A Phase 2B Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of BMS-986036 (PEG-FGF21) in Adults With Nonalcoholic Steatohepatitis (NASH) and Compensated Liver Cirrhosis
Phase: PHASE2
Conditions: Hepatic Cirrhosis, Liver Fibrosis, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 2B Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of 
BMS-986036 (PEG-FGF21) in Adults with Nonalcoholic Steatohepatitis (NASH) and Compensated Liver 
Cirrhosis 
 
PROTOCOL MB130-069 
 
NCT Number: NCT03486912 
  
Document Date (Date in which document was last revised): January 30, 2020 

30 January 2020 
BMS Confidential 
1 
A PHASE 2B RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
EVALUATING THE SAFETY AND EFFICACY OF BMS-986036 (PEG-FGF21) IN 
ADULTS WITH NONALCOHOLIC STEATOHEPATITIS (NASH) AND 
COMPENSATED LIVER CIRRHOSIS 
 
FALCON 2 Study 
 
Test Drug: 
BMS-986036 (pegbelfermin) 
Protocol Number: MB130-069 
IND 125,297 
Date and Version: Version 4.0, 30 January 2020 
 
Study Director 
Medical Monitor 
 
24-hour Emergency Telephone Number 
North America: 
 
Asia-Pacific: 
 
 
Bristol-Myers Squibb Research and Development 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
 
6-5-1 Nishi-Shinjuku, Shinjuku-ku, 
Tokyo, 163-1328, Japan 
 
This document is the confidential and proprietary information of Bristol-Myers Squibb Company and its 
global affiliates. By reviewing this document, you agree to keep it confidential and to use and disclose it 
solely for the purpose of assessing whether your organization will participate in and/or the performance of 
the proposed Bristol-Myers Squibb Sponsored study. Any permitted disclosures will be made only on a 
confidential “need to know” basis within your organization or to your independent ethics committee(s). 
Any other use, copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by Bristol-Myers Squibb. Any supplemental information (e.g., 
amendments) that may be added to this document is also confidential and proprietary to Bristol-Myers 
Squibb and must be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from Bristol-Myers Squibb is requested to return it 
to Bristol-Myers Squibb or promptly destroy it. All other rights reserved. References to Bristol-Myers 
Squibb in this protocol may apply to partners to which Bristol-Myers Squibb has transferred obligations 
(e.g., a contract research organization). 
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DOCUMENT HISTORY 
Document 
Date of Issue 
Summary of Change 
Approvers 
Original Protocol 
04 January 
2018 
Not Applicable 
Revised Protocol 1 
(Final Approved 
2.0) 
02 March 2018 
1. Incorporates changes to 
multiple Sections of the 
protocol in response to 
additional internal review: 
2. Revises secondary and 
exploratory objectives and 
endpoints 
3. Revises the protocol to more 
clearly define expectations for 
participants who discontinue 
study medication or overall 
study participation 
4. Clarifies visit intervals and 
visit windows for bone mineral 
density and immunogenicity 
follow-up visits 
5. Clarifies pregnancy reporting 
requirements  
6. Clarifies procedures for 
collection of serious adverse 
events and concomitant 
medications 
7. Updated methods of data 
analysis 
8. Provides clarifications to 
increase consistency within the 
protocol. 
Revised Protocol 2 
(Final Approved 
3.0) 
20 January 
2019 
1. Updates the Sponsor’s contact 
information and includes the 
study name (FALCON 2) and 
generic name, pegbelfermin, 
for BMS-986036  
2. Updates the 
screening/rescreening processes 
and sequence/timing of 
required testing, e.g., allows 
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extension of screening period 
(from 8 to 12 weeks) if needed 
3. Modifies the inclusion criteria 
of patients with hepatitis C 
virus sustained viral response 
(for at least 2 years) 
4. Updates inclusion/exclusion 
criteria for medications 
5. Allows inclusion of participants 
with Grade ≤ 1 varices (from 
historical 
esophagogastroduodenoscopy) 
and updates inclusion/exclusion 
criteria for Fibroscan 
elastography and medications 
7. Provides for the collection of 
medications that could impact 
bone mineral density from end 
of treatment through the 6-
month follow-up dual-energy 
X-ray absorptiometry scan 
8. Updates requirements for 
procedures and testing for 
subjects prematurely 
discontinuing study treatment 
9. Updates and clarifies study 
procedures and analysis plans 
10. Incorporates editorial updates 
Revised Protocol 3 
(Final Approved 
4.0) 
30 January 
2020 
1. Updates made throughout the 
protocol requiring all 
participants to have sample 
collection for potential 
immunogenicity testing during 
the visit at 6 months after the 
Week 52 Post-treatment 
Follow-up (PTFU) Visit. 
2. Updated Section 1 Schedule 
of Activities, Table 1 and 
Table 2, Clinical Efficacy 
Assessments, Hepatic 
Magnetic Resonance 
Elastography (MRE), 
participants to fast at least 4 
hours prior to assessment to 
align with instructions in the 
imaging manual. 
 
 
 
 
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3. Updates the number of 
randomized participants from 
approximately 100 to 
approximately 155 
(approximately 38 participants 
per arm) based on final 
enrollment. See Section 6.2 
for details. 
4. Update to Section 1 and 
Section 8.4.8 to include 
collection of any other 
nonalcoholic steatohepatitis 
(NASH) therapies taken 
during the post Week 52 
follow-up period during the 
visit at 6 months after the 
Week 52 PTFU Visit. 
5. Updates made throughout the 
protocol to clarify the 
exploratory endpoint related to 
digital pathology assessment 
of liver biopsies. 
6. Update to Section 8.5.1.1 to 
include handling of incidental 
findings and blinding of 
on-treatment biopsy results. 
7. Update to Section 9.4.4 to 
remove endpoints that 
reference relationships to align 
with the Statistical Analysis 
Plan (SAP). 
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1. SCHEDULE OF ACTIVITIES  
Schedules of procedures and assessments are described in the tables below: 
 
• Table 1 - Screening Period Activities - Study MB130-069 
• Table 2 - Double-Blind Treatment Period Activities and Post-Treatment Follow-Up 
Period Activities - Study MB130-069 
• Table 3 - Long-Term Bone Mineral Density and Immunogenicity Follow-Up Period 
Activities - Study MB130-069 
 
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Table 1 
Screening Period Activities - Study MB130-069 
Procedure/Assessment 
Screening 
Period (up to 8 
weeks; see 
Section 8.1) 
Notes 
Screening Period may be extended to a total of up to 12 weeks upon discussion with the medical 
monitor 
Screening and History Assessments 
Informed consent 
X 
The approved informed consent form must be signed before completing any protocol-specific 
procedures 
Study enrollment via interactive 
response technology (IRT) 
X 
See Section 8.4.3 
Inclusion/exclusion criteria 
X 
See Sections 8.3.1, 8.3.2, 8.3.3, and 8.3.4 
Complete medical history 
X 
See Section 8.3.5, Appendix 4 
Surgical history 
X 
See Section 8.3.5 
Diet and exercise history 
X 
See Section 8.3.5 
Prior medications 
X 
See Section 8.4.8 
Dietary and Lifestyle Counseling 
X 
See Section 8.3.6 
Clinical Efficacy Assessments 
Liver biopsy 
X 
Only to be conducted if no liver biopsy specimen collected within 6 months (26 weeks) prior to 
informed consent is available and readable by the Central Pathologist. See Section 8.5.1.1. 
Hepatic magnetic resonance 
elastography (MRE)  
X 
See Section 8.5.1.3. Participants should fast for at least 4 hours prior to assessment 
Hepatic magnetic resonance imaging 
(MRI)  
X 
See Section 8.5.1.3 
Fibroscan® elastography 
X 
See Section 8.5.1.4 
Height and weight for body mass index
(BMI) calculation  
X 
See Section 8.5.1.6 
Waist circumference 
X 
See Section 8.5.1.6 
Child-Pugh Turcotte scoring 
X 
See Section 8.5.1.7, Appendix 5 
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Procedure/Assessment 
Screening 
Period (up to 8 
weeks; see 
Section 8.1) 
Notes 
Screening Period may be extended to a total of up to 12 weeks upon discussion with the medical 
monitor 
Model for End-Stage Liver Disease 
(MELD) scoring 
X 
See Section 8.5.1.8 and Appendix 10 
Clinical Safety Assessments 
12-lead electrocardiogram 
X 
If a participant has a QT interval corrected using Fridericia’s formula (QTcF) > 480 msec, it should 
be confirmed by repeat electrocardiogram 30-60 minutes after the initial electrocardiogram. If the 
QTcF is confirmed to be > 480 msec, the participant should not be allowed to participate in the study. 
See Section 8.5.3.5 
Vital signs 
X 
See Section 8.5.3.4 
Physical examination 
X 
Examination will be a full physical examination as described in Section 8.5.3.3 
Dual-energy X-ray absorptiometry 
(DXA) assessment  
X 
See Section 8.5.3.8 
Laboratory Assessments 
Urinalysis 
X 
Includes assessments listed in Table 8 in Section 8.5.4 
Urine for inflammation and kidney 
markers 
X 
See Table 8 in Section 8.5.4 
Urine drug screen 
X 
See Table 8 in Section 8.5.4 
Serum pregnancy test 
X 
To be conducted only in women of childbearing potential. See Table 8 in Section 8.5.4 
Follicle-stimulating hormone (FSH) 
testing 
X 
To be conducted only in postmenopausal women. See Table 8 in Section 8.5.4 and Appendix 2 
Hepatitis B assessments 
X 
See Table 8 in Section 8.5.4 and Appendix 3 
Hepatitis C assessments 
X 
See Table 8 in Section 8.5.4 and Appendix 3 
Hematology 
X 
Includes the assessments listed in Table 8 in Section 8.5.4 
Blood chemistry 
X 
Includes the assessments listed in Table 8 in Section 8.5.4 
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Procedure/Assessment 
Screening 
Period (up to 8 
weeks; see 
Section 8.1) 
Notes 
Screening Period may be extended to a total of up to 12 weeks upon discussion with the medical 
monitor 
Laboratory metabolic markers 
X 
See Section 8.5.1.6 and Table 8 in Section 8.5.4. Participants should fast for at least 8 hours prior to 
the blood collection for these assessments 
Serum N-terminal type 3 collagen 
propeptide (PRO-C3) 
X 
See Table 8 in Section 8.5.4 Participants should fast for at least 8 hours prior to the blood collection 
for this assessment 
Adiponectin 
X 
See Table 8 in Section 8.5.4. Participants should fast for at least 8 hours prior to the blood collection 
for this assessment 
Micro RNA (miRNA) 
X 
See Table 8 in Section 8.5.4 
Whole blood for gene expression 
assessments 
X 
See Table 8 in Section 8.5.4 
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Table 2 
Double-Blind Treatment Period Activities and Post-Treatment Follow-Up Period Activities - Study MB130-
069 
Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Screening and History Assessment Updates 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Confirm continued study eligibility. See 
Sections 8.3.1, 8.3.2, 8.3.3, and 8.3.4 
Confirm continued eligibility and 
randomization via interactive 
response technology (IRT) 
X 
 
 
 
 
 
See Section 8.4.3 
Update medical history 
X 
 
 
 
 
 
See Section 8.3.5 
Update surgical history 
X 
 
 
 
 
 
See Section 8.3.5 
Diet and exercise history 
X 
 
X 
 
X 
 
See Section 8.3.5 
Prior medications 
X 
 
 
 
 
 
See Section 8.4.8 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Clinical Efficacy Assessments 
Liver biopsy 
 
 
 
 
X 
 
See Section 8.5.1.1 
The biopsy should be performed within 
± 7 days of the Week 48 Visit. 
However, if a biopsy cannot be 
scheduled within the window specified 
above, the biopsy should be performed 
as close to schedule as possible 
Liver biopsy will be performed at the 
ET Visit if the participant has 
completed at least Week 20. If a 
participant discontinues study 
participation prior to Week 20 they 
should consider having a liver biopsy at 
ET 
Hepatic magnetic resonance 
elastography (MRE)  
 
 
X 
 
X 
 
Assessment window ±7 days. See 
Section 8.5.1.3. Participants should fast 
for at least 4 hours prior to these 
assessments. For participants 
prematurely discontinuing study 
medication prior to Week 24, MRE 
should be conducted at the ET Visit if 
the date of discontinuation is more than 
4 weeks from the date of the previous 
MRE. For participants prematurely 
discontinuing study medication after 
Week 24, MRE should be conducted at 
the ET Visit if the date of 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
discontinuation is more than 8 weeks 
from the date of the previous MRE 
Hepatic magnetic resonance 
imaging (MRI)  
 
 
X 
 
X 
 
Assessment window ± 7 days. See 
Section 8.5.1.3. For participants 
prematurely discontinuing study 
medication prior to Week 24, MRI 
should be conducted at the ET Visit if 
the date of discontinuation is more than 
4 weeks from the date of the previous 
MRI. For participants prematurely 
discontinuing study medication after 
Week 24, MRI should be conducted at 
the ET Visit if the date of 
discontinuation is more than 8 weeks 
from the date of the previous MRI 
Fibroscan® elastography 
 
 
 
 
X 
 
See Section 8.5.1.4 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Weight for body mass index 
(BMI) calculation  
X 
 
X 
 
X 
X 
See Section 8.5.1.6. The Screening 
value for height will be used in the BMI 
calculation 
Waist circumference 
X 
 
X 
 
X 
 
See Section 8.5.1.6 
Child-Pugh Turcotte scoring 
X 
 
X 
 
X 
 
See Section 8.5.1.7, Appendix 5 
Model for End-Stage Liver 
Disease (MELD) scoring 
X 
X 
X 
X 
X 
X 
All components of the MELD score 
should be completed on the same day. If 
any individual component needs to be 
repeated on another day, all other 
components must be repeated as well. 
See Section 8.5.1.8 and Appendix 10 
Liver-related clinical outcome 
events 
X 
X 
X 
X 
X 
X 
See Section 8.5.1.9 
3-Level EuroQol 5 Dimension 
(EQ-5D-3L) quality-of-life 
questionnaire  
X 
 
X 
 
X 
 
See Section 8.5.1.10 
36-Question Short Form Health 
Survey (SF-36) Version 2 
X 
 
X 
 
X 
 
See Section 8.5.1.10 
Chronic Liver Disease 
Questionnaire-Nonalcoholic Fatty 
Liver Disease (CLDQ-NAFLD) 
X 
 
X 
 
X 
 
See Section 8.5.1.10 
Clinical Safety Assessments 
Adverse events 
X 
X 
X 
X 
X 
X 
See Section 8.5.3.1 and Appendix 9 
Concomitant medications 
X 
X 
X 
X 
X 
X 
See Section 8.3.7 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
12-lead electrocardiogram 
X 
 
X 
 
X 
X 
If a participant has a QTcF>480 msec at 
an on-treatment visit, it should be 
confirmed by repeat ECG 30-60 
minutes after the initial ECG. If the 
QTcF is confirmed to be >480 msec, the 
medical monitor should be contacted. 
See Section 8.5.3.5 and Table 9 in 
Section 8.5.5  
Vital signs 
X 
X 
X 
X 
X 
X 
See Section 8.5.3.4 
Full physical examination 
 
 
X 
 
X 
X 
See Section 8.5.3.3 
Abbreviated physical examination 
X 
X 
 
X 
 
 
See Section 8.5.3.3 
Dual-energy X-ray absorptiometry 
(DXA) 
 
 
 
 
X 
 
See Section 8.5.3.8.  
Assessment window ± 7 days 
Participants will return for a follow-up 
DXA assessment 6 months after the 
Week 52/PTFU Visit (see Table 3). One 
month is defined as 4 calendar weeks. 
The ET Visit should include a DXA 
scan only if the participant has 
completed at least the Week 16 Visit 
Laboratory Assessments - On days of study visits, participants will hold their study medication dose until all laboratory samples have been collected. 
Urinalysis 
X 
X 
X 
X 
X 
X 
See Section 8.5.4 and Table 8 in Section
8.5.4 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Serum or urine pregnancy test 
X 
X 
X 
X 
X 
X 
To be conducted in women of 
childbearing potential only. See Table 8 
in Section 8.5.4 
Enhanced Liver Fibrosis (ELF) 
Assessment 
X 
 
X 
 
X 
 
See Section 8.5.4 and Table 8 in Section
8.5.4. Participants should fast for at 
least 8 hours prior to the blood 
collection for this assessment 
Hematology 
X 
X 
X 
X 
X 
X 
See Section 8.5.4 and Table 8 in Section
8.5.4 
Blood chemistry 
X 
X 
X 
X 
X 
X 
See Section 8.5.4 and Table 8 in Section
8.5.4 
Anti-drug and anti-FGF21 
antibodies 
X 
X 
X 
X 
X 
X 
See Table 8 in Section 8.5.4. Any 
participant with anti-drug and/or anti-
FGF21 antibodies at Week 52/PTFU or 
ET who has not demonstrated 
decreasing anti-drug and/or anti-FGF21 
antibody titers will be followed for up 
to approximately 14 months after Week 
52/PTFU as described in Section 
8.5.3.6. One month is defined as 4 
calendar weeks 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Laboratory metabolic markers 
X 
 
X 
 
X 
 
See Section 8.5.1, Section 8.5.4 and 
Table 8 in Section 8.5.4. Participants 
should fast for at least 8 hours prior to 
the blood collection for these 
assessments 
Serum N-terminal type 3 
collagen propeptide (PRO-C3) 
X 
X 
Samples only 
to be collected 
at Week 4, 
Week 8, and 
Week 12 
X 
 
X 
X 
See Section 8.5.1, Section 8.5.4, and 
Table 8 in Section 8.5.4. Participants 
should fast for at least 8 hours prior to 
the blood collection for this assessment 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Adiponectin 
X 
X 
Samples only 
to be collected 
at Week 4, 
Week 8, and 
Week 12 
X 
 
X 
X 
See Section 8.5.1 and Table 8 in 
Section 8.5.4 Participants should fast 
for at least 8 hours prior to the blood 
collection for this assessment 
Micro RNA (miRNA) 
X 
X 
Samples only 
to be collected 
at Week 4, 
Week 8, and 
Week 12 
X 
 
X 
X 
See Section 8.5.4 and Table 8 in 
Section 8.5.4 
Whole blood for gene expression 
assessments 
X 
X 
Samples only 
to be collected 
at Week 4, 
Week 8, and 
Week 12 
X 
 
X 
X 
See Section 8.5.4 and Table 8 in 
Section 8.5.4 
Serum for disease, target and drug 
effect biomarkers 
X 
X 
Samples only 
to be collected 
at Week 4, 
Week 8, and 
Week 12 
X 
 
X 
X 
See Section 8.5.4 and Table 8 in 
Section 8.5.4. Participants should fast 
for at least 8 hours prior to the sample 
collection 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Plasma for disease, target and 
drug effect biomarkers 
X 
X 
Samples only 
to be collected 
at Week 4, 
Week 8, and 
Week 12 
X 
 
X 
X 
See Section 8.5.4 and Table 8 in 
Section 8.5.4. Participants should fast 
for at least 8 hours prior to the sample 
collection 
Trough pharmacokinetic (PK) 
sampling 
X 
X 
X 
X 
X 
X 
Trough (predose) samples will be 
collected at each visit. See Section 8.5.5 
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Procedure/Assessment 
Double-Blind Treatment 
Follow-Up 
 
Day 1 
Visit 
After Day 1, 
up to Week 24 
Visits every 4 
weeks 
(± 5 days) 
Week 24 
Visit 
(± 5 days) 
After Week 24, 
up to Week 48 
Visits every 8 
weeks (± 5 days) 
Week 48 
Visit 
(± 5 days)/ 
Early 
Termination 
(ET) 
Week 52/  
Post-
Treatment 
Follow-Up 
Visit 
(PTFU) 
(± 5 days) 
Study Medication 
Study medication administration 
training 
X 
 
 
 
 
 
Training maybe repeated as necessary at 
any study visit at the discretion of the 
investigator to maintain treatment 
compliance. See Section 8.4 
Dispense study medication 
X 
X 
X 
X 
 
 
See Section 8.4 
Study medication return/reconcile 
 
X 
X 
X 
X 
 
See Section 8.4 
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Table 3 
Long-Term Bone Mineral Density and Immunogenicity Follow-Up Period Activities – Study MB130-069 
Procedure/Assessment 
6 Months After 
Week 52/PTFU 
(± 14 days)a 
9 Months After 
Week 52/PTFU 
(± 14 days)b 
12 Months After 
Week 52/PTFU 
(± 14 days)b 
14 Months After 
Week 52/PTFU 
(± 14 days)b 
Notes: 
1 month is defined as 4 calendar 
weeks. 
Concomitant medications since last visit 
X 
 
 
 
Selected medications that could 
impact bone mineral density 
assessment and nonalcoholic 
steatohepatitis (NASH) therapies 
taken after the end of study treatment 
(Section 8.4.8) 
Dual-energy X-ray absorptiometry (DXA) 
X 
 
 
 
See Section 8.5.3.8. For participants 
who prematurely discontinue study 
medication, the follow-up DXA scan 
is not required unless the participant 
has completed at least Week 16 
Anti-drug and anti-FGF21 antibodies 
X 
X 
X 
X 
See Section 8.5.3.6 and Appendix 11 
Blood chemistry 
 
 
 
X 
See Section 8.5.3.6 
Hemoglobin A1c 
 
 
 
X 
See Section 8.5.3.6 
Serum for disease, target and drug effect 
biomarkers 
X 
 
 
 
See Section 8.5.4 and Table 8. 
Participants should fast for at least 8 
hours prior to the sample collection 
Plasma for disease, target and drug effect 
biomarkers 
X 
 
 
 
