Clinical trial NCT07052682
Conditions: Steatohepatitis
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2023-01-18; Completion date: 2024-12-30
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main aim of this study is to evaluate the safety and tolerability of ontamalimab in participants with a liver disease called nonalcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH) with scarring in the liver (fibrosis stage 1 to 4). The study will also check if there are any important changes in the body's health markers (biomarkers) from the beginning of the study to see if ontamalimab stops liver scarring and reduces inflammation of the liver.

Participants will be in the study for approximately up to 46 weeks.

Detailed description:

Arms: arm 1: Participants receive ontamalimab 75 milligrams (mg) subcutaneous (SC) injection using a prefilled syringe once every 4 weeks (Q4W) on Day 1 and the last dose is administered at Week 20 with a total treatment period of 24 weeks.
Interventions: intervention 1: Ontamalimab
Intervention descriptions: intervention 1: Ontamalimab SC injection.

Protocol documents:
Prot_000.pdf: 
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TAKEDA PHARMACEUTICALS
PROTOCOL
A Multicenter, Single-arm, Open-label, Phase 1b Study to Explore the Mechanism of 
Action and Evaluate the Safety of Ontamalimab in Participants With Nonalcoholic 
Steatohepatitis With Fibrosis Stage 1 Through 4
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421 USA
Study Number:
TAK-647-1001
Study Phase:
Phase 1b 
IND Number:
163193
EudraCT/CTIS 
Number:
Not applicable
Investigational 
Product:
TAK-647 (ontamalimab)
Date:
18 September 2023
Version/Amendment 
Number:
Amendment 3
Amendment History:
Date
Amendment Number
Region
02 November 2022
Initial version
Global
15 December 2022
Amendment 1
Global
25 April 2023
Amendment 2
Global
18 September 2023
Amendment 3
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. Furthermore, the information is only 
meant for review and compliance by the recipient, his or her staff, and applicable institutional 
review committee and regulatory agencies to enable conduct of the study.
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CONFIDENTIAL
Page 3
TAK-647 (ontamalimab)
Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
18 Sep 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Summary of Change(s) Since the Last Version of the Approved Protocol
Protocol Amendment 3
Amendment Date:
18 September 2023
Global/Region/Country/Site 
Specific:
Global
Overall Reason for the Amendment
The overall reasons for this protocol amendment are to: 
•
Revise inclusion and exclusion criteria to improve study feasibility.
•
Clarify the screening period eligibility and extension of its duration.
•
Clarify the acceptable conditions for including severe acute respiratory syndrome coronavirus-2 
(SARS-CoV-2)-infected participants into the study and to allow adequate time for recovery of symptoms 
before screening.
Description of Each Change and Rationale 
Section(s) Affected by 
Change
#
Description of change(s)
Rationale for change(s)
Section
1.
Revised the title of the protocol from, “A 
Multicenter, Single-arm, Open-label, 
Phase 1b Study to Explore the 
Mechanism of Action and Evaluate the 
Safety of Ontamalimab in Participants 
With Nonalcoholic Steatohepatitis With 
Fibrosis Stages 2 Through 4” to “A 
Multicenter, Single-arm, Open-label, 
Phase 1b Study to Explore the 
Mechanism of Action and Evaluate the 
Safety of Ontamalimab in Participants 
With Nonalcoholic Steatohepatitis With 
Fibrosis Stage 1 Through 4”.
Correction.
Section 1.1 Synopsis
2.
Added the word “noncirrhotic (F1-F3)” 
to define the fibrosis stages F1-F3.
Replaced “evidence for nonalcoholic 
steatohepatitis (NASH)” or “biopsy-
confirmed NASH” with “indication 
of/for NASH”.
Revised the statement from, 
“Ontamalimab will be administered at 
Day 1 and Q4W thereafter for up to 
24 weeks (last dose at Week 20)” to 
“Ontamalimab will be administered 
subcutaneously (SC) every 4 weeks 
(Q4W) starting on Day 1 and the last 
dose is administered at Week 20 (total 
treatment period is 24 weeks)”.
Added the word “clinically 
significant” to provide clarification on 
Clarification.
Section 1.1 Synopsis
Figure 1 Study Schema
Section 1.3.1 Schedule of 
Activities: Screening Period
Section 1.3.2 Schedule of 
Activities: Treatment Period
Section 4.1 Overall Design
Section 4.4 End of 
Study/Study Completion 
Definition
Section 5.1 Inclusion 
Criteria, Criteria #6 and #13
Section 5.2 Exclusion 
Criteria, Criteria #1, #2, #13,
#21
Section 5.1.1 Justification of 
Inclusion Criteria
Section 5.4 Screening
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CONFIDENTIAL
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TAK-647 (ontamalimab)
Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
18 Sep 2023
Description of Each Change and Rationale 
Section(s) Affected by 
Change
#
Description of change(s)
Rationale for change(s)
Section
“abnormal chest X-ray findings” in 
Exclusion criterion #13.
Revised Exclusion criteria #1, #2 and
#21.
Screening Period: Added a few 
statements related to screening period.
1. “(Maximum allowed time between 
historical liver biopsy and first dose 
of study drug is 34 weeks for any 
participant, except for the participants 
who test positive for SARS-CoV-2 at 
screening)”.
2. “Progression of screening is 
contingent on successful 
confirmation of eligibility along with 
the sponsor's approval”.
3. “In case of positive test for SARS-
CoV-2 infection, screening may be 
paused for an additional 2 weeks (ie, 
screening period of up to 12 weeks)”.
4. “The screening period can be 
extended by 2 weeks for any reason 
(including but not limited to a repeat 
test requirement for select and 
predefined measurements) on a 
case-by-case basis with the sponsor’s 
approval”.
5. In case of positive test for 
SARS-CoV-2 infection, the total 
study period could be up to 48 weeks 
(ie, screening period of up to 
12 weeks).
6. Revised the statement from “An 
individual who has been designated a 
screen failure may be rescreened 
once, except for participants who fail 
the histological evaluation of the liver 
biopsy.” to “An individual who has 
been designated a screen failure may 
be rescreened once”.
Schedule of Activities: Clarified in the 
Tables 1, 2 and 3.
1. Revised the table title from “Table 1. 
Schedule of Activities: Screening 
Period” to “Table 1. Schedule of 
Activities: Screening Period (Visit 1 
and 2)”.
2. Removed columns of Visit 4a and 
Visit 4a2 from Table. Schedule of 
Activities: Treatment Period, 
follow-up, and End of Study.
Section 5.4.1 Screen 
Failures
Section 5.5 Criteria for 
Temporary Delaying 
Enrollment
Section 6.1 Study Drug 
Administered
Section 8 Study 
Assessments and Procedures
Section 8.2.8 Liver Biopsy
Section 8.3.11.1 Time 
Period and Frequency for 
Collecting Adverse Event 
and Serious Adverse Event 
Information
Section 9.3 Biomarker and 
Noninvasive Test Analyses
Section 10.1.5.2 Other 
Committees
Section 10.3.1 Definition of 
Adverse Event
Section 10.3.4.9
Pretreatment-emergent 
Adverse Events
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
18 Sep 2023
Description of Each Change and Rationale 
Section(s) Affected by 
Change
#
Description of change(s)
Rationale for change(s)
Section
3. Added a table, “Table 2. Schedule of
Activities: Screening Period (Visit 4a
and 4a2)”.
4. Revised the table numbers and
footnote sequences.
5. Revised “footnote a” in Table 3.
Pro-C3/ELF score: Revised the
statements on the liver biopsy
eligibility in participants with Pro-C3
≥12.6 ng/mL and ELF score ≥7.7.
Other changes include:
o
From “During the screening period,
Pro-C3, ELF, and other exploratory
markers will be measured at 3 visits
(including Day 1 predose) to
determine intra-participant
variability.” to “Pro-C3, ELF, and
other exploratory markers will be
measured at 2 screening visits (SV1
and SV2) and Day 1 [D1] predose
measurement during treatment period
to determine intra-participant
variability.”
Screening visits: Changes include:
1. From “The following laboratory
findings are exclusionary for all
participants if found during either
screening visit (Week -8 or
Week -6)” to “The following
laboratory findings are exclusionary
for all participants if found during
screening visits (Week -8 [SV1],
Week -6 [SV2] or at Day -4 visit
[Visit 4a2])” in Exclusion criterion
#1.
2. From “For biomarkers except cT1
MRI, data from all available
sampling during screening (including
the Day 1 predose measurement) will
be averaged to establish the stable
baseline value.” to “For biomarkers
except cT1 MRI, data from all
available sampling during screening
period (SV1 and SV2) and D1
predose measurement during
treatment period will be averaged to
establish the stable baseline value.”
Adverse Events: Added a statement to
further define Adverse Event, “an
adverse event (AE) is defined as any
untoward medical occurrence in a
clinical investigation participant who
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
18 Sep 2023
Description of Each Change and Rationale 
Section(s) Affected by 
Change
#
Description of change(s)
Rationale for change(s)
Section
has signed informed consent to 
participate in a study; it does not 
necessarily have to have a causal 
relationship with the treatment”. Other 
changes include:
1. Revised “footnote b” for “Events 
NOT Meeting the AE Definition”.
2. Added a subsection to define 
“Pretreatment-emergent Adverse
Events” under section “Recording 
and Follow-up of Adverse Events”.
3. Added “including pretreatment-
emergent and treatment-emergent” in 
parenthesis.
3.
Added a statement “not more than four 
participants with F1 fibrosis will be 
enrolled in this study” in order to define 
a capping on F1 fibrosis participants 
enrollment in the study.
To have a wider and diverse 
range of participants from all 
fibrosis stages (F1 through 
F4cc) enrolled in the study.
Section 1.1 Synopsis
Section 4.1 Overall Design
4.
Removed Inclusion Criterion #4 to 
eliminate the FibroScan-aspartate 
aminotransferase (FAST) Score as an 
eligibility criterion for liver biopsy.
Revised Inclusion Criterion #6 from: 
“The participant has a diagnosis of 
NASH confirmed via biopsy (NAS ≥4 
with at least 1 point each in steatosis, 
ballooning, and lobular inflammation) 
and liver fibrosis stage F2, F3, or F4cc 
according to NASH CRN, and 
established according to appropriate 
guidelines” to “The participant has 
indication of NASH via biopsy (NAS 
≥3 with at least 1 point in lobular 
inflammation) and liver fibrosis stage 
F1 through F4cc according to NASH 
CRN”.
Revised the statement from
“Enrollment of F2 and F3 participants 
at a 1:1 ratio will not be required” to 
“Enrollment of F1, F2 and F3 
participants at a 1:1:1 ratio will not be 
required”. 
Revised the justification for the 
inclusion criteria.
To improve study feasibility 
by expanding the study 
inclusion parameters while 
maintaining a population that 
is optimal (meeting the same 
threshold for elevated Pro-C3 
and ELF) for assessing the 
anti-inflammatory/ani-
fibrogenic mechanism of this 
drug.
1.
NAS ≥4 to NAS ≥3 to 
reduce screen failures on 
NAS subscores due to 
nonreliability of the 
ballooning score.
2.
Retaining “with at least 
1 point in lobular 
inflammation”, as this is 
important for the 
mechanism of action.
3.
To lower the fibrosis 
score requirement from 
F2 to F1, improving study 
eligibility.
Section 1.1 Synopsis
Figure 1 Study Schema
Section 1.3.1 Schedule of 
Activities: Screening Period
Section 2.2.1 Indication and 
Current Treatment Options 
Section 3 Objectives and 
Endpoints
Section 4.1 Overall Design
Section 4.2 Scientific 
Rationale for Study Design
Section 5.1 Inclusion 
Criteria, Criteria #4 and #6
Section 5.1.1 Justification of 
Inclusion Criteria
Section 8.2.3
FibroScan-Aspartate 
Aminotransferase Score
Section 9.3 Biomarker and 
Noninvasive Test Analyses
5.
Revised the Exclusion criterion #6a 
increasing HbA1c requirement of ≥8% 
to ≥9% at Week -8 (SV1).
To improve study feasibility, 
recognizing the study 
population to be enrolled.
Section 1.1 Synopsis
Section 5.2 Exclusion 
Criteria, Criteria #6a
6.
Removed “dose increased” and “dose 
reduced” from Action Taken Concerning 
Intervention(s).
To correct the list of possible 
actions that can be taken in 
response to an adverse event, 
Section 10.3.4.4 Action 
Taken
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Description of Each Change and Rationale 
Section(s) Affected by 
Change
#
Description of change(s)
Rationale for change(s)
Section
given that a single dose of 
ontamalimab (75 mg) is 
available for use in this study.
7.
Removed Exclusion Criteria #17 
“severe acute respiratory syndrome 
coronavirus-2 (SARS-CoV-2) 
infection” from the exclusion criteria. 
Specified the screening period 
requirement in case of symptomatic 
and asymptomatic SARS-CoV-2 
patients to be included in the study.
Added a heading in Table 1 Schedule 
of Activities; Screening Period, as 
“SARS-CoV-2 infections”. 
Revised the footnote sequence, added
and explained “footnote s” in Table 1.
To provide clarification on 
acceptable conditions for 
including SARS-CoV-2–
infected participants into the 
study and to allow adequate 
time for recovery of 
participants (symptoms are 
resolved) before completion of 
screening.
Section 1.1 Synopsis
Section 1.3.1 Schedule of 
Activities: Screening Period
Section 5.2 Exclusion 
Criteria, Criteria #17
8.
Removed “after 4 weeks of last sample 
taken at the initial screening” from 
Screen Failures.
To allow participants to 
rescreen on a case-by-case 
basis after discussion with the 
investigator.
Section 5.4.1 Screen 
Failures
9.
Added “and samples for immunogenicity 
should be collected when worsening of a 
disease is reported as an AE” in the 
section Study Assessments and 
Procedures.
To clarify the instructions for 
collection of samples for 
immunogenicity in case of 
worsening of a disease being 
reported as an AE.
Section 8 Study 
Assessments and Procedures
10. Revised and added an additional
statement to Exclusion criterion #7 
“Treatment with leukocyte apheresis 
or selective lymphocyte, monocyte, or 
granulocyte apheresis or plasma 
exchange 30 days before baseline 
(Day 1)”.
Removed “within 6 months” from 
FAST Score subsection of Biomarker 
and Noninvasive Test Assessments.
Removed the word “baseline” and 
from “abdominal MRI visit” and added 
“Visit 4a” in parenthesis.
Removed “Visits 4a, 4a2, and 4b 
comprise the baseline visit” from 
footnote a of Table 3.
Replaced “before screening” to 
“before baseline (Day 1)” in Exclusion 
criteria #25 and #26.
Added “X” under Visit 2 (Table 1) for 
Blood sample-hematology panel.
Removed “footnote p to X” under 
Visit 1 (Table 1) for TB test.
Added “footnote p to X” under Visit 1
(Table 1) for Urine drug screening.
Correction.
Section 1.1 Synopsis
Figure 1 Study Schema
Section 1.3.1 Schedule of 
Activities: Screening Period, 
Table 1 (Visit 1 and 2)
Section 1.3.1 Schedule of 
Activities: Screening Period, 
Table 2 (Visit 4a and 4a2)
Section 1.3.2  Schedule of 
Activities: Treatment Period, 
Follow-up, and End of 
Study, Table 3
Section 4.1 Overall Design
Section 5.2 Exclusion 
Criteria, Criteria #6a, #7, 
#25, #26
Section 8.2.3
FibroScan-Aspartate 
Aminotransferase Score
Section 8.2.10
HepQuant-SHUNT Disease 
Severity Index
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
18 Sep 2023
Description of Each Change and Rationale 
Section(s) Affected by 
Change
#
Description of change(s)
Rationale for change(s)
Section
Revised “footnote h” in Table 1 and 
“footnote d” in Table 3. 
Removed the sentence in parenthesis 
“optional if the site is unable to 
perform this assessment” related to 
HepQuant-SHUNT DSI.
See Section 10.6 for protocol history, including all previous amendments.
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
18 Sep 2023
ADDITIONAL INFORMATION 
The study operations manual contains additional contact information for: 

Medical monitor, for medical advice on the protocol and the study drug 

Sponsor’s responsible medical officer

Monitor assigned to the study site, for general advice on protocol procedures 

Serious adverse event (SAE) reporting 

Pregnancy reporting 

Product complaints
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CONFIDENTIAL
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
18 Sep 2023
INVESTIGATOR AGREEMENT 
I confirm that I have read and understand this protocol, the Investigator’s Brochure, prescribing 
information, and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, life, 
dignity, integrity, confidentiality of personal information, safety, privacy, and well-being of 
study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Good Clinical Practice (GCP).

