Conditions: Non-Alcoholic Steatohepatitis
Keywords: First Line Therapy NASH
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 184
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether BMS-986036 is effective in the treatment of subjects with Non-alcoholic Steatohepatitis (NASH).

Detailed description:

Arms:
arm 1: Administered as specified on specified days arm 2: Administered as specified on specified days arm 3: Administered as specified on specified days

Interventions: intervention 1: BMS-986036 intervention 2: BMS-986036 intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
MB130045
IND Number:
125,297
EUDRACT Number
N/A
Date:
03-Feb-2015
Revised Date:
03-Jun-2016
Clinical Protocol MB130045
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multiple Dose Study to 
Evaluate the Safety, Pharmacokinetics and Pharmacodynamic Effects of BMS-986036 in Adults 
with Non-alcoholic Steatohepatitis
Revised Protocol: 03
Incorporates Amendments 01, 02 & 04 and Administrative Letter 01
Study Director
Medical Monitor
Edgar Charles, MD
 
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). 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 BMS-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 BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS 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 BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Revised Protocol No: 03
Date: 03-Jun-2016
2
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Revised Protocol No: 03
Date: 03-Jun-2016
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Amendment 04
03-Jun-2016
Adjusts the number of subjects needed to support the interim analysis 
and clarifies the unblinded BMS personnel.
Revised
Protocol 03
03-Jun-2016
Incorporates Amendment 04
Amendment 02
29-Oct-2015
Amendment Rationale:
(i)
Addition of immunogenicity testing and endogenous FGF21 
assessments at the Day 292 follow up visit
 
 
.
(ii) Extension of follow-up immunogenicity testing and endogenous 
FGF21 assessments (for subjects with positive immunogenicity testing) 
to up to 12 months post-Day 142 . This provides a longer follow-up (12 
months instead of 6 
. 
(iii) Changes to protocol inclusion criteria and concomitant medication 
allowance as follows: 

Adjustment of BMI inclusion criterion from > 30 to > 25 kg/m2

Removal of Fatty Liver Index inclusion criterion

Adjustment of restriction of Vitamin E from > 60 IU/day to 
> 120 IU/day
 
 
 
(iv) Clarification of imaging procedure schedule and assessments 
throughout the protocol to support internal consistency
(v) General clarifications related to pregnancy testing and follow-up 
schedule assessments to better support internal consistency 
(vi) Correction of  typographical errors
(vii) Update of Medical monitor assignment on title page consistent with 
administrative letter 01
Revised
Protocol 02
29-Oct-2015
Incorporates Amendment 02 items
Administrative 
letter 01
28-Jul-2015
Updated medical monitor assignment
Revised 
Protocol 01
27-May-2015
Incorporates Amendment 01 items.
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Revised Protocol No: 03
Date: 03-Jun-2016
4
Document
Date of Issue
Summary of Change
Amendment 01
27-May-2015
(i) Addition of a Data Monitoring Committee by independent reviewers 
to support safety data review for all treated subjects (ii) Revision for 
discontinuation criteria (iii) Addition of  a reference for the Common 
Terminology Criteria for Adverse Events (CTCAE) grading (iv) 
Addition of an immunogenicity sample collection at Day 15 (v)
 
 
The interim analysis is corrected to 
reflect ‘summaries’, instead of ‘summaries and graphs’. (viii) 
(ix) Correction of  
typographical errors
Original 
Protocol
03-Feb-2015
Not applicable
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
SYNOPSIS
Clinical Protocol MB130045
PEG-FGF21
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multiple Dose Study to 
Evaluate the Safety, Pharmacokinetics and Pharmacodynamic Effects of BMS-986036 in Adults with Non-alcoholic 
Steatohepatitis
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Each eligible subject will be randomized to self administer BMS-986036 by subcutaneous injection at 
a dose of 10 mg daily, or 20 mg weekly or a daily placebo injection, for 16 weeks.
Study Phase:  2A
Research Hypothesis: BMS-986036 administered daily or weekly for 16 weeks to adults with Non-alcoholic 
Steatohepatitis (NASH) will lower the percent of hepatic fat content to a greater extent than placebo.
Objectives: 
Primary Objectives
To assess the effect of 16 weeks of daily or weekly doses of BMS-986036 on safety, tolerability and change in 
hepatic fat fraction (%) by MRI in patients with NASH.
Secondary Objectives
To assess the pharmacokinetics and immunogenicity of BMS-986036 in patients with NASH. 
 
 
 
Revised Protocol No: 03
Date: 03-Jun-2016
5
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Study Design:  
Study Design Schematic
Visit Days
D -42a
D -7
D 1
D 15
D 29
D 43
D 57
D 86b
D 112c
D 142
D 292d
Screening
5 weeks
Lead-in
1 week
On treatment
4 months
Follow-up
Placebo
Treatment A: 10 mg daily
Treatment B: 20 mg weekly
Treatment C: Placebo daily
a MRI, MRE, and DXA baseline scans should be performed approximately 21 days prior to the Day 1 dose.
Eligibility should be confirmed by central imaging lab prior to entry into the lead-in period (Day -7).
b The Day 86 visit is scheduled 4 weeks (+1 Day) after the Day 57 visit, to tie in with a PK assessment.
c MRI, MRE and DXA end of treatment scans are conducted at Day 112 (+/- 1 week).
d DXA follow-up scan and immunogenicity sample collection are conducted 6 months (+/- 2 weeks) after the last 
dose.
D = Day
Study Population: Approximately 90 male and female subjects aged  21 to 75 years with a BMI of  ≥ 25 inclusive
with a liver biopsy performed within 1 year of Screening (or between Screening and Lead-in) with documented 
results of NASH with NASH CRN fibrosis stage 1-3  and a hepatic fat fraction (%) ≥ 10% by MRI.
Women of childbearing potential (WOCBP) must not be nursing or pregnant and must be using an acceptable 
method of contraception for at least 4 weeks before dosing. 
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for MB130045
Medication 
Potency 
IP/Non-IP 
Placebo for BMS-986036-01 
Injection
N/A
IP (8 vials/Kit)
BMS-986036-01 Injection, 
10mg/vial
10 mg/mL
IP (8 vials/Kit)
Study Assessments: 

Safety Outcome Measures:  Safety assessments will be based on medical review of adverse event reports 
and the results of vital sign measurements, ECGs, physical examinations, and clinical laboratory tests. The 
incidence of observed adverse events will be tabulated and reviewed for potential significance and clinical 
importance.

Pharmacokinetic Measures: serum concentration of BMS-986036 (Total and C-terminal intact). 
Revised Protocol No: 03
Date: 03-Jun-2016
6
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21

 
 
 
Statistical Considerations:
Sample Size:
The primary objective is to compare the change in hepatic fat fraction (%) from baseline to week 16 between each of 
2 doses of BMS-986036 treatment group and placebo treatment group. With 27 subjects per treatment group with 
post-baseline measurements, there will be 82% power to detect a difference of 5% in mean change from baseline at 
Week 16 in hepatic fat fraction (%) between each of 2 doses of BMS-986036 treatment groups (10 mg daily and 20 
mg weekly) and placebo at a significance level of 0.05 (one-sided). These calculations are based on an assumption 
that the hepatic fat fraction (%) change from baseline is normally distributed with a standard deviation of no greater 
than 7%, as estimated from data in a similar population. No adjustment will be made for multiplicity. 
To allow for dropouts, approximately 30 subjects per treatment group (total of 90 subjects) will need to be 
randomized, assuming up to 10% of the subjects do not complete post-baseline assessments.
Endpoints:
Baseline is defined as the last non-missing pre-dose measurement for all the endpoints.
Primary Endpoints: 

Change in hepatic fat fraction (%) from baseline to Week 16.

Safety endpoints include incidence of AEs, serious AEs, and events of special interest including injection 
site assessment, AEs leading to discontinuation, and death as well as marked abnormalities in clinical 
laboratory tests, vital sign measurements, ECGs, physical examinations and bone mineral density (BMD) 
collected by DXA scan at specified time points.
Secondary Endpoints:

Pharmacokinetic endpoint: Assess the pharmacokinetics of C-terminal and total BMS-986036 in NASH 
subjects to be assessed by the following endpoint: Ctrough

Immunogenicity endpoints: anti- BMS-986036 antibodies and anti-FGF21 antibodies
Revised Protocol No: 03
Date: 03-Jun-2016
7
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Analyses:  
Primary Analysis:
To evaluate the effect of BMS-986036 on change in hepatic fat fraction (%) by MRI in subjects with biopsy proven 
NASH after 16 weeks of treatment, a longitudinal repeated measures analysis will be used to analyze the change in 
hepatic fat fraction (%) at Week 16 from baseline in the treated population who have both a baseline and at least one 
post-baseline measurement. The model will include treatment group, week and treatment-by-week interactions as 
main effects and baseline hepatic fat fraction (%) and baseline diabetic status as covariates. An unstructured 
covariance matrix will be used to represent the correlation of the repeated measures within each subject.  The model 
will provide point estimates, standard errors and 2-sided 90% confidence intervals for mean change from baseline 
within and between treatments. P-values will be calculated to compare the treatment effect in each of two 
BMS-986036 (10 mg daily and 20 mg weekly) treatment groups to that in the placebo treatment group at Week 16. 
Each treatment group comparison will be performed at a one-sided 0.05 significance level. No adjustment will be 
made for multiplicity.
Summary statistics will be tabulated by treatment, study day for hepatic fat fraction (%) with corresponding change 
from baseline. Plot of mean profile over time will also be provided for hepatic fat fraction (%) by treatment.
Safety Analysis:
All recorded adverse events will be listed and tabulated by system organ class, preferred term and treatment group. 
Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any significant physical 
examination findings and clinical laboratory results will be listed. ECG readings will be evaluated by the 
Investigator and abnormalities, if present, will be listed.  BMD results will be tabulated.
Pharmacokinetic analyses:
Summary statistics will be tabulated for observed BMS-986036 serum concentrations (Total and C-Terminal intact). 
Immunogenicity analyses:
Responses of anti-BMS-986036 antibodies and anti-FGF21 antibodies will be listed and tabulated by treatment and 
study day. The relationship between immunogenicity and PK and/or PD may be explored.
 
 
 
 
Interim Analyses:
Because data emerging from this study may be needed for timely decision about adjustment to the development of 
the program, an interim analysis will be conducted after approximately 60 subjects have completed 8 weeks of 
treatment. Analyses will consist of summaries of the available data without revealing individual subjects' treatment 
assignments. The results of the interim analysis will be reviewed by a pre-specified panel of personnel.
Revised Protocol No: 03
Date: 03-Jun-2016
8
4.0
Approved
930087483
4.0
v


TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
 
 
 
 
 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
1.5.1 Risk Mitigation Strategy .......................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 Imaging Contraindications (MRI, MRE and DXA) ................................. 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Follow up ............................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
1
3
5
9
12
13
18
18
18
18
22
22
24
24
24
24
26
26
27
27
27
28
31
31
31
32
32
33
34
34
34
35
38
38
38
38
39
Clinical Protocol
BMS-986036
MB130045
peg-fgf21
Revised Protocol No: 03
Date: 03-Jun-2016
9
4.0
Approved
930087483
4.0
v


4.6 Blinding/Unblinding ......................................................................................... 
4.6.1 Interim Analysis Unblinding .................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Safety Imaging Assessment for the Study ................................................. 
5.3.1.1 DXA ................................................................................................. 
5.3.2 Laboratory Test Assessments ................................................................... 
5.3.3 Monitoring of Injection site reactions...................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Efficacy Imaging Assessment for the Study ............................................. 
5.4.1.1 MRI ................................................................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetics and Pharmacodynamics: Collection and Processing  
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
5.5.3 Labeling and Shipping of Biological Samples ......................................... 
 
 
 
 
 
5.7 Immunogenicity ................................................................................................ 
5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other Assessments ............................................................................................ 
5.9.1 Height and Body Mass Index (BMI) ........................................................ 
 
5.9.3 Other Supplemental (Unscheduled Visits) ............................................... 
5.10 Results of Central Assessments ...................................................................... 
5.11 Sampling for Additional Research .................................................................. 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
39
40
40
41
41
41
41
48
48
48
48
49
49
50
51
51
51
52
52
56
56
57
58
58
58
59
59
59
59
60
61
62
62
62
62
63
63
63
64
Clinical Protocol
BMS-986036
MB130045
peg-fgf21
Revised Protocol No: 03
Date: 03-Jun-2016
10
4.0
Approved
930087483
4.0
v


8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.6 Immunogenicity Analyses ......................................................................... 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.8 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 DIAGNOSTIC CRITERIA FOR DRUG AND ALCOHOL ABUSE .. 
64
64
65
65
65
65
66
66
66
66
67
67
67
67
67
67
67
67
68
68
69
69
69
69
70
70
72
73
84
Clinical Protocol
BMS-986036
MB130045
peg-fgf21
Revised Protocol No: 03
Date: 03-Jun-2016
11
4.0
Approved
930087483
4.0
v














Clinical Protocol
MB130045
BMS-986036
peg-fgf21
 
 
 
 
 
 
 
  
1.2
Research Hypothesis 
BMS-986036 administered daily or weekly for 16 weeks to obese adults with NASH will lower 
hepatic fat fraction (%) assessed by MRI to a greater extent than placebo.
1.3
Objectives(s)
1.3.1
Primary Objectives
To assess the effect of 16 weeks of daily or weekly doses of BMS-986036 on safety, tolerability 
and change in hepatic fat fraction (%) by MRI in patients with NASH. 
1.3.2
Secondary Objectives
To assess the pharmacokinetics and immunogenicity of BMS-986036 in patients with NASH.
 