See Section 8.5.4 and Table 8. 
Participants should fast for at least 8 
hours prior to the sample collection 
a  Month 6 samples will be collected from all participants. 
b Performed only in participants for whom Long-Term Immunogenicity Follow-Up Visits are required.
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2. TABLE OF CONTENTS 
DOCUMENT HISTORY ...............................................................................................................2 
1. 
SCHEDULE OF ACTIVITIES ................................................................................5 
2. 
TABLE OF CONTENTS ........................................................................................20 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .........................25 
4. 
ETHICS ....................................................................................................................28 
5. 
STUDY ADMINISTRATION AND CONTACTS ................................................29 
6. 
INTRODUCTION ...................................................................................................30 
6.1 
Background ................................................................................................................31 
6.1.1 
Nonclinical Studies ....................................................................................................31 
6.1.2 
Clinical Studies ..........................................................................................................32 
6.2 
Study Rationale ..........................................................................................................33 
6.2.1 
Scientific Rationale for Study Design .......................................................................34 
6.2.2 
Justification for Dose and Regimen ...........................................................................35 
6.3 
Benefit/Risk Assessment ...........................................................................................36 
6.3.1 
Summary of Potential Benefits ..................................................................................36 
6.3.2 
Summary of Risks......................................................................................................36 
6.3.2.1 
Gastrointestinal Events ..............................................................................................36 
6.3.2.2 
Immunogenicity .........................................................................................................37 
6.3.2.3 
Injection Reactions ....................................................................................................38 
6.3.2.4 
Effects on Bone .........................................................................................................38 
6.3.3 
Safety Monitoring ......................................................................................................39 
6.3.4 
Overall Conclusion ....................................................................................................39 
7. 
STUDY OBJECTIVES ...........................................................................................40 
7.1 
Primary Efficacy Objectives ......................................................................................40 
7.2 
Secondary Efficacy Objectives ..................................................................................40 
7.3 
Safety Objective.........................................................................................................40 
7.4 
Pharmacokinetic Objectives ......................................................................................40 
7.5 
Exploratory Objectives ..............................................................................................40 
8. 
INVESTIGATIONAL PLAN .................................................................................42 
8.1 
Overall Study Design .................................................................................................42 
8.2 
End of Study Definition .............................................................................................46 
8.3 
Study Population ........................................................................................................46 
8.3.1 
Inclusion Criteria .......................................................................................................46 
8.3.2 
Exclusion Criteria ......................................................................................................47 
8.3.4 
Imaging (MRI/MRE) Contraindications ....................................................................50 
8.3.5 
History: Medical, Surgical, Diet, and Exercise .........................................................50 
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8.3.6 
Dietary and Lifestyle Counseling ..............................................................................51 
8.3.7 
Concomitant Medication Restrictions .......................................................................51 
8.3.8 
Screen Failures and Rescreening ...............................................................................52 
8.3.8.1 
Retesting During Screening .......................................................................................52 
8.3.8.2 
Rescreening ...............................................................................................................52 
8.3.9 
Withdrawal of Participants ........................................................................................53 
8.3.9.1 
Discontinuation of Study Medication ........................................................................53 
8.3.9.2 
Discontinuation from Study Participation .................................................................54 
8.3.9.3 
Lost to Follow-Up......................................................................................................55 
8.3.9.4 
Replacement of Participants ......................................................................................56 
8.4 
Treatment ...................................................................................................................56 
8.4.1 
Treatments Administered ...........................................................................................58 
8.4.2 
Study Medication Administration ..............................................................................58 
8.4.3 
Method of Treatment Assignment .............................................................................59 
8.4.4 
Blinding of Study Medication ...................................................................................59 
8.4.4.1 
Maintaining the Blind ................................................................................................59 
8.4.4.2 
Circumstances for Unblinding ...................................................................................60 
8.4.5 
Study Medication Preparation, Handling, Storage, and Accountability ....................60 
8.4.6 
Dose Modification .....................................................................................................61 
8.4.6.1 
Modification of Dose .................................................................................................61 
8.4.6.2 
Dose Interruption .......................................................................................................61 
8.4.6.3 
Missed Doses .............................................................................................................61 
8.4.7 
Treatment Compliance...............................................................................................61 
8.4.8 
Prior and Concomitant Therapy .................................................................................61 
8.4.9 
Treatment After the End of the Study ........................................................................62 
8.5 
Efficacy and Safety Variables ...................................................................................62 
8.5.1 
Efficacy Assessments ................................................................................................62 
8.5.1.1 
Liver Biopsy ..............................................................................................................64 
8.5.1.2 
Noninvasive Scores of Hepatic Fibrosis ....................................................................66 
8.5.1.3 
Imaging ......................................................................................................................67 
8.5.1.4 
Fibroscan® Elastography............................................................................................68 
8.5.1.6 
Metabolic Assessments ..............................................................................................69 
8.5.1.7 
Child-Pugh Turcotte Score ........................................................................................70 
8.5.1.8 
MELD Scoring ..........................................................................................................70 
8.5.1.9 
Liver-Related Clinical Outcome Events ....................................................................70 
8.5.1.10 
Patient-Reported Outcomes (Health-Related Quality-of-Life Questionnaires) .........71 
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8.5.2 
Exploratory Biomarkers .............................................................................................71 
8.5.3 
Safety Assessments ....................................................................................................73 
8.5.3.1 
Adverse Events ..........................................................................................................73 
8.5.3.2 
Overdose ....................................................................................................................77 
8.5.3.3 
Physical Examinations ...............................................................................................78 
8.5.3.4 
Vital Signs .................................................................................................................78 
8.5.3.5 
Electrocardiograms ....................................................................................................78 
8.5.3.6 
Immunogenicity .........................................................................................................79 
8.5.3.7 
Adverse Events of Special Interest ............................................................................80 
8.5.3.8 
Bone Safety by DXA .................................................................................................80 
8.5.4 
Laboratory Assessments ............................................................................................81 
8.5.5 
Pharmacokinetics .......................................................................................................85 
8.5.5.1 
All Participants ..........................................................................................................85 
9. 
STATISTICAL CONSIDERATIONS ...................................................................88 
9.1 
Sample Size Determination .......................................................................................88 
9.2 
Populations for Analyses ...........................................................................................88 
9.3 
Stratification ..............................................................................................................88 
9.4 
Endpoints ...................................................................................................................89 
9.4.1 
Efficacy Endpoints.....................................................................................................89 
9.4.1.1 
Primary Efficacy Endpoint ........................................................................................89 
9.4.1.2 
Secondary Efficacy Endpoints ...................................................................................89 
9.4.2 
Safety Endpoints ........................................................................................................89 
9.4.3 
Pharmacokinetic Endpoints .......................................................................................90 
9.4.4 
Exploratory Endpoints ...............................................................................................90 
9.5 
Statistical Analyses ....................................................................................................91 
9.5.1 
Demographic and Baseline Characteristics ...............................................................91 
9.5.2 
Efficacy Analyses ......................................................................................................91 
9.5.2.1 
Primary Endpoint .......................................................................................................92 
9.5.2.2 
Secondary Efficacy Endpoints ...................................................................................92 
9.5.2.3 
Methods for Handling Treatment Discontinuations and Other Causes of Missing Data
 ...................................................................................................................................92 
9.5.3 
Safety Analyses .........................................................................................................93 
9.5.4 
Pharmacokinetic Analysis .........................................................................................93 
9.5.5 
Analyses of Exploratory Endpoints ...........................................................................93 
10. 
REFERENCE LIST.................................................................................................94 
11. 
APPENDICES ..........................................................................................................98 
Appendix 1 Study Administrative Considerations ....................................................................99 
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Appendix 2 Women of Childbearing Potential Definitions and Methods of Contraception107 
Appendix 3 Criteria for Diagnosis and Exclusion of Participants with Hepatitis B Virus (HBV) 
and Chronic Hepatitis C (HCV) Infection ...........................................................110 
Appendix 4 DSM-5 Criteria for Drug And Alcohol Abuse ....................................................111 
Appendix 5 Child-Pugh Turcotte Scoring ................................................................................113 
Appendix 6 SF-36 (Version 2) Questionnaire ..........................................................................114 
Appendix 7 EQ-5D-3L Questionnaire ......................................................................................120 
Appendix 8 CLDQ-NAFLD .......................................................................................................123 
Appendix 9 Adverse Events and Serious Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up and Reporting .............................................131 
Appendix 10 
Formulae for Measurements ...........................................................................135 
Appendix 11 
Decision Tree for Long-Term Immunogenicity Follow-Up Visits After the Week 
52/PTFU Visit .........................................................................................................136 
 
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LIST OF TABLES 
Table 1 
Screening Period Activities - Study MB130-069 ...................................................6 
Table 2 
Double-Blind Treatment Period Activities and Post-Treatment Follow-Up Period 
Activities - Study MB130-069 ...............................................................................9 
Table 3 
Long-Term Bone Mineral Density and Immunogenicity Follow-Up Period Activities 
– Study MB130-069 .............................................................................................19 
Table 4 
Model-Predicted Percent Change from Baseline in Key Biomarkers for Typical 
Participants with NASH .......................................................................................36 
Table 5 
Study Medications ................................................................................................57 
Table 6 
Study Medication Doses, Dosing Frequency, and Route of Administration ........58 
Table 7 
NAS Scoring System ............................................................................................65 
Table 8 
Laboratory Assessments .......................................................................................81 
Table 9 
Timing of Pharmacokinetic and Electrocardiogram Assessments .......................85 
 
 
LIST OF FIGURES 
Figure 1 
Study Design Schematic – Screening to Week 52/PTFU .....................................44 
Figure 2 
Study Schematic – Bone Mineral Density and Immunogenicity Follow-Up Visits 
After the Week 52/PTFU Visit (visit windows ± 14 days) (1 month is defined as 4 
calendar weeks) ....................................................................................................45 
 
 
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3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Term 
Definition 
ABV 
alcohol by volume 
ADA 
anti-drug antibody 
AE 
adverse event  
ALT 
alanine aminotransferase 
APRI 
AST-Platelet Ratio Index 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMD 
bone mineral density 
BMI 
body mass index 
BSAP 
bone-specific alkaline phosphatase  
CFR 
Code of Federal Regulations 
CLDQ-NFLD 
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease  
CMH 
Cochran Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
CPA 
collagen proportionate area 
CRN 
Clinical Research Network 
CTX-1 
C-terminal telopeptides type I collagen 
DBP 
diastolic blood pressure 
DILI 
drug-induced liver injury  
DMC 
Data Monitoring Committee 
DSM-5 
Diagnostic and Statistical Manual 5 
DXA 
dual-energy X-ray absorptiometry 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture system 
EGD 
esophagogastroduodenoscopy 
eGFR 
estimated glomerular filtration rate 
ELF 
Enhanced Liver Fibrosis 
EQ-5D-3L 
3-Level EuroQol 5 Dimension (quality-of-life questionnaire) 
ET 
early termination 
FDA 
(United States) Food and Drug Administration 
FGF 
fibroblast growth factor 
FGF19 
fibroblast growth factor 19 
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FGF21 
fibroblast growth factor 21 
FGF23 
fibroblast growth factor 23 
FGF-R 
fibroblast growth factor receptor 
FGF-R4 
fibroblast growth factor receptor 4 
FIB4 
Fibrosis 4 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HRQoL 
Health-related quality-of-life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
INR 
international normalized ratio  
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LDL 
low-density lipoprotein 
MCD 
methionine and choline-deficient 
MD 
Doctor of Medicine 
MELD 
Model for End-Stage Liver Disease 
miRNA 
micro RNA 
mITT 
modified intent-to-treat 
MRE 
magnetic resonance elastography 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging-proton density fat fraction 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NEC 
not elsewhere classified 
Non-IP 
non-investigational product 
P1NP 
N-terminal propeptide- of type 1 procollagen 
PD 
pharmacodynamic 
PDFF 
proton density fat fraction 
PEG 
polyethylene glycol 
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PK 
pharmacokinetic 
PRO-C3 
N-terminal type 3 collagen propeptide 
PTFU 
Post-Treatment Follow-Up 
QD 
once daily 
QTcF 
QT interval corrected using Fridericia’s formula 
QW 
once weekly 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SF-36 
36-question Short Form quality-of-life questionnaire (Version 2) 
T2DM 
type 2 diabetes mellitus 
TG 
triglycerides 
TIMP-1 
tissue inhibitor of metalloproteinases 1 
ULN 
upper limit of normal  
WOCBP/WOCBPs 
woman/women of childbearing potential 
 
 
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4. ETHICS 
This study will be conducted in compliance with the following: 
• Institutional Review Board (IRB)/ethics committee (EC) guidelines 
• International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines 
• The principles set forth in the Declaration of Helsinki (Fortaleza 2013) 
• Applicable regulations regarding clinical safety data management (E2A, E2B[R3]) and 
scientific integrity (E4, E8, E9, and E10) 
• The ICH Note for Guidance on GCP (ICH Harmonised Tripartite Guideline E6 [R1]) 
• United States Food and Drug Administration (FDA) Code of Federal Regulations (CFR) 
(21 CFR § 50, 56, 312) 
 
In addition, this study will adhere to all local regulatory requirements, and requirements for 
data protection. 
 
Details on the ethical conduct of the study, IRB/ECs, and participant consent are in 
Appendix 1. 
 
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5. STUDY ADMINISTRATION AND CONTACTS 
 
Contact Type/Role 
Contact 
Serious adverse event and pregnancy reporting 
 
 
 
  
 
 
 
 
Medical Monitors 
(medical advice on protocol and study medication) 
 
 
 
 
 
 
 
Study Director  
(overall responsibility for study conduct) 
 
 
 
 
Additional information regarding vendors and their respective contacts/roles, including 
central laboratory, central imaging and central pathology, are included in the applicable 
vendor manuals.  
 
Additional details on the Data Monitoring Committee (DMC) are in the DMC charter. 
 
 
Study administrative considerations are addressed in Appendix 1. 
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6. INTRODUCTION 
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 more 
advanced form of NAFLD, is defined as the presence of hepatic steatosis and inflammation 
with hepatocyte injury (ballooning), with or without fibrosis.1 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).2 
There is an urgent need to develop safe and effective therapies for NASH.3 
 
Fibroblast growth factor 21 (FGF21) is a nonmitogenic hormone that is an important 
regulator of energy metabolism.4 FGF21 is a member of a hormone-like subgroup within the 
fibroblast growth factor (FGF) superfamily. Like other members of this subfamily 
(i.e., FGF19 and FGF23), FGF21 has low binding affinity for heparin, which allows for 
transport into the circulation and subsequent action at distant sites. High-affinity binding of 
FGF21 to FGF receptors (FGF-Rs) occurs only in the presence of the FGF-R co-receptor, 
β- Klotho; the restricted expression pattern of β-Klotho defines the target tissues for FGF21 
activity. FGF-Rs and β-Klotho are co-localized in liver, pancreas and adipose tissue, which 
are responsible for glucose and fat metabolism.5 Notably, in contrast to FGF19, FGF21 does 
not signal through FGF-R4/β-Klotho6 and, therefore, is not mitogenic, nor does it regulate 
bile acid metabolism.  
 
FGF21 is most abundantly produced in the liver, where it reduces lipogenesis and glucose 
production and enhances fatty acid oxidation.7 In adipose tissue, FGF21 promotes glucose 
uptake and stimulates secretion of adiponectin, an adipokine with insulin-sensitizing, anti-
steatotic, anti-inflammatory, and anti-fibrotic activities. Initial studies in mouse models and 
primates suggested that FGF21 administration increased energy expenditure, promoted fat 
utilization and reduced body weight and hepatic steatosis in high fat diet-induced obese mice, 
and improved lipid profiles, insulin sensitivity, and glycemia in obese, diabetic rhesus 
monkeys.8,9 Increases in adiponectin and high-density lipoprotein (HDL) cholesterol and 
reductions in levels of triglycerides (TGs), low-density lipoprotein (LDL) cholesterol, and 
insulin have also been reported in a human clinical study with a FGF21 analog.10 Beneficial 
changes in circulating factors can be used as biomarkers of FGF21 activity, and they suggest 
that FGF21 mimetics could be attractive candidates for the treatment of NASH and its 
metabolic complications.  
 
Serum concentrations of FGF21 are increased in human patients with NAFLD or NASH as 
well as the methionine- and choline-deficient (MCD) mouse model of NASH.11,12,13 FGF21 
administration to FGF21 knock-out mice, however, has been shown to reverse excessive liver 
fat accumulation and fibrosis in the mouse MCD NASH model. 13 These data are consistent 
with the hypothesis that up-regulation of FGF21 seen in human NASH patients or wild-type 
mice on the MCD diet may be an insufficient compensatory response, and that administration 
of exogenous FGF21 to achieve supraphysiologic serum concentrations may ameliorate the 
steatosis and fibrosis associated with NASH. 
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6.1 Background 
BMS-986036, also known by the generic name pegbelfermin, is a polyethylene glycol 
(PEG)ylated FGF21 analog with potent FGF21 signaling activity. BMS-986036 is a slightly 
modified version of human FGF21, where the glutamine amino acid at position 108 has been 
replaced by a novel para-acetylphenylalanine residue with a linear 30-kDa PEG attached to 
improve the pharmacokinetic (PK) properties of the molecule and a methionine residue has 
been added to the amino-terminus of the protein to enable expression in Escherichia coli. 
Preclinical and clinical studies with BMS-986036 suggest that BMS-986036 is safe and well 
tolerated, and that it has the ability to increase adiponectin, improve insulin sensitivity, 
reduce liver fat, reduce liver injury, reduce fibrosis, and improve plasma lipid profiles, 
making it an attractive candidate for the treatment of patients with NASH who have advanced 
fibrosis. 
 
Refer to the Investigator’s Brochure (IB) for more details on BMS-986036. 
 
6.1.1 Nonclinical Studies 
The effects of BMS-986036 treatment have been evaluated in both prevention and 
therapeutic intervention studies in a mouse model of NASH, in which mice develop a fatty 
liver at 5 weeks of age, NASH at 7 weeks of age, and liver fibrosis at 9 weeks of age.14,15 
• In the prevention study, 5-week-old mice treated with BMS-986036 had significantly 
reduced body weight, liver weight, liver-to-body weight ratio, plasma TGs, and liver 
TGs. BMS-986036 also significantly decreased histological evidence of hepatic 
perturbations (NAFLD Activity Score, comprising assessments of steatosis, lobular 
inflammation, and hepatocyte ballooning) and significantly reduced fibrosis, 
demonstrating an anti-fibrotic effect of BMS-986036. Consistent with this observed 
anti-fibrotic effect, BMS-986036 treatment reduced hepatic expression of alpha-
smooth muscle actin, tissue inhibitor of metalloproteinases 1 (TIMP-1), and type 1 
collagen. 
• In the therapeutic intervention study, 9-week-old mice treated with BMS-986036 had 
statistically significant decreases in liver-to-body weight ratio, blood glucose, plasma 
alanine aminotransferase (ALT), liver lipid content (TG and cholesterol), as well as 
histological evidence of hepatic steatosis, hepatocyte ballooning, lobular 
inflammation, and fibrosis. 
 
BMS-986036 was not genotoxic and had no adverse effects on cardiovascular, respiratory, 
and/or central nervous systems in rats, dogs, and/or cynomolgus monkeys. BMS-986036 was 
neither embryo-lethal nor teratogenic in definitive rat or rabbit embryo-fetal development 
studies. 
 
In repeat-dose toxicity studies in rats and sexually mature monkeys up to 6 months in 
duration, BMS-986036, administered once daily (QD), was clinically well tolerated and 
evidence of pharmacology was observed at all doses (changes in adiponectin and other 
metabolic parameters). Effects on bone (decreases in bone mass, size, mineralization, and 
strength, as well as changes in formation/resorption biomarkers) were observed, and these 
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were attributed to pharmacologically mediated body weight loss/reductions and slower 
overall growth, except at the highest dose tested in monkeys (1 mg/kg/day; 19× area under 
the concentration-time curve [AUC] multiple). 
 
Expected PEGylated peptide-related effects (injection site inflammation and minimal to 
moderate tissue vacuolation) were also observed. There was also no indication that 
PEG- related vacuolation was associated with any apparent degenerative or functional 
consequences in any cells or tissues, and findings were reversible, except for choroid plexus 
vacuolation in monkeys at doses ≥ 0.75 mg/kg/day (C-terminal intact BMS-986036 AUC 
multiple of 8×). PEG-related-findings were consistent with an adaptive response associated 
with PEG clearance and were not considered adverse. 
 
Most of the observed effects in both studies did not substantially progress with extended 
duration of dosing and were generally reversible. 
 
The no-observed-adverse-effect level AUC exposure multiples for C-terminal intact BMS-
986036 was 0.8× (males) and 2× (females) in rats and 2× in monkeys relative to the highest 
planned dose of 40-mg once weekly (QW) in this study. 
 
Refer to the IB for more details on these studies. 
 
6.1.2 Clinical Studies 
In the first-in-human study (Study MB130001), BMS-986036 was administered by 
subcutaneous (SC) injection in single and multiple doses for up to 14 days to 72 obese, 
nondiabetic, healthy adult volunteers.16 C-terminal intact BMS-986036, the active 
polypeptide, displayed a half-life of approximately 20 - 24 hours and demonstrated a 
generally linear PK with 2-fold to 3-fold accumulation following QD dosing. Following 
single dose administration in the range of 1 mg to 60 mg, the drug was slowly absorbed from 
the SC injection site (abdomen) into the systemic circulation, with median time to maximum 
concentration ranging from 24 to 33 hours. Following a single weekly dose of 21 mg, the 
time to maximum concentration was like that of single doses. BMS-986036 in doses of up to 
30 mg QD for up to 14 days was well tolerated and safe; adverse events (AEs) were mild and 
showed no dose-ordered trends. In the multiple-dosing panels, BMS-986036 increased 
adiponectin levels in a dose-dependent fashion. Adiponectin increased by 41.7% in the 
BMS-986036 30 mg QD group; in contrast, it decreased by 28.5% in the placebo group. 
Adiponectin has been shown to inhibit hepatic stellate cell proliferation and hepatic fibrosis 
in vitro,17 and higher levels of adiponectin have been shown to correlate with improvements 
in fibrosis, as well as steatosis and inflammation.18 It is therefore likely that an increase in 
adiponectin in response to BMS-986036 would have beneficial anti-steatotic, anti-
inflammatory, and anti-fibrotic effects in NASH patients. BMS-986036 also improved insulin 
sensitivity, promoted favorable lipid changes (decreased TGs, apolipoprotein B, and LDL 
cholesterol), and reduced body weight compared to placebo.  
 
BMS-986036 was also studied in two Phase 2 studies. Study MB130002 was a randomized, 
double-blind, placebo-controlled, parallel-group, multiple-dose study in obese participants 
with type 2 diabetes mellitus (T2DM). Over 90% of participants had evidence of underlying 
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fatty liver, based upon the fatty liver index. In this study, participants self-administered 
BMS-986036 or placebo, SC, for 12 weeks according to one of the following dosing 
regimens: BMS-986036 (1, 5, or 20 mg QD), BMS-986036 (20 mg QW), or placebo (QD). A 
total of 96 participants received at least 1 dose of BMS-986036. BMS-986036 treatment 
improved insulin sensitivity, adiponectin, fasting TGs, LDL cholesterol, HDL cholesterol, 
apolipoprotein C3, and N-terminal type 3 collagen propeptide (PRO-C3) (a biomarker for 
type 3 collagen formation, and hence, potentially, fibrosis). Dose-dependent increases in 
adiponectin were observed in all BMS-986036 dose groups. Meaningful changes in body 
weight were not observed.19 
 
Study MB130045 was a randomized, double-blind, placebo-controlled, parallel-group, 
multiple-dose study conducted in participants with biopsy-confirmed NASH who had stage 
1-3 fibrosis according to the NASH Clinical Research Network (CRN) scoring system. In this 
study, participants self-administered BMS-986036 or placebo, SC, for 16 weeks according to 
one of the following dosing regimens: BMS-986036 (10 mg QD), BMS-986036 (20 mg 
QW), placebo (QD). A total of 50 participants received at least 1 dose of BMS-986036 in the 
study.20 Treatment with BMS-986036 for 16 weeks resulted in statistically significant 
reductions in hepatic fat fraction (as measured by magnetic resonance imaging [MRI]), 
decreases in ALT and aspartate aminotransferase (AST) (markers of liver injury), increases 
in adiponectin, and improvements in lipid profiles. Importantly, treatment with BMS-986036 
was associated with improvement in fibrosis, as determined by decreases in magnetic 
resonance elastography (MRE) (an assessment of liver stiffness) and decreases in serum 
PRO-C3. In particular, BMS-986036 treatment was associated with an increase in the 
proportion of patients with at least a 15% decrease in MRE-assessed liver stiffness, a 
reduction that has been previously associated with an improvement in liver fibrosis, as 
observed on liver biopsy.21 
 
Refer to the IB for details on these studies. 
 
6.2 Study Rationale 
The current study is designed to confirm and extend the results observed in the Phase 1 and 
2a studies with BMS-986036. Specifically, this study aims to demonstrate in participants 
with NASH and compensated cirrhosis, the efficacy of BMS-986036 using histological and 
noninvasive endpoints, and the safety of BMS-986036 as assessed by AEs, lab results and 
bone mineral density (BMD) monitoring. 
 
The protocol was planned to randomize approximately 100 participants to 1 of 4 treatment 
groups (approximately 25 participants per group). This protocol amendment (Version 4.0) 
reflects that upon close of enrollment, approximately 155 participants were randomized to 
treatment (approximately 38 participants per group). The increased number of randomized 
participants occurred following: 1) unexpectedly high enrollment rate in the final month of 
the enrollment period; 2) several participants who had initially been enrolled into FALCON 1 
(MB130-068) were determined (based on central pathology biopsy results) to qualify for 
FALCON 2 (MB130-069) during the period between the closure of enrollment and 
completion of randomization; and 3) an unexpected decrease in the actual screen failure rate 
for subjects entered in the final month of enrollment. 
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Based on the unmet medical need for patients, the benefit/risk assessment discussed in 
Section 6.3, and the strict safety monitoring of all participants, the potential clinical benefit 
outweighs the risks for those who have chosen to participate in this study. No additional 
revisions are required in Section 9 due to the increased number of randomized participants. 
 
6.2.1 Scientific Rationale for Study Design 
Complete details of the study design are provided in Section 8.1.  
 
Participants having a confirmed diagnosis of NASH and compensated cirrhosis will be 
enrolled in this multicenter, double-blind, placebo-controlled, randomized, parallel-group 
study to demonstrate the efficacy and safety of BMS-986036. 
 
