Conditions: Non-alcoholic Steatohepatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy, safety, and pharmacokinetics of BFKB8488A compared to placebo in participants with non-alcoholic steatohepatitis (NASH).

Detailed description:

Arms:
arm 1: Participants will receive a fixed dose of placebo matched to BFKB8488A. arm 2: Participants will receive BFKB8488A. arm 3: Participants will receive BFKB8488A. arm 4: Participants will receive BFKB8488A.

Interventions: intervention 1: Placebo intervention 2: BFKB8488A
Intervention descriptions: intervention 1: Participants will receive subcutaneous (SC) placebo matched to BFKB8488A. intervention 2: Participants will receive subcutaneous (SC) BFKB8488A.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
BFKB8488A—Genentech, Inc.
Protocol GC41033, Version 6
PROTOCOL
TITLE:
A PHASE II, RANDOMIZED, PARALLEL-GROUP, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF BFKB8488A COMPARED WITH PLACEBO IN 
PATIENTS WITH NON-ALCOHOLIC 
STEATOHEPATITIS
PROTOCOL NUMBER:
GC41033
VERSION NUMBER:
6
EUDRACT NUMBER:
2019-001897-27
IND NUMBER:
NCT NUMBER
NCT04171765
TEST PRODUCT:
BFKB8488A (RO7040551)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1: 3 June 2019
DATES AMENDED:
Version 2:  23 August 2019
Version 3:  9 March 2020
Version 4:  6 May 2020
Version 5:  28 October 2020
Version 6: See electronic date stamp below
 
10-May-2021 21:47:21
Title
Approver's Name
Company Signatory
Date and Time (UTC)


BFKB8488A—Genentech, Inc.
2/Protocol GC41033, Version 6
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
6
See electronic date 
stamp on title page
---
---
---
5
28 October 2020
United Kingdom
1
12-Jan-2021
4
6 May 2020
---
---
---
3
9 March 2020
---
---
---
2
23 August 2019
---
---
---
1
3 June 2019
---
---
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BFKB8488A—Genentech, Inc.
5/Protocol GC41033, Version 6
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 




BFKB8488A—Genentech, Inc.
7/Protocol GC41033, Version 6
 
 
 
 


BFKB8488A—Genentech, Inc.
8/Protocol GC41033, Version 6
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 15
PROTOCOL SYNOPSIS .................................................................................... 16
1.
BACKGROUND .......................................................................................... 29
1.1
Background on Non-Alcoholic Steatohepatitis....................... 29
1.2
Background on BFKB8488A.................................................. 29
1.3
Study Rationale and Benefit-Risk Assessment...................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 33
2.1
Efficacy Objectives ................................................................ 33
2.1.1
Primary Efficacy Objective..................................................... 33
2.1.2
Secondary Efficacy Objective................................................ 33
2.2
Safety Objective .................................................................... 33
2.3
Pharmacokinetic Objective .................................................... 34
2.4
Immunogenicity Objectives.................................................... 34
2.5
Biomarker Objectives............................................................. 34
2.6
Health Status Utility Objective ............................................... 34
3.
STUDY DESIGN......................................................................................... 35
3.1
Description of the Study......................................................... 35
37
3.1.2
Internal Monitoring Committee............................................... 38
3.2
End of Study and Length of Study......................................... 39
3.3
Rationale for Study Design.................................................... 39
3.3.1
Rationale for BFKB8488A Dose and Schedule ..................... 39
3.3.2
Rationale for Patient Population ............................................ 40
3.3.3
Rationale for Control Group................................................... 40
3.3.4
Rationale for PK Sampling Schedule..................................... 41
3.3.5
Rationale for Biomarker Assessments................................... 41
4.
MATERIALS AND METHODS .................................................................... 42
4.1
Patients.................................................................................. 42
4.1.1
Inclusion Criteria.................................................................... 42
4.1.2
Exclusion Criteria................................................................... 44


BFKB8488A—Genentech, Inc.
9/Protocol GC41033, Version 6
4.2
Method of Treatment Assignment and Blinding..................... 49
4.2.1
Treatment Assignment........................................................... 49
4.2.2
Blinding.................................................................................. 49
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 50
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 51
4.3.1.1
BFKB8488A and Placebo...................................................... 51
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 51
4.3.2.1
BFKB8488A and Placebo...................................................... 51
4.3.3
Investigational Medicinal Product Accountability ................... 51
4.3.4
Continued Access to BFKB8488A......................................... 52
4.4
Concomitant Therapy and Additional Restrictions................. 52
4.4.1
Permitted Therapy................................................................. 52
4.4.2
Prohibited Therapy ................................................................ 54
4.4.3
Additional Restrictions ........................................................... 54
4.5
Study Assessments ............................................................... 55
4.5.1
Informed Consent Forms and Screening Log........................ 55
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 56
4.5.3
Physical Examinations........................................................... 56
4.5.4
Vital Signs.............................................................................. 56
4.5.5
FibroScan........................................................................... 57
4.5.6
Ultrasound ............................................................................. 57
4.5.7
Bone Mineral Density ............................................................ 57
4.5.8
Magnetic Resonance Imaging ............................................... 57
4.5.9
Liver Biopsy........................................................................... 58
4.5.10
Histological Scoring Systems ................................................ 58
4.5.10.1
NAFLD Activity Score ............................................................ 58
4.5.10.2
NASH Clinical Research Network (CRN) Fibrosis 
Stage ..................................................................................... 58
4.5.11
Home Glucose Monitoring (Type 2 Diabetes 
Mellitus Patients Only)........................................................... 58


BFKB8488A—Genentech, Inc.
10/Protocol GC41033, Version 6
4.5.12
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 59
4.5.13
Electrocardiograms................................................................ 62
4.5.14
Clinical Outcome Assessments ............................................. 63
4.5.15
Blood Samples for Whole Genome Sequencing 
or Whole Exome Sequencing (Patients at 
Participating Sites)................................................................. 64
4.5.16
Optional Samples for Research Biosample 
Repository ............................................................................. 65
4.5.16.1
Overview of the Research Biosample Repository.................. 65
4.5.16.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 65
4.5.16.3
Sample Collection.................................................................. 66
4.5.16.4
Confidentiality........................................................................ 66
4.5.16.5
Consent to Participate in the Research 
Biosample Repository............................................................ 67
4.5.16.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 67
4.5.16.7
Monitoring and Oversight....................................................... 68
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 68
4.6.1
Study Treatment Discontinuation........................................... 68
4.6.2
Patient Discontinuation from the Study.................................. 68
4.6.3
Study Discontinuation............................................................ 69
4.6.4
Site Discontinuation............................................................... 69
5.
ASSESSMENT OF SAFETY....................................................................... 70
5.1
Safety Plan ............................................................................ 70
5.1.1
Risks Associated with BFKB8488A ....................................... 70
5.1.1.1
Gastrointestinal Effects.......................................................... 70
5.1.1.2
Injection Site Reaction/Allergic or Anaphylactic 
Reactions to BFKB8488A...................................................... 71
5.1.1.3
Loss of Lean Body Mass or Bone Mineral Density 
Related to Weight Loss.......................................................... 71
5.1.1.4
Effect on Hypothalamic-Pituitary Axis.................................... 72
5.1.1.5
Sympathetic Effects............................................................... 72
5.1.1.6
Hypoglycemia........................................................................ 73


BFKB8488A—Genentech, Inc.
11/Protocol GC41033, Version 6
5.1.1.7
CNS Effects........................................................................... 73
5.1.1.8
Exocrine Function of Pancreas.............................................. 73
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 73
5.1.2.1
Dose Modifications ................................................................ 73
5.1.2.2
Treatment Interruption ........................................................... 74
5.1.2.3
Management Guidelines........................................................ 74
5.1.2.4
Injection-Site Reaction/Allergic and Anaphylactic 
Reactions............................................................................... 78
5.1.2.5
Loss of Bone Mineral Density Related to Weight 
Loss....................................................................................... 78
5.1.2.6
Hypoglycemia........................................................................ 78
5.1.2.7
Hypothalamic Pituitary Axis ................................................... 78
5.1.2.8
CNS Effects and Mood .......................................................... 79
5.1.2.9
Management of Increases in QT Interval............................... 79
5.2
Safety Parameters and Definitions ........................................ 79
5.2.1
Adverse Events ..................................................................... 80
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 80
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 81
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 82
5.3.1
Adverse Event Reporting Period ........................................... 82
5.3.2
Eliciting Adverse Event Information....................................... 82
5.3.3
Assessment of Severity of Adverse Events ........................... 82
5.3.4
Assessment of Causality of Adverse Events ......................... 83
5.3.5
Procedures for Recording Adverse Events............................ 84
5.3.5.1
Injection Reactions ................................................................ 84
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 84
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 85
5.3.5.4
Persistent or Recurrent Adverse Events................................ 85
5.3.5.5
Abnormal Laboratory Values ................................................. 85
5.3.5.6
Abnormal Vital Sign Values ................................................... 86


BFKB8488A—Genentech, Inc.
12/Protocol GC41033, Version 6
5.3.5.7
Abnormal Liver Function Tests.............................................. 87
5.3.5.8
Deaths ................................................................................... 87
5.3.5.9
Preexisting Medical Conditions.............................................. 88
5.3.5.10
Lack of Efficacy or Worsening of NASH ................................ 88
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 88
5.3.5.12
Cases of Accidental Overdose or Medication 
Error....................................................................................... 89
5.3.5.13
Patient-Reported Outcome Data ........................................... 90
5.3.5.14
Safety Biomarker Data........................................................... 90
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 90
5.4.1
Emergency Medical Contacts................................................ 91
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 91
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 91
5.4.2.2
Events That Occur after Study Drug Initiation........................ 91
5.4.3
Reporting Requirements for Pregnancies.............................. 92
5.4.3.1
Pregnancies in Female Patients............................................ 92
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 92
5.4.3.3
Abortions ............................................................................... 92
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 93
5.5
Follow-Up of Patients after Adverse Events .......................... 93
5.5.1
Investigator Follow-Up........................................................... 93
5.5.2
Sponsor Follow-Up ................................................................ 93
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 93
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 94
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 94
6.1
Determination of Sample Size ............................................... 94
6.2
Summaries of Conduct of Study............................................ 95
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 95
6.4
Efficacy Analyses .................................................................. 95


BFKB8488A—Genentech, Inc.
13/Protocol GC41033, Version 6
6.4.1
Primary Efficacy Endpoint...................................................... 95
6.4.2
Secondary Efficacy Endpoints............................................... 96
6.5
Safety Analyses..................................................................... 96
6.6
Pharmacokinetic Analyses..................................................... 96
6.7
Immunogenicity Analyses...................................................... 96
6.8
Biomarker Analyses............................................................... 97
6.9
Health Status Utility Analyses................................................ 97
6.10
Interim Analyses .................................................................... 98
6.10.1
Planned Interim Analysis ....................................................... 98
6.10.2
Optional Interim Analyses...................................................... 98
7.
DATA COLLECTION AND MANAGEMENT ............................................... 98
7.1
Data Quality Assurance......................................................... 98
7.2
Electronic Case Report Forms............................................... 98
7.3
Electronic Patient-Reported Outcome Data........................... 99
7.4
Source Data Documentation.................................................. 99
7.5
Use of Computerized Systems ............................................ 100
7.6
Retention of Records........................................................... 100
8.
ETHICAL CONSIDERATIONS.................................................................. 100
8.1
Compliance with Laws and Regulations .............................. 100
8.2
Informed Consent................................................................ 101
8.3
Institutional Review Board or Ethics Committee.................. 102
8.4
Confidentiality...................................................................... 102
8.5
Financial Disclosure ............................................................ 103
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 103
9.1
Study Documentation .......................................................... 103
9.2
Protocol Deviations.............................................................. 104
9.3
Site Inspections ................................................................... 104
9.4
Administrative Structure....................................................... 104
9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 104
9.6
Protocol Amendments ......................................................... 105


BFKB8488A—Genentech, Inc.
14/Protocol GC41033, Version 6
10. REFERENCES ......................................................................................... 106
LIST OF TABLES
Table 1
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 75
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 83
Table 3
Causal Attribution Guidance ....................................................... 84
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 37
LIST OF APPENDICES
108
Appendix 2
Appetite Sensations Visual Analogues Scale Questionnaire .... 118
119
Appendix 4
Grading of Injection Site Reactions........................................... 123
Appendix 5
Anaphylaxis Precautions........................................................... 124


BFKB8488A—Genentech, Inc.
15/Protocol GC41033, Version 6
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, RANDOMIZED, PARALLEL-GROUP, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF BFKB8488A COMPARED WITH PLACEBO IN 
PATIENTS WITH NON-ALCOHOLIC 
STEATOHEPATITIS
PROTOCOL NUMBER:
GC41033
VERSION NUMBER:
6
EUDRACT NUMBER:
2019-001897-27
IND NUMBER:
NCT NUMBER
NCT04171765
TEST PRODUCT:
BFKB8488A (RO7040551)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form your local study monitor.