 
Revised Protocol No: 03
Date: 03-Jun-2016
18
4.0
Approved
930087483
4.0
v








Clinical Protocol
MB130045
BMS-986036
peg-fgf21
 
 
 
 
 
 
1.5
Overall Risk/Benefit Assessment
This is the first study in which BMS-986036 will be administered to patients with NASH; two 
previous studies have been conducted or are ongoing including the completed first-in-human 
study in obese, but otherwise healthy volunteers and an ongoing study in obese diabetic subjects.
The preclinical data in diabetic NASH animal models, and clinical data in non-diabetic and 
diabetic subjects, demonstrate beneficial metabolic effects with short term administration of 
BMS-986036 (up to 12 weeks). These benefits included weight loss, reduction of hepatic fat and 
improved insulin sensitivity; however, it is not known whether study subjects with obesity and 
NASH in this proof of concept study will benefit in these or other ways from BMS-986036.  In 
addition, immunogenicity, bone effects and injection site reactions will be explored as potential 
risks of BMS-986036. Data from this phase 2a study will be used to guide future clinical 
development of BMS-986036.
1.5.1
Risk Mitigation Strategy
Immunogenicity
BMS-986036 is a PEGylated recombinant variant 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 ADA 
response in animals but the presence of ADA in these species does not necessarily predict 
immunogenicity in humans.34  Following daily dosing, BMS-986036 ADA were detected in rats 
and monkeys in 1-month (up to 59% and 20%, respectively) and 4-month (up to 87% and 30%, 
respectively) toxicology studies at all doses tested. However, the presence of ADAs in these 
species had no substantial or meaningful impact on the overall toxicokinetic results of total and 
C-terminal intact BMS-986036, pharmacodynamic, toxicology, clinical pathology or 
histopathology endpoints on these studies. 
In the first in human study, three of 72 subjects (4%) dosed with BMS-986036 had positive 
results in the ADA and anti-FGF21 antibody assays at the end of study time point.  Additional 
post-study follow-up immunogenicity testing for these three subjects showed progressively 
decreasing assay titers at subsequent visits over a six month time period.  One of these three 
Revised Protocol No: 03
Date: 03-Jun-2016
22
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
subjects tested neutralizing in the neutralizing antibody assay at two out of three follow up visits. 
At the end of this follow up period, all 3 subjects were reported in good health with no adverse 
events reported.  
There is a theoretical risk of neutralizing antibody formation to BMS-986036 that could cross 
react with endogenous FGF21. FGF21 knockout mice are known to be viable, are able to 
reproduce and have a generally normal phenotype.35  The clinical consequences of a neutralizing 
anti-drug antibody (ADA) response to endogenous FGF21 are unknown, as FGF21 deficiency 
has not been reported in humans. Subject safety will be closely guarded in early clinical studies. 
All subjects administered BMS-986036 will be closely monitored for possible immunogenicity 
related adverse events (AEs), such as rash, fever and severe injection site reactions. Clinically 
relevant immune reactions (e.g. hypersensitivity reactions) considered related to BMS-986036 
will be reported as AEs and treated according to current standard of care medical practice. 
All subjects will be monitored for occurrence of ADA and anti-FGF21 antibodies during dosing, 
at approximately 4 weeks following the last dose (D142 follow-up visit), and at approximately 6 
months following the last dose (D292 follow-up visit). If present, antibodies will be assessed for 
neutralizing activity. Subjects with a positive result in the ADA and/or anti-FGF21 antibody
assays at the Day 142 or Day 292 follow-up visits, without evidence of decreasing or stable 
antibodies, will be followed afterwards with immunogenicity assessments for up to 12 months
after the D142 visit until antibody levels resolve or demonstrate a consistent decreasing trend. 
These immunogenicity follow-up visits will be conducted approximately every 6-8 weeks.
In addition, endogenous FGF21 will be measured at all follow up visits, including the D142 and 
D292 follow up visits and the immunogenicity follow up visits (for subjects with positive ADA
and/or anti-FGF21 antibodies at D142 and/or D292, without evidence of decreasing or stable 
antibodies).
Bone effects
No bone resorption marker change has been observed in subjects in the first in human study 
(MB130001). Bone formation markers were slightly reduced in all subjects in the MAD, 
including those treated with placebo, and only in subjects treated with the highest daily dose 
(30 mg daily) were bone markers reduced to an extent greater than placebo.  A 
BMS-986036-related bone risk to adult humans is considered low; unlike thiazolidinediones
(TZDs), bone resorption markers were not increased. To minimize the potential risk to subjects 
in whom a reduction of bone formation markers could impact skeletal healing, those with recent 
fracture or orthopedic surgery will be excluded.
To assess whether chronic dosing of BMS-986036 has the potential to modulate bone turnover 
and vitamin D and mineral metabolism, bone turnover markers (BSAP, P1NP and CTX-1), PTH 
and 1,25 dihydroxy vitamin D along with calcium, magnesium, phosphorus are being assessed in 
the ongoing MB130002 study in T2DM subjects. . 
Revised Protocol No: 03
Date: 03-Jun-2016
23
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
In this study, we will continue to monitor bone turnover markers, calcium, magnesium and 
phosphorus before and after the dosing period. Samples for PTH and 1,25 dihydroxy vitamin D
will be collected, and may be assayed if a perturbation is observed in the MB130002 study.
Additionally, bone mineral density (BMD) will be measured by DXA at baseline, end of 
treatment and six months following end of dosing to determine whether daily or weekly 
administration of BMS-986036 for up to 16 weeks has any acute or sustained effect on BMD.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS 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 
subjects 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). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
Revised Protocol No: 03
Date: 03-Jun-2016
24
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
In situations where consent cannot be given to subjects, 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 subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form(s) which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form(s) and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. The 
language must be non-technical and easily understood. 

Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.

Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form(s) and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.

If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.

Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form(s) must also include a statement that BMS and regulatory authorities have 
direct access to subject records.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
Revised Protocol No: 03
Date: 03-Jun-2016
25
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
Study MB130045 is a randomized, double-blind, placebo-controlled, parallel-group, multiple 
dose design. Subjects will undergo screening evaluations to determine eligibility within 42 days 
prior to randomization.  There will be a 7-day study skills training (Lead-In) period prior to 
randomization on Day 1. Eligible subjects will be randomized via IVRS on Day 1 to 1 of 3
parallel treatment groups. In total, approximately 90 randomized subjects (30 per group; ratio 
1:1:1) will self-administer double-blind treatment, once daily for 16 weeks, in an outpatient 
setting. Subjects will be stratified using a diagnosis of Type 2 diabetes mellitus (yes vs no) based 
on current American Diabetes Association (ADA) criteria. Clinic visits are scheduled 
approximately every 2 weeks initially, and then monthly, to collect safety, PK and PD measures. 
The study design schematic is presented in Table 3.1-1.
Table 3.1-1:
Study Design Schematic
Visit Days
D -42a
D -7
D 1
D 15
D 29
D 43
D 57
D 86b
D 112c
D 142
D 292d
Screening
5 weeks
Lead-in
1 week
On treatment
4 months
Follow-up
Placebo
Treatment A: 10 mg QD (daily)
Treatment B: 20 mg QW (weekly)
Treatment C: Placebo QD 
aMRI, MRE, and DXA baseline scans should be performed approximately 21 days prior to the Day 1 dose.
Eligibility should be confirmed by central imaging lab prior to entry into the lead-in period (Day -7).  
b The Day 86 visit is scheduled 4 weeks (+1 Day) after the Day 57 visit, to tie in with a PK assessment.
c MRI, MRE and DXA end of treatment scans are conducted at Day 112 (+/- 1 week).
d DXA follow-up scan and immunogenicity sample collection are conducted 6 months (+/- 2 weeks) after the last 
dose.
D = Day
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), clinical 
laboratory evaluations, MRI, MRE and DXA scans will be performed at selected times 
throughout the study. Subjects will be closely monitored for adverse events throughout the study. 
Blood will be collected for pharmacokinetic (PK) and pharmacodynamic (PD) analysis. 
Approximately 500 mL of blood will be drawn from each subject during the study.
For each subject, the total scheduled study duration from Screening to last Follow-up visit is 
approximately 12 months, comprised of screening (Day -42 to Day -8), placebo lead-in (Day -7 
to Day -1), on-treatment (Day 1 to Day 112) and a wash-out follow-up (Day 113 to Day 142) 
period, plus a scheduled follow-up visit that will be performed approximately 6 months (Day 
Revised Protocol No: 03
Date: 03-Jun-2016
26
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
292) after the last dose to perform DXA scanning and an additional immunogenicity
measurement. Of note, subjects with a positive result in the ADA and/or anti-FGF21 antibody 
assays at the Day 142 and/or Day 292 follow-up visits, and who do not have evidence of 
decreasing or stable antibodies, will be followed for up to 12 months after the D142 visit until 
antibody levels resolve or demonstrate a consistent decreasing trend (these immunogenicity 
follow-up visits will be conducted approximately every 6-8 weeks).
The end of the study is defined as the date of the last scheduled follow-up visit or 
immunogenicity follow-up visit, whichever is later, of the last subject in the study.
3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to supply study drug to subjects/investigators 
unless BMS chooses to extend the study. The investigator should ensure that the subject receives 
appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met at Screening. No exceptions will be 
granted.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a.
Signed informed consent form.
2. Target Population
a.
Liver biopsy performed within 1 year of Screening or may be performed between 
Screening and Lead-in (Day -7) with documented results of NASH with NASH CRN
fibrosis stage 1-3, or equivalent using a different scoring system.
b. Body mass index (BMI) of ≥ 25. Note: BMI = weight (kg)/[height (m)] 2
c.
Hepatic fat fraction (%) ≥ 10% by MRI performed during the Screening period.
d. Subject is able to medically tolerate the performance of the MRI or DXA scans and has
suitable weight and circumference. See Section 3.4.3 for further details.
e.
Subject agrees not to initiate a weight loss program and agrees to maintain consistent 
dietary habits and exercise regimen for the duration of the study.
f.
Subject re-enrollment: 
This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (i.e., subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-consented and will receive a 
new subject number.
3. Age and Reproductive Status
a.
Males and females, ages 21 to 75 years, inclusive
b. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24
hours prior to the start of study drug.
c.
Women must not be breastfeeding.
Revised Protocol No: 03
Date: 03-Jun-2016
27
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
d. WOCBP must agree to follow instructions for method(s) of contraception for at least 4 
weeks before dosing, for the duration of treatment with study drug (s) 16 weeks plus 5 
half-lives of study drug (30 days) plus 30 days (duration of ovulatory cycle) for a total of 
2 months post-treatment completion.
e.
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (16 weeks) plus 
5 half-lives of the study drug (30 days) plus 90 days (duration of sperm turnover) for a 
total of 4 months post-treatment completion.
f.
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements.  However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of one highly effective method of contraception.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. 

Nonhormonal IUDs, such as ParaGard

Tubal ligation 

Vasectomy

Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
3.3.2
Exclusion Criteria
1. Medical History and Concurrent Diseases
a.
Evidence of a medical condition contributing to chronic liver disease other than NASH 
(such as, but not limited to, hemochromatosis, autoimmune hepatitis, Wilson disease, 
alpha-1 antitrypsin deficiency, drug or alcohol-induced liver disease, toxin exposures, 
viral hepatitis).
b. Evidence of cirrhosis.
c.
Decompensated liver disease including, but not limited to, a history or presence of 
bleeding varices, ascites, or hepatic encephalopathy.
Revised Protocol No: 03
Date: 03-Jun-2016
28
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
d. Uncontrolled diabetes defined as HbA1c of 9.5% or higher within 8 weeks prior to 
screening, or symptoms of poorly controlled diabetes, such as marked polyuria and 
polydipsia with greater than 10% weight loss, within 12 weeks of screening.
e.
Subjects who have experienced 5% or more weight loss due to participation in a weight 
loss program or use of weight loss medication within 8 weeks of screening.
f.
Any bone trauma, fracture or bone surgery (i.e., hardware placement, joint replacement, 
bone grafting or amputation) within 8 weeks of screening.  
g. Known immunocompromised status, including but not limited to, individuals who have 
undergone organ transplantation or who are positive for the human immunodeficiency 
virus.
h. Subjects receiving regular oral or injectable glucocorticoid medication. Inhaled, nasal or 
topical steroids used at the registered dose strengths are permitted. 
i.
Any bariatric surgery or biliary diversion (e.g. gastric bypass, gastric banding, Roux-en-
Y, etc.).
j.
Subjects with a history of cancer within the last 5 years (other than treated basal or 
squamous cell carcinoma) are excluded.
k. Any major surgery within 6 weeks of screening.
l.
Donation of blood to a blood bank or in a clinical study (except a screening visit) within 
6 weeks of screening (within 4 weeks for plasma only).
m. Blood transfusion within 6 weeks of screening.
n. Any significant acute or chronic medical illness, other than the underlying condition 
being studied, including, but not limited to coronary artery disease, congestive heart 
failure, cerebrovascular disease, renal failure, serious psychiatric disease.  
o. Recent (within 1 year of study drug administration) drug or alcohol abuse as defined in 
DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 1) or significant
alcohol consumption (average > 20 g/ day females or  > 30 g/day males).
p. Inability to self-administer subcutaneous injections.
q. Inability to be venipunctured and/or tolerate venous access.
r.
Inability to comply with all protocol assessments including the follow-up visits.
s.
Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
2. Physical and Laboratory Test Findings
a.
Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG or clinical laboratory determinations beyond what 
is consistent with the target population.
b. ALT level ≥ 5xULN
c.
Albumin <3.5 g/dL (35 g/L)
d. INR (International Normalized Ratio) >1.3
e.
Total bilirubin ≥1.5 mg/dL (≥25.6 µmol/L) 
f.
Platelet count <100 x 109/L
g. Alpha fetoprotein (AFP):
Revised Protocol No: 03
Date: 03-Jun-2016
29
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21

AFP > 100 ng/mL (> 82.6 IU/mL), OR

AFP ≥ 50 and ≤ 100 ng/mL (≥ 41.3 IU/mL and ≤ 82.6 IU/mL) requires a liver 
ultrasound. Subjects with findings suspicious for HCC are excluded.
h. HbA1c ≥9.5%
i.
Positive blood screen for hepatitis C antibody, hepatitis B surface antigen (via Screening 
lab).  
j.
Subjects with a centrally read Screening DXA T-score at the total spine, total hip or 
femoral neck, less than or equal to -2.5 S.D. (a worse score would be -3.0 S.D., for 
example).
k. Uncontrolled hypertension (systolic blood pressure [SBP] >= 160, and/or diastolic blood 
pressure [DBP] >= 95 mmHg). Anti-hypertensive medications are permitted if the dose 
has been stable for >2 weeks before Screening.
l.
QTcF > 480 msec on 12-lead electrocardiogram (ECG) during the Screening period, 
confirmed by repeat.
m. Impaired renal function defined as an estimated glomerular filtration rate (GFR) of 
<49 mL/min/1.73m2 using Modification of Diet in Renal Disease (MDRD) equation.  A 
repeat measurement of screening serum creatinine is permitted when the investigator 
suspects that initial screening results may have been affected by volume contraction (e.g., 
prolonged fasting, diuretic use) or other transient conditions. Note: GFR (mL/min/1.73 
m2) = 175 × (Serum creatinine)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American).
3. Allergies and Adverse Drug Reaction
a.
History of allergy to PEGylated compounds or FGF21-related compounds. 
b. History of hypersensitivity to protein-based therapeutics.
c.
History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
4. Other Exclusion Criteria
a.
Prisoners or subjects who are involuntarily incarcerated.
b. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness.
c.
Inability to comply with restrictions and prohibited activities/treatments as listed in 
Section 3.4.
d. Subjects in whom MRI, MRE and DXA procedures cannot be performed.  Section 3.4.3
provides a list of some common conditions that may preclude the subject from having 
MRI, MRE and DXA.  However, this should not be used as a substitute for local clinical 
standards of care.  The ultimate decision to perform any of these procedures in an 
individual subject in this study rests with the site radiologist, the investigator and the 
standard set by the local ethics committee/institutional review board. 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
Revised Protocol No: 03
Date: 03-Jun-2016
30
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a documented serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.
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 period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is >40 mlU/ml at any time 
during the washout period, the woman can considered postmenopausal.