NASH patients with compensated cirrhosis have a high unmet medical need for approved 
therapies and compared to NASH patients with earlier stages of fibrosis, they are more likely 
to have a favorable benefit/risk profile for treatment with BMS-986036. Compared to NASH 
patients with stage 1-3 fibrosis, NASH patients with compensated cirrhosis have worsened 
clinical outcomes and disease-specific mortality.22,23,24 Moreover, the risk of liver-related 
mortality increases exponentially with each increase in fibrosis stage.25 Demonstration of an 
improvement in fibrosis should be highly predictive of clinical benefit. 
 
NASH grade will be assessed by liver biopsy histology. Fibrosis stage will be assessed by 
liver histology as well as a number of noninvasive measures. In addition, PRO-C3 levels in 
participants will be measured during the course of the study in order to collect more data on 
its potential as a pharmacodynamic (PD) biomarker of fibrosis. The correlation of baseline 
PRO-C3 levels with response to BMS-986036 will also be assessed. Markers of liver injury, 
metabolic improvements, and other liver-related outcomes will also be examined. Safety, 
including hematology and blood chemistry results, electrocardiograms (ECGs), and other 
potential safety issues (e.g., gastrointestinal AEs, immunogenicity, injection reactions, and 
effects on bone), will be monitored throughout the study. 
 
PK profiling of BMS-986036 will be performed on all participants based upon trough 
sampling prior to dosing at each visit. 
 
 
 
 
The primary efficacy endpoint of the study will be based on the independent histological 
evaluation of liver biopsy at 48 weeks – a timepoint at which meaningful clinical benefits in 
fibrosis and NASH disease activity are expected in the selected patient population treated 
with BMS-986036. 
 
The design and dose selection of future Phase 3 studies with BMS-986036 will be based 
upon the totality of the efficacy, safety and PK analyses from this study and from 
MB130-068, a Phase 2 study of BMS-986036 in participants with NASH and stage 3 liver 
fibrosis. 
 
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6.2.2 Justification for Dose and Regimen  
In the present study, weekly SC administration of BMS-986036 (10, 20 or 40 mg, or placebo) 
will be evaluated for efficacy and safety. Careful examination of the Phase 1 and Phase 2a 
data, along with insights gleaned from nonclinical studies in animals, support these dosing 
regimens. 
 
In Study MB130045, BMS-986036 dosed as 10 mg QD or 20 mg QW SC for 16 weeks in 
NASH participants consistently improved multiple biomarkers associated with steatosis, liver 
injury, and fibrosis. In addition to significantly decreasing hepatic fat fraction in NASH 
participants at both doses, improvement relative to placebo was observed for several 
biomarkers such as serum PRO-C3, liver stiffness (as measured by MRE), adiponectin, 
hepatic transaminases, and serum lipids. At 16 weeks, the 10 mg QD dose produced effects 
that were comparable to, albeit modestly higher than, the 20 mg QW dose for several 
biomarkers (MRI, PRO-C3, LDL cholesterol, and hepatic transaminases).  
 
In addition to data from NASH patients in Study MB130-045, PK and PD data from 2 other 
randomized, and placebo-controlled studies of BMS-986036 in obese healthy volunteers 
(MB130-001) and obese T2DM participants (MB130002) were also included and analyzed 
using population PK-PD analyses. 
 
Population PK-PD models were developed that described the PK-PD relationship between 
BMS-986036 and several PD responses across these studies, such as increase in adiponectin, 
reduction of hepatic fat fraction (MRI), reduction of TGs, LDL, and HDL, reduction of liver 
inflammation, as evidenced by reduction of elevated ALT, and reduction of fibrosis, as noted 
by improvements in PRO-C3, MRE, and adiponectin. Direct or indirect response PK-PD 
models were used to describe the relationship between PK and PD. These models were then 
used to predict biomarker responses at various candidate weekly dosing regimens of 
BMS-986036.16,19,20 
 
Given that only modestly higher PD responses were observed with 10 mg QD dosing relative 
to the 20 mg QW dose in Study MB130-045, and the consideration that a QW SC dosing 
regimen is likely to be more acceptable to participants than a daily dosing regimen, and 
therefore be associated with better compliance, 3 weekly doses were identified -i.e., 10 mg, 
20 mg, and 40 mg QW, that are expected to achieve clinically meaningful responses for key 
biomarkers of NASH, and can be administered in up to 2 injections. Model-predicted percent 
change from Baseline in key biomarkers for typical NASH study participants are noted in 
Table 4 below. 
 
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Table 4 
Model-Predicted Percent Change from Baseline in Key Biomarkers for 
Typical Participants with NASH 
Biomarker 
Model-predicted typical % change in response at trough 
concentrations with various QW doses of BMS-986036 
10 mg QW 
20 mg QW 
40 mg QW 
Hepatic fat content 
−24.8 
−29.7 
−31.9 
Alanine aminotransferase 
−16.7 
−22.6 
−26.7 
PRO-C3 
−7.0 
−12.4 
−17.4 
Adiponectin 
11.4 
18.3 
24.0 
NASH = nonalcoholic steatohepatitis; PRO-C3 = N-terminal type 3 collagen propeptide; QW = once weekly 
 
The safety and PK of 20 mg QW and 40 mg QW dosing regimens for 3 weekly doses has 
been recently characterized in a Phase 1 study in obese healthy Japanese participants. 
Preliminary results show that exposure is generally dose proportional between 20 mg and 
40 mg QW, and the 40 mg QW dose was safe and well tolerated (refer to IB for additional 
details). The 40 mg QW dose is hypothesized to provide increased efficacy compared to that 
of the 20 mg QW dose, but with lower overall BMS-986036 exposure than that of the 10 mg 
QD dose. Additionally, compared to 10 mg QD, the 40 mg QW dose is expected to provide a 
higher margin relative to the exposure associated with nonclinical bone-related AEs, and it 
also provides a lower burden of PEG. Evaluation of the 10 mg QW and 40 mg QW dose 
regimens is expected to facilitate a more complete evaluation of the dose-response profile of 
BMS-986036. 
 
6.3 Benefit/Risk Assessment 
6.3.1 Summary of Potential Benefits 
In obese participants with T2DM (many of whom had underlying fatty liver), treatment with 
BMS-986036 for 12 weeks improved several metabolic factors (insulin sensitivity, 
adiponectin, and serum lipids) and led to a reduction in PRO-C3. In participants with NASH, 
treatment with BMS-986036 for 16 weeks resulted in statistically significant reductions in 
hepatic fat fraction (measured by MRI), decreases in hepatic transaminases (markers of liver 
injury), significant increases in adiponectin, significant reductions in PRO-C3, reductions in 
liver stiffness (measured by MRE), and improvements in lipid profiles. 
 
Thus, clinical data suggest that BMS-986036 has the ability to increase adiponectin, improve 
insulin sensitivity, reduce liver fat, reduce liver injury, reduce fibrosis, and improve plasma 
lipid profiles, making it an attractive candidate for the treatment of patients with NASH who 
have advanced fibrosis. Together, these data support further development of BMS-986036 
for the treatment of patients with NASH with compensated cirrhosis. 
 
6.3.2 Summary of Risks 
6.3.2.1 
Gastrointestinal Events 
In Phase 2a studies, the frequency of gastrointestinal AEs in participants treated with 
BMS-986036 (72%) was higher than that reported in the placebo group (28%). The most 
frequent gastrointestinal AEs were diarrhea, nausea, aphthous ulcer, constipation, dyspepsia, 
frequent bowel movements, upper abdominal pain, vomiting, and abdominal pain. When they 
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occurred, these AEs were of generally mild or moderate intensity; none of these AEs were of 
severe intensity. There were no discontinuations due to gastrointestinal AEs. 
 
A total of 69 events of diarrhea, nausea, frequent bowel movements, vomiting, abdominal 
pain, and abdominal pain upper were reported in participants on both placebo and 
BMS-986036 treated arms. Among the 69 events, 55 events were reported in participants 
treated with BMS-986036 and 14 events were reported in the placebo group: 
• Among the 55 events, there were 3 events for which AE duration was not available 
for calculation. Therefore, event duration was calculated for 52 events. 
• The majority (80.7% [42/52]) of the events were of mild severity (Grade 1), were 
judged by the investigator to be not related, were resolved in a mean of 6 weeks, and 
did not require any treatment. 
• A smaller percentage (19.2% [10/52]) of the events were of moderate severity; 8 of 
the moderate grade events (5 events of diarrhea and 1 event each of abdominal pain, 
vomiting, and frequent bowel movements) did not require any treatment and were 
resolved quickly (within a mean of 8.7 days). These events were reported as not 
related by the investigator, except for frequent bowel movements. The remaining 
moderate severity events (2 events of nausea; 1 related and 1 not related) required 
treatment and were resolved in a mean of 31 days. 
 
At this time, these events are not explained by the known biological mechanism of 
PEG-FGF21. Of note, there was no evidence of gastrointestinal AEs in nonclinical models 
with BMS-986036.  
 
6.3.2.2 
Immunogenicity 
BMS-986036 is a modified version of human FGF21 and has the potential to be 
immunogenic; however, the potential safety liability of antibody formation in humans is 
considered to be low. Most human protein therapeutics can induce a rapid and strong anti-
drug antibody (ADA) response in animals, although the presence of ADAs in these species 
does not necessarily predict immunogenicity in humans.  
 
In the Phase 1 study MB130001, 3 of 72 participants (4%), who received any dose of 
BMS-986036, developed antibodies to FGF21 and BMS-986036 by the end of the study. An 
initial assay titer increase was observed, followed by stabilization or decrease in titers, during 
additional post-study immunogenicity testing over the next 6 months. No participant had 
persistent positive functional neutralizing ADAs during the Follow-Up Period, although one 
participant tested positive at 2 nonconsecutive time points. Plasma exposure of BMS-986036 
in these 3 participants did not differ from that of other treated participants during the period 
in which the concentration was detectable. Immunogenicity was not associated with an 
increased incidence of overall AEs or immunogenicity-related AEs, such as rash or fever, or 
with altered PK or PD effects.  
 
In Study MB130002, up to Study Discharge (Day 126), anti-BMS-986036 and anti-FGF21 
antibodies were detected in 68% and 70%, respectively, of the participants treated with 
BMS-986036; however, antibody titers were generally low (12.2% and 37%, respectively, 
had titers ≥ 64), and only 2 participants had neutralizing antibody responses to endogenous 
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wild-type FGF21. ADAs usually appeared after 8 weeks of dosing and they were not 
associated with immune-related AEs or injection site reactions. BMS-986036 exposures were 
similar in participants with ADAs compared with participants without ADAs. During the 
Follow-Up Period, antibody titers were observed to be either stable or declining in the 
overwhelming majority of participants, and no participant had neutralizing antibodies. 
 
In Study MB130045, up to Study Discharge (Day 142), anti-BMS-986036 and anti-FGF21 
antibodies were detected in 62.5% and 62.5%, respectively, of the participants treated with 
BMS-986036 20 mg QW; however, antibody titers were generally low (among participants 
who received BMS-986036 20 mg QW, 4/24 and 0/24, respectively, had anti-BMS-986036 
and anti-FGF21 titers ≥ 64). Furthermore, titers were not associated with immune-related 
AEs or injection site reactions. 
 
6.3.2.3 
Injection Reactions 
Injection site reactions have been monitored in completed and ongoing studies using the 
Draize scale, which rates erythema and edema at the injection site on a scale ranging from 
“none” to “severe.” In Phase 1 and Phase 2a studies, injection-related AEs were generally 
mild, transient, resolved without intervention, and did not lead to discontinuation. 
 
In the single ascending dose portion of Study MB130001, 2 participants (5.6%) who received 
BMS-986036 and 0 participants in the placebo group developed injection site erythema. In 
the multiple ascending dose portion of the study, the proportion of participants who 
developed erythema was well balanced between treatment groups (BMS-986036 at any dose 
versus placebo). Eleven participants developed injection site erythema (8 participants 
[22.2%] across all BMS-986036 groups and 3 participants [25.0%] in the placebo group). No 
participants developed injection site edema. 
 
In Study MB130002, injection site erythema and/or injection site edema were reported in 4 of 
96 participants (4.2%) who received BMS-986036 and in 1 of 24 participants (4.2%) who 
received placebo. One injection site reaction (20 mg QD) was of severe intensity, and the 
remaining 3 injection site reactions were rated as mild in intensity. Concurrent ADAs were 
present in 1 participant (10 mg QD) of the 5 participants with injection site erythema and/or 
edema. 
 
In Study MB130045, injection site erythema was reported in 3 (4.0%) participants, and 
injection site edema was reported in 1 (1.3%) participant. All AEs of injection site erythema 
and injection site edema were mild or moderate in intensity. Concurrent ADAs were present 
in 2 (20 mg QW and 10 mg QD) of the 3 participants with injection site erythema and/or 
edema. 
 
6.3.2.4 
Effects on Bone 
In the multiple ascending dose portion of Study MB130001, conducted in healthy 
participants, all dose panels had a decrease in bone formation markers (bone-specific alkaline 
phosphatase [BSAP] and N-terminal propeptide- of type 1 procollagen [P1NP]) that was 
reversible after administration of BMS-986036 had ended. The bone marker values remained 
within the normal reference range in all participants, and the percent decrease from Baseline 
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did not differ between treated participants and the pooled placebo group. Similarly, there was 
no significant change in bone resorption markers in any BMS-986036-treated participants 
compared to the pooled placebo group. 
 
Analyses from Phase 2 studies (MB130002 and MB130045) in participants with T2DM and 
in participants with NASH suggest that BMD, as measured by bone densitometry, was not 
affected by 12 or 16 weeks of dosing with BMS-986036. There were no meaningful 
differences in population mean BMD change from Baseline at the end of dosing or at 
6-months follow-up. 
 
Additionally, in both studies, BMS-986036 had no clinically meaningful impact on 
biomarkers of bone turnover (BSAP, P1NP, or C-terminal telopeptides type I collagen [CTX-
1]) during 12 or 16 weeks of treatment. 
 
Overall, the results from Phase 1 and Phase 2a studies have demonstrated that BMS-986036 
was clinically well tolerated in obese participants, in obese participants with T2DM, and in 
participants with NASH with stage 1-3 liver fibrosis and has an acceptable safety profile to 
support continued clinical development. 
 
6.3.3 Safety Monitoring 
Safety monitoring will be in place during the entire study allowing early detection of any 
safety signals. Participants will undergo safety evaluations at each clinic visit and the 
investigator will conduct a thorough safety evaluation before dosing. Safety assessments will 
be regularly performed and will include assessments for AEs, focused symptom-directed 
physical examinations, and laboratory measurements. 
 
Study results will be monitored by an independent DMC. The scope of responsibility for the 
DMC will be comprised of safety monitoring by masked treatment group however, the DMC 
may request treatment codes and/or efficacy summaries if indicated for safety/benefit 
assessment (see Appendix 1). 
 
In addition to the DMC, the sponsor (blinded to treatment assignment) will monitor safety. 
All reported AEs will be assessed, including events of special interest for BMS-986036 (see 
Section 8.5.3.7). The sponsor has developed a list of events of special interest for the 
BMS-986036 program based on the known biologic class effects, the mechanism of action, 
and data from unblinded clinical studies. These will include injection site reactions, 
gastrointestinal events, and bone-related events. Additionally, BMD and immunogenicity 
(anti-BMS-986036 and anti-FGF21 antibodies) will be monitored (see Section 8.5.3.6 and 
Section 8.5.3.8). AEs on or around the time of development of anti-BMS-986036 and/or anti-
FGF21 antibodies will be carefully evaluated. 
 
6.3.4 Overall Conclusion 
Based on nonclinical data and results available from Phase 1 and Phase 2a studies, the 
potential benefits of BMS-986036 outweigh the potential risks for patients with NASH and 
compensated cirrhosis who choose to participate in this study. 
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7. STUDY OBJECTIVES  
The endpoints for the objectives below are described in Section 9.4.1 (efficacy), Section 9.4.2 
(safety), Section 9.4.3 (PK), and Section 9.4.4 (exploratory). 
 
The overall study population is restricted to adults with NASH and compensated cirrhosis. 
Qualifying participants will receive BMS-986036 for 48 weeks. See Sections 8.3.1, 8.3.2, 
8.3.3, and 8.3.4 for detailed inclusion and exclusion criteria, respectively. 
 
7.1 Primary Efficacy Objectives 
To evaluate the efficacy of BMS-986036 in adults with NASH and compensated cirrhosis 
based on improvement in fibrosis without worsening of NASH, as determined by liver biopsy 
at Week 48. 
 
For this protocol, improvement in fibrosis is defined as a decrease of fibrosis by ≥ 1 point, as 
determined by the NASH CRN Fibrosis Score. Worsening of NASH is defined as an increase 
of the NAFLD Activity Score (NAS) by ≥ 1 point (see Section 8.5.1.1). 
 
7.2 Secondary Efficacy Objectives 
• To evaluate the impact of BMS-986036 on improvement of fibrosis as determined by 
liver biopsy at Week 48 
• To evaluate the impact of BMS-986036 on improvement in fibrosis without worsening 
of NASH or improvement of NASH as determined by liver biopsy at Week 48 
• To evaluate the impact of BMS-986036 on resolution of NASH, as determined by liver 
biopsy at Week 48 
• To evaluate the impact of BMS-986036 on improvement of NASH, as determined by 
liver biopsy at Week 48 
• To evaluate the impact of BMS-986036 on collagen proportionate area (CPA) as 
determined by liver biopsy at Week 48 
 
7.3 Safety Objective 
To demonstrate the safety of BMS-986036 in adults with NASH and compensated cirrhosis 
throughout the course of the study, including BMD and immunogenicity. 
 
7.4 Pharmacokinetic Objectives 
• To determine trough concentrations of BMS-986036 in all participants 
 
7.5 Exploratory Objectives 
To explore the impact of BMS-986036 administration on the following parameters: 
• Quantitative assessments of fibrosis and fat on biopsy 
• NAS 
• Digital pathology assessment of NASH 
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• Hepatic fat fraction by magnetic resonance imaging-proton density fat fraction 
(MRI-PDFF) 
• Noninvasive measures of fibrosis and/or cirrhosis 
• Metabolic assessments 
• Child-Pugh Turcotte score 
• MELD score 
• Liver-related clinical outcome events 
• Patient-reported outcomes  
• Exploratory biomarkers 
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8. INVESTIGATIONAL PLAN 
8.1 Overall Study Design 
This will be a multicenter, double-blind, placebo-controlled, randomized, parallel-group 
study to demonstrate the efficacy and safety of BMS-986036 in the treatment of participants 
with NASH and compensated cirrhosis. The procedures and assessments to be conducted at 
each study visit are outlined in the Schedules of Activities tables (Table 1, Table 2, and Table 
3 in Section 1) provided at the beginning of this protocol.  
 
A schematic of the study design is in Figure 1 (Screening to Week 52/Post-Treatment 
Follow-up [PTFU]) and Figure 2 (follow-up visits after the Week 52/PTFU Visit) below. 
 
The study will consist of 4 periods: 
• A Screening Period of up to 8 weeks in duration (this period may be extended to a total 
of up to12 weeks upon discussion with the medical monitor) 
• A 48-week, Double-Blind Treatment Period, during which the participants will receive 
blinded study medication (BMS-986036 10 mg, 20 mg, 40 mg QW or matching 
placebo QW) 
• A 4-week PTFU Period 
• A Follow-Up Period of up to 14 months (1 month is defined as 4 calendar weeks) after 
the Week 52/PTFU Visit for the collection of an additional dual-energy X-ray 
absorptiometry (DXA) assessment (in all participants), samples for potential 
immunogenicity testing (in all participants) as well as plasma and serum for 
biomarkers (in all participants) at 6 months (± 14 days) Post Week 52/PTFU. 
Subsequent visits at 9, 12, and 14 months after Week 52 or PTFU will be performed in 
participants for whom Long-Term Immunogenicity Follow-Up Visits are required. See 
Section 8.5.3.6 
 
At the end of the Screening Period, participants meeting all inclusion and no exclusion 
criteria will enter the Double-Blind Treatment Period. 
 
Participants will be enrolled and randomized via interactive response technology (IRT) to 
receive BMS-986036 10 mg QW, BMS-986036 20 mg QW, BMS- 986036 40 mg QW or 
matching placebo QW in a 1:1:1:1 ratio. A liver biopsy will be performed during Screening 
(if necessary) and at Week 48 in all participants. A total of approximately 100 participants 
was planned to be randomized (approximately 25 participants per arm). The final number of 
participants randomized was approximately 155 (see Section 6.2).  
 
Arm 1:  BMS-986036 (10 mg QW) 
Arm 2:  BMS-986036 (20 mg QW) 
Arm 3:  BMS-986036 (40 mg QW) 
Arm 4:  Placebo 
 
Participants will be stratified at randomization by country (Non-Japan/Japan). Participants in 
countries other than Japan will be stratified at randomization according to T2DM status 
(yes/no). Japanese participants will not be further stratified. 
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Randomized participants will receive their assigned double-blind study medication for a total 
of 48 weekly doses. The treatment will be administered by SC injection of 2 pre-filled 
syringes of study medication in the abdomen according to their assigned treatment arm (see 
Section 8.4.2). During the Double-Blind Treatment Period (Table 2 in Section 1), participants 
will be evaluated for safety and efficacy every 4 weeks (± 5 days) through Week 24 and 
every 8 weeks (± 5 days) after Week 24 through Week 48.  
 
Participants will then return at Week 52 (± 5 days) for a PTFU Visit. Participants who 
discontinue study medication earlier than Week 48 will have an Early Termination (ET) Visit 
at the time of study medication discontinuation and will return for a PTFU Visit 4 weeks 
(± 5 days) after the ET Visit. 
 
Participants will return 6 months (± 14 days) (1 month is defined as 4 calendar weeks) after 
the Week 52/PTFU Visit for DXA to assess BMD and for collection of samples for potential 
immunogenicity testing as well as serum and plasma biomarker samples (see Table 3 in 
Section 1). Participants at the Week 52/PTFU Visit may need to return at 9 months, 12 
months, and 14 months (± 14 days) (1 month is defined as 4 calendar weeks) after the Week 
52/PTFU Visit if required for immunogenicity testing, as described in Section 8.5.3.6 (see 
Table 3 in Section 1).
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Figure 1 
Study Design Schematic – Screening to Week 52/PTFU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ET = early termination; PTFU = Post-Treatment Follow-Up; QW = once weekly 
a For participants who discontinue study medication prematurely, liver biopsy will be performed at ET if the participant has completed at least Week 20. If a 
participant discontinues study participation prior to Week 20 they should consider having a liver biopsy at ET. 
Day 
1
Day 
8
Day 
15
Day 
22
Day 
29
Week 1
Week 2
Week 3
Week 4
(± 5 days)
Baseline 
Visit
Week 4 
Visit
Week 
52/PTFU 
Day 
1 
 
Week 
48/ETa 
Double-Blind 
Treatment Period 
(48 weeks) 
Screening 
Period 
(Up to 8 weeks) 
Follow-Up 
Period 
(4 weeks) 
BMS-986036 20 mg QW (n = 38) 
BMS-986036 10 mg QW (n = 38) 
Placebo QW (n = 38) 
Liver biopsy 
Screening 
Period 
Randomization on Day 1 (1:1:1:1 Ratio) 
End of treatment at Week 48/ETa 
BMS-986036 40 mg QW (n = 38) 
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Figure 2 
Study Schematic – Bone Mineral Density and Immunogenicity Follow-Up Visits After the Week 52/PTFU 
Visit (visit windows ± 14 days) (1 month is defined as 4 calendar weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DXA = dual-energy X-ray absorptiometry PTFU = Post-Treatment Follow-Up; QW = once weekly 
a All participants will return 6 months (± 14 days) (1 month is defined as 4 calendar weeks) after the Week 52/PTFU Visit for dual-energy X-ray absorptiometry (DXA) 
to assess bone mineral density (BMD) and for collection of samples for potential immunogenicity testing as well as serum and plasma biomarker samples. 
Participants will return at 9 months, 12 months, and 14 months (visit windows ± 14 days) (1 month is defined as 4 calendar weeks) after the Week 52/PTFU Visit if 
required for immunogenicity testing (See Section 8.5.3.6). 
 
