Clinical trial NCT03611101
Conditions: NASH - Nonalcoholic Steatohepatitis
Sponsor: Meridian Bioscience, Inc.
Start date: 2018-05-04; Completion date: 2021-11-10
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a companion study assessing the ¹³C-Methacetin Breath Test (MBT) in subjects participating in the Bristol Myers-Squibb (BMS) NCT03486899 and NCT03486912 referenced studies using study drug BMS-986036.

Detailed description:
Subjects that are enrolled into either of two separate BMS sponsored IND (Investigational New Drug) studies (referenced by NCT03486899 and NCT03486912) at selected study sites will be offered the opportunity to perform the MBT. These will be considered as two separate study cohorts (cohort 1 and 2 respectively) within this companion protocol. There are four (4) treatment arms (BMS-986036 Dose Level 1, Dose Level 2, Dose Level 3 or matching placebo), as defined in the respective BMS sponsored protocols.

Cohort 1 consists of Subjects with NASH and stage 3 fibrosis, as assessed by a central laboratory reader of the liver biopsies (up to 160), and who meet all the NCT03486899 referenced study criteria.

Cohort 2 consists of Subjects with NASH and compensated liver cirrhosis, as assessed by a central laboratory reader of the liver biopsies (up to100), and who meet all the NCT03486912 referenced study criteria.

Approximately 75 sites will be included in the BMS studies, but not all participating sites will elect to perform the MBT. Each subject will perform up to 3 MBTs over 1 year; approximately one every 24 weeks.

The MBT in this study will only be conducted in the USA.

The primary purpose of the BMS study is to assess an experimental treatment for the following conditions: Hepatic cirrhosis, liver fibrosis, Nonalcoholic Fatty Liver Disease (NAFLD) and NASH (Nonalcoholic Steatohepatitis).

Arms: arm 1: Administered by subcutaneous injection arm 2: Administered by subcutaneous injection arm 3: Administered by subcutaneous injection arm 4: Administered by subcutaneous injection
Interventions: intervention 1: ¹³C-Methacetin Breath Test intervention 2: BMS-986036 intervention 3: BreathID MCS device
Intervention descriptions: intervention 1: A breath analyzer will be used to measure changes in 12C (carbon 12) to 13C (carbon 13) ratio as a result of metabolism of the Methacetin substrate before and after treatment. intervention 2: Investigational drug for NASH treatment in Main BMS protocol intervention 3: The BreathID MCS device is a breath analyzer specifically used for measuring changes in the ratio of 13CO2 and 12CO2 isotopes of carbon dioxide. The device is connected to the subject via a nasal cannula and breath is passively collected before and after ingestion of labelled 13C- Methacetin substrate.

Protocol documents:
Prot_000.pdf: 
 
Exalenz Bioscience Ltd.     
 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
Companion protocol for the ¹³C-Methacetin Breath Test 
(MBT) for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols 
MB130-068 and MB130-069  
  
Protocol No. BMS-EX-0118 
 
Document No: CSP000002 
Total pages: 38 
Version Level: 1.0 
Last update on: February 20, 2018 
 
 
Name 
Position 
Author / 
Owner 
Ora Msika-Azuelos 
Clinical Regulatory Affairs Manager 
Reviewed by 
Gil Guggenheim 
Clinical Research Development Manager 
Approved by 
Ofer Schlesinger 
VP R&D 
Electronic signatures and approvals, effective information and Lifecycle Status can be 
obtained by accessing the system generated approval page associated with this document.  
The system generated approval page can be retrieved from the PDM system. 
This publication, in whole or in part, may not be reproduced, disclosed, translated into 
any language or computer language or distributed without the prior written consent of: 
Exalenz Bioscience Ltd. 4 Ha’Maayan St. Modi’in, Israel 7177872 
Versions Control: 
Version 
Date 
Responsible Person Description of Change 
1.0 
February 20, 2018 Ora Msika-Azuelos 
Initial Release 
 
 
 
 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 2 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
1 ABBREVIATIONS 
AE 
- Adverse Event 
BMS 
-  Bristol-Myers Squibb 
CDOB 
- Cumulative Delta over Baseline 
CI 
- Confidence Interval 
CL 
- Confidence Limits 
CO2 
- Carbon dioxide 
CPDRxx 
- Cumulative Percentage Dose Recovery at xx minutes from ingestion  
CRF 
- Case Report Form 
CSPH 
-  Clinically Significant Port Hypertension 
CTP 
- Child-Turcotte-Pugh Score 
DOB 
- Delta over Baseline 
eCRF 
- Electronic Case Report Form 
FDA 
- (United States) Food and Drug Administration 
GCP 
- Good Clinical Practice 
IDE 
- Investigational Device Exemption 
IRT 
- Interactive Response Technology 
MBT 
- 
13C-Methacetin Breath Test 
MCS 
- Molecular Correlation Spectrometry  
MEGX 
- Monoethylglycinexylidide 
MELD 
- Model for End-Stage Liver Disease 
MRI 
- Magnetic Resonance Imaging 
MRE 
- Magnetic Resonance Elastography 
NAFLD 
- Nonalcoholic Fatty Liver Disease 
NAS 
- NAFLD Activity Score 
NASH 
- Nonalcoholic Steatohepatitis 
NPV 
- Negative Predictive Value 
PDFF 
- Proton Density Fat Fraction 
PDR 
- Percent Dose Recovered (expressed as % per hour) 
PET 
- Thermoplastic Polyester 
PO 
- Per Os (by mouth) 
PTFU 
- Post treatment follow up 
QW 
- Once weekly 
SAE 
- Serious Adverse Event 
SF 
- Screen Failures 
SUSAR 
- Suspected unexpected serious adverse reaction 
UADE 
- Unanticipated Adverse Device Effect  


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 3 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
US 
- United States (of America) 
USA 
- United States of America 
 
 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 4 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
 
 
TABLE OF CONTENTS 
1 Abbreviations ........................................................................................................................ 2 
2 Protocol Synopsis ................................................................................................................. 7 
3 Background ......................................................................................................................... 14 
3.1 
Defining the need for a non-invasive test for the characterization of NASH progression ........... 15 
3.2 
Rationale to use the MBT for assessment of Liver Disease Progression ..................................... 16 
4 Intended Use / Indication for Use ..................................................................................... 17 
5 Study Design ....................................................................................................................... 17 
6 Subject Selection ................................................................................................................. 18 
6.1 
Inclusion Criteria .......................................................................................................................... 18 
6.2 
Exclusion Criteria......................................................................................................................... 18 
6.3 
Exclusion Criteria from MBT testing On the day of the test ....................................................... 19 
6.4 
Consenting ................................................................................................................................... 19 
7 Study Objectives ................................................................................................................. 20 
7.1 
Primary Efficacy Objective .......................................................................................................... 20 
7.2 
Secondary Efficacy Objectives .................................................................................................... 20 
7.3 
Exploratory Efficacy Objectives .................................................................................................. 21 
7.4 
MBT Safety Objective ................................................................................................................. 21 
7.5 
Primary Efficacy Endpoint ........................................................................................................... 21 
7.6 
Secondary Efficacy Endpoint measures ....................................................................................... 21 
7.7 
Efficacy Variables ........................................................................................................................ 22 
7.7.1 
Liver Biopsy .................................................................................................................................. 23 
7.7.2 
Clinical Outcome Events ............................................................................................................... 24 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 5 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
7.7.3 
Magnetic Resonance Elastography (MRE) .................................................................................... 24 
7.7.4 
Fibroscan® Elastography ............................................................................................................... 25 
7.7.5 
Magnetic Resonance Imaging (MRI) ............................................................................................ 25 
7.7.6 
Serum Biomarker Pro-C3 .............................................................................................................. 26 
7.7.7 
MELD Scoring .............................................................................................................................. 26 
7.7.8 
Child-Turcotte-Pugh (CTP) Scoring .............................................................................................. 27 
7.7.9 
13C-Methacetin Breath Test (MBT) ............................................................................................... 27 
8 Safety Termination and Early Withdrawal of Subjects or Study ................................. 28 
8.1 
Expected Study Duration ............................................................................................................. 28 
9 Statistical Considerations .................................................................................................. 28 
9.1 
Study Design and Aim ................................................................................................................. 28 
9.2 
Endpoint Measures ....................................................................................................................... 28 
9.2.1 
Primary endpoint measure ............................................................................................................. 28 
9.2.2 
Secondary endpoint measures ........................................................................................................ 29 
9.2.3 
Safety endpoints measure .............................................................................................................. 30 
9.3 
Acceptance Criteria (Study Hypotheses) ..................................................................................... 30 
9.4 
Sample Size .................................................................................................................................. 30 
9.5 
Analysis sets ................................................................................................................................. 31 
9.6 
Statistical Analysis ....................................................................................................................... 31 
9.6.1 
General Considerations .................................................................................................................. 31 
9.6.2 
Demographic and other Baseline Characteristics .......................................................................... 32 
9.6.3 
Disposition of Subjects .................................................................................................................. 32 
9.6.4 
Safety Analysis .............................................................................................................................. 32 
9.6.5 
Interim Analysis ............................................................................................................................ 32 
9.6.6 
Pooling ........................................................................................................................................... 33 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 6 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
9.6.7 
Handling of Missing Data .............................................................................................................. 33 
10 Study Procedures ............................................................................................................... 33 
10.1 General ......................................................................................................................................... 33 
10.2 Breath Test Procedure .................................................................................................................. 33 
10.3 Investigational Product Handling ................................................................................................. 35 
10.4 Investigational Product Accountability ........................................................................................ 36 
11 Ethics & Regulatory Considerations ................................................................................ 36 
12 Safety Considerations ........................................................................................................ 36 
13 Subject Confidentiality ...................................................................................................... 37 
14 Monitoring and Quality Assurance .................................................................................. 37 
15 Publication Policy and Finance ......................................................................................... 37 
16 Financial Aspects ................................................................................................................ 37 
17 Study termination ............................................................................................................... 37 
18 References ........................................................................................................................... 37 
 
 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 7 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
2 PROTOCOL SYNOPSIS 
Protocol Title: 
Companion protocol for the ¹³C-Methacetin Breath Test for use in Bristol-
Myers Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069. 
Short Title: 
Companion protocol assessing the MBT in subjects participating in the 
MB130-068 and MB130-069-studies (PEG-FGF21) 
Protocol Number: 
BMS-EX-0118 
Version and Date: 
v 1.0,  February 20, 2018 
Phase of 
Development of 
BMS-986036: 
Phase 2b (IND 125297) 
Phase of 
Development of 
MBT: 
The study is feasibility for drug response monitoring however the data may 
be used for Exalenz for future submissions 
Sponsor: 
Exalenz Bioscience Ltd. 
4 Ha’Maayan Street 
Modi'in, Israel 7177872 
Tel: +972-8-9737500 
Fax: +972-8-9737501 
Investigated 
Disease: 
Subjects with Non-Alcoholic Steatohepatitis (NASH) and stage 3 liver 
fibrosis (MB130-068 study) or compensated liver cirrhosis (MB130-069 
study) 
Combination 
Product: 
¹³C-labeled Methacetin Breath Test 
Comparators: 
Liver Fibrosis stage as assessed by biopsy and additional liver health 
measures and their changes such as NAS, MELD, CTP, PDFF, Liver 
Stiffness, Serum Biomarker Pro-C3, and Liver-related Clinical Outcome. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 8 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Study Population: 
Subjects that are enrolled into either of two separate BMS sponsored IND 
studies (MB130-068, MB130-069) at selected study sites will be offered the 
opportunity to perform the MBT. These will be considered as two separate 
study cohorts (cohort 1 and 2, respectively) within this companion protocol. 
Each cohort consists of four treatment arms (BMS-986036 10mg, 20mg, 
40mg QW or matching placebo QW), as defined in the respective BMS 
sponsored protocols. 
 
Cohort 1 consists of Subjects with NASH and stage 3 fibrosis, as assessed 
by a central laboratory reader of the liver biopsies (n=160), and who meet all 
the MB130-068 study criteria. 
 
Cohort 2 consists of Subjects with NASH and compensated liver cirrhosis 
(stage 4 fibrosis), as assessed by a central laboratory reader of the liver 
biopsies (n=100), and who meet all the MB130-069 study criteria. 
 