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.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications are described below:
1) Use of drugs (systemic administration) historically associated with NAFLD for more than 2 
weeks in the year prior to randomization and through to end of treatment (including, but not 
limited to amiodarone, selective estrogen receptor modulators [such as tamoxifen, 
raloxifene],
methotrexate, valproic acid, phenothiazines, sulfonamides, tetracycline, 
isoniazid, antithyroid drugs, phenytoin and high-dose estrogens [such as clomiphene]). 
2) Use of glucagon-like peptide-1 receptor (GLP-1) agonists (including, but not limited to 
exenatide, liraglutide, lixisenatide, albiglutide) for more than 2 weeks in the year prior to 
randomization and through to end of treatment.
3) Use of thiazolidinediones within 6 months prior to randomization and through to end of 
treatment.
4) Use of vitamin E (>120 IU/day) from screening and through to end of treatment, unless the 
subject had taken vitamin E consistently for 3 months or more prior to liver biopsy for this 
study.
5) Use of anti-obesity agents (including but not limited to orlistat) within 8 weeks prior to 
screening and through to end of treatment.
6) Use of oral, intravenous, subcutaneous or intra-articular glucocorticoids within 8 weeks of 
screening or acute, short-term glucocorticoid use more than once within one year prior to 
Screening. If systemic glucocorticoids are administered between Screening and Day 1, the 
subject may be rescreened after discontinuing glucocorticoids and stabilization of metabolic 
parameters has occurred.  
Revised Protocol No: 03
Date: 03-Jun-2016
31
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
7) Use of oral, intravenous, subcutaneous or intra-articular glucocorticoids >5 days between 
randomization through to end of treatment.
8) Initiation of anti-hyperglycemic
therapies within 8
weeks prior to screening.  
Anti-hyperglycemic therapies may be adjusted for enrolled subjects to meet treatment goals
from Screening and through to end of treatment.
9) Initiation of anti-hypertensive therapies within 8 weeks prior to screening.  Antihypertensives 
may be adjusted for enrolled subjects to meet blood pressure treatment goals from Screening 
and through to end of treatment.
10) Initiation of lipid lowering therapies within 8 weeks prior to screening. Adjustment of the 
same class of lipid lowering therapies from screening and through to end of treatment is 
allowed to meet lipid treatment goals.
11) Exposure to any investigational drug or placebo within 8 weeks of Screening. 
12) Prior exposure to BMS-986036 or other investigational drugs that contain recombinant 
versions of FGF21.
13) Prior or current exposure to prescription or investigational systemic PEGylated drug(s).
No concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during study unless they are prescribed by the investigator for treatment of specific clinical 
events. 
Medications taken within 4 weeks prior to study drug administration must be recorded on the 
CRF. Any concomitant therapies must be recorded on the CRF.
3.4.2
Other Restrictions and Precautions
All subjects will be instructed in the technique of withdrawing investigational product from a 
vial into a syringe and self-administering study drug or placebo by subcutaneous injection. All 
subjects will be instructed in the safe handling and disposal of needles and syringes.
3.4.3
Imaging Contraindications (MRI, MRE and DXA)
The imaging specialist at the study site’s imaging facility is responsible for determining if a 
subject is contraindicated from having this procedure.  The following is a list of some common 
conditions that may preclude the subject from scans. However, this 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 local Ethics Committee:
1. Subjects who have a history of claustrophobia.
2. Subjects who have a physical limitation related to fitting in the bore of the magnet or
weight greater than that allowable by the imaging instrument.
3. Subjects with a pacemaker, epicardial pacemaker wires, MRI-incompatible cardiac
valve prostheses, and MRI-incompatible vascular clips less than two-months old, or
MRI-incompatible aneurysm clips of any age.
4. Subjects with MRI-incompatible cochlear implants.
5. Subjects with spinal nerve stimulators.
6. Subjects with an infusion pump.
7. Subjects with known metallic fragments in the body.
Revised Protocol No: 03
Date: 03-Jun-2016
32
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
8. Subjects with an employment history, which involves exposure to welding.
9. Subjects who have shrapnel at any place in their body.
3.5
Discontinuation of Subjects following any Treatment with Study Drug
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Per the subjects request to stop study treatment and/or retract willingness to provide consent 
to continue participation in the study

Any clinical adverse event (AE) determined as a Grade 3 or Grade 4 or higher - (based upon
the current version of Common Terminology Criteria for Adverse Events (CTCAE)36
criteria) will be handled as follows:
a.
Any subject(s) experiencing Grade 3 and/or a Grade 4 ADR (AE or laboratory 
abnormality considered study drug related as determined by the investigator must 
discontinue investigational product.
b. Clinical data from subjects experiencing a Grade 3 AE or above which is determined to be 
unrelated to study drug will be reviewed by the BMS medical monitor/study director in 
conjunction with the investigator, to determine the risk/benefit for a subject to continue or 
discontinue in the study. The investigator will provide documented justification of the 
decision for filing purposes.

Any clinical adverse event (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 subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness

Unblinding a subject for any reason (emergency or non-emergency)

Pregnancy

Laboratory or Clinical Criteria: If any of the following laboratory or clinical criteria is 
obtained for any subject, the result must be repeated/confirmed within 72 hours and the BMS 
central medical monitor/study director should be informed. If the results are confirmed, the 
subject must discontinue treatment. Clinical criteria must have the Principal Investigator or 
sub-investigator assessment prior to discontinuation.

Evidence of confirmed hepatic decompensation (Child-Pugh Class B or C, Score >6);

ALT > 2 x baseline and > 5 x ULN, and either total bilirubin > 2 x ULN or INR > 2.

Any Grade 3 or above AE or clinically significant laboratory abnormality considered 
study drug-related (as described above and  reported according to the current version of 
the CTCAE grade criteria)
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
Revised Protocol No: 03
Date: 03-Jun-2016
33
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
All subjects who discontinue investigational product should comply with protocol specified 
follow-up as outlined in Table 5.1-2, Table 5.1-3. The only exception to this requirement is when 
a subject withdraws consent for all study procedures including post-treatment study follow-up or 
loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Follow up
Subjects who discontinue study drug may continue to be followed.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects 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 drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject 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.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the 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 subject’s informed consent, then the investigator may use a Sponsor-
retained third-party representative to assist site staff with obtaining subject’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, in order to obtain updated contact information. If after all attempts, the subject 
remains lost to follow-up, then the last known alive date as determined by the investigator should 
be reported and documented in the subject’s medical records.
Revised Protocol No: 03
Date: 03-Jun-2016
34
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(e.g., background therapy, rescue medications)

Diagnostic agents: given as part of the protocol requirements must also be included in the 
dosing data collection.
BMS-986036 will be provided as a blinded solution for subcutaneous injection. Randomized 
subjects will self-administer double-blind treatment, once daily for 16 weeks, in an outpatient 
setting. Blinded treatment is supplied in Kits.  Each Kit contains 8 vials, to support 1 week of 
treatment.  2 vials are provided for use on Day 1 of each week, and 1 vial is provided for use 
each day, on Days 2-7.  
Once-daily treatment will consist of subcutaneous injection(s) administered in the abdomen. 
Subjects will be trained to rotate injection sites relative to the umbilicus. The time of dose 
administration will be called “0” hour, with regard to pre- and postdose clinical planned events. 
On clinic visit days, the morning injections are administered at the clinic, at a time determined by 
the Investigator to coordinate with the pre- and post-dose protocol specified clinical events 
scheduled for that clinic visit day. Treatment administration is described in Table 4-1.
Table 4-1:
Treatment Administration
Treatment
Solution 
Strength
Number and volume of subcutaneous injections
Day 1a
of each treatment week
Days 2 - 7
of each treatment week
Lead-in phase
Placebo QD
N/A
2 x 1 mL
1 x 1 mL, daily
A
BMS-986036 
10 mg QD
10 mg/ml
2 x 1 mLb
1 x 1 mL, daily
B
BMS-986036 
20 mg QW
10 mg/ml
2 x 1 mL
1 x 1 mL, dailyc
C
Placebo QD
N/A
2 x 1 mL
1 x 1 mL, daily
a For all treatments, on Day 1 of each treatment week, two injections are administered concurrently, in the 
morning.
b For treatment A, on Day 1 of each treatment week, the 2 injections consist of 1 active and 1 placebo, to maintain 
the blind between daily and weekly treatment arms.
c For treatment B, on Days 2-7 of each treatment week, the injection is placebo, to maintain the blind between daily 
and weekly treatment arms.
Revised Protocol No: 03
Date: 03-Jun-2016
35
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Product description and storage information is described in Table 4-2.
Revised Protocol No: 03
Date: 03-Jun-2016
36
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 4-2:
Study Drugs for MB130045
Product Description 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/Appearance
Storage Conditions
(per label)
Placebo for 
BMS-986036-01 
Injection
N/A
IP
(8 vials/Kit)
Blinded
A clear colorless or a 
light yellow solution in a 
vial essentially free of 
particulate matter by 
visual inspection
Store Refrigerated, 2-8 
degree Celsius (36-46 
degree Fahrenheit), 
Protect from light
BMS-986036-01 
Injection, 10mg/vial
10 mg/mL
IP
(8 vials/Kit)
Blinded
A clear colorless or a 
light yellow solution in 
a vial essentially free of 
particulate matter by 
visual inspection
Store Refrigerated, 2-8 
degree Celsius (36-46 
degree Fahrenheit), 
Protect from light
Revised Protocol No: 03
Date: 03-Jun-2016
37
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined 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.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational product(s) are:

Placebo solution for subcutaneous injection

BMS-986036-01 Injection, 10mg/ml (10mg/vial)
4.2
Non-investigational Product
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-investigational products. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).
4.4
Method of Assigning Subject Identification
During the Screening visit, the investigative site will call into the enrollment option of the 
Interactive Voice Response System (IVRS) designated by BMS for assignment of a 5-digit 
subject number that will be unique across all sites. Enrolled subjects, including those not dosed, 
will be assigned sequential subject numbers starting with 00001, eg, 00001, 00002, 00003.... 
00010. The patient identification number (PID) will ultimately be comprised of the site number 
and subject number. For example, the first subject screened (ie, enrolled) at site number 1, will 
have a PID of 0001 00001.Once it is determined that the subject meets the eligibility criteria 
Revised Protocol No: 03
Date: 03-Jun-2016
38
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
following the Screening visit, the investigative site will call the IVRS to randomize the subject 
into the open dose panel.
4.5
Selection and Timing of Dose for Each Subject
At the time of entry into the lead-in period (Day -7 visit), the site will call IVRS in order for the 
lead-in medication to be assigned and dispensed. Subjects who successfully complete the lead-in 
period and meet the criteria for entry into the treatment period (see Section 3.3), will be 
randomly assigned by the IVRS to one of the following 3 double-blind treatment groups in a 
1:1:1 ratio:

BMS-986036 10 mg once daily (QD)

BMS-986036 20 mg once weekly (QW)

Placebo (QD)
Randomization will be stratified based upon diagnosis of Type 2 diabetes mellitus (yes vs. no).
The two strata for randomization are defined as follows:

Strata 1: Diabetes Mellitus - Yes

Strata 2: Diabetes Mellitus - No
Randomized subjects who discontinue will not be replaced.
Randomization schedules for both subject treatment and containers will be generated and kept by 
Bristol- Myers Squibb and stored in a secure location with restricted access.
At all study visits when study medication is dispensed, each subject will be assigned a kit 
number by the IVRS. Kit numbers will be assigned randomly and will correspond to the numbers 
printed on the packages and kits containing study drug. Kit numbers will be recorded on the 
appropriate eCRFs. The IVRS will be available 24 hours per day, 7 days per week.
4.6
Blinding/Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, i.e., that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject 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 Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Revised Protocol No: 03
Date: 03-Jun-2016
39
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
In case of an emergency, the Investigator(s) has unrestricted access to randomization information 
via the IVRS and is capable of breaking the blind through the IVRS system without prior 
approval from sponsor. Following the unblinding the Investigator shall notify the Medical 
Monitor/ Study Director.
Also, designated staff of BMS Research and Development can be unblinded at any time. The 
Bioanalytical Sciences section or its designate will be unblinded to the randomized treatment 
assignments in order to minimize unnecessary analysis of samples from control group subjects. 
A single pharmacokineticist or designate in Clinical Pharmacology Pharmacometrics and a 
Biomarker scientist may be unblinded in order to prepare preliminary summaries of 
pharmacokinetic, pharmacodynamic, and safety data, as needed before data are more generally 
unblinded. These summaries will not reveal individual subjects’ treatment assignments. Except 
as noted above, other members of BMS Research and Development will remain blinded.
4.6.1
Interim Analysis Unblinding 
In the event of an Interim Analysis, the interim analyses will be performed by unblinded 
individuals. The access to unblinded interim individual data will be limited to pre-specified 
personnel (e.g. statistician, programmer, PK scientist, pharmacometrician and data integration 
programmer from Clinical Pharmacology and Pharmacometrics) as necessary to perform the 
interim analyses and data summaries. Except as noted above, other members of BMS Research 
and Development will remain blinded to individual subjects’ data.
Data summaries will not reveal individual subjects’ treatment assignments and will be presented 
using masked treatment codes.  Data summaries will be provided to the following BMS 
personnel: Early Development Team Lead, Exploratory Clinical and Translational Research
Therapeutic Area (TA) Head, PK TA Head, Statistical TA Head and Biomarker TA Head. The 
study team other than the aforementioned personnel will be blinded to data summaries.
4.7
Treatment Compliance
During the on-treatment phase, there will be a compliance check at each scheduled visit. The kit 
containing vials of study drug should be returned at each visit, and compliance will be assessed 
based upon an interview with the subject and a count of the vials. The Investigator (or designee) 
will record the amount of study drug dispensed and returned at each visit and the dates of any 
study drug interruption. During the double-blind treatment period, if the subject is ≤ 80%
compliant with study drug (BMS-986036/matching placebo) the period of noncompliance should 
be noted as a protocol deviation and the sponsor should be notified. The subject should be 
educated/properly instructed by designated site personnel on taking the study medication in 
accordance with the protocol.
Revised Protocol No: 03
Date: 03-Jun-2016
40
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (e.g., cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are 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 SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The method of disposal, i.e., 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 
Monitor to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for the return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty 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.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty 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.
Arrangements for the return of study drug will be made by the responsible Study Monitor.
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Study assessments and procedures are presented in Table 5.1-1, Table 5.1-2 and Table 5.1-3.
Revised Protocol No: 03
Date: 03-Jun-2016
41
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.1-1:
Screening Procedural Outline (MB130045)
Procedure
Screening
Lead-in
Notes
D-42 to D-8
D-7
Visit Window (days)
+/- 2
Eligibility Assessments
Informed Consent
X
A subject is considered part of the study only when a protocol specific informed consent is 
signed.
Inclusion/Exclusion Criteria
X
X
Medical History
X
Include any toxicities or allergy related to previous treatments.
Liver biopsy
X
Performed within 1 year of screening or between Screening and Lead-in.  Must be NASH 
CRN fibrosis stage 1 to 3, or equivalent.
Patient education: 
subcutaneous injection and 
diary usage
X
Patients will be educated on the techniques/use of subcutaneous injection and patient diary. 
Subjects may return for additional visits during the Lead-in phase, if the subject or the site 
feels additional education/instruction is required. The Investigator will review subject 
diary, placebo compliance, and assess self-injection skills on Day 1 BEFORE randomizing 
the subject in IVRS. 
Practice at Home
X (D-7 to D-1)
Subcutaneous placebo injection and diary use (once per day) from Day -7 to Day -1.
Imaging Facility Assessments
Dual-emission X-ray 
Absorptiometry (DXA)
X
Performed approximately 21 days prior to the Day 1 dose.
Eligibility should be confirmed by central imaging lab prior to entry into the lead-in period 
(Day -7).   
Bone imaging (hip and lumbar spine) performed at all imaging facilities. 
Body composition (whole body), an exploratory measure, will be additionally carried out at 
imaging facilities with the appropriate hardware/software.
Magnetic Resonance 
Imaging (MRI)
X
Performed approximately 21 days prior to the Day 1 dose.
Eligibility should be confirmed by central imaging lab prior to entry into the lead-in period 
(Day -7). 
 