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) as defined in this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the Investigator as described in this protocol.
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a potential participant to obtain their informed consent to 
participate.
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study.
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor.
Signature of Investigator
Date
Investigator Name (print or type)
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
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Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
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ADMINISTRATIVE INFORMATION 
CONTACTS
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers and instructions on specific requirements for sample 
collection, assessments, and process is given in the study operations manual and relevant 
guidelines provided to the site. 
Takeda-sponsored investigators will be provided with emergency medical contact information 
cards to be carried by each participant, per individual country requirements.
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Study No. TAK-647-1001 Protocol Incorporating Amendment No. 3
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PRODUCT QUALITY COMPLAINTS
A product quality complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, strength, purity, 
effectiveness, or performance of a product, device, or combination product after it is released for 
distribution. 
Report product complaints using the form called “Clinical Trial Material Complaint Form.” 
Send it to the following email address: ctmcomplaint@takeda.com
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TABLE OF CONTENTS
APPROVALS.................................................................................................................................2
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ......................................3
ADDITIONAL INFORMATION.................................................................................................9
INVESTIGATOR AGREEMENT .............................................................................................10
ADMINISTRATIVE INFORMATION.....................................................................................12
PRODUCT QUALITY COMPLAINTS....................................................................................13
TABLE OF CONTENTS ............................................................................................................14
LIST OF TABLES.......................................................................................................................19
LIST OF FIGURES.....................................................................................................................19
1. PROTOCOL SUMMARY ......................................................................................................20
1.1 Synopsis..............................................................................................................................20
1.2 Schema ...............................................................................................................................28
1.3 Schedule of Activities........................................................................................................30
1.3.1 Schedule of Activities: Screening Period..................................................................30
1.3.2 Schedule of Activities: Treatment Period, Follow-up, and End of Study .............35
2. INTRODUCTION....................................................................................................................39
2.1 Study Rationale .................................................................................................................39
2.2 Background........................................................................................................................39
2.2.1 Indication and Current Treatment Options ............................................................39
2.2.2 Product Background and Mechanism of Action .....................................................40
2.3 Benefit/Risk Assessment...................................................................................................43
3. OBJECTIVES AND ENDPOINTS ........................................................................................45
4. STUDY DESIGN......................................................................................................................48
4.1 Overall Design ...................................................................................................................48
4.2 Scientific Rationale for Study Design..............................................................................50
4.3 Justification for Dose ........................................................................................................51
4.4 End of Study/Study Completion Definition....................................................................51
5. STUDY POPULATION ..........................................................................................................53
5.1 Inclusion Criteria ..............................................................................................................53
5.1.1 Justification of Inclusion Criteria .............................................................................54
5.2 Exclusion Criteria .............................................................................................................55
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5.2.1 Justification of Exclusion Criteria ............................................................................60
5.3 Lifestyle Considerations ...................................................................................................60
5.3.1 Meals and Dietary Restrictions .................................................................................60
5.3.2 Alcohol and Tobacco ..................................................................................................60
5.3.3 Activity.........................................................................................................................61
5.3.4 Contraception and Breastfeeding .............................................................................61
5.3.4.1 Contraception for Participants Capable of Producing Viable Ova and/or 
Becoming Pregnant..............................................................................................62
5.3.4.2 Contraception for Participants Capable of Producing Viable Sperm............62
5.3.4.3 Restrictions on Breastfeeding .............................................................................62
5.4 Screening............................................................................................................................62
5.4.1 Screen Failures............................................................................................................63
5.5 Criteria for Temporarily Delaying Enrollment .............................................................64
5.6 Enrollment .........................................................................................................................64
6. STUDY DRUG AND CONCOMITANT THERAPY...........................................................65
6.1 Study Drug Administered ................................................................................................65
6.2 Preparation, Handling, Storage, and Accountability ....................................................65
6.2.1 Accountability Throughout the Study......................................................................65
6.2.2 Receiving Product at the Site.....................................................................................66
6.2.3 Handling and Storage at the Site ..............................................................................66
6.2.4 Labeling.......................................................................................................................67
6.2.5 Dispensing/Administration ........................................................................................67
6.2.5.1 Dispensing.............................................................................................................68
6.2.5.2 Administration .....................................................................................................68
6.2.6 Destruction or Return ................................................................................................69
6.3 Measures to Minimize Bias: Randomization and Blinding...........................................69
6.3.1 Randomization............................................................................................................69
6.3.2 Blinding the Treatment Assignment.........................................................................69
6.3.3 Unblinding...................................................................................................................69
6.4 Study Drug Compliance ...................................................................................................70
6.5 Dose Modification .............................................................................................................70
6.6 Continued Access to Study Drug After the End of the Study.......................................70
6.7 Treatment of Overdose.....................................................................................................70
6.8 Concomitant Therapy.......................................................................................................71
6.8.1 Rescue Medicine .........................................................................................................71
6.8.2 Excluded Procedures and Treatments......................................................................71
6.8.3 Permitted Concomitant Medications and Procedures ............................................73
7. DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .............................................................................74
7.1 Discontinuation of Study Drug ........................................................................................74
7.1.1 Liver Chemistry Stopping Criteria...........................................................................75
7.2 Participant Discontinuation/Withdrawal from the Study.............................................77
7.3 Lost to Follow-up ..............................................................................................................78
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8. STUDY ASSESSMENTS AND PROCEDURES..................................................................79
8.1 Demographics, Medical History, and Medication History............................................80
8.1.1 Demographics .............................................................................................................80
8.1.2 Medical History ..........................................................................................................80
8.1.3 Prior and Concomitant Treatments/Medications....................................................80
8.2 Biomarker and Noninvasive Test Assessments ..............................................................81
8.2.1 Primary Efficacy Measurement ................................................................................81
8.2.2 Liver Stiffness Measurement and Liver Fat Content .............................................81
8.2.3 FibroScan-Aspartate Aminotransferase Score........................................................82
8.2.4 Agile 4 Score................................................................................................................82
8.2.5 Fibrosis-4 Index ..........................................................................................................83
8.2.6 Child-Pugh Score........................................................................................................83
8.2.7 Model for End-stage Liver Disease...........................................................................83
8.2.8 Liver Biopsy ................................................................................................................84
8.2.9 Magnetic Resonance Imaging-derived Iron-corrected T1 Mapping of the 
Liver ............................................................................................................................85
8.2.10 HepQuant-SHUNT Disease Severity Index............................................................85
8.2.11 Alcohol Screening .....................................................................................................85
8.2.12 Additional Biomarkers.............................................................................................85
8.3 Safety Assessments............................................................................................................87
8.3.1 Physical Examinations ...............................................................................................87
8.3.2 Targeted Neurological Assessment ...........................................................................87
8.3.3 Hypersensitivity Monitoring......................................................................................89
8.3.4 Vital Signs....................................................................................................................90
8.3.4.1 Weight and Height...............................................................................................91
8.3.5 Electrocardiograms ....................................................................................................91
8.3.6 Chest X-ray .................................................................................................................91
8.3.7 Contraception and Breastfeeding Check..................................................................91
8.3.8 Clinical Safety Laboratory Tests ..............................................................................91
8.3.9 Pregnancy Testing ......................................................................................................93
8.3.10 Immunogenicity Assessments..................................................................................93
8.3.11 Adverse Events, Serious Adverse Events, and Other Safety Reporting..............93
8.3.11.1 Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information.................................................................................93
8.3.11.2 Method of Detecting Adverse Events and Serious Adverse Events ..............94
8.3.11.3 Follow-up of Adverse Events and Serious Adverse Events............................94
8.3.11.4 Regulatory Reporting Requirements for Serious Adverse Events................94
8.3.11.5 Pregnancy in a Participant or Participant’s Partner During the Study.......95
8.3.11.6 Adverse Events of Special Interest...................................................................96
8.4 Pharmacokinetics..............................................................................................................96
8.5 Genetics..............................................................................................................................97
8.6 Immunogenicity Assessments...........................................................................................97
9. STATISTICAL CONSIDERATIONS ...................................................................................98
9.1 Statistical Hypotheses .......................................................................................................98
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9.2 Analysis Sets ......................................................................................................................98
9.3 Biomarker and Noninvasive Test Analyses ....................................................................98
9.3.1 Primary Endpoint.......................................................................................................98
9.3.2 Secondary Endpoints..................................................................................................98
9.3.3 Exploratory Endpoints...............................................................................................99
9.3.4 Multiplicity Adjustment.............................................................................................99
9.4 Safety Analyses..................................................................................................................99
9.5 Other Analyses ................................................................................................................100
9.5.1 Pharmacokinetic Analyses.......................................................................................100
9.6 Interim Analysis ..............................................................................................................100
9.7 Determination of Sample Size........................................................................................100
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .101
10.1 Regulatory, Ethical, and Study Oversight Considerations .......................................101
10.1.1 Regulatory and Ethical Considerations................................................................101
10.1.2 Financial Disclosure ...............................................................................................101
10.1.3 Informed Consent Process.....................................................................................102
10.1.3.1 Informed Consent Requirements in This Study ...........................................102
10.1.3.2 Standards the Informed Consent Follows .....................................................103
10.1.3.3 Who Creates the Informed Consent Materials .............................................106
10.1.3.4 Who Conducts the Informed Consent Process..............................................106
10.1.3.5 Reconsent..........................................................................................................108
10.1.4 Data Protection .......................................................................................................108
10.1.4.1 Notice Regarding the Use and Transfer of the Investigator’s Personal 
Information.........................................................................................................109
10.1.5 Committees Structure ............................................................................................111
10.1.5.1 Institutional Review Board Approval............................................................111
10.1.5.2 Other Committees............................................................................................112
10.1.6 Dissemination of Clinical Study Data...................................................................112
10.1.6.1 Study Results Disclosure .................................................................................112
10.1.7 Data Quality Assurance .........................................................................................112
10.1.7.1 Protocol Deviations..........................................................................................113
10.1.7.2 Study-Site Monitoring Visits...........................................................................114
10.1.7.3 Audits ................................................................................................................114
10.1.8 Source Documents ..................................................................................................114
10.1.8.1 Electronic Case Report Forms........................................................................115
10.1.8.2 Documentation and Retention of Records.....................................................116
10.1.8.3 Data Handling ..................................................................................................117
10.1.8.4 Record Retention .............................................................................................117
10.1.9 Study and Site Start and Closure..........................................................................118
10.1.9.1 First Act of Recruitment .................................................................................118
10.1.9.2 Study/Site Termination ...................................................................................118
10.1.10 Publication Policy.................................................................................................119
10.1.11 Responsibilities of the Sponsor and the Investigator ........................................120
10.1.11.1 Sponsor Responsibilities................................................................................120
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10.1.11.2 Investigator Responsibilities .........................................................................121
10.1.12 Site Termination or Suspension ..........................................................................123
10.1.12.1 Criteria for Premature Termination or Suspension of Study Sites ..........123
10.1.12.2 Criteria for Premature Termination or Suspension of the Study.............123
10.1.12.3 Procedures for Premature Termination or Suspension of the Study or 
the Participation of Study Site(s)......................................................................124
10.2 Clinical Laboratory Tests.............................................................................................124
10.2.1 Clinical Laboratory Assessments and Other Safety Assessments .....................126
10.3 Adverse Events and Serious Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ......................................................127
10.3.1 Definition of Adverse Event...................................................................................128
10.3.2 Definition of Serious Adverse Event.....................................................................130
10.3.3 Additional Considerations in Identifying and Defining Adverse Events ..........131
10.3.3.1 Defining Discrete Adverse Events ..................................................................131
10.3.3.2 Adverse Events of Special Interest.................................................................132
10.3.4 Recording and Follow-up of Adverse Events and/or Serious Adverse Events .136
10.3.4.1 Frequency .........................................................................................................136
10.3.4.2 Intensity ............................................................................................................137
10.3.4.3 Causality/Relatedness......................................................................................138
10.3.4.4 Action Taken ....................................................................................................139
10.3.4.5 Outcome............................................................................................................140
10.3.4.6 Follow-up ..........................................................................................................141
10.3.4.7 Reference Safety Information.........................................................................141
10.3.4.8 Unexpected Adverse Events............................................................................141
10.3.4.9 Pretreatment-emergent Adverse Events........................................................141
10.3.4.10 Treatment-emergent Adverse Events ..........................................................142
10.3.5 Expedited Reporting of Serious Adverse Events and Adverse Events of 
Special Interest.........................................................................................................142
10.3.5.1 Safety Reporting to Investigators, Institutional Review Boards, and 
Regulatory Authorities ......................................................................................143
10.4 Contraceptive and Barrier Guidance..........................................................................143
10.4.1 Definitions ...............................................................................................................143
10.4.2 Contraception Guidance........................................................................................144
10.4.2.1 Contraceptive Methods for Participants Capable of Producing Viable 
Ova and/or Becoming Pregnant .......................................................................144
10.4.2.2 Contraceptive Methods for Participants Capable of Producing Viable 
Sperm ..................................................................................................................146
10.4.3 Pregnancy................................................................................................................147
10.5 Abbreviations and Definitions .....................................................................................148
10.5.1 Abbreviations..........................................................................................................148
10.6 Protocol Amendment History ......................................................................................151
11. REFERENCES.....................................................................................................................160
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LIST OF TABLES
Table 1. Schedule of Study Activities: Screening Period (Visit 1 and 2) ................................30
Table 2. Schedule of Activities: Screening Period (Visit 4a and 4a2) .....................................33
Table 3. Schedule of Activities: Treatment Period, Follow-up, and End of Study................35
Table 4. Common Excluded Treatments ...................................................................................71
Table 5. Neurological Assessment Plan......................................................................................88
Table 6. Protocol-required Laboratory Tests .........................................................................124
Table 7. Adverse Event Subtypes Defined in This Section.....................................................127
Table 8. Clinical Criteria for Diagnosing Anaphylaxis (Type I Hypersensitivity) ..............134
Table 9. Acceptable Contraception Methods and Lactation Guidance in This Study for 
Participants Capable of Producing Viable Ova and/or Becoming Pregnant ..................145
Table 10. Unacceptable Contraception Methods for Participants Capable of Producing 
Viable Ova and/or Becoming Pregnant ..............................................................................146
Table 11. Acceptable Contraception Methods in This Study for Participants Capable of 
Producing Viable Sperm and Their Partners.....................................................................146
LIST OF FIGURES
Figure 1. Study Schema...............................................................................................................28
Figure 2. Abnormal Liver-associated Test Results: Algorithm for Study Drug 
Discontinuation........................................................................................................................77
Figure 3. Flow Diagram for Quarterly Neurological Assessments..........................................89
Figure 4. Potential Immunogenicity of Therapeutic Monoclonal Antibodies......................133
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1. PROTOCOL SUMMARY
1.1 Synopsis
Name of Sponsor(s):
Takeda Development Center Americas, 
Inc.
Compound:
TAK-647 (ontamalimab)
Study Number: 
TAK-647-1001 
Phase:
1b 
IND No.: 
163193
EudraCT No.: 
Not Applicable
Title of Protocol: 
A Multicenter, Single-arm, Open-label, Phase 1b Study to Explore the Mechanism of Action and Evaluate the 
Safety of Ontamalimab in Participants With Nonalcoholic Steatohepatitis With Fibrosis Stage 1 Through 4
Number of participants (total and per treatment arm):
Approximately 30 participants are planned to be enrolled to ensure that at least 18 participants (approximately 
12 participants with fibrosis stage [F] noncirrhotic (F1-F3) and approximately 6 participants with fibrosis stage 4 
compensated cirrhotic [F4cc]) complete the 24-week treatment period. Not more than four participants with F1 
fibrosis will be enrolled in this study.
Investigator(s): Multicenter study
Site(s) and Region(s): Up to 20 sites in the United States (US)
Study period (planned):
Approximately 2023 to 2024 
Objectives and Endpoints 
Objectives
Endpoints
Primary
To evaluate safety and tolerability of ontamalimab 
75 mg administered every 4 weeks (Q4W) in 
participants with nonalcoholic steatohepatitis 
(NASH) (defined as Nonalcoholic Fatty Liver 
Disease [NAFLD] Activity Score [NAS] ≥3 with 
at least 1 point in lobular inflammation) with 
different fibrosis stages (NASH Clinical Research 
Network [CRN] F1 through F4cc participants). 
•
Incidence of treatment-emergent adverse 
events (TEAEs)
•
Number of participants with clinically 
significant changes in the following 
parameters from baseline to the end of the 
follow-up period (Week 36):
•
Laboratory tests
•
Electrocardiograms (ECGs)
•
Vital signs
•
Body weight
Secondary
To determine if the changes from baseline in key 
biomarkers (neoepitope-specific N-terminal 
propeptide of type III collagen [Pro-C3] and 
Enhanced Liver Fibrosis [ELF] test) and in iron-
corrected T1 mapping (cT1) by magnetic 
resonance imaging (MRI) provide a signal of a 
potential role of the mucosal addressin cell 
adhesion molecule-1 (MAdCAM-1) pathway in 
participants with NASH (NAS ≥3 with at least 
1 point in lobular inflammation) with different 
fibrosis stages (NASH CRN F1 through F4cc 
participants) after 24 weeks of administration of 
ontamalimab 75 mg Q4W.
•
Percent change from baseline in Pro-C3 
through Week 24
•
Percent change from baseline in ELF 
through Week 24
•
Change from baseline in liver cT1 MRI at 
Week 24
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Rationale:
This study is designed to evaluate the safety and tolerability of ontamalimab 75 mg Q4W in participants with 
NASH with fibrosis stages F1 through F4cc and to explore the role of MAdCAM-1 in NASH by administering a 
MAdCAM-1 inhibitor (ontamalimab). Blocking MAdCAM-1 may disrupt the trafficking of α4β7+ lymphocytes 
into hepatic and portal vein endothelium and subsequent extravasation into the liver. Ontamalimab selectively 
binds MAdCAM-1 with high affinity and selectivity, preventing the MAdCAM-1/α4β7-integrin interaction. This 
is expected to reduce lymphocyte trafficking to the liver, preventing hepatic inflammation and injury, and may 
slow, halt, or reverse fibrosis.
Study drug, dose, and mode of administration:
The study drug is ontamalimab (TAK-647, previously known as PF-00547659 or SHP647; a fully human 
immunoglobulin G2 kappa antihuman MAdCAM-1 monoclonal antibody), which will be provided as a sterile 
aqueous buffered solution for subcutaneous (SC) administration in a glass prefilled syringe (PFS) with a fixed 
needle. Each PFS contains 1 mL of ontamalimab solution for injection at a concentration of 75 mg/mL. A single 
syringe will be used to provide the intended dose of drug (75 mg). Ontamalimab will be administered SC Q4W
starting on Day 1 and the last dose is administered at Week 20 (total treatment period is 24 weeks). Additional 
information is provided in the current ontamalimab investigator’s brochure (IB).
Overall Design and Methodology:
This is a multicenter, single-arm, open-label, Phase 1b study to explore the role of MAdCAM-1 in NASH by 
administering a MAdCAM-1 inhibitor (ontamalimab) in participants with indication of NASH via biopsy (NAS 
≥3 with at least 1 point in lobular inflammation) with different fibrosis stages (NASH CRN fibrosis stage F1-F3 
and F4cc participants). The role of MAdCAM-1 will be evaluated by the changes in inflammatory and fibrosis 
biomarkers, liver histology and circulating inflammatory cells, and liver chemistry tests compared with baseline. 
Magnetic resonance imaging (MRI)-derived cT1 will be used to evaluate fibroinflammatory changes in the liver. 
Safety and tolerability of ontamalimab 75 mg will be assessed. 
Approximately 30 participants are planned to be enrolled to ensure that at least 18 participants (approximately 
12 participants with F1-F3 and approximately 6 participants with F4cc) complete the 24-week treatment period. 
Not more than four participants with F1 fibrosis will be enrolled in this study. Enrollment of F1, F2 and F3 
participants at a 1:1:1 ratio will not be required. The study will be conducted at up to 20 sites in the US.
Participants will be aged ≥18 and ≤70 years and diagnosed with NASH without decompensated cirrhosis or 
neoplasia. 
The broad NASH population is targeted, and participants with documented stable type 2 diabetes mellitus or 
participants with high body mass index >25 kg/m2 with ≥1 criterion of metabolic syndrome will be permitted to 
participate in the study.
Participants with neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3) ≥12.6 ng/mL, and 
Enhanced Liver Fibrosis (ELF) score ≥7.7, who meet inclusion criteria and none of exclusion criteria for 
assessments and procedures at Screening Visit 1 (SV1; Week -8) will be eligible for liver biopsy that will be 
performed at Screening Visit 2 (SV2; Week -6). Indication for NASH (NAS ≥3 with at least 1 point in lobular 
inflammation) and liver fibrosis stage F1 through F4cc in the liver biopsy will enable these participants to enroll 
in the study.
Historical liver biopsy samples are acceptable for screening purposes if collected between 24 weeks and 4 weeks 
before the start of the screening period (maximum allowed time between historical liver biopsy and first dose of 
study drug is 34 weeks for any participant, except for the participants who test positive for SARS-CoV-2 at 
screening). For any F4cc participants who meet the inclusion and exclusion criteria before establishment of safety 
and tolerability in the first four noncirrhotic (F1-F3) participants, historical liver biopsy samples are acceptable 
for screening purposes if collected within 10 weeks before the start of the screening period (12 weeks if test 
positive for SARS-CoV-2 at screening). The first screening visit must occur at least 4 weeks after the historical 
liver biopsy to ensure that any biopsy-induced changes in liver function parameters or biomarkers have stabilized. 
If a qualifying historical liver biopsy sample or slides is available to be reviewed and read centrally by the study 
pathologists and if it meets all the criteria as defined in the histopathology manual, liver biopsy need not be 
repeated during screening. Historical liver biopsy samples must show indication for NASH (NAS ≥3 with at least 
1 point in lobular inflammation) and liver fibrosis stage F1 through F4cc. Participants with qualifying historical 
liver biopsy must have adhered to restrictions on prohibited hepatotoxic medications during the specified period 
before historical liver biopsy sampling. For participants with qualifying historical liver biopsies, the abdominal 
MRI (Visit 4a), may occur as soon as possible after liver chemistry results from SV2 become available, and SV2 
and the Day -4 visit (Visit 4a2) must be at least 2 weeks apart.
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Pro-C3, ELF, and other exploratory markers will be measured at 2 screening visits (SV1 and SV2) and Day 1 
[D1] predose measurement during treatment period to determine intra-participant variability. This will enable the 
correct interpretation of the posttreatment decrease in these biomarkers relative to the intra-participant variability 
at baseline.
After safety and tolerability have been established in the first four noncirrhotic (F1-F3) participants who have 
received at least 3 doses of ontamalimab 75 mg and have been monitored for at least 12 weeks after the first dose
of study drug, eligible F4cc participants will be allowed to enroll into the study. The screening period may be 
extended for up to 24 weeks for participants with results consistent with F4cc fibrosis (ie, compensated cirrhosis) 
(ie, a combination of Fibrosis-4 Index [FIB-4] ≥3.48 and LSM ≥20 kPa or an Agile 4 score ≥0.57) after the first 
visit during the screening period, or have a screening liver biopsy or a historical liver biopsy that confirms F4cc 
NASH (NAS ≥3 with at least 1 point in lobular inflammation), until safety and tolerability data are evaluated in 
the first four noncirrhotic (F1-F3) participants.  
All eligible participants (F1-F4cc) will enter a 24-week, single-arm, open-label treatment period with 
ontamalimab 75 mg. Ontamalimab will be administered SC Q4W starting on Day 1 and the last dose is 
administered at Week 20 (total treatment period is 24 weeks), followed by a 12-week safety follow-up period. 
Liver biopsy samples will be collected during screening and at Week 24. Fibro-inflammation will be assessed by 
cT1 MRI (iron-corrected T1 mapping by magnetic resonance imaging), liver stiffness by FibroScan, and 
hepatocellular function by the investigational HepQuant-SHUNT Disease Severity Index (DSI) at the start of the 
treatment period and at Week 24. At visits Q4W between baseline and Week 24, assessments of selected 
biomarkers (including but not limited to Pro-C3, ELF, soluble MAdCAM-1, high-sensitivity C-reactive protein 
[hsCRP], and calprotectin), liver chemistry tests, and specific safety data collection (laboratory, adverse events 
[AEs], neurological assessments) will be performed. Liver stiffness measurement by FibroScan will be also 
performed at Week 12. Safety and tolerability data will be continuously monitored and will be evaluated by the 
internal safety review committee (independent from the study team).  
All participants, including those who discontinue, will undergo a safety follow-up period through 12 weeks after 
the last dose of study drug.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
1.
The participant is willing and able to understand and fully comply with study procedures and 
requirements, in the opinion of the investigator.
2.
The participant and/or the participant’s legally acceptable representative has provided informed consent 
(that is, in writing, documented via a signed and dated informed consent form [ICF] or electronic 
consent [eConsent] if applicable) and any required privacy authorization prior to the initiation of any 
study procedures.
3.
The participant is aged 18 to 70 years, inclusive, at the time of signing the ICF.
4.
This criterion has been removed in Protocol Amendment 3.
5.
The participant has signs of fibrogenic activity (Pro-C3 ≥12.6 ng/mL, ELF score ≥7.7) at the Week -8 
(SV1) (applies to all participants regardless of whether historical biopsy results are available at 
screening).
6.
The participant has indication of NASH via biopsy (NAS ≥3 with at least 1 point in lobular 
inflammation) and liver fibrosis stage F1 through F4cc according to NASH CRN.
7.
This criterion has been removed in Protocol Amendment 2.
8.
This criterion has been removed in Protocol Amendment 2.
9.
The participant is a male participant or a nonpregnant, nonlactating female participant who, if sexually 
active, agrees to comply with the contraceptive requirements of the protocol, or a female participant of 
nonchildbearing potential. Participants of reproductive potential who are sexually active must agree to 
use appropriate contraception (ie, highly effective methods for female participants and medically 
appropriate methods for male participants) for the duration of the study and for at least 12 weeks after 
the last dose of study drug.
10. The participant, if capable of breastfeeding, agrees to forego breastfeeding for the period from informed 
consent until 12 weeks after the last dose of study drug.
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Exclusion Criteria:
1.
The following laboratory findings are exclusionary for all participants if found during screening visits
(Week -8 [SV1], Week -6 [SV2] or at Day -4 visit [Visit 4a2]):
a.
AST levels >5×the upper limit of normal (ULN). 
b.
ALT levels >5×ULN.
2.
The following laboratory findings are exclusionary for all participants if found during either screening 
visit (SV1 or SV2):
a.
ALP ≥2×ULN.
b.
Serum creatinine ≥1.5×ULN, or has an estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73 m2.
c.
INR ≥1.3 (except for participants who are receiving anticoagulant treatment).
d.
TBL ≥ULN (except for patients with a documented history of Gilbert’s syndrome if direct bilirubin is 
within normal reference range).
e.
Direct bilirubin ≥3×ULN. 
f.
Platelet count <60×109/L.
3.
The participant has been diagnosed with decompensated liver disease, or has new signs of 
decompensation and/or clinically meaningful change in disease status based on the judgment of the 
investigator (including but not limited to clinically significant changes in TBL, albumin, INR, 
creatinine, and/or AST and ALT levels*) are observed during the screening period, or has any of the 
following during screening period:
a.
Presence or history of ascites, hepatic encephalopathy, or variceal bleeding.
b.
Presence or history of Child-Pugh >6 (Class B or C), unless due to therapeutic anticoagulation.
c.
Presence or history of MELD score >12.
* Note: It is the investigator’s decision, in consultation with the sponsor, to allow participants to enter the 
study who have clinically meaningful rising tendencies in liver chemistries or significantly elevated liver 
chemistries that do not yet satisfy Exclusion Criterion #1 but could be interpreted as clinically concerning 
(ie, AST or ALT >4×ULN) at any visit during the screening period.
4.
The participant has other diagnosed causes of liver disease based on medical history and/or baseline 
evaluation of laboratory and/or histology results, including, but not limited to viral (eg, chronic 
hepatitis B, hepatitis B virus surface antigen [HBsAg] positive, or hepatitis B core antibody [HBcAB] 
positive; or chronic hepatitis C or hepatitis C virus antibody [HCVAb] positive and hepatitis C [HCV] 
RNA positive; or human immunodeficiency virus [HIV]-antibody positive)*, alcoholic (alcohol 
consumption greater than 4 units on any day or 14 units per week for male participants, or greater than 
3 units on any day or 7 units per week for female participants [1 unit of alcohol is present in one 
12 oz/355 mL beer (approximately 5% alcohol), one 5 oz/148 mL glass of wine (approximately 12% 
alcohol), and one 1.5 oz/44 mL measure of 80-proof liquor (approximately 40% alcohol)]), or 
autoimmune conditions (eg, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune 
hepatitis, drug-induced hepatotoxicity), and other rare liver disease (eg, alpha-1-antitrypsin deficiency, 
Wilson disease, hemochromatosis).
* Note: If a participant tests negative for HBsAg but positive for HBcAb, the participant would be 
considered eligible if no presence of hepatitis B virus (HBV) DNA is confirmed by HBV DNA polymerase 
chain reaction (PCR) reflex testing performed by the central laboratory.
Participants who are HCVAb positive without evidence of HCV RNA may be considered eligible 
(spontaneous viral clearance or previously treated and cured [defined as no evidence of HCV RNA at least 
12 weeks before baseline]).
5.
The participant has a history of impaired hemostasis that, in the investigator’s judgement, would 
increase the risk to the participant if he or she participates in the study.
6.
The participant has a significant concurrent medical condition at the time of screening or baseline, 
including, but not limited to, the following:
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a.
Any major illness/condition or evidence of an unstable clinical condition (eg, hepatic, renal, 
hematologic, gastrointestinal, endocrine [eg, uncontrolled diabetes* or type 1 diabetes mellitus, or 
thyroid disease], neurological [pre-existing demyelinating disorder such as multiple sclerosis or new 
onset seizures, unexplained sensory motor, or cognitive behavioral, neurological deficits, or significant 
abnormalities noted during screening], cardiovascular, pulmonary, immunologic [eg, Felty’s 
syndrome], or local active infection/infectious illness [any bacterial, fungal, or viral, eg, clinically 
active cytomegalovirus, Epstein-Barr virus, herpes simplex virus]) that, in the investigator’s judgment 
will substantially increase the risk to the participant if he or she participates in the study. 
* Note: Participants with hemoglobin A1c (HbA1c) of ≥6.5% at screening (SV1; Week -8) without a 
previous diagnosis of type 2 diabetes mellitus (T2DM) should be excluded from the study. Participants 
with a previous diagnosis for T2DM are permitted to enter the study if on a stable regimen of 
antidiabetic therapy for at least 90 days before screening. Participants who are on a stable regimen of 
antidiabetic therapy for at least 90 days before screening (SV1; Week -8) and have HbA1c of ≥9% at 
Week -8 (SV1) should be excluded.
b.
Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina pectoris) 
within 24 weeks before screening.
c.
History of significant cerebrovascular disease within 24 weeks before screening.
d.
Cancer or history of cancer, including hepatocellular carcinoma or cholangiocarcinoma, or 
lymphoproliferative disease within the previous 5 years (other than resected cutaneous basal cell 
carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix that has been treated 
with no evidence of recurrence). 
e.
Any other severe acute or chronic medical or psychiatric condition or laboratory or electrocardiogram 
(ECG) abnormality that may increase the risk associated with study participation or study drug 
administration or may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study.
f.
Transplanted organ or history of liver transplantation.
g.
Significant trauma or major surgery within 4 weeks before the first screening visit, or with any major 
elective surgery planned to occur during the study.
7.
The participant has severe active inflammatory bowel disease (IBD). Participants with inactive IBD or 
active of mild to moderate severity that was documented either by prior endoscopy or in previous 
medical records for >6 months are permitted to enter if they do not require biological treatment or JAK 
inhibitors. Treatment with leukocyte apheresis or selective lymphocyte, monocyte, or granulocyte 
apheresis or plasma exchange 30 days before baseline (Day 1).
8.
The participant has a severe immune-mediated inflammatory disease (IMID) (eg, rheumatoid arthritis, 
spondylarthritis disease spectrum, connective tissue disorders, cutaneous inflammatory conditions such 
as psoriasis, atopic dermatitis, hidradenitis suppurativa, asthma, multiple sclerosis). Participants with 
inactive IMID or active IMID of mild to moderate severity are permitted to enter the study. 
9.
The participant has a change in body weight ≥5% three months before start of the screening or after 
qualifying liver biopsy. If the participant had a liver biopsy within 24 weeks of screening, but 
experienced a weight change of ≥5% since the date of liver biopsy, the liver biopsy must be repeated at 
screening.
10. The participant has any laboratory abnormality or condition that, in the investigator’s opinion, could 
adversely affect the safety of the participant or impair the assessment of study results.
11. The participant has known hypersensitivity to ontamalimab or formulation excipient.
12. The participant has active or latent infection with Mycobacterium tuberculosis (TB) who have not 
completed a generally accepted full course of treatment before screening.
13. The participant has clinically significant abnormal chest X-ray findings at SV1 (or up to 12 weeks 
before the first screening visit if available), such as presence of active TB, general infections, heart 
failure, or malignancy.
14. The participant has a positive interferon-gamma release assay (IGRA) at screening or within 12 weeks 
before screening even in the absence of previously diagnosed active or latent TB. IGRA screening may 
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be repeated during the screening period if the initial result is indeterminate. The participant may be 
enrolled if confirmatory IGRA results from the central laboratory are negative. If the confirmatory 
IGRA results from the central laboratory are positive, the participant should be screen-failed. If both 
initial and confirmatory IGRA results are indeterminate, the participant may be enrolled after a 
Mantoux tuberculin skin test is negative and after consultation with the sponsor and a pulmonary or 
infectious disease specialist who determines low risk of infection (ie, the participant would be 
acceptable for immunosuppressant [eg, anti-tumor necrosis factor (TNF) treatment] without additional 
action). If the time for consultation exceeds the visit window, the participant should be screen-failed 
and can be rescreened after the consultation establishes eligibility for study participation. This 
consultation must be included in the participant’s medical history. 
15. The participant has any unexplained symptoms suggestive of progressive multifocal 
leukoencephalopathy (PML) based on the targeted neurological assessment during the screening period.
16. The participant has HIV.
17. This criterion has been removed in Protocol Amendment 3.
18. The participant has a medical condition (eg, morbid obesity, claustrophobia) that prevent execution of 
protocol procedures including percutaneous liver biopsy, LSM by FibroScan, and MRI.
19. The participant is receiving treatment with vitamin E, thiazolidinediones, or glucagon-like peptide-1 
receptor agonists (GLP-1 RA) unless on a stable dose for 3 months before qualifying liver biopsy and 
not initiated after qualifying liver biopsy and is anticipated to maintain the same dosing regimen 
throughout study participation.
20. The participant is using drugs, herbs, or supplements historically associated with causing or worsening 
NAFLD/NASH within 24 weeks before qualifying liver biopsy or any time after qualifying liver biopsy 
is performed, including the use of total parenteral nutrition.
21. The participant has a positive urine screen for amphetamines, cocaine, or opioids related to the use of 
these drugs at screening. 
22. The participant is receiving methadone or buprenorphine unless on stable maintenance treatment for at 
least 6 months before screening. Participants with a positive urine drug screen due to prescription 
opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the 
investigator.
23. The participant is using any prohibited concomitant medications as described in the protocol.
24. The participant has received a live (attenuated) vaccine within 4 weeks before baseline or is anticipated 
to receive a live vaccine during the study.
25. The participant has participated in another investigational study of a drug or device within 30 days
before or within 5 half-lives of the prior investigational agent (whichever is longer) before baseline 
(Day 1).
26. The participant has participated in another investigational study targeting NASH, type 2 diabetes 
mellitus, or obesity within 6 months before baseline (Day 1).
27. The participant is concurrently participating in another therapeutic clinical study.
28. The participant has previously received ontamalimab. 
29. The participant has had previous exposure to anti-integrin or anti-adhesion molecule treatment eg, 
natalizumab, efalizumab, etrolizumab, vedolizumab, or any other investigational anti-integrin/adhesion 
molecule within 90 days before baseline (Day 1).
30. The participant has had previous exposure to any other biologic drugs with immunomodulatory 
properties such as anti-TNF, including biosimilars or anti-interleukin (IL)-12/23, or any nonbiologic 
treatment with immunomodulatory properties such as JAK inhibitors within 90 days or 5 half-lives 
(whichever is longer) before baseline (Day 1).
31. The participant is unavailable for follow-up assessment or investigator concern for participant’s 
compliance with the protocol procedures.
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32. The participant is a study site employee, an immediate family member (eg, spouse, parent, child, 
sibling), or is in a dependent relationship with a study site employee who is involved in conduct of this 
study, or may consent under duress.
Intervention groups and duration including maximum duration of participant participation in the study:
The total duration of study participation for each participant includes: 
•
Planned duration of screening period: Up to 8 weeks (or up to 10 weeks on a case-by-case basis with the 
sponsor’s approval). For F4cc participants who have met the inclusion and exclusion criteria before safety 
and tolerability have been established in four noncirrhotic (F1-F3) participants, the screening period may 
be extended for up to 24 weeks. However, in case of positive test for SARS-CoV-2 infection, screening 
may be paused for an additional 2 weeks (ie, screening period of up to 12 weeks).
•
Planned duration of treatment period: 24 weeks
•
Planned duration of follow-up: 12 weeks
The participant’s maximum duration of participation in the study is expected to be approximately 46 weeks 
(11.5 months). In case of positive test for SARS-CoV-2 infection, the total study period could be up to 48 weeks 
(ie, screening period of up to 12 weeks). For any F4cc participants who have met the inclusion and exclusion 
criteria before safety and tolerability have been established in the first four noncirrhotic (F1-F3) participants. For 
these participants, the total study period is expected to be approximately 60 weeks (15 months). 
Statistical analysis:
Analysis Sets
The screened set will consist of all participants who have signed informed consent(s).
The full analysis set (FAS) will consist of all participants who are enrolled in the study, have received at least 
1 dose of study drug, and have at least 1 valid postbaseline assessment. 
The safety analysis set will consist of all participants who are enrolled in the study and have received at least 
1 dose of study drug.
The pharmacokinetic (PK) set will consist of all participants in the safety analysis set who have at least 
1 evaluable postdose PK concentration value.
Primary Endpoint Analyses (Safety)
All safety analyses will be performed using the safety analysis set. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (version 25.0 or 
higher). Treatment-emergent AEs are defined as AEs with start dates at the time of or following the first exposure 
to the study drug. The number and percentage of TEAEs will be presented by system organ class and preferred 
term. Treatment-emergent AEs will be further summarized by severity and relationship to the study drug. 
Adverse events related to the study drug, AEs leading to study drug discontinuation, SAEs, and deaths will be 
similarly summarized or listed.
Clinical laboratory test results, vital signs, body weight, and ECG findings will be summarized by visit. 
Potentially clinically significant findings will also be summarized or listed.
Secondary Endpoint Analyses
The biomarker and noninvasive test analyses will be performed on the FAS based on data from participants in all 
fibrosis stages (F1 through F4cc) using an estimation approach. The biomarker and noninvasive test data will be 
summarized descriptively by visit as observed. 
For biomarkers except cT1 MRI, data from all available sampling during screening period (SV1 and SV2) and 
D1 predose measurement during treatment period will be averaged to establish the stable baseline value. For cT1 
MRI, only one measurement will be taken during screening, which will be used for the baseline value.
For Pro-C3 and ELF, which are collected at multiple postbaseline visits, the percent change from baseline at 
Week 24 will be analyzed using a mixed effects model for repeated measure (MMRM) with visit as the fixed 
effect, participants as the random effect, and baseline values as covariates. The least-squares means of the percent 
change from baseline at Week 24 along with the corresponding 95% confidence intervals (CIs) will be presented. 
For cT1 MRI, which is collected at one postbaseline visit (Week 24), the change from baseline at Week 24 along 
with the corresponding 95% CI will be presented. 
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Determination of Sample Size
The planned sample size for this study is 18 participants who complete the 24-week treatment period. The sample 
size has been chosen to provide adequate number of participants to investigate the objectives of the study based 
on clinical experience for key biomarkers. 
This study is not statistically powered to perform any formal hypothesis testing, and the analyses will be based on 
estimation approach.
Independent Review Committee(s): Yes
An internal safety review committee (independent from the study team) will review the overall safety of the study 
participants on an ongoing basis. This review will consist of monitoring of safety of participants throughout the 
study. Recommendations made on the basis of this review to alter the conduct of the study or to amend the 
protocol will be provided to the study team for review and for a final decision. The sponsor or its designee will 
notify investigative sites and regulatory authorities as appropriate, of recommendations based on this review. 
Details regarding this review and the frequency of this review will be established in a separate charter before the 
administration of study drug to any participant. In addition, this internal safety review committee will be 
responsible for:
•
Evaluating safety and tolerability data from the first four noncirrhotic (F1-F3) participants who have 
received at least 3 doses of ontamalimab 75 mg and have been monitored for at least 12 weeks, to support 
the decision to include F4cc participants in the study. 
•
Engaging with an independent panel of experts to evaluate any liver-related events (eg, liver 
decompensation, significant deterioration of liver chemistry tests).
•
Monitoring neurological safety and consulting a panel of leading PML experts, including a neurologist, 
neuroradiologist, and a virologist, in the event of a suspected case of PML. 
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1.2 Schema
Figure 1. Study Schema
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Figure 1. Study Schema (continued)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CAP=Controlled Attenuation Parameter; 
CCR9=C-C chemokine receptor type 9; cT1 MRI=iron-corrected T1 mapping by magnetic resonance imaging; 
CXCR3=C-X-C motif chemokine receptor 3; D=Day; DSI=Disease Severity Index; ELF=Enhanced Liver Fibrosis; 
F=fibrosis stage; F4cc=fibrosis stage 4 compensated cirrhotic; FAST=FibroScan-aspartate aminotransferase; 
FIB-4=Fibrosis-4 Index; hsCRP=high-sensitivity C-reactive protein; IL=interleukin; LSM=liver stiffness 
measurement; MRI=magnetic resonance imaging; NAS=Nonalcoholic Fatty Liver Disease Activity Score; 
NASH=nonalcoholic steatohepatitis; Pro-C3=neoepitope-specific N-terminal propeptide of type III collagen; 
Q4W=every 4 weeks; SC=subcutaneous(ly); sMAdCAM-1=soluble mucosal addressin cell adhesion molecule-1; 
SV=Screening Visit
a For participants with NASH (NAS ≥3) and F4cc fibrosis (ie, cirrhosis), the screening period may be extended up to 
24 weeks until safety and tolerability information is available on first four noncirrhotic (F1-F3) participants who 
have received at least 3 doses of ontamalimab and have been monitored for at least 12 weeks after the first dose of 
study drug. Progression of screening is contingent on successful confirmation of eligibility along with the sponsor's 
approval.
b Eligibility for liver biopsy at Week -6 (SV2) will be established on the basis of results of Week -8 (SV1) 
assessments (including but not limited to Pro-C3 ≥12.6 ng/mL, ELF ≥7.7, and liver chemistry eligibility criteria as
participants should meet all inclusion criteria and none of exclusion criteria for assessments and procedures at 
Week -8 (SV1) to be eligible for liver biopsy. For participants who meet other eligibility criteria at Week -8 (SV1), 
if ALT or AST is >4×ULN and <5×ULN at Week -8 (SV1), then the ALT/AST results at Week -6 (SV2) will also 
be evaluated before liver biopsy and the abdominal MRI can be performed. Only participants with indication of 
NASH via biopsy (NAS ≥3 with at least 1 point in lobular inflammation) and liver fibrosis stage F1 through F4cc 
will be enrolled in the study. Green fonts indicate key inclusion criteria. Qualifying historical liver biopsies are 
acceptable for screening purposes if they are available to be reviewed and read centrally by the study pathologists 
and if they meet all the criteria as defined in the histopathology manual. For participants with qualifying historical 
liver biopsies, the abdominal MRI visit (Visit 4a) may occur as soon as possible after liver chemistry results from 
SV2 become available, and SV2 and the Day -4 visit must be at least 2 weeks apart. 