This feasibility companion protocol will include the 2 cohorts of subjects, 
with a planned total of up to 260 subjects from approximately 75 sites 
worldwide (USA and Japan) for the two BMS IND studies, while the MBT 
will only be conducted in the USA.  
Not all participating sites will elect to perform the MBT. The total number 
of subjects expected to perform the MBT may reach up to 250 subjects (also 
accounting for drop outs). Each subject will perform up to 3 MBTs over 1 
year; approximately one every 24 weeks. 
Primary Efficacy 
Objectives: 
To demonstrate the ability of the MBT to evaluate patient response to 
treatment with BMS-986036, comparing placebo to each treatment arm 
individually. Assessment will be performed at the 24 and 48 week visits and 
compared to day 1 (change from baseline) and the respective preceding visit 
(change between visits), when available. Assessments will be done for each 
study cohort independently, according to availability, and on the combined 
population of the two cohorts by dose of the BMS drug under study. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 9 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Secondary 
Efficacy 
Objectives: 
The following assessments will be done by treatment arm and combined 
arms for each study cohort independently, according to availability, and on 
the combined population of the two study cohorts by dose of the BMS drug 
under study:  
1. To demonstrate the short and long-term prognostic value (3 
months, 6 months and 1 year, respectively) of MBT for liver 
disease deterioration (reported as liver-related clinical outcome 
events). Assessment will be performed using MBT from the day 1, 
and 24 and 48 week visits. 
2. To assess the ability of changes in the MBT to reflect biopsy 
proven changes in fibrosis and/or NAS as assessed by a central 
reader at week 24 (or at least week 20 in cases of an early 
termination time point) (for cohort 1) or at week 48 (for cohort 2) 
compared to the baseline biopsy from the screening visit. 
3. To assess the ability of changes in the MBT to reflect changes in 
liver stiffness as measured by Magnetic Resonance Elastography 
(MRE) where available at weeks 24 and 48 (or at early termination) 
compared to baseline MRE from the screening visit. 
4. To assess the ability of changes in the MBT to reflect changes in 
Proton Density Fat Fraction (PDFF) as measured by Magnetic 
Resonance Imaging (MRI) where available - at weeks 24 and 48 (or 
early termination), compared to baseline MRI from the screening 
visit. 
 
To assess the ability of changes in the MBT to reflect changes in Serum Pro-
C3 at 24 and 48 weeks of treatment (or early termination), compared to 
baseline Pro-C3 from the screening visit. 
The following additional objectives are applicable for cohort 2 only: 
1. To assess the ability of changes in the MBT to reflect changes in 
liver stiffness as measured by “Fibroscan” elastography at the 48 
week visit (or earlier if there was an early termination) compared to 
the screening visit.  
2. To assess the ability of changes in the MBT to reflect changes in 
the Model for End-stage Liver Disease (MELD) score at 24 and 48 
week visits compared to study day 1. 
3. To assess the ability of changes in the MBT to reflect changes in 
the Child-Turcotte-Pugh Scoring (CTP) score at weeks 24 and 48 
(or early termination) compared to study day 1. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 10 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Exploratory 
Efficacy 
Objectives: 
To assess the ability of the MBT to monitor patient status in comparison to 
other available measures, such as Liver Fibrosis stage, NAS, MELD, CTP, 
PDFF, Liver Stiffness, Serum Biomarker or Pro-C3.  
Safety Objective: 
Evaluation of safety related to the MBT. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 11 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Study Design: 
This study is a feasibility companion protocol that will rely on the data 
generated by BMS's studies of BMS-986036 (PEG-FGF21) under protocols 
MB130-068 and MB130-069 (IND 125297), which are assessed in this 
companion protocol as two separate study cohorts (1 and 2, respectively) 
with the exception of the MBT. The MB130-068 and MB130-069 studies 
are Phase 2b, multicenter, double-blind, randomized, placebo-controlled, 
parallel-group studies to demonstrate the safety and efficacy of BMS-
986036 in the treatment of subjects with NASH and stage 3 liver fibrosis or 
compensated cirrhosis with up to 48 weeks of treatment. The study is 
feasibility for drug response monitoring however the data may be 
used for Exalenz for future submissions. 
 
As described in the BMS protocols, subjects will be enrolled and 
randomized via interactive response technology (IRT) to receive BMS-
9860936 10mg QW, BMS-986036 20mg QW, BMS-9860936 40mg QW or 
matching placebo QW in a 1:1:1:1 ratio. 
 
The BMS studies' treatment durations will each consist of two periods: 
1. A 48-week, Double-Blind Treatment Period, during which the 
subjects will receive blinded study medication (BMS-986036 
10mg, 20 mg, 40mg QW or matching placebo QW). During the 
Double-Blind Treatment Period, subjects will be evaluated for 
safety and efficacy every 4 weeks (±5 days) through week 24 and 
every 8 weeks (±5 days) from week 24 through week 48. 
2. A Follow up Period, during which subjects will be evaluated for 
safety and efficacy for 4 weeks through week 52. 
3. A Follow-Up Period of at least 6 months and up to 14 months after 
the week 52/ PTFU Visit for the collection of additional DXA 
assessment (in all participants) and immunogenicity assessments 
(in participants for whom Long-Term Immunogenicity Follow-Up 
Visits are required.) Any liver related complication event will be 
recorded. 
 
The last dose of study medication will be at the week 48 visit. Subjects will 
have a safety and efficacy evaluation at week 48 and return for a post-
treatment follow-up evaluation through week 52.  
 
As a sub-study of BMS protocols MB130-068 and MB130-069, MBT will 
be performed at the day 1 visit and every 24 weeks during the Double-Blind 
Treatment Period in order to allow the assessment whether BMS-986036 
compared to placebo improves liver metabolic function as determined by the 
MBT. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 12 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Inclusion Criteria: 
This protocol follows the inclusion criteria as defined in the respective main 
protocols; MB130-068 and MB130-069 are considered as two distinct study 
cohorts for this companion protocol. This feasibility companion protocol 
intends to assess the data for all subjects that perform the MBT under the 
MB130-068 and MB130-069 protocols, including their clinical follow up 
information. 
Exclusion 
Criteria: 
Exclusion criteria are defined in the respective main protocols; MB130-068 
and MB130-069, and are considered as two distinct study cohorts for this 
feasibility companion protocol. Additionally, subjects designated to perform 
the MBT that are known to be hypersensitive or allergic to Methacetin or its 
metabolites, e.g. acetaminophen (paracetamol), will not perform the MBT. 
Pre Breath Test 
Restrictions: 
1. Subject should be fasting, including all oral morning medications 
(except for beta-blockers and study drug [BMS-986036 or placebo]), for 
at least 8 hours prior to the test  
2. Subject should not smoke on the day of the breath test prior to the breath 
test  
3. Subject should not take any of the following drugs within 48 hours prior 
to the test: acyclovir, allopurinol, carbamazepine, cimetidine, 
ciprofloxacin, daidzein (herbal), disulfiram, echinacea, enoxacin, 
famotidine, 
fluvoxamine, 
methoxsalen, 
mexiletine, 
montelukast, 
norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, 
terbinafine, ticlopidine, thiabendazole, verapamil, zileuton or any 
medication that might interfere with methacetin metabolism or might 
affect CYP1A2 (cytochrome P450 1A2) 
4. Subject should not take amiodarone within 30 days prior to the test  
5. Subject should not take paracetamol (acetaminophen) related 
medications within the 24 hours prior to the test  
6. Subject should not perform the test if allergic or hypersensitive to 
Methacetin or its metabolites (paracetamol, acetaminophen) 
7. Subject should not consume any alcohol or caffeine within 24 hours 
prior to the test  
8. Subject should not have general anesthesia or sedation within 24 hours 
prior to the test 
9. Subjects on beta-blockers or statins should be on a stable dose at least 30 
days prior to the test 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 13 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Primary Efficacy 
Endpoint 
The MBT's ability to measure the effect of BMS-986036 treatment on the 
metabolic capacity of the liver at 24-week intervals during the Double-Blind 
Treatment Period, as compared to changes in placebo treated subjects. 
Secondary 
Efficacy Endpoint 
measures: 
In order to assess the correlation of MBT with other measures of liver 
disease, the following endpoint measures will be collected: 
For all study cohorts: MBT results for each MBT visit (day 1, week 24, 
week 48) as well as changes in MBT results (CPDR30/PDR peak or other 
breath test parameters).  
 
The other measures of liver disease that will also be collected in this study 
are as follows: 
 
Liver Fibrosis stage and NAS as determined by Liver Biopsy, PDFF as 
determined by MRI where available, Liver Stiffness as determined by MRE 
where available, Serum Biomarker Pro-C3.  
 
Additional measures for cohort 2 include: MELD and CTP scores, Liver 
Stiffness as determined by Fibroscan® Elastography, Liver-related Clinical 
Outcome defined as the first occurrence of any one of the following: all-
cause mortality, MELD score ≥15, liver transplant, hepatocellular carcinoma 
(HCC), ascites requiring medical intervention, hospitalization (≥ 24 hours) 
for onset of variceal bleeding, hepatic encephalopathy and spontaneous 
bacterial peritonitis. 
Statistical 
Analysis: 
The 13C-Methacetin Breath Test will primarily be assessed for its ability to 
measure the effect of BMS-986036 on the metabolic capacity of the liver at 
24-week intervals during the Double-Blind Treatment Period as compared to 
placebo, by modelling the MBT results and the change in its value from 
previous visits, including the baseline MBT, to each of the subsequent visits 
using Mixed Effect Model for Repeat Measurements (MMRM). 
Secondary endpoints will be assessed through Cox and Linear regressions in 
order to test for prognostic value and correlations between MBT and other 
Liver related outcomes and measures. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 14 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
3 BACKGROUND 
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic 
liver disease in the world today. Nonalcoholic steatohepatitis (NASH), which is the most 
progressive form of NAFLD, is defined as the presence of hepatic steatosis and 
inflammation with hepatocyte injury (ballooning), with or without fibrosis. NASH is 
associated with increased mortality rates due to cardiovascular-, liver-, and cancer-related 
deaths.  
Currently, there are no approved drugs for the treatment of NASH. With the increasing 
prevalence of obesity and obesity-related diseases, NASH could soon become the leading 
indication for liver transplantation and the leading cause of hepatocellular carcinoma 
(HCC). There is an urgent need to develop preventative and therapeutic strategies against 
NASH, as clearly described in the BMS'-studies main protocols. 
Standard biochemical and clinical tests are not capable of providing good correlations with 
disease staging and grading. Furthermore, it is known that in a substantial percentage of the 
diseased population, standard liver function tests do not show abnormal results. 
Histological parameters have been shown to be correlated to liver disease severity,(1) but 
biopsies have limitations such as sampling error and the risks involved in the biopsy 
procedure itself. Furthermore, biopsies are not a measure that can be repeated often enough 
in standard practice in order to monitor disease progression and effect of therapeutic 
treatments. 
The unmet clinical need for a non-invasive means to evaluate liver disease progression or 
response to therapy accurately is clearly a challenge that needs to be addressed as new 
NASH treatments are being developed. 
The concept of a metabolic test that could be utilized to assess the severity of liver disease 
was first explored several decades ago. Such tests are performed by administering a 
compound, either orally or intravenously, with the compound being taken up by the liver or 
metabolized. The end-products of the metabolic process can be measured in either blood, 
bile, urine, saliva or exhaled breath, supplying a measurable value to the level of liver 
metabolic activity. Several compounds have been utilized to evaluate hepatic metabolic 
function in this manner, including indocyanine green, galactose, aminopyrine, caffeine, 
lidocaine, phenylalanine, Methacetin (N-(4-Methoxy-phenyl) acetamide) and Octanoate 
(sodium-octanoate). For example, previous studies have demonstrated that hepatic 
metabolism of lidocaine to monoethylglycinexylidide (MEGX) decreases with liver 
fibrosis and cirrhosis and improves with successful treatment of the underlying liver 
disease. Furthermore, these studies showed the lidocaine test could accurately predict 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 15 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
which subjects with stable cirrhosis awaiting liver transplantation were at risk of 
developing future hepatic decompensation. Most of these methods have been abandoned 
due to impracticality or undesired side effects. 
Exalenz Bioscience Ltd. has developed breath test products consisting of a combination of 
a medical device and various 13C-labeled substrates for gastrointestinal and liver 
applications. 
The rate and pattern of changes in the 13CO2/12CO2 ratio curve in exhaled breath reflect 
substrate metabolism, i.e. the liver's metabolic capacity. 
The aim of the Company is to provide a non-invasive, point-of-care, breath test to assess 
disease severity and to monitor disease progression (improvement or deterioration) using 
13C-Methacetin. 
3.1 Defining the need for a non-invasive test for the characterization of 
NASH progression 
About 7.9% of the US population has persistently elevated liver enzymes with negative 
findings for viral hepatitis and other common causes of liver diseases(2). Over 80% of such 
cases are estimated to be due to NAFLD (NAFL or NASH). In those who have 
concomitant features of the metabolic syndrome, the likelihood of developing NAFLD 
exceeds 90%. It is also known that in a substantial percentage of the diseased population, 
standard tests do not show abnormal results, especially in the NAFLD population. 
Furthermore, the standard biochemical and clinical tests do not provide good correlation 
with disease staging and grading. 
Currently, such subjects are offered a liver biopsy as standard of care to diagnose NASH 
and assess the risk of potential cirrhosis. Although histology results have been shown to be 
correlated to liver disease severity,(1), biopsies have limitations such as sampling error and 
risks involved in the actual biopsy procedure. Additionally, given the sheer numbers of 
subjects with NASH in the world, it is not logistically feasible to biopsy all subjects with 
NASH. Furthermore, biopsies are not a measure that can be repeated often enough in 
standard practice in order to monitor disease progression or response to treatment. 
Based on all of the above, there is a great need for a simple non-invasive method to assess 
and monitor disease progression in the NAFLD/NASH population. 
Breath testing with 13C-labeled substrates provides a safe, non-invasive means for 
evaluating hepatic impairment as it pertains to liver metabolic function. 13C is a stable, non-
radioactive isotope, which can be incorporated into a specific location within a test 
substrate so it can be metabolized to 13CO2 by the liver. 13C-Methacetin has been identified 
as such an appropriate substrate. 
The device being used is a molecular correlation based spectrometer, using a patented 
technology based on specific light source emissions and the different absorption of 13CO2 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 16 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
and 12CO2 gases. This technology is already implemented in a similar device approved for 
marketing in Europe and cleared in the USA for other disease testing, namely H. pylori 
infection. 
The 13C-labeled substrates (in this case 13C-Methacetin) are metabolized by the target organ 
under investigation (in this case the liver), producing 13CO2 which in turn leads to changes 
in the 13CO2/12CO2 ratio in a subject's exhaled breath over time. These ratio changes are 
displayed in real time on the device's screen and printed at the end of the test. 
Breath tests using the 13C-Methacetin are being evaluated in this protocol in an attempt to 
find an effective non-invasive tool to monitor liver disease progression/regression with and 
without treatment in NAFLD/NASH, and to assist in assessing disease severity and risk for 
decompensation. 
3.2 Rationale to use the MBT for assessment of Liver Disease 
Progression 
Tests of true hepatic function that rely on the metabolism of administered exogenous 
compounds have not yet been widely adopted in clinical practice because they have been 
cumbersome to perform and the acquisition of results is slow. The recent development of 
the BreathID® MCS analyzer offers a unique opportunity to demonstrate a metabolism-
based test showing agreement with disease progression/regression and liver biopsy 
measures. 
In advanced liver disorders, the liver has reduced Methacetin metabolic capacity, leading to 
low MBT values. Low values of Methacetin metabolism are suggestive of Subjects who 
have advanced liver disease. Several MBT output variables (percentage dose recovery rate 
and cumulative percentage dose recovered - PDR/CPDR values at different time points and 
their combination) may be used to assess metabolic capacity and subsequently liver disease 
progression/regression. 
It has been shown in preliminary studies that MBT correlates with both CTP and MELD 
values. It may be even more sensitive and a better predictor of liver function because 
generally function deteriorates prior to the development of complications of cirrhosis and a 
decline in liver function as assessed by CTP and MELD(3).  
It is hypothesized that a decline in liver function as assessed by MBT measured serially 
over time will occur prior to the development of complications of cirrhosis (such as 
variceal bleeding, ascites and hepatic encephalopathy) and worsening in liver function as 
assessed by changes in CTP and MELD. 
The MBT, by providing immediate results, could aid in decision making in Subjects with 
cirrhosis awaiting liver transplant. Such a test may in the future help in decision-making 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 17 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
regarding transplantation priority and provide point of care assessment of therapeutic 
interventions if relevant. 
All liver-related clinical outcome events will be captured in this study (see section 7.7.2). 
One of this study’s aims is to show the ability of the 13C-methacetin breath test to identify 
Subjects at risk for decompensation and to determine the effect of BMS’ study drug BMS-
986036 on the metabolic capacity of the liver at 24-week intervals during the Double-Blind 
Treatment Period compared to placebo. 
4 INTENDED USE / INDICATION FOR USE 
The ¹³C-Methacetin Breath Test is a non-invasive test intended as an aid to assess liver 
disease progression (improvement or deterioration) with or without treatment in adult 
subjects by measuring the ability of the liver to metabolize ¹³C-Methacetin. 
 The ¹³C-
Methacetin Breath Test may also have a prognostic value in assessment of adult Subjects at 
risk for liver disease deterioration. 
5 STUDY DESIGN 
Please refer to protocols MB130-068 and MB130-069.  
This study is a feasibility companion protocol that will use the data generated by BMS's 
study of BMS-986036 under protocols MB130-068 and MB130-069 (IND 125297), which 
are considered in this companion protocol as two separate study cohorts (1 and 2, 
respectively). The MB130-068 and MB130-069 studies are Phase 2b, multicenter, double-
blind, randomized, placebo-controlled, parallel-group studies to evaluate the safety and 
efficacy of BMS-986036 in improving fibrosis without worsening of NASH, and long term 
clinical outcomes in subjects with NASH and stage 3 liver fibrosis or compensated 
cirrhosis. The study is feasibility for drug response monitoring however the data may be 
used for Exalenz for future submissions. 
 
