record for each 
sample are specified within Appendix II to this protocol. All 
parameters will be entered into the study eCRF.  
9. Any adverse events will be recorded according to GCP ICH 
guidelines. Section ‎0 below15 below relates to the reportable and 
non-reportable SAEs.    
10. All investigators will be blinded to the OBT and MBT results until 
the end of the study recruitment. This is to ensure that OBT and 
MBT results will not affect the current patient management. Hard 
copies of the device printouts will be stored separately from the 
other source data and the section within the eCRF containing the 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 36 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
breath tests results will remain inaccessible to the treating 
physician (i.e. the investigator login will keep this section hidden). 
12.2 Visit 1: Screening / enrollment  
1. Pre-screening for inclusion / exclusion criteria 
2. As part of eligibility, biopsy slides should be "up to standard" 
according to the quality requirements specified within Appendix II 
to this protocol. (Biopsy quality requirements are as follows: 
Unfragmented needle core ≥ 20mm length with ≥ 10 portal tracts is 
recommended, according to the AASLD practice guidelines or 
equivalent.) 
3. A minimum of Hematoxyline & Eosine (H&E) and Masson’s 
trichome stained slides should be available. Additional optional 
stains include: Chromotrope Aniline blue (connective tissue), 
Prussian blue (iron storage), Sirius red stain (for fibrosis) and SMA 
will be filed if available. Additional unstained slides are 
recommended.  
4. Histology slides or their respective scans, will be assessed by both 
the local pathologist and a central reader according to the 
parameters listed within Appendix II to this protocol. In case of 
significant differences in the assessment the central reader will 
always prevail.   
5. Consenting patient. 
6. Complete study eligibility and enrollment. 
7. Physical or high resolution scanned slides sent to local and central 
reading according to Appendix II. 
12.3 Visit 2: 13C-Octanoate Breath Test (OBT) 
1. Female patients of childbearing age meeting all criteria will 
undergo pregnancy test if not available from the past 7 days. 
Abstinence or oral contraceptives are requested until completion of 
MBT (second breath test). 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 37 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
2. OBT will be performed within 6 months post liver biopsy. 
3. Medical History including the following: 
a. Demographics 
b. Detailed medical history including liver directed 
and other concomitant diseases (cardiovascular, 
respiratory, renal and neurological), presentation, 
interventions, etiology, habits etc. 
c. Imaging results,- (if available) Ultrasound, CT 
and/or MRI, (liver outline, vasculature, evidence of 
fat etc.), imaging of major hepatic vessels, pancreas, 
intestines, and liver volume  
d. Other assays: e.g. HVPG 
e. Most recent laboratory blood test results within 6 
months. 
f. Concomitant medications  
4. Physical examination (targeting liver related findings) including 
liver related clinical scoring.  
5. In preparation for the OBT: 
a. Eight (8) hours fasting prior to OBT including all 
PO morning medications except for beta blockers. 
Diabetic patients that are driving should test their 
blood sugars to rule out hypoglycemia and respond 
accordingly. 
b. No general anesthesia or sedation within 24 hours 
prior to OBT 
c. No alcohol within 24 hours prior to OBT  
d. Patient should be symptom free of any prior 
intervention (e.g. biopsy) 
6. Within one hour prior to the OBT blood will be drawn for the 
following panels (note the relevant remarks): 
a. Insulin and Glucose 
b. Complete 
Blood 
count 
(WBC, 
Hemoglobin, 
Platelets) and CRP 
c. Coagulation: PT (INR) 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 38 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
d. Renal panel and electrolyte panel (BUN, creatinine, 
electrolytes (Na+ and K+),  
e. Collection of 4ml of blood for serum and freezing 
for storage (no preservative tube) where possible. 
f. Hepatic panel (AST, ALT, alkaline phosphatase, 
GGTP, total bilirubin, direct bilirubin, serum 
albumin and total protein) - if not available from 
within 3 months 
g. Additional Coagulation Panel (PTT, fibrinogen) - if 
not available from within 3 months 
h. Total 
calcium, 
PO4 
(phosphate 
corrected), 
magnesium - if not available from within 6 months 
i. Lipid profile and HbA1c - if not available within 6 
months 
j. Thyroid Panel - if not available within 12 months 
k. Other assays where routinely practiced; (optional): 
Adiponectin + Leptin + IL6 + CK18, TNFα, C-
peptide  
NOTE: if possible more than just the essential blood panels (sections a. to d.) will 
be collected adjacent to the OBT. 
7. 13C-Octanoate Breath Test: 
NOTE: Expected warm-up time for the device to be ready to measure 
patient’s breath is up to 90 minutes. Ensure the device is turned on at least 
2 hours prior to scheduled patient visit. 
The breath test is performed automatically while the patient is connected 
to the device using a nasal cannula. The test is of 2 phases: baseline and 
the sampling phase separated by the administration of the test substrate. 
The 2 phases' durations are up to 30 and up to 60 minutes respectively.  
For more information regarding the OBT procedure please refer to 
Section 5 of the Investigator’s Brochure. 
 