c Abdominal MRI may be performed between Day -7 and Day -4.
d Liver chemistry tests include ALT, AST, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase, and 
albumin. 
e Biomarkers from blood samples include serum Pro-C3; ELF; serum sMAdCAM-1; serum and plasma markers of 
inflammation, fibrosis, and trafficking (including but not limited to hsCRP, IL-8, and calprotectin); whole blood 
T cell phenotyping (including but not limited to Th17/Th1 vs Th2 ratios, β7+ T cells, CCR9, and CXCR3) (treatment 
period only); and whole blood transcriptomics (treatment period only). Pro-C3 levels and ELF score at Week -8 
(SV1) will be used to determine eligibility. Pro-C3 levels and ELF scores at Week -8 (SV1), Week -6 (SV2), and D1 
predose measurement during treatment period will be used in calculating the baseline value for each parameter. 
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2. INTRODUCTION 
2.1 Study Rationale 
This study is designed to evaluate the safety and tolerability of ontamalimab 75 mg every 
4 weeks (Q4W) in participants with nonalcoholic steatohepatitis (NASH) with fibrosis stage 1 
(F1) through F4 compensated cirrhotic (F4cc) and to explore the role of mucosal addressin cell 
adhesion molecule-1 (MAdCAM-1) in NASH by administering a MAdCAM-1 inhibitor 
(ontamalimab). Blocking MAdCAM-1 may disrupt the trafficking of α4β7+ lymphocytes into 
hepatic and portal vein endothelium and subsequent extravasation into the liver. Ontamalimab 
selectively binds MAdCAM-1 with high affinity and selectivity, preventing the 
MAdCAM-1/α4β7-integrin interaction. This is expected to reduce lymphocyte trafficking to the 
liver, preventing hepatic inflammation and injury, and may slow, halt, or reverse fibrosis. 
2.2 Background 
2.2.1 Indication and Current Treatment Options
Nonalcoholic fatty liver disease (NAFLD) is generally viewed as a spectrum of liver disease in 
which hepatic steatosis, the accumulation of triglycerides in hepatocytes, develops in the absence 
of secondary causes (eg, medications, excessive alcohol consumption, or certain heritable 
conditions). Patients with NAFLD are at a high risk for cardiovascular morbidity and mortality 
(Chalasani et al. 2018). Nonalcoholic steatohepatitis is the inflammatory subtype of NAFLD, 
with steatosis, hepatocyte injury (ballooning) and lobular inflammation, with or without fibrosis 
(Chalasani et al. 2018). Although often clinically silent, NASH with fibrosis can progress to 
cirrhosis, end-stage liver disease, and in some patients, a need for a liver transplant. More than 
20% of patients with NASH will develop cirrhosis in their lifetime (Matteoni et al. 1999) and 
patients with NASH also have increased risk of developing hepatocellular carcinoma (Stine et al. 
2018). From 2004 to 2016, there was a 114% and 80% expansion in liver transplant waitlist 
registration due to NASH for men and women, respectively (Noureddin et al. 2018), and NASH 
is now the leading indication for liver transplant listing for women and is expected to overtake 
alcoholic liver disease as the leading liver transplant indication for all patients within the next 
few years (Noureddin et al. 2018). Nonalcoholic steatohepatitis has an annual mortality 1.7 times 
higher than NAFLD overall (25.56 vs 15.44 events per 1000 person-years), and liver-specific 
mortality is 15 times higher than in NAFLD (11.77 vs 0.77 events per 1000 person-years) 
(Younossi et al. 2016). In addition, NASH is closely related to the triple epidemic of obesity, 
prediabetes, and diabetes (European Association for the Study of the Liver (EASL) et al. 2016). 
However, symptoms are often silent or nonspecific to NASH, making it difficult to diagnose. As 
a result, patients with NASH can remain unaware of their condition until late stages of the 
disease (Polis and Fernandez 2015) (mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-
disease/symptoms-causes/syc-20354567?p=1; Mayo Clinic, accessed 25 July 2022). 
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Furthermore, NASH is associated with a significant socioeconomic burden; lifetime direct 
medical costs for patients in the US with NASH in 2017 were estimated at $222 billion 
(Younossi et al. 2019). This estimate does not include indirect medical or societal costs and will 
only increase as the prevalence of NASH rises.
Currently, the primary treatment for NAFLD/NASH is lifestyle modification for weight loss 
through diet and exercise (Guirguis et al. 2021; Sheka et al. 2020). A meta-analysis of studies 
showed the weight loss of 7% or greater was associated with improvement in the Nonalcoholic 
Fatty Liver Disease Activity Score (NAS) (Musso et al. 2012). Although dietary composition 
does appear to have an effect on hepatic fat deposition, no specific macronutrient diet has been 
shown to have a benefit for NASH. Therefore, caloric restriction is the most appropriate 
recommendation for these patients (Chalasani et al. 2018). To date, no pharmacotherapy is 
approved by US Food and Drug Administration (FDA) or European Medicines Agency (EMA) 
for NASH. However, vitamin E and pioglitazone has shown some benefits in clinical studies. 
Pioglitazone, a peroxisome proliferator-activator receptor-gamma (PPAR-γ) agonist, has 
demonstrated improvement in insulin sensitivity, aminotransferase levels, steatosis, 
inflammation and ballooning in patients with NASH and prediabetes or type 2 diabetes mellitus 
(T2DM) (Belfort 2006). Vitamin E treatment in a small pilot study showed improvement by 
reducing insulin resistance and PPAR-alpha (PPAR-α) expression in NASH (Yakaryilmaz et al. 
2007). In the PIVENS trial, compared with placebo, vitamin E therapy was associated with a 
significantly higher rate (43% vs. 19%, p=0.001) of achieving the primary endpoint of an 
improvement in histological findings (ie, an improvement by 1 or more points in the 
hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the 
NAS to a score of 3 or less or a decrease in the NAS of at least 2 points, with at least a 1-point 
decrease in either the lobular inflammation or steatosis score), whereas pioglitazone did not 
reach statistical significance (34% vs. 19%, p=0.04 [Bonferroni-adjusted p-values <0.025 were 
considered statistically significant]) (Sanyal et al. 2010). A combination therapy with 
pioglitazone and vitamin E assessed in patients with T2DM and NASH showed significant 
improvement in the NAS by 2 or more points and without any worsening in fibrosis versus 
placebo (54% vs 19%, p=0.003), but not with vitamin E alone (31% vs. 19%, p=0.2604) 
(Bril et al. 2019). No improvement in fibrosis was observed in any treatment group. For patients 
with NASH, pharmacotherapy options are currently limited to off-label use of pioglitazone and 
vitamin E as large, randomized studies evaluating these therapies are lacking.
2.2.2 Product Background and Mechanism of Action
Ontamalimab (TAK-647; previously known as PF-00547659 or SHP647) is a fully human 
immunoglobulin G2 kappa monoclonal antibody that inhibits binding of the α4β7–integrin to 
human MAdCAM-1 (Pullen et al. 2009). Ontamalimab has been shown to reduce CD4+ and 
CD8+ memory T-lymphocyte homing to the gut in response to gastrointestinal (GI) inflammation 
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(Briskin et al. 1997; Liaskou et al. 2011; Shyjan et al. 1996). MAdCAM-1, while initially 
thought to be gut specific, has also been demonstrated to recruit mucosal lymphocytes to the 
liver and biliary tract (Graham et al. 2018; Grant et al. 2001; Hillan et al. 1999). In modified 
Stamper-Woodruff assays, MAdCAM-1 on hepatic vessels supported adhesion of α4β7 from 
patients who had inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) 
(Grant et al. 2001). A recent publication confirmed MAdCAM-1 expression in explanted livers 
of patients undergoing orthotopic liver transplantation for chronic liver disease (CLD) (Graham 
et al. 2022). Positive hepatic MAdCAM-1 immunoreactivity was described in more than 75% of 
patients with CLD regardless of etiology or disease severity and is largely universal in cases of 
later stages of CLD. There was increased expression of both C-C chemokine ligand 25 (CCL25) 
and MAdCAM-1, which can induce tissue infiltration of α4β7- and C-C chemokine receptor type 
9 (CCR9)-expressing CD4+ T cells and a concomitant reduction in peripheral frequencies 
(Graham et al. 2022), across all CLD groups compared with normal liver. The authors also found 
an increase in the number of α4β7+ CD4+ T-effector memory cells in livers, an increase in αEβ7+
CD8+ cells, and that these β7+ cells displayed an increased proinflammatory phenotype. 
Consistent with the work of Grant and colleagues (Grant et al. 2001), these findings were 
independent of the etiology of the liver disease. 
The liver inflammatory lymphocytes of patients with PSC are mainly non-activated memory 
T lymphocytes, a substantial proportion of which expressed the co-receptors α4β7 and/or CCR9 
(Ponsioen et al. 1999). Hepatic MAdCAM-1 expression was shown in a variety of CLDs, 
particularly in patients with PSC and autoimmune hepatitis (AIH) (Grant et al. 2001). In 
addition, peripheral T lymphocytes from patients with PSC, patients with ulcerative colitis (UC), 
and healthy controls adhered to histologically MAdCAM-1–positive PSC liver sections, 
indicating that the aberrant hepatic expression of MAdCAM-1 was functional (Grant et al. 2001).
MAdCAM-1 expression is upregulated in the cirrhotic liver and immunolocalizes to the 
peribiliary plexus and lymphoid aggregates (Ala et al. 2013). MAdCAM-1 expression was 
evaluated in tissue sections from cirrhotic individuals who underwent orthotopic liver 
transplantation and was compared with precirrhotic, fulminant hepatitis B, and noncirrhotic 
portal hypertension tissue sections. Real-time PCR was used to quantify levels of MAdCAM-1 
mRNA in the samples. MAdCAM-1 was expressed in 27 of 28 of the cirrhotic sections, and it 
was localized primarily to septal areas within the endothelium of the peribiliary vascular plexus 
and lymphoid aggregates but notably was absent from normal liver, noncirrhotic livers obtained 
from patients with portal hypertension, and precirrhotic livers. There was significant 
upregulation of MAdCAM-1 mRNA in cirrhosis (p <0.011), consistent with 
immunohistochemical analysis. 
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Takeda’s immunohistochemistry data on cirrhotic liver samples also support the key 
observations in the literature that MAdCAM-1 expression is increased in the liver of patients 
with cirrhosis, independent of the etiology.
Evidence for MAdCAM-1 immunoreactivity in diagnostic or other early-stage liver biopsies has 
not been shown consistently in PSC-IBD or other CLDs. This could be due to sampling 
limitations of biopsies. An alternate possibility is that aberrant hepatic MAdCAM-1 expression 
occurs in the later stages of CLD and thus does not mediate hepatic inflammation via gut 
lymphocyte recruitment in the early stages of disease. In line with this hypothesis, expression of 
MAdCAM-1 and α4 and β7 integrins were shown to be upregulated in the liver of patients with 
late-stage NASH (Ala et al. 2013; Rai et al. 2020; Riva et al. 2018).
The role of MAdCAM-1 in NASH progression is supported by several studies conducted in 
mice. MAdCAM-1 expression was induced in liver tissue of mice fed with a methionine- and 
choline-deficient (MCD) diet (NASH diet that promotes inflammation and fibrosis), and 
MAdCAM-1 knockout mice fed with a MCD diet for 4 weeks were protected from liver fibrosis, 
had reduced hepatic oxidative stress, and had decreased tissue inflammation, with a concomitant 
increase in regulatory T cells and anti-inflammatory macrophages (Drescher et al. 2017). Mice 
with a “leaky gut” phenotype (F11r knockout) developed more severe NASH and fibrosis on a 
Western diet, and had increased MAdCAM-1 expression and greater numbers and percentages of 
α4β7 CD4+ T cells in their livers (Rai et al. 2020). In addition, an inhibitory α4β7 antibody 
blocked hepatic and colonic T-cell recruitment and attenuated hepatic inflammation and fibrosis 
in this model. In a different model of liver damage, Madcam-1 knockout mice were less 
susceptible to concanavalin A–induced hepatitis and intrahepatic thrombosis, and the adhesion of 
lymphocytes to liver sinusoids was dependent on MAdCAM-1 and that β7 expression on T cells 
contributed to liver damage (Schippers et al. 2021). 
Further understanding of the mechanisms and identification of the timing of hepatic MAdCAM-1 
induction throughout the course of CLD could pave the way for the use of targeted anti-integrin
therapies, as used in IBD, with the aim of blocking hepatic MAdCAM-1/α4β7–mediated cell 
recruitment and inhibiting the progression of CLD. In support of pursuing similar therapeutic 
approaches in IBD and NASH, it is worthwhile to point out that there is a correlation between 
immune-mediated inflammatory diseases (IMIDs) and the prevalence of NAFLD and advanced 
liver fibrosis. It has been recently shown that IMIDs, such as IBD (Rodriguez-Duque et al. 
2022), psoriasis (van der Voort et al. 2014), and hidradenitis suppurativa (Durán-Vian et al. 
2019) represent independent risk factors for both NAFLD and NAFLD with advanced liver 
fibrosis. In a recent, cross-sectional, case-control study presented at the 2022 International Liver 
Congress (García-Nieto et al. 2022) involving 1567 patients with IMIDs and 3130 paired 
controls (paired by sex, age, body mass index, and T2DM), the presence of IMIDs significantly 
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increased the prevalence of NAFLD and NAFLD with advanced fibrosis. IMIDs have been 
found to be strong predictors of NAFLD with advanced fibrosis independent of metabolic risk 
factors (eg, obesity, T2DM). These emerging association studies suggest that chronic 
inflammation, which is known driver of IMIDs, may also play a role in progressive 
steatohepatitis in NAFLD and advanced liver fibrosis. 
Fibrosis is the single most important determinant of clinical outcomes (Angulo et al. 2015) and 
the presence of lobular inflammation is an important risk factor for the development and 
progression of hepatic fibrosis. To justify the therapeutic rationale of MAdCAM-1 inhibition in 
fibrotic NASH, it is important to note that improvement of steatohepatitis has been shown to be 
associated with fibrosis regression (Kleiner et al. 2019). Based on the strong correlation between 
intrahepatic T-cell frequency and liver stiffness in patients with NASH (Van Herck et al. 2019), 
MAdCAM-1 inhibition may decrease fibrosis and liver stiffness, ultimately improving clinical 
outcome, by virtue of decreasing T-cell infiltration into the liver and resultant inflammation.
2.3 Benefit/Risk Assessment 
As of 31 March 2022, the ontamalimab clinical program comprises 13 studies, including 
6 completed studies for UC, 6 completed studies for Crohn’s disease (CD), and 1 ongoing long-
term safety extension study for participants with UC or CD previously enrolled in the Phase 3 
induction and maintenance studies. As of 31 March 2022, 1468 participants enrolled in Phase 1 
and induction studies received at least 1 dose of study drug in the clinical development program 
(1166 participants who received ontamalimab and 302 participants who received placebo), 
including 1094 participants with UC and 374 participants with CD. A total of 598 participants 
(330 participants with UC and 268 participants with CD) rolled over to Phase 2 long-term safety 
studies where they received ontamalimab, regardless of treatment assignment in previous studies. 
Overall, 406 participants enrolled in Phase 3 maintenance studies after completing the Phase 3 
induction studies were further randomized to receive either ontamalimab or placebo 
(366 participants with UC and 40 participants with CD). A total of 557 participants have 
received ontamalimab in the ongoing Phase 3 long-term safety study, which includes participants 
previously enrolled in Phase 3 induction and maintenance studies. 
The safety data across the ontamalimab development program shows ontamalimab to be 
generally well tolerated, with the majority of treatment-emergent adverse events (TEAEs) 
distributed at similar frequencies among treatment arms. Nasopharyngitis occurred at relatively
high frequency during the long-term safety studies; however, it was not reported more frequently 
in the ontamalimab group compared with the placebo group in the induction studies. No 
liver-related safety signals have been observed in previous clinical studies of ontamalimab. 
Ontamalimab does not appear to be associated with impaired central nervous system immune 
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surveillance. No cases of progressive multifocal leukoencephalopathy (PML) or myocarditis 
have been reported. However, as continued mitigation for the potential risk of PML, targeted 
neurological assessments will be performed in this study to monitor any changes from baseline in 
the participant’s status (Section 8.3.2).
To date, no clinical data with ontamalimab in patients with NASH have been gathered; 
participants with PSC or with impaired hepatic function were excluded from enrollment in 
clinical studies of ontamalimab in the treatment of UC and CD. 
Refer to the latest version of the ontamalimab investigator’s brochure (IB) for the overall 
benefit/risk assessment in the context of IBD and the most current information regarding drug 
metabolism, pharmacokinetics (PK), efficacy, and safety of ontamalimab in participants with 
IBD.
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3. OBJECTIVES AND ENDPOINTS
The following are the objectives and endpoints of this study:
Objectives
Endpoints
Primary
To evaluate safety and tolerability of ontamalimab 
75 mg administered Q4W in participants with NASH 
(defined as NAS ≥3 with at least 1 point in lobular 
inflammation) with different fibrosis stages (NASH 
CRN) F1 through F4cc participants. 
•
Incidence of treatment-emergent adverse events 
(TEAEs)
•
Number of participants with clinically 
significant changes in the following parameters 
from baseline to the end of the follow-up period 
(Week 36):
•
Laboratory tests
•
Electrocardiograms (ECGs)
•
Vital signs
•
Body weight
Secondary
To determine if the changes from baseline in key 
biomarkers (neoepitope-specific N-terminal propeptide 
of type III collagen [Pro-C3] and Enhanced Liver 
Fibrosis test [ELF]) and in cT1 MRI (iron-corrected T1 
mapping by magnetic resonance imaging) provide a 
signal of a potential role of the MAdCAM-1 pathway 
in participants with NASH (defined as NAS ≥3 with at 
least 1 point in lobular inflammation) with different 
fibrosis stages (NASH CRN F1 through F4cc 
participants) after 24 weeks of administration of 
ontamalimab 75 mg Q4W.
•
Percent change from baseline in Pro-C3 through 
Week 24
•
Percent change from baseline in ELF through 
Week 24
•
Change from baseline in liver cT1 MRI at 
Week 24
Exploratory
To evaluate the changes from baseline in soluble 
MAdCAM-1 after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH 
(NAS ≥3 with at least 1 point in lobular inflammation) 
in each of the different fibrosis stages (NASH CRN F1 
through F4cc) and overall in all participants.
Change from baseline to Week 24 in soluble 
MAdCAM-1 for each fibrosis stage group (fibrosis 
stage 1 through 4) and overall in all participants.
To evaluate the changes from baseline in inflammatory 
and cell trafficking markers in liver biopsy and blood 
samples after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH 
(NAS ≥3 with at least 1 point in lobular inflammation) 
in each of the different fibrosis stages (NASH CRN F1 
through F4cc) and overall in all participants.
Change from baseline to Week 24 in each of the 
following biomarker readouts for each fibrosis stage 
group (fibrosis stage 1 through 4) and overall in all 
participants:
•
Serum or plasma biomarkers including but not 
limited to: high-sensitivity C-reactive protein 
(hsCRP) (serum), interleukin (IL)-8 (serum), 
and calprotectin (plasma)
•
T and immune cell trafficking in liver biopsy 
samples and circulating whole blood samples, 
including but not limited to: Th17/Th1 vs. Th2, 
β7+ T cells, CCR9, and C-X-C motif chemokine 
receptor 3 (CXCR3)
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Objectives
Endpoints
•
Liver biopsy exploratory analyses including but 
not limited to markers of inflammation, fibrosis 
and artificial intelligence/machine learning 
methods
•
Transcriptomics in liver biopsy and whole blood 
samples
To evaluate the changes in fibrosis markers from 
baseline after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH 
(NAS ≥3 with at least 1 point in lobular inflammation) 
in each of the different fibrosis stages (NASH CRN F1 
through F4cc) and overall in all participants.
Change from baseline to Week 24 in each of the 
following biomarker readouts for each fibrosis stage 
group (fibrosis stage 1 through 4) and overall in all 
participants:
•
Liver stiffness measure (LSM) by FibroScan
•
Fibrosis-4 Index (FIB-4)
•
FibroScan-aspartate aminotransferase (FAST) 
score
To evaluate the changes in liver fat content from 
baseline after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH 
(NAS ≥3 with at least 1 point in lobular inflammation) 
in each of the different fibrosis stages (NASH CRN F1 
through F4cc) and overall in all participants. 
Change from baseline to Week 24 in proton density fat 
fraction (PDFF) as measured by MRI-PDFF, part of 
the Liver MultiScan® for each fibrosis stage group 
(fibrosis stage 1 through 4) and overall in all 
participants. 
To evaluate the changes in spleen cT1 MRI from 
baseline after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH 
(NAS ≥3 with at least 1 point in lobular inflammation) 
in each of the different fibrosis stages (NASH CRN F1 
through F4cc) and overall in all participants.
Change from baseline to Week 24 in spleen cT1 MRI 
for each fibrosis stage group (fibrosis stage 1 through 
4) and overall in all participants
To evaluate the changes from baseline in liver 
histology concerning NASH CRN fibrosis stage after 
24 weeks of administration of ontamalimab 75 mg 
Q4W in participants with NASH (NAS ≥3 with at least 
1 point in lobular inflammation) in each of the different 
fibrosis stages (NASH CRN F1 through F4cc 
participants) and overall in all participants.
Change from baseline to Week 24 in each of the 
following biomarker readouts for each fibrosis stage 
group (fibrosis stage 1 through 4) and overall in all 
participants:
•
Lobular inflammation grade
•
Hepatocyte ballooning grade
•
Steatosis grade 
•
NAS
To evaluate the changes from baseline in liver function 
and biochemistry after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH 
(NAS ≥3 with at least 1 point in lobular inflammation) 
in each of the different fibrosis stages (NASH CRN F1 
through F4cc participants) and overall in all 
participants.
Change from baseline to Week 24 in each of the 
following biomarker readouts for each fibrosis stage 
group (fibrosis stage 1 through 4) and overall in all 
participants:
•
Alanine aminotransferase (ALT)
•
Aspartate aminotransferase (AST)
•
AST/ALT ratio
•
Alkaline phosphatase (ALP)
•
Gamma-glutamyl transferase
•
Total bilirubin (TBL)
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Objectives
Endpoints
•
International normalized ratio (INR)
•
Albumin
•
HepQuant-SHUNT – Disease Severity Index 
(DSI) (investigational assessment)
To evaluate the pharmacokinetics (PK) of ontamalimab 
75 mg Q4W in participants with NASH (NAS ≥3 with 
at least 1 point in lobular inflammation) (NASH CRN 
F1 through F4cc participants).
Serum concentrations of ontamalimab over the 
treatment period.
To evaluate immunogenicity of ontamalimab 75 mg 
Q4W in participants with NASH (NAS ≥3 with at least 
1 point in lobular inflammation) (NASH CRN F1 
through F4cc participants).
Incidence of formation of antidrug antibodies (ADAs) 
through the end of the follow-up period (Week 36).
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4. STUDY DESIGN 
4.1 Overall Design 
This is a multicenter, single-arm, open-label, Phase 1b study to explore the role of MAdCAM-1 
in NASH by administering a MAdCAM-1 inhibitor (ontamalimab) in participants with indication 
of NASH via biopsy (NAS ≥3 with at least 1 point in lobular inflammation) with different 
fibrosis stages (NASH CRN F1 through F4cc participants). The role of MAdCAM-1 will be 
evaluated by the changes in inflammatory and fibrosis biomarkers, liver histology and circulating 
inflammatory cells, and liver chemistry tests compared with baseline. MRI-derived cT1 
(iron-corrected T1 mapping) will be used to evaluate fibroinflammatory changes in the liver. 
Safety and tolerability of ontamalimab 75 mg will be assessed. 
Approximately 30 participants are planned to be enrolled to ensure that at least 18 participants 
(approximately 12 participants with F1-F3 and approximately 6 participants with F4cc) complete 
the 24-week treatment period. Not more than four participants with F1 fibrosis will be enrolled in 
this study. Enrollment of F1, F2 and F3 participants at a 1:1:1 ratio will not be required. The 
study will be conducted at up to 20 sites in the US.
Participants will be aged ≥18 and ≤70 years and diagnosed with NASH without decompensated 
cirrhosis or neoplasia. 
The broad NASH population is targeted, and participants with documented stable T2DM or 
participants with high body mass index >25 kg/m2 with ≥1 criterion of metabolic syndrome will 
be permitted to participate in the study.
Participants with neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3) 
≥12.6 ng/mL, and Enhanced Liver Fibrosis (ELF) score ≥7.7, who meet inclusion criteria and 
none of exclusion criteria for assessments and procedures at Screening Visit 1 (SV1; Week -8) 
will be eligible for liver biopsy that will be performed at Screening Visit 2 (SV2; Week -6).
Indication for NASH (NAS ≥3 with at least 1 point in lobular inflammation) and liver fibrosis 
stage F1 through F4cc in the liver biopsy will enable these participants to enroll in the study.
Historical liver biopsy samples are acceptable for screening purposes if collected between 
24 weeks and 4 weeks before the start of the screening period (maximum allowed time between 
historical biopsy and first dose of study drug is 34 weeks for any participant, except for the 
participants who test positive for SARS-CoV-2 at screening). For any F4 participants who meet 
the inclusion and exclusion criteria before establishment of safety and tolerability in the first 
four noncirrhotic (F1-F3) participants, historical liver biopsy samples are acceptable for 
screening purposes if collected within 10 weeks before the start of the screening period
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(12 weeks if test positive for SARS-CoV-2 at screening).The first screening visit must occur at 
least 4 weeks after the historical biopsy to ensure that any biopsy-induced changes in liver 
function parameters or biomarkers have stabilized. If a qualifying historical liver biopsy sample 
is available to be reviewed and read centrally by the study pathologists and if it meets all the 
criteria as defined in the histopathology manual, liver biopsy need not be repeated during 
screening. Historical liver biopsy samples must show indication for NASH (NAS ≥3 with at least 
1 point in lobular inflammation) and liver fibrosis stage F1 through F4cc. Participants with 
qualifying historical liver biopsy must have adhered to restrictions on prohibited hepatotoxic 
medications during the specified period before historical liver biopsy sampling. For participants 
with qualifying historical liver biopsies, the abdominal MRI visit (Visit 4a) may occur as soon as 
possible after liver chemistry results from SV2 become available, and SV2 and the Day -4 visit 
(Visit 4a2) must be at least 2 weeks apart. 
Pro-C3, ELF, and other exploratory markers will be measured at 2 screening visits (SV1 and 
SV2) and Day 1 [D1] predose measurement during treatment period to determine intra-
participant variability. This will enable the correct interpretation of the posttreatment decrease in 
these biomarkers relative to the intra-participant variability at baseline.
After safety and tolerability have been established in the first four noncirrhotic (F1-F3) 
participants who have received at least 3 doses of ontamalimab 75 mg and have been monitored 
for at least 12 weeks after the first dose of study drug, eligible F4cc participants will be allowed 
to enroll into the study. The screening period may be extended for up to 24 weeks for 
participants with results consistent with F4 fibrosis (ie, compensated cirrhosis) after the first 
screening visit (ie, a combination of Fibrosis-4 Index [FIB-4] ≥3.48 and liver stiffness 
measurement (LSM) ≥20 kPa, or an Agile 4 score ≥0.57), or have a screening liver biopsy or a 
historical liver biopsy that confirms F4 NASH (NAS ≥3 with at least 1 point in lobular 
inflammation) with F4 fibrosis (ie, cirrhosis), until safety and tolerability data are evaluated in 
the first four noncirrhotic (F1-F3) participants.  
All eligible participants (F1-F4) will enter a 24-week, single-arm, open-label treatment period 
with ontamalimab 75 mg. Ontamalimab will be administered subcutaneously (SC) Q4W starting 
on Day 1 and the last dose is administered at Week 20 (total treatment period is 24 Weeks), 
followed by a 12-week safety follow-up period. Liver biopsy samples will be collected during 
screening and at Week 24. Fibro-inflammation will be assessed by cT1 MRI, liver stiffness by 
FibroScan, and hepatocellular function by the investigational HepQuant-SHUNT Disease 
Severity Index (DSI) at the start of the treatment period and at Week 24. At visits Q4W between 
baseline and Week 24, assessments of selected biomarkers (including but not limited to Pro-C3, 
ELF, soluble MAdCAM-1, hsCRP, and calprotectin), liver chemistry tests, and specific safety 
data collection (laboratory, adverse events [AEs], neurological assessments) will be performed. 
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Liver stiffness measurement by FibroScan will also be performed at Week 12. Safety and 
tolerability data will be continuously monitored and will be evaluated by the internal safety 
review committee (independent from the study team).  
All participants, including those who discontinue, will undergo a safety follow-up period through 
12 weeks after the last dose of study drug.
The end of the study is defined as the date of the last visit (Week 36) of the last participant 
undergoing the study, unless the study is stopped earlier by the sponsor due to futility or for 
safety reasons (Section 4.4).
For a schematic of the study design, see Section 1.2. For the Schedule of Activities (SoA), see 
Section 1.3.
4.2 Scientific Rationale for Study Design 
Blocking MAdCAM-1 may disrupt the trafficking of α4β7+ lymphocytes into hepatic and portal 
vein endothelium and subsequent extravasation into the liver. Ontamalimab selectively binds 
MAdCAM-1 with high affinity and selectivity, preventing the MAdCAM-1/α4β7-integrin 
interaction. 
This is expected to reduce lymphocyte trafficking to the liver, preventing hepatic inflammation 
and injury, and may slow, halt, or reverse fibrosis. 
This study is designed to explore the role of MAdCAM-1 in NASH by administering a 
MAdCAM-1 inhibitor (ontamalimab) and to evaluate the safety and tolerability of ontamalimab 
75 mg in participants with NASH with fibrosis stages F1 through F4cc. 
Due to the potential mechanism of action on inflammation and secondary effects on fibrosis, the 
changes in fibrosis parameters in response to ontamalimab treatment may take longer to detect 
than would be expected for anti-fibrotic compounds. It is expected that 24 weeks is a sufficient 
duration to see changes in key fibrosis markers (Pro-C3, ELF score) as well as decreases in 
fibro-inflammation that can be detected by the cT1 parameter of the MRI. The investigational 
HepQuant-SHUNT DSI, which is thought to be a true measure of liver function, has been shown 
to be a dynamic biomarker that can change significantly after 12 weeks of obeticholic acid 
treatment (which is a mixed acting choleretic, anti-inflammatory and anti-fibrotic agent); 
therefore, it is likely that 24 weeks is long enough to detect a change in DSI following 
ontamalimab treatment that also targets fibro-inflammation albeit by a different mechanism. 
Soluble MAdCAM-1 concentrations decreased significantly, in a dose-related manner, at Week 2 
compared with baseline and remained low during Phase 2 ontamalimab IBD studies. After 
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12 weeks, median suppression of soluble MAdCAM-1 of 88.7%, 96.5%, and 97.8% was 
observed following monthly dosing of 22.5 mg, 75 mg, and 225 mg, respectively, whereas a 
median increase of 6.7% was seen with placebo. It is expected that there will be a decrease 
soluble MAdCAM-1 with ontamalimab treatment in participants with NASH, assuming the 
baseline levels in NASH are high, as was observed in IBD. The observed PK/pharmacodynamic 
properties and safety profiles of ontamalimab in participants with IBD support evaluation of the 
molecule in participants with NASH with fibrosis stages F1 through F4cc.
Baseline and after-treatment biopsy samples can help to understand the potential changes in liver 
immunology. Because this study is a single arm, open-label study, the estimated level of 
participant consent/interest (due to participant preference for active treatment versus placebo) 
may be higher than in a placebo-controlled study. Twenty-four weeks of treatment is reasonably 
long enough to expect changes in inflammatory and fibrosis biomarkers.
4.3 Justification for Dose 
Ontamalimab has been evaluated for the treatment of UC and CD in 13 studies. There are 
6 completed studies for UC, 6 completed studies for CD, and 1 ongoing study. After the Phase 2 
program, the 25 mg and 75 mg doses were selected for the Phase 3 program based on efficacy 
and safety profile of the previously tested doses (22.5 mg, 75 mg, and 225 mg) in the Phase 2 
program. The highest dose (225 mg) did not show efficacy benefit over the lower doses.  
Based on (1) the pooled analyses results of the SHP647-301 and SHP647-302 UC induction 
Phase 3 studies showing an enhanced clinical and endoscopic benefit of the ontamalimab 75 mg 
dose over placebo (with no statistically significant difference in remission between the 
ontamalimab 25 mg group and placebo group at Week 12); and (2) the similar safety profile of 
the 25 mg and the 75 mg doses observed, the recommended dose of ontamalimab to induce 
remission in participants with moderate to severe UC is 75 mg. As the assumption is that 
ontamalimab will block tissue MAdCAM-1 in the liver in a similar way as in the gut, the 75 mg 
dose was selected for this Phase 1b study as the dose showing the best profile for inducing 
anti-inflammatory changes in IBD.
4.4 End of Study/Study Completion Definition
The end of the study is defined as the date of the last visit (Week 36) of the last participant 
undergoing the study, unless the study is stopped earlier by the sponsor due to futility or for 
safety reasons.
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The final analyses for the primary endpoints and single final clinical study report (CSR) will be 
conducted after all participants enrolled in the study have had the opportunity to complete the 
Week 36 safety follow-up visit.
The participant’s maximum duration of participation in the study is expected to be approximately 
46 weeks (11.5 months). In case of positive test for SARS-CoV-2 infection, the total study 
period could be up to 48 weeks (ie, screening period of up to 12 weeks). For any F4 cirrhotic 
participants who have met the inclusion and exclusion criteria before safety and tolerability have 
been established in the first four noncirrhotic (F1-F3) participants. For these participants, the 
total study period is expected to be approximately 60 weeks (15 months).
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5. STUDY POPULATION
Informed consent must be obtained before any screening procedures, other than activities the 
Institutional Review Board (IRB) has specifically approved for use as prescreening procedures. 
Specifically, informed consent must be obtained before the participant is asked to fast before a 
screening laboratory sample is collected. Informed consent requirements are described in 
Section 10.1.3.
All entry criteria, including test results, must be confirmed before enrollment. Prospective 
approval of protocol deviations to recruitment and enrollment criteria, also known as protocol 
waivers or exemptions, is not permitted. 
Investigators must account for all individuals who sign informed consent forms (ICFs), 
regardless of the outcome of the screening, by completing the required electronic case report 
forms (eCRFs). 
Rescreening will be allowed under circumstances described in Section 5.4.
5.1 Inclusion Criteria 
Participants must meet all of the following criteria to be eligible for inclusion in the study:
Informed Consent
1. The participant is willing and able to understand and fully comply with study procedures 
and requirements, in the opinion of the investigator.
2. The participant and/or the participant’s legally acceptable representative has provided 
informed consent (that is, in writing, documented via a signed and dated ICF or electronic 
consent [eConsent] if applicable) and any required privacy authorization prior to the 
initiation of any study procedures. 
Age 
3. The participant is aged 18 to 70 years, inclusive, at the time of signing the ICF.
Type of Participant and Disease Characteristics
4. This criterion has been removed in Protocol Amendment 3.
5. The participant has signs of fibrogenic activity (Pro-C3 ≥12.6 ng/mL, ELF score ≥7.7) at 
the Week -8 (SV1) (applies to all participants regardless of whether historical biopsy 
results are available at screening).
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6. The participant has indication of NASH via biopsy (NAS ≥3 with at least 1 point in 
lobular inflammation) and liver fibrosis stage F1 through F4cc according to NASH CRN, 
and established according to appropriate guidelines. 
7. This criterion has been removed in Protocol Amendment 2.
8. This criterion has been removed in Protocol Amendment 2.
Contraception and Breastfeeding
9. The participant is a male participant or a nonpregnant, nonlactating female participant 
who, if sexually active, agrees to comply with the contraceptive requirements of the 
protocol, or a female participant of nonchildbearing potential. Participants of 
reproductive potential who are sexually active must agree to use appropriate 
contraception (ie, highly effective methods for female participants and medically 
appropriate methods for male participants) for the duration of the study and for at least 
12 weeks after the last dose of study drug.
10. The participant, if capable of breastfeeding, agrees to forego breastfeeding for the period 
from informed consent until 12 weeks after the last dose of study drug.
5.1.1 Justification of Inclusion Criteria
Elevated Pro-C3 and ELF signify active steatohepatitis and subsequently increased fibrogenic 
drive. The inhibition of MAdCAM-1 is expected to decrease steatohepatitis, reduce 
inflammatory cell infiltrate, and lower Pro-C3 and ELF levels. The Pro-C3 threshold 
(≥12.6 ng/mL) has been selected based on a recent publication (Erhardtsen et al. 2021) that 
indicates that participants with Pro-C3 values above this threshold are likely to have active 
fibrotic NASH. The ELF score threshold has been provided by the manufacturer (Siemens 
Healthineers) of this score; below this threshold, the participant is likely to have no fibrosis to 
mild fibrosis.
Progression of screening is contingent on successful confirmation of eligibility along with the 
sponsor's approval. All participants, independent from the timing of their liver biopsy (new or 
historical), are expected to have elevated Pro-C3 (≥12.6 ng/mL) and ELF (≥7.7), that indicate 
active fibrogenesis. For participants who are subject to liver biopsy during the screening period, 
these measurements are a part of the strategy to decrease biopsy screen failure rate, participant 
burden, and risks associated with performing liver biopsy. 
The protocol allows the enrollment of up to four participants with stage 1 fibrosis with 
Pro-C3≥12.6 ng/mL and ELF≥7.7 who also satisfy all other inclusion and exclusion criteria, 
because based on available Pro-C3 information in each fibrosis stages (Nielsen et al. 2021) it is 
believed that these patients represent a subpopulation of F1 patients who likely have more active, 
ongoing fibrogenesis with a potential for faster progression and could benefit from TAK-647 that 
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is aimed to decrease this fibrogenic process. It has been recently shown that Pro-C3 is an 
independent prognostic factor for predicting clinical events (Nielsen et al. 2023). 
5.2 Exclusion Criteria 
The participant will be excluded from the study if any of the following exclusion criteria are met: 
Medical Conditions
1. The following laboratory findings are exclusionary for all participants if found during 
screening visits (Week -8 [SV1], Week -6 [SV2] or at Day -4 [Visit 4a2]): 
a.
AST levels >5×the upper limit of normal (ULN). 
b. ALT levels >5×ULN.
2. The following laboratory findings are exclusionary for all participants if found during 
either screening visit (SV1 or SV2):
a.
ALP ≥2×ULN.
b. Serum creatinine ≥1.5×ULN, or has an estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73 m2.
c.
INR ≥1.3 (except for participants who are receiving anticoagulant treatment).
d. TBL ≥ULN (except for patients with a documented history of Gilbert’s syndrome if 
direct bilirubin is within normal reference range).
e.
Direct bilirubin ≥3×ULN.
f.
Platelet count <60×109/L.
3. The participant has been diagnosed with decompensated liver disease, or has new signs of 
decompensation and/or clinically meaningful change in disease status based on the 
judgment of the investigator (including but not limited to clinically significant changes in 
TBL, albumin, INR, creatinine, and/or AST and ALT levels*) are observed during the 
screening period, or has any of the following during the screening period:
a.
Presence or history of ascites, hepatic encephalopathy, or variceal bleeding.
b. Presence or history of Child-Pugh >6 (Class B or C), unless due to therapeutic 
anti-coagulation.
c.
Presence or history of MELD score >12.
* Note: It is the investigator’s decision, in consultation with the sponsor, to allow 
participants to enter the study who have clinically meaningful rising tendencies in liver 
chemistries or significantly elevated liver chemistries that do not yet satisfy Exclusion 
Criterion #1 but could be interpreted as clinically concerning (ie, AST or ALT >4×ULN) 
at any visit during the screening period.
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4. The participant has other diagnosed causes of liver disease based on medical history 
and/or baseline evaluation of laboratory and/or histology results, including, but not 
limited to viral (eg, chronic hepatitis B, hepatitis B virus surface antigen [HBsAg] 
positive, or hepatitis B core antibody [HBcAb] positive; or chronic hepatitis C or
hepatitis C virus antibody [HCVAb] positive and hepatitis C virus [HCV] RNA positive; 
or human immunodeficiency virus [HIV]-antibody positive)*, alcoholic (alcohol 
consumption greater than 4 units on any day or 14 units per week for male participants, 
or greater than 3 units on any day or 7 units/week for female participants [1 unit of 
alcohol is present in one 12 oz/355 mL beer (approximately 5% alcohol), 
one 5 oz/148 mL glass of wine (approximately 12% alcohol), and one 1.5 oz/44 mL 
measure of 80-proof liquor (approximately 40% alcohol)]), or autoimmune conditions 
(eg, PSC, primary biliary cirrhosis, autoimmune hepatitis, drug-induced hepatotoxicity), 
and other rare liver disease (eg, alpha-1-antitrypsin deficiency, Wilson disease, 
hemochromatosis).
* Note: If a participant tests negative for HBsAg but positive for HBcAb, the participant 
would be considered eligible if no presence of hepatitis B virus (HBV) DNA is confirmed 
by HBV DNA polymerase chain reaction (PCR) reflex testing performed by the central 
laboratory.
Participants who are HCVAb positive without evidence of HCV RNA may be considered 
eligible (spontaneous viral clearance or previously treated and cured [defined as no 
evidence of HCV RNA at least 12 weeks before baseline]).
5. The participant has a history of impaired hemostasis that, in the investigator’s judgement, 
would increase the risk to the participant if he or she participates in the study.
6. The participant has a significant concurrent medical condition at the time of screening or 
baseline, including, but not limited to, the following:
a.
Any major illness/condition or evidence of an unstable clinical condition (eg, hepatic, 
renal, hematologic, GI, endocrine [eg, uncontrolled diabetes* or type 1 diabetes 
mellitus, or thyroid disease], neurological [pre-existing demyelinating disorder such 
as multiple sclerosis or new onset seizures, unexplained sensory motor, or cognitive 
behavioral, neurological deficits, or significant abnormalities noted during screening], 
cardiovascular, pulmonary, immunologic [eg, Felty’s syndrome], or local active 
infection/infectious illness [any bacterial, fungal, or viral, eg, clinically active 
cytomegalovirus, Epstein-Barr virus, herpes simplex virus]) that, in the investigator’s 
judgment will substantially increase the risk to the participant if he or she participates 
in the study. 
* Note: Participants with hemoglobin A1c (HbA1c) ≥6.5% at screening (SV1; 
Week -8) without a previous diagnosis of T2DM must not take part in the study. 
Participants with a previous diagnosis for T2DM are permitted to enter the study if on 
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a stable regimen of antidiabetic therapy for at least 90 days before screening. 
Participants who are on a stable regimen of antidiabetic therapy for at least 90 days 
before screening (SV1; Week -8) and have HbA1c of ≥9% at Week -8 (SV1) should 
be excluded.
b. Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable 
angina pectoris) within 24 weeks before screening.
c.
History of significant cerebrovascular disease within 24 weeks before screening.
d. Cancer or history of cancer, including hepatocellular carcinoma or 
cholangiocarcinoma, or lymphoproliferative disease within the previous 5 years 
(other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, or 
carcinoma in situ of the uterine cervix that has been treated with no evidence of 
recurrence). 
e.
Any other severe acute or chronic medical or psychiatric condition or laboratory or 
ECG abnormality that may increase the risk associated with study participation or 
study drug administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the participant inappropriate for 
entry into this study.
f.
Transplanted organ or history of liver transplantation.
g. Significant trauma or major surgery within 4 weeks before the first screening visit, or 
with any major elective surgery planned to occur during the study.
7. The participant has severe active IBD. Participants with inactive IBD or active of mild to 
moderate severity that was documented either by prior endoscopy or in previous medical 
records for >6 months are permitted to enter if they do not require biological treatment or 
JAK inhibitors. Treatment with leukocyte apheresis or selective lymphocyte, monocyte, 
or granulocyte apheresis or plasma exchange 30 days before baseline (Day 1).
8. The participant has a severe immune-mediated inflammatory disease (IMID) (eg, 
rheumatoid arthritis, spondylarthritis disease spectrum, connective tissue disorders, 
cutaneous inflammatory conditions such as psoriasis, atopic dermatitis, hidradenitis 
suppurativa, asthma, multiple sclerosis). Participants with inactive IMID or active IMID 
of mild to moderate severity are permitted to enter the study. 
9. The participant has a change in body weight ≥5% three months before start of the 
screening or after qualifying liver biopsy. If the participant had a liver biopsy within 
24 weeks of screening, but experienced a weight change of ≥5% since the date of liver 
biopsy, the liver biopsy must be repeated at screening.
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10. The participant has any laboratory abnormality or condition that, in the investigator’s 
opinion, could adversely affect the safety of the participant or impair the assessment of 
study results.
11. The participant has known hypersensitivity to ontamalimab or formulation excipient.
12. The participant has active or latent infection with Mycobacterium tuberculosis (TB) who 
have not completed a generally accepted full course of treatment before screening.
13. The participant has clinically significant abnormal chest X-ray findings at SV1 (or up to 
12 weeks before the first screening visit if available), such as presence of active TB, 
general infections, heart failure, or malignancy.
14. The participant has a positive interferon-gamma release assay (IGRA) at screening or 
within 12 weeks before screening even in the absence of previously diagnosed active or 
latent TB. IGRA screening may be repeated during the screening period if the initial 
result is indeterminate. The participant may be enrolled if confirmatory IGRA results 
from the central laboratory are negative. If the confirmatory IGRA results from the 
central laboratory are positive, the participant should be screen-failed. If both initial and 
confirmatory IGRA results are indeterminate, the participant may be enrolled after a 
Mantoux tuberculin skin test is negative and after consultation with the sponsor and a 
pulmonary or infectious disease specialist who determines low risk of infection (ie, the 
participant would be acceptable for immunosuppressant [eg, anti- tumor necrosis factor 
(TNF)] treatment without additional action). If the time for consultation exceeds the visit 
window, the participant should be screen-failed and can be rescreened after the 
consultation establishes eligibility for study participation. This consultation must be 
included in the participant’s medical history.
15. The participant has any unexplained symptoms suggestive of PML based on the targeted 
neurological assessment during the screening period.
16. The participant has HIV. 
17. This criterion has been removed in Protocol Amendment 3.
18. The participant has a medical condition (eg, morbid obesity, claustrophobia) that prevent 
execution of protocol procedures including percutaneous liver biopsy, LSM by 
FibroScan, and MRI.
Prior/Concomitant Therapy
19. The participant is receiving treatment with vitamin E, thiazolidinediones (TZDs), or 
glucagon-like peptide-1 receptor agonists (GLP-1 RA) unless on a stable dose for 
3 months before qualifying liver biopsy and not initiated after qualifying liver biopsy and 
is anticipated to maintain the same dosing regimen throughout study participation (see 
Section 6.8.3).
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20. The participant is using drugs, herbs, or supplements historically associated with causing 
or worsening NAFLD/NASH within 24 weeks before qualifying liver biopsy or any time 
after qualifying liver biopsy is performed, including the use of total parenteral nutrition.
21. The participant has a positive urine screen for amphetamines, cocaine, or opioids related 
to the use of these drugs at screening. 
22. The participant is receiving methadone or buprenorphine unless on stable maintenance 
treatment for at least 6 months before screening. Participants with a positive urine drug 
screen due to prescription opioid-based medication are eligible if the prescription and 
diagnosis are reviewed and approved by the investigator.
23. The participant is using any prohibited concomitant medications as described in 
Section 6.8.2.
24. The participant has received a live (attenuated) vaccine within 30 days before baseline 
(Day 1) or is anticipated to receive a live vaccine during the study.
Prior/Concurrent Clinical Study Experience
25. The participant has participated in another investigational study of a drug or device 
within 30 days before or within 5 half-lives of the prior investigational agent (whichever 
is longer) before baseline (Day 1).
26. The participant has participated in another investigational study targeting NASH, T2DM, 
or obesity within 6 months before baseline (Day 1).
27. The participant is concurrently participating in another therapeutic clinical study.
28. The participant has previously received ontamalimab. 
29. The participant has had previous exposure to anti-integrin or anti-adhesion molecule 
treatment eg, natalizumab, efalizumab, etrolizumab, vedolizumab, or any other 
investigational anti-integrin/adhesion molecule within 90 days before baseline (Day 1).
30. The participant has had previous exposure to any other biologic drugs with 
immunomodulatory properties such as anti-TNF, including biosimilars or anti-IL-12/23, 
or any nonbiologic treatment with immunomodulatory properties such as JAK inhibitors, 
within 90 days or 5 half-lives (whichever is longer) before baseline (Day 1).
Other Exclusion Criteria 
31. The participant is unavailable for follow-up assessment or investigator concern for 
participant’s compliance with the protocol procedures.
32. The participant is a study site employee, an immediate family member (eg, spouse, 
parent, child, sibling), or is in a dependent relationship with a study site employee who is 
involved in conduct of this study, or may consent under duress.
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5.2.1 Justification of Exclusion Criteria
Participants with active and severe IMIDs (including IBD, rheumatoid arthritis, psoriasis, etc.) 
are to be excluded from this study because IMIDs have been shown to be independent predictors 
of advanced fibrotic NASH and an active flare up during the study period would represent a 
confounder with uncertain implications on the outcome of the study.
5.3 Lifestyle Considerations 
Participants should be encouraged to maintain their pre study exercise routine and diet 
throughout the study.
Participants must agree not to have weight loss surgery during the period of participation in the 
study.
5.3.1 Meals and Dietary Restrictions 
Laboratory samples for blood sugar and triglycerides, including those during the screening, 
treatment, and follow-up periods, should be obtained in a fasting state.
For the purposes of this protocol, dietary supplements (such as vitamins, minerals, purified food 
substances, and herbals with pharmaceutical properties) are considered to be concomitant 
medications (Section 6.8).
Restrictions on the consumption of other products with known pharmacological effects is also 
described in Section 5.3.2 (Alcohol and Tobacco), Section 6.2.5.2 (Administration), and 
Section 6.8.2 (Excluded Procedures and Treatments).
5.3.2 Alcohol and Tobacco 
Consumption of alcohol more than 4 units on any day or more than 14 units per week for male 
participants, or more than 3 units on any day or more than 14 units per week for female 
participants (1 unit of alcohol is present in one 12 oz/355 mL beer [approximately 5% alcohol], 
one 5 oz/148 mL glass of wine [approximately 12% alcohol], and a 1.5 oz/44 mL measure of 
80-proof liquor [approximately 40% alcohol]) is not permitted within 24 weeks before the first 
dose of study drug through the end of the safety follow-up period (Week 36).
Participants will be instructed to abstain from consuming alcohol for at least 48 hours before 
their clinic visit on dosing days, and during the clinic visit.
Use of nicotine-containing preparations should be recorded as concomitant medication.
For a comprehensive list of prohibited medications and procedures, see Section 6.8.2 and 
Table 4.
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5.3.3 Activity 
Participants should refrain from strenuous physical activity (eg, weightlifting, strenuous yard 
work, intensive exercise workouts) for 48 hours before study visits and laboratory evaluations.
5.3.4 Contraception and Breastfeeding 
The potential effects of ontamalimab on embryofetal or postnatal development have not been 
assessed in humans. An enhanced pre- and postnatal development toxicity study of ontamalimab 
in nonhuman primates indicated that ontamalimab by intravenous injection once every 10 days 
from GD20-22 until parturition was tolerated in pregnant cynomolgus monkeys at levels up to 
60 mg/kg (approximately 172 times the clinical exposure at the highest dose investigated in 
Phase 3 studies [75 mg Q4W]). For fetuses aborted, infants that died/euthanized early, and 
infants that survived until the scheduled terminal necropsy, there were no ontamalimab-related 
effects observed in the placenta (when available) or effects on fetal or infant morphometric 
measurements, or teratologic external, visceral, heart, or skeletal (infants only) evaluations. At 
30 and 60 mg/kg, the abortion rate was similar to controls, but infant losses were increased in 
both ontamalimab dose groups. Histopathologic findings of mononuclear cell infiltration and/or 
inflammation mainly in the GI tract were observed in 1 infant decedent in each dose group as 
well as at the terminal necropsy. The weight of evidence suggests an ontamalimab-related effect 
on infant survival and GI histopathology, considered potentially secondary to the 
pharmacological effects of ontamalimab and ontamalimab-related decreased immune 
surveillance. 
To minimize the risk of unintentional exposure of the embryo or fetus in the clinical study, all 
sexually active participants who, in the opinion of the investigator, are biologically capable of 
having children, or with their partners are at risk of pregnancy, must agree to use an appropriate 
form of contraception (ie, highly effective methods for participants capable of producing viable 
ova and/or becoming pregnant, and medically appropriate methods for participants capable of 
producing sperm), in accordance with the package instructions/leaflet.
Ontamalimab was detected in the milk of lactating monkeys. It is not known if ontamalimab is 
secreted in human milk.
During the screening visit (SV1), the investigator or designee in consultation with the participant 
will confirm the participant’s childbearing potential status. For participants of childbearing 
potential, it must be confirmed and documented that the participant has selected the most 
appropriate method of contraception (ie, highly effective methods for female and medically 
appropriate methods for male study participants) from the permitted list of contraception 
methods (see Section 10.4). Participants must affirm the consistent and correct use of at least 
one of these selected methods. Participants who are capable of breastfeeding must affirm that 
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they are not using their breastmilk to feed an infant. Regular contraception and breastfeeding 
check discussions will take place at the time points specified in the SoA (Section 1.3) (ie, at each 
site visit) and will be documented. In addition, the participant must be instructed to call the site 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected. 
5.3.4.1 Contraception for Participants Capable of Producing Viable Ova and/or Becoming 
Pregnant
Participants who are of childbearing potential (that is, capable of producing viable ova and/or 
becoming pregnant) must use highly effective contraception as agreed to in Inclusion 
Criterion #9. Section 10.4 defines childbearing potential and lists acceptable methods of 
contraception. If used, hormonal contraceptives should be administered according to the package 
insert.
5.3.4.2 Contraception for Participants Capable of Producing Viable Sperm
Participants who are capable of producing viable sperm must use medically appropriate 
contraception as agreed to in Inclusion Criterion #9. Section 10.4 provides further definitions and 
lists acceptable methods of contraception.
5.3.4.3 Restrictions on Breastfeeding
Participants capable of breastfeeding must forgo breastfeeding as agreed to in Inclusion 
Criterion #10.
5.4 Screening
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The screening period can be extended by 2 weeks for any reason 
(including but not limited to a repeat test requirement for select and predefined measurements) 
on a case-by-case basis with the sponsor’s approval. In case of positive test for SARS-CoV-2 
infection, screening may be paused for an additional 2 weeks.
The investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
timeframe defined in the SoA. 
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5.4.1 Screen Failures
An individual who has provided informed consent to participate in the study (but has not yet 
been allocated to receive study drug) may be categorized as a screen failure for any of the 
following reasons: 