The study will consist of 4 periods:  
 A 4 to 8-week Screening Period 
 A 48-week, Double-Blind Treatment Period, during which the subjects will receive 
blinded study medication (BMS-9860936 10mg QW, BMS-986036 20mg QW, BMS-
9860936 40mg QW or matching placebo QW in a 1:1:1:1 ratio). 
 Study visits every 4 weeks up to week 24 and every 8 weeks after week 24 up to 
week 48, while MBT will only be performed every 24 weeks. 
 A Follow up Period, during which subjects will be evaluated for safety and efficacy 
for 4 weeks through week 52. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 18 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
 A Follow-Up Period of at least 6 months and up to 14 months after the week 
52/PTFU Visit for collection of any liver related complication event. 
 
As part of the MB130-068 and MB130-069 studies, the MBT will be performed on Day1 
and every 24 weeks during the Double-Blind Treatment Period, to assess whether BMS-
986036 compared to placebo improves liver metabolic function as determined by the 
Methacetin Breath Test. 
6 SUBJECT SELECTION 
This feasibility companion protocol assesses the data for all subjects being enrolled under 
MB130-068 and MB130-069 protocols that consent to perform the MBT at sites 
performing MBT. Subjects will be screened according to the inclusion/exclusion criteria of 
the MB130-068 and MB130-069 protocols, and will be randomly assigned to a study 
treatment arm if they meet all the criteria. Those Subjects enrolled into those two separate 
BMS sponsored studies (MB130-068, MB130-069, respectively) and will be considered as 
two separate study cohorts (cohort 1 and 2, respectively) for this companion protocol. 
6.1 Inclusion Criteria  
This protocol follows the inclusion criteria as defined in the respective main protocols; 
MB130-068 and MB130-069 considered as two distinct study cohorts for this companion 
protocol. This feasibility companion protocol assesses the data for all subjects that perform 
the breath test under the MB130-068 and MB130-069 protocols, including their clinical 
follow up information. 
Cohort 1 includes study Subjects with NASH and stage 3 fibrosis that meet all the MB130-
068 study criteria that performed the MBT. 
Cohort 2 includes study Subjects with NASH and compensated liver cirrhosis that meet all 
the MB130-069 study criteria that performed the MBT. 
6.2 Exclusion Criteria  
Exclusion criteria are as those in the respective BMS protocols; MB130-068 and MB130-
069 considered as two distinct study cohorts for this companion protocol. Additionally, 
subjects designated to perform the MBT that are known to be hypersensitive or allergic to 
Methacetin or its metabolites, e.g. acetaminophen (paracetamol), may not perform the 
MBT. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 19 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
6.3 Exclusion Criteria from MBT testing On the day of the test 
1. 
Subject should be fasting, including all oral morning medications (except for 
beta-blockers and study drug [BMS-986036 or placebo]), for at least 8 hours 
prior to the test  
2. 
Subject should not smoke on the day of the breath test prior to the breath test  
3. 
Subject should not take any of the following drugs within 48 hours prior to 
the test: acyclovir, allopurinol, carbamazepine, cimetidine, ciprofloxacin, 
daidzein (herbal), disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, 
methoxsalen, mexiletine, montelukast, norfloxacin, phenylpropanolamine, 
phenytoin, propafenone, rifampin, terbinafine, ticlopidine, thiabendazole, 
verapamil, zileuton or any medication that might interfere with methacetin 
metabolism or might affect CYP1A2 (cytochrome P450 1A2) 
4. 
Subject should not take amiodarone within 30 days prior to the test  
5. 
Subject should not take paracetamol (acetaminophen) related medications 
within the 24 hours prior to the test  
6. 
Subject should not perform the test if allergic or hypersensitive to Methacetin 
or its metabolites (paracetamol, acetaminophen) 
7. 
Subject should not consume any alcohol or caffeine within 24 hours prior to 
the test  
8. 
Subject should not have general anesthesia or sedation within 24 hours prior 
to the test 
9. 
Subjects on beta-blockers or statins should be on a stable dose at least 30 
days prior to the test 
6.4 Consenting 
Prior to study participation Subjects’ and/or their representative will be consented and sign 
two informed consent forms (ICFs): One appropriate consent form as part of BMS's 
MB130-068 or MB130-069 studies  and another appropriate separate ICF as part of BMS' s 
MBT sub-study according to IRB preference. 
The consent will include willingness to share data with Exalenz and allow acquisition and 
collation of blood, clinical and imaging data taken on entry to the study, and incorporate all 
other data from the time of admission until the subject's termination from the study. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 20 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
7 STUDY OBJECTIVES  
The feasibility companion study aims to evaluate the capabilities of the MBT to assess the 
progression of NASH and monitor changes in NASH subjects with significant fibrosis or 
compensated cirrhosis with and without treatment. 
7.1 Primary Efficacy Objective 
To demonstrate the ability of the MBT to evaluate patient response to treatment with 
BMS-986036 comparing placebo to each treatment arm individually. Assessment will be 
performed at 24 and 48 weeks and compared to day 1 (change from baseline) and the 
respective preceding visit (change between visits), when available. Assessments will be 
done for each study cohort independently, according to availability and on the combined 
population of the two cohorts by dose of the BMS drug under study. 
7.2 Secondary Efficacy Objectives 
The following assessments will be done by treatment arm and combined arms for each 
study cohort independently, according to availability, and on the combined population of 
the two study cohorts by dose of the BMS drug under study:  
1. To demonstrate the short and long-term prognostic value (3 months, 6 months and 
1 year, respectively) of MBT for liver disease deterioration (reported as liver-
related clinical outcome events). Assessment will be performed using MBT from 
the day 1, and 24 and 48 week visits. 
2. To assess the ability of changes in the MBT to reflect biopsy proven changes in 
fibrosis and/or NAS as assessed by a central reader at week 24 (or at least week 20 
in cases of an early termination time point) (for cohort 1) or at week 48 (for cohort 
2) compared to the baseline biopsy from the screening visit. 
3. To assess the ability of changes in the MBT to reflect changes in liver stiffness as 
measured by Magnetic Resonance Elastography (MRE) where available at weeks 
24 and 48 (or at early termination) compared to baseline MRE from the screening 
visit. 
4. To assess the ability of changes in the MBT to reflect changes in Proton Density 
Fat Fraction (PDFF) as measured by Magnetic Resonance Imaging (MRI)  where 
available - at weeks 24  and 48 (or early termination), compared to baseline  MRI 
from the screening visit. 
5. To assess the ability of changes in the MBT to reflect changes in Serum Pro-C3 at 
24 and 48 weeks of treatment (or early termination), compared to baseline Pro-C3 
from the screening visit. 
 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 21 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
The following additional objectives are applicable for cohort 2 only: 
1. To assess the ability of changes in the MBT to reflect changes in liver stiffness as 
measured by "Fibroscan" elastography at the 48 week visit (or earlier if there was 
an early termination) compared to the screening visit.  
2. To assess the ability of changes in the MBT to reflect changes in the Model for 
End-stage Liver Disease (MELD) score at 24 and 48 week visits compared to study 
day 1. 
3. To assess the ability of changes in the MBT to reflect changes in the Child-
Turcotte-Pugh Scoring (CTP) score at weeks 24 and 48 (or earlier if there was an 
early termination) compared to study day 1. 
7.3 Exploratory Efficacy Objectives 
To assess the ability of the MBT to monitor patient status in comparison to other available 
measures, such as Liver Fibrosis stage as assessed by NAS, MELD, CTP, PDFF, Liver 
Stiffness, Serum Biomarker or Pro-C3.  
7.4 MBT Safety Objective 
All adverse events, serious adverse events (SAEs), suspected unexpected serious adverse 
reactions (SUSAR) and unanticipated adverse device effects (UADE) will be reported 
according to local regulations. The actual reporting is discussed in section 11. No breath-
test related serious adverse events are expected. For more information please refer to the 
Investigator's Brochure.  
7.5 Primary Efficacy Endpoint 
MBT measurements throughout this feasibility companion study and all clinical measures 
and outcomes as assessed under protocols MB130-068 and MB130-069 will be collected 
in order to assess the MBT's ability to measure the effect of BMS-986036 treatment on the 
metabolic capacity of the liver at 24 week intervals during the Double-Blind Treatment 
Period, up to 48-weeks, as compared to changes in placebo treated subjects. 
Assessments will be done for each study cohort independently and according to 
availability, on the combined population of the two study cohorts by dose of the BMS 
drug under study. 
7.6 Secondary Efficacy Endpoint measures 
In order to assess the correlation of MBT with other measures of liver disease the following 
endpoint measures will be collected: 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 22 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
For all study cohorts: MBT results for each MBT visit (day 1, week 24, week 48,) as well 
as changes in MBT results (CPDR30/PDR peak or other breath test parameters).  
 