BFKB8488A—Genentech, Inc.
16/Protocol GC41033, Version 6
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, RANDOMIZED, PARALLEL-GROUP, DOUBLE-
BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF BFKB8488A COMPARED WITH 
PLACEBO IN PATIENTS WITH NON-ALCOHOLIC 
STEATOHEPATITIS
PROTOCOL NUMBER:
GC41033
VERSION NUMBER:
6
EUDRACT NUMBER:
2019-001897-27
IND NUMBER:
NCT NUMBER
NCT04171765
TEST PRODUCT:
BFKB8488A (RO7040551)
PHASE:
Phase II 
INDICATION:
Non-alcoholic steatohepatitis
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of BFKB8488A compared with 
placebo in patients with non-alcoholic steatohepatitis (NASH).  Specific objectives and 
corresponding endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of BFKB8488A compared 
with placebo on the basis of the following endpoint:

Proportion of patients with resolution of NASH on overall histopathological reading, without 
worsening of fibrosis at Week 52.  Resolution of NASH is defined as a NAS of 0–1 for 
inflammation, 0 for ballooning, and any value for steatosis as determined by a central reader.  
Worsening of fibrosis is defined as any increase in NASH Clinical Research Network (CRN) 
fibrosis stage as determined by a central reader.
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of BFKB8488A 
compared with placebo on the basis of the following endpoints:

Change from baseline in hepatic fat fraction as assessed by magnetic resonance 
imagingderived proton density fat fraction (MRI-PDFF) at Week 52

Proportion of patients with improvement in liver histology from baseline, defined as 2 points 
reduction in NAS with at least a 1-point reduction in either lobular inflammation or 
hepatocellular ballooning AND no worsening of fibrosis stage as determined by a central 
reader at Week 52 

Proportion of patients with improvement in liver fibrosis greater than or equal to one stage
(as defined by the NASH CRN fibrosis stage) and no worsening of steatohepatitis (defined 
as no increase in NAS for ballooning, inflammation, or steatosis), determined by a central 
reader at Week 52
















BFKB8488A—Genentech, Inc.
24/Protocol GC41033, Version 6
–
Other bone active drugs including anti-convulsants (e.g., phenytoin, carbamazepine, 
valproate, primidone, and phenobarbital) (except benzodiazepines) and heparin 
–
Systemic glucocorticoids, chronic systemic ketoconazole, androgens, 
adrenocorticotropic hormone (ACTH), cinacalcet, aluminum, lithium, protease inhibitors, 
gonadotropin-releasing hormone agonists 
–
Calcineurin inhibitors

Treatment with investigational therapy within 30 days or within 5 half-lives of the 
investigational product, whichever is longer, prior to randomization

Treatment with any biological therapy within 90 days or within 5 half-lives of the biological 
product, whichever is longer, prior to randomization

Treatment with live, attenuated vaccine within 14 days prior to initiation of study treatment, or 
anticipation of need of such a vaccine during study treatment or within 6 weeks after the final 
dose of BFKB8488A, unless specifically reviewed and approved by the investigator

Illicit drug or marijuana use that would interfere with the conduct of the study in the 
investigator's judgment; the Medical Monitor should be consulted prior to enrollment for all 
positive drug screen tests

Current or history (for a period of more than 3 consecutive months within 1 year prior to 
screening) of significant alcohol consumption, as defined by either of the following, 
whichever is the lower amount indicated:
–
Local guidelines (e.g., 20152020 Dietary Guidelines for Americans, 8th Edition), or
–
AASLD Diagnosis and Management of NAFLD Practice Guidance (Chalasani et al. 
2018), defined as 21 standard drinks per week in men and 14 standard drinks per 
week in women, on average

Current use of more than one pack of cigarettes a day or equivalent nicotine-containing 
products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine 
patches, nicotine lozenges, or nicotine gum)

History of severe allergic, anaphylactic, or other hypersensitivity reactions

HIV infection as defined by presence of HIV antibody 

Poor peripheral venous access that precludes acquisition of adequate samples

Serious infections requiring oral or IV antibiotics within 28 days prior to randomization

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study

Blood transfusion within 8 weeks prior to randomization

Donation or loss of blood (excluding the volume of blood that will be drawn during screening 
procedures) as follows:  50499 mL of blood within 30 days or 499 mL of blood within 
56 days prior to study drug administration

Significant cardiac disease as determined by the investigator, including but not limited to 
coronary heart disease that is symptomatic or with ongoing ischemia demonstrated by 
diagnostic testing or having had an event within the past 1 years, unstable angina, 
congestive heart failure, known arrhythmias of ventricular etiology, unexplained syncope or 
seizures related to arrhythmia, ventricular dysrhythmias or risk factors for ventricular 
dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic 
dysfunction, left ventricular hypertrophy), clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome

History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion, including complete left bundle branch block, second- or third-degree atrioventricular 
heart block

QT interval corrected using Fridericia's formula (QTcF) 450 ms in male patients and 
470 ms in female patients demonstrated by at least two ECGs 30 minutes apart




BFKB8488A—Genentech, Inc.
26/Protocol GC41033, Version 6
The Sponsor may choose to conduct interim efficacy analyses of select endpoints.  The decision 
to conduct an optional interim analysis and the timing of the analysis will be documented in the 
Sponsor's trial master file prior to the conduct of the interim analysis.  The interim analysis will be 
reviewed by an IMC.  Details of the interim will be pre-specified in the DAP prior to review by the 
IMC.


BFKB8488A—Genentech, Inc.
27/Protocol GC41033, Version 6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
A1AT
Alpha-1-antitrypsin
AASLD
American Association for the Study of Liver Disease
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody
BLM
baseline measurement
C-SSRS
Columbia-Suicide Severity Rating Scale
CAP
controlled attenuation parameter
CRF
Case Report Form
CRN
Clinical Research Network
CRO
contract research organization
DAP
data analysis plan
DXA
dual-energy X-ray absorptiometry
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
Fab
fragment antigen binding
Fc
fragment crystallizable
FDA
Food and Drug Administration
FFA
free fatty acid
FGFR1
fibroblast growth factor receptor 1c
GI
gastrointestinal
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBcAb
total hepatitis B core antibody
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HPA
hypothalamic- pituitary- adrenal
ICH
International Council for Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio
IRB
Institutional Review Board
IRF
independent review facility
IxRS
interactive voice or web-based response system


BFKB8488A—Genentech, Inc.
28/Protocol GC41033, Version 6
Abbreviation
Definition
KLB
Klotho 
mg/dL
milligrams/deciliter
mITT
modified intent-to-treat
MRI-PDFF
magnetic resonance imaging-derived proton density fat fraction  
NAFLD
non-alcoholic fatty liver disease
NAS
NAFLD Activity Score
NASH
non-alcoholic steatohepatitis
NGS
next-generation sequencing
PD
pharmacodynamic
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetic
PRO
patient-reported outcome
PTH
parathyroid hormone
Q2W
every 2 weeks
Q4W
every 4 weeks
QTcF
QT interval corrected through use of Fridericia's formula
QW
weekly
RBR
Research Biosample Repository
SERM
selective estrogen receptor modulator
SIB
suicidal ideation and behavior
T2DM
type 2 diabetes mellitus
TSH
thyroidstimulating hormone
UFC
urinary free cortisol
ULN
upper limit of normal
VAS
Visual Analogue Scale
WES
whole exome sequencing
WGS
whole genome sequencing


BFKB8488A—Genentech, Inc.
29/Protocol GC41033, Version 6
1.
BACKGROUND
1.1
BACKGROUND ON NON-ALCOHOLIC STEATOHEPATITIS
Non-alcoholic steatohepatitis (NASH) is a condition stemming from excess liver fat in 
combination with hepatic inflammation and cell damage.  Despite limited epidemiological 
data, the estimated prevalence of NASH in the general population ranges between 1.5% 
and 6.45% (Younossi et al. 2016).  
NASH poses a significant burden to both the patient and the healthcare system.  
Patients with NASH typically present with comorbid metabolic syndrome.  Associated 
conditions that are considered risk factors for NASH include obesity, type 2 diabetes 
mellitus (T2DM), and dyslipidemia.  Considering the current obesity epidemic in the 
United States, NASH incidence is expected to increase over time. 
Furthermore, NASH can progress to fibrosis, and eventually cirrhosis and hepatocellular 
carcinoma. The degree of fibrosis determines NASH stage, and time to progression is 
typically 7 years per fibrosis stage (Singh et al. 2015). Patients in the earlier fibrosis 
stages may be treated by their primary care provider or endocrinologist, but those who 
progress to the higher stages may require more specialized care from a hepatologist. 
NASH-related cirrhosis is currently the second leading indication for liver transplants in 
the United States (Wong et al. 2015). 
The American Association for the Study of Liver Disease (AASLD) recommends 
managing NASH by treating liver disease as well as the associated metabolic 
comorbidities mentioned above (Chalasani et al. 2018).  Available treatment modalities 
include lifestyle interventions and bariatric surgery (in eligible obese individuals), but 
none of the current non-pharmacologic options have demonstrated efficacy in NASH.  
Pharmacologic treatments such as thiazolidinediones, vitamin E, metformin, bile acid 
sequestrants, and omega-3 fatty acids have been either ineffective in the treatment of 
NASH or undesirable due to their side effect profiles (Patel et al. 2015; Singh et al. 
2017). At present, no pharmacologic agents are approved by regulatory agencies for 
the treatment of NASH.
1.2
BACKGROUND ON BFKB8488A
BFKB8488A is a full-length, Chinese hamster ovary cell-derived, humanized agonistic 
bispecific antibody targeting cells expressing both fibroblast growth factor receptor 1c 
(FGFR1) and Klotho (KLB), most significantly adipocytes.  One fragment 
antigen-binding (Fab) region of the antibody is directed against the extracellular domain 
of KLB.  The other Fab is directed against the extracellular domain of FGFR1.  
Heterodimerization of the two half-antibodies is driven by "knob" and "hole" modifications 
of the CH3 domain of the Fc region (Atwell et al. 1997; Spiess et al. 2013).  BFKB8488A 
contains the N296G and N300G amino acid substitutions in the fragment crystallizable 
(Fc) regions for the "knob" and "hole," respectively, which results in non-glycosylated 


BFKB8488A—Genentech, Inc.
30/Protocol GC41033, Version 6
heavy chains that have minimal binding to Fcreceptors and, consequently, prevents 
Fc-effector function.
To avoid non-selective activation of FGFR1 and its potentially adverse consequences 
(Wu et al. 2013), this bispecific antibody was designed to specifically activate only the 
FGFR1/KLB complex.  Activation of the FGFR1/KLB complex in adipose tissues by 
FGF21 analogs or by agonistic antibodies has been proposed as a therapeutic strategy 
for treatment of obesity-associated metabolic derangements including hepatosteatosis, 
dyslipidemia, T2DM, insulin resistance, and hyperglycemia (Foltz et al. 2012; 
Kolumam et al. 2015).  Anticipated beneficial effects include insulin sensitization, 
increased energy expenditure, and reduction of ectopic fat deposits. Based on this, 
BFKB8488A is being developed as a therapy for NASH.
Results from Study GC29819, a Phase Ia, placebo-controlled, single-dose study in 
otherwise healthy overweight and obese volunteers with likely insulin resistance showed 
that BFKB8488A had acceptable tolerability at single SC doses of up to 342 mg.  At the 
highest SC dose (681 mg), 6 out of 8 subjects reported adverse events of mild to 
moderate nausea.  Based on these gastrointestinal adverse events, a single dose of 
681-mg dose is considered non-tolerated, and a single dose of 342 mg was considered 
to be the maximum tolerated dose in the study.  There were no serious adverse events, 
dose-limiting adverse events, or discontinuations due to adverse events. 
In the ongoing Phase Ib Study GC39547 (a randomized, blinded, placebo-controlled, 
multiple ascending dose study in patients with T2DM and patients with non-alcoholic 
fatty liver disease [NAFLD]), an acceptable safety and tolerability profile for BFKB8488A 
has been observed in patients treated with BFKB8488A doses up to 50 mg SC weekly 
(QW), 
 SC every 2 weeks (Q2W), and 100 mg SC every 4 weeks (Q4W).
Refer to the BKFB8488A Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The available nonclinical data for BFKB8488A are consistent with the expected 
pharmacologic activity of BFKB8488A to mimic certain metabolic activities of 
recombinant FGF21 via selective activation of FGFR1/KLB but not FGFR2/KLB or 
FGFR3/KLB complexes.  The therapeutic strategy of BFKB8488A thus involves selective 
activation of the FGFR1/KLB complex while minimizing the interference of endogenous 
FGF signaling.  Previously reported clinical activity of FGF21 analogs in overweight 
individuals with T2DM suggested weight loss, glucose and insulin lowering, and other 
metabolic benefits as well as side effects (Gaich et al. 2013; Calle et al. 2014; Talukdar 
et al. 2016).  