BMS-986036 20 mg QW (n = 38) 
BMS-986036 10 mg QW (n = 38) 
Placebo QW (n = 38) 
BMS-986036 40 mg QW (n = 38) 
Week 
52/PTFU 
6 months after 
Week 52/PTFU: 
DXA and 
immunogenicitya 
Follow-Up 
9 months after 
Week 52/PTFU: 
immunogenicitya 
Follow-Up 
12 months after 
Week 52/PTFU: 
immunogenicitya 
Follow-Up 
14 months after 
Week 52/PTFU: 
immunogenicitya 
Follow-Up 
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8.2 End of Study Definition 
The start of the study is defined as the visit at which the first participant signs informed 
consent. End of study is defined as the last scheduled procedure shown in Table 3 of the 
Schedule of Activities in Section 1 for the last participant. 
 
For sites and participants, the end of participant participation is defined as the last visit or 
scheduled procedure shown in the Schedule of Activities (Section 1), including DXA and 
Immunogenicity Follow-Up Visits after the Week 52/PTFU Visit.  
 
The end of the study for sample analysis is defined as 2 years after final clinical study report. 
 
8.3 Study Population 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study participants and the integrity of the study results. It is imperative that participants meet 
all eligibility criteria prior to randomization. 
 
 
To be eligible for the study, participants must meet the criteria in Sections 8.3.1 and 8.3.2. 
 
8.3.1 Inclusion Criteria 
1. Signed written informed consent 
a) Participants must be willing to participate in the study and sign the informed consent 
form(s) (ICF[s]) 
b) Participants (and caregivers as applicable) must be willing and able to complete all 
study-specific procedures and visits 
2. Liver biopsy performed within 6 months (26 weeks) prior to the Screening Period. Biopsy 
performed prior to ICF must be available to the central reader prior to randomization. If 
historical biopsy is not available, a liver biopsy will be performed during the Screening 
Period (see Section 8.5.1.1). Biopsy must be consistent with NASH and cirrhosis 
according to the NASH CRN classification, as assessed by the central reader. 
3. Participants taking anti-diabetic, anti-obesity, or anti-dyslipidemic medications must have 
been on stable regimens for at least 3 months (12 weeks) (6 weeks for statins) prior to and 
during the Screening Period. The investigator may contact the medical monitor regarding 
the stability of a participant’s regimen when determining eligibility for study 
participation. Participants taking vitamin E at doses ≥800 IU/day must have been on 
stable doses for at least 6 months (26 weeks) prior to and during the Screening Period. 
Vitamin E treatment (≥800 IU/day) must not have been initiated after the qualifying liver 
biopsy was performed. 
4. Age and reproductive status 
a) Men or women 18 to 75 (inclusive) years of age 
b) Women of childbearing potential (WOCBP) must have a negative pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 
within 24 hours prior to the start of study medication 
c) Women must not be breastfeeding at any time during the study 
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d) WOCBPs must agree to follow instructions for method(s) of contraception for the 
duration of treatment (BMS-986036 or placebo) plus 5 half-lives of study medication 
(5 days) plus 30 days (duration of ovulatory cycle) for a total of 35 days after the end 
of the Double-Blind Treatment Period 
e) WOCBPs who are continuously not heterosexually active are exempt from 
contraceptive requirements but must undergo pregnancy testing as described in the 
Schedule of Activities in Section 1 
Investigators will counsel WOCBP participants and male participants who are sexually 
active with WOCBP, on the importance of pregnancy prevention and the implications of 
an unexpected pregnancy. Investigators shall advise on the use of methods of 
contraception (see Appendix 2). 
 
8.3.2 Exclusion Criteria 
1. Other causes of liver disease (e.g., alcoholic liver disease, hepatitis B virus infection (see 
Appendix 3), chronic hepatitis C virus infection (see Appendix 3), autoimmune hepatitis, 
drug-induced hepatotoxicity, Wilson disease, α-1-antitrypsin deficiency, iron overload, 
and hemochromatosis) 
2. Current or past history of HCC 
3. Medical conditions 
a) Past or current evidence of hepatic decompensation (e.g., ascites, variceal bleeding, 
hepatic encephalopathy and/or spontaneous bacterial peritonitis) or liver 
transplantation 
b) Medical history of gastroesophageal varices, except if esophagogastroduodenoscopy 
[EGD] performed within 12 months prior to the Screening Period has shown 
≤ Grade 1 varices and without red wale signs, as assessed by the investigator)26 
c) Screening Fibroscan® elastography > 25 kPa (not applicable if EGD performed within 
12 months prior to the Screening Period has shown ≤ Grade 1 varices and without red 
wale signs, as assessed by the investigator)26 
d) Recent history (within 2 years prior to the biopsy used to determine eligibility) of 
drug or alcohol abuse as defined in the Diagnostic and Statistical Manual 5 (DSM-5), 
Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 4) OR in the 
investigator’s judgment, a pattern of excessive alcohol consumption ≥ 30 g/day 
(males) or ≥ 20 g/day (females). This alcohol consumption is equal to approximately 
2 alcoholic drinks per day for males, and approximately 1.5 alcoholic drinks per day 
for females. One alcoholic drink is equal to 12 ounces (355 mL) of 5% alcohol by 
volume (ABV) beer, 5 ounces (148 mL) of 12% ABV wine, or 1.5 ounces (44.4 mL) 
of 40% ABV distilled spirits 
e) Use of illicit intravenous drugs within 5 years prior to or during the Screening Period 
f) A urine drug screen result positive for amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, methadone, opiates, or phencyclidine during Screening, unless 
a prescribed drug accounts for the positive test 
g) History of bariatric surgery or intestinal bypass surgery within the 5 years prior to 
informed consent or planned during the conduct of the study 
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h) History of major surgery (i.e., surgery involving a risk to the life of the patient; 
specifically, an operation upon an organ within the cranium, chest, abdomen, or 
pelvic cavity) within 6 weeks prior to or during the Screening Period 
i) History of fracture or bone surgery (i.e., hardware placement, joint replacement, bone 
grafting, or amputation) within 8 weeks prior to or during the Screening Period 
j) History of a blood transfusion within 60 days prior to or during the Screening Period 
k) History of cancer within the last 5 years (other than treated and believed to be cured 
basal or squamous cell carcinoma of the skin or resected carcinoma of the cervix) 
l) History of weight gain/loss ≥ 10% of body weight within 6 months (26 weeks) prior 
to or during the Screening Period 
m) Uncontrolled hypertension, as defined by systolic blood pressure (SBP) > 160 and/or 
diastolic blood pressure (DBP) > 100 during Screening, unless discussed with medical 
monitor. Blood pressure may be rechecked as clinically indicated 
n) QT interval corrected using Fridericia’s formula (QTcF) > 480 msec on 12-lead ECG 
during Screening, confirmed by repeat ECG 30-60 minutes after the initial ECG 
o) Any acute or chronic cardiovascular condition (e.g., ischemic heart disease, 
congestive heart failure) considered clinically significant by the investigator 
p) Known immunocompromised status, including but not limited to, individuals who 
have undergone organ transplantation, who are known to be positive for human 
immunodeficiency virus, or who have recurrent or chronic systemic bacterial, fungal, 
viral or protozoal infections 
q) Major episode of infection requiring hospitalization within 4 weeks prior to or during 
the Screening Period 
r) Inability to tolerate SC medication 
s) Inability to tolerate venipuncture 
t) Women who are breastfeeding 
4. Prior and concomitant therapy 
a) Participants who have taken systemic corticosteroids at a dose exceeding 20 mg/day 
prednisone or equivalent for more than 7 consecutive days at any time within 
3 months (12 weeks) prior to or during the Screening Period 
b) Inability to comply with restrictions and prohibited treatments 
c) Prior exposure to BMS-986036 or other FGF21 analogs 
d) Other investigational agents must be discontinued at least 4 weeks or 5 half-lives 
before the first dose of study medication, whichever is longer 
5. Physical and laboratory test findings 
a) Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, or clinical laboratory determinations beyond what is 
consistent with the target population 
b) ALT value > 5× the upper limit of normal (ULN) as defined by the central laboratory 
c) AST value > 5× ULN as defined by the central laboratory 
d) Total bilirubin > 1.5 mg/dL  
e) Serum albumin < 3.5 g/ dL 
f) Platelet count < 100 × 103/µL 
g) International normalized ratio (INR) > 1.4, unless due to therapeutic anticoagulation 
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h) Fasting plasma glucose < 60 mg/dL (< 3.33 mmol/L) or > 350 mg/dL 
(> 19.43 mmol/L) 
i) Hemoglobin A1c ≥ 10% 
j) Fasting TGs > 500 mg/dL 
k) Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease equation 
l) Evidence of significant worsening of ALT, AST or bilirubin during the Screening 
Period, in the opinion of the investigator or medical monitor 
m) A centrally read DXA BMD T-Score of -2.5 or less at the femoral neck, total hip, or 
lumbar spine during Screening (exclusionary only if participant is 40 years of age or 
older) 
6. Allergies and adverse drug reactions 
a) History of allergy to FGF21, PEG, or related compounds 
b) History of drug-induced liver injury (DILI) 
7. Other exclusion criteria 
a) Prisoners or participants who are involuntarily incarcerated. Note:  Under certain 
specific circumstances, a person who has been imprisoned may be included or 
permitted to continue as a participant. Strict conditions apply, and sponsor approval is 
required 
b) Participants who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness 
c) Any factor that, in the opinion of the investigator, would jeopardize the evaluation or 
safety of the participant or be associated with poor adherence to the protocol 
d) Participants who are incapable of completing study-related assessments (i.e., 
participant questionnaires) as they MUST be completed by the participant 
 
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8.3.4 Imaging (MRI/MRE) Contraindications  
The imaging specialist at the site’s imaging facility will be responsible for determining 
whether a participant is contraindicated from undergoing these procedures. In addition to the 
study inclusion and exclusion criteria (Sections 8.3.1 and 8.3.2), the following conditions will 
exclude the participant from scans: 
1. History of claustrophobia, unless controlled with an anxiolytic 
2. Physical limitations related to fitting into the bore of the magnet or weight greater than 
that allowable by the imaging instrument 
3. Participants with a pacemaker, epicardial pacemaker wires, MRI-incompatible cardiac 
valve prostheses, MRI-incompatible vascular clips less than 2 months old, or 
MRI-incompatible aneurysm clips of any age 
4. Participants with MRI-incompatible cochlear implants 
5. Participants with spinal nerve stimulators 
6. Participants with a nondetachable infusion pump 
7. Participants with known metallic fragments in the body 
8. Employment history that involves exposure to welding 
9. Participants who have shrapnel anywhere in their body 
 
The above list should not be used as a substitute for local clinical standards of care. The 
ultimate decision to perform any scan should rest with the site radiologist, the investigator, 
and the standard set by the IRB/EC and local institution. 
 
If imaging is contraindicated for a participant, but the participant is otherwise eligible for the 
study, the participant may still participate in the study. 
 
8.3.5 History: Medical, Surgical, Diet, and Exercise 
Medical and surgical history will be collected during Screening and updated on Day 1. 
Medical history should be complete and comprehensive, including any history of alcohol, 
marijuana, and caffeine use. Surgical history should include all gastrointestinal and endocrine 
surgical procedures in the participant’s lifetime and all other surgical procedures that 
occurred in the previous 5 years. Medical history will also include a fall risk assessment at 
Screening, and a diet and exercise history at Week 24 and Week 48/ET. 
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8.3.6 Dietary and Lifestyle Counseling 
During Screening, after receiving the signed ICF, sites will provide all participants with the 
following dietary and lifestyle counseling: 
• Reduce body weight (if obese or overweight) through diet and exercise 
• Follow a balanced diet 
• Increase physical activity 
• Avoid alcohol as much as possible. However, if alcohol is consumed, do not consume 
≥ 30 g/day (males) or ≥ 20 g/day (females) of alcohol during the study. This is equal 
to approximately 2 alcoholic drinks per day for males, and approximately 1.5 
alcoholic drinks per day for females. One alcoholic drink is equal to 12 ounces 
(355 mL) of 5% ABV beer, 5 ounces (148 mL) of 12% ABV wine, or 
1.5 ounces (44.4 mL) of 40% ABV distilled spirits 
 
8.3.7 Concomitant Medication Restrictions 
Anti-diabetic, anti-obesity, and anti-dyslipidemic medications are allowed if participants 
have been on stable dosing regimens for at least 3 months (12 weeks) (6 weeks for statins 
prior to and during the Screening Period. The investigator may contact the medical monitor 
regarding the stability of a participant's regimen when determining eligibility for study 
participation. 
 
During study treatment, participants should refrain from using cannabinoid products. 
 
Vitamin E is allowed; however, vitamin E doses ≥ 800 IU/day are allowed only if 
participants have been on stable doses for at least 6 months (26 weeks) prior to and during 
the Screening Period and if vitamin E treatment (≥ 800 IU/day) was not initiated after the 
qualifying liver biopsy was performed. 
 
Vitamin D and calcium supplementation are permitted per local standard of care. Use of 
bisphosphonates, selective estrogen receptor modulators, estrogen, or teriparatide for 
treatment of osteoporosis is permitted if participants have been on stable doses for at least 6 
months (26 weeks) prior to and during the Screening Period.  
 
Any change in dose of these medications should be recorded in the electronic case report 
form (eCRF). Consult with the medical monitor if medications which could impact bone 
density assessments are to be added during the Double-Blind Treatment Period or during the 
first 6 months after the Week 52 / PTFU Visit. 
 
Medical or surgical treatments for obesity should not be initiated while the participant is 
participating in the first 52 weeks of the study (i.e., from the time of informed consent until 
the participant completes the Week 52/PTFU Visit or discontinues participation in the study, 
whichever comes first).  
 
Concomitant medications and medical and surgical treatments will not be limited after the 
Week 52/PTFU Visit. 
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8.3.8 Screen Failures and Rescreening 
Screen failures are defined as participants who consent to take part in the clinical study but 
are not subsequently randomized. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes date of consent, demography, screen 
failure details, eligibility criteria, and any serious AEs (SAEs). 
8.3.8.1 
Retesting During Screening 
Laboratory parameters and/or assessments that are included in the Screening procedures 
(Table 1 in Section 1) may be repeated during the Screening Period in an effort to find all 
possible qualified participants. Consultation with the medical monitor may be needed to 
identify whether repeat testing of any particular parameter is clinically relevant. 
 
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current clinical state. 
 
8.3.8.2 
Rescreening 
This study will permit the rescreening of a participant who has discontinued the study as a 
pre-treatment failure (i.e., the participant has not been randomized/has not been treated). 
Consultation with the medical monitor may be needed to identify whether rescreening is 
clinically relevant. If rescreened, the participant must sign a new ICF. 
 
In the event that histologic evaluation of the biopsy of an otherwise qualified participant 
results in a diagnosis of NASH with stage 3 fibrosis, that individual is not eligible for the 
present study (MB130-069) but may be considered for enrollment under protocol 
MB130-068 (A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study Evaluating 
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the Safety and Efficacy of BMS-986036 (PEG-FGF21) in Adults with Nonalcoholic 
Steatohepatitis [NASH] and Stage 3 Liver Fibrosis). Laboratory parameters and/or 
assessments that were collected as Screening procedures for this study (MB130-069; Table 1 
in Section 1) may be utilized for the same purpose for MB130-068. 
 
Conversely, in the event that histologic evaluation of the biopsy of an otherwise qualified 
participant for MB130-068 results in a diagnosis of NASH with cirrhosis, that individual is 
not eligible for the MB130-068 study but can be considered for enrollment under the present 
study (MB130-069). Laboratory parameters and/or assessments that were collected as 
Screening procedures for MB130-068 may be utilized for the same purpose (Table 1 in 
Section 1) in this study (MB130-069). 
 
For participants who are rescreened, consult with the medical monitor to confirm which 
parameters and/or assessments that were collected as part of the original Screening Period 
procedures may be utilized. 
 
8.3.9 Withdrawal of Participants 
8.3.9.1 
Discontinuation of Study Medication 
Participants MUST discontinue investigational product (IP) (and non-investigational product 
[non-IP] at the discretion of the investigator) for any of the following reasons. 
• Participant’s request to stop study medication. Participants who request to discontinue 
study medication will be expected to complete an ET (Week 48/ET) Visit and subsequent 
follow-up visits/procedures per the Schedule of Activities (e.g., Week 52/PTFU; 
Section 1). The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by 
participant to provide this information. Participants’ withdrawal of consent should be 
explained in detail in the medical records by the investigator as to whether the withdrawal 
is from further treatment with study medication only or also from study procedures and/or 
Week 48/ET, Week 52/PTFU Visit, etc. (see Section 8.3.9.2) 
• Any clinical AE, laboratory abnormality or intercurrent illness, which, in the opinion of 
the investigator, indicates that continued participation in the study is not in the best 
interest of the participant 
• The participant experiences a major bone fracture or is diagnosed with osteoporosis that 
requires treatment 
• Abnormal liver tests as defined in Section 8.5.3.1 
• On 2 consecutive visits (at least 2 weeks apart), a participant has an eGFR 
< 30 mL/min/1.73 m2, according to the Modification of Diet in Renal Disease Study 
equation 
• If there is a significant protocol violation. The violation should be discussed with the 
medical monitor prior to discontinuing study medication 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
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illness (Note: Under specific circumstances, a participant who has been imprisoned may 
be permitted to continue as a participant. Strict conditions apply, and sponsor approval is 
required) 
• The participant becomes pregnant (study medication must be discontinued immediately) 
In the case of pregnancy (see Section 8.5.3.1), the investigator must immediately notify 
the medical monitor or designee of this event. In the event a participant becomes 
pregnant during a clinical study, the study medication must be discontinued 
immediately. In most cases, the study medication will be permanently discontinued in an 
appropriate manner. The medical monitor should be contacted within 24 hours of 
awareness of the pregnancy 
• Termination of the study or program by the sponsor 
• If a participant loses more than 10% of their total body weight, the investigator should 
contact the medical monitor. The investigator, together with the medical monitor, will 
then determine whether the participant should continue to take study medication 
 
If study medication is discontinued prior to the participant’s completion of the study, the 
reason for the discontinuation must be documented in the participant’s medical records and 
entered on the appropriate eCRF page. The discontinuation should also be reported via the 
IRT. As indicated, appropriate follow-up and/or alternate medical care must be arranged for 
the participant. Please notify the medical monitor as soon as possible when discontinuation of 
study medication is being considered. 
 
See Section 8.4.6 for details regarding dose modification and/or treatment interruption. 
 
Participants who prematurely discontinue study medication will be expected to complete an 
ET Visit and subsequent follow-up visits/procedures per the Schedule of Activities, including 
a Week 52/PTFU Visit (Table 2 in Section 1), DXA and Immunogenicity Follow-Up Visit(s) 
(Table 3 in Section 1) (see Section 8.5.3.6). The only exception to this requirement is when 
consent is withdrawn for all study procedures or the participant loses the ability to consent 
freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric 
or physical illness). Participants who discontinue study medication will not be replaced (see 
Section 8.3.9.4). 
 
8.3.9.2 
Discontinuation from Study Participation 
When a participant (or caregiver as applicable) requests to discontinue study participation, 
the participant will undergo an ET Visit as described in Table 2 in Section 1. 
 
The only exception to this requirement is when consent is withdrawn for all study procedures 
or the participant loses the ability to consent freely (e.g., is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). 
 
Expectations are as follows: 
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• Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible 
• The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study medication 
only (see Section 8.3.9.1), or also from study procedures and/or Week 52/PTFU (see 
Section 1), and entered on the appropriate eCRF page 
• In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as 
appropriately directed in accordance with local law 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent 
 
The following procedures must be followed upon participant withdrawal:  
• Assessments for the ET Visit must be performed, provided that the participant has not 
withdrawn consent for these activities 
• All required eCRF pages must be completed, including the date of and explanation for 
the withdrawal 
• As indicated, appropriate follow-up and/or alternate medical care must be arranged 
for the participant outside of sponsor responsibility 
• Participants who discontinue from study participation (yet have not withdrawn 
consent) may decline further study visits, however, they will be offered additional 
visits for the purpose of BMD assessment (see Section 8.5.3.8) and immunogenicity 
testing (see Section 8.5.3.6). 
 
8.3.9.3 
Lost to Follow-Up 
• All reasonable efforts must be made to locate participants to determine and report 
their ongoing status. This includes follow-up with persons authorized by the 
participant 
• Lost to follow-up is defined as the inability to reach the participant after a minimum 
of 3 documented phone calls, faxes, or emails as well as lack of response by 
participant to one registered mail letter. All attempts should be documented in the 
participant’s medical records 
• If it is determined that the participant has died, the site will use permissible local 
methods to obtain date and cause of death 
• If investigator’s use of third-party representative to assist in the follow-up portion of 
the study has been included in the participant’s informed consent, then the 
investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining participant’s contact information or other public vital status data 
necessary to complete the follow-up portion of the study 
• The site staff and representative will consult publicly available sources, such as public 
health registries and databases to obtain updated contact information 
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• If, after all attempts, the participant remains lost to follow-up, then the last known 
alive date as determined by the investigator should be reported and documented in the 
participant’s medical records 
 
8.3.9.4 
Replacement of Participants 
Participants who discontinue from study medication or from study after randomization will 
not be replaced. Participants who discontinue participation in the study after randomization 
will not be allowed to reenroll. 
 
8.4 Treatment 
Study medication is defined as any investigational treatment(s), marketed product(s), placebo 
or medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation. 
 
Each study medication must be listed as either an IP or non-IP. 
 
Study treatment includes both IP and non-IP and can consist of the following: 
• All products, active or placebo, being tested or used as a comparator in a clinical 
study.  
• Study required premedication 
• Other drugs administered as part of the study that are critical to claims of efficacy 
(e.g., background therapy, rescue medications) 
• If specific criteria are required for treatment in a given phase of the study 
(e.g., extension phase), provide detailed criteria in this Section 
• Diagnostic agents: (such as glucose for glucose challenge) given as part of the 
protocol requirements must also be included in the dosing data collection. 
 
An IP, also known as investigational medicinal product in some regions, is defined as a 
pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
 
Study medication includes both BMS-986036 and placebo and is described in Table 5 below. 
 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-IPs. 
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Table 5 
Study Medications 
Product  
Potency 
IP/Non-IP 
Blinded or Open 
Label 
Packaging/Appearance 
Storage Conditions 
(per Label) 
BMS-986036 
10 mg/mL 
IP 
Blinded 
Pre-Filled Syringe 
Refer to the label on the 
container 
BMS-986036 
20 mg/mL 
IP 
Blinded 
Pre-Filled Syringe 
Refer to the label on the 
container 
Placebo 
0 mg/mL 
IP 
Blinded 
Pre-Filled syringe 
Refer to the label on the 
container 
IP = investigational product; non-IP = non-investigational product 
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8.4.1 Treatments Administered 
The investigator must ensure that the IP will be used only in accordance with the protocol. 
The study medication doses, dosing frequency and route of administration for each 
participant are shown in Table 6 below. 
 
Table 6 
Study Medication Doses, Dosing Frequency, and Route of Administration 
Study Treatment 
Unit Dose 
Strength(s)/Dosage Level(s) 
Frequency of 
Administration 
Route of Administration 
BMS-986036 
10 mg arm 
1 mL/10 mg/mL 
BMS- 986036 
Once weekly 
Subcutaneous 
1 mL placebo 
BMS-986036 
20 mg arm 
1 mL/20 mg/mL 
BMS- 986036 
Once weekly 
Subcutaneous 
1 mL placebo 
BMS-986036 
40 mg arm 
2 × 1 mL/20 mg/mL BMS-
986036 
Once weekly 
Subcutaneous 
Placebo 
2 × 1 mL placebo 
Once weekly 
Subcutaneous 
 
8.4.2 Study Medication Administration 
Participants should be instructed to make every effort to administer study medication on 
the same day each week at approximately the same time of day. Each weekly 
administration will consist of 2 SC injections. 
 