The other measures of liver disease that will be collected in this study are as follows: 
 
Liver Fibrosis stage and NAS as determined by Liver Biopsy, PDFF as determined by MRI 
where available, Liver Stiffness as determined by MRE where available, Serum Biomarker 
Pro-C3  
 
Additional measures for cohort 2: MELD and CTP scores, Liver Stiffness as determined by 
Fibroscan® Elastography, Liver-related Clinical Outcome defined as the first occurrence of 
any one of the following: all-cause mortality, MELD score ≥15, liver transplant, 
hepatocellular carcinoma (HCC), ascites requiring medical intervention, hospitalization (≥ 
24 hours) for onset of variceal bleed, hepatic encephalopathy, spontaneous bacterial 
peritonitis. 
7.7 Efficacy Variables 
Study procedures and timing are summarized in the Schedule of Events of protocols 
MB130-068 and MB130-069. 
The following procedures or tools will be used to assess subjects’ disease activity during 
the study: 
 MBT at selected sites in subjects who opt in at Day 1, week 24 and week 48.  
 Liver biopsy at Screening (if no biopsy is available from within 6 months of the 
Screening Visit), week 24 (for subjects in protocol MB130-068/cohort 1) or week 48 
(for subjects in protocol MB130-069/cohort 2) 
o Histological assessments of fibrosis stage and NASH activity (NAS) 
 Liver stiffness as determined by MRE at selected sites at screening, week 24 and week 
48 
 Hepatic fat fraction as determined by MRI at selected sites at screening, week 24 and 
week 48.  
 Serum Biomarker Pro-C3 at Screening, Day 1, week 24, week 48 and week 52. 
Additional variables for cohort 2: 
 Fibroscan® elastography at Screening and week 48 or early termination 
 MELD Scores at Screening, Day 1, every 4 weeks up to week 24, every 8 weeks up to 
week 48 and week 52.  


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 23 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
 Child-Pugh scores at Screening, Day 1, every 4 weeks up to week 24 and every 8 weeks 
up to week 48 and week 52.  
 Liver-related Clinical outcome events at each visit from Day 1 through week 52 and 
during the Long-Term Bone Mineral Density and Immunogenicity Follow-Up Period 
(up to 14 Months after week 52).  
7.7.1 Liver Biopsy 
Liver biopsy will be conducted at Screening if no liver biopsy is available within 6 months 
prior to Screening. Liver biopsy will also be performed at week 24 (for cohort 1) or week 
48 (for cohort 2). 
All histological assessments will be performed by a blinded central reader. The central 
reader will be a medical doctor, board certified in pathology, with experience in liver 
pathology in a clinical study setting. Details on the acquisition, quality requirements, 
histological preparation, and shipping of histological samples are in the respective Study 
Reference Manual. 
7.7.1.1 Histological Assessments 
The NASH Clinical Research Network (CRN) system will be used to score the histologic 
samples. The NASH CRN system is based on the concept that necro-inflammatory lesions 
and stage of fibrosis should be evaluated separately; it assesses liver biopsies for degree of 
steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2), and fibrosis (0-
4). The first 3 components are added together in an unweighted fashion to determine the 
NASH activity score (NAS) that ranges from 0 to 8. Fibrosis is staged separately on a 0-4 
scale: 0 (none); 1 (perisinusoidal or periportal); 2 (perisinusoidal and portal/periportal); 3 
(bridging fibrosis); 4 (cirrhosis). It should be noted, the NAS should not be considered a 
replacement for a pathologist’s diagnosis of NASH. 
Table 1 NAS Scoring System 
Histology Variable 
Grade 
Score 
Steatosis Grade 
< 5% 
0 
5-33% 
1 
> 33-66% 
2 
>66% 
3 
Lobular Inflammationa 
none 
0 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 24 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Histology Variable 
Grade 
Score 
< 2 
1 
2-4 
2 
> 4 
3 
Ballooning 
none 
0 
few 
1 
many 
2 
a foci per x200 field 
Liver biopsy samples will be used by the site to assess NASH and fibrosis stage as per the 
site's standard practice. 
7.7.2 Clinical Outcome Events 
Cohort 2 will be evaluated for the following liver-related clinical outcome events at every 
visit during the treatment periods: 
o All-cause mortality 
o MELD score ≥15 (with at least a 2-point increase from Baseline) 
o Liver transplant 
o Ascites requiring medical intervention 
o Hospitalization (≥24 hours) for onset of variceal bleed 
o Hospitalization (≥ 24 hours) for hepatic encephalopathy 
o Hospitalization (≥ 24 hours) for spontaneous bacterial peritonitis 
o HCC 
7.7.3 Magnetic Resonance Elastography (MRE) 
Magnetic Resonance Elastography (MRE) is a non-invasive medical imaging technique 
that measures the stiffness of soft tissues by introducing shear waves and imaging their 
propagation using MRI. In NASH Subjects, MRE is reproducible, and it has a higher inter-
observer agreement for staging fibrosis compared to histopathology. Additionally, an 
improvement in MRE has been associated with an improvement in liver fibrosis, as 
observed on liver biopsy.  
While the ability to perform MRE is expanding, appropriate hardware and software is not 
available at every institution and therefore, MRE use is still limited. In this study, MRE 
will only be conducted at selected sites with MRE capability. Images will be collected by 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 25 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
the site and submitted to a central imaging vendor for evaluation. Sites will be trained 
before collecting images. 
Adequacy of MRE should be confirmed by the central imaging vendor prior to 
randomization and throughout the study and repeat imaging may be required due to QC 
failure. 
Detailed instructions on the conduct of the MRE, and the acquisition and submission of 
MRE data to the central reader will be provided in the study specific Imaging Manual. 
Any incidental findings of potential clinical relevance that are not directly associated with 
the objectives of the study should be evaluated and handled by the investigator per the 
site’s standard of care and clinical judgment. 
MRE will be performed at selected sites at Screening, week 24 and week 48 or early 
termination. 
For subjects discontinuing study treatment, MRE will only be conducted if the date of 
discontinuation is more than 8 weeks from the date of the previous MRE. 
7.7.4 Fibroscan® Elastography 
Fibroscan® is a non-invasive device that assesses the ‘hardness’ (or stiffness) of the liver 
via the technique of transient elastography. This procedure will only be performed for 
study cohort 2. Liver hardness is evaluated by measuring the velocity of a vibration wave 
(also called a ‘shear wave’) generated on the skin. Shear wave velocity is determined by 
measuring the time the vibration wave takes to travel to a particular depth inside the liver. 
Because fibrous tissue is harder than normal liver, the degree of hepatic fibrosis can be 
inferred from the liver hardness. 
With the subject lying supine, an ultrasound-like probe is placed on the skin over the liver 
area, typically in the right mid-axillary line. The subject will feel a gentle ‘flick’ each time 
a vibration wave is generated by the probe.  
A minimum of 10 valid readings, with at least a 60% success rate and an interquartile range 
of ≤ 30% of the median value, are taken with the results expressed in kilopascals (kPa). 
7.7.5 Magnetic Resonance Imaging (MRI) 
At selected sites, proton density hepatic fat fraction Hepatic Magnetic Resonance Imaging 
(MRI) will be employed to determine hepatic fat fraction. This is a non-invasive and 
accurate MRI-based biomarker utilized for liver fat quantification by measuring the 
proportion of mobile proton density of the liver. In NASH Subjects, MRI-Proton Density Fat 
Fraction accurately classifies grades and changes in hepatic steatosis, and a ≥ 29% 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 26 of 38 
 
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CONFIDENTIAL AND PROPRIETARY 
reduction in MRI-Proton Density Fat Fraction has been associated with histological NAS 
improvement. 
Images will be collected by the site and submitted to a central imaging vendor for 
evaluation. Sites will be trained before collecting images. 
Adequacy of MRI will be confirmed by the central imaging vendor prior to randomization 
and throughout the study and repeat may be required due to QC failure. 
Detailed instructions on the conduct of the MRI, and the acquisition and submission of 
MRI data to the central reader will be provided in the study specific Imaging Manual. 
Any incidental findings of potential clinical relevance that are not directly associated with 
the objectives of the study are intended to be evaluated and handled by the investigator per 
the site’s standard of care and clinical judgment. 
Hepatic fat fraction is determined by MRI-based proton density fat fraction (PDFF) at 
Screening, week 24, and week 48/ET 
For subjects discontinuing study treatment, MRI should only be conducted if the date of 
discontinuation is more than 8 weeks from the date of the previous MRI 
7.7.6 Serum Biomarker Pro-C3 
Blood samples will be collected at each visit for the assessment of exploratory biomarkers. 
Exploratory biomarkers in serum, plasma, and whole blood, will be used to assess markers 
of fibrosis and associated diseases and pathways (including cardiovascular disease, 
inflammation, diabetes, kidney disease as well as liver disease, and possibly bone). These 
studies include amongst others, Serum Pro-C3, AN N-terminal propeptide of type 3 
procollagen (P3NP) and specific fragment of MMP-9-mediated degradation of type III 
collagen (C3M) 
Pro-C3 levels in Subjects will be measured at week 4, week 8, week 12, week 24, week 48, 
and week 52 (post treatment follow up) 
7.7.7 MELD Scoring 
MELD scoring, to be performed for cohort 2 (see Appendix 10 of study protocol MB130-
069) is a score for assessing the severity of chronic liver disease that does not include 
subjective variables such as ascites and encephalopathy. It employs the subject’s bilirubin, 
serum creatinine, and prothrombin time (INR).  
Blood samples will be taken for bilirubin, serum creatinine, and prothrombin time as part 
of the hematology and serum chemistry assessments conducted at each visit. The same 
central laboratory will be used for each evaluation. The central laboratory will calculate the 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 27 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
MELD score based on the laboratory values and communicate the score to the site. MELD 
scores will be determined at each study visit. 
7.7.8 Child-Turcotte-Pugh (CTP) Scoring 
The Child-Turcotte-Pugh (CTP) score assesses the severity of cirrhosis and will be done 
for cohort 2 Subjects. It has been shown to be an accurate measure across a broad spectrum 
of liver disease. It employs numerical scores of 5 measures of liver disease: total bilirubin, 
serum albumin, international normalized ratio for INR, ascites, and encephalopathy and is 
scored according to the scheme in Appendix 8 of study protocols MB130-068 and MB130-
069. The sum of scores from each component is the final score. 
Blood samples will be collected for the total bilirubin, serum albumin, and prothrombin 
time assessments used to calculate the CTP score as part of the hematology and serum 
chemistry assessments conducted at each visit. The same central laboratory will be used for 
each evaluation. Evaluations of ascites and encephalopathy are to be conducted by the 
same site personnel at each visit wherever possible. 
CTP scores will be determined at each study visit. 
7.7.9 13C-Methacetin Breath Test (MBT) 
The 13C-Methacetin Breath Test (MBT) is a non-invasive tool that provides an estimate of 
liver function by assessing microsomal capacity to metabolize the non-radioactive 13C-
labeled Methacetin. MBT measures carbon dioxide exhaled into a nasal cannula before and 
after drinking a non-radioactive solution (called ¹³C-methacetin), using a device called the 
BreathID® MCS device. The amount of 13carbon dioxide (13CO2) exhaled over 60-85 
minutes will then be measured. The MBT, which consists of both a device and an 
unapproved drug component, is considered an investigational device that has not been 
reviewed, approved or cleared by the FDA for marketing purposes.  
In Subjects evaluated/listed for liver transplantation, a reduction in exhaled 13CO2 has been 
associated with an increased risk of cirrhotic complications (3). MBT will be conducted at 
selected sites in subjects who provide consent. The test will be performed after an 8-hour 
fast according to study guidelines and as per the manufacturer’s instructions. 
MBT will be conducted at Day 1 visit prior to first dose of treatment, week 24 and week 
48. For participants discontinuing study treatment at sites selected for the MBT sub-study, 
MBT should be conducted only if the date of discontinuation is more than 12 weeks from 
the date of the previous MBT. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 28 of 38 
 
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CONFIDENTIAL AND PROPRIETARY 
8 SAFETY TERMINATION AND EARLY WITHDRAWAL OF 
SUBJECTS OR STUDY 
For safety termination and early withdrawal of subjects please refer to BMS’s protocols 
MB130-068 and MB130-069. 
8.1 Expected Study Duration 
BMS’s protocols MB130-068 and MB130-069 plan to have subjects remain on study for a 
total of at least 52 weeks including the Double-Blind Treatment Period and the post-
treatment follow-up visit (PTFU), unless intolerable side effects develop or the subject is 
withdrawn from study participation. Subjects will have up to an 8-week screening period, a 
4 week post-treatment follow-up visit and a Follow-Up Period of at least 6 months and up 
to 14 months after the week 52/PTFU.  
For participants discontinuing study treatment at sites selected for the MBT sub-study, 
MBT should be conducted only if the date of discontinuation is more than 12 weeks from 
the date of the previous MBT. 
9 STATISTICAL CONSIDERATIONS 
9.1 Study Design and Aim 
This study is designed as a feasibility companion protocol that will use the data generated 
by BMS’ studies of BMS-986036 under protocols MB130-068 and MB130-069 for which 
one of the exploratory objectives is to assess whether BMS-986036 compared to placebo 
improves liver metabolic function as assessed by the 13C-Methacetin Breath Test.  
Additional analyses may be performed by Exalenz on the data to be received from these 
BMS studies. The study is feasibility for drug response monitoring however the data may 
be used for Exalenz for future submissions. 
9.2 Endpoint Measures 
9.2.1 Primary endpoint measure 
In order to show the ability of the MBT to measure the effect of BMS-986036 
treatment on the metabolic capacity of the liver after 24 weeks, 48-weeks, as compared 
to changes in placebo treated subjects the primary endpoint will be analyzed using a 
Mixed Effect Repeated Measures (MMRM) Model. An unstructured correlation matrix 
will be used to model within-patient errors and restricted maximum likelihood 
estimation will be used. The Kenwood-Roger method will be used for the denominator 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 29 of 38 
 