Screen Failure (Did Not Meet Entrance Criteria)

Adverse Event

Lost to Follow-up

Pregnancy

Withdrawal by Subject

Study Terminated by Sponsor 

Other (Specify)
Participants are not considered screen failures if they were allocated to receive study drug but 
not treated. See Section 7.2. 
Participant identification numbers assigned to participants who fail screening should not be 
reused.
An individual who has been designated a screen failure may be rescreened once. Rescreening 
can be considered at the judgment of the investigator in consultation with the sponsor; however, 
a participant who has been designated as a screen failure may be rescreened up to one time. 
Rescreened participants must be reconsented, must begin the screening procedure again, and will 
be assigned a new participant number. Additionally, a participant’s abnormal screening 
laboratory results may be repeated once for confirmation before designating a participant as a 
screen failure as long as the repeated assessment is conducted prior to the next scheduled 
screening visit. If the second attempt would also result in a screen failure, the participant cannot 
be further rescreened.
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5.5 Criteria for Temporarily Delaying Enrollment 
Enrollment may be delayed for the following reason: 

For F4 cirrhotic participants who have met the inclusion and exclusion criteria before safety 
and tolerability have been established in the first four noncirrhotic (F1-F3) participants, the 
screening period may be extended for up to 24 weeks. After the first four noncirrhotic 
(F1-F3) participants have received at least 3 doses with ontamalimab 75 mg and have been 
monitored for at least 12 weeks after the first dose of study drug, eligible F4cc participants 
may enroll in the study.
5.6 Enrollment
A participant is defined as enrolled when all of the following have occurred: 

The participant or the participant’s legally acceptable representative has provided informed 
consent (that is, in writing, documented via a signed and dated ICF [or eConsent if 
applicable]).

The participant has completed screening, having satisfied all entry criteria.

The participant takes part in any study activity after screening.
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6. STUDY DRUG AND CONCOMITANT THERAPY 
6.1 Study Drug Administered 
The study drug is ontamalimab (TAK-647, previously known as PF-00547659 or SHP647; a 
fully human immunoglobulin G2 kappa antihuman MAdCAM-1 monoclonal antibody), which 
will be provided as a sterile aqueous buffered solution for SC administration in a glass prefilled 
syringe (PFS) with a fixed needle. Each PFS contains 1 mL of ontamalimab solution for injection 
at a concentration of 75 mg/mL. Ontamalimab will be administered SC Q4W starting on Day 1 
and the last dose is administered at Week 20 (total treatment period is 24 Weeks). Additional 
information is provided in the current ontamalimab IB.
6.2 Preparation, Handling, Storage, and Accountability 
6.2.1 Accountability Throughout the Study
The investigator or designee must ensure that the sponsor-supplied study product is used in 
accordance with the protocol and is only used for participants enrolled in the study. 
To document appropriate use of sponsor-supplied study product (Section 6.1), the investigator or 
designee must maintain 100% accountability for all sponsor-supplied study drugs that the site 
receives and dispenses during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

The investigator or designee must maintain records of all sponsor-supplied study drugs 
delivery to the site, current site inventory, dispensing for use by each participant, and return 
to the sponsor or designee. 

The investigator or designee must record this inventory on a sponsor-approved drug 
accountability log. 

Based on entries in the log, it must be possible to reconcile study products delivered with 
those used and returned. 

All study products must be accounted for, and all discrepancies investigated and documented 
to the sponsor’s satisfaction. 

If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.
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6.2.2 Receiving Product at the Site
Investigators will be provided with sufficient amounts of the study drug to carry out this protocol 
for the agreed number of participants. 
Upon receipt of sponsor-supplied study drug, the investigator or designee must verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct, and the medication is in good condition. 
This may include an examination of temperature-monitoring devices.
If quantity and conditions are acceptable, the investigator or designee should acknowledge the 
receipt of the shipment by signing the packing list, scanning the signed packing list, and 
returning the signed packing list per instructions provided on the form. If there are any 
discrepancies between the packing list and the actual product received, the sponsor must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file.
6.2.3 Handling and Storage at the Site
The investigator bears the overall responsibility for ensuring that the study drug is stored in an 
appropriate location. Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented. 
An appropriate storage location is one that is secure, with access that is limited to the 
investigator and authorized site staff, and that is environmentally controlled (manually or 
automated) in accordance with labeled storage requirements. 
The study drug must remain in the original container until dispensed.
The study drug should be protected from light and should not be frozen. Do not shake.
The investigator is responsible for ensuring that the study drug is maintained within an 
established temperature range of 2°C to 8°C, that the temperature is monitored throughout the 
duration of the study, and that records are maintained. The temperature should be monitored 
continuously by using either an in-house system, a mechanical recording device such as a 
calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording.
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The sponsor must be notified immediately upon discovery of any excursion from the established 
range. Temperature excursions will require site investigation as to cause and remediation. The 
sponsor will determine the ultimate impact of excursions on the study drug and will provide 
supportive documentation as necessary. Under no circumstances should the product be dispensed 
to participants until the impact has been determined and the product is deemed appropriate for 
use by the sponsor.
Study drug must be kept in these conditions until it is used or returned to the sponsor for 
destruction.
The sponsor should be notified immediately if there are any changes to the storage area of the 
study drug that could affect the integrity of the product(s), eg, fumigation of a storage room.
6.2.4 Labeling
The study drug is packaged in the following labeled containers: PFS with nominal fill volume of 
1 mL. The PFS will be packaged in a labeled carton.
The sponsor will provide the investigator with packaged study drug labeled in accordance with 
local regulatory requirements.
Space is allocated on the label so that the site representative can record a unique participant 
identifier.
Changes to sponsor-supplied packaging, including the addition of labels prior to dosing, may not 
be made without full agreement in advance by the sponsor. Such additional labels (eg, those used 
when dispensing marketed product) may, on a case-by-case basis, be applied to the study drug in 
order to satisfy local or institutional requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study participant by name.
6.2.5 Dispensing/Administration
The investigator has overall responsibility for administering the study drug.
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
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The investigator or their designee will administer the study drug only to participants enrolled in 
this study, following the procedures set out in the study protocol.  
6.2.5.1 Dispensing
Please refer to the pharmacy manual for additional details regarding study drug supply 
dispensation and management and inventory management and supply ordering.
Participants will receive treatment according to the study schedule.
Participant numbers are assigned to all participants as they consent to take part in the study. 
Within each site (numbered uniquely within a protocol), a participant number is assigned to each 
participant according to the sequence of presentation for study participation.
Participants will be assigned to receive the next available medication identification (ID) number 
allocated to each study site. The medication ID number will be entered onto the eCRF.
The pharmacist/designee will enter the participant ID on the study drug carton labels as they are 
distributed. All administered medication will be documented in the participant’s source and/or 
other study drug record.
No study drug stock or returned inventory may be removed from the site to which it was 
originally shipped without prior knowledge and consent by the sponsor. If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
6.2.5.2 Administration
The study drug (ontamalimab) will be administered SC Q4W by qualified site personnel at the 
time points specified in the SoA (Section 1.3). See Section 8 for the timing of dosing relative to 
other procedures.
The study drug should be administered in the anterolateral right or left thigh. The injection site 
should be rotated. If there are clinical reasons why the drug cannot be administered in the thigh, 
the drug may be administered in the deltoid area or abdomen with appropriate documentation.
After the first administration of study drug, the participant must be observed by a member of the 
study staff for at least 30 minutes (the total duration should be determined at the discretion of the 
investigator). For subsequent administrations, observation of the participant is at the discretion of 
the investigator. Injection site and allergic reaction monitoring should be completed by a member 
of the study staff.
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Investigator-directed delays in dosing due to abnormal laboratory findings or AEs should be 
discussed with the medical monitor to determine whether the participant should continue with 
the treatment.
The investigator, or an approved representative (eg, pharmacist), will ensure that all study drug is 
administered by qualified staff members.
Additional information will be provided in a separate pharmacy manual.
6.2.6 Destruction or Return 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied product accountability and reconciliation before sponsor-supplied 
products are returned to the sponsor or its designee for destruction. The investigator or designee 
will retain a copy of the documentation regarding sponsor-supplied study drugs’ accountability, 
return, and/or destruction. Originals will be sent to the sponsor or designee.
With the written agreement of the sponsor, at the end of the study all unused study drug may be 
returned to a local facility for destruction. Any empty/used study drug packaging must be 
destroyed at the site. In this case, destruction records identifying what was destroyed, when and 
how, must be obtained with copies provided to the sponsor. Destruction of study drug must be in 
accordance with local, state, and national laws.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
Further instructions regarding the final disposition of unused study drugs are provided in the 
study reference manual.
6.3 Measures to Minimize Bias: Randomization and Blinding 
6.3.1 Randomization 
This is not a randomized study; therefore, no randomization schedule will be generated.
6.3.2 Blinding the Treatment Assignment 
Not applicable.
6.3.3 Unblinding 
Not applicable.
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6.4 Study Drug Compliance 
When participants are dosed at the site, they will receive study drug directly from the 
investigator or designee under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The dose of study drug and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study drug.
6.5 Dose Modification 
Not Applicable.
6.6 Continued Access to Study Drug After the End of the Study 
No aftercare is planned for this study.
6.7 Treatment of Overdose 
In this study, an overdose is defined as a known deliberate or accidental administration of the 
study drug at a dose above that assigned to that individual participant, or intentional or 
unintentional administration of ontamalimab 75 mg at a dosing interval that is less than 2 weeks 
between doses.
There is no specific antidote for overdose with ontamalimab. In the event of a drug overdose, 
treatment should be symptomatic and supportive.
An overdose can occur as a result of abuse, misuse, or a medication error, as defined below. 
These terms are not mutually exclusive.

Abuse: Persistent or sporadic intentional intake of study drug when used for a nonmedical 
purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society.

Misuse: Intentional use of study drug other than as directed or indicated at any dose (Note: 
This includes a situation where the study drug is not used as directed at the dose prescribed 
by the protocol.)

Medication Error: An error made in prescribing, dispensing, administration, and/or use of a 
study drug. Medication errors are reportable to the sponsor only as defined below.
The administration and/or use of an expired study drug should be considered as a reportable 
medication error.
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Cases of participants missing doses of the study drug are not considered reportable as medication 
errors.
All cases of overdose, abuse, misuse, or medication error must be documented, including the 
quantity of the excess dose and the duration of the overdose. Because these events are not, in and 
of themselves, AEs, they should be reported regardless of whether any manifested signs or 
symptoms are considered AEs. If there are signs and symptoms meeting the criteria for reporting 
as AEs or SAEs, they should also be reported, as described in Section 10.3.
Overdose, abuse, misuse, or medication error must be reported to the sponsor according to the 
SAE reporting procedure whether or not it resulted in an AE/SAE.
6.8 Concomitant Therapy 
6.8.1 Rescue Medicine 
The use of rescue medications is not allowed at any time during the study.
6.8.2 Excluded Procedures and Treatments
Participants must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
Table 4 details the minimum required time before baseline (Day 1) for common prior treatments 
that are excluded medications for this study.
Table 4. Common Excluded Treatments
Permanently 
Excluded
Minimum Required Time Before 
Baseline (Day 1)
Prohibited Concomitant Medication or Therapy
30 days
90 days
Ontamalimab (TAK-647, SHP647, PF-00547659) in a 
previous study
X
Anti-integrin or antiadhesion molecule treatment 
(eg, natalizumab, efalizumab, etrolizumab, 
vedolizumab, or any other investigational 
anti-integrin/adhesion molecule)
X
Investigational products
Xa
Live (attenuated) vaccine
X
Leukocyte apheresis or selective lymphocyte, monocyte, 
or granulocyte apheresis or plasma exchange
X
Biologics with immunomodulatory properties (such as 
anti-TNFs) including biosimilars (including 
ustekinumab)
Xa
Nonbiologics with immunomodulatory propertiesb (such 
as JAK inhibitors)
Xa
TNF=tumor necrosis factor
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Table 4. Common Excluded Treatments
Permanently 
Excluded
Minimum Required Time Before 
Baseline (Day 1)
Prohibited Concomitant Medication or Therapy
30 days
90 days
a Or 5 half-lives if longer.
b With the exception of participants who are on stable doses of nonbiologic therapies with immunomodulatory 
properties (eg, azathioprine, 6-mercaptopurine, or methotrexate).
Antiplatelet and anticoagulant medications must be temporarily discontinued, if safe to do so, 
before liver biopsies during the study as described below (Neuberger et al. 2020), or according to 
local guidelines if more stringent:

Clopidogrel, prasugrel, ticagrelor: stop for 7 days before liver biopsy.

Aspirin: stop for 3 to 7 days before liver biopsy.

Dual antiplatelet therapy (eg, aspirin/clopidogrel): stop clopidogrel as above but continue 
aspirin.

Dipyridamole: omit on day of liver biopsy.

Low molecular weight heparin: stop for 12 hours before liver biopsy for prophylactic dose; 
stop for 24 hours before liver biopsy for higher than prophylactic dose.

Direct oral anticoagulants: stop for 2 days before liver biopsy.
Systemic administration of antibiotics that can potentially influence the composition of intestinal 
flora (including but not limited to clindamycin, ciprofloxacin, amoxicillin/clavulanic acid, 
cefprozil, imipenem, colistin/amoxicillin, amoxicillin/clavulanate potassium, tetracycline) are 
prohibited for more than 2 weeks sequentially within 3 months before first dose of study drug 
(and if applicable, within 3 months before a qualifying historical liver biopsy and not initiation 
after qualifying liver biopsy) and are excluded while on study.
The following list of prohibited drugs should not be taken within 6 months before the first dose 
of study drug (and if applicable, within 6 months before a qualifying historical liver biopsy and 
not initiated after qualifying liver biopsy) and are excluded while on study:

Tamoxifen

Amiodarone

Alcohol as described in exclusion criterion #4 (Section 5.2)

Griseofulvin

Total parenteral nutrition
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
Obeticholic acid

Valproate

Nucleoside analogues (except acyclovir)

Estrogens at doses greater than 2 mg once daily used for hormone replacement

Anabolic steroids

Any known hepatotoxins including over-the-counter therapies and herbal therapies such as 
germander, chaparral, and ma-huang
This is not a comprehensive list. Treatments not listed above are generally considered allowable, 
unless considered a potential hepatotoxin. 
6.8.3 Permitted Concomitant Medications and Procedures
Medications and supplements including but not limited to vitamin E, betaine, 
s-adenosyl-l-methionine, ursodeoxycholic acid, statins, milk thistle, fibrates (eg, gemfibrozil), 
probiotics, biguanides (metformin), bile acid sequestrants (eg, cholestyramine or colestipol), 
TZDs, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and GLP-1 RA that have been used 
to treat NAFLD/NASH are allowed during the course of the study if the participant has been on a 
stable dosing regimen (ie, same dose and frequency in the previous 3 months before the 
qualifying liver biopsy and not initiated after qualifying liver biopsy) and is anticipated to 
maintain this dosing regimen throughout study participation. Use of antiplatelet medications is 
also allowed, except when restricted before liver biopsy as described in Section 6.8.2. The 
investigator must contact the contract research organization (CRO) medical monitor to discuss 
any changes to concomitant medications that may impact the study. 
Participants taking 5-aminosalicylic acid, glucocorticoids, or immunosuppressants (eg, 
azathioprine, 6-mercaptopurine, or methotrexate) for IMIDs should be on a stable dose for at 
least 12 weeks before screening and anticipated to remain stable throughout the study. 
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7. DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
This section describes the circumstances under which individual participants would withdraw or 
be discontinued from the study drug or from the study itself. 
Section 10.1.9.2 describes circumstances in which specific sites or the study itself would be 
discontinued.
7.1 Discontinuation of Study Drug 
In rare instances, it may be necessary for a participant to permanently discontinue study drug. 
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study drug 
and follow-up and for any further evaluations that need to be completed.
See Section 7.1.1 for liver chemistry stopping criteria.
NOTE: Participants who do not qualify for the study (screen failures) are not considered to have 
discontinued; instead see Section 5.4.1.
If the study drug is discontinued, regardless of the reason, the evaluations listed for the 
Week 24/early termination visit will be performed as completely as possible. 
Comments (spontaneous or elicited) or complaints made by the participant must be recorded in 
the source documents.
The investigator must determine the primary reason for discontinuation of study drug and/or the 
participant from the study, date of discontinuation of the study drug, and the total amount of 
study drug administered and record this information in the eCRF.
The primary reason for discontinuation or withdrawal should be recorded using 1 of the 
following categories:
Adverse event. The participant has experienced an AE that may require early termination if 
continued participation would impose an unacceptable risk to the participant’s health or the 
participant is unwilling to continue because of the AE.
Death.
Protocol deviation. The discovery after the first dose of study drug that the participant did not 
meet protocol entry criteria or did not adhere to protocol requirements and continued 
participation poses an unacceptable risk to the participant’s health.
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Lost to follow-up. The participant did not attend visits and attempts to contact the participant 
were unsuccessful. Attempts to contact the participant must be documented in the participant’s 
source documents. See Section 7.3 for additional procedures for participants lost to follow-up.
Withdrawal by subject. The participant (or participant’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be recorded in 
the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (for example, withdrawal due 
to an AE should not be recorded in the “voluntary withdrawal” category). 
Study terminated by sponsor. 
Pregnancy. The participant is found to be pregnant. 
Note: If the participant is found to be pregnant, the participant must be withdrawn immediately. 
The procedure is described in Section 10.4.3.
Other (specify).
7.1.1 Liver Chemistry Stopping Criteria
Liver-related decisions to discontinue or temporarily interrupt a study drug should be considered 
based on factors that include how much higher baseline ALT and AST were relative to ULN and 
how much the on-study ALT and AST levels increased relative to baseline, in addition to 
whether there is concomitant elevation of TBL or INR. In this study, the baseline measurement 
(BLM) for evaluating liver chemistry stopping criteria is determined by the last liver chemistry 
value before dosing.
For participants with ALT or AST <5×ULN at screening visits (SV1, SV2 and Visit 4a2) but 
have ALT or AST >5×ULN at Day 1 after having received the first dose of study drug, a repeat 
test should be performed as soon as possible, the participant should be closely monitored 
according to guidance provided below, and the participant’s continued study participation should 
be evaluated by the internal safety review committee, in consultation with an independent panel 
of hepatic experts.
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The investigator, after discussion with the sponsor, is responsible for making the final decision to 
discontinue study drug. The study drug will be discontinued if any of the following criteria are 
met (see Figure 2):
1. ALT ≥3×ULN, ALT ≥2×BLM (or nadir*) and TBL ≥2×ULN (exception for individuals 
with Gilbert’s syndrome: doubling of direct bilirubin or INR >1.5, instead of TBL 
≥2×ULN).
2. ALT ≥8×ULN, if ALT was normal at baseline.
3. ALT ≥5×BLM (or nadir), if ALT was abnormal at baseline.
4. ALT ≥500 IU/L.
5. ALT ≥5×ULN for participants with normal baseline value, or ALT ≥3×BLM for 
participants with abnormal baseline (or nadir), and symptoms (eg, severe fatigue, nausea, 
vomiting, right upper quadrant pain).
*Nadir is the lowest ALT value after-treatment initiation.
The decision to discontinue study drug does not mean discontinuation of the participant from the 
clinical study; safety evaluations, including assessments of vital signs and liver chemistry values, 
should continue to be made in accordance with the SoA (Section 1.3) (see Section 7.1).
Discontinuation of an investigational drug is usually the only available therapy to treat suspected 
drug-induced liver injury and may not result in an immediate improvement, as test values and 
symptoms can last (sometimes even progress) for days or weeks after the drug has been 
discontinued.
Closer Monitoring Criteria

ALT ≥3×ULN and ALT ≥2×BLM (or nadir*), but not meeting stopping criteria.

ALT ≥5×ULN for participants with normal baseline value or ALT ≥3×BLM for participants 
with abnormal baseline (or nadir) without symptoms and who do not meet stopping criteria.
It is recommended to repeat with closer monitoring of ALT and bilirubin until levels return 
toward normal or until levels reach stopping criteria.
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Figure 2. Abnormal Liver-associated Test Results: Algorithm for Study Drug 
Discontinuation
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BILI=bilirubin; 
INR=international normalized ratio; TBIL=total bilirubin; ULN=upper limit of normal.
Source: Derived from (Regev et al. 2019).
7.2 Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the physician or at the institution or may be withdrawn at any time at 
the discretion of the investigator or sponsor (eg, in the interest of participant safety). The 
investigator is encouraged to discuss withdrawal of a participant with the medical monitor when 
possible. 
The investigator may discontinue a participant’s study participation at any time during the study 
when the participant meets the study termination criteria described in Section 7.1.
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At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Section 1.3). The primary criterion for termination must be 
recorded by the investigator. See SoA for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.3 Lost to Follow-up
A minimum of 3 documented attempts must be made to contact any participant (or their legally 
authorized representative) who is lost to follow-up at any time point prior to the last scheduled 
contact (in person or by phone or video). At least 1 of these documented attempts must include a 
written communication sent to the participant’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that the participant be assessed for final safety 
evaluations. 
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8. STUDY ASSESSMENTS AND PROCEDURES 
Written or electronic informed consent must be obtained (signed and dated) before study 
assessments and procedures can be performed, as described in Section 10.1.3.
The following sections describe the study procedures and data to be collected at planned time 
points per the SoA (Section 1.3). Protocol waivers or exemptions are not allowed. 
Repeat or unscheduled samples may be taken for safety reasons or due to technical issues with 
the samples at any time during the study and samples for immunogenicity should be collected 
when worsening of a disease is reported as an AE. For the screening laboratory tests indicated in 
the Schedule of Study Activities (Table 1 and Table 2), sampling may be repeated once during 
the screening period if a result is considered by the investigator to be transient and inconsistent 
with the participant’s clinical condition, for confirmation before the participant is considered a 
screen failure as long as the repeated assessment is conducted prior to the next scheduled 
screening visit (see Section 5.4.1). The screening period can be extended by 2 weeks for any 
reason (including but not limited to a repeat test requirement for select and predefined 
measurements) on a case-by-case basis with the sponsor’s approval. In case of positive test for 
SARS-CoV-2 infection, screening may be paused for an additional 2 weeks (Section 5.4). For 
biomarker assessments (Section 8.2.12), repeating a sample is not permitted for any reason other 
than technical issues with the sample.
Whenever possible, the same person should perform each assessment.
When timing of procedures and assessments coincide, the following order should be followed: 

Vital signs and ECG

Laboratory sample collection

Transient elastography and imaging techniques

Prognosis and clinical scores (eg, Child Pugh, Model for End-stage Liver Disease [MELD])

Study drug administration
Blood and tissue samples may be stored for up to the duration allowed by local regulations, but 
for no longer than 15 years.
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8.1 Demographics, Medical History, and Medication History
8.1.1 Demographics
Participant demographic information will be collected prior to the participant receiving the first 
dose of study drug.
Demographic information to be obtained will include:

Date of birth.

Sex.

Race.

Hispanic ethnicity.

Height and weight at screening. 
8.1.2 Medical History
Medical and medication history, including concurrent medical conditions, will be collected and 
recorded in the participant’s source documents and in the eCRF. 
Medical history to be obtained will include determining whether the participant has any 
significant conditions or diseases relevant to the disease under study that resolved before, or at 
the time when, the participant provided informed consent. Ongoing conditions are considered 
concurrent medical conditions.
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present when informed consent is provided. This includes clinically significant laboratory, ECG, 
physical examination, and/or vital signs abnormalities noted at screening examination, according 
to the judgment of the investigator. The condition (ie, diagnosis) should be described.
8.1.3 Prior and Concomitant Treatments/Medications
Prior and concomitant treatments and medications will be collected and recorded in the 
participant’s source document.
Such treatments/medications include but are not limited to:

medications or vaccines.

over-the-counter or prescription medicines.

recreational drugs.

vitamins.
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
herbal supplements.

medications relevant to the eligibility criteria.

other specific categories of interest.
Prior medications/treatments are defined as those that were received within 30 days (or PK 
equivalent of 5 half-lives, whichever is longer) of the date of first dose of study drug.
Concomitant medications/treatments are defined as those given in addition to the study drug 
between the dates of the first dose of study drug and the end of the follow-up period, inclusive.
Concomitant medications may be prescribed by a physician or obtained by the participant over 
the counter. Concomitant medication is not provided by the sponsor. 
At the time of the medical history, any available prior medication/treatment information will be 
collected.
At each study visit, participants will be asked whether they have taken any medication or 
received any treatment other than the study drug.
Information to be recorded will include:

Identification of the medication or treatment.

Reason for use.

Dates of treatment/medication administration: start and end dates.