 
  
Safety Assessments
Physical Examination (PE)
X
To include general appearance, head, eyes, ears, nose, throat, neck, cardiovascular, lungs, 
abdomen, lymph nodes, and extremities, neurological, skin, and musculoskeletal.
Targeted PE
X
A targeted physical exam should be performed by the investigator or qualified professional.  
It includes assessment of heart, lung, abdomen and injection site reactions (as measured by 
the Draize Scale for erythema and edema (see Section 5.3.3) and should also be guided by 
the examiner’s observations and/or patient complaints on new or changed conditions, 
Revised Protocol No: 03
Date: 03-Jun-2016
42
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.1-1:
Screening Procedural Outline (MB130045)
Procedure
Screening
Lead-in
Notes
D-42 to D-8
D-7
symptoms or concerns.
Physical Measurements
X
X
Weight, BMI and waist circumference measurement. See Section 5.9
Height at screening only.
Vital Signs
X
Includes body temperature, respiratory rate, seated blood pressure and heart rate. Blood 
pressure and heart rate should be measured after the subject has been seated quietly for at 
least 5 minutes. 
Electrocardiogram (ECGs)
X
ECGs should be recorded after the subject has been supine for at least 5 minutes. ECG 
parameters including QTcF will be collected on the CRF.
IVRS Call
X
X
IVRS call to be conducted on the day of each subject visit where indicated
Laboratory Tests 
(hematology, clinical 
chemistry, urinalysis, INR)
X
Subjects are required to fast for at least 10 hours prior to the collection of specimens for 
clinical laboratory tests.
Pregnancy Testing
X
Female subjects of child bearing potential. Serum pregnancy testing performed at screening
Lipid panel
X
Triglycerides, total cholesterol, LDL and HDL
FSH
X
In women <55 years, to confirm menopause.
Clinical Drug Supplies
Dispense Lead-in supply
X
Review injection technique
X
Adverse Event Reporting
Monitor for Non-Serious 
Adverse Events
X
All non-serious AEs will be collected from the start of the Lead-In phase until 30 days after 
discontinuation of dosing. AEs should be followed to resolution or stabilization.
Monitor for Serious 
Adverse Events
X
X
All SAEs must be collected from the date of subject’s written consent until 30 days after
discontinuation of dosing. In addition, the investigator should report any SAE that occurs 
after 30 days post-dosing that is believed to be related to study drug or protocol-specified 
procedure
Abbreviations: D = Day
Revised Protocol No: 03
Date: 03-Jun-2016
43
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.1-2:
On Treatment Procedural Outline (MB130045)
Procedure
D 
1
D 
15
D 
29
D 
43
D 
57
D 
86
End of 
Treatment
D 112
Early 
Termination 
Visita
Notes
Clinic Visit Window 
(days)
0
+3
+3
+3
+3
+3
-3
Patient education: 
subcutaneous injection and 
diary usage
X
The Investigator will review subject diary, placebo 
compliance, and assess self-injection skills on Day 1 
BEFORE randomizing the subject. 
IVRS call
X
X
X
X
X
X
X
X
IVRS call to be conducted on the day of each subject visit
Randomize
X
Predose on Day 1.
Safety Assessments
Inclusion/Exclusion Criteria
X
Predose on Day 1.
Physical Examination (PE)
X
X
X
Predose on Day 1. Injection site reactions (as measured by the 
Draize Scale for erythema and edema (see Section 5.3.3)
Targeted PE
X
X
X
X
X
See note in screening procedures.
Physical Measurements
X
X
X
X
X
X
X
X
Weight, BMI and waist circumference measurement.  Weight 
must be recorded using a calibrated scale. Predose on Day 1.
Vital Signs
X
X
X
X
X
X
X
X
See note in screening procedures.
Electrocardiogram (ECGs)
X
X
X
See note in screening procedures, or as clinically indicated.
Laboratory Tests 
(hematology, clinical 
chemistry, urinalysis, INR)
X
X
X
X
X
X
X
X
Pre-dose on Day 1.  See note in screening procedures and 
Section 5.3.2.
.
Pregnancy Testing
X
X
X
X
X
X
Female subjects of child bearing potential. Urine pregnancy 
testing performed at all specified visits, with a reflex to serum 
pregnancy testing if urine pregnancy testing is positive. 
Dual-emission X-ray 
Absorptiometry (DXA)
X
X
Window +/- 1 week
Bone imaging (hip and lumbar spine) at all imaging facilities.  
Adverse Event Reporting
Monitor for Non-Serious 
Adverse Events
X
X
X
X
X
X
X
X
Day 1 assessment occurs after study drug administration.
Monitor for Serious 
Adverse Events
X
X
X
X
X
X
X
X
See note in screening procedures.
Efficacy Assessments
MRI
X
X
X
MRI should be conducted within +/- 1 week.  At early 
termination, MRI conducted only if subject received ≥ 6 
weeks of study drug and was ≥1 month from previous MRI.
Revised Protocol No: 03
Date: 03-Jun-2016
44
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.1-2:
On Treatment Procedural Outline (MB130045)
Procedure
D 
1
D 
15
D 
29
D 
43
D 
57
D 
86
End of 
Treatment
D 112
Early 
Termination 
Visita
Notes
Pharmacokinetic (PK) Assessments 
PK Sampling
See Table 5.5.1-1
Immunogenicity testing
See Table 5.5.1-1
Refer to Section 5.7
 
  
  
 
Clinical Drug Supplies
Review injection technique
X
Dispense Study Drug
X
X
X
X
X
X
Supplied by BMS.
Blinded drug administration
X
X
X
X
X
X
X
Blinded treatment will be administered at the site on clinic 
visit days.
Patient diary review
X
X
X
X
X
X
X
X
a Early Termination is not a scheduled visit. For early termination PK and PD assessments, refer to Table 5.5.1-1
Abbreviations: D = Day
Revised Protocol No: 03
Date: 03-Jun-2016
45
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.1-3:
Post Treatment Follow-up Procedural Outline (MB130045)
Procedure
D 142 (30 days 
after last dose)
D 292 (6 
mo after 
last dose)
Follow-up  for 
immunogenicitya
(up to 12 months 
post Day 142)
Early 
Termination 
Visitb
Notes
Visit Window
+/- 3 days
+/-2 wk
n/a
IVRS Call
X
X
Safety Assessments
Physical Examination
X
X
Targeted Physical Examination
Injection site reactions (as measured by the 
Draize Scale for erythema and edema (see 
Section 5.3.3), others as clinically indicated.  
See note in Screening procedures.
Physical Measurements
X
X
Weight (using calibrated scale), BMI and 
waist circumference measurement. 
Vital Signs
X
X
See note in screening procedures.
Electrocardiograms (ECGs)
X
X
See note in screening procedures.
Laboratory Tests (hematology, 
clinical chemistry, urinalysis, 
INR)
X
X
See note in screening procedures.
Pregnancy Testing
X
X
Female subjects of child-bearing potential.
Urine pregnancy testing to be performed at 
post treatment specified visits with reflex to 
serum if urine pregnancy testing is positive.
Dual-emission X-ray 
Absorptiometry (DXA)
X
Bone imaging (hip and lumbar spine) at all 
imaging facilities.  
Adverse Event Reporting
Monitor for Adverse Events
X
X
Up to 30 days after the last dose.
Monitor for Serious Adverse 
Events
X
X
See note in screening procedures.
Pharmacokinetic (PK) Assessments
PK Sampling
X
X
Refer to Table 5.5.1-1
Immunogenicity testing
X
X
X
X
Refer to Table 5.5.1-1 and Section 5.7
Revised Protocol No: 03
Date: 03-Jun-2016
46
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
a Applies only to subjects with positive immunogenicity at D142 and/or D292. (Refer to Section 5.7). These immunogenicity follow-up visits will commence 
after D142 or D292, if immunogenicity results are positive at D142 or D292, respectively, without evidence of decreasing or stable antibodies.
b Early Termination is not a scheduled visit. For early termination PK and PD assessments, refer to Table 5.5.1-1
Abbreviations: D = Day
Revised Protocol No: 03
Date: 03-Jun-2016
47
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value).
Any new result will override the previous result (i.e., the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
5.2
Study Materials
Supplied by the site:
The site will provide all required materials for the tests performed locally (i.e., relevant clinical 
laboratory tests and urine drug screens). The site will have available a well-calibrated scale for 
recording body weight, a 12-lead ECG machine, and a calibrated sphygmomanometer and 
thermometer for vital signs assessments. The site will have a centrifuge (refrigerated, if 
possible), a monitored and alarmed refrigerator, and freezer (-20°C or below, -70°C preferred),
as well as containers and dry ice for shipment and storage of blood samples. The site will provide 
all materials required for accurate source documentation of study activities and for housing the 
subjects during the study. 
Supplied by the Central Lab
The Central Lab will supply the Laboratory manual, tubes and labels for collection of samples. 
Supplied by the Central Imaging Lab
The central imaging lab will supply the Imaging manual(s) for MRI for hepatic fat fraction, MRE 
for liver stiffness, DXA scanning and, if applicable, phantoms.
Supplied by the Sponsor
BMS will provide a BMS-approved protocol and any amendment(s) or administrative letter(s) (if 
required), an Investigator Brochure, electronic case report forms, patient education training 
materials and subject supplies to support subcutaneous injections, site support tools and forms
study drug logs, emergency contact cards and patient diaries.
5.3
Safety Assessments
5.3.1
Safety Imaging Assessment for the Study
Image acquisition guidelines and submission processes will be outlined in the MB130045 
Imaging Manual, to be provided by the central imaging lab.
A central imaging lab will perform all imaging analyses.
The clinical site will be trained in imaging procedures prior to scanning the first study subject. 
Images will be submitted to the central imaging lab for central review. The site will be informed 
of quality issues or needs for repeat scanning via queries from the central imaging lab. 
Revised Protocol No: 03
Date: 03-Jun-2016
48
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.3.1.1
DXA
DXA is recognized as the reference method to measure BMD as well as soft-tissue composition 
(body composition: lean mass, fat mass) with acceptable accuracy errors and good precision and 
reproducibility. Subjects with a centrally read screening DXA T-score (total spine, total hip or 
femoral neck) greater than a -2.5 S.D. will be enrolled and randomized for treatment.  Adequacy 
of DXA scans should also be confirmed by the central imaging lab prior to randomization.
Screening results to confirm eligibility (DXA T-score) will be returned to the site by the central 
imaging lab.  No other results will be provided to the site.  
Bone imaging (hip and lumbar spine) will be performed at all imaging facilities and body 
composition (whole body), an exploratory measure, will be additionally carried out at imaging 
facilities with the appropriate hardware/software.
DXA will be conducted at baseline, end of treatment (Day 112, (+/- 1 week) and approximately 6 
months after the end of the treatment (Day 292, +/- 2 weeks).   
Screening DXA should be performed approximately 21 days prior to the Day 1 dose.  Eligibility 
should be confirmed by central imaging lab prior to entry into the lead-in period (Day -7).   
A repeat DXA may be performed if clinically indicated.
Imaging assessments will be performed at time points indicated in Table 5.1-1, Table 5.1-2  and 
Table 5.1-3.
5.3.2
Laboratory Test Assessments
A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests. Results of clinical laboratory tests performed prior to Day 1 must be available prior to 
dosing.
The following clinical laboratory tests will be performed:
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Total Protein
Albumin
Sodium
Potassium
Revised Protocol No: 03
Date: 03-Jun-2016
49
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Gamma-glutamyl transferase (GGT)
Creatinine
Blood Urea Nitrogen (BUN)
Uric acid
Fasting glucose
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase
Creatine Clearance (ClCr) - at Screening only
calculated using Modification of Diet in
Renal Disease (MDRD) equation.
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen (screening only)
Other Analyses
INR (per Table 5.1-1. Table 5.1-2 and Table 5.1-3)  
HbA1c (Screening, and per Table 5.5.1-1)
AFP (Screening - for inclusion/exclusion)
FSH (Screening only; females)
Lipid panel (triglycerides, total cholesterol, LDL and HDL at Screening and per Table 5.5.1-1)
Pregnancy test (WOCBP only: per Table 5.1-1, Table 5.1-2 and Table 5.1-3)
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
investigator and BMS (e.g., provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the
appropriate AE page of the CRF (see Section 6.3 Laboratory Test Result Abnormalities).
5.3.3
Monitoring of Injection site reactions
Injection site reactions will be monitored from Day -7 though the end of the out-patient 
follow-up period. The Draize Scale for erythema and edema will be used as a guide for reporting 
AEs at the blinded study drug injection site, see Table 5.3.3-1.
Revised Protocol No: 03
Date: 03-Jun-2016
50
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.3.3-1:
Monitoring of injection site reactions
Erythema
Edema
Description
AE Grade
Description
AE Grade
No erythema
-
No edema
-
Very slight erythema (barely perceptible)
Mild
Very slight edema (barely perceptible)
Mild
Well defined erythema
Mild
Well defined edema
Mild
Moderate erythema
Moderate
Moderate edema (raised approx. 1 mm)
Moderate
Severe erythema (beet redness to slight 
eschar formation)
Severe
Severe edema (raised more than 1 mm and 
beyond exposure area)
Severe
5.4
Efficacy Assessments
5.4.1
Efficacy Imaging Assessment for the Study
Image acquisition guidelines and submission processes will be outlined in the MB130045 
Imaging Manual, to be provided by the central imaging lab. A central imaging lab will perform 
all imaging analyses. The clinical site will be trained in imaging procedures prior to scanning the 
first study subject. Images will be submitted to the central imaging lab for central review. The 
site will be informed of quality issues or needs for repeat scanning via queries from the central 
imaging lab. 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.4.1.1
MRI
Proton density hepatic fat-fraction MRI will be employed at screening phase to determine 
hepatic fat fraction (%). Subjects with a centrally read hepatic fat fraction ≥10% at screening will 
be enrolled and randomized for treatment. Adequacy of MRI should also be confirmed by the 
central imaging lab prior to randomization.
Screening results to confirm eligibility (hepatic fat fraction) will be returned to the site by the 
central imaging lab.  No other results will be provided to the site.  
MRI will be conducted during the screening period, Day 57 (+/- 1 week), and at the end of 
treatment visit (Day 112, +/- 1 week), or if applicable, at the early termination visit (conducted 
only if subject received ≥ 6 weeks of study drug and was ≥1 month from previous MRI).  
Screening MRI should be performed approximately 21 days prior to the Day 1 dose.  Eligibility 
should be confirmed by central imaging lab prior to entry into the lead-in period (Day -7). A 
repeat MRI may be performed if clinically indicated.
Imaging assessments will be performed at time points indicated in Table 5.1-1, Table 5.1-2  and 
Table 5.1-3.  
Revised Protocol No: 03
Date: 03-Jun-2016
51
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
5.5
Pharmacokinetic Assessments
The following pharmacokinetic parameters of BMS-986036 (Total and C-Terminal intact) will
be generated and summarized 
Ctrough
Observed serum concentration before the next dose is administered; the 
pre-dose concentration 
5.5.1
Pharmacokinetics and Pharmacodynamics:  Collection and Processing
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics 
and pharmacodynamics. Further details of blood and urine collection and processing will be 
provided to the site in the procedure manual.
Revised Protocol No: 03
Date: 03-Jun-2016
52
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.5.1-1:
Pharmacokinetic and Pharmacodynamic Sampling Schedule for BMS-986036
Study 
Day 
Event
Time 
(Relative To 
BMS-986036 Dose)
Hour: Min
BMS-986036 
(a) PEG-C-Term-Intact  
(b) PEG-Total 
(c)  Endogenous FGF21  
Immunogenicity  
aFasting lipids
cNASH FibroSure
Additional Research
1
Predose
0:00
X
X
X
X
X
15
Predose
0:00
X
X
29
Predose
0:00
X
X
X
43
Predose
0:00
X
57
Predose
0:00
X
X
X
57 
6:00
X
86
Predose
0:00
X
X
X
112
Predose
0:00
X
X
X
X
142
Follow-
up
Xh
X
X
Approxim
ately 
every 6-8 
weeks 
between 
D142 or 
Immuno
genicity 
Follow-
Up
Xh,i
Xi
Revised Protocol No: 03
Date: 03-Jun-2016
53
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Table 5.5.1-1:
Pharmacokinetic and Pharmacodynamic Sampling Schedule for BMS-986036
Study 
Day 
Event
Time 
(Relative To 
BMS-986036 Dose)
Hour: Min
BMS-986036 
(a) PEG-C-Term-Intact  
(b) PEG-Total 
(c)  Endogenous FGF21  
Immunogenicity  
aFasting lipids
cNASH FibroSure
Additional Research
D292 and 
up to 12 
months 
after D142
292
Follow-
up
Xh
X
Early 
Term Visit
on 
treatment
Early 
Term 
X
X
X
X
Early 
Term visit
(post 
treatment
prior to 
Day 142
Early 
Term
Xh,i
Xi
X
a Lipids include triglycerides, total cholesterol, LDL and HDL
b Residual samples will analysis of be banked for further biomarkers defined in the section.
c NASH FibroSure includes measurement for α2-macroglobulin, ApoA1, haptoglobin, gamma-glutamyl transpeptidase (GGT), bilirubin; fasting glucose, 
triglycerides, cholesterol, ALT, AST, age and BMI.
d Bone biomarkers: BSAP, P1NP, CTX.
Revised Protocol No: 03
Date: 03-Jun-2016
54
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
h Only Endogenous FGF21 to be collected.
i
Only applies to subjects with positive immunogenicity at D142 and/or D292. Immunogenicity follow-up visits will commence after D142 or D292, if 
immunogenicity results are positive at D142 or D292, respectively, without evidence of decreasing or stable antibodies. Assessments may continue, 
approximately every 6-8 weeks, for up to 12 months following the Day 142 visit and will be discontinued when antibodies have resolved or are judged by the 
Medical Monitor to be decreasing or stable.
Revised Protocol No: 03
Date: 03-Jun-2016
55
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
5.5.2
Pharmacokinetic Sample Analyses
The serum samples for BMS-986036 (C-terminal intact and Total) will be analyzed by a 
validated assay. Pharmacokinetic samples collected for BMS-986036 (C-terminal intact and 
Total) from a subject who received placebo will not be analyzed. 
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
Revised Protocol No: 03
Date: 03-Jun-2016
56
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
 