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In the preliminary data from a Phase II study in patients with NASH, BMS-986036 
(pegylated FGF21) significantly decreased hepatic fat fraction (Sanyal et al. 2017).  The 
pegylated analog of FGF21 also improved biomarkers of fibrosis (magnetic resonance 
elastography [MRE] and pro-C3), adiponectin, and markers of hepatic injury (ALT and
AST).  These results, presented at the European Association for the Study of the Liver 
(EASL) 2017, suggest that a molecule that mimics FGF21 activity would potentially 
improve steatosis, liver injury, and fibrosis in NASH. 
BFKB8488A is hypothesized to directly and indirectly improve NASH via multiple 
mechanisms.  BFKB8488A can potentially reduce hepatic fat by suppressing de novo 
lipogenesis and gluconeogenesis in the liver and reduce hepatic free fatty acid (FFA) 
uptake through suppressing adipose tissue lipolysis.  In turn, removal of liver fat may 
improve NAFLD activity score (NAS) and fibrosis in patients with NASH.
The molecule may work on various target organs that indirectly affect hepatic steatosis.  
BFKB8488A may work on the nervous system to increase energy expenditure, decrease 
hunger, and decrease sweets and alcohol preference.  By reducing food and sugar 
intake, the molecule may increase FFA oxidation.  In genetic loss-of-function studies in 
the mouse model, KLB in neurons was essential for FGF21 to cause weight loss and 
lower glucose and insulin levels (Lan et al. 2017).  In the same studies, the FGF21 
mimetic antibody that activates FGFR1/KLB also required neuronal KLB for its metabolic 
effects.  
In the Phase Ia study (GC29819) in overweight or obese, otherwise healthy subjects, 
BFKB8488A increased plasma adiponectin, lowered fasting plasma insulin, and 
decreased serum triglycerides following single doses of BFKB8488A over a range of 
doses (Arora et al. 2017a; Arora et al. 2017b).  These observed effects of BFKB8488A 
might be mediated by an improvement in adipose tissue function.  Improving adipose 
tissue function and preventing overnutrition may restore metabolic homeostasis and 
prevent/reverse the fibrotic liver damage caused by ectopic fat deposition. BFKB8488A 
may also alter pancreatic enzyme secretion in the pancreas, and consequently reduce 
nutrient absorption in the gut.  By the aforementioned mechanisms, the drug may reduce 
body weight and prevent weight gain, increase metabolic rate, and improve insulin 
sensitivity and lipid profile, with a safety profile potentially equivalent or superior to 
glucagon-like peptide-1 receptor agonists.  As an agent that has the potential to treat 
fatty liver changes as well as metabolic comorbidities, BFKB8488A may become a 
therapeutic option for the treatment of NASH.
Clinical experience with BFKB8488A to date has not generated safety concerns that 
would preclude further evaluation in patients.  In Study GC29819, there were no deaths, 
serious adverse events, hypersensitivity reactions, or withdrawals due to adverse events 
and no dose-limiting adverse events as defined in the protocol. One adverse event of 
special interest of weight decrease was reported in a subject who received BFKB8488A 
at the highest dose (681 mg SC). Moderate gastrointestinal (GI) symptoms (nausea, 


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vomiting, diarrhea and abdominal distension) seen at the highest dose (681 mg SC) 
determined tolerability, making 342 mg the maximum tolerated dose (MTD) currently 
tested.  All GI manifestations were manageable and reversible. In the ongoing Phase Ib 
Study GC39547, based on preliminary data, there have been no deaths related to the 
study drug.  One serious adverse event of Grade 3 gastritis, suspected to be related to 
the study drug by the Investigator, was reported in a single patient and has resolved.
Study GC41033 includes patients with NASH, many of whom may also have 
concomitant type 2 diabetes, obesity, and hypertension.  In the setting of the 
COVID-19 pandemic, patients with metabolic diseases, such as obesity (Hendren et al. 
2020); Type 2 diabetes (Williamson et al. 2020); and chronic liver diseases, such as 
NASH and cirrhosis (Ji et al. 2020; Wang et al. 2020; Zheng et al. 2020) are considered 
vulnerable populations, due to a higher potential for progression to severe COVID-19, 
serious complications, and longer viral shedding time.  As BFKB8488A is in early 
clinical development, it is not known whether or how BFKB8488A treatment impacts 
the incidence or severity of COVID-19. Based on the mechanism of action of 
BFKB8488A, it is not anticipated that it will increase the risk or the severity of 
infection with SARS-CoV-2.  Clinical trials with BFKB8488A have been ongoing 
during this pandemic and, although the study numbers are small, no patients receiving 
BFKB8488A have developed COVID-19.  Some of the symptoms associated with 
COVID-19 (e.g., nausea, vomiting, and diarrhea) are also adverse events that have been 
reported with BFKB8488A at frequencies higher than 10%.  In the event of potential 
overlapping toxicity for these events, the current protocol management guidelines 
clearly lay out criteria for drug interruption and discontinuation.  Additionally, the 
protocol recommends interruption for study drug in instances of any National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3 
adverse events and discontinuation if they do not resolve to Grade 1 with symptomatic 
treatment or standard of care.  The protocol also mandates study drug discontinuation 
for all CTCAE Grade 4 events, regardless of attribution.  The sites will be instructed to 
follow local guidelines and standard of care for preventing and managing COVID-19 
infection.  
 
 
 
In summary, the aim of this study is to determine if BFKB8488A can effectively treat 
patients with NASH. Several measures will be taken to ensure the safety of patients 
participating in this study based on the potential risks for BFKB8488A based on 
nonclinical and clinical studies and published literature (see Section 5.1.1). Eligibility 
criteria have been designed to exclude patients at higher risk for potential toxicities (see 
Section 4.1).  In addition, safety objectives have been established to monitor for potential 
toxicities.


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of BFKB8488A 
compared with placebo in patients with NASH.  Specific objectives and corresponding 
endpoints for the study are outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of BFKB8488A 
compared with placebo on the basis of the following endpoint:

Proportion of patients with resolution of NASH on overall histopathological reading, 
without worsening of fibrosis at Week 52.  Resolution of NASH is defined as a NAS 
of 0–1 for inflammation, 0 for ballooning, and any value for steatosis as determined 
by a central reader. Worsening of fibrosis is defined as any increase in NASH 
Clinical Research Network (CRN) fibrosis stage as determined by a central reader.
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of BFKB8488A 
compared with placebo on the basis of the following endpoints:

Change from baseline in hepatic fat fraction as assessed by magnetic resonance 
imagingderived proton density fat fraction (MRI-PDFF) at Week 52

Proportion of patients with improvement in liver histology from baseline, defined as 
2 points reduction in NAS with at least a 1-point reduction in either lobular 
inflammation or hepatocellular ballooning AND no worsening of fibrosis stage as 
determined by a central reader at Week 52

Proportion of patients with improvement in liver fibrosis greater than or equal to one 
stage (as defined by the NASH CRN fibrosis stage) and no worsening of 
steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or 
steatosis), determined by a central reader at Week 52
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of BFKB8488A compared 
with placebo on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) grading scale

Change from baseline in targeted vital signs 

Change from baseline in targeted clinical laboratory test results


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2.3
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective for this study is to evaluate the BFKB8488A PK 
profile on the basis of the following endpoint:

Serum concentration of BFKB8488A at specified timepoints
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
BFKB8488A on the basis of the following endpoint:

Incidence of anti-drug antibodies (ADAs) during the study relative to the prevalence 
of ADAs at baseline
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, exploratory biomarker, or PK 
endpoints
2.5
BIOMARKER OBJECTIVES
The exploratory biomarker objectives for this study are the following:

To identify biomarkers that are predictive of response to BFKB8488A (i.e., predictive 
biomarkers), are early surrogates of efficacy, are associated with progression to a 
more severe disease state (i.e., prognostic biomarkers), are associated with 
susceptibility to developing adverse events or can lead to improved adverse event 
monitoring or investigation (i.e., safety biomarkers), can provide evidence of 
BFKB8488A activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of 
the following endpoint:
–
Relationship between MRI-derived biomarkers, adipokines, triglycerides, lipids, 
liver enzymes, pro-C3, and other biomarkers in blood and tissue samples and 
efficacy, safety, and PK 

To predict or evaluate histologic changes in response to BFKB8488A on the basis of 
the following endpoint:
–
Automated image analysis of H&E and trichrome-stained liver biopsies
2.6
HEALTH STATUS UTILITY OBJECTIVE
The exploratory health status utility objective for this study is to assess the patient 
perspective on response to BFKB8488A on the basis of the following endpoint:

Change from baseline in Appetite Sensations Visual Analogue Scale (VAS) scores 
at specified timepoints


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase II, randomized, parallel-group, double-blind, placebo-controlled, 
multicenter study to evaluate the efficacy, safety, and pharmacokinetics of BFKB8488A 
compared with placebo in patients with NASH.  
 
 as determined by the Sponsor's Internal 
Monitoring Committee [IMC]; see Section 3.1.2 for additional details) will be enrolled at 
multiple investigational sites across the globe.  Patients will be randomly assigned to 
receive either BFKB8488A or placebo in the fixed dosing cohort
 
 
 
 
 
 
In the fixed dose arms, patients 
will be randomly assigned to receive BFKB8488A 50 mg, BFKB8488A 75 mg, 
BFKB8488A 100 mg, or placebo. 
  Randomized patients will be 
stratified by diabetes status and fibrosis stage (F1 vs. F2/F3).  A maximum of up to 
approximately 20% of patients with F1 will be enrolled in this study.
The study will consist of a screening period (up to 8 weeks; including an initial screening
and a main screening), a subsequent 52-week treatment period, and a 6-week safety 
follow-up period.  The total duration of the study for each patient will be approximately 
66 weeks.  
During screening (up to 8 weeks), eligibility screening assessments should be completed 
as early as possible.  All eligibility assessments must be completed within the 8-week 
screening period with the exception of delays in laboratory (including biopsy) and MRI 
reporting or due to unforeseen scheduling issues. All eligibility assessments should be 
completed prior to randomization. 
Patients will be required to undergo a liver biopsy prior to randomization in order to 
confirm diagnosis of NASH.  An archival liver sample collected within 6 months prior to 
randomization may be used provided it meets eligibility requirements (see Section 4.1); 
otherwise, a fresh biopsy will be taken during the screening period. 
To ensure an accurate baseline, two measurements will be taken for AST and ALT for all 
patients, first during the initial screening and then during the main screening 
approximately 4 weeks later (at least 2 weeks apart).  A Fibroscanassessment will also 
be performed during the initial screening to establish a baseline for all patients; a 






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3.1.2
Internal Monitoring Committee
The incidence and nature of any adverse events, serious adverse events, and laboratory 
abnormalities will be assessed on an ongoing basis by the Sponsor's IMC.  This 
committee will not be blinded to treatment assignments, and will include a medical 
monitor, drug safety scientist, and biostatistician from the Sponsor.  The PI, site 
investigators, and site personnel will remain blinded until the completion of the study, 
except in circumstances where unblinding is determined by the investigator or by the 
IMC to be important for the safety of a patient.  The IMC may request that additional 
Sponsor scientists (e.g., PK or clinical scientists) participate in data analysis 
either blinded or unblinded. Members of the IMC will be independent of the operational 
team responsible for executing the study.
The IMC will review cumulative unblinded safety data at regular intervals during the 
study.  In addition, the IMC will conduct the interim analysis of the efficacy data as 
needed.  Ad hoc meetings may be called in addition to scheduled meetings to help 
evaluate, and provide recommendations for management of, any emerging potential 
safety signals. During periodic blinded safety analyses, events that would trigger an ad 
hoc IMC meeting and review of unblinded data to decide the safety of continuing the 
study include, but are not limited to, the following:

Three patients develop the same Grade 3 CTCAE attributed to study drug OR

Two patients develop any Grade 4 CTCAE attributed to study drug OR

One patient develops a Grade 5 CTCAE
After reviewing the data, the IMC may make recommendations such as the following:

The study will continue as planned

The study will continue with a change in dose level 
 or 
frequency within a treatment arm
In cases where a dose level or frequency is changed during the study, the IMC 
may recommend that the study team consider adding up to 30 additional patients 
to the study, in order to ensure that an adequate number of patients receive the 
changed dose for an adequate duration.
 