On Day 1 and at the Week 4, 8, 12, 16, 20, 24, 32, and 40 Visits, study medication will be 
self-administered by the participant or administered by their designee at the study site as part 
of the participant’s scheduled study visits. At those visits, study medication dosing 
should be held until all study-related assessments, including participant questionnaires, 
vital signs, ECG, AE evaluation, physical examinations, and laboratory sample 
collection (including trough [predose] PK) have been completed.
 
 
If a study visit occurs on a day 
that is not a planned dosing day, the participant should continue to administer the medication 
on the planned dosing day; all study-related assessments will continue to be performed at the 
planned study visit (in-clinic administration of study drug would not occur). 
 
 
 
 
Study medication is blinded and is supplied in a pre-filled syringe. Each participant will be 
dispensed a treatment kit containing 2 smaller boxes (for each weekly administration). Each 
smaller box will contain 1 prefilled syringe of the medication. Both syringes will be 
administered in the abdominal area at different locations per training guidelines. Study 
medication will be assigned by the IRT system. 
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Guidance and training on administration should be given to the participant (or caregiver, if 
applicable) prior to the first administration. At a minimum, the first administration should be 
done by the participant under the supervision of qualified site personnel. Training may be 
repeated as necessary at any study visit at the discretion of the investigator to maintain 
treatment compliance. When injections are administered at the site during study visits, site 
staff may observe the injection to ensure proper technique is being employed. Participants 
will be required to capture the date, time, and location of each injection on the supplied study 
medication administration card. 
 
Specific instructions for study medication administration as well as training materials for 
participants (or caregivers, if applicable) are in the Pharmacy Manual. 
 
8.4.3 Method of Treatment Assignment 
After receiving the signed ICF but before any other study-related procedures are performed, 
the investigative site will access the enrollment option of the IRT system for assignment of a 
participant number (including participants not subsequently randomized or treated). This 
number is assigned sequentially by the system and will be unique across all sites. If a 
potential participant is rescreened, a new identification number will be used. 
 
Randomization will be conducted in the following manner: 
• Eligible participants will be randomized by the IRT using a prespecified schedule in a 
double-blind manner to 10 mg BMS-986036, 20 mg BMS-986036, 40 mg BMS-986036, 
or placebo arms in a 1:1:1:1 ratio based on the stratification factors specified in 
Section 8.1 
• The IRT will provide study medication kit numbers that contain the appropriate study 
medication (BMS-986036 or placebo) for dispensation to that participant 
 
At subsequent study visits as listed in the Schedule of Activities (Section 1), the investigator 
or designee will access the IRT to receive the corresponding kit numbers assigned to the 
participant for the purpose of dispensing study medication.  
 
8.4.4 Blinding of Study Medication 
8.4.4.1 
Maintaining the Blind 
Blinded treatment assignments will be managed using the IRT. All syringes and syringe 
contents (BMS-986036 10 mg/mL, BMS-986036 20 mg/mL, and placebo) are identical in 
appearance. Investigative site staff, sponsor and designee personnel, and participants and 
their families will remain blinded to treatment assignments. Study medication will be 
administered in a double-dummy manner as described in Section 8.4.2 in order to maintain 
the blind. 
 
Sponsor and designee personnel may be unblinded once all participants have completed the 
Week 52/PTFU Visit and all data have been collected through that time point to facilitate 
analyses. Designated sponsor staff may be unblinded (obtain the randomization codes) prior to 
database lock to facilitate the bioanalytical analysis of PK samples and immunogenicity. A 
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bioanalytical scientist in the sponsor Bioanalytical Sciences department (or a designee in the 
external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples. 
 
8.4.4.2 
Circumstances for Unblinding 
In the event of a medical emergency or pregnancy in an individual participant where 
knowledge of the study medication is critical to the participant’s medical management, the 
blind for that participant may be broken by the investigator. The participant’s safety takes 
priority over any other considerations in determining if a treatment assignment should be 
unblinded. 
 
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary (i.e., that it will alter the participant’s 
immediate management). In many cases, particularly when the emergency is clearly not 
related to the IP, the problem may be properly managed by assuming that the participant is 
receiving active product. It is highly desirable that the decision to unblind treatment 
assignment be discussed with the medical monitor, but the investigator always has ultimate 
authority for the decision to unblind. The actual TASK of unblinding can be delegated by the 
investigator to a designee assigned the task on the Delegation of Authority. The principal 
investigator or appointed designee should only call in for emergency unblinding AFTER the 
decision to unblind the participant has been documented. 
 
For this study, the method of unblinding for emergency purposes is through the IRT system. 
In case of an emergency, the investigator has unrestricted access to randomization 
information via IRT and is capable of breaking the blind through the IRT system without 
prior approval from the sponsor. After the unblinding, the investigator shall notify the 
medical monitor and/or study director. The method of unblinding for emergency purposes is 
described in the IRT Manual. Participant and unblinded treatment information and the reason 
for the blind being broken must be recorded on the appropriate study status page of the 
eCRF. 
 
In cases of accidental unblinding, the site should contact the medical monitor and ensure 
every attempt is made to preserve the blind. Any request to unblind a participant for 
nonemergency purposes should be discussed with the medical monitor. 
 
8.4.5 Study Medication Preparation, Handling, Storage, and Accountability 
The IP should be stored in a secure area according to local regulations. It is the responsibility 
of the investigator to ensure that IP is dispensed only to study participants. The IP must be 
dispensed only from official study sites by authorized personnel according to local 
regulations. 
 
The product should be stored in a refrigerator (2°C through 8°C [35.6°F through 46.4°F]) and 
protected from light. If concerns regarding the quality or appearance of the study medication 
arise, the study medication should not be dispensed, and the sponsor should be contacted 
immediately. 
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IP documentation must be maintained. This includes documentation of all processes required 
to ensure drug is accurately administered, drug storage, administration, and, as applicable, 
storage temperatures, and use of required processes. 
 
Further details on accountability of study medication are in the Pharmacy Manual. 
 
Further guidance and information on final disposition of unused and returned study 
medication and study supplies is provided in Appendix 1.  
 
8.4.6 Dose Modification 
8.4.6.1 
Modification of Dose 
No dose reductions or modifications are allowed. If a participant interrupts treatment due to 
an AE, study medication may be restarted after consultation with the medical monitor. 
 
8.4.6.2 
Dose Interruption 
If a participant has abnormal laboratory test result(s) and/or clinical AE(s) that, in the 
judgment of the investigator, could place the participant at risk, study medication 
administration should be interrupted, and the investigator should notify the medical monitor. 
Participants may receive further study medication when the AE or abnormal laboratory 
finding is resolved. 
 
8.4.6.3 
Missed Doses 
If a participant misses a dose according to the protocol-outlined schedule, the participant (or 
caregiver, as applicable) should administer the dose as soon as possible and continue on the 
original schedule with the exception that 2 doses of medication should not be administered 
less than 48 hours apart. 
 
8.4.7 Treatment Compliance 
Study medication compliance will be monitored periodically using standard drug 
accountability procedures. Drug accountability will be reviewed by the site study staff at each 
visit to confirm treatment compliance. If a participant misses 2 consecutive doses (not related 
to an AE/SAE), site staff will discuss discrepancies with the participant at each on-treatment 
study visit and counsel the participant of the importance of compliance with the assigned 
regimen. Participants and/or caregivers (as applicable) may be re-trained in study medication 
administration, if necessary to address study medication compliance issues. If the participant 
misses 2 more consecutive doses during the study, the investigator should consult with the 
medical monitor to determine the appropriate course of action for the continued treatment of 
the participant, which may include withdrawal of study medication. 
 
8.4.8 Prior and Concomitant Therapy 
All medications taken from within 3 months (12 weeks) before the Screening Period until the 
Week 52/PTFU Visit must be recorded on the eCRF. In addition, medications administered 
between the Week 52/PTFU Visit and the 6 Month Post PTFU Visit that could potentially 
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impact bone mineral density assessments, as well as other therapies for NASH whether 
approved or investigational, will be recorded on the eCRF. 
 
Prior medications are defined as medications taken prior to the first dose of study medication 
and discontinued before the first dose of study medication. Concomitant medications are 
defined as any medication taken after the first dose of study medication until the Week 
52/PTFU Visit. Concomitant medications (e.g., prescription, over-the-counter, or herbal) 
should be administered during the study only if they are prescribed for treatment of specific 
clinical events. 
 
Restrictions and prohibitions on prior and concomitant medications are described in 
Section 8.3.7. 
 
8.4.9 Treatment After the End of the Study 
At the end of the study, the sponsor will not continue to provide sponsor-supplied study 
medication to participants/investigators unless the sponsor chooses to extend the study. The 
investigator should ensure that each participant receives appropriate standard of care to treat 
the condition under study. 
 
The sponsor reserves the right to terminate access to sponsor-supplied study medication if 
any of the following occur: a) the study is terminated due to safety concerns or other reasons; 
b) the development of BMS-986036 for treatment of NASH or other indications is terminated 
for other reasons, including but not limited to lack of efficacy and/or not meeting the study 
objectives; c) the participant can obtain medication from a government-sponsored or private 
health program. In all cases, the sponsor will follow local regulations. 
 
8.5 Efficacy and Safety Variables 
Study procedures and timing are summarized in the Schedule of Activities (Section 1). 
Waivers or exemptions from protocol-required evaluations are not allowed. 
 
8.5.1 Efficacy Assessments  
Every effort must be made to ensure that the same evaluator(s) complete the assessment for 
each participant. If the evaluator(s) is unable to complete the evaluation, then a qualified 
individual with overlapping experience may perform the evaluation. Documentation of who 
performed the evaluation is to be recorded in source documents. Assessments should be 
performed at approximately the same time of day throughout the duration of the study. 
Baseline assessments must be performed prior to dosing with study medication. Procedures 
not specified in the protocol that are part of standard care may be performed if they do not 
interfere with study procedures; any data arising from such procedures are not to be reported 
in the eCRF. 
 
All efficacy assessments will be completed prior to study medication administration. 
Participant questionnaires will be administered electronically, and information gathered 
electronically (i.e., electronic patient-reported outcome) will serve as the source document 
where possible.  
 
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The following procedures or tools will be used to assess participant’s disease activity during 
the study (see the Schedule of Activities in Section 1): 
 
• Liver biopsy (see Section 8.5.1.1) submitted to the central pathologist at Screening, and 
at Week 48 or the ET Visit, if applicable 
o Histological assessments of fibrosis stage and NASH activity 
o Assessments of CPA and fat in stained tissue by morphometry 
o Assessments of fibrosis using digital pathology 
• Noninvasive measures of fibrosis and/or cirrhosis 
o Noninvasive scores of hepatic fibrosis (see Section 8.5.1.2) (AST-Platelet Ratio 
Index [APRI], Fibrosis 4 [FIB4] Index, Enhanced Liver Fibrosis [ELF] Score, 
NAFLD Fibrosis Score) at Day 1, Week 24, and Week 48/ET 
o Liver stiffness as determined by MRE (see Section 8.5.1.3) at Screening, Week 
24, and Week 48/ET 
o Liver stiffness as determined by Fibroscan® elastography (see Section 8.5.1.4) at 
Screening and Week 48/ET 
• Hepatic fat fraction as determined by MRI-based proton density fat fraction (PDFF) 
(see Section 8.5.1.3) at Screening, Week 24, and Week 48/ET 
• Physical metabolic assessments (see Section 8.5.1.6) at Screening, Day 1, Week 24, 
and Week 48/ET 
o Body weight 
o Body mass index (BMI) 
o Waist circumference 
• Laboratory Metabolic Assessments (see Section 8.5.1.6) at Screening, Day 1, 
Week 24, and Week 48/ET 
o Lipids (LDL, HDL, TGs) 
o Fasting plasma glucose  
o Fasting plasma insulin 
o Hemoglobin A1c 
• Child-Pugh Turcotte Score (see Section 8.5.1.7) at Screening, Day 1, Week 24, and 
Week 48/ET 
• MELD Score (see Section 8.5.1.8) at each visit through Week 52/PTFU 
• Liver-Related Clinical Outcome Events (see Section 8.5.1.9) at each visit from Day 1 
through Week 52/PTFU 
• Exploratory Biomarkers (see Section 8.5.2) 
o Transaminases at each visit through Week 52/PTFU 
o Adiponectin at Day 1, Week 4, Week 8, Week 12, Week 24, Week 48/ET, and 
Week 52/PTFU 
o PRO-C3 at Day 1, Week 4, Week 8, Week 12, Week 24, Week 48/ET, and Week 
52/PTFU 
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• Health-related quality-of-life (HRQoL) questionnaires (see Section 8.5.1.10) at Day 1, 
Week 24, and Week 48/ET 
o 3-Level EuroQol 5 Dimension (EQ-5D-3L) questionnaire 
o 36-question Short Form (SF-36) quality-of-life questionnaire 
o Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease 
(CLDQ-NAFLD) questionnaire 
 
8.5.1.1 
Liver Biopsy 
A liver biopsy will be performed at Screening if no liver biopsy specimen collected within 
6 months (26 weeks) prior to informed consent is available and readable by the Central 
Pathologist.  
 
The on-treatment liver biopsy should be performed within ± 7 days of the Week 48 Visit. 
However, if a biopsy cannot be scheduled within the window specified above, the biopsy 
should be performed as close to schedule as possible. 
 
For participants prematurely discontinuing study medication, liver biopsy will be performed 
at the ET Visit if the participant has completed at least Week 20. If a participant discontinues 
study participation prior to Week 20 they should consider having a liver biopsy at ET. 
 
Histological assessment of the tissue sample will be conducted by a blinded Central 
Pathologist. The central reader will be a medical doctor, board certified in pathology, with 
experience in liver pathology in a clinical study setting.  
 
The on-treatment liver biopsy results will remain blinded to site personnel until after the 
study database is locked; incidental findings of potential clinical relevance (as determined by 
the medical monitor) from the central pathologist will be provided to the investigator. 
 
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. 
 
Liver tissue should be collected using a 16 gauge (or larger) cutting needle (e.g., Bard, 
Microvasive, or TruCut) whenever possible. Use of suction needles (e.g., Menghini, 
Jamshedi, or Klatskin) are allowed, but may cause fragmentation of fibrotic specimens and 
impede the evaluation of fibrosis, and should therefore be avoided, if possible. At least 2 cm 
length of tissue should be obtained. 
 
Additional details on the acquisition, quality requirements, histological preparation, and 
shipping of histological samples are in the Central Laboratory Manual and the Central 
Pathology Manual. 
 
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Histological Scoring 
NASH CRN 
For associated primary and secondary endpoints, the NASH CRN system27 will be used to 
score the histologic samples and results are reported as the NAFLD Activity Score (NAS) 
and the NASH CRN Fibrosis Score. The NASH CRN system is based on the concept that 
necroinflammatory 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). 
NAS 
The 3 categories of steatosis, lobular inflammation, and ballooning scores are added together 
in an unweighted fashion to determine the NAS, which ranges from 0 to 8 (see Table 7 
below).  
The NAS should not be considered a replacement for the Central Pathologist’s diagnosis of 
NASH. 
Table 7 
NAS Scoring System 
Histology Variable 
Grade 
Score 
Steatosis 
< 5% 
0 
5% - 33% 
1 
> 33% - 66%
2 
> 66%
3 
Lobular Inflammationa 
none 
0 
< 2 
1 
2 - 4 
2 
> 4
3 
Ballooning 
none 
0 
few 
1 
many 
2 
NAS = NAFLD Activity Score 
a Foci per x200 field
Fibrosis 
NASH CRN Fibrosis 
Fibrosis is staged separately from NAS on a 0-4 scale: 0 (none); 1 (perisinusoidal or 
periportal fibrosis); 2 (perisinusoidal and portal/periportal fibrosis); 3 (bridging fibrosis); 
4 (cirrhosis). 
Ishak 
A modified Ishak scoring system will also be used to stage fibrosis in the histologic samples. 
The Ishak system (0-6 scale) was originally developed to grade portal-based liver fibrosis 
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associated with viral hepatitis.28 The modified Ishak system has been adapted to stage 
central-based liver fibrosis associated with NASH, and it also uses a 0-6 scale: 
 
• 
0: No fibrosis 
• 1: centrilobular pericellular fibrosis  
• 2: centrilobular and periportal fibrosis 
• 3: bridging fibrosis (few bridges) 
• 4: bridging fibrosis (many bridges) 
• 5: early or incomplete cirrhosis 
• 6: established or advanced cirrhosis 
 
Morphometric Analysis of CPA and Fat Percentage in Stained Tissue 
There is considerable intra- and inter-individual variation of hepatopathologist assessment of 
fibrosis stage on liver biopsy. Assessment of CPA is a method by which the amount 
(percentage) of collagen in stained tissue Sections is analyzed using morphometric image 
analysis. This allows for a quantitative assessment of fibrosis. Percentage of fat in stained 
tissue Sections is also analyzed using morphometric image analysis. These morphometric 
assessments will be performed by a blinded Central Pathologist. Additional details on these 
morphometric assessments are in the Central Pathology Manual. 
 
Assessment of NASH and Fibrosis Using Digital Pathology 
Liver biopsy samples will be evaluated using digital pathology, which may include automated 
techniques.29 
 
8.5.1.2 
Noninvasive Scores of Hepatic Fibrosis 
The ELF, FIB4, APRI, and NAFLD Fibrosis Score are composite indices that have been 
correlated with fibrosis stage in NASH study participants.23 
 
 
 
 
ELF assay, FIB4, APRI, and NAFLD Fibrosis Score use a variety of algorithms combining a 
number of physical attributes and biochemical and hematologic test values to determine the 
level of the participant’s liver fibrosis (see Appendix 10). The scores will be calculated by a 
computerized system based on laboratory values and nonlaboratory parameters entered into 
the eCRF by personnel at the site. The sites will not be required to calculate scores. 
 
Details on the collection, processing, and shipping of samples for fibrosis scoring are in the 
Central Pathology Manual. 
• ELF assessment combines hyaluronic acid, procollagen 3 amino terminal peptide, and 
TIMP-1. A proprietary algorithm is used to evaluate each of these markers by 
immunoassay, to create an ELF Score 
• FIB4 scores fibrosis by combining participant age, ALT, AST, and platelet count. The 
formula used to calculate the FIB4 score is provided in Appendix 10 
• APRI scores fibrosis by combining AST and platelet count. The formula used to calculate 
the APRI Score is provided in Appendix 10 
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• The NAFLD Fibrosis Score scores fibrosis by combining participant age, BMI, fasting 
glucose, presence of diabetes, ALT, AST, platelet count, and albumin. The formula used 
to calculate the NAFLD Fibrosis Score is provided in Appendix 10 
 
8.5.1.3 
Imaging  
All participants will have imaging performed unless imaging is contraindicated (see 
Section 8.3.4). Participants for whom imaging is contraindicated may still participate in the 
study. 
 
Magnetic Resonance Elastography 
MRE is a noninvasive medical imaging technique that measures the stiffness of soft tissues 
by introducing shear waves and imaging their propagation using MRI. In NASH patients, 
MRE is reproducible,33 and it has a higher interobserver agreement for staging fibrosis 
compared to histopathology.34 Additionally, an improvement in MRE has been associated 
with an improvement in liver fibrosis, as observed on liver biopsy.33,34 
 
Images will be collected by the site and submitted to a central imaging vendor for evaluation. 
Sites should be trained and qualified before collecting study images. 
 
Detailed instructions on the conduct of the MRE, and the acquisition and submission of MRE 
data to the central imaging vendor will be provided in the Imaging Manual. 
 
The on-treatment MRE results will remain blinded to site personnel until after the study 
database is locked. 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. 
 
For participants prematurely discontinuing study medication prior to Week 24, MRE should 
be conducted at the ET Visit if the date of discontinuation is more than 4 weeks from the date 
of the previous MRE. For participants prematurely discontinuing study medication after 
Week 24, MRE should be conducted at the ET Visit if the date of discontinuation is more 
than 8 weeks from the date of the previous MRE. 
 
Magnetic Resonance Imaging 
Hepatic MRI is a noninvasive and accurate biomarker utilized for liver fat quantification. In 
NASH patients, MRI-PDFF accurately classifies grades and changes in hepatic steatosis,31 
and a ≥ 29% reduction in MRI-PDFF has been associated with histological NAS 
improvement.32 
 
Images will be collected by the site and submitted to a central imaging vendor for evaluation. 
Sites should be trained by the imaging vendor before collecting images. 
 
Detailed instructions on the conduct of the MRI, and the acquisition and submission of MRI 
data to the central imaging vendor will be provided in the Imaging Manual. 
 
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The on-treatment MRI results will remain blinded to site personnel until after the study 
database is locked. 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. 
 
For participants prematurely discontinuing study medication prior to Week 24, MRI should 
be conducted at the ET Visit if the date of discontinuation is more than 4 weeks from the date 
of the previous MRI. For participants prematurely discontinuing study medication after Week 
24, MRI should be conducted at the ET Visit if the date of discontinuation is more than 8 
weeks from the date of the previous MRI. 
 
8.5.1.4 
Fibroscan® Elastography 
Fibroscan® is a noninvasive device that assesses the ‘hardness’ (or stiffness) of the liver via 
the technique of transient elastography. 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 participant lying supine, an ultrasound-like probe is placed on the skin over the liver 
area, typically in the right mid-axillary line. The participant will feel a gentle ‘flick’ each 
time a vibration wave is generated by the probe. Investigators and site personnel should refer 
to the equipment manufacturer’s information for detailed instructions. 
 
A minimum of 10 valid readings, with at least a 60% success rate of all measurements taken 
and an interquartile range of ≤ 30% of the median value, are taken with the results expressed 
in kilopascals (kPa). 
 
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8.5.1.6 
Metabolic Assessments 
Physical Metabolic Marker Assessments 
Body weight, waist circumference, and BMI will be monitored as metabolic assessments. 
 
Weight must be recorded using a calibrated scale, preferably the same scale at each clinic 
visit. The participant should remove shoes and heavy clothing before standing on scale. 
 
Waist circumference will be measured at the natural waist (smallest waist circumference). If 
there is no natural waist, the measurement should be made midway between the iliac crest 
and the bottom of the rib with the measuring tape horizontal all the way around the waist. 
Measurement should be made at the end of normal inspiration with the participant standing. 
The waist measurement reported on the eCRF should represent the average of at least 2 
measurements. The average measurement should agree within 1 cm. If not, additional 
measurement(s) should be taken. 
 
BMI is used as an index of obesity and is a method of defining normal body weight and 
excess body fat. It correlates in a population with percent body fat. BMI is determined by 
weight (kg) divided by height (m) squared. 
 
Note: All analysis calculations for BMI will be derived internally by the sponsor using height 
at Screening and weight at the specified time point. 
 
Laboratory Metabolic Assessments 
Blood will be drawn according to the Schedule of Events in Section 1 for the following 
laboratory metabolic marker assessments. Participants should fast for at least 8 hours prior to 
collection of the blood samples for these assessments. 
• Fasting lipids, including LDL, HDL, and TGs. The HDL/LDL ratio will be calculated 
using the results of these assessments 
• Glucose homeostasis markers including fasting plasma glucose, fasting plasma 
insulin, and hemoglobin A1c 
 
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8.5.1.7 
Child-Pugh Turcotte Score 
The Child-Pugh Turcotte Score assesses the severity of cirrhosis, and 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, INR, ascites, and encephalopathy 
and is scored according to the scheme in Appendix 5. 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 Child-Pugh Turcotte Score as part of the hematology and 
serum chemistry assessments conducted at each visit. The same laboratory will be used for 
each evaluation. Evaluations of ascites and encephalopathy should be conducted by the same 
site personnel at each visit wherever possible. 
 
8.5.1.8 
MELD Scoring 
MELD scoring (see Appendix 10) is a formula for assessing the severity of chronic liver 
disease that does not include subjective variables such as ascites and encephalopathy. It 
employs the participant’s bilirubin, serum creatinine, and 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 
laboratory will be used for each evaluation. The central laboratory will calculate the MELD 
Score based on the laboratory values and communicate the score to the site. MELD Scores 
will be determined at each visit through Week 52/PTFU. 
 