 
 
 
 
 
 
 
 
 
 
5.7
Immunogenicity
Subjects will be monitored for antibodies to study medication using a validated ADA
homogenous bridge assay with BMS-986036 and electrochemical luminescence detection.  
Samples will first be screened for potential positive ADA responses. Then the samples with 
positive ADA responses will be confirmed for specificity using an immunodepletion format with 
drug BMS-986036 and un-PEGylated 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 tittered to determine the relative positive response.  The 
sensitivity was determined to be 20 ng/mL and the drug tolerance at antibody concentrations of 
50, 100, 500, and 10,000 ng/mL was determined to be 1, 4, 16, and 48µg/mL of BMS-986036 
respectively.
Subjects will also be monitored for antibodies to FGF21 using a validated homogenous bridge 
assay with Met-FGF21 (recombinant produced) and electrochemical luminescence detection.  
Samples will first be screened for potential positive anti-FGF21 responses. Then the samples 
with positive anti-FGF21 responses will be confirmed for specificity using an immunodepletion 
format with wild type sequence FGF21 (WSFGF-21).  Samples with confirmed positive 
anti-FGF21 responses will be titrated to determine the relative positive response.  The sensitivity 
was determined to be ≤ 5 ng/mL and the drug tolerance at antibody concentrations of 50, 100, 
500, and 10,000 ng/mL was determined to be > 48 µg/mL of BMS-986036.
Revised Protocol No: 03
Date: 03-Jun-2016
57
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Samples positive for ADA or positive for anti-FGF21 antibodies will be tested for neutralizing 
activity in a validated cell based neutralizing antibody assay. The assay measures the ability of 
an ADA or anti-FGF21 antibody to inhibit or block Elk1 activation that is induced when FGF21 
or drug binds to the βKlotho and FGF receptors.  The sensitivity was determined to be 
4000 ng/mL and the drug tolerance at antibody concentrations of 400, 16,000 and 32,000 ng/mL 
was determined to be 0.4, >1.0, and >1.0 µg/mL of BMS-986036 respectively.
Samples will be banked for additional immunogenicity characterization if needed.
Subjects with positive ADA and /or anti-FGF21 antibody results at the Day 142 visit and/or the 
Day 292 visit may be asked to return for antibody testing. Immunogenicity follow-up visits will 
commence after D142 or D292, if immunogenicity results are positive at D142 or D292, 
respectively, without evidence of decreasing or stable antibodies. Assessments may continue, 
approximately every 6-8 weeks, for up to 12 months following the Day 142 visit and will be 
discontinued when antibodies have resolved or are judged by the Medical Monitor to be 
decreasing or stable.
5.8
Outcomes Research Assessments
Not applicable.
5.9
Other Assessments 
5.9.1
Height and Body Mass Index (BMI)

Measurement of height should be performed with the subject’s shoes removed. The subject’s 
knees should be straightened, head held erect and eyes forward

Weight must be recorded using a calibrated scale, preferably the same scale at each clinic 
visit.  Subject should remove shoes and heavy clothing before standing on scale.

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
Method of BMI Calculation:

Use actual height and weight

To calculate BMI:

Convert pounds (lbs) to kilograms (kg = lb / 2.2)

Convert inches (in) to centimeters (cm = in X 2.54)

BMI = (weight in kg) / (height in cm/100)2

Round to one decimal place (if 0.05 or greater, round up)
The BMI calculation is used for assessment for inclusion. All analysis calculations for BMI 
will be derived internally by BMS using the weight and height at the specified time point or 
the most recent high measurement (if not applicable).
 
 
Revised Protocol No: 03
Date: 03-Jun-2016
58
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
 
 
 
 
 
5.9.3
Other Supplemental (Unscheduled Visits)
At any time during the study, the Investigator may at his/her discretion, arrange for a subject to 
have an unscheduled (supplemental) assessment(s) including immunogenicity especially in the 
case of AEs that require follow-up. If the subject is seen for an unscheduled assessment, the 
appropriate Supplemental Pages of the eCRF must be completed.  
5.10
Results of Central Assessments
Centrally analyzed DXA and MRI data supporting eligibility will be returned to the site.  Any 
subsequent imaging results from centralized analyses will not be returned to the site.  Safety 
samples will be assayed at a Central Laboratory and results returned to the Site. 
5.11
Sampling for Additional Research
Where individual subjects have provided separate consent for Additional research collection, 
prospective samples of blood will be collected at selected time points (see Table 5.5.1-1) and 
banked. Additionally, residual serum from adiponectin, insulin and 7α-hydroxy-cholesten-3-one 
(C4) collections will also be retained by the BMS Biobank for additional research purposes. No 
additional sampling is required for residual collections. Additional research collections and 
retention should be presented to all subjects, except where prohibited by local laws or 
regulations. However, enrollment into the main study is not contingent upon consent to 
participate in future additional research sample banking. Further details of sample collection and 
processing will be provided to the site in the procedure manual.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug 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 drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
Revised Protocol No: 03
Date: 03-Jun-2016
59
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject 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)

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 subject 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.) Potential drug induced liver injury (DILI) is also 
considered an important medical event. (See Section 6.6 for the definition of potential 
DILI.)
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See 
Section 6.1.1 for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS 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
Revised Protocol No: 03
Date: 03-Jun-2016
60
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21

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).

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB)7 represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting.
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing. If applicable, SAEs must be collected that relate 
to any later protocol-specified procedure (e.g., a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF.  The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning.  In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
Revised Protocol No: 03
Date: 03-Jun-2016
61
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject 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).
6.4
Pregnancy
If following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (e.g., 
dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Revised Protocol No: 03
Date: 03-Jun-2016
62
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
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.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
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 an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
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 Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as:
1. ALT ≥ 5 times baseline or nadir value, whichever is lower, AND ≥ 10 x ULN (upper limit of 
normal),
AND
2. Total bilirubin ≥2 times ULN, 
AND
3. No other immediately apparent possible causes of ALT 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.
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
Revised Protocol No: 03
Date: 03-Jun-2016
63
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
An independent Data Monitoring Committee (DMC) will meet at prespecified times as outlined 
in the DMC charter, and at times when the following criteria are met: 
o
More than 3 subjects develop an adverse event of Grade 3 or higher in the same 
CTCAE category, OR 
o
If more than 2 subjects develop an AE of CTCAE Grade 4 or higher. 
When meeting at the regularly scheduled times, the DMC will review data by masked treatment 
group, but can request unblinded data by treatment group or by individual subject as they deem 
necessary. When meeting based on preset criteria, the DMC will review unblinded data to 
determine clinical significance.
Data to be reviewed at DMC meetings will include, but is not limited to adverse events and 
laboratory value(s). In addition, all expedited serious adverse event report(s) will be provided to 
the DMC members concurrent with the submission to the regulatory authorities. Available 
efficacy data will also be provided to the DMC to facilitate an assessment of benefit vs. risk. 
After each review, the DMC will provide the Medical Safety Team (MST) with meeting minutes 
blinded to treatment assignment and any further recommendations as discussed and to be 
considered for implementation. After consideration, the MST will inform the DMC of any action 
that will be taken in response to the recommendations from the DMC.
The role and responsibilities of the DMC, its operational procedures and method(s) of 
communication with the Sponsor will be described in further detail in a separate DMC Charter. 
The DMC will consist of a minimum of 3 members with previous DMC knowledge and 
expertise who are independent of the Sponsor. The members will be appointed by the Sponsor 
based on their expertise in biostatistics, hepatology, and internal medicine. All DMC members 
will have experience in the conduct of clinical trials. DMC members will not include any 
investigator or sub investigator involved in the study, nor will selected members hold any 
conflict of interest with the Sponsor. DMC membership will not include BMS Sponsor 
representatives.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The primary objective is to compare the change in hepatic fat fraction (%) from baseline to week 
16 between each of 2 doses of BMS-986036 treatment group and placebo treatment group. With 
27 subjects per treatment group with post-baseline measurements, there will be 82% power to 
detect a difference of 5% in mean change from baseline at Week 16 in hepatic fat fraction (%)
between each of 2 doses of BMS-986036 treatment groups (10 mg daily and 20 mg weekly) and 
placebo at a significance level of 0.05 (one-sided). These calculations are based on an 
assumption that the hepatic fat fraction (%) change from baseline is normally distributed with a 
standard deviation of no greater than 7%, as estimated from data
reported in a similar 
population37,38. No adjustment will be made for multiplicity.
Revised Protocol No: 03
Date: 03-Jun-2016
64
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
To allow for dropouts, approximately 30 subjects per treatment group (total of 90 subjects) will 
need to be randomized, assuming up to 10% of the subjects do not complete post-baseline 
assessments.
8.2
Populations for Analyses

All Enrolled Subjects, defined as all subjects who signed an informed consent;

All Randomized Subjects, defined as all subjects who are randomized to a treatment; 

All Treated Subjects, defined as all subjects who have received at least one dose of study 
treatment; 

Pharmacodynamic (PD) Population, defined as all subjects who have received any study 
medication and have PD biomarker data available. Only subjects who have both a 
baseline and at least one post-baseline PD biomarker data available are included in the 
statistical analysis.

Pharmacokinetic (PK) Population, defined as all subjects who receive any study 
medication and have any available concentration-time data.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective to assess the effect of daily or weekly doses of BMS-986036 on safety, 
tolerability and hepatic fat fraction (%) by MRI in patients with biopsy proven NASH will be 
assessed by the primary endpoint of: 

Change in percent hepatic fat fraction (%) by MRI from baseline to Week 16.

Safety endpoints include incidence of AEs, serious AEs, and events of special interest 
including injection site assessment, AEs leading to discontinuation, and death as well as 
marked abnormalities in clinical laboratory tests, vital sign measurements, ECGs, 
physical examinations and bone mineral density (BMD) collected by DXA scan at 
specified time points in Table 5.1-1, Table 5.1-2 and Table 5.1-3.
8.3.2
Secondary Endpoint(s)
The first secondary objective is to assess the pharmacokinetics of C-terminal and total
BMS-986036 in NASH subjects to be assessed by the following secondary endpoint:

Ctrough
The second secondary objective (to assess the effect of daily or weekly doses of BMS-986036 on 
immunogenicity) will be measured by the following secondary endpoints:

anti-BMS-986036 antibodies and anti-FGF21 antibodies, from the time points specified 
in Table 5.5.1-1.
 