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CONFIDENTIAL AND PROPRIETARY 
degrees of freedom. Should the model fail to converge with an unstructured covariance 
matrix, Toeplitz and Compound-Symmetric structures will be applied. 
The MMRM model will include change from baseline as outcome, and Study Arm, 
Visit, Study Arm*Visit Interaction, Baseline value and site as covariates. 
Assessments will be done for each study cohort independently and according to 
availability and on the combined population of the two study cohorts by dose of the 
BMS drug under study.  
A sensitivity analysis of the primary endpoint will be performed excluding subjects 
with significant protocol violations. Additional sensitivity analyses will be performed if 
deemed necessary. Such analyses as well as additional details will be described in the 
SAP. 
9.2.2 Secondary endpoint measures 
The following assessments will be done by treatment arm and combined arms for each 
study cohort independently, according to availability and on the combined population of 
the two study cohorts by dose of the BMS drug under study: 
1. In order to assess the prognostic value of MBT in prediction of liver disease 
deterioration (reported as liver-related clinical outcome events), the endpoint 
measures will be point estimates of Cox Regression's Hazard Ratio or Logistic 
Regression's Relative Risk (as appropriate) at least at 48 weeks for classifying 
Subjects into risk groups for clinical deterioration with respective exact two-sided 
95% confidence intervals in the placebo and treatment arms as determined by MBT. 
2. Repeat MBT results (CPDR30/PDR peak or other breath test parameters) and their 
changes in subjects with and without treatment (BMS-986036) for nonalcoholic 
steatohepatitis (NASH) at Day 1, week 24 and 48 (or early termination) will be 
compared and tested for correlation to baseline as well as repeat results for the 
following measurements: 
a. Biopsy based Fibrosis and/or NAS score 
b. Liver stiffness as measured by MRE 
c. PDFF as measured by MRI  
d. Serum Pro-C3 results 
e. Liver elastography by Fibroscan (in cohort 2 only) 
f. MELD scores (in cohort 2 only) 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 30 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
CTP scores (in cohort 2 only) Linear Regression will be applied in order to test for 
significance of the correlations between MBT and the liver measurements listed 
above. 
Changes in MBT are measured as the difference between baseline and each of the 
MBT visits as well as the change in measurements between two subsequent visits in 
each of the two treatment groups. 
The metabolic capacity of the liver as determined by the MBT cumulative 
percentage dose recovery at 30 minutes (CPDR30) will be the main MBT parameter 
of interest. 
Nevertheless, available breath test parameters (Delta Over Baseline - DOB at the 
respective times) will be collected from the completed eCRFs. The DOBs will be 
transformed to percentage dose recovery – PDR, by normalizing the DOB using 
patient weight and height. The Area under the DOB and under the PDR curve will 
be calculated at 5-minute time intervals resulting in cDOB and cPDR at 5, 10, 15, 
20, 25, 30, 35, 40, 45, 50, 55 and 60 minutes respectively. Analyses may be done 
using any of the MBT derived parameters. 
9.2.3 Safety endpoints measure 
The cumulative incidence of adverse events, serious adverse events (SAE), suspected 
unexpected serious adverse reactions (SUSAR) and unanticipated adverse device effects 
(UADE) possibly or probably related to the use of the BreathID MCS device and its 
substrate or related to the procedure, will be collected and reported. 
9.3 Acceptance Criteria (Study Hypotheses) 
At least one cut-off in changes of MBT values will be determined to show that MBT is a 
potential measure that can assess the response to treatment for BMS-986036. 
At least one cut-off, to be determined by the algorithm being developed by Exalenz using 
data from IDE# G080227, will be validated in this study to classify Subjects into risk 
groups for deterioration of liver function related events.  
9.4 Sample Size  
Subjects that are enrolled into two separate BMS sponsored IND studies (MB130-068, 
MB130-069, respectively) at selected study sites will be offered the opportunity to perform 
the MBT and will be considered as two separate study cohorts (cohort 1 and 2, 
respectively) for this companion protocol. Each cohort consists of four treatment arms 
(BMS-986036 10mg, 20mg, 40mg QW or matching placebo QW) as defined in the 
respective BMS sponsored protocols. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 31 of 38 
 
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CONFIDENTIAL AND PROPRIETARY 
 
Cohort 1 consists of Subjects with NASH and stage 3 fibrosis, as assessed by a central 
laboratory reader of the liver biopsies (n=160), and who meet all the MB130-068 study 
criteria. 
 
Cohort 2 consists of Subjects with NASH and compensated liver cirrhosis (stage 4 fibrosis) 
as assessed by a central laboratory reader of the liver biopsies (n=100), and who meet all 
the MB130-069 study criteria. 
 
This feasibility companion protocol will include those 2 cohorts of subjects, which are 
planned for up to 260 subjects) from approximately 75 sites worldwide (USA and Japan) 
for the two BMS IND studies, while the MBT will only be conducted in the USA. 
Not all participating sites will elect to perform the MBT. The total number of subjects 
expected to perform the MBT may reach up to 250 subjects (also accounting for drop outs). 
Each subject will perform up to 3 MBTs over 1 year. 
9.5 Analysis sets 
Safety Analysis Set: 
All subjects enrolled under BMS' MB130-068 and MB130-069 studies who have 
performed the MBT test at least one time. 
Efficacy Analysis Set: 
All subjects enrolled under BMS' MB130-068 and MB130-069 studies who have 
successfully performed the MBT test and did not have any major protocol deviations for 
the current study. 
Safety analyses will be performed on the safety analysis set and efficacy analyses on the 
efficacy analysis set. 
9.6 Statistical Analysis  
9.6.1 General Considerations 
Statistical analyses will be performed using R software version 3.4.3 or higher (R 
Development Core Team. Vienna, Austria). 
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 (CL) are 
appropriate, the confidence level will be 95%. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 32 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
Baseline values are defined as the last valid value prior to investigational treatment start. 
Study data will be summarized by descriptive statistics. Continuous variables will be 
summarized by a mean, standard deviation, minimum, median and maximum, and 
categorical variables by a count frequency and percentage. Confidence intervals will be 
provided where relevant. 
9.6.2 Demographic and other Baseline Characteristics 
Demographic, medical and clinical history variables will be tabulated. Continuous 
variables will be summarized by a mean, standard deviation, minimum, median and 
maximum, and categorical variables by a count frequency and percentage. 
9.6.3 Disposition of Subjects 
The numbers of subjects who were enrolled will be provided, as well as the reasons for all 
enrollment discontinuations, grouped by major reason (e.g., lost to follow-up, adverse 
event, poor compliance). A list of discontinued subjects, protocol deviations, and subjects 
excluded from the efficacy analysis will be provided as well. 
9.6.4 Safety Analysis 
The adverse events possibly or probably related to Methacetin and/or the BreathID® MCS 
device will be presented along with a two sided 95% exact binomial confidence interval. 
The analysis of all adverse events will include incidence tables and will include analyses by 
severity, relationship to device or drug and baseline variables. 
9.6.5 Interim Analysis 
As part of BMS's MB130-068 protocol, an unblinded interim analysis of efficacy data will 
be conducted by a team separate from the blinded study team conducting and monitoring 
the study for the purpose of re-assessment of the response rate assumptions for the primary 
endpoint for BMS-986036 and placebo and re-estimate the sample size to provide adequate 
power if necessary. This interim analysis will be performed at a time to maximize the 
information available for the primary endpoint but without necessitating a pause in the 
recruitment for the study. Based on enrollment projections and given the 48-week follow-
up prior to liver biopsy, this interim analysis is expected to occur when post-treatment liver 
biopsy measurements are available for at least the first 100 randomized subjects from 
cohort 1. The sample size re-estimation will be based only on the primary histological 
endpoint from the liver biopsy, proportion of subjects with ≥ 1-stage improvement in 
fibrosis without worsening of NASH. The primary histology endpoint will be compared 
between BMS-986036 and placebo using a Wald statistic at a one-sided level of 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 33 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
significance of 0.005. It is also expected that the final sample size will be no more than 
50% higher than the original planned sample size. 
9.6.6 Pooling 
As there will be very few subjects enrolled at any given site, data from all sites will be 
pooled for analyses for each study cohort separately and combined cohorts.  
9.6.7 Handling of Missing Data 
The study variables cannot be evaluated for subjects for whom BreathID® MCS device 
MBT results are not available and therefore these subjects will be left out of the efficacy 
analysis. Subjects missing clinical outcome and biopsy results will be excluded from the 
analyses.  
10 STUDY PROCEDURES 
10.1  General 
The schedule of the breath tests is based on the schedule of the MB130-068 and MB130-
069 protocols. The first MBT will be performed on Day 1. The subsequent MBTs will be 
performed at 24 -week interval visits in the Double-Blind Treatment Period. 
10.2  Breath Test Procedure 
Preparation of the study subject 
Once consented, the Subjects will perform the breath test on day 1 prior to first dose 
treatment, at 24 and 48 weeks of treatment prior to dose uptake and biopsy procedure if 
relevant. In preparation for each breath test the patient will be asked to comply with the 
following precautions: 
1. Subject should be fasting, including all oral morning medications (except for beta-
blockers and study drug [BMS-986036 or placebo]), for at least 8 hours prior to the 
test  
2. Subject should not smoke on the day of the breath test prior to the breath test  
3. Subject should not take any of the following drugs within 48 hours prior to the test: 
acyclovir, allopurinol, carbamazepine, cimetidine, ciprofloxacin, daidzein (herbal), 
disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, 
montelukast, norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, 
terbinafine, ticlopidine, thiabendazole, verapamil, zileuton or any medication that 
might interfere with methacetin metabolism or might affect CYP1A2 (cytochrome 
P450 1A2) 
4. Subject should not take amiodarone within 30 days prior to the test  


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 34 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
5. Subject should not take paracetamol (acetaminophen) related medications within 
the 24 hours prior to the test  
6. Subject should not perform the test if allergic or hypersensitive to Methacetin or its 
metabolites (paracetamol, acetaminophen) 
7. Subject should not consume any alcohol or caffeine within 24 hours prior to the test  
8. Subject should not have general anesthesia or sedation within 24 hours prior to the 
test 
9. Subjects on beta-blockers or statins should be on a stable dose at least 30 days prior 
to the test 
Preparation of 13C-Methacetin 
Exalenz Bioscience Ltd. will provide 75 mg 13C-Methacetin doses in a 0.05% solution of 
¹³C-Methacetin in purified water, supplied, in amber thermoplastic polyester (PET) bottles 
with a child resistant plastic cap. No preparation is needed other than pouring the contents 
of the solution into a cup for ingestion. 
Performance of the breath test 
Only trained personnel will perform the breath test procedure. The actual breath collection 
is automatically performed by the device and is not operator dependent. If the IDcircuit (a 
nasal cannula manufactured specifically for Exalenz) is not connected properly to the 
subject (e.g. the breath does not reach the device), the BreathID® MCS device will prompt 
the operator to adjust the IDcircuit. 
1. Turn on the device from the switch in the rear and allow up to 1 hour for warm-up 
to complete. To perform the test, ensure that the BreathID® MCS screen shows that 
the device is in ‘Ready’ state. 
2. The IDcircuit will be attached to the BreathID® MCS device and to the patient. 
Pressing the “Start” button on the device will begin the collection of the patient’s 
baseline exhaled breath. This will take approximately 5-10 minutes. 
3. The 13C-Methacetin solution is poured into a disposable cup and administrated to 
the patient when prompted by the device. The solution should be administered by a 
medical practitioner registered on the delegation log or a research nurse if specific 
training for administration has been given. Immediately after ingestion, the operator 
will press the "Continue" button, which activates the actual measurement. CO2 
production with 13C may be visible within a few minutes in cases with relatively 
functional livers. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 35 of 38 
 