All components of the MELD score should be completed on the same day. If any individual 
component needs to be repeated on another day, all other components must be repeated as 
well. 
 
8.5.1.9 
Liver-Related Clinical Outcome Events 
Participants will be evaluated for the following liver-related clinical outcome events at each 
visit from Day 1 through Week 52/PTFU: 
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 
 
If a participant experiences one of the above events, the investigator should contact the 
medical monitor within 48-72 hours to discuss further participation in the study. 
 
Liver-related clinical outcome events will also be reported as AEs/SAEs, as applicable, as per 
Section 8.5.3.1 and Appendix 9. 
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8.5.1.10 
Patient-Reported Outcomes (Health-Related Quality-of-Life Questionnaires) 
HRQoL questionnaires will be completed electronically by the participant and data 
transferred as source. Due to potential bias, the questions should not be read to the 
participant. Participant questionnaires will be assessed at specific visits throughout the study. 
See Section 1 for details.  
 
The EQ-5D-3L questionnaire (see Appendix 7) is a general quality-of-life instrument that 
consists of 2 components, health state description and evaluation. The health state description 
component measures mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Participants will rate their level of impairment in each dimension using a 
3-level scale. In the evaluation component, participants evaluate their overall health status 
using a visual analog scale. 
 
The SF-36 questionnaire (see Appendix 6) is a commonly used patient-reported outcome 
instrument used to assess quality of life. The SF-36 is a 36-question instrument, which 
assesses 8 health concepts: 1) limitations in physical activities because of health problems; 2) 
limitations in social activities because of physical or emotional problems; 3) limitations in 
usual role activities because of physical health problems; 4) bodily pain; 5) general mental 
health (psychological distress and well-being); 6) limitations in usual role activities because 
of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. 
Each question has 5 answers scored 1 (unable to) to 5 (no difficulty). The scale score of each 
domain is calculated based on the summed score across items included in the domain and is 
rescaled to 0 to 100. Version 2 of the SF-36 questionnaire will be used in the study. 
 
The CLDQ-NAFLD questionnaire 30 (see Appendix 8) is a disease-specific quality-of-life 
instrument for NAFLD and NASH. The CLDQ-NAFLD consists of 36 items in 6 domains: 
abdominal symptoms, activity, emotional function, fatigue, systemic symptoms, and worry. 
Each item is on a Likert scale with 1 representing the most impairment and 7 representing the 
least impairment. 
 
The questionnaires should be administered prior to dosing and before any other study 
assessments are conducted. 
 
8.5.2 Exploratory Biomarkers 
Blood samples will be collected for the assessment of exploratory biomarkers as described in 
Table 8 in Section 8.5.4. Exploratory biomarkers will include the collection of serum, breath, 
plasma, 
 and whole blood, which will be used to assess markers of fibrosis and 
associated diseases and pathways (including cardiovascular disease, inflammation, diabetes, 
and liver disease as well as kidney disease and bone). Work may also include studies on the 
FGF21 pathway and mechanism of action as well as pathways impacted by BMS-986036. 
The goal is to better understand NASH and associated diseases/syndromes and the effects of 
BMS-986036. These studies may include, but are not limited to, assessments listed in Table 8 
in Section 8.5.4. 
• PRO-C3 
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• Metabolic biomarkers such as adiponectin 
• Serum and plasma biomarkers associated with drug target pathway or pathways 
impacted by target, liver disease, NASH, fibrosis, apoptosis, diabetes mellitus, 
metabolic syndrome, inflammation, kidney and bone. Biomarkers may include but are 
not limited to cluster of differentiation 163 (CD163), C-reactive protein (CRP), 
pulmonary and activation-regulated cytokine, TIMP-1 and plasminogen activator 
inhibitor 1 (PAI-1) 
• Blood (serum or plasma) samples to develop new or improved assays for pathway and 
functional markers associated with either the target, fibrosis, NASH, liver or drug 
• Ribonucleic acid (RNA) from whole blood and from liver biopsies (when available), 
for broad gene expression profiling and directed gene analyses. Common RNA 
technologies may be employed, including but not limited to quantitative polymerase 
chain reaction, hybridization microarrays, and RNA sequencing. The sponsor has in 
place a system for restricting access to RNA sequencing data such that only gene 
expression data are made available 
• Micro RNA (miRNA)  
 
Information on the collecting, processing, and submission of samples to the central laboratory 
is in the Study Laboratory Manual. 
 
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8.5.3 Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Section 1). All urgent safety concerns must be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment. 
 
Safety will be assessed using incidence of all AEs; the incidence of SAEs; the incidence of 
AEs leading to withdrawal of study medication; the incidence of AEs of special interest, 
immunogenicity, laboratory data, ECG monitoring, physical examinations, and monitoring of 
BMD via DXA. 
 
8.5.3.1 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 9. 
 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative).  
 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study medication or the study, or that caused the 
participant to discontinue before completing the study. 
 
For weight change (increase or decrease) to be considered an AE, the change should be 10% 
or more from Baseline that cannot be explained by lifestyle modifications alone. 
 
Contacts for SAE reporting are specified in Appendix 9. 
 
Time Period and Frequency for Collecting AE and SAE Information 
Sections 5.6.1 and 5.6.2 in the IB represent the Reference Safety Information to determine 
expectedness of SAEs for expedited reporting. 
 
The collection of nonserious AEs should begin at initiation of study medication and continue 
until the Week 52/PTFU Visit (Section 1).. 
 
Following the participant’s written consent to participate in the study, all SAEs, whether 
related or not related to study medication, must be collected, including those considered by 
the investigator to be related to study medication or protocol-specified procedures. All SAEs 
will be collected through the Week 52/PTFU Visit and will be reported as described in 
Appendix 9.  
 
The investigator must report any SAE occurring after the Week 52/PTFU Visit that is 
believed to be related to study medication or a protocol-specified procedure. 
• Medical occurrences that begin before the start of study medication but after 
obtaining informed consent will be recorded on the appropriate Section of the eCRF 
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• All SAEs will be recorded and reported to sponsor or designee within 24 hours, as 
indicated in Appendix 9 
• The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of this information being available 
 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event reasonably 
related to the study medication or study participation, the investigator must promptly notify 
the sponsor. 
 
The method of evaluating intensity and assessing causality of AEs and SAEs and the 
procedures for completing and reporting/transmitting SAE reports are provided in 
Appendix 9. 
 
Method of Detecting AEs and SAEs 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a participant. Care should be taken not to introduce bias when collecting AEs 
and/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in the 
context of known AEs, when appropriate for the program or protocol. 
 
Follow-Up and Recording of AEs and SAEs 
• Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs 
if they become serious (see Appendix 9) 
• Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study medication and for those present at the end of study 
medication, as appropriate 
• All nonserious AEs and SAEs must be recorded and described on the corresponding 
pages of the eCRF. Completion of supplemental eCRFs may be requested for 
AEs/SAEs and/or laboratory abnormalities that are reported/identified during the 
course of the study 
 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest (as 
defined in Section 8.5.3.7) will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the participant is lost to follow-up (as defined 
in Section 8.3.9.3). 
 
Further information on follow-up procedures is given in Appendix 9. 
 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of SAEs is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a product under clinical investigation are met 
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• An investigator who receives an investigator safety report describing SAEs or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements 
 
Sponsor or designee will be reporting AEs to regulatory authorities and IRB/ECs according 
to local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A suspected unexpected serious adverse reaction is a 
subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements. 
 
Pregnancy 
Urine or serum samples will be collected at each visit through the Week 52/PTFU Visit for 
pregnancy testing for WOCBPs. A negative serum pregnancy test is required during 
Screening. After the Screening Period, urine pregnancy testing will be conducted instead of 
serum testing at any site where it is allowed by the IRB/EC overseeing study conduct at that 
site. 
 
Investigators shall counsel WOCBPs on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise on the use of highly 
effective methods of contraception (i.e., those that have a failure rate of < 1% when used 
consistently and correctly as discussed in Appendix 2). 
 
If, following initiation of the study medication, it is subsequently discovered that a 
participant is pregnant or may have been pregnant at the time of study exposure, including 
during at least 5 half-lives after product administration (5 days) plus 30 days (duration of 
ovulatory cycle) for a total of 35 days after the end of the Double-Blind Treatment Period, 
the investigator must immediately notify the sponsor medical monitor/designee of this event 
and complete and forward a Pregnancy Surveillance Form to the sponsor designee within 24 
hours of awareness of the event and in accordance with SAE reporting procedures described 
in Appendix 9. 
 
The study medication will be permanently discontinued in an appropriate manner (e.g., dose 
tapering if necessary for participant safety). Please call the sponsor medical monitor within 
24 hours of awareness of the pregnancy. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form (Appendix 2). 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to sponsor or designee during at least 5 half-lives after product administration (5 days) plus 
30 days (duration of ovulatory cycle) for a total of 35 days after the end of the Double-Blind 
Treatment Period. In order for the sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of 
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this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE 
eCRF page or SAE eCRF page, as appropriate. Paper forms are to be used only in the event 
that the electronic system is not functioning. 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the participant to have study 
medication discontinued or interrupted 
• Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used 
by the reporting investigator (e.g., anemia versus low hemoglobin value). 
 
Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs (see Appendix 9 for reporting 
details). Repeat laboratory testing may be performed locally, and the results should be 
promptly communicated to the investigator site. 
 
For the purpose of evaluating a potential DILI, the Baseline value is defined as the mean of 
the test results from analysis of samples collected during Screening and on Day 1. 
 
Note that the evaluation processes below do not replace SAE reporting per defined criteria in 
Appendix 9. 
 
Evaluation of Participants with New Elevations of Aminotransferases and/or Total Bilirubin 
Repeat laboratory testing (including ALT, AST, fractionated bilirubin and alkaline phosphatase) 
and physical examination should be performed within 48-72 hours when: 
 
• Participants with normal Baseline aminotransferase (ALT and/or AST) values 
develop elevations greater than 3× the ULN based upon the central lab, or 
• Participants with elevated Baseline aminotransferase values experience additional 
increases greater than 2× the Baseline (with concomitant elevations of total bilirubin 
> 2× ULN) AND ALT and/or AST is > 200 U/L. 
 
If the new elevations in aminotransferases persist and the participant is symptomatic, 
then the drug should be discontinued, and the participant should be evaluated for other 
causes of liver injury or disease. The medical monitor should be contacted within 48-72 
hours. 
 
If the participant is asymptomatic, the participant should be placed under “close observation”, 
defined as physical examination and laboratory evaluation 2-3 times per week.  
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If close observation is not possible, study medication should be discontinued. The frequency 
of retesting can decrease to once a week or less if abnormalities stabilize or the study 
medication has been discontinued and the participant is asymptomatic.  
 
Discontinuation or Temporary Interruption of Study Medication 
 
In addition to the reasons for discontinuation described above, study medication should be 
discontinued or temporarily interrupted if either of the 2 following scenarios occur: 
 
1) Aminotransferases (ALT and/or AST) > 2× Baseline and aminotransferases > 3× ULN and 
either: 
 
i. 
the increase is accompanied by a concomitant increase in total bilirubin to 
> 2× Baseline OR the INR concomitantly increases by > 0.2; 
 
OR 
 
ii. 
there are concomitant signs and symptoms of new-onset fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%). 
 
2) Total bilirubin increases to > 2× ULN AND: 
i. 
there are concomitant signs and symptoms of new-onset fatigue nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%) 
 
If the above rule is met, a potential DILI work up for competing etiologies (e.g., alcohol 
use, viral hepatitis, biliary obstruction, autoimmune liver disease) must be performed, and 
a complete liver profile including INR must be repeated within 48-72 hours. The medical 
monitor should be contacted within 48-72 hours. Study medication can be restarted only 
if an alternative etiology is definitively identified and liver tests (aminotransferases, total 
bilirubin and/or INR) have returned to Baseline. 
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical exams, ECGs, or any other 
potential safety assessments required or not required by protocol should also be recorded as a 
nonserious AE or a serious AE, as appropriate, and reported accordingly. ECGs will be read 
and interpreted at the site or by a local reader. 
 
8.5.3.2 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs (see Appendix 9). 
 
In the event of an overdose, the investigator should do the following: 
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1. Contact the medical monitor immediately 
2. Closely monitor the participant for AEs/SAEs and laboratory abnormalities for 14 days 
after the overdose 
3. Obtain a plasma sample for PK analysis within 4 days from the date of the last dose of 
study medication if requested by the medical monitor (determined on a case-by-case 
basis) 
4. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF 
 
8.5.3.3 
Physical Examinations 
Physical examinations may be performed by a Doctor of Medicine (MD) or equivalent, or 
someone who is authorized to perform the examinations by training and has been delegated 
this task by the principal investigator.  
 
Full examinations and abbreviated examinations will be performed as specified in the 
Schedule of Activities (Section 1).  
 
A full examination will include general appearance, skin, head, eyes, ears, nose, throat, neck, 
thyroid, chest/lungs, heart, abdomen, lymph nodes, extremities, and body weight.  
 
Abbreviated examinations will include an abdominal exam and symptom-focused 
assessments. An abbreviated examination may note any changes in the participant’s condition 
(body systems) since the last assessment and does not preclude examination of any of the 
other body systems as clinically indicated. Every effort should be made to ensure the same 
evaluator will complete the examination for each participant at all visits throughout the study. 
Documentation of who performed the examination is to be recorded in source notes. 
 
8.5.3.4 
Vital Signs 
Schedules for vital sign collection are provided in Section 1. Vital signs will include heart 
rate, respiratory rate, sitting SBP and DBP (to be taken after at least 5 minutes sitting at rest), 
and oral temperature. 
 
8.5.3.5 
Electrocardiograms 
Twelve-lead ECGs should be collected at similar times during Baseline and on-treatment 
visits. ECGs may be collected at any time prior to study medication dosing or PK sample 
collection. ECGs should be recorded after the participant has been supine for at least 
5 minutes. ECG parameters, including QTcF, will be collected on the eCRF. 
 
If a participant has a QTcF > 480 msec during the Screening Period, it should be confirmed 
by repeat ECG 30-60 minutes after the initial ECG. If the QTcF is confirmed to be 
> 480 msec, the participant should not be allowed to participate in the study. 
 
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If a participant has a QTcF>480 msec at an on-treatment visit, it should be confirmed by 
repeat ECG 30-60 minutes after the initial ECG. If the QTcF is confirmed to be >480 msec, 
the medical monitor should be contacted. 
 
8.5.3.6 
Immunogenicity 
Throughout the study, the potential for immunogenicity of BMS-986036 will be monitored as 
indicated in the Schedule of Activities (Section 1). In participants that experience 
immunogenicity, neutralizing activity and exposure-efficacy relationship will be assessed for 
evidence of a clinical impact on safety and efficacy. 
 
Immunogenicity Assessment Methodology 
Participants will be monitored for antibodies to BMS-986036 (drug) using an ADA 
homogenous bridge assay with electrochemical luminescence detection. Samples will first be 
screened for potential positive anti-BMS-986036 responses. Then, the samples with positive 
anti-BMS-986036 responses will be confirmed for specificity using an immunodepletion 
format with BMS-986036 and nonPEGylated drug. The reactivity of confirmed positive 
responses will be characterized as “BMS-986036” (specific to the FGF21 region) or “PEG” 
(specific to the PEGylated region) based on the immunodepletion specificity. Additionally, 
samples with confirmed positive responses will be titrated to determine the relative positive 
response. 
 
Participants will also be monitored for antibodies to FGF21 using recombinant Met-FGF21 in 
a homogenous bridge assay with electrochemical luminescence detection. Samples will first 
be screened for potential positive anti-FGF21 responses. Then the samples with positive 
antiFGF21 responses will be confirmed for specificity using an immunodepletion format with 
wild-type sequence FGF21. Samples with confirmed positive anti-FGF21 responses will be 
titrated to determine the relative positive response. 
 
Samples positive for anti-BMS-986036 antibodies or positive for anti-FGF21 antibodies will 
be tested for neutralizing activity in a functional cell based neutralizing antibody assay. The 
assay measures the ability of an anti-BMS-986036 or anti-FGF21 antibody to inhibit or block 
Erk1 activation that is induced when FGF21 or drug binds to the β-Klotho and FGF-Rs. 
 
Long-Term Immunogenicity Follow-Up 
All participants will have samples collected for immunogenicity at 6 months (± 14 days) after 
the Week 52/PTFU Visit. Samples collected from participants may not be analyzed if: 1) 
participant is not on active drug, 2) participant is negative for anti-drug and/or anti-FGF21 
antibody titers at the Week 52/PTFU Visit, or 3) participant has evidence of stable or 
decreasing antibody titers for 2 visits prior to the 6-month posttreatment visit. 
 
Participants with positive anti-drug and/or anti-FGF21 antibodies at the Week 52/PTFU Visit 
and without evidence of 2 consecutive stable or decreasing antibody titers will be followed 
for up to 14 months after the Week 52/PTFU Visit (1 month is defined as 4 calendar weeks) 
until antibody titers decrease for 2 consecutive visits (these additional visits will be 
conducted at approximately 9 months and 12 months after the Week 52/PTFU Visit). The 
sponsor or designee will inform the clinical site if a participant needs to return for 
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immunogenicity follow-up beyond 6 months. If, at 12 months after the Week 52/PTFU Visit, 
a participant has an increasing titer (compared to the previous titer), an additional follow-up 
visit will be performed at approximately 14 months (1 month is defined as 4 calendar weeks) 
after the Week 52/PTFU Visit; at this visit, anti-drug and anti-FGF21 antibodies, as well as 
additional laboratory assessments (basic metabolic panel, hemoglobin A1c 
 
), will be collected. 
 
Participants who discontinue from the study prior to the Week 48 Visit will be offered 
additional Long-Term Immunogenicity Follow-Up Visits, as above. For these participants, 
prior immunogenicity results will be used to determine whether the participant should be 
offered Long-Term Immunogenicity Follow-Up Visits beyond the 6-month posttreatment 
assessment. Additional Long-Term Immunogenicity Follow-Up Visits should occur 
approximately 9, 12, and 14 months, if applicable (1 month is defined as 4 calendar weeks) 
after their last study visit. 
 
Refer to the decision tree in Appendix 11 for more details regarding Long-Term 
Immunogenicity Follow-Up Visits. 
 
8.5.3.7 
Adverse Events of Special Interest 
The sponsor has developed a list of AEs of Special Interest for the BMS-986036 program 
based on the known biologic class effects, the mechanism of action, and clinical study data. 
These will include the following: 
• Injection site reactions 
• Gastrointestinal events 
o Diarrhea, frequent bowel movements, nausea, vomiting, abdominal pain 
• Bone-related events 
o Osteoporosis, osteopenia, bone and joint injuries, fractures (except tooth fracture), 
endocrine abnormalities of gonadal function not elsewhere classified (NEC), 
hyperparathyroid disorders, hypoparathyroid disorders, parathyroid disorders NEC, 
parathyroid analyses, metabolic bone disorders, vitamin D abnormal, vitamin D 
decreased, vitamin D deficiency, and miscellaneous events related to bone density 
 
8.5.3.8 
Bone Safety by DXA 
Potential effects of BMS-986036 on BMD will be evaluated by DXA scans of the hip 
(including femoral neck) and spine that will be performed during the Screening Period and at 
the Week 48 Visit (or ET, if applicable) as indicated in the Schedule of Activities (Section 1). 
Participants will return for a follow-up DXA assessment 6 months (1 month is defined as 4 
calendar weeks) after the Week 52/PTFU Visit. DXA may be performed within a window of 
± 7 days of the scheduled Week 48/ET Visit and within a window of ± 14 days of the 
scheduled 6-month follow-up visit. DXA scans will be evaluated by central reading. 
Acquisition guidelines, instructions on calibration and the handling and submission of DXA 
scans are included in the Imaging Laboratory Manual. Note that at least one of the requested 
anatomic sites (hip [including femoral neck] or spine) must be evaluable for participants to be 
eligible for the study (See Section 8.3.2). 
 
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For participants prematurely discontinuing study medication DXA scans should be conducted 
at the ET Visit only if the participant has completed at least the Week 16 Visit. If a 
participant has not completed at least Week 16, the follow-up DXA scan at 6 months after 
PTFU Visit should also not be performed. 
 
8.5.4 Laboratory Assessments 
Participants should not administer study medication on the days of clinic visits until after all 
laboratory samples have been collected (see Table 8 below). Blood samples will be collected 
according to the schedule in Section 1. In addition, a number of hematology and blood 
chemistry values collected as part of the safety laboratory assessments will also be used to 
determine FIB4 index, APRI, and NAFLD Fibrosis Scores according to the schedule in 
Section 1. 
 
Safety (hematology, blood chemistry, and urinalysis), efficacy, and exploratory laboratory 
assessments to be conducted during the study are listed in Table 8 below. The schedule for 
collection of samples for each assessment is in Section 1. Laboratory assessments will be 
conducted by central or specialty laboratories. Additional details on the collection, 
processing, and submission of samples for laboratory assessments are in the Study 
Laboratory Manual. If clinically indicated, repeat laboratory testing may be performed at a 
local lab. 
 
Investigators must document their review of each laboratory safety report. A central 
laboratory will perform the safety analyses and will provide reference ranges for these tests. 
Results of clinical laboratory tests performed during Screening must be available prior to 
dosing. 
 
In addition to those detailed assessments outlined in Table 8 below, serum, plasma and urine 
may be assayed for exploratory markers associated with liver, fibrosis, 
 or 
metabolic syndrome disease including markers associated with the BMS-986036 target 
pathway or with organs or pathways impacted by FGF21.  
 
Urine or serum samples will be collected for pregnancy testing for WOCBPs. A negative 
serum pregnancy test is required during Screening. After the Screening Period, urine 
pregnancy testing will be conducted instead of serum testing at any site where it is allowed 
by the IRB/EC committee overseeing study conduct at that site. Women who are considered 
postmenopausal will have follicle-stimulating hormone testing performed during Screening. 
 
Urine samples to test for drugs of abuse will be collected during Screening. 
 
Repeat assessments for any laboratory assessment will be permitted according to the 
investigator’s clinical judgment. 
 