Revised Protocol No: 03
Date: 03-Jun-2016
65
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated by treatment group. Summary 
statistics for age, body weight, height, and Body Mass Index (BMI) and diabetic status will be 
tabulated by treatment group.
8.4.2
Efficacy Analyses
To evaluate the effect of BMS-986036 on change in hepatic fat fraction (%) by MRI in subjects 
with biopsy-proven NASH after 16 weeks of treatment, a longitudinal repeated measures 
analysis will be used to analyze the change in hepatic fat fraction (%) at Week 16 from baseline 
in the treated population who have both a baseline and at least one post-baseline measurement. 
The model will include treatment group, week and treatment-by-week interactions as main 
effects and baseline hepatic fat fraction (%) and baseline diabetic status as covariates. An 
unstructured covariance matrix will be used to represent the correlation of the repeated measures 
within each subject.  The model will provide point estimates, standard errors and 2-sided 90% 
confidence intervals for mean change from baseline within and between treatments. P-values will 
be calculated to compare the treatment effect in each of two BMS-986036 (10 mg daily and 20 
mg weekly) treatment groups to that in the placebo treatment group at Week 16. Each treatment 
group comparison will be performed at a one-sided 0.05 significance level. No adjustment will 
be made for multiplicity.
Summary statistics will be tabulated by treatment, study day for hepatic fat fraction (%) with 
corresponding change from baseline. Plot of mean profile over time will also be provided for 
hepatic fat fraction (%) by treatment.
8.4.3
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term 
and treatment group. Vital signs and clinical laboratory test results will be listed and summarized 
by treatment. Any significant physical examination findings and clinical laboratory results will 
be listed. ECG readings will be evaluated by the Investigator and abnormalities, if present, will 
be listed.  Bone mineral density (BMD) results will be tabulated.
Revised Protocol No: 03
Date: 03-Jun-2016
66
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
8.4.4
Pharmacokinetic Analyses
Summary statistics will be tabulated for observed BMS-986036 serum concentrations (Total and 
C-Terminal intact). 
 
 
 
 
 
8.4.6
Immunogenicity Analyses
Responses of anti-BMS-986036 antibodies and anti-FGF21 antibodies will be listed and 
tabulated by treatment and study day. The relationship between immunogenicity and PK and/or 
PD may be explored.
8.4.7
Outcomes Research Analyses
Not applicable.
8.4.8
Other Analyses 
Not applicable.
8.5
Interim Analyses
Because data emerging from this study may be needed for a timely decision about adjustment to 
the development of the program, an interim analysis will be conducted after approximately 60
subjects have completed 8 weeks of treatment. Analyses will consist of summaries of the 
available data without revealing individual subjects' treatment assignments. Refer to section 
4.6.1 for details regarding blinding/unblinding.  The results of the interim analysis will be 
reviewed by a pre-specified panel of personnel.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
Revised Protocol No: 03
Date: 03-Jun-2016
67
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
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 subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS 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 BMS 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. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
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 trial 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 
(EMRs/EHRs), adverse event 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. 
Revised Protocol No: 03
Date: 03-Jun-2016
68
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator 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 BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator 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, IRB). Notice of such
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product. 
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 subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (e.g., lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

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.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
Revised Protocol No: 03
Date: 03-Jun-2016
69
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
9.2.3
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 CRF 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. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects 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 CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, 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 .For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator(s) will be selected as appropriate based on the 
following criteria:

Involvement in trial design

Subject recruitment (e.g., among the top quartile of enrollers)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
Revised Protocol No: 03
Date: 03-Jun-2016
70
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
Revised Protocol No: 03
Date: 03-Jun-2016
71
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests.  Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Medical Research
Those scientific activities which cannot be reasonably 
anticipated at the time of trial design, for which we would 
like to collect and/or retain samples from study participants.  
Examples of additional research include, but are not limited 
to, new assay development and validation, companion 
diagnostic development, new hypotheses in the interaction of 
drug and the human body, and exploration of emerging 
science in the understanding of disease.
Revised Protocol No: 03
Date: 03-Jun-2016
72
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ADA
anti drug antibody
AFP
Alpha fetoprotein
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMD
Bone mineral density
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
Revised Protocol No: 03
Date: 03-Jun-2016
73
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Term
Definition
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu 
or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CRF
Case Report Formelectronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTA
Clinical trial agreement
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTCAE
Common Terminology Criteria for Adverse Events (CTCAE)
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D
Day
DBP
Diastolic Blood Pressure
D/C
discontinue
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
dL
deciliter
Revised Protocol No: 03
Date: 03-Jun-2016
74
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Term
Definition
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
DXA
Dual Energy X-Ray Absorptiometry
E
% response relative to baseline prior to dosing
Eo
Placebo effect
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
EHR
electronic health records
EMR
electronic medical records
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FGF
Fibroblast Growth Factor
FSH
follicle stimulating hormone
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GGT
gamma-glutamyl transpeptidase OR glutamyl transferase
GLT
gluacogon-like peptide 1 receptor
GFR
glomerular filtration rate
h
hour
HDL
High-Density Lipoprotein
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
Revised Protocol No: 03
Date: 03-Jun-2016
75
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Term
Definition
HCO3
-
bicarbonate
HDL
high density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HOMA
Homeostasis Model Assessment
HOMA-IR
Homeostasis Model Assessment - Insulin resistance
HPF
hepatic Fat Fraction
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICF
informed consent
ICH
International Conference on Harmonisation 
IDF
International Diabetes Federation
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IP
Investigational product
IND
Investigational New Drug Exemption
INR
international normalized ratio
IRB
Institutional Review Board
IU
International Unit
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system 
K
slope of the terminal phase of the log concentration-time curve
K+
potassium
kg
kilogram
z
terminal disposition rate constant
L
liter
Revised Protocol No: 03
Date: 03-Jun-2016
76
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Term
Definition
LDH
lactate dehydrogenase
LDL
Low-Density Lipoprotein
LLN
Lower Limit normal
MAD
Multiple ascending dose
MDRD
Modification of Diet in Renal Disease
mg
milligram
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
MRE
Magnetic Resonance Elastography
MRI
Magnetic resonance imaging 
MS
mass spectrometry
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NAFLD
Non-alcoholic fatty liver disease 
NASH
Non-alcoholic Steatohepatitis
ng
nanogram
NIMP
non-investigational medicinal products 
NOAEL
no observed adverse effect level 
NSAID
nonsteroidal anti-inflammatory drug
OCA
Obeticholic acid
PD
pharmacodynamics
Revised Protocol No: 03
Date: 03-Jun-2016
77
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Term
Definition
PE
physical exam
PEG
polyethylene glycol
PID
patient identification number
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PSF
pregnancy surveillance form 
PT
prothrombin time
PTH
parathyroid hormone
Pu
percent of unbound drug
QC
quality control
QD, qd
quaque die, once daily
QW
quaque die, once weekly
R2
coefficient of determination
RBC
red blood cell
SAD
single ascending dose
SAE
serious adverse event
SBP
systolic blood pressure 
SD
standard deviation
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TBILI
total bilirubin
T2DM
Type 2 Diabetes Mellitus
TG
triglyceride levels
T-HALF
Half life
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TZD 
thiazolidinedione
Revised Protocol No: 03
Date: 03-Jun-2016
78
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
Term
Definition
ULN
upper limit normal
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
Revised Protocol No: 03
Date: 03-Jun-2016
79
4.0
Approved
930087483
4.0
v










Clinical Protocol
MB130045
BMS-986036
peg-fgf21
APPENDIX 1
DIAGNOSTIC CRITERIA FOR DRUG AND ALCOHOL ABUSE
The following is taken from DSM-IV:
Diagnostic Criteria for Psychoactive Substance Dependence
A maladaptive pattern of substance use, leading to clinically significant impairment or distress as 
manifested by three (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-induce 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 six months, some use of the substance and some 
symptoms of dependence.
Revised Protocol No: 03
Date: 03-Jun-2016
84
4.0
Approved
930087483
4.0
v


Clinical Protocol
MB130045
BMS-986036
peg-fgf21
In Full Remission:  During the past six 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.
Revised Protocol No: 03
Date: 03-Jun-2016
85
4.0
Approved
930087483
4.0
v

SAP_001.pdf: 
Official Title of Study: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, 
MULTIPLE DOSE STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS 
AND PHARMACODYNAMIC EFFECTS OF BMS-986036 IN ADULTS WITH NONALCOHOLIC 
STEATOHEPATITIS 
 
NCT Number: NCT02413372 
Document Date (Date in which document was last revised): September 18, 2017 


STATISTICAL ANALYSIS PLAN
FOR MB130045
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, 
MULTIPLE DOSE STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS
AND PHARMACODYNAMIC EFFECTS OF BMS-986036 IN ADULTS WITH NON-
ALCOHOLIC STEATOHEPATITIS
VERSION # 2.0
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR MB130045 .................................................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................4
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment..............................................................................................8
2.3
Blinding and Unblinding...........................................................................................9
2.3.1
Interim Analysis Unblinding ...................................................................................10
2.4
Protocol Amendments.............................................................................................10
3
OBJECTIVES ........................................................................................................10
3.1
Primary Objectives .................................................................................................10
3.2
Secondary Objectives .............................................................................................10
4
ENDPOINTS..........................................................................................................11
4.1
Efficacy Endpoints .................................................................................................11
4.2
Safety Endpoints.....................................................................................................11
4.3
Pharmacokinetic Endpoints.....................................................................................11
4.4
Immunogenicity Endpoints.....................................................................................11
5
SAMPLE SIZE AND POWER...............................................................................12
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................12
6.1
Study Periods..........................................................................................................12
6.2
Treatment Regimens...............................................................................................12
6.3
Populations for Analyses ........................................................................................13
7
STATISTICAL ANALYSES..................................................................................13
7.1
General Methods ....................................................................................................14
7.2
Study Conduct........................................................................................................14
7.3
Study Population ....................................................................................................14
7.3.1
Subject Disposition.................................................................................................14
7.3.2
Demographic Characteristics .................................................................................14
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
3
7.3.3
Baseline Disease Characteristics............................................................................14
7.3.4
Physical Measurements ..........................................................................................15
7.3.5
Medical History and Previous Medications.............................................................15
7.4
Extent of Exposure .................................................................................................15
7.5
Efficacy..................................................................................................................15
7.6
Safety.....................................................................................................................16
7.6.1
Deaths ....................................................................................................................16
7.6.2
Serious Adverse Events...........................................................................................16
7.6.3
Adverse Events .......................................................................................................16
7.6.4
Clinical Laboratory Evaluations.............................................................................18
7.6.5
ECG .......................................................................................................................18
7.6.6
Vital Signs ..............................................................................................................19
7.6.7
Physical Examination Findings...............................................................................19
7.6.8
Bone Mineral Density.............................................................................................20
7.7
Immunogenicity Analyses.......................................................................................20
7.8
Pharmacokinetics....................................................................................................20
7.10
Interim Analyses.....................................................................................................21
8
CONVENTIONS....................................................................................................22
8.1
Decimal Places .......................................................................................................22
8.1.1
Pharmacokinetic Summaries...................................................................................22
8.1.3
Visit Windows.........................................................................................................23
9
CONTENT OF REPORTS .....................................................................................23
APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS.............................................24
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
4
LIST OF TABLES
Table 2.1-1:
Study Design Schematic...........................................................................8
Table 6.2-1:
Treatment Administration.......................................................................13
Table 7.6.5-1:
Criteria for ECG Results Outside of a Pre-specified Range.....................19
Table 7.6.6-1:
Criteria for Vital Signs Results Outside of a Pre-specified Range ...........19
2.0
Approved
930089304
1.0
v






Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
7
 
Research Hypothesis:  
BMS-986036 administered daily or weekly for 16 weeks to obese adults with NASH will lower 
hepatic fat fraction (%) assessed by MRI to a greater extent than placebo.
Schedule of Analyses:
When approximately 60 subjects have completed 8 weeks of treatment, an interim analysis will be 
performed. Analyses will consist of summaries of the available data without revealing individual 
subjects' treatment assignments. The results of the interim analysis will be reviewed by a pre-
specified panel of personnel.
Primary Analysis will be performed following the database lock after all subjects complete the end 
of treatment. Final analysis will be performed following the data base lock after all subjects have 
completed the study.
2
STUDY DESCRIPTION
2.1
Study Design
Study MB130045 is a randomized, double-blind, placebo-controlled, parallel-group, multiple dose 
design. Subjects will undergo screening evaluations to determine eligibility within 42 days prior 
to randomization.  There will be a 7-day study skills training (Lead-In) period prior to 
randomization on Day 1. Eligible subjects will be randomized via Interaction Voice Response 
System (IVRS) on Day 1 to 1 of 3 parallel treatment groups. In total, approximately 90 randomized 
subjects (30 per group; ratio 1:1:1) will self-administer double-blind treatment, once daily for 16 
weeks, in an outpatient setting. Subjects will be stratified using diagnosis of Type 2 diabetes 
mellitus (yes vs no) based on current American Diabetes Association criteria. Clinic visits are 
scheduled approximately every 2 weeks initially, and then monthly, to collect safety, PK and PD 
measures. The study design schematic is presented in Table 2.1-1:
For each subject, the total scheduled study duration from Screening to last Follow-up visit is 
approximately 12 months, comprised of screening (Day -42 to Day -8), placebo lead-in 
(approximately Day -7 to Day -1), on-treatment (Day 1 to Day 112) and a wash-out follow-up 
(Day 113 to Day 142) period, plus a scheduled follow-up visit that will be performed 
approximately 6 months (Day 292) after the last dose to perform DXA scanning and an additional 
immunogenicity measurement. Of note, subjects with a positive result in the ADA and/or anti-
FGF21 antibody assays at the Day 142 and/or Day 292 follow-up visits, and who do not have 
evidence of decreasing or stable antibodies, will be followed for up to 12 months after the D142 
visit until antibody levels resolve or demonstrate a consistent decreasing trend (these 
immunogenicity follow-up visits will be conducted approximately every 6-8 weeks).
The end of the study is defined as the date of the last scheduled follow-up visit, or immunogenicity 
follow-up visit, whichever is later, of the last subject in the study.
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
8
Table 2.1-1:
Study Design Schematic
Visit Days
D -42a
D -7
D 1
D 15
D 29
D 43
D 57
D 86b
D 112c
D 142
D 292d
Screening
5 weeks
Lead-in
1 week
On treatment
4 months
Follow-up
Placebo
Treatment A: 10 mg QD (daily) 
Treatment B: 20 mg QW (weekly)
Treatment C: Placebo QD 
a MRI, MRE, and DXA baseline scans should be performed approximately 21 days prior to the Day 1 dose. Eligibility 
should be confirmed by central imaging lab prior to entry into the lead-in period (Day-7).
b The Day 86 visit is scheduled 4 weeks +1 day after the Day 57 visit, to tie in with a PK assessment.
c MRI, MRE and DXA end of treatment scans are conducted at Day 112 (+/- 1 week).
d DXA follow-up scan and immunognoicty sample collection are conducted 6 months (+/- 2 weeks) after the last 
dose.
D = Day
2.2
Treatment Assignment
During the Screening visit, the investigative site will call into the enrollment option of the IVRS
designated by BMS for assignment of a 5-digit subject number that will be unique across all sites. 
Enrolled subjects, including those not dosed, will be assigned sequential subject numbers starting 
with 00001, eg, 00001, 00002, 00003.... 00010. The patient identification number (PID) will 
ultimately be comprised of the site number and subject number. For example, the first subject 
screened (ie, enrolled) at site number 1, will have a PID of 0001 00001.Once it is determined that 
the subject meets the eligibility criteria following the Screening visit, the investigative site will 
call the IVRS to randomize the subject into the open dose panel.
At the time of entry into the lead-in period (Day -7 visit), the site will call IVRS in order for the 
lead-in medication to be assigned and dispensed. Subjects who successfully complete the lead-in 
period and meet the criteria for entry into the treatment period, will be randomly assigned by the 
IVRS to one of the following 3 double-blind treatment groups in a 1:1:1 ratio:

BMS-986036 10 mg once daily (QD)

BMS-986036 20 mg once weekly (QW)

Placebo QD
Randomization will be stratified based upon diagnosis of Type 2 diabetes mellitus (yes vs. no).
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
9
The two strata for randomization are defined as follows:

Strata 1: Diabetes Mellitus - Yes

Strata 2: Diabetes Mellitus - No
Randomized subjects who discontinue will not be replaced.
Randomization schedules for both subject treatment and containers will be generated and kept by 
Bristol- Myers Squibb and stored in a secure location with restricted access.
At all study visits when study medication is dispensed, each subject will be assigned a kit number 
by the IVRS. Kit numbers will be assigned randomly and will correspond to the numbers printed 
on the packages and kits containing study drug. Kit numbers will be recorded on the appropriate 
eCRFs. The IVRS will be available 24 hours per day, 7 days per week.
2.3
Blinding and Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, i.e., that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject 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 Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
In case of an emergency, the Investigator(s) has unrestricted access to randomization information 
via the IVRS and is capable of breaking the blind through the IVRS system without prior approval 
from sponsor. Following the unblinding the Investigator shall notify the Medical Monitor and/or 
Study Director.
Also, designated staff of BMS Research and Development can be unblinded at any time. The 
Bioanalytical Sciences section or its designate will be unblinded to the randomized treatment 
assignments in order to minimize unnecessary analysis of samples from control group subjects. A 
single pharmacokineticist or designate in Clinical Pharmacology Pharmacometrics and a 
Biomarker scientist may be unblinded in order to prepare preliminary summaries of 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
10
pharmacokinetic, pharmacodynamic, and safety data, as needed before data are more generally 
unblinded. These summaries will not reveal individual subjects’ treatment assignments. Except as 
noted above, other members of BMS Research and Development will remain blinded.
2.3.1
Interim Analysis Unblinding
In the event of an Interim Analysis, the interim analyses will be performed by unblinded 
individuals. The access to unblinded interim individual data will be limited to pre-specified 
personnel (e.g. statistician, programmer, PK scientist, pharmacometrician, and data integration 
programmer from Clinical Pharmacology and Pharmacometrics) as necessary to perform the 
interim analyses and data summaries Except as noted above, other members of BMS Research and 
Development will remain blinded to individual subjects’ data.
Data summaries will not reveal individual subjects’ treatment assignments and will be presented 
using masked treatment codes. Data summaries will be provided to the following BMS personnel: 
Early Development Team Lead, Exploratory Clinical and Translational Research Therapeutic Area 
(TA) Head, PK TA Head, Statistical TA Head and Biomarker TA Head. The study team other than 
the aforementioned personnel will be blinded to data summaries.
2.4
Protocol Amendments
This analysis plan reflects all protocol amendments including Amendment01 (dated 27-May-
2015), Amendment02 (dated 29-Oct-2015) and Amendment 04 (03-Jun-2016).
3
OBJECTIVES
3.1
Primary Objectives
The primary objective of this study is to assess the effect of 16 weeks of daily or weekly dose 
treatment of BMS-986036 on safety, tolerability and change in hepatic fat fraction (%) by MRI in 
patients with NASH.
3.2
Secondary Objectives
The secondary objectives are to assess the pharmacokinetics and immunogenicity of BMS-986036 
in patients with NASH.
 
 
 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
11
4
ENDPOINTS
4.1
Efficacy Endpoints
The primary efficacy endpoint is the change in hepatic fat fraction (%) by MRI from baseline to 
Week 16.
4.2
Safety Endpoints
The primary safety endpoints include incidence of AEs, serious AEs, and events of special interest 
including injection site assessment, AEs leading to discontinuation, and death as well as marked 
abnormalities in clinical laboratory tests, vital sign measurements, ECGs, physical examinations 
and bone mineral density (BMD) collected by DXA scan at specified time points in Table 5.1-1, 
Table 5.1-2 and Table 5.1-3 of the Protocol.
4.3
Pharmacokinetic Endpoints
The first secondary objective is to assess the pharmacokinetics of Total and C-Terminal intact
BMS-986036 in NASH subjects. PK endpoints include Ctrough.
4.4
Immunogenicity Endpoints
The second secondary objective to assess the effect of daily or weekly doses of BMS-986036 on 
immunogenicity in NASH subjects will be measured by anti-BMS-986036 antibodies and anti-
FGF21 antibodies at the specified time points in Table 5.5.1-1 of the Protocol. 
 
 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
12
.
5
SAMPLE SIZE AND POWER
The primary objective is to compare the change in hepatic fat fraction (%) from baseline to week 
16 between each of 2 doses of BMS-986036 treatment group and placebo treatment group. With 
27 subjects per treatment group with post-baseline measurements, there will be 82% power to 
detect a difference of 5% in mean change from baseline at Week 16 in hepatic fat fraction (%) 
between each of 2 doses of BMS-986036 treatment groups (10 mg daily and 20 mg weekly) and 
placebo at a significance level of 0.05 (one-sided). These calculations are based on an assumption 
that the hepatic fat fraction (%) change from baseline is normally distributed with a standard 
deviation of no greater than 7%, as estimated from data reported in a similar population8,9. No 
adjustment will be made for multiplicity.
To allow for dropouts, approximately 30 subjects per treatment group (total of 90 subjects) will 
need to be randomized, assuming up to 10% of the subjects do not complete post-baseline 
assessments.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
Screening: refers a period from the time the Informed Consent form is signed until initiation of
the first lead-in placebo dose.
Lead in period: refers to a period from the first lead-in placebo dose until initiation of the first 
treatment dose.
On-Treatment period: refers to a period from the first treatment dose date to 14 days after the 
last treatment dose.
Follow-up period: refers to a period 15 days after the last treatment dose date.
6.2
Treatment Regimens
Approximately 30 subjects will be randomized to self-administer double-blinded study medication 
by subcutaneous injection at a dose of 10 mg BMS-986036 daily, 20 mg BMS-986036 weekly, or 
placebo daily for 16 weeks. The following table shows the total dose and number of subcutaneous 
injections per dose for each treatment group.
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
13
Table 6.2-1:
Treatment Administration
Treatment
Solution 
Strength
Number and volume of subcutaneous injections
Day 1a
of each treatment week
Days 2 - 7
of each treatment week
Lead-in phase
Placebo QD
N/A
2 x 1 mL
1 x 1 mL, daily
A
BMS-986036 10 
mg QD
10 mg/ml
2 x 1 mLb
1 x 1 mL, daily
B
BMS-986036 20 
mg QW
10 mg/ml
2 x 1 mL
1 x 1 mL, dailyc
C
Placebo QD
N/A
2 x 1 mL
1 x 1 mL, daily
a For all treatments, on Day 1 of each treatment week, two injections are administered concurrently, in the morning.
b For treatment A, on Day 1 of each treatment week, the 2 injections consist of 1 active and 1 placebo, to maintain 
the blind between daily and weekly treatment arms.
c For treatment B, on Days 2-7 of each treatment week, the injection is placebo, to maintain the blind between daily 
and weekly treatment arms.
All analyses will be based on actual treatment regimens (“as treated”). Observations on safety 
parameters will be assigned to the most recent treatment regimen received.
6.3
Populations for Analyses

All Enrolled Subjects, defined as all subjects who signed an informed consent;

All lead-in subjects, defined as all subjects who have received at least one dose of placebo 
during the placebo lead-in period;

All Randomized Subjects, defined as all subjects who are randomized to a treatment during 
the treatment period; 

All Treated Subjects, defined as all subjects who have received at least one dose of study 
treatment during the treatment period; 

Pharmacokinetic Population, defined as all subjects who receive any study medication and 
have any available concentration-time data. Additionally, the Evaluable PK Population is 
defined as subjects who have adequate PK profiles. 
All available derived PK parameter values will be included in the PK data set and reported, but 
only subjects with adequate PK profiles will be included in the summary statistics and statistical 
analysis.
7
STATISTICAL ANALYSES
SAS® version 8.2 or higher will be used for statistical analyses, tabulations and graphic 
presentations. S-Plus® may also be used for graphical presentations. 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
14
7.1
General Methods
Descriptive summaries will be presented for continuous variables using number of subjects (N), 
mean, standard deviation (SD), median, minimum and maximum. Geometric mean and coefficient 
of variation (%CV) will also be presented for sample plasma concentration-time data and PK 
parameters. Descriptive summaries for categorical variables will utilize counts and percentages. 
Adverse events and medical history will be coded according to the most recent Medical Dictionary 
for Regulatory Activities (MedDRA) version. Previous and concomitant medications will be coded 
using the most recent WHO Drug Dictionary version. 
Longitudinal summaries of hepatic fat fraction (%), safety and biomarker endpoints use 
pre-defined visit windows (see Section 8.1.3).
7.2
Study Conduct
Relevant deviations from the study protocol, unscheduled corresponding unblinding events, 
protocol amendments and administrative changes will be documented and accounted for in 
presenting the data summaries, listings and descriptive statistical analyses. Relevant protocol 
deviations will be listed for all treated subjects. Any changes from planned protocol-specified 
analysis will be defined in the SAP and reported in the CSR. APPENDIX 1 describes the relevant 
protocol deviations that will be programmed from the database.
7.3
Study Population
7.3.1
Subject Disposition
Subject disposition will be listed. Summary tables reflecting the number of subjects who are 
enrolled, who enter lead-in period, reasons for not entering the lead-in period, who are randomized, 
and reasons for not being randomized will be presented as overall for all enrolled subjects.
The number of subjects who complete the treatment period, who do not complete the treatment 
period, who continue the follow up period, who do not continue the follow up period, who 
complete the study and reasons for discontinuation from the treatment period study, will also be 
summarized for all treated subjects, as overall and by treatment.
7.3.2
Demographic Characteristics
Demographic characteristics such as gender, age, race and ethnicity will be listed for all treated 
subjects. Demographic characteristics will also be summarized for all treated subjects, as overall 
and by treatment.
7.3.3
Baseline Disease Characteristics
The following baseline disease characteristics will be summarized for all treated subjects as overall 
and by treatment:

Type 2 diabetes mellitus (yes, no);

Hepatic fat fraction (%);

NASH CRN fibrosis staging (1, 2, 3);

NAS(NAFLD activity score);
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
15

Fatty liver index

ALT levels
7.3.4
Physical Measurements
Physical measurements such as body weight, height, waist circumference and body mass index 
(BMI) will be listed for all treated subjects. Measurements will also be summarized by nominal 
visit for all treated subjects, as overall and by treatment.
7.3.5
Medical History and Previous Medications
Medical history and previous medications taken prior to dosing will be listed for all treated 
subjects.
7.4
Extent of Exposure
Extent of exposure for 16-week double blinded treatment period will be summarized for all treated 
subjects, presenting the numbers and percentage of subjects with an extent of exposure within the 
following day ranges by treatment group: 1 to 15, 16 to 29, 30 to 43, 44 to 57, 58 to 86, 87 to 112 
and > 112. Also the mean, SD, median and range of the extent of exposure to blinded treatment 
will be presented by treatment group. Study drug administration, randomization schedule will be 
documented as per subject listings. Any non-study medications taken by subjects, any conducted 
non-study medical treatment procedures, and any utilized non-study diagnostic procedures will 
also be listed.
7.5
Efficacy
To evaluate the effect of BMS-986036 on change in hepatic fat fraction (%) by MRI in subjects 
with biopsy-proven NASH after 16 weeks of treatment, a longitudinal repeated measures analysis 
will be used to analyze the change in hepatic fat fraction (%) from baseline to Week 16 in the 
treated population who have both a baseline and at least one post-baseline measurement. The 
model will include treatment group, week and treatment-by-week interactions as main effects and 
baseline hepatic fat fraction (%) and baseline diabetic status as covariates. An unstructured 
covariance matrix will be used to represent the correlation of the repeated measures within each 
subject. The model will provide point estimates, standard errors and 2-sided 90% confidence 
intervals for mean change from baseline at all time points within and between treatments. P-values 
will be calculated to compare the treatment effect in each of two BMS-986036 (10 mg daily and 
20 mg weekly) treatment groups to that in the placebo treatment group at Week 16. Each treatment 
group comparison will be performed at a one-sided 0.05 significance level. No adjustment will be 
made for multiplicity.
Summary statistics will be tabulated for all treated subjects by treatment, study day for hepatic fat
fraction (%) with corresponding change from baseline. Plot of mean profile over time will also be 
provided for hepatic fat fraction (%) by treatment. In addition, the descriptive statistics for hepatic 
fat fraction (%) will be summarized by baseline NASH CRN fibrosis staging (1, 2, 3), type 2 
diabetes mellitus (yes, no), NAS (NAFLD activity score) and fatty liver index.
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
16
Two sensitivity analyses will be performed in the longitudinal repeated measure analysis.

For patients without measurement at week 16 for hepatic fat fraction (%), last observation for 
hepatic fat fraction (%) measured on or after Day 86 will be carried forward to be the value at 
week 16. 