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CONFIDENTIAL AND PROPRIETARY 
Note: In rare cases, the administration of fluids may cause vomiting. If this happens, the 
test should be aborted and repeated on one of the subsequent days. The experienced 
adverse event should be reported in the appropriate CRF section.  
4. The patient should remain in a seated position breathing in a normal manner for up 
to 85 minutes, while data is collected. 
5. The BreathID® MCS device continuously measures and analyzes the patient’s 
exhaled breath in real time. As the 13C-Methacetin is metabolized, the value of the 
13CO2/12CO2 ratio in the exhaled breath will change and will be calculated in real 
time by the device. 
6. If at any time the device does not detect patient’s breath, or if there is any other 
deviation from the desired test requirements, the device will produce an appropriate 
warning message on the screen. 
7. At the completion of the MBT, the device screen will indicate that the test is 
completed and a printout will be generated. The IDcircuit is then removed and the 
patient is disconnected from the BreathID® MCS device. 
The patient will be under the supervision of the physician or any other qualified medical 
staff during the entire test. 
The operators will be trained how to terminate the breath test early. In the following 
situations, the MBT will be terminated and a termination form will be completed: 
1. The patient vomits after ingestion of the substrate. 
2. The BreathID® MCS device malfunctions (in this case, the operator will complete a 
technical complaint form in addition to the termination form and contact Exalenz 
immediately for further instructions) after ingestion of the substrate. 
In all these cases, MBT cannot be repeated the same day for that specific subject that has 
already ingested 13C-Methacetin. Efforts should be made to repeat the MBT on one of the 
subsequent days. An entry will be made in the drug/kit accountability log and the 13C-
Methacetin bottles will be kept for inspection by the study monitor. 
10.3  Investigational Product Handling 
The Investigator and Research Pharmacist (if relevant) will be provided with 
Investigational Product Handling Guidelines that will provide details regarding the 
packaging and labeling requirements, receipt of investigational product, dispensing and 
accountability procedures, preparation instructions, storage and stability of the 
Investigational product and disposition of the Investigational Product. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 36 of 38 
 
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CONFIDENTIAL AND PROPRIETARY 
10.4  Investigational Product Accountability 
The Investigator and Study Pharmacist (if relevant) are responsible for ensuring that all 
study supplies received at the site are inventoried and accounted for throughout the study. 
The dispensing of study substrate to the subject must be documented in the respective 
accountability form. The study Investigational Product must be stored in a limited access 
area or in a locked cabinet under appropriate environmental conditions. Unused study 
materials must be available for verification by the sponsor’s site monitor during on-site 
monitoring. The destruction of unused study materials (both, expired or unexpired) will be 
documented on the return/disposition form. The Sponsor will authorize destruction of 
excess supplies on site according to local policy or arrange collection of unused supplies. 
In the case of local destruction, before proceeding, the site must seek authorization from 
the Sponsor using the return/destruction form and this must also be documented on the 
Study Supply Return Form. 
Study substrate should be dispensed under the supervision of the investigator, a qualified 
member of the investigational staff, or by hospital clinical pharmacist. 
11 ETHICS & REGULATORY CONSIDERATIONS 
The protocol will be conducted in the US and Japan by BMS as Phase 2b studies of BMS-
986036, MB130-068 and MB130-069. As such, regulatory requirements that are relevant 
for pharmaceutical investigations in US and Japan that will be applicable during the studies 
are to be conducted and overseen by BMS. 
BMS will obtain for the main study an IND (IND-125297) and the applicable regulatory 
approvals for the MBT sub-study and the use  of clinical data from all regulatory 
authorities (if relevant) and ethics committees/IRBs. 
12 SAFETY CONSIDERATIONS 
All adverse events (AE), serious adverse events (SAE), suspected unexpected serious 
adverse reactions (SUSAR) and unanticipated adverse device effects (UADE) possibly or 
probably related to the use of the MBT product or related to the MBT procedure will be 
collected and reported according to local regulations. 
Safety assessments of the BMS study drug (BMS-986036) will be performed as described 
in BMS protocols MB130-068 and MB130-069. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 37 of 38 
 
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CONFIDENTIAL AND PROPRIETARY 
13 SUBJECT CONFIDENTIALITY 
The subject’s name and personal data will remain confidential and will not be published in 
any way. All data will be coded and stored in locked offices or on password protected 
computers. 
14 MONITORING AND QUALITY ASSURANCE 
This study is a companion protocol that will use the data generated by the BMS Phase 2b 
studies of BMS-986036, under protocols MB130-068 and MB130-069. BMS will ensure 
compliance with GCP, local regulations and scientific integrity and will manage and 
oversee the study conduct.  
15 PUBLICATION POLICY AND FINANCE 
It is intended that the results of the companion study will be reported and disseminated at 
international conferences and in peer-reviewed scientific journals. The policy regarding 
publications appears in the non-disclosure agreement signed by each study participant prior 
to signing of the contract. 
16 FINANCIAL ASPECTS  
The BreathID® MCS device and test kit including a nasal cannula and a solution containing 
13C-Methacetin will be provided by Exalenz Bioscience. BMS will be responsible for the 
funding of regulatory approvals in regards to their main protocols and administration as 
well as for the funding for study support of staff at local sites. 
17 STUDY TERMINATION 
This study is a companion protocol that will use the data generated by BMS from its Phase 
2b studies of BMS-986036 under protocols MB130-068 and MB130-069. BMS will be 
responsible for study termination procedures, when applicable. 
18 REFERENCES 
1. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, 
Goodman Z. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol 
agreement and ability to predict liver-related mortality. Hepatology 2011;53:1874-
1882. 
2. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated 
aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960-967. 


Exalenz Bioscience Ltd. 
Last update: February 20, 2018 
Study Title: Companion protocol for the ¹³C-Methacetin Breath 
Test (MBT)  for use in Bristol-Myers Squibb phase 2b studies 
for BMS-986036 (PEG-FGF21), under Protocols MB130-068 
and MB130-069 
Protocol: BMS-EX-0118 
Version: 1.0 
Document No: CSP000002 
Page 38 of 38 
 
Exalenz Bioscience Ltd.    2018 
 
CONFIDENTIAL AND PROPRIETARY 
3. Stravitz RT, Reuben A, Mizrahi M, Lalazar G, Brown K, Gordon SC, Ilan Y, et al. Use 
of the methacetin breath test to classify the risk of cirrhotic complications and mortality 
in Subjects evaluated/listed for liver transplantation. J Hepatol 2015;63:1345-1351. 
 

SAP_001.pdf: 
Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
 
Statistical Analysis Plan for: Companion 
protocol for the ¹³C-Methacetin Breath 
Test (MBT) for use in Bristol-Myers Squibb 
phase 2b studies for BMS-986036 (PEG-
FGF21), under Protocols MB130-068 and 
MB130-069 
  
SAP for Protocol No. BMS-EX-0118 
 
Document No: CSD00114 
Total pages: 21 
Version Level: 1.0 
Last update on: May 05, 2021 
Based On: BMS-EX-0118 Companion Protocol Version 1.0 from Feb 20, 2018 
 
 
Name 
Position 
Author / 
Owner 
Gil Guggenheim 
Clinical Research Development Manager 
Reviewed by 
Yishai Friedlander 
Biostatistician from StatistX  
Approved by 
Ofer Schlesinger 
Director  R&D  
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: 
Meridian Bioscience Israel Ltd.  4 Ha’Maayan St. Modiin, Israel 7177872 
 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
Page 2 of 21 
 
Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
Versions Control: 
Version 
Date 
Responsible Person Description of Change 
1.0 
May 05, 2021 
Gil Guggenheim 
Initial Release 
 
 
 
 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
Page 3 of 21 
 
Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
  
TABLE OF CONTENTS 
1 Abbreviations ........................................................................................................................ 5 
2 INTRODUCTION ................................................................................................................ 7 
3 STUDY OBJECTIVES AND ENDPOINTs ....................................................................... 8 
 
Study Objectives ............................................................................................................................. 8 
3.1.1 
Primary Objective ............................................................................................................................ 8 
3.1.2 
Secondary Objective ........................................................................................................................ 8 
3.1.3 
Exploratory Objective .................................................................................................................... 10 
3.1.4 
Safety Objective ............................................................................................................................. 10 
 
Study Endpoints ............................................................................................................................ 10 
3.2.1 
Primary Endpoint ........................................................................................................................... 10 
3.2.2 
Secondary Endpoints ..................................................................................................................... 10 
4 STUDY DESIGN ................................................................................................................ 11 
 
Sample Size Considerations ......................................................................................................... 12 
5 GENERAL CONSIDERATIONS FOR HANDLING OF MISSING DATA ............... 13 
 
Premature Withdrawal and Missing Data ..................................................................................... 13 
6 SIGNIFICANCE LEVELS AND HANDLING OF TYPE I ERROR........................... 14 
 
Type I Error .................................................................................................................................. 14 
7 ANALYSIS SETS ............................................................................................................... 14 
 
Safety Analysis Set (SA) .............................................................................................................. 14 
 
Efficacy Analysis Set (EA) ........................................................................................................... 14 
 
Modified Efficacy Analysis Set (mEA) ........................................................................................ 14 
8 STATISTICAL ANALYSES ............................................................................................. 15 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
Page 4 of 21 
 
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General Considerations for Data Analyses ................................................................................... 15 
 
Baseline Definitions...................................................................................................................... 15 
 
Disposition of Patients .................................................................................................................. 15 
 
Efficacy Analyses ......................................................................................................................... 16 
8.4.1 
Primary Endpoint ........................................................................................................................... 16 
8.4.2 
Secondary Endpoints ..................................................................................................................... 16 
 
Site Poolability ............................................................................................................................. 18 
 
Safety Analyses ............................................................................................................................ 18 
Appendix A - – Methacetin Breath Test Parameters .......................................................... 19 
 
 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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1 ABBREVIATIONS 
AE 
- Adverse Event 
cDOB 
- Cumulative Delta over Baseline 
CI 
- Confidence Interval 
CL 
- Confidence Limits 
CO2 
- Carbon dioxide 
cPDRxx 
- Cumulative Percentage Dose Recovery at xx minutes from ingestion  
CRF 
- Case Report Form 
CSR 
- Clinical Study Report 
CTP 
- Child-Turcotte-Pugh (score) 
DOB 
- Delta over Baseline 
DXA 
- Dual-Energy X-Ray Absorptiometry  
EA 
- Efficacy Analysis (set) 
eCRF 
- Electronic Case Report Form 
GCP 
- Good Clinical Practice 
HCC 
- Hepatocellular Carcinoma 
HE 
- Hepatic Encephalopathy 
HR 
- Hazard Ratio 
IRT 
- Interactive Response Technology 
ITT 
- Intent to treat (population) 
MBT 
- 
13C-Methacetin Breath Test 
MCS 
- Molecular Correlation Spectrometry  
MELD 
- Model for Endstage Liver Disease 
mEA 
- modified Efficacy Analysis (set) 
MMRM 
- Mixed Effect Repeated Measures (Model)  
NAFLD 
- Nonalcoholic Fatty Liver Disease 
NASH 
- Nonalcoholic Steatohepatitis 
PDR 
- Percent Dose Recovery rate (expressed as % per hour) 
PDRpeak 
- Maximal Percent Dose Recovery rate 
PP 
- Per Protocol (analysis set) 
PTFU 
- Post-Trial Follow-Up 
QW 
- One per week 
SA 
- Safety Analysis (set) 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
SAE 
- Serious Adverse Event 
SAP 
- Statistical Analysis Plan 
SBP 
- Spontaneous Bacterial Peritonitis 
SD 
- Standard Deviation 
SDV 
- Source Data Verification 
SF 
- Screen Failures 
SUSAR 
- Suspected unexpected serious adverse reaction 
UADE 
- Unanticipated Adverse Device Effect  
US 
- United States (of America) 
USA 
- United States of America 
 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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2 INTRODUCTION 
This Statistical Analysis Plan (SAP) was developed based on the original companion study 
protocol BMS-EX-0118 version 1.0, dated 20 February 2018, titled “Companion Protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers Squibb phase 2b studies for 
BMS-986036 (PEG-FGF21), under Protocols MB130-068 and MB130-069”. This SAP is an 
updated and more detailed companion to the “Statistical Methods” section of the original 
companion study protocol. 
The original protocol and most of the study documents were written and maintained by Exalenz 
Bioscience Ltd. before being acquired by and integrated into Meridian Bioscience, Inc., and 
renamed Meridian Bioscience Israel Ltd. Therefore “Meridian” and “Exalenz” can be referred 
to as interchangeable terms in this SAP. 
The companion protocol and this SAP describe how Exalenz intends to use the clinical data 
being obtained during the studies conducted by BMS sponsored IND studies: MB130-068 and 
MB130-069. The data collected as part of MB130-068 will be referred to as ‘cohort 1’ and the 
data collected as part of MB130-069 will be referred to as ‘cohort 2’. 
The enrollment phase and all MBT testing (incl. Day1, Week 24 and Week 48 visits) for the 
aforementioned BMS sponsored studies has been completed. The data is still being reviewed by 
BMS and the respective databases are planned to be made available to Exalenz between July and 
November 2021, after their respective data lock and release from BMS.  
The initially planned sample size of 250 subjects, per statistical section in the companion 
protocol, was not reached for multiple reasons: 
- 
The MBT testing as part of the BMS studies, was an opt in substudy, requiring an 
additional consent process. Subjects enrolled to the BMS studies were reluctant to add an 
additional investigational test to their study schedule. 
- 
The COVID-19 outbreak further complicated the enrollment and especially the follow up 
testing of already enrolled subjects, as visits were more and more conducted remotely and 
any breath testing was avoided during in person visits. 
Since the actual final sample size of subjects with valid MBT results at baseline and post-
treatment phase, across both BMS studies, is expected to be lower than 80, the statistical analyses 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
Page 8 of 21 
 
Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
for the study will be descriptive by nature. No formal statistical testing will be performed. 
Nominal p-values from statistical tests will be reported for suplementary information. 
When differences exist in methods, descriptions or explanations provided in the protocol and 
this SAP, the SAP prevails. 
Since this study is a companion to a pharmaceutical company’s study, the data management for 
the main study can independently determine as to when a data freeze or a data lock shall be 
performed. Therefore, for the Exalenz companion protocol purposes, any amendments to the 
SAP will be made prior to Exalenz independently accessing the data from the database freeze or 
lock, if available. In case additional analyses not described in the final SAP or deviations from 
the final SAP are required, they will be documented in the Clinical Study Report (CSR). 
3 STUDY OBJECTIVES AND ENDPOINTS 
 Study Objectives 
3.1.1 Primary Objective 
The data generated in this companion study will be used to demonstrate the ability of the 
MBT to evaluate patient response to treatment with BMS-986036, comparing placebo to 
each treatment arm individually. Primary efficacy assessment will be performed using 
the Week 24 and the Week 48 visit measures compared to Day 1 (change from baseline) 
for the combined population of the two cohorts, according to availability, by dose of the 
BMS drug under study.  
The same assessments for each study cohort independently will be reported.  
3.1.2 Secondary Objective 
The following assessments will be done by treatment arm by dose of the BMS drug under 
clinical invstigation and combined arms on the combined population of the two study 
cohorts: 
1. To demonstrate the short and long-term prognostic value (3 months, 6 months and 1 
year, respectively) of MBT for liver disease deterioration (reported as liver-related 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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clinical outcome events). Assessment will be performed using MBT from the Day 1, 
Week 24 and Week 48 visits. 
2. To assess the ability of changes in the MBT to reflect biopsy proven changes in 
fibrosis and/or NAS as assessed by a central reader, where available, at Week 24 (or 
at least Week 20 in cases of an Early Termination time point) (for cohort 1) or at 
Week 48 (for cohort 2) compared to the baseline biopsy from the screening visit. 
3. To assess the ability of changes in the MBT to reflect changes in liver stiffness as 
measured by Magnetic Resonance Elastography (MRE), where available, at Week 24 
and Week 48 (or at Early Termination) compared to baseline MRE from the screening 
visit. 
4. To assess the ability of changes in the MBT to reflect changes in Proton Density Fat 
Fraction (PDFF) as measured by Magnetic Resonance Imaging (MRI), where 
available, at Week 24 and Week 48 (or Early Termination), compared to baseline 
MRI from the screening visit. 
5. To assess the ability of changes in the MBT to reflect changes in Serum Pro-C3, 
where available, at Week 24 and Week 48 of treatment (or Early Termination), 
compared to baseline Pro-C3 from the screening visit. 
The same assessments for each study cohort independently will be reported. 
The following additional objectives are applicable for cohort 2 only: 
1. To assess the ability of changes in the MBT to reflect changes in liver stiffness as 
measured by “Fibroscan” elastography, where available, at the Week 48 visit (or 
earlier if there was an Early Termination) compared to the screening visit. 
2. To assess the ability of changes in the MBT to reflect changes in the Model for End-
stage Liver Disease (MELD) score, where available, at Week 24 and Week 48 visits 
compared to study Day 1. 
3. To assess the ability of changes in the MBT to reflect changes in the Child-Turcotte-
Pugh Scoring (CTP) score, where available, at Week 24 and Week 48 (or Early 
Termination) compared to study Day 1. 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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3.1.3 Exploratory Objective 
• To assess the ability of the MBT to monitor patient status in comparison to 
other available measures, such as Liver Fibrosis stage, NAS, MELD, CTP, 
PDFF, Liver Stiffness, Serum Biomarker or Pro-C3. 
3.1.4 Safety Objective 
Evaluation of safety related to the MBT. 
 Study Endpoints  
3.2.1 Primary Endpoint  
The MBT's ability to measure the effect of BMS-986036 treatment on the metabolic 
capacity of the liver at Week 24 and Week 48 visits during the Double-Blind Treatment 
Period, as compared to changes in placebo treated subjects. 
3.2.2 Secondary Endpoints  
In order to assess the correlation of changes in MBT with changes in other measures of 
liver disease, the following endpoint measures will be collected, where available: 
For all study cohorts: MBT results for each MBT visit (Day 1, Week 24, Week 48, or 
Early Termination visits) as well as changes in MBT results (cPDR30, PDRpeak or other 
breath test parameters). 
The other measures of liver disease that will also be collected in this study are as follows: 
1. Liver-related Clinical Outcome defined as the first occurrence of any one of the 
following: all-cause mortality, MELD score ≥15, liver transplant, hepatocellular 
carcinoma (HCC), ascites requiring medical intervention, hospitalization (≥ 24 hours) 
for onset of variceal bleeding, hepatic encephalopathy and spontaneous bacterial 
peritonitis. 
2. Liver Fibrosis stage and NAS as determined by Liver Biopsy assessed by a central 
reader. 
3. Liver Stiffness as determined by MRE. 
4. PDFF as determined by MRI. 
5. Serum Biomarker Pro-C3. 


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Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
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Additional measures for cohort 2 include:  
1. Liver Stiffness as determined by Fibroscan® Elastography  
2. MELD scores 
3. CTP scores 
4 STUDY DESIGN 
Please refer to BMS’ protocols MB130-068 and MB130-069 - IND 125297.  
This study is a feasibility companion protocol that will rely on the data generated by BMS's 
studies of BMS-986036 (PEG-FGF21) under protocols MB130-068 and MB130-069 (IND 
125297), which are defined in this companion protocol as two separate study cohorts (1 and 2, 
respectively) with the exception of the MBT, for which Exalenz may extract additional data 
based on the recorded MBT results. The MB130-068 and MB130-069 studies are Phase 2b, 
multicenter, double-blind, randomized, placebo-controlled, parallel-group studies to 
demonstrate the safety and efficacy of BMS-986036 in the treatment of subjects with NASH and 
stage 3 liver fibrosis or compensated cirrhosis with up to 48 weeks of treatment. The study is 
feasibility for drug response monitoring however the data may be used by Exalenz for future 
submissions. 
As described in the BMS protocols, subjects will be enrolled and randomized via interactive 
response technology (IRT) to receive BMS-9860936 10mg QW, BMS-986036 20mg QW, BMS-
9860936 40mg QW or matching placebo QW in a 1:1:1:1 ratio. 
The BMS studies' treatment durations will each consist of two periods: 
1. A 48-week, Double-Blind Treatment Period, during which the subjects will receive 
blinded study medication (BMS-986036 10mg, 20 mg, 40mg QW or matching placebo 
QW). During the Double-Blind Treatment Period, subjects will be evaluated for safety 
and efficacy every 4 weeks (±5 days) through Week 24 and every 8 weeks (±5 days) 
from Week 24 through Week 48. 
2. A Follow up period, during which subjects will be evaluated for safety and efficacy for 
4 weeks through Week 52. 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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3. A Follow up period of at least 6 months and up to 14 months after the Week 52/ PTFU 
Visit for the collection of additional DXA assessment (in all participants) and 
immunogenicity assessments (in participants for whom Long-Term Immunogenicity 
Follow-Up Visits are required.) Any liver related complication event will be recorded. 
The last dose of study medication will be at the Week 48 visit. Subjects will have a safety and 
efficacy evaluation at week 48 and return for a post-treatment follow-up evaluation through 
Week 52. 
As a sub-study of BMS protocols MB130-068 and MB130-069, MBT will be performed at the 
Day 1 visit and every 24 weeks during the Double-Blind Treatment Period in order to allow the 
assessment whether BMS-986036 compared to placebo improves liver metabolic function as 
determined by the MBT. 
 Sample Size Considerations 
Subjects, that were enrolled into two separate BMS sponsored IND studies (MB130-068, 
MB130-069, respectively) at selected study sites, were offered the opportunity to perform the 
MBT, and are considered as two separate study cohorts (cohort 1 and 2, respectively) for this 
companion protocol. Each cohort consists of four treatment arms (BMS-986036 10mg, 20mg, 
40mg QW or matching placebo QW) as defined in the respective BMS sponsored protocols. 
Cohort 1 consists of subjects with NASH and stage 3 fibrosis, as assessed by a central laboratory 
reader of the liver biopsies, and who meet all the MB130-068 study criteria. The sample size for 
this MB130-068 study is n=160. 
Cohort 2 consists of subjects with NASH and compensated liver cirrhosis (stage 4 fibrosis) as 
assessed by a central laboratory reader of the liver biopsies, and who meet all the MB130-069 
study criteria. The sample size for this MB130-069 study is n=100. 
This feasibility companion protocol includes those two cohorts of subjects, which were planned 
for up to 260 subjects) from approximately 75 sites worldwide (USA and Japan) for the two 
BMS IND studies, while the MBT was only conducted in the USA. 
It was expected that not all participating sites would elect to perform the MBT. The total number 
of subjects expected to perform the MBT was initlly planned for up to 250 subjects (also 
accounting for drop outs). Each subject would perform up to 3 MBTs over 1 year. 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
Page 13 of 21 
 
Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
However, as aforementioned in the Introduction (section 2), the enrollment phase and all MBT 
testing (incl. Day1, Week 24 and Week 48 visits) for the aforementioned BMS sponsored studies 
has been completed. The data is still being assessed by BMS and the respective databases are 
planned to be made available to Exalenz between July and November 2021, after their respective 
data lock and release from BMS.  
The initially planned sample size of 250 subjects, per statistical section in the companion 
protocol, was not reached for multiple reasons: 
- 
The MBT testing as part of the BMS studies, was an opt in substudy, requiring an 
additional consent process. Subjects enrolled to the BMS studies were reluctant to add an 
additional investigational test to their study schedule. 
- 
The COVID-19 outbreak further complicated the enrollment and especially the follow up 
testing of already enrolled subjects, as visits were more and more conducted remotely and 
any breath testing was avoided during in person visits. 
Since the actual final sample size of subjects with valid MBT results at baseline and post-
treatment phase, across both BMS studies, is expected to be lower than 80, the statistical analyses 
for the study will be descriptive by nature. No formal statistical testing will be performed. 
Nominal p-values from statistical tests will be reported for suplementary information. 
5 GENERAL CONSIDERATIONS FOR HANDLING OF MISSING 
DATA 
 Premature Withdrawal and Missing Data 
For patients who are withdrawn from the study prior to study completion, all data compiled up 
to the point of discontinuation will be used for analysis. All withdrawals will be included in all 
analyses up to the time of withdrawal. 
There will be no imputation for missing data. 
The study variables cannot be evaluated for subjects for whom BreathID® MCS device MBT 
results are not available and therefore these subjects will be left out of the efficacy analysis. 
Subjects missing clinical outcome or biopsy results or other endpoints will be excluded from the 
respective analyses. 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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6 SIGNIFICANCE LEVELS AND HANDLING OF TYPE I ERROR 
 Type I Error 
All analyses in this study will be considered descriptive by nature. No formal statistical testing 
will be performed. Nominal p-values from statistical tests will be reported for suplementary 
information. 
7 ANALYSIS SETS 
 Safety Analysis Set (SA) 
The Safety Analysis set will include all subjects enrolled under BMS' MB130-068 and MB130-
069 studies that initiated at least one MBT (had taken the 13C-Methacetin solution), even if the 
MBT was not completed or the result was not valid. 
 Efficacy Analysis Set (EA) 
The Efficacy Analysis set will include all subjects enrolled under BMS' MB130-068 and 
MB130-069 studies who have successfully performed the MBT test and did not have any major 
protocol deviations for the current study. 
 Modified Efficacy Analysis Set (mEA) 
The modified Efficacy Analysis set will include all subjects enrolled under BMS' MB130-068 
and MB130-069 studies who have successfully performed the MBT test. Visit specific major 
protocol deviation will be excluded, while keeping subjects in this analysis set for other valid 
visits. 
Safety analyses will be performed on the SA set and efficacy analyses on the mEA set. 
Sensitivity analysis will be performed on the SA (corresponding to ITT) and EA set. 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
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8 STATISTICAL ANALYSES 
 General Considerations for Data Analyses 
All analyses will be performed using either SAS® v9.4 or higher (SAS Institute, Cary NC, US) 
or the R software version 4.0.3 or higher (R Development Core Team. Vienna, Austria).  
The standard summary statistics for continuous variables are: N, mean, standard deviation, 
median, minimum and maximum. The standard summary statistics for categorical variables are: 
count and proportion. 
The analyses will be descriptive by nature, nominal p-values will be reported for suplementary 
information. Any statistical tests performed, will be two-sided. The significance level of findings 
will be equal to or lower than 5%. Where confidence limits are appropriate, the confidence level 
will be 95%. Nominal p-values and unadjusted confidence intervals will be presented. 
 Baseline Definitions 
The study baseline will be defined as the Day 1 visit value, unless specifically mentioned 
otherwise. In case of repeat measurements, the latest value associated with the Day 1 visit will 
be considered the baseline value. 
For survival models: The baseline MBT test will be defined as the baseline and day 0 of follow 
up.  
 Disposition of Patients 
Subject dispositions will be summarized based on all subjects screened into the study separated 
by study cohort (and combined), and for each treatment group.  
The following subject disposition information will be presented: 
• The number and percentage of subjects who had valid MBT for each visit. 
• The number and percentage of reasons for not having a valid MBT for each visit.  
• The number and percentages of subjects that were excluded from the EA and mEA 
analysis sets, by reason for exclusion. 