8. Adverse events recording until the subject completes the protocol. 
NOTE: Any AEs reported that are possibly or probably related to 
the use of the product or related to the procedure within 36 months 
post OBT or until subject termination will be followed until 
resolution and if laboratory work is done secondary to AEs and 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 39 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
found abnormal, these tests will be followed until normalization or 
stabilization. 
 
9. Diabetic patients will be followed throughout the entire visit and 
should be instructed to resume their medication immediately after 
the breath tests. 
12.4 Visit 3: 13C-Methacetin Breath Test (MBT) 
1. MBT will be conducted within 6 months post liver biopsy and 
within 30 days of the OBT but not less than 48 hours post OBT.  
2. In preparation for the MBT: 
a. Eight (8) hours fasting prior to MBT including all 
PO morning medications except for beta blockers. 
Diabetic patients that are driving should test their 
blood sugars to rule out hypoglycemia and respond 
accordingly. 
b. No smoking on the day of the MBT 
c. No paracetamol (acetaminophen) based medications 
within 24 hours prior to MBT 
d. No general anesthesia or sedation within 24 hours 
prior to MBT 
e. No alcohol within 24 hours prior to MBT  
f. Patient should be symptom free of any prior 
intervention (e.g. biopsy) 
3. 13C-Methacetin Breath Test: 
NOTE: Expected warm-up time for the device to be ready to measure 
patient’s breath is up to 90 minutes. Ensure the device is turned on at least 
2 hours prior to scheduled patient visit. 
The breath test is performed automatically while the patient is connected 
to the device using a nasal cannula. The test is of 2 phases: baseline and 
the sampling phase separated by the administration of the test substrate. 
The 2 phases' durations are up to 30 and up to 60 minutes respectively.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 40 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
For more information regarding the OBT procedure please refer to 
Section 5 of the Investigator’s Brochure. 
4. Adverse events recording until the subject completes the protocol. 
NOTE: Any AEs reported that are possibly or probably related to 
the use of the product or related to the procedure within 36 months 
post last breath test performed or until subject termination will be 
followed until resolution and if laboratory work is done secondary 
to AEs and found abnormal, these tests will be followed until 
normalization or stabilization. 
5. Diabetic patients will be followed throughout the entire visit and 
should be instructed to resume their medication immediately after 
the breath tests. 
12.5 Visit 4: 48 safety hours phone call  
1. 48 hours post the last breath-test (presumably MBT) a safety 
oriented phone call will be conducted.  
2. All adverse events post OBT will be recorded until the subject 
completes the protocol. 
NOTE: Any AEs reported that are possibly or probably related to 
the use of the product or related to the procedure within 36 months 
post last breath test performed or until subject termination will be 
followed until resolution and if laboratory work is done secondary 
to AEs and found abnormal, these tests will be followed until 
normalization or stabilization. 
3. This visit determines the last safety reporting point to be reported 
in to the safety endpoint.  
12.6 Visit 5: Clinical Follow-Up 18 Months  
18 months ± 4 weeks post the last breath test performed a phone / in-person visit 
will be conducted in order to assess major clinical events (i.e. Death, liver 
transplant, 
liver 
decompensation 
events 
including: 
ascites, 
hepatic 
encephalopathy, variceal bleeding, hepato-renal syndrome, spontaneous bacterial 
peritonitis). In addition, the patient's clinical records will be reviewed. 
 