Baseline NASH CRN fibrosis staging and the treatment-by-baseline diabetic status interactions 
will be included in the model. The effect of BMS-986036 on the change in hepatic fat fraction 
(%) from baseline to week 16 within each stratum will be analyzed.
7.6
Safety
Analysis of all safety data will follow the BMS guideline of analysis of safety data.10
The evaluation of safety is based on clinical adverse events (AEs), vital signs, ECGs results, 
physical examinations, clinical laboratory results, the result of DXA scan for bone mineral density 
as well as injection assessment reported during the study.
All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
treatment and overall. Any physical examination findings will be listed. ECG, vital signs and 
clinical laboratory test results and corresponding change from baseline will be listed and 
summarized by treatment group. Values for ECG, vital signs and clinical laboratory test results 
outside the pre-specified criteria will also be listed and summarized. ECG readings will be 
evaluated by the Investigator and abnormalities, if present, will be listed. Bone mineral density 
(BMD) results will be tabulated.
Where appropriate, baseline is defined as the last non-missing result with a collection date-time 
less than the date-time of the first active dose of study medication, for laboratory results, vital 
signs, ECG and BMD results.
7.6.1
Deaths
All reported deaths after a subject is enrolled (i.e., has signed the informed consent) will be listed 
separately by subject for all enrolled subjects.
7.6.2
Serious Adverse Events
All reported serious adverse events (SAEs) will be listed for all enrolled subjects and may also be 
summarized for all treated subjects by treatment as needed.
7.6.3
Adverse Events
All AEs will be coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), 
using current version of Medical Dictionary for Regulatory Activities (MedDRA). All AEs will 
be summarized and listed by SOCs and PTs.
Adverse events which occur during the lead-in period will be tabulated for all lead-in subjects as 
overall. And adverse events which occur on or after the first active dose of study treatment will be 
tabulated for all treated subjects by treatment. Events will be assigned to the study treatment 
administered to the subject. The proportion of subject having an adverse event will be calculated 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
17
as the number of subjects experiencing the event, divided by the total number of subjects receiving 
study treatment.
All AE listings will indicate the unique subject identifier, age, gender, current treatment, the date 
of onset, the date of resolution, day of onset relative to the start of treatment, action taken, 
investigator’s assessment of severity and relationship to study drug. Additional listings will be 
provided for adverse events leading to discontinuation and adverse events without recorded 
resolution. Summaries of adverse events will include adverse events, adverse events by intensity 
and adverse events by relationship. Adverse events leading to discontinuation may also be 
summarized as needed.
Where a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the subject will only be counted once at the preferred terminology 
level in adverse event frequency tables.
Where a subject has multiple adverse events within the same system organ class in a single analysis 
period, the subject will only be counted once at the system organ class level in adverse event 
frequency tables.
When a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables:

Relationship to study medication

Intensity of event

Onset date and time
When reporting adverse events by intensity, in addition to providing a summary table based on the 
event selection criteria detailed above, summary tables will also be provided based on the most 
intense event during the analysis period - independent of relationship to study medication. For 
these tables, the following criteria, in order of precedence, will be used to select the event to be 
included in summary tables:

Intensity of event

Onset date and time
Subjects will only be counted once in the ‘Total’ at their maximum intensity, regardless of SOC 
or PT. 
In addition, a summary of exposure adjust AEs including multiple occurrences of unique events 
will be reported if there are at least 5% of treated subjects with multiple occurrences of unique 
events in any treatment group during double-blinded period. A by-subject listing of unique events 
will be provided.
Injection site reactions as a target physical examination will be monitored from Day -7 through 
the end of the out-patient follow-up period. The Draize Scale for erythema and edema will be used 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
18
as a guide for reporting AEs at the blinded study drug injection site, see Table 5.3.3-1 in the 
protocol. In addition, for injection site reaction will be summarized as a separate frequency table 
and listed.
7.6.4
Clinical Laboratory Evaluations
The results of all protocol-specified clinical laboratory tests, as well as laboratory results outside 
of the normal range, will be listed for all treated subjects. Scheduled laboratory measurements and 
corresponding change from baseline values will be summarized by treatment and nominal visit for 
each laboratory test. Laboratory abnormalities are determined from laboratory measurements 
analyzed at the central or local laboratory, and are graded using the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events.11
For each laboratory test, emergent laboratory abnormalities (not emergent, grade 1, grade 2, grade 
3, grade 4, grade 1 to 4; grade 3 to 4) are summarized by treatment for all treated subjects. 
On-treatment emergent abnormalities are those with a higher toxicity grade than the baseline 
toxicity grade (including missing baseline). Laboratory abnormalities regardless of baseline 
toxicity grade are also summarized analogously by treatment. Commonly collected laboratory tests 
with DAIDS toxicity grades may include the following: hemoglobin, leukocytes, lymphocytes 
(absolute), neutrophils + bands (absolute), platelet, ALT, AST, total bilirubin, Direct bilirubin, 
alkaline phosphatase, GGT, albumin, INR, creatinine, calcium, phosphorus, magnesium, fasting 
glucose.
Laboratory abnormalities on treatment are also summarized by baseline toxicity grade (grade 0; 
grade 1, grade 2; grade 3, grade 4) and treatment regimen for the following laboratory tests: ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, calcium.
The laboratory value during the study period with the highest toxicity grade is reported for each 
test.
Laboratory results for subjects with any laboratory abnormality with grade 3 and grade 4 
(scheduled and unscheduled) will be listed.
7.6.5
ECG
All recorded electrocardiograms will be listed.
If Fridericia’s corrected QT (QTcF) is not available in the database, QTcF will be calculated using 
the reported uncorrected QT Interval and Heart Rate, and the following formula:


3
/
1
60
RATE
HEART
QT
QTcF 
If Bazzett’s corrected QT(QTcB) is not available in the database, QTcB will not be calculated.
Summaries of ECG parameters (heart rate (HR), QT (QT, Bazett’s corrected QT [QTcB], 
Fridericia's corrected QT [QTcF]), PR and QRS intervals) will be tabulated for all treated subjects 
by study day and treatment. Summaries of ECG parameters will include change from baseline at 
list of time points.
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
19
Subjects with ECG intervals outside of a pre-specified range will also be listed.
The following criteria (Table 7.6.5-1) will be used to determine ECG results that are outside of a
pre-specified range:
Table 7.6.5-1:
Criteria for ECG Results Outside of a Pre-specified Range
PR (msec):
Value > 200
QRS (msec):
Value > 120
QT (msec):
Value > 500 or change from baseline > 30
QTcB (msec):
Value > 450 or change from baseline > 30
QTcF (msec):
Value > 450 or change from baseline > 30
7.6.6
Vital Signs
Vital signs parameters (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate 
and body temperature) will be listed. Summaries of vital sign parameters will be provided for each 
vital sign parameter at corresponding visits for all treated subjects by treatment and respective 
changes from baseline.
Subjects with vital signs outside of a pre-specified range will also be listed.
The following criteria will be used to determine vital sign results that are outside of a pre-specified 
range, where changes from baseline are based on matched postural positions and are calculated as 
parameter value - baseline parameter value:
Table 7.6.6-1:
Criteria for Vital Signs Results Outside of a Pre-specified Range
Heart Rate(bpm)
Value > 100 and change from baseline > 30, or
Value < 55 and change from baseline < -15
Systolic BP(mmHg)
Value > 140 and change from baseline > 20, or
Value < 90 and change from baseline < -20
Diastolic BP(mmHg) 
Value > 90 and change from baseline > 10, or
Value < 55 and change from baseline < -10
Respiration(breaths/min)
Value > 16 or change from baseline > 10
Temperature (°C)
Value > 38.3°C or change from baseline > 1.6°C
7.6.7
Physical Examination Findings
All physical examination abnormal findings will be listed for all treated subjects per subject and 
visit.
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
20
7.6.8
Bone Mineral Density
Bone mineral density (BMD) results will be summarized for all treated subjects by treatment group 
using descriptive statistics of values and percent change from baseline at each scheduled time 
point. The relationship between BMS-986036 (Total and C-Terminal intact) exposure and changes 
in bone mineral density may be explored.
7.7
Immunogenicity Analyses
Subjects on active drug will be tested for Anti-BMS-986036 and Anti-FGF21 antibody on Day 1, 
Day 29, Day 57, Day 86, Day 112, Day 142 and Day 292. Subjects testing positive ADA and/or 
anti-FGF21antibody results at the Day 142 and/or Day292 without evidence of decreasing or stable 
antibodies may be asked to return for antibody testing. These assessments may continue,
approximately every 6-8 weeks, for up to 12 months following the Day 142 visit and will be 
discontinued when antibodies have resolved or are judged by Medical Monitor to be decreasing or 
stable.
A positive BMS-986036-induced immunogenicity response is defined as:
1) a missing baseline immunogenicity measurement and a positive laboratory reported 
immunogenicity response post-baseline
2) a negative laboratory reported baseline immunogenicity response and a positive laboratory 
reported immunogenicity response post-baseline
3) a positive laboratory reported baseline immunogenicity response and a positive laboratory 
reported immunogenicity response post-baseline that has a titer value at least 4 fold greater 
than the baseline titer value
Immunogenicity results (anti-BMS-986036 antibody response, anti-FGF21 antibody response, and 
neutralizing antibody [NAB] response) will be summarized and listed. The relationship between 
immunogenicity and PK and/or PD may be explored for assessment of impact of immunogenicity. 
Post-dose positive results at 2 or more consecutive timepoints, where the first and last positive 
result are at least 16 weeks apart, is defined as persistently positive.
7.8
Pharmacokinetics
The Pharmacokinetic (PK) population will be used for all listings. Evaluable PK population will 
be used for summaries and statistical analyses. Analyses will include BMS-986036 (C-Terminal 
Intact) and BMS-986036 (Total) data in the PK dataset for BMS-986036.
Subject BMS-986036 serum concentration-time data will be listed for BMS-986036 (C-Terminal 
Intact) and BMS-986036 (Total). Summary statistics will be tabulated for observed serum Trough 
concentrations (C-terminal intact and Total) by treatment, study day and nominal time. Geometric 
means for Ctrougth will be plotted against study day or week by BMS-986036 dose.
 
 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
21
 
 
 
 
 
 
 
7.10
Interim Analyses
Because data emerging from this study may be needed for a timely decision about adjustment to 
the development of the program, an interim analysis will be conducted after approximately 
60 subjects have completed 8 weeks of treatment. Analyses will consist of summaries of the 
available data without revealing individual subjects' treatment assignments. Refer to section 2.3.1
for details regarding blinding/unblinding. The results of the interim analysis will be reviewed by a 
pre-specified panel of personnel. The following reports will be included for the interim analysis.

Demographic Characteristics Summary

Baseline Disease Characteristics Summary

Summary Statistics for Hepatic Fat Fraction (%) and Change from Baseline Overtime

Summary Statistics for Hepatic Fat Fraction (%) and Change from Baseline Overtime By 
Baseline Disease Characteristics

Summary Statistics for Physical Measurements: Body Weight and Waist Circumference

Summary Statistics for Fasting Lipids: Total Cholesterol, Triglyceride, LDL-C and HDLC
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
22
8
CONVENTIONS
EmBARC (Enhanced Biometric Analysis & Reporting Capability) standard time windowing, 
imputation rules, and counting rules will be applied.  
8.1
Decimal Places
The number of decimal places displayed in efficacy, safety, and biomarker listings will be 
determined by the number of decimal places in the raw data.  
Unless otherwise specified, minimum and maximum will be reported to the precision as the data 
collected, one more decimal place for the mean and median, and two more decimal places for the 
standard deviation.  The adjusted geometric mean, geometric mean ratio and the lower and upper 
limits of confidence interval will be displayed to three decimal places.
8.1.1
Pharmacokinetic Summaries
In-text Tables
For in-text pharmacokinetic tables, coefficient of variation (%CV) will be reported as integers. For 
other statistics except for standard deviations, values of 100 or higher will be presented as integers, 
values of 10 - <100 will be displayed to one decimal place, and values of 1 - < 10 will be displayed 
to two decimal places. Values less than 1 will be displayed to three decimal places.  Ratios will 
also be displayed to three decimal places. Standard deviations will be reported to a precision of 1 
decimal place more than the mean.
Handling of Non-Quantifiable Concentrations
For the summaries of serum concentration-time data, concentrations that are less than the lower 
limit of quantification (LLOQ) should be displayed as “< LLOQ” in the listings and be treated as 
missing in summary tables and plots. For the purpose of calculating PK parameters, other than 
Ctrough, pre-dose concentrations that are less than LLOQ and concentrations prior to the first 
quantifiable concentration that are less than LLOQ will be set to zero, and all other concentrations 
less than LLOQ will be set to missing.
All available concentration-time data and derived pharmacokinetic parameter values will be 
included in the PK data set and listed accordingly.
Treatment of Outliers
Individual subject serum concentrations, if deemed to be anomalous, may be excluded from the 
analysis following a review of available documentation (e.g., bioanalytical report, clinical data). 
Any such exclusion will be clearly listed in the study report along with justification for exclusion.
Certain concentrations at certain time points for a subject may be excluded in the population PK 
model following review of available documentation (e.g., bioanalytical report, clinical data). 
However, results of analysis with and without the excluded profiles may be presented in the study 
report. Any such exclusion will be clearly listed in the study report along with justification for 
exclusion.
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
23
PK Exclusions12
PK Analysis, Reporting, and Exclusion criteria should following the BMS PK Harmonization 
document Version 2.0. Specific guideline for exclusionary criteria for half-life and how other PK 
parameters are affected for exclusion is under section 9.2 of the BMS PK Harmonization 
document.
Exclusion of one or more parameters or the entire dataset may be considered due to incomplete 
profile such as AUC(INF) or when T-HALF cannot be reliably calculated, or there is no sample 
around the suspected Cmax. In addition, subjects may be excluded from the analysis if they missed 
doses or any other considerations which may impact drug absorption. 
 
 
8.1.3
Visit Windows
All visit windowing are according to the visit number windowing defined in the EmBARC 
metadata workbook. Time is measured from the first active dose date of study therapy. For 
longitudinal summaries of data, windows around planned measurement times are based on the 
midpoint between planned study visits unless specified otherwise. If there are multiple records 
within the same visit window, then the value in the visit window closest to the day of the planned 
visit is selected.
The analysis visit window for imaging endpoints (MRI and MRE) are defined as follows:
Screening Window: (-60d / +0d), D57 Window: (-14d / +40d) and D112 window: (-14d / +40d)
9
CONTENT OF REPORTS
Statistical components for the clinical study report will be based on the content of this statistical 
analysis plan (SAP). Details of the tables, listings, and figures to be prepared for the final CSR 
will be included in a study-specific Data Presentation Plan (DPP).
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
24
APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS
Relevant protocol deviations that can be programmed from the database are identified below. The 
list would be updated as appropriate if, in the course of monitoring the study, additional protocol 
deviations are found and considered relevant.

No signed informed consent;

Liver biopsy with documented results of NASH with NASH CRN fibrosis stage <1 or >3, or 
equivalent using a different scoring system.

Body mass index (BMI) of < 25

Hepatic fat fraction (%)< 10% by MRI performed during the Screening period

Males and females, age< 21 or > 75 years

Positive pregnancy test result during screening;

Laboratory test values meeting any of the following criteria at screening:

ALT level 5xULN

Albumin <3.5 g/dL (35 g/L)

INR (International Normalized Ratio) >1.3

Total bilirubin 1.5 mg/dL (25.6 µmol/L) 

Platelet count <100 x 109/L

Alpha fetoprotein (AFP) > 100 ng/mL (> 82.6 IU/mL)
 

Positive blood screen for hepatitis C antibody, hepatitis B surface antigen.

Subjects with a centrally read Screening DXA T-score at the total spine, total hip or femoral 
neck, less than or equal to -2.5 S.D.

Uncontrolled hypertension (systolic blood pressure [SBP] 160, and/or diastolic blood 
pressure [DBP] 95 mmHg). 

QTcF > 480 msec on 12-lead electrocardiogram (ECG) during the Screening period, 
confirmed by repeat.

Impaired renal function defined as an estimated glomerular filtration rate (GFR) of 
<49 mL/min/1.73m2 using Modification of Diet in Renal Disease (MDRD) equation.

Use of oral, intravenous, subcutaneous or intra-articular glucocorticoids 5 days between 
randomization through to end of treatment.

Randomized subjects who receive no study medication for 2 consecutive weeks during the 
double-blind treatment period.
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
25
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0
Approved
930089304
1.0
v


Statistical Analysis Plan
MB130-045
BMS-986036
PEG-FGF21
26
 
2.0
Approved
930089304
1.0
v