The study will continue with discontinuation of enrollment in a treatment arm

The study will stop for unfavorable benefit-risk

Additional analyses will need to be performed

Enrollment will be held pending further safety evaluation


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Specific operational details such as committee composition, frequency and timing of 
meeting, and member roles and responsibility of the IMC will be detailed in a separate 
IMC charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis (i.e., MRI-PDFF or 
biopsy) or safety follow-up is received from the last patient, whichever occurs later.  The 
end of the study is expected to occur 6 weeks after the last patient completes the 
52-week treatment period.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 30 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for BFKB8488A Dose and Schedule
In the proposed Phase II study in patients with NASH, 
 dosing paradigms will be 
evaluated: fixed dosing 
.  These dosing paradigms will be 
explored in light of the considerable variability observed in patient PK, PD, and 
tolerability in the Phase I studies in order to determine how to best optimize the benefit-
risk of BFKB8488A treatment on both the patient and population levels.
The fixed dose regimens of 50 mg Q2W, 75 mg Q2W, and 100 mg Q2W were selected 
on the basis of the Phase I PK, PD, and safety and tolerability results.  In preliminary 
results from the Phase Ib (GC39547) study, mean relative decreases in liver fat from 
baseline (as measured by MRI-PDFF) of 6.2%, 23%, and 41% were observed in patients 
with NAFLD who were treated with 50, 75, and 100 mg BFKB8488A Q2W, respectively, 
for 12 weeks compared with a decrease of 2.2% in patients treated with placebo.  A 
decrease in liver fat after 12 weeks of treatment is expected to be associated with 
improvement in NASH-related endpoints after 52 weeks of treatment; hence, these 
dosing regimens are expected to be efficacious in some proportion of patients with 
NASH in the Phase II study.  Doses of 50, 75, and 100 mg BFKB8488A Q2W were 
tolerated in the Phase Ib study and are expected to be tolerated in the proposed Phase 
II study as well. 
 
 
 
 


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The evaluation of 
 different dosing paradigms (fixed and 
) across the 
range of doses proposed (50 mg Q2W, 75 mg Q2W, 100 mg Q2W, 
) is 
expected to provide valuable information as to how best to administer BFKB8488A to 
maximize the benefit-risk ratio 
 NASH patient 
population as a whole.
3.3.2
Rationale for Patient Population
Patients with biopsy-confirmed NASH, with a NAS4 and Fibrosis Stage 1, 2, or 3, have 
been chosen for this study in order to assess the effects of BFKB8488A.  These patients 
have significant disease but the damage may still be reversible as they have not yet 
progressed to cirrhosis.  These patients are expected to be representative of the 
population which would derive the greatest benefit from a NASH treatment should one 
be approved.
3.3.3
Rationale for Control Group
Overall, patients enrolled in this study will be randomly assigned in a 10:3 ratio to 
receive BFKB8488A or matching placebo.  Patients in the fixed dose arms will be 
randomly assigned in a 1:3:3:2 ratio to receive either fixed doses of BFKB8488A 50 mg, 
BFKB8488A 75 mg, BFKB8488A 100 mg, or matching placebo. 
 
 
  Placebo-treated control groups will be used in this study to assess 
differences in histological endpoints defining NASH and fibrosis, liver fat as assessed by 
MRI-PDFF, and safety in patients who receive BFKB8488A compared with patients who 
receive placebo.  The two placebo arms are separated to preserve blinding in the 
variable dosing arm, and, other than adjustment of placebo administered, are identical 
and can be pooled for analysis. The use of a control group is necessary given the 
inherent variability in response due to lifestyle changes, sustained weight loss, and other 
factors that may contribute to a placebo response. 


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All patients enrolled in the study, including those randomly assigned to receive placebo, 
will be provided with adequate counseling regarding patient lifestyle changes around diet 
and activity as described in Section 4.4.3.  Therefore, patients assigned to placebo may 
benefit from participation in the study.
3.3.4
Rationale for PK Sampling Schedule
The sampling schedule specified in the protocol is designed to capture data to enable 
characterization of the pharmacokinetic profile of BFKB8488A, including the potential 
impact of ADA on pharmacokinetics, and consists of pre-dose serum collections after 
initial doses and at steady-state, and a post-dose serum collection at steady-state.
3.3.5
Rationale for Biomarker Assessments
Clinical toxicity may not be a reliable surrogate of target modulation by BFKB8488A.  
Therefore, PD biomarkers will be measured in plasma, serum and other samples to 
determine whether clinically achievable exposures are sufficient for producing the 
desired effect on the intended molecular target. 
NASH is a heterogeneous disease, and the expression of both the endogenous ligand 
for FGFR1-KLB as well as KLB receptor expression on target tissues has been shown to 
vary among patients with metabolic dysfunction (Roesch et al. 2015).  Therefore, all 
patients may not be equally likely to benefit from treatment with BFKB8488A.  Predictive 
biomarker samples collected prior to dosing will be assessed in an effort to identify those 
patients with defects in endogenous FGF21 pathways that may be more likely to 
respond to BFKB8488A.  PD biomarkers will be assessed to demonstrate evidence of 
biologic activity of BFKB8488A in patients, to support selection of a recommended dose 
and dosing regimen, and to inform potential revisions to the PK sample collection 
schedule. 
Tissue samples will be collected for DNA extraction to enable whole genome sequencing 
(WGS) or whole exome sequencing (WES) to identify variants that are predictive of 
response to study drug, are associated with progression to a more severe disease state, 
are associated with susceptibility to developing adverse events, can lead to improved 
adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.  Data will 
be analyzed in the context of this study but will also be explored in aggregate with data 
from other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development.




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If an archival liver sample is unavailable or does not meet eligibility criteria, liver 
tissue must be obtained from a biopsy performed at screening.  

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below:
Women must remain abstinent or use a contraceptive method with a failure rate of 
1% per year during the treatment period and for at least 42 days after the final 
dose of study drug.  Women must refrain from donating eggs during this same 
period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).  The definition of childbearing 
potential may be adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With a female partner of childbearing potential who is not pregnant, men who are 
not surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during 
the treatment period and for at least 132 days after the final dose of study drug.  
Men must refrain from donating sperm during this same period.
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for the duration of the pregnancy to avoid 
exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.




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
Treatment with drugs historically associated with NAFLD (e.g., amiodarone, 
methotrexate, tetracyclines, sodium valproate and valproic acid) for more than 
2 weeks within the year prior to randomization

History of Cushing’s disease (including pituitary Cushing’s disease), diabetes 
insipidus or other condition causing polyuria and/or polydipsia

History of adrenal insufficiency or actively taking any form of systemic glucocorticoid 
at screening

History of autoimmune endocrinopathy or polyglandular disorder

History of primary gonadal failure 

History of growth hormone deficiency or acromegaly

History of Addison’s disease

History of hyper- or hypoparathyroidism

 
 
 

 

History of liver transplantation

Confirmed cirrhosis on screening liver sample collection

Platelet count below 150,000/mm3

Evidence of functional hepatic impairment as defined by the presence of any of the 
following abnormalities:
–
Serum albumin 3.5 grams/deciliter (g/dL)
–
International Normalized Ratio (INR) 1.3 (unless on anticoagulants)

History of esophageal varices, ascites or hepatic encephalopathy

History of any liver disease other than NASH (such as alcoholic liver disease and 
cirrhosis), except for resolved, self-limited illnesses such as hepatitis A or E, and 
previous Hepatitis C that meets the Hepatitis C criteria in the next bullet

Evidence of other forms of chronic liver disease at screening such as the following:
–
Hepatitis B virus (HBV): patients with active HBV infection (chronic or acute; 
defined as having positive hepatitis B surface antigen [HBsAg] test at 
screening)
Patients with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible if confirmed with negative HBV DNA performed at screening.


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–
Positive hepatitis C virus (HCV) antibody test, unless the patient has 
undetectable HCV RNA levels for 6 months and a negative HCV RNA test at 
screening
–
Evidence of ongoing autoimmune liver disease as defined by compatible liver 
histology or recent serological markers
–
Known primary biliary cholangitis 
–
Primary sclerosing cholangitis
–
Evidence of or previously diagnosed Wilson's disease as defined by 
ceruloplasmin below the limits of normal and compatible liver histology
–
Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver 
histology (confirmed by A1AT level less than normal)
–
History of hemochromatosis or iron overload as defined by the presence of 
3+ or 4+ stainable iron on screening liver sample collection (archival or fresh) 
–
Drug-induced liver disease as defined on the basis of typical exposure and 
history
–
Known bile duct obstruction
–
Active history of any other type of liver disease (e.g., liver cancer) other than 
NASH

Estimated glomerular filtration rate (eGFR) 60 mL/min/1.73m2

History of biliary diversion

Liver enzymes (ALT, AST) levels 5upper limit of normal (ULN) at screening. In 
addition to the two baseline measurements, levels may be repeated once more at 
the discretion of the investigator during the screening period, and the average of the 
three readings will be used.
–
Alkaline phosphatase 2 ULN at screening. Levels may be repeated once at 
the discretion of the investigator during the screening period, and the lower of 
the two readings may be used.
–
Total bilirubin ULN at screening.  Patients with a history of Gilbert's syndrome 
may have direct bilirubin measured and would be eligible for this study provided 
the direct bilirubin level is ULN; and the subject has normal transaminases, 
alkaline phosphatase, hemoglobin and reticulocyte count.

History of eating disorders within 2 years prior to randomization
 

Weight gain 10% or loss 5% within 3 months prior to randomization


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–
For patients with qualifying archival liver biopsies, stable (within 5%) body 
weight will be required from the time of the biopsy to randomization or 3 months 
prior to randomization, whichever is longer 

History of procedures for weight loss (e.g., lap band (unless the lap band or balloon 
was removed and the weight is stable for at least 3 months prior to screening) or 
gastric bypass)

Planned medical procedure or surgery during the study that in the investigator’s 
opinion would interfere with participant safety, achieving the study objectives or 
compliance with the protocol

Patients with osteoporosis (T-score of -2.5 or lower) 

History of fracture, bone surgery (e.g., hardware placement, joint replacement, bone 
grafting, or amputation), or clinically significant bone trauma within 8 weeks of 
screening

Vitamin D deficiency (25-hydroxy vitamin D level 20 ng/mL) unless high-dose 
vitamin D (e.g., 50,000 IU weekly 6 weeks) is initiated prior to randomization, and 
vitamin D Institute of Medicine 2011 recommendations (8002000 IU/day) are 
followed throughout the study.