Dosage information including dose and frequency.
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
8.2 Biomarker and Noninvasive Test Assessments 
8.2.1 Primary Efficacy Measurement 
Not applicable.
8.2.2 Liver Stiffness Measurement and Liver Fat Content
Liver stiffness, as measured by elastography, is a marker for hepatic fibrosis. It will be quantified 
in the study by ultrasound-based transient elastography (FibroScan). Transient elastography 
correlates well with histology (Metavir and Ishak stages), performing best at extreme stages, 
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meaning severe fibrosis versus nonfibrosis (Corpechot et al. 2006; Muir et al. 2019). In addition, 
the rate of change over time has a correlation with clinical outcomes. 
Assessments by FibroScan (LSM by FibroScan and liver fat content by Controlled Attenuation 
Parameter [CAP]) will be performed at the time points specified in the SoA (Section 1.3). 
The results will be read locally; the baseline reading at the first screening visit will be used to 
calculate FAST scores (see Section 8.2.3).
8.2.3 FibroScan-Aspartate Aminotransferase Score
The FAST score (>0.35) has been used to decrease biopsy screen failure rate as it is an efficient 
non-invasive tool to exclude patients who most likely do not have fibrotic NASH (Newsome et 
al. 2020) and thus would not benefit from potential pharmacologic therapy. The FAST score 
consists of LSM by vibration-controlled transient elastography and CAP, both measured by 
FibroScan, and AST (Newsome et al. 2020). The FAST score provides an efficient way to non-
invasively identify patients at risk of progressive NASH for clinical trials, thereby reducing 
unnecessary liver biopsies.
The FAST score will be calculated by the following formula:
 =
	
..×().×× 
!.!×"#
1 + 	
..×&'().×× 
!.!×"#
To calculate the FAST score, LSM, and CAP should come from a single FibroScan exam. The 
FibroScan exam and blood collection for AST assessment should be performed. The FAST score 
will be calculated using the FibroScan software.
The FAST score will be calculated at the time points specified in the SoA (Section 1.3).
8.2.4 Agile 4 Score
The Agile 4 score was developed as a noninvasive test to identify cirrhosis in patients with 
NAFLD (Boursier et al. 2021). The Agile 4 score is a FibroScan-derived score that includes 
LSM, AST, ALT, platelets, diabetes status, and gender (Boursier et al. 2021). Agile 4 was 
externally and independently validated to identify patients with cirrhosis with a positive 
predictive value that is superior to FIB-4 or LSM alone. Agile 4’s rule-out and rule-in cut-offs 
are associated with a much smaller indeterminate zone compared to FIB-4 and LSM alone to rule 
out or rule in cirrhosis. Agile 4 could be used in clinical practice to identify patients in need of 
hepatocellular carcinoma and esophageal varices screening.
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An Agile 4 score ≥0.57 during screening is consistent with a high likelihood of F4 fibrosis 
(ie, cirrhosis). 
The Agile 4 score will be calculated at the time points specified in the SoA (Section 1.3).
8.2.5 Fibrosis-4 Index
The FIB-4 index is a noninvasive test for liver fibrosis (Sterling et al. 2006). The FIB-4 score 
consists of age, ALT, AST, and platelet count, and is calculated using the following formula: age 
[years]×AST [U/L]/(platelet count [109/L]×√ALT [U/L]). FIB-4 has utility in identifying 
participants with advanced liver fibrosis (Srivastava et al. 2019) and prognosticating mortality 
and liver-related outcomes (Vieira Barbosa et al. 2022). 
A FIB-4 score ≥3.48, along with LSM ≥20 kPa, at screening would indicate a high likelihood of 
F4 fibrosis (ie, cirrhosis).
The FIB-4 score will be calculated at the at the time points specified in the SoA (Section 1.3).
8.2.6 Child-Pugh Score
The Child-Pugh score is a scoring system to measure the severity of CLD inclusive of cirrhosis 
(Pugh et al. 1973). It consists of 5 clinical features, 3 of which assess the synthetic function of 
the liver (TBL level, serum albumin, and INR) and 2 of which are based on clinical assessment 
(degree of ascites and degree of hepatic encephalopathy).
The Child-Pugh score will be calculated at the time points specified in the SoA (Section 1.3).
8.2.7 Model for End-stage Liver Disease
The original MELD score is a prospectively developed and validated chronic liver disease 
severity scoring system that uses a patient’s laboratory values for serum bilirubin, serum 
creatinine, and the INR for prothrombin time to predict 3-month survival. In patients with 
cirrhosis, an increasing MELD score is associated with increasing severity of hepatic dysfunction 
and increased 3-month mortality risk.
The MELD score changes over time depending on the course of the chronic liver disease and 
ranges from 6 to 40; increasing scores indicate progression/worsening of disease.
The MELD score will be calculated at the time points specified in the SoA (Section 1.3).
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8.2.8 Liver Biopsy
Liver biopsies will be taken as described in both the SoA (Section 1.3) and the histopathology 
manual. The histopathology manual must be followed for all liver biopsies as study standard 
operating procedure. Reasonable attempts should be made to acquire a needle core liver biopsy 
specimen using a 16-gauge needle of at least 2.0 cm (expected to have >11 portal tracts) in 
length. Specimens less than 1.5 cm will not be accepted for evaluation. If the first sample is not a 
minimum of 1.5 cm, a second core sample should be collected. The anatomical location (right or 
left liver lobe) and the specimen adequacy (needle size, tissue length) should be recorded. All of 
the collected biopsy tissues should be submitted for central pathology review. 
Liver biopsy samples will be processed into formalin fixed paraffin embedded blocks, routinely 
stained with hematoxylin and eosin (H&E) and Masson’s trichrome (MTR) by a central 
laboratory. Stained slides will be used for confirmation of the diagnosis of NASH, assessment 
and grading of NAS activity including scoring of steatosis, lobular inflammation, ballooning, as 
well as fibrosis using the NASH CRN scoring system by a hepatopathologist. The NASH CRN 
fibrosis score and components of NAS (ie, lobular inflammation, hepatocyte ballooning, steatosis 
grade) will be used for comparison of pre- versus post treatment. Additional analyses of liver 
biopsies are outlined in Section 8.2.12.
A previous biopsy conducted between 24 weeks and 4 weeks before the start of the screening 
period (or within 12 weeks before the start of the screening period for any F4cc participants who 
met the inclusion and exclusion criteria before establishment of safety and tolerability in the first 
four noncirrhotic [F1-F3] participants) as part of standard of care that meets the above criteria for 
an adequate liver biopsy may substitute for a fresh biopsy, provided sufficient numbers of 
sections (stained or unstained) and uncut biopsy block, as outlined in the histopathology manual 
are made available to the sponsor. If the biopsy is found to be inadequate by the study 
pathologist, a fresh biopsy will be required. The Week 24 liver biopsy should be taken from the 
same lobe as the screening biopsy.
Leftover tissue samples may be retained and stored for RNA sequencing (transcriptomics) 
analysis or other possible additional future analyses. Any retained samples will be deidentified 
and will not be labeled with patient identifying information. After 15 years from the end of the 
study, or earlier as required by local regulations, samples may be returned to the sponsor 
repository or destroyed per local regulations. Additionally, with the participant’s consent, 
samples may be used for further research by the sponsor or others, such as universities or other 
companies, to contribute to the understanding of NASH or other diseases, the development of 
related or new treatments, or development of research methods. Instructions for returns and 
destruction of tissue samples will be provided to the study sites in documentation outside of the 
protocol. 
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8.2.9 Magnetic Resonance Imaging-derived Iron-corrected T1 Mapping of the Liver
Liver MultiScan® MRI is a fast, contrast-free MRI scan that provides quantitative assessment of 
the whole liver tissue by measuring biomarkers for fibrosis and inflammation, fat, and iron. As 
part of the Liver MultiScan® technology, the owner company segments an entire slice of the liver 
parenchyma and quantifies iron-corrected T1 (cT1) relaxation time values across that slice of 
liver tissue, so capturing disease heterogeneity in analysis. The cT1 measurement has shown to 
be correlated with histopathological hallmarks of NASH (Dennis et al. 2021).
The abdominal MRI (to obtain liver cT1 as well as other MRI-based exploratory biomarkers 
described in Section 8.2.12) will be performed at the time points specified in the SoA 
(Section 1.3).
8.2.10 HepQuant-SHUNT Disease Severity Index
The dual cholate test (HepQuant®-SHUNT) is an investigational assay. The test yields a DSI 
that quantifies global liver function and physiology through the measurement of hepatic filtration 
rates that are defined from clearances of cholic acid-24-13C (20 mg administered intravenously; 
“systemic”) and cholic acid-2,2,4,4-d4 (40 mg administered orally; “portal”). The 
HepQuant-SHUNT DSI quantifies hepatic impairment and is thought to be reproducible over a 
broad spectrum of etiologies of liver disease, stages of fibrosis, and clinical severity.
The HepQuant-SHUNT DSI will be performed at the time points specified in the SoA 
(Section 1.3).
8.2.11 Alcohol Screening
The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item screening tool developed 
by the World Health Organization (WHO) to assess alcohol consumption, drinking behaviors, 
and alcohol-related problems (nida.nih.gov/sites/default/files/audit.pdf). Both a 
clinician-administered version and a self-report version of the AUDIT are included in this 
assessment. Participants will be encouraged to answer the AUDIT questions in terms of standard 
drinks. A score of 8 or more is considered to indicate hazardous or harmful alcohol use. The 
AUDIT has been validated across genders and in a wide range of racial/ethnic groups and is well 
suited for use in primary care settings. 
The AUDIT will be performed at the time points specified in the SoA (Section 1.3).
8.2.12 Additional Biomarkers
C-reactive protein and calprotectin are key biomarkers of inflammation. There is a significant 
relationship between hsCRP and risk of disease progression in NAFLD and NASH (Yoneda et 
al. 2007). Pro-C3 is a key biomarker of liver fibrosis. Mixed acting anti-metabolic agents 
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(FGF19/21 analogues) that affect inflammatory pathways (eg, NF-kB) decreased Pro-C3 within 
short trials ≤16 weeks by at least 20%, which is considered a clinically significant change (ie, 
associated with improvement in liver fibrosis by ≥1 stage improvement in longitudinal studies) 
(Luo et al. 2018). In the open label, 12-week Phase 2a trial with aldafermin, levels of Pro-C3 and 
ELF had greater reductions in patients who demonstrated histological response (histological 
response was defined as a 2-point or greater improvement in NAS without worsening of fibrosis 
or improvement in fibrosis of one stage or more without worsening of NASH [defined as no 
increase in NAS for ballooning, inflammation, or steatosis]), compared to non-responders 
(Harrison et al. 2021). Biomarkers of liver disease such as ELF will be derived as a composite 
score from serum levels of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal 
propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA). The ELF is the first 
prognostic tool for patients with advanced fibrosis (F3 or F4) due to NASH to be granted 
De Novo marketing authorization by FDA. Elevated ELF levels are prognostic for progression to 
cirrhosis (ELF ≥9.8) and liver-related clinical events (ELF ≥11.3) in NASH patients with 
advanced fibrosis (Fagan et al. 2015; Harrison et al. 2017). Magnetic resonance imaging-proton 
density fat fraction (MRI-PDFF) is a part of Liver MultiScan® and has an excellent correlation 
with histological steatosis across the spectrum of NAFLD and high diagnostic accuracy in 
stratifying all grades of hepatic steatosis (Dennis et al. 2021). Spleen cT1 significantly correlates 
with the hepatic venous pressure gradient (HVPG) and has an excellent diagnostic accuracy for 
portal hypertension (HVPG >5 mmHg) and clinically significant portal hypertension (HVPG 
≥10 mmHg) with an area under the receiver operating characteristic (AUROC) curve of 0.92 for 
both (Levick et al. 2019).
Blood and liver biopsy samples will be collected at the time points specified in the SoA 
(Section 1.3) for each of the following biomarkers:

Serum Pro-C3.

Serum ELF and its components (TIMP-1, PIIINP, and HA).

Serum soluble MAdCAM-1.

Serum and plasma markers of inflammation, fibrosis, and trafficking including but not 
limited to: hsCRP, calprotectin (plasma), IL-8, CTXIII, C3M, TSP2, and Pro-C5.

Exploratory analyses in liver biopsies including but not limited to markers of inflammation, 
fibrosis, and trafficking and may utilize artificial intelligence/machine learning methods.

T and immune cell trafficking in liver biopsy samples (immunohistochemistry) and 
circulating whole blood samples, including but not limited to Th17/Th1 vs. Th2, β7+ T cells, 
CCR9, and CXCR3.
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
Transcriptomics using residual liver biopsies and whole blood samples.

Potential analyses of extracellular vesicles using residual serum samples.
Blood samples must be collected before administration of study drug. The ELF score is 
calculated from the concentrations of serum biomarkers: TIMP-1, PIIINP, and HA. 
Details of sample collection, handling, shipment, and analysis will be provided in the laboratory 
manual.
The sponsor may store samples for up to 15 years after the end of the study to achieve study 
objectives. Additionally, with the participant’s consent, samples may be used for further research 
by the sponsor or others, such as universities or other companies, to contribute to the 
understanding of NASH or other diseases, the development of related or new treatments, or 
development of research methods.
8.3 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.3.1 Physical Examinations 
Complete physical examinations will be performed at the time points specified in the SoA 
(Section 1.3). Complete physical examination will include the review of the following body 
systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; breast 
(optional); abdomen; external genitalia (optional); extremities; neurologic function; back; and 
lymph nodes.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
Any changes from SV1 in physical examination results that are deemed clinically significant in 
the opinion of the investigator are to be recorded as an AE.
8.3.2 Targeted Neurological Assessment
Targeted neurological assessments to monitor the development of signs and/or symptoms of 
PML will be performed at the time points specified in the SoA (Section 1.3). Participants will be 
evaluated to reveal any potential abnormalities in the following neurological domains: vision, 
motor, tactile sensation, coordination/cerebellar function, speech, verbal comprehension, and 
cognition/behavior.
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If any abnormalities are indicated, participants will be further evaluated to help clarify any 
potential abnormal responses. Focus will be placed on possible alternative etiology (eg, fracture 
or stroke). If additional evaluation reveals an unexplained new abnormality, neurological 
examination(s), targeted to the abnormal domain, will be performed by the investigator or 
qualified personnel.
Participants with any unexplained positive neurological assessment item at the first screening 
visit that is suggestive of PML should be excluded from enrollment in the study (exclusion 
criterion #15, Section 5.2).
A step-wise approach for the proposed neurological assessment plan is summarized in Table 5.
Table 5. Neurological Assessment Plan
Domain
Step 1: Targeted Neurological 
History
Step 2: If Abnormal Response
Vision
Diplopia or visual/visual field loss
Perform visual field assessment
Motor
Major motor weakness (eg, legs, arms)
Test leg strength (hopping, foot tapping), 
finger tapping, pronator drift and 
bilateral muscle strength
Tactile sensation
Paresthesia, anesthesia in any domain 
(peripheral, central)
Pinprick test
Coordination/cerebellar
Clumsiness, difficulty with walking, 
writing, or fine motor skills, etc.
Finger-nose, heel-shin, heel-toe walk, 
writing sample, draw a clock
Speech
Dysarthria, expressive aphasia
Naming objects, repeat multipart phrase, 
observe for dysarthria or aphasia
Verbal comprehension
Agnosia, receptive aphasia
Test to follow routine commands, 
eg, close eyes, touch finger to ear
Cognition/behavior
New onset of difficulties with memory 
or thinking, important changes in 
behavior
Recall 3 objects over 1 minute, serial 7s, 
proverbs. Changes in activities of daily 
living over prior 24 weeks
Additionally, should there be any unexplained abnormal neurological findings, the participant is 
to be urgently referred to a neurologist. The sites will immediately inform the sponsor of any 
such occurrences. If the neurologist confirms the presence of PML, appropriate actions, 
including discontinuation of study drug, will be taken. Suspected PML cases will be reviewed 
promptly by the internal safety review committee with an external panel of PML experts and 
presented at the next meeting(s) of the internal safety review committee (Section 10.1.5.2). If 
PML is diagnosed, there will be an urgent meeting of the internal safety review committee with 
the PML expert panel. A flow diagram of the quarterly assessments and actions is presented in 
Figure 3. Any concerns from the internal safety review committee will be promptly 
communicated to the sponsor study team, investigator, and treating neurologist.
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Figure 3. Flow Diagram for Quarterly Neurological Assessments
IND=investigational new drug; Neuro=neurological; PML=progressive multifocal leukoencephalopathy
It is important to note that assessments based on neurological evaluations are collected and 
evaluated in a different manner than observed or volunteered AEs. Given these differences, no 
attempt will be made to reconcile any apparent discrepancies between observed or volunteered 
AEs and data from neurological assessment collected from participants. Investigators will 
determine whether any finding on neurological testing constitutes an AE. At each visit, 
participants will be queried for adverse events of special interest (AESIs) related to PML 
(Section 8.3.11.6, Section 10.3.3.2.2, and Section 10.3.5). Adverse event incidence rates will not 
be calculated from these neurological evaluation data but rather from the AE information 
recorded by the investigator.
8.3.3 Hypersensitivity Monitoring
Participants will be monitored for the presence of Type I (anaphylaxis) and Type III (immune 
complex) hypersensitivity reactions at the time points specified in the SoA (Section 1.3).
Participants will be educated on the signs and symptoms of Type III hypersensitivity reactions 
(eg, fever, rash [including hives], arthralgia, myalgia, vasculitis, Arthus reaction, general ill 
feeling, itching, and swollen lymph nodes) and how to respond to them should they occur during 
the outpatient portion of the study. In addition, participants will be instructed to report 
hypersensitivity AEs to the investigator at the time of occurrence, and to seek immediate medical 
care if necessary. At each visit, the participant will be queried for AESIs related to 
hypersensitivity. 
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Participants who experience an AE suggestive of a Type I hypersensitivity reaction should have 
a blood sample (3 mL) collected for anti-ontamalimab immunoglobulin E antibody 
determination, results of which will be available at the end of the study. Participants who have a 
suspected Type III hypersensitivity reaction should have a blood sample (4 mL) collected for 
complement determination (C3a, C5b-9).
Further details of hypersensitivity reactions as AESIs are provided in Section 8.3.11.6 and 
Section 10.3.3.2.
8.3.4 Vital Signs 
Vital signs will be collected before collection of blood samples for laboratory assessments, 
where applicable.
Additional collection times or changes to collection times will be permitted as necessary to 
ensure appropriate collection of safety data.
Vital signs will include: 

body temperature 

respiratory rate 

sitting blood pressure (systolic and diastolic, resting more than 5 minutes) 

pulse (bpm)
Single measurements of sitting blood pressure will be recorded at each time point. Blood 
pressure should be determined by cuff with the participant’s arm supported at the level of the 
heart and recorded to the nearest mmHg using the same method, the same arm (preferably the 
dominant arm), and the same position throughout the study.
Respiratory rate will be measured with the participant in a comfortable position. The observer 
should hold the extremity of the participant as a distraction for the patient (ie, pretending he/she 
is taking the participant’s radial pulse) and count the respiration for 1 minute.
Body temperature should be taken using a thermometer and reported in degrees Celsius or 
Fahrenheit.
The investigator will assess whether a change in vital signs from baseline (Day 1/Week 0) may 
be deemed clinically significant on the vital signs eCRF and whether the change should be 
considered and recorded as an AE on the AE eCRF.
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8.3.4.1 Weight and Height
Weight and height will be measured at the time points specified in the SoA (Section 1.3).
A participant should have weight and height measured while wearing indoor clothing and with 
shoes off. Weight is collected in kilograms (kg). Height is recorded in centimeters (cm). 
8.3.5 Electrocardiograms
A 12-lead ECG will be obtained as outlined in the SoA (Section 1.3).
A local ECG reader will be used in this study. The eligibility of the participant will be based on 
the assessment of the ECG by the investigator. If abnormal results are observed following 
assessment by the local reader, the investigator, in consultation with the appointed sponsor or 
CRO medical monitor, will reconfirm the participant’s eligibility to continue.
8.3.6 Chest X-ray
A chest X-ray will be performed at the first screening visit; however, if a participant has had a 
chest X-ray performed up to 12 weeks before the first screening visit then it does not need to be 
repeated as a part of screening. The official reading must be located in the participant’s source 
documentation.
8.3.7 Contraception and Breastfeeding Check
During the screening visit (Visit 1), the investigator or designee in consultation with the 
participant will confirm the participant’s childbearing potential status. For participants of 
childbearing potential, it must be confirmed and documented that the participant has selected the 
most appropriate method of contraception (ie, highly effective methods for female and medically 
appropriate methods for male study participants) from the permitted list of contraception 
methods (see Section 10.4). Participants must affirm the consistent and correct use of at least one 
of these selected methods. Participants who are capable of breastfeeding must affirm that they 
are not using their breastmilk to feed an infant. Regular contraception and breastfeeding check 
discussions will take place at the time points specified in the SoA (Section 1.3) (ie, at each site 
visit) and will be documented. 
8.3.8 Clinical Safety Laboratory Tests 
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3). Details about these procedures 
and required safety monitoring will be given in the laboratory manual.
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The maximum volume of blood at any single visit is approximately 100 mL, and the approximate 
total volume of blood for the study participant is 500 mL (approximate volumes do not include 
potential repeat measurements). 
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. 
The central laboratory will return these results, along with their reference ranges, to the 
investigator. The investigator is responsible for reviewing the laboratory report, documenting 
this review, and filing the laboratory report with the source documents.
If serum liver chemistry measurements at Week -8 (SV1) or Week -6 (SV2) are repeated (ie, as 
described in the SoA), the Week -8 (SV1) or Week -6 (SV2) value will be calculated as the mean 
of the initial and repeat measurements for the given visit, except if the repeat sampling was 
conducted because of a technical issue with the initial sample. 
Abnormal laboratory findings associated with the underlying disease should not be considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
Clinically significant abnormal laboratory values obtained during participation in the study or 
within 12 weeks after the last dose of study drug should be repeated until the values return to 
normal or the baseline value or are no longer considered clinically significant by the investigator 
or medical monitor. The investigator should evaluate whether the laboratory result meets the AE 
criteria in Section 10.3.1.
Abnormal clinical laboratory values that are unexpected or not explained by the participant’s 
clinical condition, may, at the discretion of the investigator or sponsor, be repeated as soon as 
possible until confirmed, explained, or resolved.
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor notified.
Investigators must document their review of each laboratory safety report.
The investigator must record the following types of laboratory test results on the laboratory 
eCRF and, if applicable, on the AE eCRF:

any changes that are considered clinically significant by the investigator (eg, SAE or AE or 
dose modification)
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
any laboratory test results (central laboratory, local laboratory, non-protocol-specific local 
laboratory) that are used to make a study drug decision, that require a change in participant 
management, or that are used to make a response evaluation.
8.3.9 Pregnancy Testing 
A beta-human chorionic gonadotropin (β-hCG) pregnancy test will be performed on all 
participants of childbearing potential at times described in the SoA (Section 1.3); if pregnancy is 
suspected; or on withdrawal of the participant from the study.
A serum pregnancy test will be performed at the first screening visit; all other pregnancy tests 
will be urine tests (a confirmatory serum β-hCG pregnancy test will only be required for 
participants who have a positive urine pregnancy test at any time).
Pregnancy tests are not required for participants of nonchildbearing potential (see Section 10.4.1
for definitions).
If a participant or a participant’s partner becomes pregnant during the study, the pregnancy must 
be followed as described in Section 10.4.3.
8.3.10 Immunogenicity Assessments
A blood sample for measurement of ADA will be collected at the time points specified in the 
SoA (Section 1.3). Blood samples must be collected before administration of the study drug at 
that visit. The detection and characterization of ADA will be performed using a validated assay 
method by or under the supervision of the sponsor.
8.3.11 Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs are provided in Section 10.3. 
The investigator and any qualified designees are responsible for collecting, detecting, 
documenting, and recording events that meet the definition of an AE or SAE. They remain 
responsible for follow-up of these events (see Section 10.3.3.2.1). 
8.3.11.1 Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information
All AEs (including pretreatment-emergent and treatment-emergent) will be collected from the 
signing of the ICF until the end of the 12-week safety follow up period at the time points 
specified in the SoA (Section 1.3). 
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All SAEs will be recorded and reported to the sponsor or designee immediately. Under no 
circumstance should this exceed 24 hours. The investigator will also submit any updated SAE 
data within 24 hours of it being available.
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study and he/she considers the event to be 
reasonably related to the study drug or study participation, the investigator must promptly notify 
the sponsor via the reporting method described in Section 10.3.5.
8.3.11.2 Method of Detecting Adverse Events and Serious Adverse Events
At each study visit specified in the SoA, the participant or the participant’s legally authorized 
representative will be questioned in a general way to ascertain if AEs have occurred since the 
previous visit. Open-ended and nonleading verbal questioning of the participant is the preferred 
method to inquire about AE occurrences without introducing bias. Participants will report AEs 
occurring at any time during the study.
8.3.11.3 Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All participants experiencing AEs, whether considered associated 
with the use of the study drug or not, will be documented in the AE page of the eCRF. 
All AEs must be monitored until the end of the study or until the event resolves, stabilizes, is 
otherwise explained, or the participant is lost to follow-up as defined in Section 7.3. 
SAEs must be monitored until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up. 
Information to be documented for each event is defined in Section 10.3.4.
Further information on follow-up procedures is provided in Section 10.3. 
8.3.11.4 Regulatory Reporting Requirements for Serious Adverse Events 
All SAEs must be recorded and reported to the sponsor or designee immediately, via the 
procedure described in Section 10.3.5. Under no circumstance should this exceed 24 hours. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
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drug under clinical investigation are met. The sponsor has a legal responsibility to notify both the 
local regulatory authority and other regulatory agencies about the safety of a study drug under 
clinical investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs, and investigators.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB, if appropriate according to local requirements.
The sponsor or designee must prepare safety reports for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and forward 
them to investigators as necessary.
8.3.11.5 Pregnancy in a Participant or Participant’s Partner During the Study
Details about all pregnancies in participants or their partners will be collected after the start of 
study drug and until the end of the 12-week safety follow-up period. Collection of pregnancy 
data from a participant’s partner requires the partner’s informed consent. 
To the extent possible, the investigator will collect follow-up information on the outcome of the 
pregnancy and the neonate, and the information will be forwarded to the sponsor.
Once a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours.
Pregnancy itself is not considered to be an AE or SAE; however, AEs or SAEs associated with 
pregnancy must be reported as such, including: 

Any pregnancy complication or elective termination of a pregnancy for medical reasons (to 
be reported as an AE or SAE)

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) (to be reported as SAEs)

Any poststudy pregnancy-related SAE considered reasonably related to the study drug by the 
investigator will be reported to the sponsor as described in Section 10.3.5. Although the 
investigator is not obligated to actively seek poststudy pregnancy-related SAE information 
from former study participants or their partners, he or she may learn of an SAE through 
spontaneous reporting.
Any participant who becomes pregnant while participating in the study will be withdrawn from 
the study. 
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8.3.11.6 Adverse Events of Special Interest
Adverse events of special interest in this study include potential hypersensitivity, serum sickness, 
vasculitis, Arthus reactions to ontamalimab, and PML.
Participants will be monitored for the presence of Type I (anaphylaxis) and Type III (immune 
complex) hypersensitivity reactions at the time points specified in the SoA (Section 1.3).
Participants will be educated on the signs and symptoms of Type III hypersensitivity reactions 
(eg, fever, rash [including hives], arthralgia, myalgia, vasculitis, Arthus reaction, general ill 
feeling, itching, and swollen lymph nodes) and how to respond to them should they occur during 
the outpatient portion of the study. In addition, participants will be instructed to report 
hypersensitivity AEs to the investigator at the time of occurrence, and to seek immediate medical 
care if necessary. At each visit, the participant will be queried for AESIs related to 
hypersensitivity. 
Participants who experience an AE suggestive of a Type I hypersensitivity reaction should have 
a blood sample (3 mL) collected for anti-ontamalimab immunoglobulin E antibody 
determination, results of which will be available at the end of the study. Participants who have a 
suspected Type III hypersensitivity reaction should have a blood sample (4 mL) collected for 
complement determination (C3a, C5b-9).
Further details of hypersensitivity reactions as AESIs are provided in Section 10.3.3.2.
Participants will be monitored for signs and symptoms of suspected PML at specified time points 
(Section 8.3.2). At each visit, the participant will be queried for AESIs related to PML.
Adverse events of special interest that occur during the treatment period or the follow-up period 
must be recorded as AEs in the eCRF. An evaluation form along with all other required 
documentation must be submitted to the sponsor.
8.4 Pharmacokinetics 
A blood sample for determination of serum ontamalimab concentrations will be collected at the 
time points specified in the SoA (Section 1.3). Blood samples must be collected before study 
drug administration. Details of sample collection, handling, shipment, and bioanalysis will be 
provided in the laboratory manual. 
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8.5 Genetics 
Genetics will not be evaluated in this study.
8.6 Immunogenicity Assessments
See Section 8.3.10 for a description of immunogenicity assessments. 
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9. STATISTICAL CONSIDERATIONS
A statistical analysis plan (SAP) will be prepared and finalized before the first participant 
completes informed consent. The SAP will provide further details regarding the definition of 
analysis variables and the statistical analysis methodology to address all study objectives.
9.1 Statistical Hypotheses 
No statistical hypothesis testing will be performed in this study.
9.2 Analysis Sets

The screened set will consist of all participants who have signed informed consent(s).

The full analysis set (FAS) will consist of all participants who are enrolled in the study, have 
received at least 1 dose of study drug, and have at least 1 valid postbaseline assessment. 

The safety analysis set will consist of all participants who are enrolled in the study and have 
received at least 1 dose of study drug.

The PK set will consist of all participants in the safety analysis set who have at least 
1 evaluable postdose PK concentration value.
9.3 Biomarker and Noninvasive Test Analyses
The biomarker and noninvasive test analyses will be performed on the FAS based on data from 
participants in all fibrosis stages (F1 through F4cc) using an estimation approach. The biomarker 
and noninvasive test data will be summarized descriptively by visit as observed. 
For biomarkers except cT1 MRI, data from all available sampling during screening period (SV1 
and SV2) and D1 predose measurement during treatment period will be averaged to establish the 
stable baseline value. For cT1 MRI, only one measurement will be taken during screening, which 
will be used for the baseline value.
9.3.1 Primary Endpoint
See Section 3 for the primary endpoints related to the assessment of safety. See Section 9.4 for a
description of the safety analyses.
9.3.2 Secondary Endpoints
The secondary endpoints are presented in Section 3. 
For Pro-C3 and ELF, which are collected at multiple postbaseline visits (SoA; see Section 1.3), 
the percent change from baseline at Week 24 will be analyzed using a mixed effects model for 
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repeated measure (MMRM) with visit as the fixed effect, participants as the random effect, and 
baseline values as covariates. The least-squares means of the percent change from baseline at 
Week 24 along with the corresponding 95% confidence intervals (CI) will be presented. 
For cT1 MRI, which is collected at one postbaseline visit (Week 24), the change from baseline at 
Week 24 along with the corresponding 95% CI will be presented. 
9.3.3 Exploratory Endpoints
The exploratory endpoints are presented in Section 3.
All continuous endpoints collected at multiple postbaseline visits will be analyzed using a 
MMRM with visit as the fixed effect, participants as the random effect, and baseline values as 
covariates. The least-squares means of the change from baseline at Week 24 along with the 
corresponding 95% Cis will be presented. 
For binary endpoints, the count and proportion of participants achieving the endpoint status 
along with the corresponding 2-sided 95% Clopper-Pearson Cis will be presented.
9.3.4 Multiplicity Adjustment
Not applicable.
9.4 Safety Analyses
The primary endpoints of the study are related to the assessment of safety (see Section 3).
All safety analyses will be performed using the safety analysis set. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(version 25.0 or higher). Treatment-emergent AEs are defined as AEs with start dates at the time 
of or following the first exposure to the study drug. The number and percentage of TEAEs will 
be presented by system organ class and preferred term. Treatment-emergent AEs will be further 
summarized by severity and relationship to the study drug. Adverse events related to the study 
drug, AEs leading to study drug discontinuation, SAEs, and deaths will be similarly summarized 
or listed.
Clinical laboratory test results, vital signs, body weight, and ECG findings will be summarized 
by visit. Potentially clinically significant findings will also be summarized or listed.
Antidrug antibody data will be summarized by visit.
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9.5 Other Analyses
9.5.1 Pharmacokinetic Analyses
Pharmacokinetic samples will be collected at predose on Day 1 and predose at Weeks 4, 8, 12, 
16, 20, and 24 during the treatment period, and approximately 1 week after the dose on Day 1. 
Concentrations of ontamalimab over the sampling time will be descriptively summarized and 
graphed.
As part of the exploratory endpoints, PK properties of ontamalimab and relationships between 
PK and target engagement (as measured by soluble MAdCAM-1) in participants with NASH 
will be evaluated using a population PK/target engagement modeling and simulation approach 
and reported separately. 
9.6 Interim Analysis
No interim analysis is planned.
9.7 Determination of Sample Size
The planned sample size for this study is 18 participants who complete the 24-week treatment 
period. The sample size has been chosen to provide adequate number of participants to 
investigate the objectives of the study based on clinical experience for key biomarkers 
(Anstee et al. 2022; Harrison et al. 2018; Jabor et al. 2018). 
This study is not statistically powered to perform any formal hypothesis testing, and the analyses 
will be based on estimation approach. 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations
This study will be conducted with the highest respect for the individual participants (ie, 
participants) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Harmonised Tripartite 
Guideline for Good Clinical Practice (GCP). Each investigator will conduct the study according 
to applicable local or regional regulatory requirements and align his or her conduct in accordance 
with the “Responsibilities of the Investigator” that are listed in Section 10.1.11.2. The principles 
of Helsinki are addressed through the protocol and through appendices containing requirements 
for informed consent and investigator responsibilities.
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP Guidelines, as well as all applicable national 
and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, participants’ 
source documents, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or designee) is responsible for the preparation, submission, and confirmation 
of receipt of any regulatory authority approvals required prior to release of study drug for 
shipment to the site.
10.1.2 Financial Disclosure
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and subinvestigators must declare potential 
conflicts of interests to the sponsor. The sponsor will provide a form for the disclosure of their 
financial arrangements during the course of the study and for 1 year after the completion of the 
study. The financial disclosure form must be signed by each investigator and subinvestigator 
before the study starts at their study site; in addition, any potential conflicts of interests that are 
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not covered by this financial disclosure form should be disclosed separately to the sponsor prior 
to the start of the study at their site.
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to the sponsor prior to the start of the study.
Upon submission of a marketing application to the US FDA for any drug, Takeda must provide 
the US FDA with a list of clinical investigators who conducted a Takeda-sponsored clinical 
study and certify or disclose financial arrangements.
Specific financial arrangements requiring disclosure would include any arrangement whereby the 
outcome of the study could be influenced by the value of the compensation for conducting the 
study, or other payments the investigator received from the sponsor. The following information 
is collected: any significant payments from the sponsor or subsidiaries such as a grant to fund 
ongoing research, compensation in the form of equipment, retainer for ongoing consultation or 
honoraria; any proprietary interest in study drug; any significant equity interest in the sponsor or 
subsidiaries as defined in 21 Code of Federal Regulations (CFR) 54 2(b) (1998).
10.1.3 Informed Consent Process
10.1.3.1 Informed Consent Requirements in This Study
The goal of the informed consent process is to provide a potential participant or their legally 
authorized representative with sufficient information about the research to allow for an informed 
decision about their voluntary participation in the research study. The informed consent process 
must facilitate the participant’s comprehension of the information and allow adequate 
opportunity for the participant to ask questions and consider whether or not to participate. This 
process may extend beyond a participant’s initial consent due to changing circumstances within 
the study, the therapeutic landscape, or the participant’s situation.
When a participant or their authorized representative consents to participate in the study, their 
informed consent must be documented in writing via either a signed and dated ICF or via an 
eConsent system, if applicable. The date of the informed consent will also be collected in the 
eCRF along with the initial protocol version.
In this study, informed consent will be required from all participants and/or their legally 
authorized representatives.
A legally authorized representative is defined as “an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant, to the 
participant’s participation in the procedure(s) involved in the study”.
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In this study, informed consent will be obtained using paper forms, an electronic system, or both 
(eg, eConsent, if applicable).
10.1.3.2 Standards the Informed Consent Follows
Informed consent documents, regardless of whether they are presented on paper or electronically, 
must embody the elements of informed consent as described in the Declaration of Helsinki and 
the ICH Guidelines for GCP and will be in accordance with all applicable laws and regulations. 
The ICF and related materials (eg, participant authorization form, participant information sheet):

explain the nature of the study, its objectives, potential risks and benefits.

describe the participant’s rights and responsibilities, including what the study will require of 
the participant.

describe the planned and permitted uses, transfers, and disclosures of the participant’s 
personal and personal health information for purposes of conducting the study, including the 
use of electronic devices and associated technologies, if applicable.

state the fact the participant is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
More specifically, in seeking informed consent, the following information shall be provided to 
each participant:

A statement that the study involves research.

An explanation of the purposes of the research.

The expected duration of the participant’s participation.

A description of the procedures to be followed, including invasive procedures.

The identification of any procedures that are experimental.

The estimated number of participants involved in the study.

A description of the participant’s responsibilities.

A description of the conduct of the study.

A statement describing the treatment(s) and the probability for random assignment to each 
treatment.

A description of the possible side effects of the treatment that the participant may receive.

A description of any reasonably foreseeable risks or discomforts to the participant and, when 
applicable, to an embryo, fetus, or nursing infant.
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
A description of any required restrictions related to contraception, pregnancy, and 
breastfeeding.

Contraception requirements for participants of childbearing potential and for participants 
capable of making a partner pregnant.

Definition of relevant terms such as “childbearing potential.” 

Statement that participants of childbearing potential will undergo regular pregnancy tests 
during the study. 

Explanation of required actions (such as discontinuation or treatment or from the study) if a 
participant or their partner becomes pregnant during study. 

Statement that the participant must avoid breastfeeding during the study.

A description of any benefits to the participant or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the participant, the participant 
should be made aware of this.

Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the participant and their important potential risks and benefits.

A statement describing the extent to which confidentiality of records identifying the 
participant will be maintained, and a note of the possibility that regulatory agencies, 
auditor(s), IRB, and the monitor may inspect the records. By signing an ICF, the participant 
or the participant’s legally acceptable representative is authorizing such access.

For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained.

The anticipated prorated payment(s), if any, to the participant for participating in the study.

The anticipated expenses, if any, to the participant for participating in the study.

An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), participant’s rights, and IRB and whom to contact in the event of a research-
related injury to the participant.

A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the participant otherwise is entitled.

A statement that the participant or the participant’s legally acceptable representative may 
discontinue participation at any time without penalty or loss of benefits to which the 
participant is otherwise entitled.
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
The consequences of a participant’s decision to withdraw from the research and procedures 
for orderly termination of participation by the participant.

A statement that the participant or the participant’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
participant’s willingness to continue participation in the study.

A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.

The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated.