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Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
 Efficacy Analyses 
8.4.1 Primary Endpoint 
In order to show the ability of the MBT to measure the effect of BMS-986036 treatment on the 
metabolic capacity of the liver after Week 24 and Week 48 visits, as compared to changes in 
placebo treated subjects, the primary endpoint will be analyzed using a responder analysis, where 
any increase of MBT value will be considered as a response while a same value or a decrease of 
the MBT value will be considered as non-respose.  
The primary analysis will be conducted on the mEA set, with the PDRpeak and cPDR30 responder 
rate of Week 24 and Week 48 of data from both BMS’ studies.  
Individual analyses for each cohort separately will also be reported. 
8.4.2 Secondary Endpoints 
8.4.2.1 Prognostic Value of MBT in Overall Event-Free Survival 
In order to assess the prognostic value of MBT in prediction of liver disease deterioration 
(reported as liver-related clinical outcome events), the endpoint measures will be point estimates 
of Cox Regression's Hazard Ratio for classifying Subjects into risk groups for clinical 
deterioration with respective exact two-sided 95% confidence intervals in the placebo and 
treatment arms as determined by MBT. The MBT parameter to be used to predict liver-related 
clinical outcome events is PDRpeak. Any PDRpeak value of less or equal to 20 %/h (see Appendix 
A for detailed description of parameter calculation) will be considered as ‘high risk’ and any 
value above that threshold will be considered as ‘lesser risk’ (additional cut-off values may be 
explored). The dichotomic MBT result will be tested for significance using the Cox proportional 
hazards regression model with site and randomized arm as covariates. If the randomized arm 
factor is found non-significant (i.e. p-value > 0.05), then this factor will not be a covariate for 
the main analysis to be performed. If the randomized arm factor is found statistically significant 
(i.e. p-value ≤ 0.05), then the main analysis will be performed keeping this factor as a covariate 
(to ‘adjust’ the analysis for treatment).  
The time-to-first event will be derived as the number of days between the Day 1 MBT test and 
the date when the first event occurs or when a subject is censored (i.e., event/censored date minus 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
Page 17 of 21 
 
Meridian Bioscience Israel Ltd. confidential and proprietary information. © Meridian Bioscience Israel Ltd. All rights reserved. 
Day 1 MBT date plus 1). Subjects will be censored at their last study visit for the following 
reasons:  
• If a subject discontinues the study prior to the end of the study without experiencing an 
event 
• If a subject reaches the Final Treatment visit without experiencing an event  
 
Survival analysis will be conducted using the Cox proportional hazard model. The model 
summary will include the number of subjects in the model, and a table with each covariate in a 
separate line specifying the coefficient's value, Hazard Ratio, Hazard Ratio 95% Confidence 
Interval and p-value. In addition, a Kaplan-Meier plot for event-free survival will be presented, 
stratified by MBT parameter along with the MBT parameter log-rank p-value. Additionally, a 
crosstab table of MBT parameter and events will be presented. 
8.4.2.2 Correlations between changes in MBT parameters and changes in other liver related 
parameters 
Repeat MBT results (cPDR30,PDRpeak or other breath test parameters) and their changes in 
subjects with and without treatment (BMS-986036) for nonalcoholic steatohepatitis (NASH) at 
Day 1, Week 24 and Week 48 (or Early Termination visits) will be compared and tested for 
correlation to baseline, as well as repeat results (change from baseline), for the following 
measurements: 
a. Biopsy based Fibrosis and/or NAS score 
b. Liver stiffness as measured by MRE 
c. PDFF as measured by MRI 
d. Serum Pro-C3 results 
e. Liver elastography by Fibroscan (in cohort 2 only) 
f. MELD scores (in cohort 2 only) 
g. CTP scores (in cohort 2 only)  
Linear Regression will be applied in order to test for significance of the correlations between 
MBT and the liver measurements listed above. 
Changes in MBT are measured as the difference between baseline and each of the MBT visits 
as well as the change in measurements between two subsequent visits in each of the two 
treatment groups. 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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The metabolic capacity of the liver as determined by the MBT PDRpeak and cPDR30 will be the 
main MBT parameters of interest. 
Nevertheless, available breath test parameters (Delta Over Baseline - DOB at the respective 
times) will be collected from the completed eCRFs. The DOBs will be transformed to percentage 
dose recovery – PDR, by normalizing the DOB using patient weight and height. The Area under 
the DOB and under the PDR curve will be calculated at 5-minute time intervals resulting in 
cDOB and cPDR at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 and 60 minutes respectively. Analyses 
may be done using any of the MBT derived parameters. 
 Site Poolability 
Primary efficacy analysis will be reported for each cohort separately as well as for each site/ 
group of sites (see next section) separately.  
For sites with less than 10 subjects, the following pooling of sites method will be applied for 
each cohort separately: Sites will be sorted from smallest to largest based on the number of 
randomized subjects with valid baseline MBT results. The smallest site will be pooled with the 
second smallest, and if necessary with the next sites in line until the site group reaches 10 subjects 
or more. The site value for those sites will be assigned "Site Group 1". Then the next site in line, 
if lower than 10 subjects, will be pooled with the sites after it until the site group reaches at least 
10, and so forth until all sites or site groups have at least 10 subjects. Furthermore, site by MBT 
dichotomy interaction will be added to the Linear and Cox regression models as a covariate to 
test for site effect on the exploratory endpoints. 
 Safety Analyses 
The adverse events possibly or probably related to Methacetin and/or the BreathID® MCS device 
will be presented along with a two sided 95% exact binomial confidence interval. The analysis 
of all adverse events will include incidence tables and will include analyses by severity, 
relationship to device or drug and baseline variables.  
No inferential statistical testing will be performed for safety variables. 
 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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APPENDIX A - – METHACETIN BREATH TEST PARAMETERS 
The BreathID MCS System measures the change of the 13CO2/12CO2 ratio in exhaled breath 
following ingestion of 13C-Methacetin compared to the 13CO2/12CO2 ratio before ingestion. This 
measure is called 'Delta Over Baseline' (DOB) and is automatically measured every 2-3 minutes, 
resulting in approximately 23 DOB's and corresponding time points over one hour. Subjects visit 
height and weight as well as all available DOB measures with corresponding time point (T) will 
be retrieved from the completed eCRFs. 
1. DOB values must be sorted by time before any calculation, while a first pair of data 
points should always be added with time T0=0 min and DOB0 =0. 
 
2. The DOBs will be transformed into percentage dose recovery rates (PDRs) by 
normalizing the DOB using patient body weight and height at each observed time point 
(i) by using the following formula: 
 
𝑃𝐷𝑅𝑖= 0.01817853 ∙𝐷𝑂𝐵𝑖∙𝑊𝑒𝑖𝑔ℎ𝑡0.5378 ∙𝐻𝑒𝑖𝑔ℎ𝑡0.3963 
While Weight is in kg, and Height is in cm 
The units of PDR is %/hour 
3. The maximum rate at which metabolism occurs results in a peak value of the breath test 
called DOBPeak and PDRPeak, respectively. Both occur at the same time, which is called 
the Peak time. 
a. DOBpeak: DOBpeak is defined as the maximum DOB. 
 
𝐷𝑂𝐵𝑝𝑒𝑎𝑘= max⁡(𝐷𝑂𝐵0, 𝐷𝑂𝐵1, 𝐷𝑂𝐵2, … , 𝐷𝑂𝐵24) 
b. PDRpeak: PDRpeak is defined as the maximum PDR. 
 
𝑃𝐷𝑅𝑝𝑒𝑎𝑘= max⁡(𝑃𝐷𝑅0, 𝑃𝐷𝑅1, 𝑃𝐷𝑅2, … , 𝑃𝐷𝑅24) 
4. The area under the DOB curve will be calculated for each time point. This area 
represents the cumulative DOB (cDOB) at any given time point.  
a. DOBx_min and cDOBx_min: The following steps will be followed to obtain the 
DOB and cDOB at 5 minutes intervals (e.g. 5, 10, 15,…,60 min), where 'x' is 
05, 10, 15, …, 60 respectively. For each 'x' the following steps shall be 
followed: 
 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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b. Find 'a', the index for which: 
𝑇𝑎−1 < 𝑥⁡ ≤𝑇𝑎 
c. Calculate DOBx_min using the following formula: 
𝐷𝑂𝐵𝑥_𝑚𝑖𝑛= 𝐷𝑂𝐵𝑎−1 + 𝐷𝑂𝐵𝑎−𝐷𝑂𝐵𝑎−1
𝑇𝑎−𝑇𝑎−1
∙(𝑥−𝑇𝑎−1) 
d. Calculate cDOBx_min using the following formula: 
𝑐𝐷𝑂𝐵𝑥_𝑚𝑖𝑛= ∑(
𝑇𝑖−𝑇𝑖−1
60
∙(𝐷𝑂𝐵𝑖+ 𝐷𝑂𝐵𝑖−1)
2
)
𝑎−1
𝑖=1
+
𝑥−𝑇𝑎−1
60
∙(𝐷𝑂𝐵𝑥_𝑚𝑖𝑛+ 𝐷𝑂𝐵𝑎−1)
2
 
MBT parameters results that do not have data points for at least 'x' 
minutes cannot be calculated 
5. The PDR as well as the area under the PDR curve will be calculated for each time 
point. This area represents the cumulative PDR (cPDR) at any given time point in units 
of %.  
a. PDRx_min and cPDRx_min: The following steps will be followed to obtain the 
PDR and cPDR at 5 minutes intervals (e.g. 5, 10, 15,…,60 min), where 'x' is 05, 
10, 15, …, 60 respectively. For each 'x' the following steps shall be followed: 
 
b. Find 'a', the index for which: 
𝑇𝑎−1 < 𝑥⁡ ≤𝑇𝑎 
c. Calculate PDRx_min using the following formula: 
𝑃𝐷𝑅𝑥_𝑚𝑖𝑛= 𝑃𝐷𝑅𝑎−1 + 𝑃𝐷𝑅𝑎−𝑃𝐷𝑅𝑎−1
𝑇𝑎−𝑇𝑎−1
∙(𝑥−𝑇𝑎−1) 
d. Calculate cPDRx_min using the following formula: 
𝑐𝑃𝐷𝑅𝑥_𝑚𝑖𝑛= ∑(
𝑇𝑖−𝑇𝑖−1
60
∙(𝑃𝐷𝑅𝑖+ 𝑃𝐷𝑅𝑖−1)
2
)
𝑎−1
𝑖=1
+
𝑥−𝑇𝑎−1
60
∙(𝑃𝐷𝑅𝑥_𝑚𝑖𝑛+ 𝑃𝐷𝑅𝑎−1)
2
 
MBT parameters results that do not have data points for at least 'n' 
minutes cannot be calculated 


Meridian Bioscience Israel Ltd. 
Last update: May 05, 2021 
SAP for Protocol BMS-EX-0118: Companion protocol for 
the ¹³C-Methacetin Breath Test (MBT) for use in Bristol-Myers 
Squibb phase 2b studies for BMS-986036 (PEG-FGF21), under 
Protocols MB130-068 and MB130-069 
Document Version: 1.0 
 
Document No: CSD00114 
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6. The cDOB and cPDR at the peak time are called cDOBpeak and cPDRpeak, respectively. 
They are calculated as described in steps 4 and 5, respectively, while 'x' is the actual 
time 'T' of the observed peak value. The cPDRpeak divided by Peak time is named 
cPDRpeak_div_Peaktime. 
 
7. The following list of MBT result parameters will thus be used in the statistical analysis: 
DOBpeak, cDOBpeak, PDRpeak, cPDRpeak, cPDRpeak_div_Peaktime, Time to Peak, 
DOB5_min, DOB10_min, DOB15_min, DOB20_min, DOB25_min, DOB30_min, DOB35_min, 
DOB40_min, DOB45_min, DOB50_min, DOB55_min, DOB60_min, cDOB5_min, cDOB10_min, 
cDOB15_min, cDOB20_min, cDOB25_min, cDOB30_min, cDOB35_min, cDOB40_min, 
cDOB45_min, cDOB50_min, cDOB55_min, cDOB60_min, PDR5_min, PDR10_min, PDR15_min, 
PDR20_min, PDR25_min, PDR30_min, PDR35_min, PDR40_min, PDR45_min, PDR50_min, 
PDR55_min, PDR60_min, cPDR5_min, cPDR10_min, cPDR15_min, cPDR20_min, cPDR25_min, 
cPDR30_min, cPDR35_min, cPDR40_min, cPDR45_min, cPDR50_min, cPDR55_min, cPDR60_min.