NOTE: Patients undergoing intervention for NASH / NAFLD, including both 
approved and experimental approaches prior to the defined time points will be 
terminated hence will not be evaluated for this endpoint. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 41 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
12.7 Visit 6: Clinical Follow-Up 36 Months  
36 months ± 8 weeks post the last breath test performed a phone / in-person visit 
will be conducted  in order to assess major clinical events (i.e. Death, liver 
transplant, 
liver 
decompensation 
events 
including: 
ascites, 
hepatic 
encephalopathy, variceal bleeding, hepato-renal syndrome, spontaneous bacterial 
peritonitis). In addition, the patient's clinical records will be reviewed. 
 
NOTE: Patients undergoing intervention for NASH / NAFLD, including both 
approved and experimental approaches prior to the defined time points will be 
terminated hence will not be evaluated for this endpoint. 
 
NOTE: Any AEs reported that are possibly or probably related to the use of the 
product or related to the procedure within 36 months post last breath test 
performed or until subject termination will be followed until resolution and if 
laboratory work is done secondary to AEs and found abnormal, these tests will be 
followed until normalization or stabilization. 
13 ETHICS & REGULATORY CONSIDERATIONS 
13.1 Ethics & Regulatory Approvals 
The study will be conducted in both the United States of America and Europe. As such, 
regulatory bodies that are relevant for all countries will be mentioned in this section. 
The study will be conducted in compliance with the principles of the Declaration of 
Helsinki (1996), the principles of GCP and in accordance with all applicable regulatory 
requirements. 
This protocol and related documents will be submitted for review to all relevant ethics 
committees delegated to approve the study at their respective sites. Any amendment to 
the protocol may be proposed by the principal investigator. The amendment must be 
submitted to the Sponsor and, when approved to the relevant institutional review board 
(IRB) or ethics committee (EC). When applicable, the implementation of the amendment 
will take place only once approved by the appropriate ethics committee. 
Annual progress and safety reports and a final report at conclusion of the study will be 
submitted by Exalenz Bioscience (or on behalf of the Sponsor) to the applicable 
regulatory bodies within the timelines defined in the Regulations. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 42 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
14 INVESTIGATOR RESPONSIBILITIES 
The investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current ICH guidelines on GCP, and applicable regulatory 
requirements. GCP is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki, and that the clinical study data are credible. 
The investigational devices will bear an identification number and their accountability 
will be filed in the Investigator’s Study File. Study supplies logged in will be kept by the 
investigator or the delegated persons in a secure place. All supplies (device, substrate and 
cannulae) will be used for this study only. After completion of the study, the device, drug 
and all unused accessories must be returned to Exalenz Bioscience Ltd. as per their 
request or alternatively, destroyed according to local regulations after receiving explicit 
authorization by Exalenz to do so and provide Exalenz with a confirmation. 
The Principal Investigator will act as custodian for the study data. Patient data will be 
anonymized and all the anonymized data will be stored on a password protected 
computer. All data will be compliant with CFR and GCP.  
14.1 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 
Investigational product, disposition of Investigational product, with the following forms 
required: Proof of Receipt Form, Temperature Logs, Accountability Logs, Investigational 
Product and Material Transfer/Disposition Form and Pharmacy Staff Identification Log 
(if applicable). 
Local forms may be authorized for use after being approved by the Sponsor or his 
assigned representative. 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 43 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
14.2 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 handled in strict 
accordance with the protocol and the container label and will 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 to destroy 
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. 
15 SAFETY CONSIDERATIONS 
15.1 Adverse Event Definitions  
An adverse event (AE) is any undesirable or unintentional event that occurs during use of 
the study medical device or drug, whether or not considered related to the investigational 
product; this includes clinically significant changes in laboratory values related to 
acetaminophen exposure. As this study is not therapeutic in nature, there will be no 
therapeutic failures to report. Regardless of severity or relationship to the study 
investigational product, these are recorded in the patient’s CRF, all adverse events 
occurring during the time period when study investigational product is being 
administered. Associated with the use of the investigational product is defined as a 
reasonable possibility that the event may have been caused by the medical device or drug. 
NOTE: Any AEs reported that are possibly or probably related to the use of the 
product or related to the procedure within 36 months post last breath test 
performed or until subject termination will be recorded and followed until 
resolution and if laboratory work is done secondary to AEs and found abnormal, 
these tests will be followed until normalization or stabilization. 
Serious Adverse Event (SAE) and Suspected Unexpected Serious Adverse Reactions 
(SUSAR) 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 44 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
A serious adverse event (SAE) is an event that is either: 
a) fatal 
b) life-threatening 
c) results in persistent or significant disability/incapacity 
d) requires or prolongs inpatient hospitalization  
e) is a congenital anomaly or birth defect. 
 