Table 8 
Laboratory Assessments 
ELF Assay (to be collected at Day 1, Week 24, and Week 48/ET). Participants will fast for 8 hours 
prior to collection of blood samples for these assessments: 
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• 
Hyaluronic acid 
• 
Procollagen 3 amino terminal peptide 
• 
Tissue inhibitor of metalloproteinases 1 (TIMP-1) 
Laboratory Metabolic Markers (to be collected at Screening, Day 1, Week 24, and Week 48/ET). 
Participants will fast for 8 hours prior to collection of blood samples for these assessments: 
• 
Low-density lipoprotein cholesterol 
• 
High-density lipoprotein cholesterol 
• 
Triglycerides 
• 
Plasma glucose – Also used for NAFLD Fibrosis Score 
• 
Plasma insulin 
• 
Hemoglobin A1c – also to be collected at Long-Term Immunogenicity Follow-Up Visits as applicable 
(see Section 8.5.3.6) 
Hepatitis Assessments (to be collected at Screening only- see Appendix 3 for diagnosis and exclusion 
criteria): 
• 
Hepatitis B core antigen antibody 
• 
Hepatitis B surface antigen antibody 
• 
Hepatitis B surface antigen 
• 
Hepatitis B virus DNA 
• 
Hepatitis C virus antibody 
• 
Hepatitis C virus RNA 
Pregnancy Testing (to be collected at each visit through the Week 52/PTFU Visit): 
• Serum or urine β-HCG. Women of childbearing potential only. Serum β-HCG to be collected at 
Screening and serum or urine β-HCG to be collected thereafter according to local laws and regulations 
and Institutional Review Board/Ethics Committee requirements) 
• Follicle-stimulating hormone (Screening only for postmenopausal women) 
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Hematology (to be collected at each visit through the Week 52/PTFU Visit): 
• 
Complete Blood Count 
o White blood cells, including differential 
o Red blood cells 
o Hemoglobin 
o Hematocrit 
o Platelet count – Also used for FIB4, APRI, and NAFLD Fibrosis Score 
o Mean corpuscular hemoglobin (MCH) 
o Mean corpuscular hemoglobin concentration (MCHC) 
o Red cell distribution width (RDW) 
• 
Prothrombin time 
• 
Partial thromboplastin time 
• 
International normalized ratio – Also used in MELD and Child-Pugh Turcotte scoring 
Blood Chemistry (to be collected at each visit through Week 52/PTFU and at Long-Term 
Immunogenicity Follow-Up Visits as applicable [see Section 8.5.3.6]): 
• 
AST – Used as both safety and efficacy 
endpoints. Also used for FIB4, APRI, and 
NAFLD Fibrosis Score 
• 
ALT – Used as both safety, efficacy endpoints, 
and for FIB4, APRI, and NAFLD Fibrosis 
Score 
• 
Serum glucose 
• 
Total bilirubin 
• 
Indirect bilirubin 
• 
Alkaline phosphatase 
• 
Lactate dehydrogenase 
• 
Creatinine 
• 
Blood Urea Nitrogen 
• 
Uric acid  
• 
Total Protein 
• 
Albumin – Also used for NAFLD Fibrosis Score. 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Carbon dioxide 
• 
Calcium 
• 
Phosphorus 
• 
Glomerular filtration rate 
Urinalysis (to be collected at each visit through the Week 52/PTFU Visit): 
• 
pH 
• 
Specific gravity 
• 
Protein 
 
• 
Glucose 
• 
Ketones 
• 
Blood 
• 
Leukocyte esterase 
• 
Nitrite 
• 
Creatinine 
 
• 
Albumin 
 
• 
Microscopic examination (only to follow-up abnormal findings) 
• 
Drug Screen (Screening only) 
Immunogenicity (to be collected at Day 1 and each subsequent visit through the Week 52/PTFU Visit 
and at Long-Term Immunogenicity Follow-Up Visits as applicable [see Section 8.5.3.6]): 
• Serum anti-BMS-986036 antibody 
• Serum anti-FGF21 antibody 
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PRO-C3 (to be collected at Screening, Day 1, Week 4, Week 8, Week 12, Week 24, Week 48/ET, and 
Week 52 [PTFU]). Participants will fast for 8 hours prior to collection of blood samples for these 
assessments: 
• 
N-terminal type 3 collagen propeptide (PRO-C3) – Will include blood collection for additional serum for 
new or improved assays 
Adiponectin (to be collected at Screening, Day 1, Week 4, Week 8, Week 12, Week 24, Week 48/ET, 
and Week 52/PTFU). Participants will fast for 8 hours prior to collection of blood samples for these 
assessments 
Plasma and Serum for disease, target and drug effect biomarkers (to be collected at Day 1, Week 4, 
Week 8, Week 12, Week 24, Week 48, ET [if applicable], Week 52/PTFU, and 6 months after Week 
52/PTFU). Participants will fast for 8 hours prior to collection of these samples 
Gene Expression (to be collected at Screening, Day 1, Week 4, Week 8, Week 12, Week 24, and Week 
48/ET and Week 52/PTFU):  
• 
Whole blood for RNA analysis (broad and/or directed gene expression profiling) 
Micro RNA (miRNA) (to be collected at Screening, Day 1, Week 4, Week 8, Week 12, Week 24, Week 
48/ET, and Week 52/PTFU) 
 ALT = alanine aminotransferase; APRI = AST-Platelet Ratio Index; 
AST = aspartate aminotransferase; DNA = deoxyribonucleic acid; β-HCG = beta human chorionic 
gonadotropin; ELF = Enhanced Liver Fibrosis; ET = early termination; FGF21 = fibroblast growth factor 
21; FIB4 = Fibrosis 4 Index; NAFLD = nonalcoholic fatty liver disease; NAS = NAFLD Activity Score; 
NASH = nonalcoholic steatohepatitis; PTFU = Post-Treatment Follow-up; RNA = ribonucleic acid; 
 
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8.5.5 Pharmacokinetics 
8.5.5.1 
All Participants 
Serum concentrations of BMS-986036 will be derived from trough (predose) blood samples 
collected from each participant before the administration of BMS-986036 dosing at each 
visit. Participants will be instructed to not administer study medication on the days of clinic 
visits until the trough PK sample has been collected. 
 
Table 9 
Timing of Pharmacokinetic and Electrocardiogram Assessments 
Study Day 
Event 
Time Postdose 
(sample window) 
Pharmacokinetic 
Sample 
Electrocardiogram 
Assessments Associated with the Day 1 Visit  
Day 1 (Day of Week 1 dose) 
Predose 
0 h  
X 
X 
Day 1 
Dose 
 
 
 
Day 8 (Day of Week 2 dose) 
Predose 
0 h 
X 
 
Day 8 
Dose 
 
 
 
Assessments Associated with the Week 24 Visit 
Day 169 (Day of Week 25 dose) 
Predose 
0 h  
X 
X 
Day 169 
Dose 
 
 
 
Day 176 (Day of Week 26 dose) 
Predose 
0 h 
X 
 
Day 176 
Dose 
 
 
 
 
  
Pharmacokinetic samples should be taken after the electrocardiogram assessments are performed at times 
where both pharmacokinetic samples and electrocardiograms are to be collected. 
Day 1 is defined as the day of administration of the first dose of study medication. 
 
BMS-986036 concentrations will be evaluated by a central laboratory. Further details of 
sample collection, processing, submission and storage are provided in the Study Laboratory 
Manual. 
 
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9. STATISTICAL CONSIDERATIONS 
9.1 Sample Size Determination 
The primary efficacy endpoint is the proportion of participants with a ≥ 1-stage improvement 
in fibrosis (as defined by NASH CRN Fibrosis Score) without worsening of NASH (as 
defined by the NAFLD Activity Score) at Week 48, as determined by liver biopsy. 
 
It is planned to randomize approximately 100 participants to 1 of the 4 treatment groups 
(approximately 25 participants per group), BMS-986036 10 mg QW, BMS-986036 20 mg 
QW, BMS-986036 40 mg QW or matching placebo QW in a 1:1:1:1 ratio. 
 
A Cochran-Armitage trend test of proportions, with an estimated response rate of 15% for the 
primary endpoint for placebo and response rates for BMS-986036 10 mg QW, BMS-986036 
20 mg QW, and BMS-986036 40 mg QW of 20%, 30%, and 40%, respectively, would 
provide at least 70% power at a 1-sided α = 0.05 (based on original sample size estimate of 
approximately 100 participants). The final sample size was approximately 155 participants 
(see Section 6.2). 
 
9.2 Populations for Analyses 
The following populations are defined for analysis purposes:  
 
Population 
Description 
Enrolled  
All participants who sign informed consent. 
Randomized 
All participants who are randomized, analyzed as per 
randomized treatment.  
Modified intent-to-treat 
(mITT) 
All participants who are randomized and receive at least 1 
dose of study medication, analyzed according to randomized 
treatment. All primary efficacy analyses will be conducted 
using this population. 
As treated (Safety) 
All participants who are randomized and receive at least 1 
dose of study medication, analyzed according to treatment 
actually received. This population will be essentially the same 
as the mITT unless a participant received an incorrect 
treatment, i.e., a treatment different from what he/she was 
randomized to. All safety analyses will be conducted using this 
population. 
 
9.3 Stratification 
Randomization of participants will be stratified by country (Non-Japan/Japan). For 
participants in countries other than Japan, the randomization will be further stratified 
according to T2DM status (yes/no). 
 
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9.4 Endpoints 
9.4.1 Efficacy Endpoints 
9.4.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of participants who achieve a ≥ 1-stage 
improvement in fibrosis (as defined by NASH CRN Fibrosis Score) without worsening of 
NASH (as defined by the NAFLD Activity Score) at Week 48, as determined by liver biopsy. 
 
For this protocol, improvement in fibrosis is defined as a decrease of fibrosis by ≥ 1 point, as 
determined by the NASH CRN Fibrosis Score. Worsening of NASH is defined as an increase 
of the NAFLD Activity Score (NAS) by ≥ 1 point. (see Section 8.5.1.1). 
 
9.4.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are as follows: 
• Proportion of participants with Ishak Score improvement at Week 48 
• Proportion of participants who achieve a ≥ 1-stage improvement (as defined by NASH 
CRN Fibrosis Score) in fibrosis without worsening of NASH or NASH improvement 
(reduction of NAFLD Activity Score by ≥ 2 points with contribution from > 1 NAS 
component) at Week 48 as determined by liver biopsy 
• Proportion of participants who achieve a ≥ 1-stage improvement (as defined by NASH 
CRN Fibrosis Score) in fibrosis 
• Proportion of participants with a decrease in CPA at Week 48 
• Proportion of participants with NASH resolution (NAS component of ballooning = 0 
and inflammation = 0-1) at Week 48 
• Proportion of participants with NASH improvement (reduction of NAFLD Activity 
Score by ≥ 2 points with contribution from > 1 NAS component) at Week 48 
 
9.4.2 Safety Endpoints 
Safety will be assessed by the following: 
• Incidence and frequency of treatment-emergent AEs and SAEs 
• ECGs at Week 24, and Week 48 
• Vital signs at each visit 
• Physical examinations (full or abbreviated as shown in Section 8.5.3) at each visit 
through Week 52/PTFU 
• Laboratory evaluations at each visit through Week 52/PTFU 
• BMD as measured by DXA Week 48/ET, and 6 months (1 month is defined as 4 
calendar weeks) after the Week 52/PTFU Visit 
• Anti-BMS-986036 antibodies at each visit with follow-up for up to 14 months (1 month 
is defined as 4 calendar weeks) after the Week 52/PTFU Visit as described in 
Section 8.5.3.6 
• Anti-FGF21 antibodies at each visit with follow-up for up to 14 months (1 month is 
defined as 4 calendar weeks) after the Week 52/PTFU Visit as described in 
Section 8.5.3.6 
 
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9.4.3 Pharmacokinetic Endpoints 
• Trough (predose) BMS-986036 concentrations from samples collected at each visit 
 
9.4.4 Exploratory Endpoints 
• Quantitative measurements of fibrosis and fat on biopsy 
o Assessment of NASH CRN Fibrosis Score at Week 48 
o Assessment of Ishak Fibrosis Score at Week 48 
o Assessment of fibrosis using digital pathology at Week 48 
o Assessment of CPA at Week 48 
o Assessment of fat in stained tissue by morphometry at Week 48 
o Assessment of alpha smooth muscle actin at Week 48 
• Assessment of NAS at Week 48 
• Assessment of NASH using digital pathology at Week 48 
• Hepatic fat fraction as measured using MRI-PDFF at Week 24 and Week 48 
• Noninvasive measures of fibrosis and/or cirrhosis 
o Liver stiffness as determined by MRE at Week 24 and Week 48 
o Fibroscan elastography results at Week 48 
o Noninvasive scores of hepatic fibrosis (APRI, FIB-4, ELF, and NAFLD Fibrosis 
Score) at Week 24 and Week 48 
• Metabolic assessments at Week 24 and Week 48 
o Physical assessments (body weight, waist circumference, and BMI) 
o Serum lipids (LDL, HDL, and TGs) 
o Plasma glucose 
o Plasma insulin 
o Hemoglobin A1c 
• Child-Pugh Turcotte Score at Week 24 and Week 48 
• MELD Score at each visit through Week 52/PTFU 
• The event rate for any one (first occurrence) of the liver-related clinical outcome 
events described in Section 8.5.1.9 by Week 48 
• Patient-reported outcomes at Week 24 and Week 48 
o EQ-5D-3L questionnaire 
o SF-36 questionnaire 
o CDLQ-NAFLD questionnaire 
• Exploratory biomarkers 
o Transaminases 
- ALT normalization (ALT ≤ ULN) at Week 24 and Week 48 
- AST normalization (AST ≤ ULN) at Week 24 and Week 48 
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- ALT at each visit through Week 52/PTFU 
- AST at each visit through Week 52/PTFU 
- Change from Baseline (Day 1 predose) ALT levels at each visit through Week 
52/PTFU Visit 
- Change from Baseline (Day 1 predose) AST levels at each visit through Week 
52/PTFU Visit 
o PRO-C3 
- Assessment of PRO-C3 levels at each visit through Week 52/PTFU 
- Change from Baseline (Day 1 predose) in PRO-C3 levels at each visit through 
Week 52/PTFU Visit 
o Assessment of adiponectin at each visit through Week 52/PTFU 
  
9.5 Statistical Analyses 
A full Statistical Analysis Plan (SAP) will be developed that will provide more details for the 
statistical analysis methods to be used. The SAP will be finalized before database lock for the 
Week 52 analysis and will provide detailed specifications of the analysis of all efficacy 
endpoints and safety. The SAP will also provide more details on the definition of analysis 
populations to be used in the analyses and procedures for accounting for missing data. The 
following provides a summary of planned statistical analyses of the primary and secondary 
endpoints; exploratory analyses will be described in the SAP. 
 
9.5.1 Demographic and Baseline Characteristics  
A description of the participant population will be included in a statistical output report, 
including subgroups of age, gender and race. 
 
Demographic and Baseline characteristics will be summarized using frequency distributions 
and descriptive statistics using the Randomized Participants and modified intent-to-treat 
(mITT) populations. No statistical analyses will be performed to compare treatment groups at 
Baseline. 
 
9.5.2 Efficacy Analyses 
Efficacy analyses will be performed using the mITT population unless otherwise specified 
below. 
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9.5.2.1 
Primary Endpoint 
The primary endpoint is the proportion of participants who achieve a ≥ 1-stage improvement 
in fibrosis (as defined by NASH CRN Fibrosis Score) without worsening of NASH (as 
defined by the NAFLD Activity Score) at Week 48, as determined by liver biopsy. 
 
For this protocol, improvement in fibrosis is defined as a decrease of fibrosis by ≥ 1 point, as 
determined by the NASH CRN Fibrosis Score. Worsening of NASH is defined as an increase 
of the NAFLD Activity Score (NAS) by ≥ 1 point (see Section 8.5.1.1). 
 
A Cochran-Armitage trend test with a one-sided 0.05 level of significance will be used to 
examine the linear trend among the proportions across treatment groups. Also, 95% 
confidence intervals for the odds-ratio of each BMS treatment group to placebo will be 
provided. 
 
A sensitivity analysis using an extended Cochran Mantel-Haenszel (CMH) correlation test37 
will be used to assess the trend among the proportions for treatment groups with an 
adjustment to strata. A two-sided 0.10 level of significance will be used. 
 
Since this is a Phase 2 study, no adjustment for multiplicity will be applied. 
 
 
All participants who prematurely discontinue from treatment without a biopsy at Week 48 (or 
ET, if applicable) or otherwise have a missing Week 48 (or ET, if applicable) biopsy result 
will be considered nonresponders for the primary analysis of the primary efficacy endpoint. 
In addition, a completer analysis of the primary endpoint will be performed excluding 
participants without a Week 48 biopsy. 
 
9.5.2.2 
Secondary Efficacy Endpoints 
Secondary endpoints will be analyzed using methodology consistent with that of the primary 
endpoint unless otherwise specified in the SAP. 
 
Further details of the primary and secondary analyses, any additional sensitivity analyses and 
data handling details regarding issues such as missing data will be provided in the SAP. 
 
9.5.2.3 
Methods for Handling Treatment Discontinuations and Other Causes of Missing 
Data 
Participants who prematurely discontinue study medication will be expected to complete an 
Early Termination visit (Week 48/ET) and must continue to be followed for follow-up 
visits/procedures per the Schedule of Activities (e.g., Week 52/PTFU; Section 1).  
 
Primary efficacy analyses will include all data that are collected on a participant during the 
study even after treatment discontinuation. All primary efficacy analyses will be performed 
with the mITT population, analyzed according to randomized treatment.  
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Additional details for handling of missing data will be provided in the SAP. 
 
9.5.3 Safety Analyses 
Safety analyses will be performed using the As Treated population. For analysis, all 
treatment-emergent (i.e., occurring after the first dose of study medication) AEs, SAEs, and 
AEs of special interest will be summarized by system organ class, preferred term, and 
treatment. Vital signs, immunogenicity, BMD, and laboratory data will be summarized by 
treatment. ECG abnormalities, physical examination abnormalities, if present, will be 
summarized. 
 
Responses of anti-BMS-986036 antibodies and anti-FGF21 antibodies will be listed and 
tabulated by treatment and study day. 
 
 
 
9.5.4 Pharmacokinetic Analysis 
Trough BMS-986036 serum concentrations (in all participants at all visits)
 
 
will be summarized by 
treatment and visit. 
 
The PK data obtained in this study may be combined with data from other studies of 
BMS-986036 to develop a population PK/PK-PD model. This model will be used to evaluate 
the effects of intrinsic and extrinsic (if applicable) covariates (e.g., immunogenicity and renal 
function) on the PK of BMS-986036 and to determine measures of individual exposure (such 
as peak, trough, and time-averaged concentration following a single dose) of BMS-986036. 
Model determined exposures will be used for exposure-response analyses of selected efficacy 
and safety endpoints, as appropriate. Details of the planned population PK and exposure-
response analyses will be covered in a separate pharmacometric analysis plan and the results 
of the population PK and exposure-response analyses presented in a pharmacometric report, 
separate from the clinical study report. 
 
9.5.5 Analyses of Exploratory Endpoints 
Analyses for the exploratory efficacy endpoints will be described in the SAP, which will 
detail the derivation of the endpoints and associated statistical methods and models. 
 
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10. REFERENCE LIST 
 
1 
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of 
nonalcoholic fatty liver disease: Practice guidance from the American Association for the 
Study of Liver Diseases. Hepatology 2017;Jul 17. [Epub ahead of print]. 
 
2 
Wong R, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the US. 
Hepatology 2014;59(6):2188-95. 
 
3 
Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations 
from an American Association for the Study of Liver Diseases (AASLD) - Food and 
Drug Administration (FDA) joint workshop. Hepatology 2015;61(4):1392-405. 
 
4 
Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic 
regulator. J Clin Invest 2005;115:1627-35. 
 
5 
Kharitonenkov A, Dunbar JD, Bina HA, et al. FGF21/FGF21 receptor interaction and 
activation is determined by betaKlotho. J Cell Physiol 2008;215:1-7. 
 
6 
Yang C, Jin C, Li X, et al. Differential specificity of endocrine FGF19 and FGF 21 to 
FGFR1 and FGFR4 in complex with KLB. PLoS One 2012;7(3):e33870. 
 
7 
Badman MK, Pissios P, Kennedy AR, et al. Hepatic fibroblast growth factor 21 is 
regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic 
states. Cell Metab 2007;5:426-37. 
 
8 
Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, 
increases energy expenditure, and improves insulin sensitivity in diet-induced obese 
mice. Diabetes 2009;58:250-9. 
 
9 
Kharitonenkov A, Wroblewski VJ, Koester A, et al. The metabolic state of diabetic 
monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007;148:774-81. 
 
10 Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese 
human participants with type 2 diabetes. Cell Metab 2013;18:333-40. 
 
11 Dushay J, Chui PC, Gopalakrishnan GS, et al. Increased fibroblast growth factor 21 in 
obesity and nonalcoholic fatty liver disease. Gastroenterology 2010;139:456-63. 
 
12 Li H, Fang Q, Gao F, et al. Fibroblast growth factor 21 levels are increased in 
nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J 
Hepatol 2010;53:934–40. 
 
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13 Fisher FM, Chui PC, Nasser IA, et al. Fibroblast growth factor 21 limits lipotoxicity by 
promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. 
Gastroenterology 2014;147:1073–83. 
 
14 Study Report for Study MD00007: In vivo efficacy study of BMS-986036 in STAM 
model of nonalcoholic steatohepatitis (Study MD00007). Stelic Institute and Co.; 2014. 
BMS Document Control No. 930084152.  
 
15 Study Report for Study MD00007: In vivo efficacy study of BMS-986036 and LA-Ex4 in 
STAM model of nonalcoholic steatohepatitis. Stelic Institute and Co.; 2015. BMS 
Document Control No. 930085767. 
 
16 Study Report for Study MB130001: Randomized, placebo-controlled, ascending single 
and multiple-subcutaneous dose study to evaluate the safety, tolerability, 
pharmacokinetics and pharmacodynamics of BMS-986036 in healthy obese subjects. 
Bristol-Myers Squibb Company; 2014. Document Control No. 930080359. 
 
17 Adachi M, Brenner DA. High molecular weight adiponectin inhibits proliferation of 
hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase. 
Hepatology 2008;47:677-85. 
 
18 Polyzos SA, Kountouras J, Zavos C, et al. The role of adiponectin in the pathogenesis and 
treatment of nonalcoholic fatty liver disease. Diabetes Obes Metab 2010;12:365-83. 
 
19  Charles ED, Neuschwander-Tetri BA, Frias JP, et al. Pegbelfermin (BMS-986036), 
PEGylated FGF21, in Patients with Obesity and Type 2 Diabetes: Results from a 
Randomized Phase 2 Study. Obesity 2019;27:41-9. 
 
20 
 Sanyal A, Charles ED, Neuschwander-Tetri BA, et al. Pegbelfermin (BMS-986036), a 
PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic 
steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 
2018;392:2705-17. 
 
21 Loomba R, Lawitz E, Mantry PS, et al. GS-4997, an inhibitor of apoptosis signal-
regulating kinase (ASK1), alone or in combination with simtuzumab for the treatment of 
nonalcoholic steatohepatitis (NASH): A randomized, Phase 2 trial. Presented at: The 
Liver Meeting® 2016 (American Association for the Study of Liver Disease [AASLD]), 
Boston Massachusetts, November 11-15, 2016. 
 
22 Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic 
features, is associated with long-term outcomes of patients with nonalcoholic fatty liver 
disease. Gastroenterology 2015;149:389-97. 
 
23 Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-
specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 
2015;61:1547-54. 
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24 Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and 
time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 
2017;Aug 10. [Epub ahead of print]. 
 
25 Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in 
nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 
2017;65:1557-65. 
 
26 Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Practice Guidelines Committee of the 
American Association for the Study of Liver Diseases; Practice Parameters Committee of 
the American College of Gastroenterology. Prevention and management of 
gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 
2007;46(3):922-38. 
 
27 Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological 
scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41(6):1313-21. 
 
28 Sanyal AJ, Harrison SA, Ratziu V, et al. The Natural History of Advanced Fibrosis Due 
to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials. Hepatology 2019 
(epub ahead of print). 
 
29 Wang Y, Vincent R, Yang J, et al. Dual-photon microscopy-based quantitation of 
fibrosis-related parameters (q-FP) to model disease progression in steatohepatitis. 
Hepatology 2017;65(6):1891-1903. 
 
30 Younossi ZM, Stepanova M, Henry L, et al. A disease-specific quality of life instrument 
for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: CLDQ-NAFLD. 
Liver Int 2017;37(8):1209-18. 
 
31 Patel J, Bettencourt R, Cui J, et al. Association of noninvasive quantitative decline in 
liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Therap 
Adv Gastroenterol 2016;9(5):692-701. 
 
32 Middleton MS, Heba ER, Hooker CA, et al. Agreement between magnetic resonance 
Imaging proton density fat fraction measurements and pathologist-assigned steatosis 
grades of liver biopsies From adults with Nonalcoholic Steatohepatitis. Gastroenterology 
2017;153(3):753-61. 
 
33 Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately 
classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than 
transient elastography. Gastroenterology 2016;150(3):626-37. 
 
34 Runge JH, Bohte AE, Verheij J, et al. Comparison of interobserver agreement of 
magnetic resonance elastography with histopathological staging of liver fibrosis. Abdom 
Imaging 2014;39(2):283-90. 
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37 Stokes ME; Davis CS; Koch GG. Categorical Data Analysis Using SAS, 3rd Edition. 
Cary, NC: SAS Institute Inc. 2012. 
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11. APPENDICES 
 
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Appendix 1 
Study Administrative Considerations 
The term ‘participant’ is intended to refer to a person who has consented to participate in the 
clinical research study. 
 