History of osteomalacia

History of Paget’s disease of bone 

History of any other bone diseases which affect bone metabolism 
(e.g., osteopetrosis, osteogenesis imperfecta) 

Received bone active treatment with the following guidelines: 
–
Oral bisphosphonate use 3 months cumulatively in the past 2 years, OR 
–
1 month in the past year, OR 
–
Any use during the 3-month period prior to randomization

Administration of intravenous bisphosphonate, fluoride, or strontium within the last 
5 years prior to randomization

Parathyroid hormone (PTH) or PTH derivatives (e.g., teriparatide, abaloparatide) 
within the last year prior to randomization

Current or history of treatment with denosumab 

Administration of any of the following treatment within 3 months prior to 
randomization:
–
Any selective estrogen receptor modulator (SERM) (e.g., tamoxifen, raloxifene,
and toremifene)
–
Tibolone 
–
Anabolic steroids or testosterone 
–
Systemic hormone replacement therapy
–
Calcitonin 


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–
Active Vitamin D analogs (e.g., calcitriol, tacalcitol, paricalcitol, doxercalciferol)
–
Other bone active drugs including anti-convulsants (e.g., phenytoin, 
carbamazepine, valproate, primidone, and phenobarbital) (except 
benzodiazepines) and heparin 
–
Systemic glucocorticoids, chronic systemic ketoconazole, androgens, 
adrenocorticotropic hormone (ACTH), cinacalcet, aluminum, lithium, protease 
inhibitors, gonadotropin-releasing hormone agonists 
–
Calcineurin inhibitors 

Treatment with investigational therapy within 30 days or within 5 half-lives of the 
investigational product, whichever is longer, prior to randomization

Treatment with any biological therapy within 90 days or within 5 half-lives of the 
biological product, whichever is longer, prior to randomization

Treatment with live, attenuated vaccine within 14 days prior to initiation of study 
treatment, or anticipation of need of such a vaccine during study treatment or within 
6 weeks after the final dose of BFKB8488A, unless specifically reviewed and 
approved by the investigator 

Illicit drug or marijuana use that would interfere with the conduct of the study in the 
investigator's judgment; the Medical Monitor should be consulted prior to enrollment 
for all positive drug screen tests

Current or history (for a period of more than 3 consecutive months within 1 year 
prior to screening) of significant alcohol consumption, as defined by either of the 
following, whichever is the lower amount indicated:
–
Local guidelines (e.g., 20152020 Dietary Guidelines for Americans, 8th
Edition), or 
–
AASLD Diagnosis and Management of NAFLD Practice Guidance (Chalasani et 
al. 2018), defined as 21 standard drinks per week in men and 14 standard 
drinks per week in women, on average

Current use of more than one pack of cigarettes a day or equivalent 
nicotine-containing products (including but not limited to cigarettes, pipes, cigars, 
chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum)

History of severe allergic, anaphylactic, or other hypersensitivity reactions

HIV infection as defined by presence of HIV antibody 

Poor peripheral venous access that precludes acquisition of adequate samples

Serious infections requiring oral or IV antibiotics within 28 days prior to 
randomization

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study

Blood transfusion within 8 weeks prior to randomization


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
Donation or loss of blood (excluding the volume of blood that will be drawn during 
screening procedures) as follows:  50499 mL of blood within 30 days or 499 mL 
of blood within 56 days prior to study drug administration

Significant cardiac disease as determined by the investigator, including but not 
limited to coronary heart disease that is symptomatic or with ongoing ischemia 
demonstrated by diagnostic testing or having had an event within the past 1 years, 
unstable angina, congestive heart failure, known arrhythmias of ventricular etiology, 
unexplained syncope or seizures related to arrhythmia, ventricular dysrhythmias or 
risk factors for ventricular dysrhythmias such as structural heart disease (e.g., 
severe left ventricular systolic dysfunction, left ventricular hypertrophy), clinically 
significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, 
hypocalcemia), or family history of sudden unexplained death or long QT syndrome

History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion, including complete left bundle branch block, second- or 
third-degree atrioventricular heart block

QT interval corrected using Fridericia's formula (QTcF) 450 ms in male patients 
and 470 ms in female patients demonstrated by at least two ECGs 30 minutes 
apart

Baseline PHQ-9 score that is confirmed with a repeat test separated by at least 
2 weeks meeting the following criteria:
–
At or above 15 (moderately severe depression), or
–
At or above 10 (moderate depression) and a score of 2 or 3 for the question 
“Thoughts that you would be better off dead, or thoughts of hurting yourself in 
some way?”
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Treatment Assignment
Patients will be randomized to the treatment arms through an interactive voice or 
web-based response system (IxRS).  After written informed consent has been obtained, 
all patients will receive a screening number, which will be assigned by the IxRS.  
Following completion of the screening period and after all patient eligibility requirements 
are confirmed on Day 1, patients will be assigned an identification number (a different 
number from the screening number) and will be randomized to one of the six study arms 
(fixed dose arms: 50 mg BFKB8488A Q2W, 75 mg BFKB8488A Q2W, 100 mg 
BFKB8488A Q2W, or placebo; 
 
.
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment during the 
study with the exception of the site-designated unblinded staff who will prepare the 
syringes.  The Sponsor and its agents will also be blinded to treatment assignment, with 
the exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial. These roles include the unblinding group 


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responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and IMC members.
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis.  PK samples from patients assigned to the comparator 
arm will not be analyzed for study drug PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  Baseline immunogenicity samples will be analyzed 
for all patients.  Postbaseline immunogenicity samples from patients assigned to the 
comparator arm will not be analyzed for ADAs except by request.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which subject management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.  Once the treatment code is broken, the investigator 
should contact the Medical Monitor.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to subject unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are BFKB8488A and 
placebo.


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4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
BFKB8488A and Placebo
BFKB8488A and placebo will be supplied by the Sponsor as sterile liquid in 2-mL Type I, 
colorless, borosilicate glass vials.  For information on the formulation and handling of 
BFKB8488A, see the pharmacy manual and BFKB8488A Investigator's Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 
5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.2.
 
4.3.2.1
BFKB8488A and Placebo
BFKB8488A or placebo will be administered subcutaneously, preferably in the thigh, 
using syringes provided to the study site. 
 
 
  IMP will be administered by a healthcare professional with 
a physician available at the time of administration. IMP will be administered at the 
clinical site, and at applicable sites.
 
 
  Study drug will be administered according to the 
dosing schedule in the schedule of activities 
.  
Refer to the pharmacy manual for additional details on the study drug administration.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (BFKB8488A and placebo) will be provided 
by the Sponsor.  The study site will acknowledge receipt of IMPs supplied by the 
Sponsor, using the IxRS to confirm the shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 


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documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to BFKB8488A
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMP BFKB8488A or any other study treatments to patients 
who have completed the study.  The Sponsor may evaluate whether to continue 
providing BFKB8488A in accordance with the Roche Global Policy on Continued Access 
to Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, over-
the-counter drugs, vaccines, topical medications, herbal or homeopathic remedies, 
nutritional supplements) used by a patient from 7 days prior to initiation of study drug 
until 6 weeks after the final dose of study drug.  All such medications should be reported 
to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients may continue on stable regimens of drugs they are receiving as treatment for 
coexistent stable diseases (e.g., antihypertensives, cholesterol-lowering drugs, or 
bronchodilators) unless listed as prohibited therapy (Section 4.4.2).  In general, 
investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  

Concomitant treatment with any of the following anti-diabetic medications is 
permitted if the dose has been stable for at least 3 months prior to randomization or 
since liver biopsy, whichever is longer:  
–
Metformin
–
Sulfonylureas
–
Dipeptidyl peptidase-4 inhibitors
–
Insulin
–
Sodium-glucose transport protein 2 inhibitors

Concomitant treatment with GLP-1 receptor agonists is permitted if the dose has 
been stable for at least 3 months prior to randomization or since liver biopsy, 
whichever is longer.




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4.4.2
Prohibited Therapy
The following medications should not be taken within window as described below and 
throughout the duration of the study (unless the study treatment has been discontinued):

Treatment with thiazolidinediones (e.g., pioglitazone)

Any treatment for hyperthyroidism

Oral or intravenous bisphosphonate

Intravenous fluoride or strontium

PTH or PTH derivatives (e.g., teriparatide, abaloparatide)

Denosumab

Any SERMs (e.g., tamoxifen, raloxifene, and toremifene)

Tibolone 

Anabolic steroids or testosterone 

Systemic hormone replacement therapy (except for thyroid hormone)

Calcitonin 

Active Vitamin D analogs (e.g., calcitriol, tacalcitol, paricalcitol, doxercalciferol)

Other bone active drugs including anti-convulsants (e.g., phenytoin, carbamazepine, 
valproate, primidone, and phenobarbital) (except benzodiazepines) and heparin 

Systemic glucocorticoids (
, chronic 
systemic ketoconazole, androgens, ACTH, cinacalcet, aluminum, lithium, protease 
inhibitors, gonadotropin-releasing hormone agonists. 

Calcineurin inhibitors 

Investigational therapy within 30 days or within 5 half-lives of the investigational 
product, whichever is longer, prior to randomization 

Any biological therapy within 90 days or within 5 half-lives of the biological product, 
whichever is longer, prior to randomization

Treatment with live, attenuated vaccine within 14 days prior to randomization, during 
study treatment, or within 6 weeks after the final dose of BFKB8488A, unless 
specifically reviewed and approved by the investigator.
4.4.3
Additional Restrictions

No food or fluids, with the exception of water, will be allowed for at least 8 hours 
prior to all study visits collecting fasting laboratory samples until after study 
laboratory samples are obtained.  Patients should be appropriately instructed to 
hold medications as needed until they are able to eat. 

No food or fluids, with the exception of water, will be allowed for at least 4 hours 
prior to all MRI scans and FibroScan. Patients should be appropriately instructed 
to hold medications as needed until they are able to eat.

From screening until completion of the study, patients will abstain from significant 
alcohol consumption (defined as the lower of the following: local guidelines [e.g.,


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20152020 Dietary Guidelines for Americans, 8th Edition], or AASLD Diagnosis and 
Management of NAFLD Practice Guidance of 21 standard drinks per week in men 
and 14 standard drinks per week in women, on average [Chalasani et al. 2018]), 
and smoke no more than 1 pack of cigarettes per day.  Patients must agree to 
completely abstain from alcohol consumption 12 hours prior to every screening and 
study visit. 

Patients are advised to refrain from strenuous exercise that is unusual for them or 
that they are not accustomed to performing (e.g., heavy lifting, construction activity, 
competitive sports, running other than light jogging and aerobics) for the duration of 
the study. Walking at a normal pace, light jogging, and similar activities will be 
permitted. Patients can otherwise maintain their normal level of physical activity 
throughout the entire study but should not begin a new exercise program.

Additionally, patients should refrain from donating blood during the study and for 
90 days after the last dose of study drug.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in 
.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
 
 
 
 
 
 
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.