A Suspected Unexpected Serious Adverse Reactions (SUSAR) is an SAE, for which the 
nature or severity is not consistent with the expected outcomes of the treatment being 
offered. 
Life threatening is defined as an event in which the patient is at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have cause death if it 
was more severe. Disability is defined as a substantial disruption of a person’s ability to 
conduct normal life functions. An unexpected adverse event is one that has not been 
previously observed, or one that is of a specificity or severity not consistent with the 
current investigator brochure. 
When an adverse event occurs, record the following information and assessments in the 
adverse event section of the CRF: 
 The signs, symptoms, or diagnosis of the event 
 The date and time of onset of the event using the 24 hour clock where midnight is 
00:00 and noon is 12:00 
 The adverse event severity using the criteria outlined below  
 The relationship of the event to the study medical device as outlined below 
 Describe any action taken regarding study medical device disposition  
 List any required therapy, medication, treatment, or diagnostic procedure. 
15.2 Relationship to Study medical device 
Use the following definitions to assess the relationship between an adverse event and the 
study medical device. 
 Not Related:  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 45 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
The event is clearly related to other factors such as the patient's clinical state, therapeutic 
interventions or concomitant drugs. 
 Remotely Related:  
The event was most likely produced by other factors such as the patient's clinical state, 
therapeutic interventions or concomitant drugs and does not follow a known response 
pattern to the study medical device. 
 Possibly Related:  
The event has a reasonable temporal relationship to study medical device administration 
and follows a known response pattern to the study medical device. However, a potential 
alternate etiology may be responsible for the event. The effect of medical device 
withdrawal is unclear. Re-challenge information is unclear or lacking. 
 Probably Related:  
The event follows a reasonable temporal sequence from the time of medical device 
administration and follows a known response pattern to the study medical device and 
cannot be reasonably explained by other factors. There is a reasonable response to 
withdrawal of the medical device. Re-challenge information is not available or advisable. 
 Related:  
The event follows a temporal sequence from the time of medical device administration 
and follows a known response pattern to the study medical device and either occurs 
immediately following study medical device administration, or improves on stopping the 
medical device, or reappears on repeat exposure. 
15.3 Adverse Event Severity 
 Mild Adverse Events 
A mild adverse event is one that the symptoms are barely noticeable to the patient. It does 
not influence performance, require drug treatment or prevent the patient from carrying on 
with normal life activities. 
 Moderate Adverse Events 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 46 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
A moderate adverse event is one that the symptoms make the patient uncomfortable and 
causes some impairment to normal life activities. Treatment for symptom(s) may be 
required. 
 Severe Adverse Events 
A severe adverse event is one that the symptoms cause severe discomforts to the patient 
and severely limits the patient’s normal daily activities. Treatment for symptom(s) is 
given.  
Note: Serious and severe are not synonymous. A serious adverse event must fulfill the 
requirements listed in the definition above.  
15.4 Adverse Event Reporting 
All adverse events will be recorded in the case report form. The investigator is 
responsible for the appropriate medical management of all adverse events. Any serious 
and unexpected adverse event will be reported to the medical monitor immediately by 
telephone or fax and follow-up the call with a written report within five days. Full details 
of the event, any sequealae and an assessment of the relationship to the study medical 
device will be provided in the report. Any serious and unexpected adverse events and all 
deaths will also be reported to the EC or IRB within ten days and a copy of this report 
will be sent to the medical monitor. Exalenz Bioscience will notify all investigators of 
serious or unexpected adverse events when this information is of global importance to 
subject safety and welfare. Exalenz Bioscience or its designee will report all adverse 
events to the FDA, EC and other competent authorities. 
A written report is required for all patients who die within 30 days after the end of their 
participation in the study. This report must document the events surrounding the patient’s 
death and the cause of death. Attach a copy or summary of autopsy findings, if 
performed. 
15.5 Study-Specific Exceptions 
Disease complications or death as a result of disease progression is expected and it is not 
necessary to report them as SUSARs, but they should be reported in the follow-up section 
of the case report form (CRF). 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 47 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
Furthermore, the following situations and non-fatal toxicities that fulfill the definition of 
an AE are excluded from expedited notification on an AE form, but should be reported in 
the follow-up section of the CRF form: 
 