A participant authorization (either contained within the ICF or provided as a separate 
document) describing to the participant the contemplated and permissible uses and 
disclosures of the participant’s personal information (including personal health information) 
for purposes of conducting the study. The participant authorization must contain the 
following statements regarding the uses and disclosures of the participant’s personal 
information:
-
That de-identified personal information (including personal health information) may 
be processed by or transferred to other parties in other countries for clinical research 
and safety reporting purposes, including, without limitation, to the following: 
(1) Takeda, its affiliates, and licensing partners; (2) business partners assisting 
Takeda, its affiliates, and licensing partners; (3) regulatory agencies and other health 
authorities; and (4) IRBs;
-
That is possible that de-identified personal information (including personal health 
information) may be processed and transferred to countries that do not have data 
protection laws that offer participants the same level of protection as the data 
protection laws within this country; however, Takeda will make every effort to keep 
your personal information confidential, and your name will not be disclosed outside 
the clinic unless required by law;
-
That de-identified personal information (including personal health information) may 
be added to Takeda’s research databases for purposes of developing a better 
understanding of the safety and effectiveness of the study drug(s), studying other 
therapies for participants, developing a better understanding of disease, and 
improving the efficiency of future clinical studies;
-
That participants agree not to restrict the use and disclosure of their personal 
information (including personal health information) upon withdrawal from the study 
to the extent that the restricted use or disclosure of such information may impact the 
scientific integrity of the research; and
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That the participant’s identity will remain confidential in the event that study results 
are published.
-
A statement that clinical trial information from this trial may be publicly disclosed in 
a publicly accessible website, such as ClinicalTrials.gov.
-
A description of the electronic devices and associated technology and its usage in the 
study.
10.1.3.3 Who Creates the Informed Consent Materials
The sponsor or designee will provide sample ICFs and related materials to the investigator. 
The investigator is responsible for the preparation, content, and IRB approval of the ICF and 
related materials. 
The principal investigator will provide the sponsor with a copy of the ICF and related materials 
that was reviewed by the IRB and received their favorable opinion/approval. A copy of the IRB’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB requires modification of the 
sample documents that the sponsor provided, the documentation supporting this requirement 
must be provided to the sponsor. Both the IRB and the sponsor must approve the ICF and related 
materials before use.
In the event that consent materials are provided electronically, and/or if consent is obtained 
electronically (eg, eConsent, if applicable), the sponsor or designee will provide the 
IRB-approved version of the ICF to the site in an electronic form with 21 CFR–compliant 
eConsent functionality.
10.1.3.4 Who Conducts the Informed Consent Process
It is the responsibility of the investigator and the study personnel to:

explain the detailed elements of the ICF and related materials to the participant or the 
participant’s legally authorized representative, as applicable. 

answer all of the participant’s or participant’s legally authorized representative’s questions 
about the study.

provide the participant or the participant’s legally authorized representative, as applicable, 
ample time to decide whether or not to participate in the study.
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
obtain written and/or electronic informed consent from all participants or the participants’ 
legally authorized representatives, as applicable, prior to any study-related procedures 
including screening assessments.
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB. (Oral and written information may be provided via remote or 
virtual visits, eg, via telehealth [video, phone] and eConsent systems.) If the participant is not 
capable of rendering adequate written informed consent, then the participant’s legally acceptable 
representative may provide such consent for the participant in accordance with applicable laws 
and regulations.
If the participant, or the participant’s legally acceptable representative, determines they will 
participate in the study, then they must sign and date the ICF (and participant authorization form, 
as applicable) at the time of consent and prior to entering into the study. 
For paper consent forms, the participant or the participant’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using a ballpoint pen with 
either blue or black ink in the case of written informed consent. If applicable, eConsent provides 
the same information as written consent forms, but in an electronic format that may include 
multimedia components. eConsent does not replace the important discussion between the study 
participant and site staff or investigator. Regardless of the consent format – written or eConsent –
the investigational site is responsible for the consenting process.
A copy of the informed consent documentation (ie, a complete set of participant information 
sheets and fully executed signature pages) must be provided to the participant or the participant’s 
legally authorized representative.
The investigator must also sign and date the ICF or eConsent (if applicable) and the participant 
authorization form (if applicable) at the time of consent or after receipt of participant signature 
(in the case of eConsent) and before the participant enters the study. However, the sponsor may 
allow a designee of the investigator to sign to the extent permitted by applicable law.
Signed consent forms or certified copies of electronic signatures must remain in each 
participant’s study file at the site and must be available for verification at any time.
The investigator must document the date the participant signs the ICF in the participant’s source 
documents.
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10.1.3.5 Reconsent
Participants or participants’ legally authorized representatives, as applicable, are required to 
re-consent if changes are made to the protocol or if new information is made available that may 
affect the willingness of current participants (those who are already enrolled and actively 
participating) to continue in the clinical investigation. Re-consent should be obtained as 
described in Section 10.1.3.1. 
Updated ICFs, individual consents, individual assents, individual re-consents and re-assents will 
be placed in the Trial Master File. Re-consent information including the protocol version and 
re-consent date will also be recorded in the eCRFs.
10.1.4 Data Protection
The confidentiality of records that may be able to identify participants will be protected in 
accordance with applicable laws, regulations, and guidelines.
After participants have consented to take part in the study, the sponsor and/or its representatives 
reviews their source documents and data collected during the study. These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market ontamalimab; national or local regulatory authorities; and the IRB(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of participants’ identities. Participants are assigned a 
unique identifying number; however, their initials and date of birth may also be collected, if 
permitted under local laws governing privacy. 
The results of studies containing participants’ unique identifying number, relevant source 
documents, and possibly initials and dates of birth, where allowed per local law, may be 
transferred to, and used in, other countries which may not afford the same level of protection that 
applies within the countries where this study is conducted. The purpose of any such transfer 
would include: to support regulatory submissions, to conduct new data analyses to publish or 
present the study results, or to answer questions asked by regulatory or health authorities.
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
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explained to the participant who will be required to give consent for their data to be used as 
described in the ICF. 
The participant must be informed that their source documents may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB or ethics committee members, and by inspectors from regulatory authorities.
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor or designee.
10.1.4.1 Notice Regarding the Use and Transfer of the Investigator’s Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and telephone number, and other personally identifiable information such as education 
and professional details, payment-related details (if applicable), identity information (eg, medical 
registration number) and information relating to his or her interactions and activities with or 
involving Takeda. In addition, investigator’s personal information may be transferred to other 
parties located in countries throughout the world (eg, the United Kingdom, US, and Japan), 
including the following:

Takeda, its affiliates, and their licensing partners.

Business partners assisting Takeda, its affiliates, and their licensing partners.

Regulatory agencies and other health authorities.

IRBs and ethics committees.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.
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
Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
In addition, where required by law or industry codes of practice, Takeda and/or its affiliates may 
have to report or publicly disclose any payments or transfers of value made in connection with 
the study by or on behalf of Takeda and/or its affiliates or their service providers to the 
investigator or their institution.
The legal basis on which Takeda and its affiliates will process the Investigator’s personal 
information for the above purposes are in order to comply with a legal obligation; or to perform 
any contract in place with the investigator (if applicable); or to meet the legitimate research, 
scientific and business interests of Takeda and its affiliates, including ensuring the proper 
performance of this study to the applicable standards, appropriate reporting of study results and 
archiving of study-related records and information, and further development and registration of 
the study drug or other compounds. The investigator may not be able to opt-out of this 
processing, or the investigator’s choice to opt-out may impact his or her ability to continue to 
participate in this study and/or future studies involving Takeda and/or its affiliates.  
Takeda and its affiliates will maintain physical, administrative, and technical safeguards to 
protect the Investigator’s personal information from loss, misuse, unauthorized access, 
disclosure, alteration or destruction. Investigator’s personal information may be transferred to 
other countries that do not have data protection laws that offer the same level of protection as 
data protection laws in investigator’s own country.
However, where Investigator’s personal information is transferred to Takeda affiliates, licensing 
partners, business partners or service providers in such countries, Takeda will ensure that all 
adequate safeguards are in place and that all applicable laws and regulations are complied with in 
connection with such transfers.
The Investigator’s personal information will only be stored as long as necessary for the purposes 
for which it was collected subject to local laws and regulations and legitimate scientific, research 
and business needs.
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Investigator acknowledges and authorizes the use of his or her personal information by Takeda 
and other parties for the purposes described above.
10.1.5 Committees Structure
10.1.5.1 Institutional Review Board Approval
IRBs must be constituted according to the applicable state and federal requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRBs. If any member of the IRBs has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
also be obtained. 
Those sites in the US unwilling to provide names and titles of all members due to privacy and 
conflict of interest concerns should instead provide a Federalwide Assurance Number or 
comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRBs
for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, participant recruitment materials and/or advertisements and other documents required 
by all applicable laws and regulations, must be submitted to a central or local IRBs for approval. 
The IRB’s written approval of the protocol and participant ICF must be obtained and submitted 
to the sponsor or designee before commencement of the study (ie, before shipment of the 
sponsor-supplied drug).
The IRB’s approval must refer to the study by exact protocol title, number, and version date; 
identify versions of other documents (eg, ICF) reviewed; and state the approval date. If required 
by country or regional regulations or procedures, approval from the competent regulatory 
authority will be obtained before commencement of the study or implementation of a substantial 
amendment. The sponsor will ship drug once the sponsor has confirmed the adequacy of site 
regulatory documentation. Until the site receives drug, no protocol activities, including 
screening, may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRBs regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by participants, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRBs, 
and submission of the investigator’s final status report to IRBs. All IRBs approvals and relevant 
documentation for these items must be provided to the sponsor or designee.
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Participant incentives should not exert undue influence for participation. Payments to 
participants must be approved by the IRBs and sponsor.
10.1.5.2 Other Committees
An internal safety review committee (independent from the study team) will review the overall 
safety of the study participants on an ongoing basis. This review will consist of monitoring of 
safety of participants throughout the study. Recommendations made on the basis of this review 
to alter the conduct of the study or to amend the protocol will be provided to the study team for 
review and for a final decision. The sponsor or its designee will notify investigative sites, and 
regulatory authorities as appropriate, of recommendations based on this review. Details 
regarding this review and the frequency of this review will be established in a separate charter 
before the administration of study drug to any participant. In addition, the internal safety review 
committee will be responsible for:

Evaluating safety and tolerability data from the first four noncirrhotic (F1-F3) participants 
who have received at least 3 doses of ontamalimab 75 mg and have been monitored for at 
least 12 weeks, to support the decision to include F4cc participants in the study. 

Engaging with an independent panel of experts to evaluate any liver-related events (eg, liver 
decompensation, significant deterioration of liver chemistry tests).

Monitoring neurological safety and consulting a panel of leading PML experts, including a 
neurologist, neuroradiologist, and a virologist, in the event of a suspected case of PML (see 
Section 8.3.2).
10.1.6 Dissemination of Clinical Study Data
10.1.6.1 Study Results Disclosure 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 
interventional clinical trials and disclose the results of those trials in a manner and timeframe 
compliant with Takeda policy and all applicable laws and regulations. Clinical trial registration 
and results disclosures will occur on the applicable clinical trial registry(ies)/database(s) as 
required by law.
10.1.7 Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
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Guidance on completion of CRFs will be provided in the study CRF Completion Guidelines or 
similar. 
The investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents.
Quality tolerance limits (QTLs) will be predefined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These predefined parameters will be 
monitored during the study, and important deviations from the QTLs and remedial actions taken 
will be summarized in the clinical study report.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan or contracts.
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data.
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations).
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time frame specified in the Clinical Study Site Agreement 
unless local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. No records
may be transferred to another location or party without written notification to the sponsor.
10.1.7.1 Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study participants. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB, as required) to determine the appropriate course of action. There 
will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion 
criteria.
The sponsor will assess any protocol deviation. If it is likely to affect to a significant degree the 
safety and rights of a participant or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
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The site should document all protocol deviations in the participant’s source documents. In the 
event of a significant deviation, the site should notify the sponsor or its designee (and IRB, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the participant, or confound interpretation of primary 
study assessment.
Protocol deviations should be captured in a Part 11–compliant clinical trial management system. 
10.1.7.2 Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site head guarantee access to source documents by the sponsor or 
its designee (CRO) and by the IRB.
Alternative approaches may be used to ensure data quality, data integrity, and participant safety 
(eg, remote source data review/source data verification via phone or video) as permitted by 
regional and local regulations. See the monitoring plan for additional details.
10.1.7.3 Audits
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the US FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor should 
be notified immediately. 
The investigator and study site guarantee access for quality assurance auditors to all study 
documents as described in Section 10.1.8.
10.1.8 Source Documents 
All key data must be recorded in the participant’s source documents unless otherwise noted in 
the protocol. Source documents may be paper or electronic, including data obtained using 
electronic devices and associated technologies. Original source data to be reviewed during this 
study will include, but are not limited to: participant’s medical file, appointment books, diaries, 
clinical outcome assessments, original clinical laboratory reports, histology reports, pathology 
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reports, X-rays. The investigator (as listed on the US FDA Form 1572) is responsible for 
maintaining adequate and accurate source documents. 
The investigator must provide direct access to inspect facilities, including original source records 
relevant to this study (regardless of media), to: the sponsor or its authorized representatives; the 
respective national, local, or foreign regulatory authorities; the IRB/ethics committee; and 
auditors. These records must be made available within reasonable times for inspection and 
duplication, if required, by a properly authorized representative of any regulatory agency (eg, the 
US FDA, EMA, United Kingdom Medicines and Healthcare products Regulatory Agency) or an 
auditor. The ICF includes a statement granting this access to source data.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.1.8.1 Electronic Case Report Forms
Completed eCRFs are required for each participant who has completed the consent process. The 
eCRFs are designed to record all observations and other data pertinent to the clinical 
investigation unless otherwise noted in the protocol. 
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. eCRFs must be completed in English. 
The investigator or the investigator’s designee (ie, authorized site personnel, as stated in the site 
delegation log) must enter data from the source documents (Section 10.1.8) into the eCRF with 
guidance from the study CRF Completion Guidelines or similar.
The principal investigator must review the eCRFs for completeness and accuracy and must 
e-sign the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
A study monitor from the sponsor or its designee will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Auditors, IRB members, or regulatory inspectors may also check the eCRF entries 
against the source documents.
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Discrepancies between source data and data entered on the CRF will be addressed by qualified 
site personnel. When a data discrepancy warrants correction, the correction will be made by 
authorized site personnel. 
After the lock of the study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should also be included. The 
principal investigator must review the data change for completeness and accuracy, and must 
sign, or sign and seal, and date.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor. 
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data. Alternative approaches may be used to ensure data quality, data integrity, 
and participant safety (eg, remote source data review via phone or video) as permitted by 
regional and local regulations. Additional details are in the monitoring plan.
10.1.8.2 Documentation and Retention of Records
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Source documents provide evidence for the existence of the 
participant and substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
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previous source documents or transfer records, depending on the study. Also, current source 
documents must be available.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
10.1.8.3 Data Handling
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
10.1.8.4 Record Retention
The investigator agrees to keep the records stipulated in Section 10.1.8 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, source documents, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated ICFs (including consent to use digital tools and 
applications, if applicable), participant authorization forms regarding the use of personal health 
information (if separate from the ICFs), query responses/electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the participant’s chart to ensure long term legibility. Furthermore, ICH E6(R2) Section 5.5.11 
requires the investigator to retain essential documents specified in ICH E6(R2) (Section 8) until 
at least 2 years after the last approval of a marketing application for a specified drug indication 
being investigated or, if an application is not approved, until at least 2 years after the 
investigation is discontinued and regulatory authorities are notified. In addition, ICH E6(R2) 
Section 5.5.11 states that the study records should be retained until an amount of time specified 
by applicable regulatory requirements or for a time specified in the study site agreement between 
the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
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10.1.9 Study and Site Start and Closure
10.1.9.1 First Act of Recruitment 
The first act of recruitment is the first site open.
For clinical trial disclosure purposes, the study start date is the date when the first participant 
signed the ICF.
10.1.9.2 Study/Site Termination 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
The sponsor reserves the right to close the study site at its sole discretion. Study sites will be 
closed upon study completion. A study site is considered closed when all required documents 
and study supplies have been collected and a study-site closure visit has been performed.
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs are notified as appropriate. Additionally, the discontinuation of a registered 
clinical study which has been posted to a designated public website will be updated accordingly.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

For study termination:
-
Discontinuation of further study drug development.

For site termination:
-
Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines.
-
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator.
-
Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
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10.1.10 Publication Policy
During this study, until the open access period, only Takeda may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation.
Both during and after this study, all public disclosures containing data/information from this 
study must undergo review and receive written approval by the appropriate Takeda 
representative(s) before any public disclosure (including but not limited to submission, 
presentation, posting on online platforms for archiving, and distribution of unpublished 
preprints). 
This policy applies to all publication types, including: abstracts and presentations (oral and 
poster, including invited presentations) for scientific congresses; articles (original research 
manuscripts, review articles, invited articles), letters to the editor, and editorials, in scientific 
peer-reviewed journals; print, electronic and enhanced multimedia publications associated with 
traditional congress and journal publishing (such as, but not limited to, audio, visual/graphical or 
video abstracts or manuscript summaries; video or animated posters; augmented reality, etc.); 
books and book chapters. 
Authorship will be determined in line with the requirements of the International Committee of 
Medical Journal Editors (ICMJE) Recommendation for the Conduct, Reporting, Editing and 
Publication of Scholarly Work in Medical journals, unless otherwise required by the journal or 
forum where the publication appears.
All publications must be developed with a dataset (such as statistical tables and listings, a CSR, 
and/or final report) that has been verified by a qualified Takeda employee per Takeda’s internal 
standards. Data relevant to the development of Takeda publications must be shared with all 
authors via a secure site. 
Publications derived from this study may never contain participants’ direct identifiers (such as 
participant ID, initials) but may contain indirect/quasi identifiers (for example sex/gender, 
age/birth date, geographic indicators). Publications derived from this study may not include 
products’ direct identifiers (lot numbers or batch numbers) unless specifically required by the 
journal or conference guidelines and if approved by Takeda. 
Takeda requires the submission of all manuscripts resulting from this study, regardless of the 
intended audience or language, to journals that offer public availability via an Open Access 
platform. 
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The following types of information are required by ICH to be in the protocol if not addressed in 
another document (such as the site contracts):
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments.
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site 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.
10.1.11 Responsibilities of the Sponsor and the Investigator
10.1.11.1 Sponsor Responsibilities
10.1.11.1.1 Study-related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform these activities 
either in full or in partnership with the sponsor.
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and subinvestigators must declare potential 
conflicts of interests to the sponsor. The sponsor will provide a financial disclosure form that 
must be signed by each investigator and subinvestigator before the study starts at their study site; 
in addition, any potential conflicts of interests that are not covered by this financial disclosure 
form should be disclosed separately to the sponsor before the start of the study at their site.
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to sponsor before the start of the study.
10.1.11.1.2 Insurance
Each participant in the study must be insured in accordance with the regulations applicable to the 
site where the participant is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
participants. Refer to the study site agreement regarding the sponsor’s policy on participant 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.
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10.1.11.2 Investigator Responsibilities 
Clinical research studies sponsored by the sponsor are subject to ICH GCP, FDA, and all other 
applicable local laws and regulations. 
The responsibilities imposed on investigators by the FDA are summarized in the “Statement of 
Investigator” (Form FDA 1572), which must be completed and signed before the investigator 
may participate in this study.
The investigator agrees to assume the following responsibilities:

Conduct the study in accordance with the protocol.

Personally conduct or supervise the staff who will assist in the protocol.

If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated.

Ensure that study related procedures, including study specific (non-routine/non-standard 
panel) screening assessments are NOT performed on potential participants, before the receipt 
of written approval from relevant governing bodies/authorities.

Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.

Secure prior approval of the study and any changes by an appropriate IRB that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.

Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB all changes in research activity and all anticipated 
risks to participants. Make at least yearly reports on the progress of the study to the IRB, and 
issue a final report within 3 months of study completion.

Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.

Obtain valid informed consent from each participant who participates in the study, and 
document the date of consent in the participant’s medical chart. A valid ICF is the most 
current version approved by the IRB. Each ICF should contain a participant authorization 
section that describes the uses and disclosures of a participant’s personal information 
(including personal health information) that will take place in connection with the study. If 
an ICF does not include such a participant authorization, then the investigator must obtain a 
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separate participant authorization form from each participant or the participant’s legally 
acceptable representative.

Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.

Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.

Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 

Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
It is the investigator’s responsibility to ensure that adequate time, appropriately trained 
personnel, and resources are available prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable participants within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research participant has a primary care physician, the investigator should, with the 
participant’s consent, inform them of the participant’s participation in the study.
10.1.11.2.1 Protocol Adherence and Investigator Agreement
The investigator and any subinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those participants who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRBs and provide them with a detailed written explanation. The 
investigator will also return all study drug, containers, and other study materials to the sponsor. 
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Upon study completion, the investigator will provide the sponsor, IRB, and regulatory agency 
with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs, to ensure accurate and timely information is provided at all 
phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.1.11.2.2 Principal Investigator/Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study.
Selection criteria for this investigator will include significant knowledge of the study protocol, 
the study drug, their expertise in the therapeutic area and the conduct of clinical research, as well 
as study participation. 
The coordinating investigator will be required to review and sign the final clinical study report 
and by doing so agrees that it accurately describes the results of the study, in compliance with 
Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.1.11.2.3 Compliance With all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation 
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the investigator must at all times comply with all local, state, and national laws pertaining to 
registration and reporting with the appropriate regulatory body and control and handling of such 
substances.
10.1.12 Site Termination or Suspension
10.1.12.1 Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement; is unable to ensure 
adequate performance of the study; or as otherwise permitted by the contractual agreement.
10.1.12.2 Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for ontamalimab, such that the 
risk/benefit profile is no longer acceptable for participants participating in the study.
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-
Three participants develop the same TEAE or SAE considered possibly or probably 
related to study drug that is severe or medically significant, but not immediately 
life-threatening; or where hospitalization or prolongation of hospitalization is 
indicated; or is disabling; or limits self-care activities of daily living.
-
Two participants develop any TEAE or SAE, regardless of attribution to study drug, 
that has life-threatening consequences or requires urgent intervention.
-
Death of any participants at any time related to an AE.

The internal safety review recommends that the study should be suspended or terminated or 
that cirrhotic participants are not to be enrolled in the study. 

Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises participant safety.
10.1.12.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) 
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend the 
study or the participation of a study site, a study-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable study 
sites during the course of termination or study suspension.
10.2 Clinical Laboratory Tests
Table 6 lists the tests that will be obtained for each laboratory specimen. These tests will be 
performed by the central laboratory or other identified specialty laboratories (refer to laboratory 
manual for details).
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations.
Table 6. Protocol-required Laboratory Tests
Laboratory Tests
Parameters
Hematology
Platelet count 
Hemoglobin
Hematocrit
RBC count
RBC indices:
Mean corpuscular volume 
Mean corpuscular hemoglobin 
%Reticulocytes
White blood cell count with 
differential (both % and 
absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
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Table 6. Protocol-required Laboratory Tests
Clinical Chemistrya
Albumin
Blood urea nitrogen
Creatinine
Calcium
Carbon dioxide
Chloride
Glucoseb
Magnesium
Phosphate
Potassium
Sodium
AST 
ALT
Alkaline 
phosphatase 
γ-Glutamyl 
transferase
Lactate 
dehydrogenase 
Total bilirubin 
Direct bilirubin
Total protein
Total cholesterol
HDL-C
LDL-C
Triglyceridesb
Coagulation
INR
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick
Microscopic examination (if blood or protein is abnormal)
Other safety tests 
ADA
HbA1c
eGFR (CKD-EPI)
Creatine kinase
Anti-ontamalimab IgEc
Complement determination (C3a, C5b-9)d
Pregnancy Testing
For participants of childbearing potential only: Highly sensitive serum or urine human 
chorionic gonadotropin pregnancy test 
Other screening tests
If menopause is suspected: Follicle-stimulating hormone 
Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines)
Serology (HIV antibody, HbsAg, HbcAb, and HCVAb; HBV DNA reflex testing if HbsAg 
is negative and HbcAb is positive; HCV RNA polymerase chain reaction if HCVAb is 
positive)
Infection disease panel (includes cytomegalovirus, Epstein-Barr virus, and herpes simplex 
virus)
Vitamin D 
Serum α-fetoprotein
AMA
ANA, SMA, alpha-1-antitrypsin, and ceruloplasmin
IgG4
TB (IGRA)
PK and Biomarkers
Serum ontamalimab concentration
Biomarkers:
•
Pro-C3 (serum)
•
ELF score (serum)
•
Soluble MAdCAM-1 (serum)
•
hsCRP (serum)
•
Calprotectin (plasma)
•
Whole blood T cell phenotyping
•
Whole blood transcriptomics
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Table 6. Protocol-required Laboratory Tests
ADA=antidrug antibody; ALT=alanine aminotransferase; AMA=antimitochondrial antibody; ANA=antinuclear 
antibody; AST=aspartate aminotransferase; CKD=Chronic Kidney Disease Epidemiology Collaboration; 
eGFR=estimated glomerular filtration rate; ELF=Enhanced Liver Fibrosis; HbA1c=hemoglobin A1c; 
HbcAb=hepatitis B core antibody; HbsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCVAb=hepatitis C 
virus antibody; HDL-C=high-density lipoprotein cholesterol; HIV=human immunodeficiency virus; 
hsCRP=high-sensitivity C-reactive protein; Ig=immunoglobulin; IGRA=interferon-gamma release assay; 
IL=interleukin; INR=international normalized ratio; LDL-C=low-density lipoprotein cholesterol; 
MAdCAM-1=mucosal addressin cell adhesion molecule-1; PK=pharmacokinetic(s); Pro-C3=neoepitope-specific 
N-terminal propeptide of type III collagen; RBC=red blood cell; TB=tuberculosis
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.1 Liver 
Chemistry Stopping Criteria.  
b To be collected under fasting conditions.
c For participants who experience an AE suggestive of a Type I hypersensitivity reaction (see Section 8.3.3).
d For participants who have a suspected Type III hypersensitivity reaction (see Section 8.3.3).
10.2.1 Clinical Laboratory Assessments and Other Safety Assessments
A change in the value of a clinical laboratory parameter, physical examination finding, vital sign 
measure, or ECG assessment can represent an AE if the change is clinically relevant or if, during 
administration of study drug, a shift of a parameter is observed from a value in the normative 
range to a value that is outside the normal range and considered clinically significant, or a further 
waning of an already clinically significant value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range, either while 
continuing administration or after the end of administration with the study drug, and the range of 
variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), physical examination, vital sign, or ECG values that were not 
present at the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of the 
participant, whether a change in a clinical laboratory value, physical examination, vital sign, or 
ECG parameter is clinically significant and represents an AE. The assessment of clinical 
significance is recorded on the eCRF related to the assessment (for example, the clinical 
laboratory value eCRF), but an event that is also classified as an AE will be recorded on the 
AE page. 
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
A degenerative concurrent medical condition (eg, cataracts, rheumatoid arthritis): Worsening 
of the condition should only be recorded as an AE if it occurs to a greater extent than 
expected. 

Worsening or complication of an AE after any change in study drug: The worsening or 
complication should be recorded as a new AE.
Complications associated with preplanned procedures:

Changes in plan and surgical complications associated with preplanned or elective surgeries, 
therapies, or procedures should be recorded as AEs. 

If a preplanned procedure is performed early (eg, as an emergency) due to a worsening of the 
pre-existing condition, the worsening of the condition should be recorded as an AE. 

Complications resulting from an elective surgery should be recorded as AEs.
Changes in intensity of AEs:

If the participant experiences changes in intensity of an AE, the event should be recorded 
once with the maximum intensity recorded.
10.3.3.2 Adverse Events of Special Interest
An AESI (serious or nonserious) is one of scientific and medical concern specific to the 
compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them.
Adverse events of special interest will be captured and monitored during this study. Investigators 
will report all AESIs to the sponsor, regardless of causality, using the same timelines as 
described for SAE reporting (see Section 10.3.5). The following text describes the AESIs and the 
criteria for reporting AESIs.
10.3.3.2.1 Hypersensitivity
Potential hypersensitivity reactions to ontamalimab will be regarded as AESIs. These events 
must be reported using the process described for SAEs and within the time frame mandated for 
SAEs (see Section 10.3.5).
It is well known that the administration of foreign proteins can cause immune responses 
including hypersensitivity reactions such as anaphylaxis and serum sickness. Other immune 
responses to foreign proteins include the development of ADA and neutralizing antibodies.
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Monoclonal antibodies have been used in human therapeutics since the 1980s. The first 
monoclonal antibody approved for human use (Orthoclone OKT3®), was a murine protein which 
caused rapid production of neutralizing antibodies. Since then, much effort has been expended to 
reduce the immunogenicity of these useful therapeutic proteins by reducing the extent of 
“foreignness” from chimeric antibodies such as infliximab, to humanized antibodies such as 
vedolizumab, and finally to fully human antibodies such as adalimumab and ontamalimab 
(Isabwe et al. 2018) (see Figure 4).
Figure 4. Potential Immunogenicity of Therapeutic Monoclonal Antibodies
Ontamalimab is a fully human antibody of the immunoglobulin G2 subclass. In Phase 1 and 
Phase 2 clinical trials of ontamalimab, in which over 700 participants were treated for up to 
3 years, there has been no case of anaphylaxis. There have been 2 reported cases of drug 
hypersensitivity: serum sickness attributed to concomitant administration of penicillin; and a 
reaction characterized by dyspnea, facial erythema, and chest pain with onset 2 days after 
administration of the fifth dose of ontamalimab. The latter event mimicked a reaction that the 
participant had previously experienced after 4 doses of infliximab. In addition, low titer activity 
has been observed in ADA assays, including pretreatment samples and placebo-treated 
participants, and no participant has had a 2-fold or greater increase in ADA titer. Analysis of 
pharmacokinetic and clinical parameters has shown no difference between participants whose 
ADA assay results are positive as compared with those whose are negative.
Nonetheless, the possibility of a hypersensitivity reaction occurring after drug exposure cannot 
be fully ruled out. The reactions of concern in this clinical trial are Type I (anaphylaxis) and 
Type III (immune complex) reactions. The clinical presentation of anaphylactic reactions is 
described below in Table 8.
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Table 8. Clinical Criteria for Diagnosing Anaphylaxis (Type I Hypersensitivity)
Anaphylaxis is highly likely when below criterion and at least any one of the following criteria a and b are 
fulfilled:
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
Reduced BPa or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence)
BP=blood pressure; mmHg=millimeters of mercury; PEF=peak expiratory flow.
a Low systolic BP for children is defined as less than 90 mmHg from 11 to 17 years.
Source: Adapted from Sampson et al. 2006 (Sampson et al. 2006). 
Type III hypersensitivity responses, including those mediated by immune complexes and T cells 
(also referred to as delayed hypersensitivity responses), are relatively rare with respect to 
therapeutic protein products and a high degree of clinical suspicion is necessary for the diagnosis 
(US FDA Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products, 
August 2014). Type III hypersensitivity reactions involve the formation of biologic/ADA 
immune complexes in the circulation which, when present in the correct stoichiometric ratio, 
become deposited in tissues. Once immune complexes are deposited, they can elicit complement 
activation and inflammation, leading to tissue damage. When immune complexes are deposited 
in tissues, they tend to localize in small postcapillary venules where there is loss of laminar 
blood flow, in sites of ultrafiltration where there is high pressure and fenestrated endothelium 
(eg, choroid plexus, ciliary body, synovium, and glomeruli), in sites of turbulent blood flow (eg, 
coronary artery branches off aorta, aortic bifurcations, and cardiac valve leaflets), and in renal 
glomerular endothelium.
Signs and symptoms of immune complex deposition typically have onset 1 to 3 weeks after 
exposure (Warrington et al. 2018) usually improving in 7 to 10 days, with full recovery in 2 to 
4 weeks and may include fever, rash (including hives), arthralgia, myalgia, vasculitis, Arthus 
reaction, general ill feeling, itching, and swollen lymph nodes.
10.3.3.2.2 PML
Suspected PML/PML will be regarded as an AESI. These events must be reported using the 
process described for SAEs and within the time frame mandated for SAEs (see Section 10.3.5).
Ontamalimab prevents the binding of α4β7+ lymphocytes to MAdCAM-1 expressing sites with 
high affinity and selectivity. Although the selective targeting of MAdCAM-1 is a novel 
anti-inflammatory approach, the basic interference of lymphocyte homing by preventing the 
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binding of these α4β7+ lymphocytes to MAdCAM-1, and the resultant efficacy in CD is well 
established by natalizumab and more recently by vedolizumab. The main difference between 
ontamalimab and other agents that interfere with the MAdCAM-1:integrin axis is that 
ontamalimab selectively binds to endothelial MAdCAM-1 rather than to the α4β7+ integrin on 
lymphocytes to block the interaction. Principal organs of MAdCAM-1 expression include 
intestine, pancreas, stomach, esophagus, spleen, and nasopharyngeal tissue and to a lesser extent 
lung, liver, and bladder but not in normal central nervous system. Ontamalimab also does not 
bind to vascular cell adhesion molecule and is, therefore, expected to be ineffective for multiple 
sclerosis, and it is not expected to increase the risk of PML since it does not affect lymphocyte 
homing or surveillance in the central nervous system. 
No cases of PML have been reported with ontamalimab in previous clinical studies. However, as 
continued mitigation for the potential risk of PML, targeted neurological assessments will be 
performed in this study to monitor any changes from baseline in the participant’s status 
(Section 8.3.2).
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10.3.5.1 Safety Reporting to Investigators, Institutional Review Boards, and Regulatory 
Authorities
The sponsor will be responsible for identifying and reporting all SUSARs and any other 
applicable SAEs to regulatory authorities including the FDA, investigators, and IRB in 
accordance with national regulations in the US. Adverse events that are already classified as 
expected (and therefore are not SUSARs) are listed in the RSI (see Section 10.3.4.7 for the 
location of the RSI).
The following specialized types of events have their own reporting windows: 
Suspected unexpected serious adverse reactions will be submitted to the regulatory authorities as 
an expedited report within 7 days for fatal and life-threatening events and 15 days for other 
serious events, relative to the first awareness of an event by/or further provision to the sponsor or 
sponsor’s designee, unless otherwise required by national regulations. 
The sponsor will prepare an expedited report for other safety issues that might materially alter 
the current benefit-risk assessment of a study drug/sponsor-supplied drug or that would be 
sufficient to consider changes in the study drug/sponsor-supplied drug administration or in the 
overall conduct of the trial. 
The study site will forward a copy of all expedited reports to its IRB in accordance with local
regulations.
10.4 Contraceptive and Barrier Guidance
10.4.1 Definitions
For the purposes of this study, reproductive status is defined as follows: 

Nonpregnant: Negative urine and/or serum β-hCG pregnancy test result. 
Person who is not of childbearing potential:
-
Premenarchal and 1 of the following: 
◦
Tanner stage 1 
◦
Less than 9 years of age
-
Surgically sterile for at least 6 weeks at screening (defined as having undergone one 
of the following procedures: hysterectomy, bilateral tubal ligation, bilateral 
oophorectomy, or bilateral salpingectomy).
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-
Postmenopausal at screening (defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient).

Person who is of childbearing potential: following menarche and until becoming 
postmenopausal unless permanently sterile by the definition above.

Male who is not fertile: prepuberty OR post puberty but permanently sterile by bilateral 
orchidectomy.