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IRF and/or to the Sponsor, as described in the MRI scanning manual, for central 
assessment.  
4.5.9
Liver Biopsy
Biopsy specimens will be assessed at baseline and at the end of treatment (see 
).  An archival liver biopsy collected no more than 6 months prior to 
randomization, or a biopsy collected during screening may be used as the baseline.  The 
archival biopsy must be performed while the patient is not on any treatment prescribed 
for the purpose of this study or on any investigational therapy for the treatment of NASH.  
The method of biopsy collection should include approaches to lessen the effect of 
regional variability or sampling error.  Additional details on the liver biopsy collection and 
storage will be provided in a separate biopsy manual.
4.5.10
Histological Scoring Systems
Histological outcome will be assessed by the pathologist through the NAS and NASH 
CRN fibrosis stage. 
4.5.10.1
NAFLD Activity Score 
The NAS will be assessed at screening and at end-of-treatment. 
NAS is a system of histologic evaluation that includes the disease spectrum from NAFLD 
to NASH.  NAS assesses three types of lesions that comprise-grade steatosis, lobular 
inflammation, and ballooning (Kleiner et al. 2005).  The aggregate NAS is the 
unweighted sum of the scores of each component of the NAS (steatosis [03], lobular 
inflammation [03], ballooning [02]). 
4.5.10.2
NASH Clinical Research Network (CRN) Fibrosis Stage
The NASH CRN fibrosis stage will be assessed at screening and at end-of-treatment.
Fibrosis stage ranges from 04, with higher stages indicating more severe fibrosis 
(Kleiner et al. 2005).  Fibrosis scores for Stage 1 are subdivided to distinguish between 
mild (1A) and moderate (1B) Zone 3, perisinusoidal fibrosis, and portal/ periportal 
fibrosis (Stage 1C).  Stage 2 is perisinusoidal and portal/periportal fibrosis, Stage 3 is 
bridging fibrosis, and Stage 4 is cirrhosis.
4.5.11
Home Glucose Monitoring (Type 2 Diabetes Mellitus Patients 
Only)
A glucose monitor with supplies (including lancets, test strips, and control solution) will 
be provided to all patients with T2DM along with proper training in the use of all 
equipment to monitor blood glucose levels at home.  The investigator should counsel 
patients on the signs and symptoms of hypoglycemia, how to treat the hypoglycemia, 
and when to contact medical personnel.  Starting after the Week 0 visit, any blood 
glucose level 54 mg/dL or 270 mg/dL should be specifically logged as well as any 
symptoms of hypoglycemia experienced.  The investigator should evaluate all reported 


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episodes of hypoglycemia or hyperglycemia to determine the clinical significance and 
the appropriate follow up.
Patients who are not taking insulin therapy should be instructed to measure and log 
fasting blood glucose levels at least twice weekly or if they experience any symptoms of 
hypoglycemia.  
Patients on basal insulin should have at a minimum three-times weekly fasting 
measurements or if they experience any symptoms of hypoglycemia.  Patients on 
regimens with basal and prandial insulin should additionally have fasting, pre-prandial, 
post-prandial, and before-bedtime measurements.
4.5.12
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis unless alternative instructions are provided:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct 
bilirubin, ALP, ALT, AST, uric acid, LDH, gamma-glutamyl transferase (GGT), and 
pre-albumin

Coagulation:  INR, aPTT, and PT

Thyroid function testing:  thyroid-stimulating hormone (TSH) and free thyroxine (T4)
(if abnormal, repeat testing for confirmation)

IGF-1 (if abnormal, repeat testing for confirmation)

Blood alcohol level 


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
Viral serology
–
HIV antibody
–
HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total 
HBcAb test is positive) reflex HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the 
patient has an HBV infection.
–
HCV serology:  HCV antibody and (if HCV antibody test is positive) reflex HCV 
RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA 
test must also be performed to determine if the patient has an HCV 
infection.

HbA1C

Fasting insulin 

Fasting lipids:  cholesterol, LDL cholesterol, HDL cholesterol, very low-density 
lipoprotein (VLDL), and triglycerides 

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed locally at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test (performed by a central or local laboratory).

FSH to confirm postmenopausal state in women without menses for 12 or more 
months without an alternative medical cause

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and reflex microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria) for abnormal urine dipsticks, and urine drug test (at 
screening)

24-hour urine including cortisol and creatinine (reflex testing within 2 week if 24-hour 
urinary cortisol 1.5ULN and 2baseline)

ACTH

25-hydroxy vitamin D
If patient has vitamin D 20 ng/mL at screening, high-dose vitamin D 
(e.g., 50,000 IU weekly 6 weeks) must be initiated prior to randomization, and 
vitamin D Institute of Medicine 2011 recommendations (8002000 IU/Day) 
should be followed throughout the study.
If Week 36 vitamin D level is 20 ng/mL, replenishment must be repeated.

PTH

Bone serum biomarkers (CTX and P1NP)

Serum samples for PK analysis


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
Serum samples for immunogenicity analysis

Blood (plasma and serum) samples for exploratory research on candidate 
biomarkers

Stool samples for exploratory research on the microbiota 

Archival or newly collected liver tissue sample obtained at baseline for determination 
of patient eligibility and for exploratory research on biomarkers

Liver tissue sample obtained at end of treatment, if deemed clinically feasible, for 
determination of response to study treatment and exploratory research on 
biomarkers
In some cases, safety-related decisions, and interventions, e.g., close observation, may 
be made on the basis of local laboratory test results, before central lab results are 
available. 
Exploratory biomarker research may include, but will not be limited to, adipokines, 
cleaved CK18, lipids, biomarkers of fibrosis and MRI-related imaging markers.  
Research may involve extraction of DNA, cell-free DNA, or RNA; analysis of mutations, 
single nucleotide polymorphisms, and other genomic variants; and genomic profiling 
through use of next-generation sequencing (NGS) of a comprehensive panel of genes.  
Genomic research will be aimed at exploring inherited characteristics.  NGS methods 
may include WGS or WES of blood samples, but only at participating sites (see 
Section 4.5.15)
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.16), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Whole blood, plasma, serum, liver tissue, urine and stool samples collected for 
exploratory biomarker research will be destroyed no later than 10 years after the 
final Clinical Study Report has been completed.

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination.


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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on genomic variants, will be patient to 
the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.13
Electrocardiograms
ECG recordings will be obtained at specified timepoints, as outlined in the schedule of 
activities (see 
).  ECGs acquired on different days should be as closely time-
matched as feasible.  Single ECG recordings may be additionally obtained at 
unscheduled timepoints as indicated. 
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting for at least 10 minutes.  All ECGs are to be 
obtained prior to other procedures scheduled at that same time (e.g., vital sign 
measurements, blood draws) and should be obtained around the same time after any 
meal, preferably after a minimum of 3 hours.  Circumstances that may induce changes in 
heart rate, should be avoided during the pre-ECG resting period and during ECG 
recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following should be recorded in the appropriate eCRF:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF based 
on the machine readings of the individual ECG tracings.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  If considered 
appropriate by the Sponsor, ECGs may be analyzed retrospectively at a central 
laboratory.
If at a particular post-dose timepoint the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 
drug discontinuation should be made, as described in Section 4.6.1.  The investigator 


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should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia).
4.5.14
Clinical Outcome Assessments
Patient-reported outcome (PRO) instruments will be completed to assess the treatment 
benefit and more fully characterize the safety profile of BFKB8488A.  In addition, PRO 
instruments will enable the capture of each patient's direct experience with BFKB8488A. 
PRO data will be collected through use of the following instruments:  The Columbia-
Suicide Severity Rating Scale (C-SSRS), the Patient Health Questionnaire-9 (PHQ-9), 
and the Appetite Sensations Visual Analogue Scale (VAS).
The C-SSRS is a tool used to assess the lifetime suicidality of a patient as well as any 
new instances of suicidality.  The electronic self-rated version of the C-SSRS will be 
used to assess suicidal ideation and behavior (SIB) at baseline and monitor for changes 
in SIB at subsequent visits.  For positive scores, the investigator will be alerted and 
should follow up with the patient to provide the appropriate intervention as soon as 
possible. 
The PHQ-9 will be administered for monitoring of potential depression throughout the 
study.  The PHQ-9 is a self-administered diagnostic instrument that scores each of the 
9 Diagnostic and Statistical Manual of Mental Disorders criteria of depression. Following 
study of construct and criterion validity, the PHQ-9 has been shown as a reliable and 
valid measure of depression severity (Kroenke et al. 2001). 
The Appetite Sensations VAS (see Appendix 2) consists of eight items with words 
anchored at each end expressing the most positive and the most negative rating of 
hunger, satiety, fullness, prospective food consumption, desire to eat something fatty, 
salty, sweet, or savory. This scale has reproducibility, power, and validity (Flint et al. 
2000).  The scales have been used with both immediate ("Right Now") and retrospective 
("Past Week") recall periods (Womble et al. 2003) and have demonstrated sensitivity to 
effects of lorcaserin on prospective food consumption (Martin et al. 2011).
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study 
. 
 
,
instruments will be administered before the patient receives any information on disease 
status, prior to the performance of non-PRO assessments, and prior to the 
administration of study treatment, unless otherwise specified.
PRO instruments, translated into the local language as appropriate, will be completed 
through use of an electronic device provided by the Sponsor.  The device will be 
pre-programmed to enable the appropriate instruments to be administered in the correct 
order at each specified timepoint.  The electronic device and instructions for completing 


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the instruments electronically will be provided by the site staff.  The data will be 
transmitted to a centralized database maintained by the electronic device vendor. The 
data will be available for access by appropriate study personnel.
During clinic visits, PRO instruments should be administered as outlined below:

Patients' health status should not be discussed prior to administration of the 
instruments.

Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for patients to complete the instruments.

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions.

Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers.

Site staff should not interpret or explain questions, but may read questions verbatim 
upon request.

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments.
4.5.15
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites)
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  Research will be aimed at exploring inherited characteristics.  The samples 
may be sent to one or more laboratories for analysis.
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's Institutional Review Board 
or Ethics Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a 
site has not been granted approval for WGS or WES, this section of the protocol 
(Section 4.5.15) will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but will also 
be explored in aggregate with data from other studies.  The availability of a larger 


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dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).
Refer to Section 4.5.12 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses.
4.5.16
Optional Samples for Research Biosample Repository
4.5.16.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
 drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.16.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.16) 
will not be applicable at that site.


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4.5.16.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to BFKB8488A, diseases, or 
drug safety:

Leftover blood, serum, plasma, urine, stool, and liver tissue samples (with the 
exception of remaining archival tissue blocks, which will be returned to sites) and 
any derivatives thereof (e.g., DNA, RNA, proteins, peptides)
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.16.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.


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Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.16.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.16.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.


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4.5.16.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Any adverse event CTCAE Grade 4 or higher, regardless of attribution to study drug

Positively detected suicidal ideation type 4 or 5 or suicidal behavior 

24-hour urinary cortisol 1.5ULN and 2baseline, if confirmed on follow up visit
within 2 weeks.

If any signs or symptoms of hyper- or hypothyroidism that accompany changes in 
thyroid function tests (TSH or free T4) that are confirmed by repeat testing.

Abnormal IGF-1 that is confirmed by repeat testing.

Nontraumatic bone fracture 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.  Patients who discontinue treatment prior to study treatment completion will 
participate in the end-of-treatment visit at the time of early discontinuation and will enter 
a follow-up period for a total of 6 weeks.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.


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Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  Patients in the fixed dose cohorts who withdraw from the study 
will not be replaced unless the IMC elects to change the dose, see Section 3.1.2.  
Patients in the 
 may be replaced as determined by the IMC, 
see Section 3.1.2.  Patients who discontinue from the study will participate in the 
end-of-treatment visit at the time of discontinuation.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)




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Patients should be closely monitored for GI adverse events and early intervention is 
recommended.  Patients should be treated as necessary according to standard of care 
(see Table 1).
5.1.1.2
Injection Site Reaction/Allergic or Anaphylactic Reactions to 
BFKB8488A 
Monoclonal antibodies such as BFKB8488A may be associated with localized reactions 
at the site of injection.  Systemic injection-related reactions as well as allergic or 
anaphylactic reactions could possibly also occur.  These reactions can be severe or 
even life threatening. 
Patients will be monitored for these types of reactions during and after receiving 
BFKB8488A and treated as per institutional guidelines.  Study personnel will monitor for 
any injection-site reactions (per criteria in Appendix 4) or drug-related toxicities such as 
anaphylactic and other hypersensitivity reactions after receiving BFKB8488A, including 
assessing vital signs as clinically indicated.
5.1.1.3
Loss of Lean Body Mass or Bone Mineral Density Related to 
Weight Loss
 
 
 
 
 
 
In the dose ranging Phase Ib multiple-dose study in 
humans, there was no significant difference overall between the BFKB8488A- and 
placebo-treated patients. 
 
 
  
 
 
 
 
 
  Additional 
tests may be done if clinically indicated.  Reported fractures will be closely monitored by 




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pressure.  Marked hypertension as defined by a systolic blood pressure 180 mmHg 
that is at least 20 mmHg higher than the baseline measurement will be considered an 
adverse event of special interest, immediately reportable to the Sponsor (see 
Section 5.2.3). 
5.1.1.6
Hypoglycemia
In murine models, BFKB8488A induced antibody-mediated activation of FGFR1/KLB 
complex and improvements in obesity-associated metabolic derangements including 
hyperglycemia (Kolumam et al. 2015).  
 