Regulatory and Ethical Considerations 
 
Good Clinical Practice 
 
This study will be conducted in accordance with: 
• GCP guidelines 
• as defined by ICH guidance 
• in accordance with the ethical principles underlying European Union Directive 
2001/20/EC 
• United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)  
• applicable local requirements 
 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the participant informed consent will receive approval/favorable opinion by 
IRB/EC, and regulatory authorities according to applicable local regulations prior to initiation 
of the study. 
All potential serious breaches must be reported to sponsor or designee immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the 
study or the protocol, which is likely to affect, to a significant degree, the safety or physical 
or mental integrity of the participants of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, 
debarment). 
 
Institutional Review Board/Independent Ethics Committee 
 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/EC for the protocol, consent form, participant recruitment materials 
(e.g., advertisements), and any other written information to be provided to participants. The 
investigator or sponsor should also provide the IRB/EC with a copy of the IB or product 
labeling information to be provided to participants and any updates.  
 
The investigator, sponsor or designee should provide the IRB/EC with reports, updates and 
other information (e.g., expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures. 
 
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Compliance with the Protocol and Protocol Revisions 
 
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/EC (and 
if applicable, also by local health authority) except where necessary to eliminate an 
immediate hazard(s) to study participants.  
 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining relevant approval/favorable opinion(s) the deviation or change will be 
submitted, as soon as possible to: 
• IRB/EC 
• Regulatory Authority(ies), if applicable by local regulations (per national requirements) 
 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB/EC(s) and if applicable, also by local health authority must be sent to the sponsor. 
 
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB/EC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
participants currently enrolled in the study if they are affected by the amendment; and (3) the 
new form must be used to obtain consent from new participants prior to enrollment. 
 
If the revision is done via an administrative letter, investigators must inform their IRB/EC(s). 
 
Financial Disclosure 
 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
 
Informed Consent Process 
 
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate.  
 
In situations where consent cannot be given to participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant 
volunteers to participate.  
 
The sponsor or designee will provide the investigator with an appropriate (i.e., global or 
local) sample ICF which will include all elements required by ICH, GCP, and applicable 
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regulatory requirements. The sample ICF will adhere to the ethical principles that have their 
origin in the Declaration of Helsinki. 
 
 
Investigators must: 
• Provide a copy of the ICF and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language 
must be nontechnical and easily understood 
• Allow time necessary for participant or participant’s legally acceptable representative to 
inquire about the details of the study 
• Obtain an ICF signed and personally dated by the participant or the participant’s legally 
acceptable representative and by the person who conducted the informed consent 
discussion 
• Obtain the IRB/EC’s written approval/favorable opinion of the written ICF and any other 
information to be provided to the participants, prior to the beginning of the study, and 
after any revisions are completed for new information 
 
If informed consent is initially given by a participant’s legally acceptable representative or 
legal guardian, and the participant subsequently becomes capable of making and 
communicating his or her informed consent during the study, consent must additionally be 
obtained from the participant. 
 
Revise the ICF whenever important new information becomes available that is relevant to the 
participant’s consent. The investigator, or a person designated by the investigator, should 
fully inform the participant or the participant’s legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant’s willingness to continue participation in the study. This communication should 
be documented.  
 
The confidentiality of records that could identify participants must be protected, respecting 
the privacy and confidentiality rules applicable to regulatory requirements, the participants’ 
signed ICF and, in the United States, the participants’ signed Health Insurance Portability and 
Accountability Act Authorization. 
 
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The consent form must also include a statement that the sponsor and regulatory authorities 
have direct access to participant records.  
 
Participants unable to give their written consent (e.g., those with stroke or severe dementia) 
may only be enrolled in the study with the consent of a legally acceptable representative. The 
participant must also be informed about the nature of the study to the extent compatible with 
his or her understanding, and should this participant become capable, he or she should 
personally sign and date the consent form as soon as possible. The explicit wish of a 
participant who is unable to give his or her written consent, but who is capable of forming an 
opinion and assessing information to refuse participation in, or to be withdrawn from, the 
clinical study at any time should be considered by the investigator. 
 
The rights, safety, and well-being of the study participants are the most important 
considerations and should prevail over interests of science and society. 
 
Source Documents 
 
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, 
archived, retrieved, or transmitted electronically via computerized systems (and/or any other 
kind of electronic devices) as part of regulated clinical study activities, such systems must be 
compliant with all applicable laws and regulations governing use of electronic records and/or 
electronic signatures. Such systems may include, but are not limited to, electronic 
medical/health records, AE tracking/reporting, protocol-required assessments, and/or drug 
accountability records. 
 
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists 
of a copy of original information that has been verified, as indicated by a dated signature, as 
an exact copy having all of the same attributes and information as the original.  
 
Study Medication Records 
 
The study personnel will account for all study medications dispensed to and returned from 
the participant. Study site personnel will account for all unused study medications at the site, 
and unused study medication will be destroyed at the site or returned to the sponsor or 
designee for appropriate destruction, depending on circumstances. Records for study 
medications (whether supplied by the sponsor, its vendors, or the site) must substantiate 
study medication integrity and traceability from receipt, preparation, administration, and 
through destruction or return. Records will be reconciled with existing study medication by a 
study monitor prior to destruction of the product. Certificates of destruction should be signed 
and will be included in the Trial Master File. Records must be made available for review at 
the request of sponsor/designee or a health authority. 
 
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If 
Then 
Supplied by the sponsor (or its vendors): 
Records or logs must comply with applicable 
regulations and guidelines and should include: 
• 
amount received and placed in storage area 
• 
amount currently in storage area 
• 
label identification number or batch number 
• 
amount dispensed to and returned by each 
participant, including unique participant 
identifiers 
• 
amount transferred to another area/site for 
dispensing or storage 
• 
nonstudy disposition (e.g., lost, wasted)  
• 
amount returned to the sponsor or designee 
• 
retain samples for 
bioavailability/bioequivalence, if applicable  
• 
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form. 
The sponsor or designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements. 
 
Case Report Forms 
 
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated or entered as a control in the investigation. Data that are derived from 
source documents and reported on the eCRF must be consistent with the source documents or 
the discrepancies must be explained. Additional clinical information may be collected and 
analyzed in an effort to enhance understanding of product safety. eCRFs may be requested 
for AEs and/or laboratory abnormalities that are reported or identified during the course of 
the study. 
 
For sites using the sponsor or designee electronic data capture (EDC) tool, eCRFs will be 
prepared for all data collection fields with the exclusion of data collection associated with 
pregnancy, which will be reported on the Pregnancy Surveillance Form. Spaces may be left 
blank only in those circumstances permitted by study-specific eCRF completion guidelines 
provided by sponsor or designee. 
 
The confidentiality of records that could identify participants must be protected, respecting 
the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of all 
persons authorized to make entries and/or corrections on eCRFs.  
 
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The completed eCRF and SAE/pregnancy eCRFs, must be promptly reviewed, signed, and 
dated by the investigator or qualified physician who is a subinvestigator and who is delegated 
this task on the Delegation of Authority Form. Subinvestigators in Japan may not be 
delegated the eCRF approval task. For eCRFs, review and approval/signature should be 
completed electronically through the study EDC tool. The investigator must retain a copy of 
the eCRFs including records of the changes and corrections. 
 
Each individual electronically signing electronic eCRFs must meet sponsor or designee 
training requirements and must only access the study EDC tool using the unique user account 
provided by sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals. 
 
Monitoring 
 
The sponsor or designee representatives will review data centrally to identify potential issues 
to determine a schedule of on-site visits for targeted review of study records. 
 
Representatives of the sponsor or designee must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity. On site, they will review study 
records and directly compare them with source documents, discuss the conduct of the study 
with the investigator, and verify that the facilities remain acceptable. Certain eCRF pages 
and/or electronic files may serve as the source documents. 
 
In addition, the study may be evaluated by the sponsor or designee internal auditors and 
government inspectors who must be allowed access to case report forms, source documents, 
other study files, and study facilities. The sponsor audit reports will be kept confidential. 
 
The investigator must notify the sponsor promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to sponsor or designee. 
 
Records Retention 
 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by the sponsor or designee, whichever is 
longer. The investigator (or head of the study site in Japan) must contact the sponsor prior to 
destroying any records associated with the study. 
 
The sponsor or designee will notify the investigator (or head of the study site in Japan) when 
the study records are no longer needed. 
 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, 
IRB/EC). Notice of such transfer will be given in writing to the sponsor or designee.  
 
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Return of Study Medication 
 
For this study, study medications (those supplied by the sponsor, a vendor, or sourced by the 
investigator) such as partially used study medication containers and syringes may be 
destroyed on site (as applicable; some sites will return unused study medications depending 
on circumstances).  
 
If … 
Then 
Study medications supplied by the sponsor 
(including its vendors) 
Any unused study medications supplied by 
the sponsor can only be destroyed after 
being inspected and reconciled by the 
responsible study monitor unless study 
medications containers must be 
immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
cytotoxics or biologics). 
If study medications will be returned, the 
return will be arranged by the responsible 
study monitor. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local, and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. The following minimal standards must be met: 
• On-site disposal practices must not expose humans to risks from the drug 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances 
• Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s standard operating procedures and a copy provided to the sponsor 
upon request 
• Records are maintained that allow for traceability of each container, including the date 
disposed, quantity disposed, and identification of the person disposing the containers. The 
method of disposal (e.g., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor) must be documented 
• Accountability and disposal records are complete, up-to-date, and available for the study 
monitor to review throughout the clinical study period 
 
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty 
containers. 
If conditions for destruction cannot be met, the responsible study monitor will make 
arrangements for return of study medications provided by the sponsor (or its vendors). 
Destruction of nonstudy medications sourced by the site, not supplied by the sponsor, is 
solely the responsibility of the investigator or designee. 
 
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For sites that will not destroy study medication on site, it is the investigator’s or designee’s 
responsibility to arrange for disposal of all empty study medication containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local, and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. The return of full or partially used study medications supplied by the 
sponsor or its vendors will be arranged by the responsible study monitor. 
 
Clinical Study Report and Publications 
 
A signatory investigator must be selected to sign the clinical study report.  
For this protocol, the signatory investigator will be selected as appropriate based on one or 
more of the following criteria: 
• External principal investigator designated at protocol development 
• National coordinating investigator  
• Participant recruitment (e.g., among the top quartile of enrollers) 
• Involvement in study design 
• Regional representation (e.g., among top quartile of enrollers from a specified region or 
country) 
• Other criteria (as determined by the study team) 
 
The data collected during this study are confidential and proprietary to sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication 
requirements set forth in the clinical trial agreement (CTA) governing study site or 
investigator participation in the study. These requirements include, but are not limited to, 
submitting proposed publications to sponsor or designee at the earliest practicable time prior 
to submission or presentation and otherwise within the time period set forth in the CTA. 
 
Data Monitoring Committee 
 
This study will utilize a DMC for the duration of the study. Additional details can be found in 
the DMC charter and will be provided upon request. 
 
 
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Appendix 2 
Women of Childbearing Potential Definitions and 
Methods of Contraception 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBPs: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
− A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone 
(FSH) level > 40 mIU/mL to confirm menopause. 
 
Note:  Females treated with hormone replacement therapy (HRT) are likely to have 
artificially suppressed FSH levels and may require a washout period in order to obtain a 
physiologic FSH level. The duration of the washout period is a function of the type of HRT 
used. The duration of the washout periods below are suggested guidelines and the 
investigators should use their judgment in checking serum FSH levels.  
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
 
Other parenteral products may require washout periods as long as 6 months. If the serum 
FSH level is > 40 mIU/mL at any time during the washout period, the woman can be 
considered postmenopausal. 
Contraception Guidance for Female Participants of Child Bearing 
Potential 
At minimum, one of the highly effective methods of contraception listed below is required 
during study duration and until the end of relevant systemic exposure, as defined in 
Section 8.3.1. 
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Local laws and regulations may require use of alternative and/or additional contraception 
methods (e.g., one highly effective method plus another method). 
Contraceptive Methods Classified as Highly Effective 
User Dependent Methods 
Failure rate of < 1% per year when used consistently and correctly.a  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
− oral  
− intravaginal 
− transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
− oral  
− injectable  
User Independent Methods 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
• Intrauterine device (IUD)c  
• Intrauterine hormone releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.  
• 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
medication. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected.  
• WOCBPs who choose complete abstinence must continue to have pregnancy tests.  
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP chooses to forego complete abstinence. 
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NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies.  
b Hormonal contraception may be susceptible to interaction with the study medication, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, 
alternative methods of contraception should be utilized.  
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness. 
 
Contraceptive Methods Not Classified as Highly Effective 
User Dependent Methods 
Failure rate of > 1% per year when used consistently and correctly. 
• Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
Unacceptable Methods of Contraception 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus). 
• Spermicide only 
• Lactation amenorrhea method  
Methods of Contraception Not Considered Effective in Japan 
• Diaphragm with spermicide* 
• Cervical cap with spermicide* 
• Vaginal Sponge with spermicide* 
• Male condom with spermicide* or male condom without spermicide or male condom 
applied spermicide 
• Female condom with spermicide* or without spermicide* 
* These methods are not approved or certified in Japan. 
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Appendix 3 
Criteria for Diagnosis and Exclusion of Participants with 
Hepatitis B Virus (HBV) and Chronic Hepatitis C (HCV) 
Infection 
HBV Infection 
 
HBsAg  
HBsAb 
HBcAb 
HBV 
Infection 
Excluded? 
Positive 
Negative 
Positive 
Yes 
Yes 
Negative 
Negative 
Positive 
Maybe 
See (a) 
Positive 
Positive 
Negative 
Maybe 
See (b) 
Negative 
Negative 
Negative 
No 
No 
Negative 
Positive 
Negative 
No 
No 
 
(a) Perform HBV DNA: 
• 
If HBV DNA is detected, then participant must be excluded. 
• 
If HBV DNA is not detected, then the participant may be considered eligible for enrollment 
based on the investigator’s judgment and after discussion with the study medical monitor. 
 
(b) Participant must be excluded unless: 
• Participant was recently vaccinated for HBV (within 2 weeks of testing) AND repeat HBsAg 
is negative (repeat HBsAg should occur 4-6 weeks after vaccination). 
HCV Infection 
 
A participant who is HCV Ab positive must be excluded unless: 
 
• The participant has a history of HCV sustained viral response (undetectable HCV RNA) 
for at least 2 years prior to biopsy confirming study eligibility. 
 
 
 
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Appendix 4 
DSM-5 Criteria for Drug And Alcohol Abuse 
Diagnostic Criteria for Psychoactive Substance 
Dependence 
A maladaptive pattern of substance use, leading to clinically significant impairment or 
distress as manifested by 3 (or more) of the following, occurring at any time in the same 12-
month period: 
1. Tolerance, as defined by either of the following: 
a) A need for markedly increased amounts of the substance to achieve intoxication or 
desired effect, 
b) Markedly diminished effect with continued use of the same amount of the substance. 
2. Withdrawal, as manifested by either of the following: 
a) The characteristic withdrawal syndrome for the substance, 
b) The same (or closely related) substance is taken to relieve or avoid withdrawal 
symptoms. 
3. The substance is often taken in larger amounts or over a longer period than was intended. 
4. There is a persistent desire or unsuccessful efforts to cut down or control substance use. 
5. A great deal of time is spent in activities necessary to obtain the substance (e.g., visiting 
multiple doctors or driving long distances), use the substance (e.g., chain-smoking) or 
recover from its effects. 
6. Important social, occupational or recreational activities are given up or reduced 
because of substance use. 
7. The substance use is continued despite knowledge of having a persistent or recurring 
physical or psychological problem that is likely to have been caused or exacerbated by 
the substance (e.g., current cocaine use despite recognition of cocaine-induced 
depression, or continued drinking despite recognition that an ulcer was made worse by 
alcohol consumption.) 
 
Criteria for Severity of Psychoactive Substance Dependence: 
Mild: Few, if any, symptoms in excess of those required to make the diagnosis, and the 
symptoms result in no more than mild impairment in occupational functioning or in usual 
social activities or relationships with others. 
Moderate: Symptoms or functional impairment between “mild” and “severe”. 
Severe: Many symptoms in excess of those required to make the diagnosis, and the symptoms 
markedly interfere with occupational functioning or with usual social activities or 
relationships with others. 
In Partial Remission: During the past 6 months, some use of the substance and some symptoms 
of dependence. 
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In Full Remission: During the past 6 months, either no use of the substance, or use of the 
substance and no symptoms of dependence. 
Diagnostic Criteria for Psychoactive Substance Abuse 
A. A maladaptive pattern of psychoactive substance use, leading to clinically significant 
impairment or distress as manifested by one (or more) of the following, occurring at any 
time in the same 12-month period: 
1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, 
school, or home (e.g., repeated absences or poor work performance related to 
substance use; substance-related absences, suspensions, or expulsions from school, 
neglect of children or household). 
2. Recurrent substance use in situations in which it is physically hazardous (e.g., 
driving an automobile or operating a machine when impaired by substance use). 
3. Recurrent substance-related legal problems (e.g., arrests for substance-related 
disorderly conduct). 
4. Continued substance use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of the substance (e.g., arguments with 
spouse about consequences of intoxication, physical fights). 
B. The symptoms have never met the criteria for substance dependence for this class of 
substance. 
 
 
 
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Appendix 5 
Child-Pugh Turcotte Scoring 
Parameter 
Classification 
Score 
Bilirubin (Total) 
< 2 mg/dL (< 34.2 µmol/L) 
+1 
2-3 mg/dL (34.2-51.3 µmol/L) 
+2 
> 3 mg/dL (> 51.3 µmol/L) 
+3 
Albumin 
> 3.5 g/dL (> 35 g/L) 
+1 
2.8-3.5 g/dL (28-35 g/L) 
+2 
< 2.8 g/dL (< 28 g/L) 
+3 
International Normalized Ratio 
< 1.7 
+1 
1.7-2.2 
+2 
> 2.2 
+3 
Ascites 
Absent 
+1 
Slight 
+2 
Moderate 
+3 
Encephalopathy 
No encephalopathy 
+1 
Grade 1-2 
+2 
Grade 3-4 
+3 
 
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Appendix 6 
SF-36 (Version 2) Questionnaire 
 
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Appendix 7 
EQ-5D-3L Questionnaire 
 
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Appendix 8 
CLDQ-NAFLD 
 
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Appendix 9 
Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-Up 
and Reporting 
Adverse Events 
Adverse Event Definition: 
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a clinical investigation participant after initiation of study medication 
(BMS-986036 or placebo) and that does not necessarily have a causal relationship with this 
treatment.  
An AE can therefore be any unfavorable and unintended sign (such as an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of study 
medication, whether or not considered related to the study medication. 
 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
NOTE:  
The following hospitalizations are not considered SAEs in sponsor clinical studies:  
• A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
• Elective surgery, planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for Baseline/trending of health status 
(e.g., routine colonoscopy) 
• Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason) 
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Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the participant or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above); examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.  
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs. 
Potential DILI is defined as: 
• ALT or AST > 3× ULN 
 
AND 
• Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
 
AND 
• No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic 
 
Suspected transmission of an infectious agent via the study medication is an SAE.  
Although pregnancy, overdose, cancer, and potential DILI are not always serious by 
regulatory definition, these events must be handled as SAEs. 
Evaluating AEs and SAEs 
Assessment of Intensity 
The intensity of AEs is determined by a physician and will use the following level: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities 
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• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an even; and both AEs and SAEs can be assessed as severe. 
Assessment of Causality 
The causal relationship to study medication is determined by a physician and should be 
used to assess all AEs. The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study medication administration 
and the AE. 
Not related: There is not a reasonable causal relationship between study medication 
administration and the AE.  
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.  
Follow-Up of AEs and SAEs 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study medication or if new 
information becomes available, the SAE report must be updated and submitted within 
24 hours to the sponsor (or designee) using the same procedure used for transmitting the 
initial SAE report. 
All SAEs must be followed to resolution or stabilization. 
 
Reporting of SAEs to Sponsor or Designee 
SAEs, whether related or not related to study medication, and pregnancies must be 
reported to 
 Drug Safety within 24 hours of awareness of the event. 
SAEs must be recorded on the SAE Report Form. For studies capturing SAEs through 
EDC, electronic submission is the required method for reporting. In the event the 
electronic system is unavailable for transmission, paper forms must be used and submitted 
immediately. When paper forms are used, the original paper forms are to remain on site. 
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission to: 
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SAE Email Address: 
 
SAE Fax Number:  
 
Americas: 
 
 
 
Europe/East Asia-Pacific: 
  
SAE Telephone Contact - For questions on SAE/pregnancy reporting, please call:  
 
Americas: 
 
 
Europe/East Asia-Pacific: 
 
 
 
 
 
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Appendix 10 
Formulae for Measurements 
• MELD Score = (9.57*ln[creatinine]) + (3.78 * ln[Bilirubin]) + (11.20* ln[INR]) + 6.43 
• ELF assay combines hyaluronic acid, procollagen 3 amino terminal peptide, and tissue 
inhibitor of metalloproteinase 1. An algorithm is used to evaluate each of these markers 
by immunoassay, to create an ELF Score. 
• FIB4 score = (age [years] × AST level [U/L])/(platelet count [x109/L] × square root of 
ALT [U/L]) 
• APRI score = ([AST divided by AST Upper Limit of Normal]/platelet count [x109/L]) × 
100 
• NAFLD Fibrosis Score = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × 
fasting glucose/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio – 0.013 × platelet 
count – 0.66 × albumin (g/dL) 
Method of BMI Calculation: 
 
• Use actual height and weight collected on the same day. Whenever possible, body weight 
should be measured using the same scale throughout the study. 
• To calculate BMI: 
o Convert weight pounds to kg (kg = pounds/2.2) 
o Convert height inches to centimeters (cm = inches × 2.54) 
o BMI = (weight in kg)/(height in cm/100)2 
o Round to 1 decimal place (if 0.05 or greater, round up) 
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Appendix 11 
Decision Tree for Long-Term Immunogenicity Follow-
Up Visits After the Week 52/PTFU Visit 
Participants who discontinue study medication prior to Week 48 are expected to complete an 
ET Visit and to remain in the study and continue to have immunogenicity monitored 
according to the Schedule of Events in Section 1. 
 
Participants who discontinue study participation will be offered immunogenicity follow-up 
visits, as per the diagram. All participants will have immunogenicity samples collected at 6 
months after the Week 52/PTFU Visit. Additional immunogenicity follow-up visits may 
occur approximately 9, 12, and 14 months, if applicable, (visit window ± 14 days) (1 month 
is defined as 4 calendar weeks) after the last completed study visit. 
 
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FU = Follow-Up; IMG = Immunogenicity (anti-drug and anti-FGF21 antibodies); Mo = month (defined as 4 calendar weeks) 
a All participants will have samples collected for immunogenicity at 6 months (± 14 days) after the Week 52/PTFU Visit. Samples collected from 
participants may not be analyzed if: 1) participant is not on active drug, 2) participant is negative for anti-drug and/or anti-FGF21 antibody titers at the 
Week 52/PTFU Visit, or 3) participant has evidence of stable or decreasing antibody titers for 2 visits prior to the 6-month posttreatment visit 
b Additional assessments include: basic metabolic panel, hemoglobin A1c 
 
Post-Treatment 
FU Visit
6 Mo IMG FU 
Visit
All subjects will
have samples 
collected at this 
visita
IMG testing 6 
months after 
Post-Treatment 
FU Visit
Negative, or 
titers have 
decreased or 
stabilized for the 
last 2 
consecutive 
visits
No further IMG 
testing
Positive, but 
titers have not 
decreased or 
stabilized for 
the last 2 
consecutive 
visits
9 Mo IMG FU 
Visit
IMG testing 9 
months after 
Post-Treatment 
FU Visit
Negative, or titers 
have decreased or 
stabilized for the 
last 2 consecutive 
visits
No further IMG testing
Positive, but titers 
have not 
decreased or 
stabilized for the 
last 2 consecutive 
visits
12 Mo IMG FU 
Visit
IMG testing 12 
months after 
Post-Treatment 
FU Visit
Negative, or titers have 
decreased or stabilized for 
the last 2 consecutive visits
No further IMG 
testing
Positive, with increasing 
titers
14 Mo IMG FU 
Visit
IMG testing and 
additional 
laboratory 
assessmentsb
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