Male who is fertile: post puberty, unless permanently sterile by the definition above.
10.4.2 Contraception Guidance
In this study, the use of highly effective contraception is generally required unless otherwise 
noted. In addition, contraceptive use should be consistent with local regulations regarding the use 
of contraceptive methods for participants in clinical studies.
The failure rates of contraceptives that are used consistently and correctly may differ in typical 
use. Therefore, when study participation requires any of these methods of contraception to be 
used, participants must commit to using them:

consistently throughout the required period.

correctly, as described below and in any labeling associated with the method.
Contraception requirements depend in part on the reproductive status of the participant and the 
participant’s partner. 
10.4.2.1 Contraceptive Methods for Participants Capable of Producing Viable Ova and/or 
Becoming Pregnant
This section describes contraception methods appropriate for participants capable of producing 
viable ova and/or becoming pregnant in the present study, as well as pregnancy and lactation-
related guidance, based on guidance provided by the Clinical Trial Facilitation Group. 
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Table 9. Acceptable Contraception Methods and Lactation Guidance in This Study for 
Participants Capable of Producing Viable Ova and/or Becoming Pregnant
Highly Effective Contraceptives
Failure rate of <1% per year when used consistently and correctly
User Dependent

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationa
-
Oral 
-
Intravaginal 
-
Transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulation 
-
Oral 
-
Injectable

Sexual abstinenceb 
Low User Dependency

Implantable progestogen-only hormonal contraception associated with inhibition of ovulationa

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partnerc
Measures Intended to Prevent Neonatal Exposure via Breastmilk

Participants who are lactating must agree not to use their breastmilk to feed an infant.
IUD=intrauterine device; IUS=intrauterine hormone-releasing system.
a Hormonal contraceptives must be stabilized for at least 30 days prior to the start of the screening period.
b Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
c For participants of childbearing ability, having a vasectomized partner is a highly effective contraception method 
provided that the partner is the participant’s sole partner and that the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.
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Table 10. Unacceptable Contraception Methods for Participants Capable of Producing 
Viable Ova and/or Becoming Pregnant
Methods that are unacceptable in any study requiring contraception

Periodic abstinence (calendar, symptothermal, postovulation methods) 

Withdrawal (coitus interruptus) 

Spermicides only

Lactational amenorrhea method 

Use of both female condom and male condom together at the same time
Contraceptives that are effective but have a failure rate of >1% per year when used consistently and 
correctly are unacceptable in a study requiring highly effective contraception (ie, <1% failure rate)

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide
10.4.2.2 Contraceptive Methods for Participants Capable of Producing Viable Sperm
This section describes contraception methods appropriate for participants capable of producing 
viable sperm in the present study and for their partners of childbearing potential.
Table 11. Acceptable Contraception Methods in This Study for Participants Capable of 
Producing Viable Sperm and Their Partners
Acceptable Methods For Male Participants 

Sexual abstinencea

Male condom with spermicide

Combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier 
methods)

Male sterilization (vasectomy) with documented absence of sperm in the postvasectomy ejaculate

Refraining from donating spermc
Acceptable Methods For Female Sexual Partners of Male Participants (Unless Not of Childbearing 
Potential)

Highly effective method of contraception listed in Table 9b

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
actionb

Female condom with spermicide

Cap, diaphragm, or sponge with spermicide
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Table 11. Acceptable Contraception Methods in This Study for Participants Capable of 
Producing Viable Sperm and Their Partners

Combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier 
methods)
Measures Intended to Prevent Fetal and Neonatal Exposure via Sperm or Breastmilk

Participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration during the treatment period and 
for at least 12 weeks after the last dose of study treatment. 
a Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
b Hormonal contraceptives must be stabilized for at least 30 days prior to the start of the screening period.
c Refrain from donating sperm for the duration of the study and for 12 weeks after the last dose of study 
treatment.
In addition, male participants must be advised not to donate sperm from signing of the ICF to 
12 weeks after the last dose of study drug.
10.4.3 Pregnancy
If any participant is found to be pregnant during the study, the participant should be withdrawn
and any sponsor-supplied study drug should be immediately discontinued.
If a participant’s partner becomes pregnant during the study or for 12 weeks after the last dose, 
the participant’s partner should be asked for consent to record and follow the pregnancy.
If the pregnant participant or the participant’s pregnant partner agrees, the investigator should 
notify their primary care physician that the participant/participant’s partner was participating in a 
clinical study when they became pregnant and provide details about the study drug the 
participant received.
If the pregnancy occurs from the time of informed consent until the end of the 12-week 
follow-up period, the pregnancy should be reported immediately, using a pregnancy notification 
form, to the contact listed in the study operations manual.
All pregnancies in participants on study drug or their partners will be followed up to final 
outcome, using the pregnancy form. The outcome, including any premature termination, must be 
reported to the sponsor. An evaluation after the birth of the child will also be conducted.
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10.5 Abbreviations and Definitions
10.5.1 Abbreviations
ADAs
antidrug antibodies
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUDIT
Alcohol Use Disorders Identification Test
AUROC
area under the receiver operating characteristic
β-hCG
beta-human chorionic gonadotropin
BLM
baseline measurement
CAP
Controlled Attenuation Parameter
CCR9
C-C chemokine receptor type 9
CD
Crohn’s disease
CFR
Code of Federal Regulations
CLD
chronic liver disease
cm
centimeters
CRN
Clinical Research Network
CRO
contract research organization
CSR
clinical study report
cT1
iron-corrected T1 mapping
cT1 MRI
iron-corrected T1 mapping by magnetic resonance imaging
CXCR3
C-X-C motif chemokine receptor 3
DSI
disease severity index
ECG
electrocardiogram
eConsent
electronic consent
eCRF
electronic case report form(s) 
ELF
Enhanced Liver Fibrosis
EMA
European Medicines Agency
F
fibrosis stage
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F4cc
fibrosis stage 4 compensated cirrhotic
FAS
full analysis set
FAST
FibroScan-aspartate aminotransferase
FDA
Food and Drug Administration 
FIB-4
Fibrosis-4 Index
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HA
hyaluronic acid
HbA1c
hemoglobin A1c
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
HVPG
hepatic venous pressure gradient
IB
investigator’s brochure
IBD
inflammatory bowel disease
ICF
informed consent form(s) 
ICH
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identification
IGRA
interferon-gamma release assay
IL
interleukin
IMID
immune-mediated inflammatory disease
INR
international normalized ratio
IRB
Institutional Review Board
LSM
liver stiffness measurement
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MCD
methionine- and choline-deficient
MELD
Model for End-stage Liver Disease
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MMRM
mixed effects model for repeated measure
MRI
magnetic resonance imaging
NAFLD
nonalcoholic fatty liver disease
NAS
Nonalcoholic Fatty Liver Disease Activity Score
NASH
nonalcoholic steatohepatitis
PDFF
proton density fat fraction
PFS
prefilled syringe
PIIINP
amino-terminal propeptide of type III procollagen
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PPAR
peroxisome proliferator-activator receptor
Pro-C3
neoepitope-specific N-terminal propeptide of type III collagen
PSC
primary sclerosing cholangitis
Q4W
every 4 weeks
RSI
reference safety information
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus-2
SAP
statistical analysis plan
SC
subcutaneous(ly)
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction
SV
screening visit 
T2DM
type 2 diabetes mellitus
TB
tuberculosis
TBL
total bilirubin 
TEAE
treatment-emergent adverse event
TIMP-1
tissue inhibitor of metalloproteinases 1
TZD
thiazolidinedione
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
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10.6 Protocol Amendment History
Date
Document
Global/Country/Site Specific
02 Nov 2022
Original Protocol
Global 
15 Dec 2022
Amendment 1
Global
25 Apr 2023
Amendment 2
Global
18 Sep 2023
Amendment 3
Global
Summary of Change(s) Since the Last Version of the Approved Protocol
Protocol Amendment 2
Amendment Date:
25 Apr 2023
Global/Region/Country/Site Specific:
Global
Overall Reason for the Amendment
The overall reasons for this protocol amendment are to: 
•
Revise inclusion and exclusion criteria to improve feasibility of study conduct at a variety of clinical sites.
•
Clarify contraception methods for male study participants and for female sexual partners of male 
participants.
•
Add an additional part to the baseline visit to allow confirmation of eligibility on the basis of liver 
chemistry tests before dosing. 
•
Clarify acceptable conditions for repeating screening laboratory samples.
•
Allow flexibility to perform Week -6 and Week 24 assessments on different days within the specified visit 
window. 
Description of Each Change and Rationale 
Section(s) Affected by Change
#
Description of change(s)
Rationale for change(s)
Section
1.
Removed Inclusion Criteria #7 and #8 
and revised Exclusion Criteria #1 and 
#2 to eliminate separate entry criteria 
for fibrosis stage (F)2/F3 versus F4 
compensated cirrhotic (F4cc) staging.
Criteria for aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), total and 
direct bilirubin, albumin, international 
normalized ratio (INR), creatinine, and 
platelet count for all study participants 
were removed from Exclusion Criterion 
#1 and revised under Exclusion 
Criterion #2.
Removed biopsy-confirmed fibrosis 
stage F4cc from Exclusion Criterion #2, 
so the subcriteria apply to all study 
participants.
To provide uniformity 
so that all study 
participants, regardless 
of biopsy-confirmed 
staging (F2/F3/F4cc), 
will have the same 
laboratory requirements 
for study entry, with no 
required presence or 
history of previously 
defined hepatic and 
abdominal diagnoses.
Section 1.1 Synopsis
Section 5.1 Inclusion Criteria,
Criteria #7 and #8
Section 5.2 Exclusion Criteria,
Criteria #1 and #2
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Description of Each Change and Rationale 
Section(s) Affected by Change
#
Description of change(s)
Rationale for change(s)
Section
2.
Revised the inclusion criterion to lower 
the FibroScan-aspartate 
aminotransferase (FAST) score for 
eligible participants from ≥0.5 to >0.35.
Revised justification for the FAST score 
threshold of >0.35.
To allow easier influx of 
participants into the 
study while maintaining 
the same neoepitope-
specific N-terminal 
propeptide of type III 
collagen (Pro-C3) and 
Enhanced Liver Fibrosis 
(ELF) threshold to 
determine ultimate 
eligibility for liver 
biopsy, by identifying 
participants who do not 
have NASH with 
NAS≥4 and fibrosis 
F≥2.
Section 1.1 Synopsis
Figure 1 Study Schema, 
footnote b
Table 1 Schedule of Study 
Activities: Screening Period, 
footnote w
Section 4.1 Overall Design
Section 5.1 Inclusion Criteria, 
Criterion #4
Section 5.1.1 Justification of 
Inclusion Criteria
Section 8.2.3 FibroScan-
Aspartate Aminotransferase Score
3.
Changed the maximum age of eligible 
participants from 65 to 70 years at the 
time of providing informed consent.
To improve feasibility 
of study conduct at a 
variety of clinical sites 
where the proportion of 
newly retired people is 
significant.
Section 1.1 Synopsis
Section 4.1 Overall Design
Section 5.1 Inclusion Criteria, 
Criterion #3
4.
Specified that ALT/AST values at 
Week -8 will determine eligibility for 
liver biopsy at Week -6, and that 
ALT/AST results at Week -6 will be 
evaluated for eligibility for liver biopsy 
and abdominal magnetic resonance 
imaging (MRI) if Week -8 results are 
between 4×upper limit of normal (ULN) 
and 5×ULN. 
Noted that it is the investigator’s 
decision, in consultation with the 
sponsor, the to allow participants to 
enter the study who have clinically 
meaningful rising tendencies in liver 
chemistries or significantly elevated 
liver chemistries that do not yet satisfy 
Exclusion Criterion #1 but could be 
interpreted as clinically concerning (ie, 
AST or ALT >4×ULN) at any visit 
during the screening period.
To clarify the liver 
chemistry-related 
assessments that 
determine eligibility for 
the screening liver 
biopsy and abdominal 
MRI, and to provide 
guidance for cases of 
borderline elevations in 
ALT or AST during 
screening.
Figure 1 Study Schema, footnote 
b
Table 1 Schedule of Study 
Activities: Screening Period, 
footnote w
Section 4.1 Overall Design
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria, 
Exclusion Criterion #3
5.
Added an additional baseline visit on 
Day -4 (Visit 4a2; Baseline Part 2) to 
assess liver chemistry. 
To allow for 
confirmation of 
eligibility on the basis of 
ALT and AST before 
dosing and to reduce 
constraint of conducting 
all baseline assessments 
at a single visit. 
Figure 1 Study Schema
Table 2 Schedule of Activities: 
Treatment Period, Follow-up, and 
End of Study
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Description of Each Change and Rationale 
Section(s) Affected by Change
#
Description of change(s)
Rationale for change(s)
Section
6.
Extended the Visit 2 (Week -6) window 
to up to 14 days.
To allow adequate time 
for processing of Week -
6 study assessments 
during screening. 
Table 1 Schedule of Study 
Activities: Screening Period
7.
Added new subsection to list acceptable 
contraception methods for male study 
participants and their female sexual 
partners. 
To specify the 
contraception methods 
that are considered 
medically appropriate 
for male study 
participants, and to 
clarify contraception 
requirement for female 
sexual partners of male 
participants.
Section 10.4.2.2 Contraceptive 
Methods for Participants Capable 
of Producing Viable Sperm
Table 10 Acceptable 
Contraception Methods in This 
Study for Participants Capable of 
Producing Viable Sperm and 
Their Partners
8.
Revised tables to reflect contraception 
information applicable only to 
participants of childbearing potential.
Clarification.
Section 10.4.2.1 Contraceptive 
Methods for Participants Capable 
of Producing Viable Ova and/or 
Becoming Pregnant
Table 8 Acceptable Contraception 
Methods and Lactation Guidance 
in This Study for Participants 
Capable of Producing Viable Ova 
and/or Becoming Pregnant
Table 9 Unacceptable 
Contraception Methods for 
Participants Capable of Producing 
Viable Ova and/or Becoming 
Pregnant
9.
Removed a footnote requiring 2 highly 
effective methods of contraception 
during the treatment period from the 
table of acceptable contraception 
methods of participants of childbearing 
potential. 
To correct the table to 
accurately reflect the 
requirements for a single 
highly effective method 
of contraception during 
the treatment period.
Table 8 Acceptable 
Contraception Methods and 
Lactation Guidance in This Study 
for Participants Capable of 
Producing Viable Ova and/or 
Becoming Pregnant
10.
Specified that if liver chemistry 
measurements at the Week -8 or Week -
6 visits are repeated, the Week -8 or 
Week -6 value will be calculated as the 
mean of the initial and repeat 
measurements for the given visit, except 
if the repeat sampling was conducted 
because of a technical issue with the 
initial sample. 
To clarify instructions 
for repeat liver 
chemistry laboratory 
measurements during 
the screening period.
Section 8.3.8 Clinical Safety 
Laboratory Tests
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Description of Each Change and Rationale 
Section(s) Affected by Change
#
Description of change(s)
Rationale for change(s)
Section
11.
Clarified that for the screening 
laboratory tests indicated in the 
Schedule of Study Activities, sampling 
may be repeated once during the 
screening period if a result is considered 
by the investigator to be transient and 
inconsistent with the participant’s
clinical condition, for confirmation 
before the participant is considered a 
screen failure as long as the repeated 
assessment is conducted during the 
screening window. 
Revised “Repeat samples” to “Samples” 
in the footnote applicable to biomarker 
samples.
Added statement that for biomarker 
assessments, repeating a sample due to 
reasons other than technical issues with 
the sample is not permitted. 
To provide clarification 
on acceptable conditions 
for repeating a screening 
laboratory sample, and 
to specify that repeated 
sampling for biomarkers 
is not permitted for 
reasons other than 
technical issues. 
Table 1 Schedule of Study 
Activities: Screening Period, 
footnote x
Table 2 Schedule of Activities: 
Treatment Period, Follow-up, and 
End of Study, footnote q
Section 8 Study Assessments and 
Procedures
12.
Added statement to allow for extension 
of the screening period by up to 2 weeks 
based on select measurements that 
require a repeat test (case-by-case basis 
with the sponsor’s approval).
To reduce potential 
screen failures due to a 
lack of adequate time 
for select repeat 
measurements. 
Section 1.1 Synopsis
Table 1 Schedule of Study 
Activities: Screening Period
Table 2 Schedule of Activities: 
Treatment Period, Follow-up, and 
End of Study 
Section 5.4 Screening
Section 8 Study Assessments and 
Procedures
13.
Added that for participants with 
qualifying historical liver biopsies, the 
baseline abdominal MRI visit may 
occur as soon as possible after liver 
chemistry results from Screening Visit 2 
become available, and Screening Visit 2 
and the Day -4 visit (Visit 4a2) must be 
at least 2 weeks apart. 
To reduce participant 
burden by shortening the 
screening period when a 
qualifying historical 
biopsy is available.
Section 1.1 Synopsis
Figure 1 Study Schema, footnote 
b
Table 2 Schedule of Activities: 
Treatment Period, Follow-up, and 
End of Study, new footnote a
Section 4.1 Overall Design
14.
Added that for participants with ALT or 
AST <5×ULN at both screening visits 
and Visit 4a2 but have ALT or AST 
>5×ULN at Day 1 after having received 
the first dose of study drug, a repeat test 
should be performed as soon as 
possible, the participant should be 
closely monitored according to 
guidance provided in Section 7.1.1, and 
the participant’s continued study 
participation should be evaluated by the 
internal safety review committee.
To ensure participant 
safety if liver chemistry 
abnormalities emerge at 
the Day 1 of the study. 
Section 7.1.1 Liver Chemistry 
Stopping Criteria
15.
Changed the maximum duration of the 
screening period from 20 weeks to 
24 weeks for participants with F4cc 
fibrosis (either based on screening tests 
at Screening Visit 1 or based on 
To increase flexibility in 
screening and enrolling 
F4cc participants.
Section 1.1 Synopsis
Figure 1 Study Schema, footnote 
a
Section 4.1 Overall Design
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#
Description of change(s)
Rationale for change(s)
Section
screening biopsy or historical biopsy 
results) who start screening before 
safety and tolerability data after 
12 weeks of treatment are evaluated in 
the first four F2/F3 participants. 
Section 5.5 Criteria for 
Temporarily Delaying Enrollment
16.
Changed the participant’s maximum 
duration of study participation from 
approximately 44 weeks to 
approximately 46 weeks, or from 56 to 
60 weeks for F4cc participants who are 
eligible before safety and tolerability 
are established in the first four F2/F3 
participants.
To increase flexibility of 
maximum duration of 
study participation for 
all participants. 
Section 1.1 Synopsis
Section 4.4 End of Study/Study 
Completion Definition
17.
Added a footnote to specify that 
procedures at the Week -6 and Week 24 
visits may be performed on different 
days within the visit window.
To increase flexibility 
and improve feasibility 
of the protocol at 
diverse study sites. 
Table 1 Schedule of Study 
Activities: Screening Period, new 
footnote a
Table 2 Schedule of Activities: 
Treatment Period, Follow-up, and 
End of Study, new footnote b
18.
Changed the restriction on antibiotic use 
from 6 months to 3 months before first 
dose of study drug (or before qualifying
historical liver biopsy).
Limited the restriction of antibiotic use 
to systemic administration of antibiotics 
that can potentially influence the 
composition of intestinal flora.
Changed the requirement of stable 
regimen for permitted medications, 
including antidiabetic therapies, from 
6 months to 3 months before the 
qualifying liver biopsy.
To improve feasibility 
of the protocol while 
maintaining participant 
safety, and to align the 
exclusion criterion with 
Food and Drug 
Administration (FDA) 
recommendations for 
enrolling participants 
with type 2 diabetes 
mellitus (T2DM) (FDA, 
Draft Guidance: 
Nonalcoholic 
Steatohepatitis with 
Compensated Cirrhosis: 
Developing Drugs for 
Treatment Guidance for 
Industry, June 2019).
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria, 
Exclusion Criteria #19
Section 6.8.2 Excluded 
Procedures and Treatments
Section 6.8.3 Permitted 
Concomitant Medications and 
Procedures
19.
Added a footnote to specify that the 
liver biopsy must be conducted as the 
last assessment for the Week 24/End of 
Treatment/Early Termination visit.
To provide clarity to 
ensure that the liver 
biopsy procedure does 
not impact other 
assessments, such as 
serum liver chemistry 
measurements.
Table 2 Schedule of Activities: 
Treatment Period, Follow-up, and 
End of Study, new footnote l
20.
Revised Exclusion Criterion #13 to 
exclude participants with abnormal 
chest X-ray at screening or within 12 
weeks before the screening visit (if 
available), and to remove the 
requirement of Mantoux tuberculin skin 
test for all participants at screening or 
within 12 weeks before screening.
To simplify exclusion 
criteria related to 
Mycobacterium 
tuberculosis (TB) 
infection and to provide 
guidance for retesting to 
ensure absence of TB 
infection during 
screening. 
Section 1.1 Synopsis
Table 1 Schedule of Study 
Activities: Screening Period, 
footnote s
Section 5.2 Exclusion Criteria, 
Exclusion Criteria #13 and #14
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#
Description of change(s)
Rationale for change(s)
Section
Specified that interferon-gamma release 
assay (IGRA) screening may be 
repeated during the screening period if 
the initial result is indeterminate.
Included statements regarding screen 
failure procedure and permitting entry 
of participants if initial and 
confirmatory IGRA results are in 
determinate, after a negative tuberculin 
skin test and a consultation with the 
sponsor and a pulmonary or infectious 
disease specialist who determines low 
risk of infection.
21.
Added exclusion of participants who 
may have new signs of liver 
decompensation and/or clinically 
meaningful change in disease status 
based on the judgment of the 
investigator during the screening period.
To ensure participants 
whose liver disease is 
progressing to 
decompensation are 
excluded from the study 
and receive appropriate 
treatment.
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria, 
Exclusion Criterion #3
22.
Added hemochromatosis to the list of 
examples of excluded liver diseases.
To ensure participants 
with hemochromatosis 
are excluded from this 
study. 
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria, 
Exclusion Criterion #4
23.
Revised Exclusion Criterion #5 and 
Table 3 to remove restriction of 
anticoagulant medication. 
Added temporary restrictions on 
antiplatelet and anticoagulant 
medications before liver biopsy.
To improve feasibility 
of the protocol while 
ensuring participant
safety in line with 
published guidelines on 
anticoagulant and 
antiplatelet medication 
restrictions before liver 
biopsy.
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria, 
Exclusion Criterion #5
Table 3 Common Excluded 
Treatments
Section 6.8.2 Excluded 
Procedures and Treatments
Section 6.8.3 Permitted 
Concomitant Medications and 
Procedures
24.
Included clinically active infections of 
cytomegalovirus, Epstein-Barr virus, 
and herpes simplex virus as examples of 
local active viral infection/infectious 
disease that would be exclusionary.
Added that in case of suspicion of 
clinically active bacterial, fungal, or 
viral infection, additional testing should 
be performed at the investigator’s 
discretion.
To clarify exclusion 
related to infections and 
allow for additional 
testing at the 
investigator’s discretion 
if active infection is 
suspected. 
Section 1.1 Synopsis
Table 1 Schedule of Study 
Activities: Screening Period, 
footnote r 
Section 5.2 Exclusion Criteria, 
Exclusion Criterion #6a
25.
Revised Exclusion Criterion #6a to 
exclude participants with hemoglobin 
A1c (HbA1c) ≥6.5% at screening 
(Week -8) with no previous diagnosis of 
T2DM, and to exclude participants with 
HbA1c of ≥8% at screening (Week -8) 
with a previous diagnosis of T2DM on a 
stable regimen of antidiabetic therapy 
for at least 90 days before screening.
To define the acceptable 
range of HbA1c levels 
and disease status at 
baseline for participants 
with T2DM and to 
exclude participants 
with HbA1c ≥8% at 
screening with a 
previous diagnosis of 
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria
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#
Description of change(s)
Rationale for change(s)
Section
T2DM on a stable 
regimen of antidiabetic 
therapy for at least 
90 days before 
screening.
26.
Added exclusion of participants who are 
anticipated to receive a live vaccine 
during the study.
To specify that live 
vaccines are not 
permitted during the 
study, in addition to the 
4 weeks before baseline.
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria, 
Exclusion Criterion #24
27.
Corrected the table to apply the footnote 
including 5 half-lives (if longer than
90 days) to biologics with 
immunomodulatory properties.
Corrected Exclusion Criterion #30 to 
reflect the minimum required washout 
time of both biologic drugs and 
nonbiologic drugs with 
immunomodulatory properties of 
90 days or 5 half-lives (whichever is 
longer) before baseline, in line with 
Table 3. 
Correction.
Section 1.1 Synopsis
Section 5.2 Exclusion Criteria,
Exclusion Criterion #30
Table 3 Common Excluded 
Treatments
28.
Clarified that the FAST score criterion 
does not apply participants with a 
qualifying historical liver biopsy that 
provides evidence of F2, F3, or F4cc 
staging.
Clarification
Section 5.1 Inclusion Criteria, 
Criterion #4
29.
Added that the baseline measurement 
for evaluating liver chemistry stopping 
criteria is determined by the last liver 
chemistry value before dosing.
To add the definition of 
baseline measurement 
for evaluating liver 
chemistry stopping 
criteria.
Section 7.1.1 Liver Chemistry 
Stopping Criteria
30.
Changed the name of the internal group 
responsible for evaluating the overall 
safety of the study participants to the 
internal safety review committee.
To provide a more 
precise committee name 
in line with the 
committee’s charter.
Section 1.1 Synopsis
Section 4.1 Overall Design
Section 7.1.1 Liver Chemistry 
Stopping Criteria
Section 8.3.2 Targeted 
Neurological Assessment
Section 10.1.5.2 Other 
Committees
31.
Specified that the approximate daily and 
overall blood volumes do not include 
potential repeat measurement samples. 
Clarification 
Section 8.3.8 Clinical Safety 
Laboratory Tests
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Description of Each Change and Rationale 
Section(s) Affected by Change
#
Description of change(s)
Rationale for change(s)
Section
32.
Changed reporting procedure for 
adverse events of special interest 
(AESIs) from using the serious adverse 
event (SAE) form to reporting as an 
adverse event (AE) in the electronic 
case report form (eCRF).
Clarified that investigators will report 
AESIs, in addition to SAEs, to the 
sponsor or designee within 24 hours of 
receipt of the information.
Included AESIs in the expedited 
reporting procedures for SAEs.
Corrected the procedures for SAE/AESI 
reporting via telephone to the medical 
monitor rather than an SAE coordinator.
Removed the statement that initial 
notification via telephone does not 
replace the need for the investigator to 
complete and sign the SAE paper form.
To clarify AESI 
procedures for reporting 
AESIs via the electronic 
data capture, which will 
notify the sponsor’s 
safety team.
Section 8.3.11.6 Adverse Events 
of Special Interest
Section 10.3.4.6 Follow-up
Section 10.3.5 Expedited 
Reporting of Serious Adverse 
Events and Adverse Events of 
Special Interest
33.
Addition of progressive multifocal 
leukoencephalopathy (PML) as an 
AESI, including instructions for 
monitoring and event reporting. 
To clarify the procedure 
by which suspected 
PML cases are 
immediately reported to 
the sponsor, following 
the timeline for SAE 
reporting. 
Section 8.3.2 Targeted 
Neurological Assessment
Section 8.3.11.6 Adverse Events 
of Special Interest
Section 10.3.3.2.2 PML
Section 10.3.5 Expedited 
Reporting of Serious Adverse 
Events and Adverse Events of 
Special Interest
34
Added “approximately” to footnote w.
To align with the 
analogous footnote for 
the treatment period 
regarding time of day of 
biomarker sampling 
across visits.
Table 1 Schedule of Study 
Activities: Screening Period, 
footnote x
35.
Specified that the Week -1 visit can 
occur on Day -7 to -4.
Changed the visit window of ±5 days to 
+3 days for the abdominal MRI at the 
Week -1 visit.
To clarify the acceptable 
timing of the baseline 
abdominal MRI.
Figure 1 Study Schema
Table 2 Schedule of Activities: 
Treatment Period, Follow-up, and 
End of Study
36.
Added a footnote stating that abdominal 
ultrasound at screening is intended for 
morphological evaluation of liver and 
other organs and structures during 
screening. 
Clarification
Table 1 Schedule of Study 
Activities: Screening Period, new 
footnote n
37.
Revised footnote to remove exclusion 
criterion of liver stiffness >25 kPa and 
to provide cross-reference to 
methodology section related to 
FibroScan.
To align footnote with 
revised exclusion 
criterion.
Table 1 Schedule of Study 
Activities: Screening Period, 
footnote v
38.
Removed “Caffeine” from section 
heading.
To correct the heading 
to accurately reflect the 
content of the section. 
Section 5.3.2 Alcohol and 
Tobacco
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Section(s) Affected by Change
#
Description of change(s)
Rationale for change(s)
Section
39.
Removed “previous” from the statement 
regarding a fresh biopsy being required 
if a biopsy being found to be inadequate 
by the study pathologist.
To clarify that a fresh 
biopsy is required if any 
biopsy, whether 
historical or performed 
as part of this study, is 
found to be inadequate 
by the study pathologist.
Section 8.2.8 Liver Biopsy
40.
Added statement that instructions for 
returns and destruction of tissue 
samples will be provided to the study 
sites in documentation outside of the 
protocol.
Clarification
Section 8.2.8 Liver Biopsy
41.
Added that analyses of extracellular 
vesicles may be performed using 
residual serum samples. 
To describe additional 
biomarker analyses to 
support exploratory 
objectives of the study.
Section 8.2.12 Additional 
Biomarkers
Summary of Change(s) Since the Last Version of the Approved Protocol
Protocol Amendment 1
Amendment Date:
15 Dec 2022
Global/Region/Country/Site Specific:
Global
Overall Reason for the Amendment
The overall reason for this protocol amendment is to update study stopping criteria.
Description of Each Change and Rationale 
Section(s) Affected by Change
#
Description of change(s)
Rationale for change(s)
Section
1.
Updated stopping criteria for 
safety-related events that 
would trigger temporary 
suspension or early 
termination of the study.
To specify safety-related 
criteria that would trigger 
temporary suspension or 
early termination of the 
study.
Section 10.1.12.2 Criteria for Premature 
Termination or Suspension of the Study
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Tytgat, G. N. 1999. Immunohistochemical analysis of inflammation in primary sclerosing 
cholangitis. Eur J Gastroenterol Hepatol, 11(7), 769-74.
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Pugh, R. N., Murray-Lyon, I. M., Dawson, J. L., Pietroni, M. C. and Williams, R. 1973. 
Transection of the oesophagus for bleeding oesophageal varices. Br J Surg, 60(8), 646-9.
Pullen, N., Molloy, E., Carter, D., Syntin, P., Clemo, F., Finco-Kent, D., et al. 2009. 
Pharmacological characterization of PF-00547659, an anti-human MAdCAM monoclonal 
antibody. Br J Pharmacol, 157(2), 281-93.
Rai, R. P., Liu, Y., Iyer, S. S., Liu, S., Gupta, B., Desai, C., et al. 2020. Blocking integrin 
α(4)β(7)-mediated CD4 T cell recruitment to the intestine and liver protects mice from 
western diet-induced non-alcoholic steatohepatitis. J Hepatol, 73(5), 1013-22.
Regev, A., Palmer, M., Avigan, M. I., Dimick‐Santos, L., Treem, W. R., Marcinak, J. F., et al. 
2019. Consensus: guidelines: best practices for detection, assessment and management of 
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associated invariant T cells link intestinal immunity with antibacterial immune defects in 
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Schippers, A., Hübel, J., Heymann, F., Clahsen, T., Eswaran, S., Schlepütz, S., et al. 2021. 
MAdCAM-1/α4β7 Integrin-Mediated Lymphocyte/Endothelium Interactions Exacerbate 
Acute Immune-Mediated Hepatitis in Mice. Cell Mol Gastroenterol Hepatol, 11(4), 
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Sheka, A. C., Adeyi, O., Thompson, J., Hameed, B., Crawford, P. A. and Ikramuddin, S. 2020. 
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alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment 
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Vieira Barbosa, J., Milligan, S., Frick, A., Broestl, J., Younossi, Z., Afdhal, N. H., et al. 2022. 
Fibrosis-4 Index as an independent predictor of mortality and liver-related outcomes in 
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Warrington, R., Silviu-Dan, F. and Wong, T. 2018. Drug allergy. Allergy, Asthma & Clinical 
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vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and 
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sensitivity C-reactive protein is an independent clinical feature of nonalcoholic 
steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J Gastroenterol,
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Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L. and Wymer, M. 2016. Global 
epidemiology of nonalcoholic fatty liver disease—Meta‐analytic assessment of 
prevalence, incidence, and outcomes. Hepatology, 64(1), 73-84.
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REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
1.0 
 
Not Applicable 
2.0 
 
Incorporate changes from Protocol Amendment 3. 
Removed liver biopsy, HepQuant, and MAdCAM1 assessments at 
the end of treatment. 
 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................8 
1.1 
Objectives ......................................................................................................................8 
1.1.1 
Primary Objective ..................................................................................................8 
1.1.2 
Secondary Objective ..............................................................................................8 
1.1.3 
Exploratory Objectives ..........................................................................................8 
1.2 
Endpoints .......................................................................................................................9 
1.2.1 
Primary Endpoints .................................................................................................9 
1.2.2 
Secondary Endpoints .............................................................................................9 
1.2.3 
Exploratory Endpoints ...........................................................................................9 
1.3 
Estimand(s) ..................................................................................................................10 
2.0 
STUDY DESIGN...............................................................................................................10 
2.1.1 
Study Schedule ....................................................................................................12 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................13 
3.1 
Statistical Hypotheses ..................................................................................................13 
3.2 
Statistical Decision Rules ............................................................................................13 
3.3 
Multiplicity Adjustment ...............................................................................................13 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................13 
5.0 
ANALYSIS SETS .............................................................................................................13 
5.1 
Screened Analysis Set ..................................................................................................13 
5.2 
All Enrolled Analysis Set.............................................................................................13 
5.3 
Full Analysis Set ..........................................................................................................14 
5.4 
Per-Protocol Analysis Set ............................................................................................14 
5.5 
Safety Analysis Set ......................................................................................................14 
5.6 
Pharmacokinetic Analysis Set......................................................................................14 
6.0 
STATISTICAL ANALYSIS .............................................................................................14 
6.1 
General Considerations ................................................................................................14 
6.1.1 
Statistics and Precision ........................................................................................14 
6.1.2 
Definition of Baseline ..........................................................................................14 
6.1.3 
Definition of Study Day and Visit Windows ......................................................15 
6.2 
Disposition of Participants ...........................................................................................15 
6.3 
Demographic and Other Baseline Characteristics .......................................................16 
6.3.1 
Demographics ......................................................................................................16 
6.3.2 
Baseline Characteristics .......................................................................................16 
6.4 
Medical History and Concurrent Medical Conditions .................................................16 
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6.5 
Medication History and Concomitant Medications .....................................................17 
6.6 
Extent of Exposure and Compliance ............................................................................17 
6.7 
Biomarker and Noninvasive Test Analysis ..................................................................17 
6.7.1 
Secondary Endpoints Analysis ............................................................................18 
6.7.1.1 
Main Analysis Approach.............................................................................18 
6.7.1.2 
Supplementary Analysis..............................................................................18 
6.7.2 
Exploratory Endpoints Analysis ..........................................................................18 
6.7.3 
Subgroup Analyses ..............................................................................................19 
6.8 
Safety Analysis ............................................................................................................19 
6.8.1 
Adverse Events ....................................................................................................19 
6.8.2 
Adverse Events of Special Interest ......................................................................20 
6.8.3 
Clinical Laboratory Assessments ........................................................................20 
6.8.4 
Vital Signs and Weight ........................................................................................21 
6.8.5 
12-Lead ECGs .....................................................................................................21 
6.9 
Pharmacokinetic Analyses ...........................................................................................21 
6.10 
Interim Analyses ..........................................................................................................21 
6.11 
Other Committees ........................................................................................................21 
6.12 
Changes to Protocol Planned Analysis ........................................................................22 
7.0 
REFERENCES ..................................................................................................................22 
8.0 
APPENDIX ........................................................................................................................23 
8.1 
Changes From the Previous Version of the Statistical Analysis Plan (SAP) ..............23 
8.2 
Appendix A - Definition of Analysis Visit Windows ..................................................23 
8.3 
Appendix B - Missing/Partial Dates for Adverse Event/Concomitant Medication .....27 
8.4 
Appendix C – Criteria for Clinically Significant Values .............................................28 
9.0 
ELECTRONIC SIGNATURE ...........................................................................................30 
 