 Elevation of bilirubin 
 Elevation liver enzymes 
 Nausea, vomiting , diarrhea  
 
Lastly, the following elective procedures should be excluded from expedited notification 
on an SAE form and should be reported in the follow-up section of the CRF form: 
 Central and arterial line insertion, intubation and ventilation, tracheostomy 
 
Liver transplantation 
 
16 ACCESS TO SOURCE DATA AND DOCUMENTS 
16.1 Availability of Source Data and Documents 
The Investigator will permit study-related monitoring, audits, EC review, and regulatory 
inspections (where appropriate) by providing direct access to source data and other 
documents (i.e. patients’ case sheets, blood test reports, histology reports etc.). 
16.2 Patient Confidentiality 
The patient’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. 
17 MONITORING AND QUALITY ASSURANCE 
Monitoring of this study will be to ensure compliance with GCP, local regulations, 
Exalenz Standard Operating Procedure  (SOP) for Clinical Monitoring, scientific 
integrity and will be managed and oversight retained by Exalenz Bioscience (the 
Sponsor) or its assigned representative.  

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 48 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
17.1 Data Collection and Monitoring 
An eCRF will be completed for each patient.  The EDC (electronic data capture) system 
will be 21 CRF Part 11 and Annex 11 compliant and the site staff and all involved parties 
will be trained on the system prior to patient enrolment. 
The frequency of monitoring will be determined based on enrollment, but is estimated at 
a minimum of  once every 3 months per site or every 10 subjects, whichever comes first.  
Source data verification is deemed necessary for at least 10% of the subjects. 
IRB and EC members and regulatory authorities will be permitted to review study 
documents at the site according to local and federal regulations. 
18 PUBLICATION POLICY AND FINANCE 
It is intended that the results of the 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 contract. 
19 FINANCIAL ASPECTS  
The device and drug compounds will be provided by the Sponsor. Funding for regulatory 
approvals and administration will also be provided by the Sponsor. Funding will also be 
provided for a study support staff at local sites. 
20 STUDY TERMINATION 
The study may be terminated after appropriate consultation between the study sponsor 
and the chief investigator and co investigators. Conditions warranting termination 
include, but are not limited to: 
 Failure of the investigator to enroll patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Failure to adhere to GCP 
 Decision by the study sponsor to suspend or discontinue development of the 
device or kit 
 
 
 

Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 49 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
 
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Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 50 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
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Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 51 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
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Exalenz Bioscience Ltd. 
Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 52 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
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Fusarium toxin-contaminated triticale, either untreated or treated with sodium 
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Powers HJ. The potential of a 13C-methacetin breath test for estimating ascorbic 
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Braun R, Dittmar W, Hubner GE, Maurer HR. Influence of valtrate/isovaltrate 
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Study Title: Clinical Study of the BreathID® System to 
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respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
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Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 54 of 61 
 
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CONFIDENTIAL AND PROPRIETARY 
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A, et al. Breath tests with stable isotopes: have they a role in liver 
transplantation? Eur Rev Med Pharmacol Sci 2004;8:55-58. 