 
Patients will be monitored for signs and symptoms of hypoglycemia and have blood 
glucose measured at baseline and throughout study.  Patients with T2DM will also be 
provided with a home glucose monitor, supplies, and training to monitor their fasting 
blood glucose levels at least twice weekly or if they experience any symptoms of 
hypoglycemia. Patients taking insulin will have more frequent home glucose monitoring
as instructed in Section 4.5.11. 
5.1.1.7
CNS Effects
 
 
 
 
 
 Additionally, to assess the potential 
CNS effects, mood, suicidal ideation and behavior will be assessed in the study for the 
duration of this trial by administration of the C-SSRS every 2 weeks. Prospective scales 
that monitor depression such as the PHQ-9 will also be administered periodically.
5.1.1.8
Exocrine Function of Pancreas
 
 
 
 Patients that develop diarrhea should be monitored for 
steatorrhea and, if needed, for malabsorption.
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose Modifications
In the fixed dose arms, there will be no dose modifications (dose reductions) for 
BFKB8488A or placebo in this study due to adverse events in individual patients.
 


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5.1.2.2
Treatment Interruption
BFKB8488A treatment may be temporarily suspended in patients who experience a 
treatment-emergent adverse event considered to be related to study drug.  If the event 
improves to Grade 1 or better, treatment will resume at the next scheduled dose.  If one 
or more scheduled dose is missed because of an ongoing adverse event, the study 
treatment may be restarted based on the investigator’s judgment.  Study treatment may 
be suspended for reasons other than a treatment-emergent adverse event (e.g., surgical 
procedures) with Medical Monitor approval.  The investigator and the Medical Monitor 
will determine the acceptable length of treatment interruption.
5.1.2.3
Management Guidelines
Toxicities associated or possibly associated with study treatment should be managed 
according to the management guidelines provided in this protocol or, if not specifically 
mentioned, according to standard medical practice.  
In general, events of Grade 1 and 2 severity as per the Common Terminology Criteria for 
Adverse Events (CTCAE) scale should be treated symptomatically if needed while 
continuing the use of BFKB8488A. Study drug must be interrupted in instances of 
CTCAE Grade 3 adverse events related to study drug, and discontinued if they do not 
resolve to Grade 1 with symptomatic treatment or standard of care, or recur following 
resumption of dosing. All cases of CTCAE Grade 4 regardless of attribution require
study drug discontinuation. A detailed list of adverse events and laboratory 
abnormalities necessitating study treatment discontinuation is included in Section 4.6.1.
Guidelines for management of specific adverse events are outlined in Table 1.




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Table 1
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Hypertension
Grade 1 

Continue study drug.

If 20 mm Hg increases on 2 visits, consider starting anti-
hypertensive medication.
Grade 2 

Continue study drug.

Increase or start anti-hypertensive medication as per local 
standard of care.

Closely monitor blood pressure.
Grade 3

Withhold study drug. 

Manage marked acute hypertension as per institutional 
guidelines.

If the event improves to Grade 1 or less prior to the next 
scheduled dose, study drug may be resumed after discussion 
with the Medical Monitor.
Grade 4 

Discontinue study drug.

Treat per local standard of care.
Increased Liver Enzymes
In patients with BLM of
ALT and AST 1.5ULN:
If ALT or AST 3ULN or 
TBL 1.5BLM
OR
In patients with BLM of 
ALT or AST 1.5 ULN:
If AST or ALT
2BLM or
TBL 1.5BLM

Repeat testing of ALT, AST, ALP and TBL within 4872 hours, 
with inquiry about symptoms.  
If repeat testing above confirms initial result:

Repeat ALT, AST, ALP, and TBL two or three times weekly.  
Frequency of retesting can decrease to once a week or less if 
abnormalities stabilize or the trial drug has been discontinued 
and the subject is asymptomatic.

Obtain a more detailed history of symptoms and prior or 
concurrent diseases.

Obtain a history of concomitant drug use (including 
nonprescription medications and herbal and dietary 
supplement preparations), alcohol use, recreational drug use, 
and special diets.

Rule out acute viral hepatitis types A, B, C, D, and E;
autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease.

Obtain a history of exposure to environmental chemical 
agents.

Obtain additional tests to evaluate liver function, as 
appropriate (e.g., INR, direct bilirubin).

Consider gastroenterology or hepatology consultations.

Consider liver biopsy


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Table 1
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (cont.)
Event
Action to Be Taken
Increased Liver Enzymes (cont.)
In patients with BLM of ALT and 
AST 2ULN: 
If ALT or AST increases to 5BLM

Interrupt or discontinue BFKB8488A.
In patients with BLM of ALT and AST 
2ULN but 5ULN: 
If ALT or AST increases to 3BLM

Interrupt or discontinue BFKB8488A.
In patients with BLM of ALT and AST 
5ULN: 
If ALT or AST increases to 2BLM

Interrupt or discontinue BFKB8488A.
In patients with BLM in normal range or 
ALT or AST 1.5ULN:
If ALT or AST increases to 3ULN 
accompanied by:
a concomitant increase in TBL to 
2ULN 
OR
the INR concomitantly increases by 
0.2 in any patients with signs and 
symptoms of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (5%)

Interrupt or discontinue BFKB8488A.
In patients with BLM of ALT or AST 1.5
ULN:
If ALT or AST increases to 2BLM 
accompanied by: 
a concomitant increase in TBL to
2BLM 
OR 
the INR concomitantly increases 
by 0.2 in any patients with signs and 
symptoms of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (5%)

Interrupt or discontinue BFKB8488A.

In all the above instances, continue monitoring the liver enzymes.  If the levels of liver 
enzymes return to baseline levels, or alternate causes are clearly identified, resumption of 
dosing may be considered in some cases after discussion with the Medical Monitor.
BLMbaseline measurement; INRInternational Normalized Ratio; TBLtotal bilirubin; 
ULNupper limit of normal.


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5.1.2.4
Injection-Site Reaction/Allergic and Anaphylactic Reactions
Local injection site reactions, will be treated as per local or institutional standard 
operating procedures. The severity of local reaction, including pain, erythema, 
tenderness, itching, induration, ulceration, necrosis, etc., should be graded per FDA 
Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (see Appendix 4). Additionally, maximal 
diameter of individual ISR, duration of symptoms and treatment if any, should be 
recorded (see Section 5.3.5.1 and Appendix 4).
Guidance for managing anaphylaxis is described in Appendix 5.
5.1.2.5
Loss of Bone Mineral Density Related to Weight Loss
Patients will be closely monitored for bone fractures and discontinued from treatment in 
the event of non-traumatic bone fractures.
5.1.2.6
Hypoglycemia
Patients will be monitored for signs and symptoms of hypoglycemia and have blood 
glucose measured at baseline and throughout study.  In the event that a patient shows 
signs or symptoms of hypoglycemia, has one documented blood glucose level 
of 54 mg/dL, or has two documented blood glucose levels of 270 mg/dL, the 
investigator should use clinical judgement to implement glycemic rescue treatment 
consistent with the local standard of care.  Patients should be advised on the 
management of hypoglycemia according to local standard of care, and dosage of 
concurrent antidiabetic medication should be adjusted as necessary.  Any treatment 
administered as part of glycemic rescue should be documented and reported to the 
Medical monitor immediately (see Section 5.2.3).  For patients with blood glucose levels 
of 270 mg/dL, continuation of the patient in the study will be determined by the Medical 
Monitor after discussion with the investigator.
5.1.2.7
Hypothalamic Pituitary Axis
Patients will be monitored for abnormalities in free T4, TSH, IGF-1, ACTH, 24-hour 
urinary cortisol, and 24-hour urinary creatinine periodically during the study. If a patient
is found to have an elevated 24-hour urinary free cortisol [UFC] 1.5ULN and 
2baseline, a repeat UFC will be performed within two weeks for confirmation. If the 
confirmatory test is 1.5ULN and 2baseline, the patient must be discontinued from 
BFKB8488A treatment and referred to an endocrinologist for further evaluation and 
treatment. BFKB8488A will also be discontinued in any patient who develops an 
abnormal IGF-1 levels, based on age-adjusted values for the population, during the 
study that is confirmed by a repeat measurement. For any patients who develop 
abnormalities in TSH and/or free T4 (based on reference values for the population), 
repeat testing to confirm the increase, followed by further evaluation by an 
endocrinologist needs to be done. BFKB8488A must be discontinued if any signs or 
symptoms of hyperthyroidism or hypothyroidism accompany the changes in TSH and/or 
free T4.


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5.1.2.8
CNS Effects and Mood
The effects on CNS and mood will be closely monitored. If a patient has a PHQ-9 score 
at or above 15 (moderately severe depression), at or above 10 (moderate depression)
with a score of 2 or 3 for the question “Thoughts that you would be better off dead, or 
thoughts of hurting yourself in some way?”, or a C-SSRS suicidal ideation type 4 or 5 or 
behavior, he/she would be referred for timely psychiatric evaluation and/or discontinued
from treatment.  Study drug should be held while awaiting psychiatric evaluation.
Additional monitoring of anxiety or insomnia may be performed if needed.
5.1.2.9
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms and 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms 

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 
of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  In 
such a situation, saving all available ECG data is highly suggested.
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients.  The Medical Monitor should be notified as soon as 
possible.
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 


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signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9
and 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug


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
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Marked hypertension as defined by a systolic blood pressure 180 mm of Hg that is 
at least 20 mm higher than the baseline measurement.

Weight loss greater than 10% of baseline (Day 1) body weight within a 12-week 
period at any point in the study

Glucose measurements, serum or home glucometer readings, 54 mg/dL 

Symptomatic hypoglycemia causing altered mental status, seizures, or requiring IV 
dextrose for treatment

Increases in QT interval, unless there is a clear alternative cause for the changes

Sustained (at least 2 ECG measurements 30 minutes apart) QTcF that is 
500 ms and/or 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms
An episode of torsades de pointes or a new ECG finding of clinical concern

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 


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considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 42 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of anaphylactic reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms


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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.


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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of NASH.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to progression of NASH, "nonalcoholic steatohepatitis 
progression" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of NASH
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on histologic and imaging criteria.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Planned hospitalization required by the protocol

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours


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5.3.5.12
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For BFKB8488A (or matching placebo), adverse events 
associated with special situations should be recorded as described below for each 
situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with BFKB8488A (or matching placebo), 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.


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As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events.
5.3.5.14
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Covance Medical Monitor contact information:
Medical Monitors:
, M.D.
Telephone No.:
 (United States)
Telephone No.:
(ex-United States)
Alternate Medical Monitor contact information for all sites:
Medical Monitor:
, M.D., Ph.D.
Telephone Nos.:
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 42 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 42 days after the final dose 
of study treatment are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 42 days after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
132 days after the final dose of study drug.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  When permitted by the site, the pregnant partner would
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form with additional
information on the pregnant partner and the course and outcome of the pregnancy as it
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).


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If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
42 days after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 


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Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

BFKB8488A Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary efficacy objective for this study is to evaluate the efficacy of BFKB8488A 
compared with placebo on the basis of the proportion of patients with resolution of NASH 
and no worsening of fibrosis.  The primary and secondary efficacy analyses will be 
based on a modified intent-to-treat (mITT) approach.  All patients who received at least 
one dose of study drug will be included in the mITT population, with patients grouped 
according to the treatment assigned at randomization.  Analyses will be based on the 
final biopsy at Week 52 or MRI-PDFF measured over the course of the study.
The final analysis of data from the study will be performed when all patients have either: 
(i) completed the Week 52 visit and associated liver biopsy or (ii) withdrawn from the 
study prior to Week 52.  The data analysis plan (DAP) will be specified prior to 
unblinding.
6.1
DETERMINATION OF SAMPLE SIZE
 will be enrolled in two cohorts: 180 patients in the 
fixed dose cohort and 
. In the four fixed 
dose arms patients are randomized in 1:3:3:2 ratio among 3 active drug arms and a 
placebo arm, with approximately 20 patients in the 50 mg BFKB8488A Q2W arm, 


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approximately 60 patients in both the 75 mg BFKB8488A Q2W and 100 mg BFKB8488A
Q2W arm and approximately 40 in the placebo arm.  
  