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Study Title: Clinical Study of the BreathID® System to 
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or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 55 of 61 
 
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CONFIDENTIAL AND PROPRIETARY 
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13C-methacetin and 13C-galactose breath tests can assess restricted liver 
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2006;41:1336-1341. 

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Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 56 of 61 
 
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CONFIDENTIAL AND PROPRIETARY 
80. 
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methacetin breath test for monitoring hepatic function in cirrhotic patients before 
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patients with liver cirrhosis. Z Gastroenterol 1999;37:1139-1143. 
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[13C]methacetin breath test for evaluation of liver damage. Dig Dis Sci 
1987;32:344-348. 
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Candelli M, Pompili M, Suppressa P, Lenato GM, Bosco G, Rapaccini GL, 
Gasbarrini A, et al. Liver involvement in hereditary hemorrhagic telangiectasia: 
can breath test unmask impaired hepatic first-pass effect? Intern Emerg Med 
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The LiMAx test: a new liver function test for predicting postoperative outcome 
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al. Prediction of postoperative outcome after hepatectomy with a new bedside 
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Liver function as assessed by breath tests in patients with hepatocellular 
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Sedlakova M, et al. Correlation of NT-proBNP with metabolic liver function as 

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Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
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assessed with (13)C-methacetin breath test in patients with acute decompensated 
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Correlation of the functional liver mass with left ventricular ejection fraction and 
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Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 58 of 61 
 
Exalenz Bioscience Ltd.    2014 
 
CONFIDENTIAL AND PROPRIETARY 
 
APPENDIX I - PROTOCOL APPROVAL SIGNATURE PAGE 
 
 
Protocol No: NASH-EX-1114 
 
Protocol Title: Clinical Study of the BreathID® System to train the algorithm for the ¹³C-
Octanoate Breath Test with or without the ¹³C-Methacetin Breath Test (OBT 
and MBT respectively) for correlation with histological features associated with 
findings of Non-Alcoholic Fatty Liver Disease (NAFLD). 
Version:  
01f 
 
Date of Protocol: 1-MAY-2016 
 
Site Name: 
_____________ 
 
Principal Investigator: __________________ 
 
 
 
 
      Print name 
 
I have read this protocol and agree to conduct the study as outlined herein and as per 
GCP and local regulations. 
 
Principal/ Chief Investigator____________________ Date_____________________ 

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Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 59 of 61 
 
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CONFIDENTIAL AND PROPRIETARY 
APPENDIX II - HISTOPATHOLOGICAL READING OF LIVER 
BIOPSY SPECIMEN 
 
The clinical study protocol (NASH-EX-1114) calls for all liver biopsy tissue slides (or 
their respective scans, if relevant) to be read twice; once by the local (study site) 
pathologist and once by the central reading pathologist. The characteristics to record for 
each set of samples are specified within this appendix. 
It has to be noted that there may be shrinkage after formalin fixation, and that biopsy 
length reported by the hepatologist at the bedside is often reported on the unfixed 
specimen, whereas the pathologist has to report the size of the fixed specimen. 
1. Characterization of Specimen Quality: 
It is essential that the resulting liver biopsy specimen be adequate so as to allow detailed 
interpretation. This means that the biopsy should be of large enough size to view a 
representative amount of parenchyma and number of portal tracts. The clinical study 
protocol requires samples to be of significant tissue volume to allow histological 
evaluation; at least 2 cm of length (after formalin fixation) with at least 10 portal tracts to 
be obtained with a 16-gauge cutting needle or larger are commonly considered the 
standard qualifications for such evaluation or the equivalent. The actual size and number 
of tracts should be noted on the pathology report. 
2. Tissue Processing 
The tissue cuts should be prepared according to the standard process of the local 
pathology laboratory. Ideally twelve (12) cuts, with a minimum of 2 should be prepared 
to allow the following staining.  
The following stains should be performed at minimum: 
   (i) Hematoxylin & Eosin (used for grading of inflammation) 
   (ii) Masson Trichrome (used for staging of fibrosis) 
The following stains are elective, but recommended by the protocol: 
   (i) Sirius Red (used in computer-assisted morphometric quantification of fibrosis) 
   (ii) Chromotrope Aniline blue (connective tissue) 
   (iii) Prussian blue (iron storage) 