 
 
 
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, diabetes status, and 
important liver indicators of disease) will be summarized using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate.  Summaries will be presented overall and by treatment group.
6.4
EFFICACY ANALYSES
Efficacy analysis will be conducted for the modified intent-to-treat population, defined as 
all randomly allocated patients who received at least one dose of BFKB8488A or 
placebo.  Sensitivity analyses of additional study populations (e.g., completers, or per 
protocol [excluding major protocol violators]) may also be performed for the primary 
endpoint or key secondary endpoints and will be detailed in the DAP.  Statistical tests 
will be conducted at the 0.05 significance level for the modified intent-to-treat (mITT) 
population. No multiple testing- adjustment is planned.  Further details will be specified 
in the DAP prior to unblinding.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint for this study is resolution of NASH with no worsening of 
fibrosis at Week 52 as determined by histology as defined in Section 2.1.1.  The primary 
endpoint will be compared between each of the two fixed BFKB8488A arms and the 
single variable dose arm of BFKB8488A against the pooled placebo arms using an 
appropriate method such as the Cochran-Mantel-Haenszel test statistic, stratified by the 
factors used at randomization.  Reporting details and methodology including missing 
data handling will be specified in the DAP.


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6.4.2
Secondary Efficacy Endpoints
Secondary endpoints for this study are as follows:

Reduction in liver fat from baseline at Week 52 as measured by MRI-PDFF

Improvement in NAS score by at least 2 points from baseline at Week 52

Improvement in fibrosis of at least 1 stage from baseline with no worsening of NASH 
at Week 52
See Section 2.1.2 for definition of the endpoints.  The secondary endpoints will be 
analyzed in the same fashion as the primary endpoint except MRI-PDFF which will use 
an appropriate method for continuous measurements.
Further details for the secondary efficacy analyses will be specified in the DAP.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all subjects who received at least one dose 
of study drug with subjects grouped according to treatment received.  All verbatim 
adverse event terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms, and adverse event severity will be graded according 
CTCAE grading scale as specified in Section 5.
6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of subjects with at least one post-dose serum PK 
sample in which BFKB8488A is detectable, with subjects grouped according to treatment 
received. 
Individual and mean serum BFKB8488A concentration data will be tabulated and 
summarized (mean, standard deviation, coefficient of variation, median, minimum, and 
maximum) at relevant timepoints by dose level.  Inter-subject variability will be 
evaluated. 
Additional PK analyses (e.g. using a population PK approach) will be conducted as 
appropriate and may be reported separately.
6.7
IMMUNOGENICITY ANALYSES 
Patient sample assessment for the presence of ADA are triaged by first testing in a 
screening assay, followed by testing screen ADA-positive samples in a confirmatory 
assay.  Confirmed ADA-positive sample are then evaluated for the relative quantitation 
of ADA in a titration assay.  


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Patient ADA status is defined as follows:

ADA-negative:  Any patient with no post-baseline ADA-positive sample

ADA-positive: 
–
Patients with baseline ADA-negative and any post-baseline ADA-positive 
sample (treatment-induced); 
–
Patients who are baseline ADA-positive and whose ADA titer is 4-fold greater 
than the baseline value (i.e., 0.6 titer units greater than baseline; treatment-
enhanced).

Treatment-emergent ADA-positive:  Treatment-induced and treatment-enhanced 

Treatment-unaffected:  Baseline ADA-positive with post-baseline ADA-positive titers 
4-fold baseline (i.e., 0.6 titer unit increase)
Further characterization of the ADA-positive responses may be conducted based upon 
the initial assessment of the data, for example domain mapping of the ADA binding site.
Both baseline prevalence and post-baseline incidence of ADA-positive patients will be 
reported.  An impact assessment of ADA on clinical endpoints of interest will be 
conducted.  This will include the assessment of ADA impact on PK parameters, PD, 
safety, and efficacy endpoints.  Included in this analysis will be a comparison of ADA-
negative versus treatment-emergent ADA-positive patients, and potentially by ADA-
positive titer subgroups.  Additional analyses may be conducted based upon these 
results.  The relationship between ADA status and safety, activity, PK, and biomarker 
endpoints may be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Exploratory analyses will be conducted to evaluate the effect of BFKB8488A on 
exploratory biomarkers such as those listed in Section 2.5.  Exploratory biomarkers may 
be analyzed before and after dosing with BFKB8488A to determine the relationship 
between PK exposure and exploratory biomarker levels.  In addition, relationships 
amongst biomarkers may be assessed.
WGS data will be analyzed in the context of this study and explored in aggregate with 
data from other studies to increase researcher's understanding of disease pathobiology 
and guide the development of new therapeutic approaches.
6.9
HEALTH STATUS UTILITY ANALYSES
Change from baseline in VAS scores will be calculated at specified timepoints.


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6.10
INTERIM ANALYSES
6.10.1
Planned Interim Analysis
A single planned interim analysis will be conducted when at least 
 of the patients in 
the fixed dose arms have completed the Week 16 MRI-PDFF.  The interim analysis 
results will be reviewed.  A DAP will be drafted prior to the interim, including the 
variables that will be assessed by treatment arm as well as a list of individuals who will 
be unblinded including the IMC.
6.10.2
Optional Interim Analyses
The Sponsor may choose to conduct interim efficacy analyses of select endpoints.  The
decision to conduct an optional interim analysis and the timing of the analysis will be 
documented in the Sponsor's trial master file prior to the conduct of the interim analysis.  
The interim analysis will be reviewed by an IMC.  Details of the interim will be 
pre-specified in the DAP prior to review by the IMC.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data, pharmacokinetic, 
biomarker, and imaging results will be sent directly to the Sponsor, using the Sponsor's 
standard procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
PRO data will be collected through the use of an electronic device provided by a vendor 
(see Section 7.3 for details).
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
An electronic device will be used to capture PRO data.  The device is designed for entry 
of data in a way that is attributable, secure, and accurate, in compliance with U.S. Food 
and Drug Administration (FDA) regulations for electronic records (21 CFR Part 11).  The 
data will be transmitted to a centralized database maintained by the electronic device 
vendor.
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 


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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.


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A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.


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Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.5).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for controlling and monitoring these risks. Risk monitoring will 


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include the selection of risk-based parameters (e.g., adverse event rate, protocol 
deviation rate) and the establishment of quality tolerance limits for these 
parameters. Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed. Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored by Genentech, Inc., a member of the Roche group, and will 
be managed by a contract research organization (CRO). The CRO deliverables will 
include but not be limited to clinical operations management, safety support, and 
medical monitoring support to the Sponsor. 
Sites globally will participate to enroll up to 
.  Enrollment will 
occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of MRI and DXA scans throughout the trial.  The review facility will 
retain copies of scans for centralized assessments of imaging-related endpoints.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 


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with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
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improves the cardiometabolic profile in otherwise healthy obese 
subjects-preliminary results from the first-in-human single ascending dose study 
[abstract]. American Diabetes Association Annual Meeting 2017a; abstract 1096-P.
Arora PS, Wong C, Baruch A, et al. Weight loss unrelated to decrease in calorie intake 
after a single dose of a bispecific antibody to FGFR1/Klothoin obese subjects 
[abstract]. European Association for the Study of Diabetes 2017b; abstract110.
Atwell S, Ridgway JB, Wells JA, et al. Stable heterodimers from remodeling the domain 
interface of a homodimer using a phage display library. J Mol Biol 1997;270:2635.
Calle RA, Rossulek MI, Dong J, et al. Metabolic effects of a novel FGF21 analogue 
administered for 4 weeks to patients with T2DM [abstract]. Diabetes 
2014;63(Suppl 1):A126-OR.
Chalasani N, Younossi Z, Lavine JE, et al. The Diagnosis and Management of 
Nonalcoholic Fatty Liver Disease: Practice Guidance from the American 
Association for the Study of Liver Diseases. Hepatology 2018;67:328357.
Flint A, Rabe A, Blundell JE, et al. Reproducibility, power and validity of visual analogue 
scales in assessment of appetite sensations in single test meal studies. Intl J Obes 
Relat Metab Disord 2000;24:3848.
Foltz IN, Hu S, King C, et al. Treating diabetes and obesity with an FGF21-mimetic
antibody activating the Klotho/FGFR1c receptor complex. Sci Transl Med 
2012;4:162ra153.
Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese 
human subjects with type 2 diabetes. Cell Metab 2013;18:33340.
Kleiner DE, Brunt EM, Natta MV, et al. Design and validation of a histological scoring 
system for nonalcoholic fatty liver disease. Hepatology 2005;41:131321.
Kolumam G, Chen MZ, Tong R, et al. Sustained brown fat stimulation and insulin 
sensitization by a humanized bispecific antibody agonist for fibroblast growth factor 
receptor 1/βKlotho complex. EBioMedicine 2015;2:73043.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med 2001;16:60613.
Lan T, Morgan DA, Rahmouni K, et al. FGF19, FGF21, and an FGFR1/β-Klotho-
activating antibody act on the nervous system to regulate body weight and 
glycemia. Cell metabolism 2017;26:70918.
Martin CK, Redman LM, Zhang J, et al. Lorcaserin, a 5-HT(2C) receptor agonist, 
reduces body weight by decreasing energy intake without influencing energy 
expenditure. J Clin Endocrinol Metab 2011;96:83745.


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Muntner P, Shimbo D, Carey RM. Measurement of blood pressure in humans: a 
scientific statement from the American Heart Association. Hypertension 
2019;73:e3566.
Nelson JE, Roth CL, Wilson L, et al. Vitamin D Deficiency is Associated with Increased 
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Resonance Imaging Estimation of Liver Fat and Volume in Patients With 
Nonalcoholic Steatohepatitis. Clinical Gastroenterology and Hepatology 2015;13:
5618.
Roesch SL, Styer AM, Wood GC, et al. Perturbations of Fibroblast Growth Factors 19 
and 21 in Type 2 Diabetes. Plos One 2015;10:e0116928.
Sanyal A, Charles ED, Neuschwander-Tetri B, et al. BMS-986036 (pegylated FGF21) in 
patients with non-alcoholic steatohepatitis: a phase 2 study. J Hepatol 
2017;66:S89-S90.
Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonalcoholic fatty liver vs 
nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-
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Womble LG, Wadden TA, Chandler JM, et al. Agreement between weekly vs. daily 
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Wu AL, Feng B, Chen MZ, et al. Antibody-mediated activation of FGFR1 induces FGF23 
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Appendix 2
Appetite Sensations Visual Analogues Scale Questionnaire
I was not hungry at all.
How hungry did you feel?
I had never been hungrier.
I was completely empty.
How satisfied did you feel?
I could not eat another bite.
Not at all full
How full did you feel?
Totally full
Nothing at all
How much did you think you 
could eat?
A lot
Yes, very much
Did you want to eat 
something sweet?
No, not at all
Yes, very much
Did you want to eat 
something salty?
No, not at all
Yes, very much
Did you want to eat 
something savory?
No, not at all
Yes, very much
Did you want to eat 
something fatty?
No, not at all


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Appendix 4
Grading of Injection Site Reactions
These guidelines are adapted from the FDA Guidance on Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
and intended as a reference for grading injection site reactions.  Injection-site reactions 
should be treated as per pertinent local or institutional standard operating procedures.
Local Reaction to 
Injectable Product
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Pain 
Does not 
interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever 
24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Tenderness 
Mild 
discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/redness a
2.55 cm
5.1–10 cm 
10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/swelling b
2.5–5 cm 
and does 
not interfere 
with activity 
5.1–10 cm or 
interferes with 
activity 
10 cm or 
prevents daily 
activity 
Necrosis 
ERemergency room.
a In addition to grading the measured local reaction at the greatest single diameter, the 
measurement should be recorded as a continuous variable.
b Induration/swelling should be evaluated and graded using the functional scale as well as the 
actual measurement.


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Appendix 5
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
RECOMMENDED EQUIPMENT AND MEDICATION
The following equipment and medication are recommended in the event of a suspected 
anaphylactic reaction during study treatment injection in a hospital setting:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment injection, 
the following procedures are recommended:
1.
Stop the study treatment injection, if possible.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.
7.
Collect serum samples for immunogenicity testing.
8.
Ask the patient to return for immunogenicity sample collection at the time of 
washout, if appropriate.