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Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 60 of 61 
 
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CONFIDENTIAL AND PROPRIETARY 
   (iv) SMA  
 
The remaining cuts (ideally 4) should be prepared for slides suited for 
immunohistochemistry and should be stored unstained for further immune-histochemical 
analysis. 
 
Stained slides may be scanned with a high resolution scanner at x200 to x400 
magnification. 
3. Histo-Morphological Assessment 
The tissue will be examined by light microscopy and scored based upon the NASH CRN 
NAFLD/NASH scoring system  (NAS) as well as the FLINT Consortium (SAF) including: 
a. Adequacy of the biopsy sample for reading (including sample length, number of 
portal tracts or equivalent and adequacy of staining); 
b. Steatosis (including grade of 0-3, location, and whether microvesicular); 
i. 0 = <5% hepatocytes involved 
ii. 1 = 5–33% hepatocytes involved 
iii. 2 = 34–66% hepatocytes involved 
iv. 3 = >66% hepatocytes involved 
c. Fibrosis based upon Masson’s trichrome stain as 0-4 with: 
i. 0 = none 
ii. 1a = mild zone 3 perisinusoidal 
iii. 1b = moderate zone 3 perisinusoidal 
iv. 1c = portal/periportal only 
v. 2 = zone 3 and periportal OR both perisinusoidal and periportal fibrosis 
vi. 3 = bridging 
vii. 4 = cirrhosis 
d. Lobular inflammation as (including grade of 0-3 seen under 20-fold 
magnification) and as presence or absence of microgranulomas and 
lipogranulomas: 
i. 0 = none 
ii. 1 = <2 foci per x 200 field 
iii. 2 = 2–4 foci per x 200 field 
iv. 3 = >4 foci per x 200 field 
e. Portal inflammation (including grade of 0-2): 
i.  0 = none 
ii. 1 = mild 
iii. 2 = greater than mild 

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Last update on: May1, 2016 
Study Title: Clinical Study of the BreathID® System to 
train the algorithm for the ¹³C-Octanoate Breath Test with 
or without the ¹³C-Methacetin Breath Test (OBT and MBT 
respectively) for correlation with histological findings of 
Non-Alcoholic Fatty Liver Disease (NAFLD) 
Protocol No.: NASH-EX-1114 
Version: 1f 
Document No: CSD00080 
Page 61 of 61 
 
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CONFIDENTIAL AND PROPRIETARY 
f. Liver cell injury: 
i. Ballooning: 
 
0 = none 
 
1 = few ballooned cells 
 
2 = many cells ⁄ prominent ballooning 
ii. Presence of acidophilic bodies: 
 
0 =rare/absent 
 
1 = many 
iii. Pigmented macrophages: 
 
0 = rare/absent 
 
1 = many 
iv. Megamitochrondria: 
 
0 = rare/absent 
 
1 = many 
g. Mallory bodies: 
i. 0 = rare/absent 
ii. 1 = many 
h. Glycogen nuclei: 
i. 0 = rare/absent 
ii. 1 = many 
i. 
Hepatocellular iron grade based on iron stain: 
i. 0 = absent or barely discernible, 40x 
ii. 1 = barely discernable granules, 20x 
iii. 2 = discrete granules resolved, 10x 
iv. 3 = discrete granules resolves, 4x 
v. 4 = masses visible by naked eye 
j. 
Steatohepatitis finding 
i. Pathologists own decision (NASH present, absent, probable and 
Comments) 
k. Resulting NAS score 
l. 
Resulting SAF score  
 
4. Computerized Quantitative Morphometric Analysis