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ABBREVIATIONS 
ADA 
antidrug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AR1 
homogeneous first order autoregressive 
ARH1 
heterogeneous first order autoregressive 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic class 
BMI 
body mass index 
CCR9 
C-C chemokine receptor type 9 
CI 
confidence interval 
CRN 
Clinical Research Network 
CS 
compound symmetry 
CSH 
heterogenous compound symmetry 
CSR 
clinical study report 
cT1 
iron-corrected T1 mapping 
cT1 MRI 
iron-corrected T1 mapping by magnetic resonance imaging 
CXCR3 
C-X-C motif chemokine receptor 3 
DSI 
disease severity index 
ECG 
Electrocardiogram 
eCRF 
electronic case report form(s) 
ELF 
Enhanced Liver Fibrosis 
F 
fibrosis stage 
F2 
fibrosis stage 2 
F3 
fibrosis stage 3 
F4cc 
fibrosis stage 4 compensated cirrhotic 
FAS 
Full Analysis Set 
FAST 
FibroScan-aspartate aminotransferase 
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FIB-4 
Fibrosis-4 Index 
GGT 
gamma-glutamyl transferase 
GLM 
generalized linear model 
hsCRP 
high-sensitivity C-reactive protein 
IL 
Interleukin 
INR 
international normalized ratio 
LLN 
lower limit of normal 
LS Means 
least-square means 
LSM 
liver stiffness measurement 
MAdCAM-1 
mucosal addressin cell adhesion molecule-1 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MELD 
Model for End-stage Liver Disease 
MMRM 
mixed effects model for repeated measure 
MRI 
magnetic resonance imaging 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
Nonalcoholic Fatty Liver Disease Activity Score 
NASH 
nonalcoholic steatohepatitis 
PDFF 
proton density fat fraction 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PPAS 
Per-Protocol Analysis Set 
Pro-C3 
neoepitope-specific N-terminal propeptide of type III collagen 
PT 
preferred term 
Q4W 
every 4 weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SOC 
system organ class 
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T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin  
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
To evaluate safety and tolerability of ontamalimab 75 mg administered every 4 weeks (Q4W) in 
participants with nonalcoholic steatohepatitis (NASH) (defined as Nonalcoholic Fatty Liver 
Disease [NAFLD] Activity Score [NAS]ı3 with at least 1 point in lobular inflammation) with 
different fibrosis stages (NASH Clinical Research Network [CRN] F1 through F4cc 
participants). 
1.1.2 
Secondary Objective 
To determine if the changes from baseline in key biomarkers (neoepitope-specific N-terminal 
pro-peptide of type III collagen [Pro-C3] and Enhanced Liver Fibrosis test [ELF]) and in cT1 
MRI (iron-corrected T1 mapping by magnetic resonance imaging) provide a signal of a potential 
role of the MAdCAM-1 pathway in participants with NASH (defined as NAS ı3 with at least 
1 point in lobular inflammation) with different fibrosis stages (NASH CRN F1 through F4cc 
participants) after 24 weeks of administration of ontamalimab 75 mg Q4W. 
1.1.3 
Exploratory Objectives 
x To evaluate the changes from baseline in inflammatory and cell trafficking markers in blood 
samples after 24 weeks of administration of ontamalimab 75 mg Q4W in participants with 
NASH (defined as NAS ≥3 with at least 1 point in lobular inflammation) with different 
fibrosis stages (NASH CRN F1 through F4cc participants) and overall. 
x To evaluate the changes in fibrosis markers from baseline after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH (defined as NAS ≥3 with at least 1 point 
in lobular inflammation) with different fibrosis stages (NASH CRN F1 through F4cc 
participants) and overall. 
x To evaluate the changes in liver fat content from baseline after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH (defined as NAS ≥3 with at least 1 point 
in lobular inflammation) with different fibrosis stages (NASH CRN F1 through F4cc 
participants) and overall. 
x To evaluate the changes in spleen cT1 MRI from baseline after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH (defined as NAS ≥3 with at least 1 point 
in lobular inflammation) with different fibrosis stages (NASH CRN F1 through F4cc 
participants) and overall. 
x To evaluate the changes from baseline in biochemistry after 24 weeks of administration of 
ontamalimab 75 mg Q4W in participants with NASH (defined as NAS ≥3 with at least 1 point 
in lobular inflammation) with different fibrosis stages (NASH CRN F1 through F4cc 
participants) and overall. 
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x To evaluate the pharmacokinetics (PK) of ontamalimab 75 mg Q4W in participants with 
NASH (NAS ı3 with at least 1 point in lobular inflammation) (NASH CRN F1 through F4cc 
participants). 
x To evaluate immunogenicity of ontamalimab 75 mg Q4W in participants with NASH (NAS ı
3 with at least 1 point in lobular inflammation) (NASH CRN F1 through F4cc participants). 
1.2 
Endpoints 
1.2.1 
Primary Endpoints 
x Incidence of treatment-emergent adverse events (TEAEs) 
x Number of participants with clinically significant changes in the following parameters from 
baseline to the end of the follow-up period (Week 36): 
x Laboratory tests 
x Electrocardiograms (ECGs) 
x Vital signs 
x Body weight 
1.2.2 
Secondary Endpoints  
x Percent change from baseline in Pro-C3 through Week 24 
x Percent change from baseline in ELF through Week 24 
x Change from baseline in liver cT1 MRI at Week 24 
1.2.3 
Exploratory Endpoints 
x Change from baseline to Week 24 in each of the following biomarker readouts for each 
fibrosis stage group (fibrosis stage 1 through 4) and overall in all participants: 
x Serum or plasma biomarkers including but not limited to: high-sensitivity C-reactive 
protein (hsCRP) (serum), interleukin (IL)-8 (serum), and calprotectin (plasma) 
x T and immune cell trafficking in circulating whole blood samples, including but not 
limited to: Th17/Th1 vs. Th2, β7+ T cells, CCR9, and C-X-C motif chemokine receptor 
3 (CXCR3) 
x Transcriptomics in liver biopsy and whole blood samples 
x Change from baseline to Week 24 in each of the following biomarker readouts for each 
fibrosis stage group (fibrosis stage 1 through 4) and overall in all participants: 
x Liver stiffness measure (LSM) by FibroScan 
x Fibrosis-4 Index (FIB-4) 
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x FibroScan-aspartate aminotransferase (FAST) score 
x Change from baseline to Week 24 in proton density fat fraction (PDFF) as measured by 
MRI-PDFF, part of the Liver MultiScan® for each fibrosis stage group (fibrosis stage 1 
through 4) and overall in all participants. 
x Change from baseline to Week 24 in spleen cT1 MRI for each fibrosis stage group (fibrosis 
stage 1 through 4) and overall in all participants. 
x Change from baseline to Week 24 in each of the following biomarker readouts for each 
fibrosis stage group (fibrosis stage 1 through 4) and overall in: 
x Alanine aminotransferase (ALT) 
x Aspartate aminotransferase (AST) 
x AST/ALT ratio 
x Alkaline phosphatase (ALP) 
x Gamma-glutamyl transferase (GGT) 
x Total bilirubin (TBL) 
x International normalized ratio (INR) 
x Albumin 
x Serum concentrations of ontamalimab over the treatment period. 
x Incidence of formation of antidrug antibodies (ADAs) through the end of the follow-up 
period (Week 36). 
1.3 
Estimand(s) 
Not applicable. This is a Phase 1b exploratory biomarker study. 
2.0 
STUDY DESIGN 
This is a multicenter, single-arm, open-label, Phase 1b study to explore the role of MAdCAM-1 
in NASH by administering a MAdCAM-1 inhibitor (ontamalimab) in participants with 
indication of NASH via biopsy (NAS ≥3 with at least 1 point in lobular inflammation) with 
different fibrosis stages (NASH CRN F1 through F4cc participants). The role of MAdCAM-1 
will be evaluated by the changes in inflammatory and fibrosis biomarkers, liver histology and 
circulating inflammatory cells, and liver chemistry tests compared with baseline. MRI-derived 
cT1 
(iron-corrected T1 mapping) will be used to evaluate fibroinflammatory changes in the liver. 
Safety and tolerability of ontamalimab 75 mg will be assessed. 
Approximately 30 participants are planned to be enrolled to ensure that at least 18 participants 
(approximately 12 participants with F1-F3 and approximately 6 participants with F4cc) complete 
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the 24-week treatment period. Not more than four participants with F1 fibrosis will be enrolled in 
this study. Enrollment of F1, F2 and F3 participants at a 1:1:1 ratio will not be required. The 
study will be conducted at up to 20 sites in the US. 
Participant eligibility with full inclusion/exclusion criteria are listed in the study protocol. 
Pro-C3, ELF, and other exploratory markers will be measured at 2 screening visits and Day 1 
predose measurement during treatment period to determine intra- participant variability. This will 
enable the correct interpretation of the posttreatment decrease in these biomarkers relative to the 
intra-participant variability at baseline. 
After safety and tolerability have been established in the first four noncirrhotic (F1-F3) 
participants who have received at least 3 doses of ontamalimab 75 mg and have been 
monitored for at least 12 weeks after the first dose of study drug, eligible F4cc participants will 
be allowed to enroll into the study. The screening period may be extended for up to 24 weeks 
for participants with results consistent with F4 fibrosis (ie, compensated cirrhosis) after the 
first screening visit (ie, a combination of Fibrosis-4 Index [FIB-4] ≥3.48 and liver stiffness 
measurement (LSM) ≥20 kPa, or an Agile 4 score ≥0.57), or have a screening liver biopsy or a 
historical liver biopsy that confirms F4 NASH (NAS ≥3 with at least 1 point in lobular 
inflammation) with F4 fibrosis (ie, cirrhosis), until safety and tolerability data are evaluated in 
the first four noncirrhotic (F1-F3) participants. 
All eligible participants (F1-F4) will enter a 24-week, single-arm, open-label treatment period 
with ontamalimab 75 mg. Ontamalimab will be administered subcutaneously (SC) Q4W 
starting on Day 1 and the last dose is administered at Week 20 (total treatment period is 24 
Weeks), followed by a 12-week safety follow-up period. Liver biopsy samples will be collected 
during screening. Fibro-inflammation will be assessed by cT1 MRI, liver stiffness by 
FibroScan at the start of the treatment period and at Week 24. At visits Q4W between baseline 
and Week 24, assessments of selected biomarkers (including but not limited to Pro-C3, ELF, 
hsCRP, and calprotectin), liver chemistry tests, and specific safety data collection (laboratory, 
adverse events [AEs], neurological assessments) will be performed. 
Liver stiffness measurement by FibroScan will also be performed at Week 12. Safety and 
tolerability data will be continuously monitored and will be evaluated by the internal safety 
review committee (independent from the study team). 
All participants, including those who discontinue, will undergo a safety follow-up period through 
12 weeks after the last dose of study drug. 
The end of the study is defined as the date of the last visit (Week 36) of the last participant 
undergoing the study, unless the study is stopped earlier by the sponsor due to futility or for 
safety reasons (Section 4.4 of the protocol). 
 
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2.1.1 
Study Schedule 
The study schema is presented below (Figure 2.a). Please refer to Section 1.3 of the protocol for 
detailed information pertaining to the schedule of assessments and procedures at each visit. 
Figure 2.a 
Study Schema 
 
a For participants with NASH (NAS ≥3) and F4cc fibrosis (ie, cirrhosis), the screening period may be extended up 
to 24 weeks until safety and tolerability information is available on first four noncirrhotic (F1-F3) participants 
who have received at least 3 doses of ontamalimab and have been monitored for at least 12 weeks after the first 
dose of study drug. Progression of screening is contingent on successful confirmation of eligibility along with the 
sponsor's approval. 
b Eligibility for liver biopsy at Week -6 (SV2) will be established on the basis of results of Week -8 (SV1) 
assessments (including but not limited to Pro-C3 ≥12.6 ng/mL, ELF ≥7.7, and liver chemistry eligibility criteria 
as participants should meet all inclusion criteria and none of exclusion criteria for assessments and procedures 
at Week -8 (SV1) to be eligible for liver biopsy. For participants who meet other eligibility criteria at Week -8 
(SV1), if ALT or AST is >4×ULN and <5×ULN at Week -8 (SV1), then the ALT/AST results at Week -6 
(SV2) will also be evaluated before liver biopsy and the abdominal MRI can be performed. Only participants 
with indication of NASH via biopsy (NAS ≥3 with at least 1 point in lobular inflammation) and liver fibrosis 
stage F1 through F4cc will be enrolled in the study. Green fonts indicate key inclusion criteria. Qualifying 
historical liver biopsies are acceptable for screening purposes if they are available to be reviewed and read 
centrally by the study pathologists and if they meet all the criteria as defined in the histopathology manual. For 
participants with qualifying historical liver biopsies, the abdominal MRI visit (Visit 4a) may occur as soon as 
possible after liver chemistry results from SV2 become available, and SV2 and the Day -4 visit must be at least 
2 weeks apart. 
c Abdominal MRI may be performed between Day -7 and Day -4. 
d Liver chemistry tests include ALT, AST, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase, and 
albumin. 
e Biomarkers from blood samples include serum Pro-C3; ELF; serum sMAdCAM-1; serum and plasma markers of 
inflammation, fibrosis, and trafficking (including but not limited to hsCRP, IL-8, and calprotectin); whole blood 
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T cell phenotyping (including but not limited to Th17/Th1 vs Th2 ratios, β7+ T cells, CCR9, and CXCR3) (treatment 
period only); and whole blood transcriptomics (treatment period only). Pro-C3 levels and ELF score at Week -8 
(SV1) will be used to determine eligibility. Pro-C3 levels and ELF scores at Week -8 (SV1), Week -6 (SV2), and D1 
predose measurement during treatment period will be used in calculating the baseline value for each parameter. 
Footnote on End-of-Treatment Liver Biopsy, HepQuant, and MAdCAM1: The sponsor has removed the end-of 
treatment liver biopsy, HepQuant, and soluble MAdCAM-1 assessment from the study design due to the program's 
termination for strategic reasons. 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES 
The statistical objective of this study is to estimate the effect of ontamalimab on biomarkers 
described in Sections 1.1.2 and 1.1.3. No formal hypothesis testing will be performed. 
3.1 
Statistical Hypotheses 
Not applicable. 
3.2 
Statistical Decision Rules 
Not applicable. 
3.3 
Multiplicity Adjustment 
Not applicable. 
4.0 
SAMPLE-SIZE DETERMINATION 
Approximately 30 participants are planned to be enrolled to ensure that at least 18 
participants complete the 24-week treatment period. The sample size has been chosen to 
provide adequate number of participants to investigate the objectives of the study based on 
clinical experience for key biomarkers (Anstee et al. 2022; Harrison et al. 2018; Jabor et al. 
2018).  
This study is not statistically powered to perform any formal hypothesis testing, and the analyses 
will be based on estimation approach. 
5.0 
ANALYSIS SETS 
5.1 
Screened Analysis Set 
The screened analysis set will consist of all participants who have signed informed consent(s). 
5.2 
All Enrolled Analysis Set 
The all enrolled analysis set will consist of all participants who are enrolled (as defined in 
Section 5.6 of the protocol) in the study. 
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5.3 
Full Analysis Set 
The full analysis set (FAS) will consist of all participants who are enrolled in the study, have 
received at least 1 dose of study drug, and have at least 1 valid postbaseline assessment. 
5.4 
Per-Protocol Analysis Set 
The per-protocol analysis set (PPAS) is a subset of the FAS and will include all participants who 
did not have any important protocol deviations affecting the efficacy evaluations. All decisions 
to exclude participants from the PPAS will be made before database lock. Analyses on the 
secondary endpoints using the PPAS will be provided as supplementary analysis. 
5.5 
Safety Analysis Set 
The safety analysis set will consist of all participants who are enrolled in the study and have 
received at least 1 dose of study drug. 
5.6 
Pharmacokinetic Analysis Set  
The PK analysis set will consist of all participants in the safety analysis set who have at least 1 
evaluable postdose PK concentration value. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
6.1.1 
Statistics and Precision  
For continuous variables, descriptive statistics will include the number of participants (n), mean, 
standard deviation (SD), median, minimum, and maximum. The number of decimal places 
displayed for each statistic will be determined as follows: 
x Mean and median: 1 more decimal place than the recorded data. 
x SD: 2 more decimal places than the recorded data. 
x Minimum and maximum: equal to the number of decimal places in the recorded data. 
x Confidence intervals (CIs) will be presented using the same number of decimal places as 
the parameter estimate. 
For categorical variables, the counts and proportions of each possible value will be presented. 
The denominator for the proportion will be based on the number of participants who provided 
non-missing responses to the categorical variable. Percentages will be reported to 1 decimal 
place. 
6.1.2 
Definition of Baseline 
For biomarkers that are measured multiple times during screening, data from all available 
sampling (including the Day 1 predose measurement) will be averaged to establish the stable 
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baseline value. For all other biomarker and safety parameters, baseline values are defined as the 
last non-missing value collected before the first dose of study drug. 
The change from baseline is calculated by subtracting the baseline values from the individual 
postbaseline values. If either the baseline or postbaseline value is missing, the change from 
baseline is set to missing. 
The percent change from baseline is calculated by dividing the change from baseline values with 
the baseline values and multiplying by 100. If either the baseline or postbaseline values is 
missing, the percent change from baseline is set to missing. 
6.1.3 
Definition of Study Day and Visit Windows 
A windowing convention will be used to determine the analysis value for a given study visit. 
Study Day 1 is defined as the date on which a participant is administered their first dose of the 
study drug. Other study days are defined relative to Study Day 1. Relative day is calculated as 
(date of interest – date of first dose + 1) for study days on or after the first dose date, and as (date 
of interest – date of first dose) for study days prior to the first dose date. 
For each visit, the analysis windows for biomarker and safety parameters are specified in 
Appendix A. More than one result for a parameter may be obtained in an analysis visit window. 
In such an event, the result with date closest to the scheduled visit day will be used. If two 
observations are equidistant to the scheduled visit day, the later of the observations will be used. 
The analysis window convention will not be applied to the electronic case report form (eCRF) 
data listings. The data listings for eCRF data will display the raw data as collected and entered in 
the eCRF. 
6.2 
Disposition of Participants 
A summary of screen failures by site and overall will be presented. 
Disposition of all enrolled participants will be tabulated for the all enrolled analysis set. 
Categories will include: 
x Participants who were enrolled but not treated. 
x Participants who completed study drug. 
x Participants who prematurely discontinued study drug and reason for discontinuation. 
x Participants who completed the Week 24 visit. 
x Participants who prematurely discontinued the study before Week 24 and reason for 
discontinuation. 
x Participants who completed the study. 
x Participants who prematurely discontinued the study and reason for discontinuation. 
 
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6.3 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the safety analysis set. 
Individual participant demographic and baseline characteristic data will be listed. 
6.3.1 
Demographics 
Demographics summary will include descriptive statistics for age, height, weight, and body mass 
index (BMI). The number and percentage of participants within each category will be presented 
for sex, race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian/Other Pacific Islander, White, and Not Reported), and ethnicity (Hispanic or Latino, 
Not Hispanic or Latino, Not Reported, and Unknown). 
6.3.2 
Baseline Characteristics 
The summary of baseline characteristics will include descriptive statistics for continuous 
variables and counts and percentages for categorical variables.  
Table 5.a 
Baseline Characteristics 
Baseline Characteristics 
Summarized as 
Categories 
Fibrosis stage 
Categorical 
F1, F2, F3, F4cc 
T2DMa at baseline 
Categorical 
Yes, No 
Overall NASb score 
Continuous 
 
Assessment of lobular inflammation 
Categorical 
0, 1, 2, 3 
a T2DM = type 2 diabetes mellitus 
b NAS = Nonalcoholic fatty liver disease activity score 
6.4 
Medical History and Concurrent Medical Conditions 
Medical history refers to significant conditions or diseases relevant to the disease under study 
that resolved before, or at the time when, the participant provided informed consent. Ongoing 
conditions are considered concurrent medical conditions. 
Medical history and concurrent medical conditions will be coded using the latest version of 
Medical Dictionary for Drug Regulatory Activities (MedDRA) and will be summarized using 
system organ class (SOC) and MedDRA preferred term (PT) based on the safety analysis set. A 
participant will only be counted once within a particular MeDRA level even if they have 
multiple conditions/symptoms in that level. 
All medical history and concurrent medical condition data will be listed by site (study center) 
and participant number. 
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6.5 
Medication History and Concomitant Medications  
Prior medications/treatments are defined as those that were received within 30 days of the date of 
first dose of study drug. 
Concomitant medications/treatments are defined as those given in addition to the study drug 
between the dates of the first dose of study drug and the end of the follow-up period, inclusive. 
In the case of missing or partial dates, the rules of imputation are defined in Appendix B. 
Medication/treatment history and concomitant medications/treatments will be coded using the 
lates version of the World Health Organization (WHO) Drug Dictionary and summarized using 
PT within each anatomical therapeutic class (ATC) based on the safety analysis set. If a 
participant reports taking more than one drug belonging to the same WHO Drug level, they will 
only be counted once within that level. 
6.6 
Extent of Exposure and Compliance 
The safety analysis set will be used for all summaries in this section. Study drug exposure, 
completed injections, and compliance will be summarized descriptively (n, mean, SD, median, 
minimum, maximum). The following parameters will be included: 
x Duration of exposure (weeks) to study drug defined as (date of last dose – date of first 
dose +1)/7. 
x Number and percentage of participants in the following duration category: ≤4 weeks, >4 
and ≤8 weeks, >8 and ≤12 weeks, >12 and ≤16 weeks, >16 and ≤20 weeks, and >20 
weeks. 
x Total number of injections received. 
x Overall compliance (%), calculated as the percentage of completed injections out of the 
total number of planned injections. 
x  Number and percentage of participants in the following overall compliance categories: 
<80%, and ≥80%. 
All study drug administration data will be listed by site (study center) and participant number. 
6.7 
Biomarker and Noninvasive Test Analysis 
The measurements of biomarkers and noninvasive tests collected at each scheduled visit will be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and maximum). In 
addition, the change from baseline (including percent change from baseline for Pro-C3 and ELF) 
will be summarized descriptively for all postbaseline visits.  
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6.7.1 
Secondary Endpoints Analysis 
6.7.1.1 
Main Analysis Approach 
The secondary endpoint analysis for Pro-C3 and ELF, which are collected at multiple 
postbaseline visits, will be performed on the FAS. The percent change from baseline for these 
two biomarkers will be analyzed using a mixed effects model for repeated measure (MMRM) 
with visit as the fixed effect, participants as the random effect, and the baseline values as 
covariates. Least-square means (LS means) of the percent change from baseline at Week 24 
along with the corresponding 95% CIs will be presented for Pro-C3 and ELF. Line chart of LS 
mean percent change from baseline over time obtained from the MMRM model may be 
displayed. 
For the MMRM, an unstructured covariance structure will be used to model the within-
participant errors. If the model fails to converge, the following changes will be applied in order: 
x The model will be fitted using covariance matrices in the following order: heterogenous 
first order autoregressive (ARH1), homogenous first order autoregressive (AR1), 
heterogenous compound symmetry (CSH), and compound symmetry (CS). 
x If the model still fails to converge, the percent change from baseline at Week 24 for Pro-
C3 and ELF will be summarized descriptively. 
The secondary endpoint analysis for liver cT1 MRI, which is collected at one postbaseline visit 
(Week 24), will be performed using participants from the FAS who have non-missing 
measurements of liver cT1 MRI at baseline and Week 24. No imputation will be carried out for 
missing measurements of liver cT1 MRI. The change from baseline at Week 24 for this 
biomarker will be summarized descriptively. 
Distributional assumptions underlying the model will be assessed by visual inspection of residual 
plots. The assumption of normality will be assessed by examination of the normal probability 
plot. The assumption of homogeneity of variance will be assessed by plotting the residuals 
versus the predicted values from the model. If assumptions appear to be violated, the biomarker 
data at each visit will be summarized descriptively. 
6.7.1.2 
Supplementary Analysis 
If the PPAS is different from the FAS, the main analysis approach for secondary endpoints 
described in Section 5.7.2.1 will be repeated on the PPAS to evaluate the robustness of key 
biomarker results. 
6.7.2 
Exploratory Endpoints Analysis 
The exploratory endpoint analysis will be performed separately for each of the following 
biomarkers using participants from the FAS in fibrosis stages F1/F2/F3 and overall who have 
non-missing measurements of the biomarker at baseline and Week 24: 
x Liver chemistry panel (ALT, AST, ALP, and TBL). 
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x Fibrosis markers (LSM, FIB-4, and FAST score). 
The mean observed change from baseline at Week 24 will be summarized descriptively for 
fibrosis stages F1/F2/F3 and overall. 
Exploratory biomarkers listed in Section 1.2.3 but not included in the exploratory endpoint 
analysis will not be included in the clinical study report (CSR) but analyzed and reported 
separately. The details of such analysis may be described in the Biomarker Analysis Plan as 
appropriate. 
6.7.3 
Subgroup Analyses  
Subgroup analyses of all secondary endpoints will be performed on the FAS by fibrosis stage 
(F1/F2/F3 vs overall) and summarized descriptively. Tabulations and forest plots will be 
generated to display the results of each analysis. 
6.8 
Safety Analysis 
All safety analysis will be performed using the safety analysis set. 
Clinical laboratory test results, vital signs, body weight, and ECG findings will be summarized 
by visit. Potentially clinically significant findings will also be summarized or listed. 
Antidrug antibody data will be summarized by visit. 
6.8.1 
Adverse Events 
AEs will be coded using the MedDRA (version 25.0 or higher). 
TEAEs are defined as AEs or serious adverse events (SAEs) that started or worsened in either 
intensity or frequency after receiving study drug (AE start date ≥ first dose date). Partial or fully 
missing AE dates will be imputed as defined in Appendix B.  
TEAEs will be summarized by giving the number and percentage of participants reporting any 
event for each term. The following summaries will be presented: 
x Overview of TEAEs. 
x TEAEs by SOC and PT. 
x TEAEs by severity, SOC, and PT. 
x TEAEs by relationship to the study drug, SOC, and PT. 
x Treatment-related TEAEs by SOC and PT. 
x TEAEs leading to study drug discontinuation by SOC and PT. 
x Treatment-related TEAEs leading to study drug discontinuation by SOC and PT. 
x Treatment-emergent SAEs by SOC and PT. 
x Treatment-emergent SAEs by severity, SOC, and PT. 
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x Treatment-emergent SAEs by relationship to study drug, SOC, and PT. 
x Most frequent TEAEs (≥5%) by PT (in descending order) 
SOCs will be sorted by alphabetical order. Within a SOC, PTs will be sorted in descending order 
based on the total number of participants with AEs. For each category and overall, participants 
reporting more than 1 occurrence for a term (SOC or PT) being summarized will be counted only 
once using the most extreme incident (most severe for intensity tables and related for the 
relationship to study drug tables). AEs with missing severity will be classified as having the 
highest severity and AEs with missing relationship will be classified as having the highest 
relationship to study drug. 
Data listings will be provided for all TEAEs, treatment-related TEAEs, TEAEs leading to study 
drug discontinuation, SAEs, and AEs that resulted in death. 
6.8.2 
Adverse Events of Special Interest 
An AESI (serious or nonserious) is one of scientific and medical concern specific to the 
compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. AESIs will be reported by the investigators as part of 
the AE reporting process. 
Adverse events of special interest in this study include potential hypersensitivity, serum sickness, 
vasculitis, Arthus reactions to ontamalimab, and PML. Participants will be monitored for the 
presence of Type I (anaphylaxis) and Type III (immune complex) hypersensitivity reactions at 
the time points specified in the Section 1.3 of the protocol. The following summaries of AESIs 
will be presented: 
x Overview of AESIs. 
x AESIs by SOC and PT. 
A listing of all AESIs will be provided. 
6.8.3 
Clinical Laboratory Assessments 
Clinical laboratory assessments that will be performed for the study are listed in Section 10.2 of 
the protocol. 
The observed value and change from baseline in clinical laboratory assessments will be 
summarized descriptively by visit. 
The number and percentage of participants with clinically significant laboratory values, as 
defined in Appendix C, will be summarized for each visit. 
A listing of all laboratory data will be provided in standard units. Laboratory data outside of the 
normal reference range will be indicated in the listing. 
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6.8.4 
Vital Signs and Weight 
Vital sign measurements (body temperature [°C], respiratory rate [breaths/min], sitting blood 
pressure [mmHg], and pulse rate [beats/min]) and body weight (kg) will be collected before the 
collection of blood samples for laboratory assessments, where applicable. 
The observed value and change from baseline in vital sign measurements and weight will be 
summarized descriptively by visit. 
The number and percentage of participants with clinically significant vital sign and weight 
values, as defined in Appendix C, will be summarized for each visit. 
A listing of all vital sign and weight data will be provided. 
6.8.5 
12-Lead ECGs 
A local ECG reader will be used in this study. The investigator’s ECG interpretation (i.e., within 
normal limits, abnormal but not clinically significant, abnormal and clinically significant, or not 
evaluable) will be summarized by visit. 
A listing of all ECG data will be provided. 
6.9 
Pharmacokinetic Analyses 
The PK analysis set will be used for all PK analyses. 
PK samples will be collected at predose on Day 1 and predose at Weeks 4, 8, 12, 16, 20, and 24 
during the treatment period, and approximately 1 week after the dose on Day 1. PK 
concentrations of ontamalimab over the sampling time will be descriptively summarized and 
graphed. 
A listing of all PK concentrations will be provided. 
6.10 
Interim Analyses 
No interim analysis is planned. 
6.11 
Other Committees 
An internal group (independent from the study team) will review the overall safety of the study 
participants on an ongoing basis. This review will consist of monitoring of safety of participants 
throughout the study. Recommendations made on the basis of this review to alter the conduct of 
the study or amend the protocol will be provided to the study team for review and for a final 
decision. The sponsor or its designee will notify investigative sites, and regulatory authorities as 
appropriate, of recommendations based on this review. Details regarding this review and the 
frequency of this review will be established in a separate charter before the administration of 
study drug to any participant. In addition, this internal group will be responsible for: 
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x Evaluating safety and tolerability data from the first four noncirrhotic (F1-F3) participants 
who have received at least 3 doses of ontamalimab 75 mg and have been monitored for at 
least 12 weeks, to support the decision to include F4cc participants in the study. 
x Engaging with an independent panel of experts to evaluate any liver-related events (eg, 
liver decompensation, significant deterioration of liver chemistry tests). 
x Monitoring neurological safety and consulting a panel of leading progressive multifocal 
leukoencephalopathy (PML) experts, including a neurologist, neuroradiologist, and a 
virologist, in the event of a suspected case of PML (see Section 8.3.2 of the protocol). 
6.12 
Changes to Protocol Planned Analysis 
The change from baseline at Week 24, in fibrosis stages F1/F2/F3 and overall, for cT1 MRI and 
exploratory endpoints will be summarized descriptively instead of analyzed using MMRM. This 
was simplified to fit the exploratory nature of these endpoints. 
7.0 
REFERENCES 
1. Anstee, Q. M., Hallsworth, K., Lynch, N., Hauvespre, A., Mansour, E., Kozma, S., et al.
2022. Real-world management of non-alcoholic steatohepatitis differs from clinical practice
guideline recommendations and across regions. JHEP Rep, 4(1), 100411.
2. Harrison, S. A., Dennis, A., Fiore, M. M., Kelly, M. D., Kelly, C. J., Paredes, A. H., et al.
2018. Utility and variability of three non-invasive liver fibrosis imaging modalities to
evaluate efficacy of GR-MD-02 in participants with NASH and bridging fibrosis during a
phase-2 randomized clinical trial. PLoS One, 13(9), e0203054.
3. Jabor, A., Kubíček, Z., Fraňková, S., Šenkeříková, R. and Franeková, J. 2018. Enhanced liver
fibrosis (ELF) score: Reference ranges, biological variation in healthy participants, and
analytical considerations. Clin Chim Acta, 483, 291-5.
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8.0 
APPENDIX 
8.1 
Changes From the Previous Version of the Statistical Analysis Plan (SAP) 
x Removed liver biopsy, HepQuant, and MAdCAM1 assessments at the end of treatment and associated exploratory 
objectives/endpoints. 
x Changed subgroup analyses for secondary and exploratory endpoints to F1/F2/F3 vs overall to prevent lack of model 
convergence due to small subgroups. 
x Added additional AESI to match Protocol Amendment 3. 
8.2 
Appendix A - Definition of Analysis Visit Windows 
Table 7.2.a 
Analysis Visit Window for Key Biomarkers 
Visit 
Scheduled Day 
Pro-C3 
ELF 
Abdominal MRI 
Baseline (Part 1) 
Day -7 
NA 
NA 
≤1 
Baseline (Part 2) 
Day 1 
1 
1 
NA 
Week 1 
Day 8 
[2, 18] 
[2, 18] 
NA 
Week 4 
Day 29 
[19, 43] 
[19, 43] 
NA 
Week 8 
Day 57 
[44, 71] 
[44, 71] 
NA 
Week 12 
Day 85 
[72, 99] 
[72, 99] 
NA 
Week 16 
Day 113 
[100, 127] 
[100, 127] 
NA 
Week 20 
Day 141 
[128, 155] 
[128, 155] 
NA 
Week 24 
Day 169 
[156, 211] 
[156, 211] 
≥85 
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Week 28 
Day 197 
NA 
NA 
NA 
Week 32 
Day 225 
NA 
NA 
NA 
Week 36 
Day 253 
≥212 
≥212 
NA 
 
 
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Table 7.2.b 
Analysis Visit Window for Exploratory Biomarkers 
Visit 
Scheduled Day 
Soluble 
MAdCAM-1, 
Liver 
chemistrya 
Liver biopsyb 
HepQuant-
SHUNT DSI, 
Child-Pugh 
score, MELD 
score 
hsCRP, 
calprotectin  
LSM, CAP, 
Agile 4 score, 
FAST score, 
FIB-4 score 
Immunogenicityc 
Baseline (Part 1) 
Day -7 
NA 
NA 
NA 
NA 
NA 
NA 
Baseline (Part 2) 
Day 1 
1 
NA 
1 
1 
1 
1 
Week 1 
Day 8 
[2, 18] 
NA 
NA 
NA 
NA 
NA 
Week 4 
Day 29 
[19, 43] 
NA 
NA 
[2, 43] 
NA 
NA 
Week 8 
Day 57 
[44, 71] 
NA 
NA 
[44, 71] 
NA 
NA 
Week 12 
Day 85 
[72, 99] 
NA 
NA 
[72, 99] 
[2, 127] 
[2, 127] 
Week 16 
Day 113 
[100, 127] 
NA 
NA 
[100, 127] 
NA 
NA 
Week 20 
Day 141 
[128, 155] 
NA 
NA 
[128, 155] 
NA 
NA 
Week 24 
Day 169 
[156, 211] 
≥85 
≥85 
[156, 211] 
≥128 
[128, 183] 
Week 28 
Day 197 
NA 
NA 
NA 
NA 
NA 
[184, 211] 
Week 32 
Day 225 
NA 
NA 
NA 
NA 
NA 
[212, 239] 
Week 36 
Day 253 
≥212 
NA 
NA 
≥212 
NA 
≥240 
a Liver chemistry includes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total 
bilirubin (TBL). 
b Baseline liver biopsy is collected during screening. 
c Immunogenicity includes antidrug antibodies (ADA). 
 
 
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Table 7.2.c 
Analysis Visit Window for Safety Assessments 
Visit 
Scheduled Day 
Vital signs, body 
weight 
12-lead ECG 
Laboratory testsa 
Baseline (Part 1) 
Day -7 
NA 
NA 
NA 
Baseline (Part 2) 
Day 1 
1 
1 
1 
Week 1 
Day 8 
NA 
NA 
[2, 18] 
Week 4 
Day 29 
[2, 43] 
NA 
[19, 43] 
Week 8 
Day 57 
[44, 71] 
NA 
[44, 71] 
Week 12 
Day 85 
[72, 99] 
NA 
[72, 99] 
Week 16 
Day 113 
[100, 127] 
NA 
[100, 127] 
Week 20 
Day 141 
[128, 155] 
NA 
[128, 155] 
Week 24 
Day 169 
[156, 183] 
≥85 
[156, 211] 
Week 28 
Day 197 
[184, 211] 
NA 
NA 
Week 32 
Day 225 
[212, 239] 
NA 
NA 
Week 36 
Day 253 
≥240 
NA 
≥212 
a Laboratory tests includes clinical chemistry and hematology tests. 
 
 
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Statistical Analysis Plan 
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8.3 
Appendix B - Missing/Partial Dates for Adverse Event/Concomitant Medication 
Missing data imputation for start dates: 
If the stop date is non-missing and the imputed start date is after the stop date, the stop date will 
be used as the start date. 
(1) Missing day only 
x If the month and year are the same as the month and year of the first dose date, the first 
dose date will be used. 
x If the month and year are before the month and year of the first dose date, the last day of 
the month will be assigned to the missing day. 
x If the month and year are after the month and year of the first dose date, the first day of 
the month will be assigned to the missing day. 
(2) Missing day and month 
x If the year is the same as the year of the first dose date, the first dose date will be used. 
x If the year is prior to the year of the first dose date, December 31st will be assigned to the 
missing fields. 
x If the year is after the year of the first dose date, January 1st will be assigned to the 
missing fields. 
(3) Missing day, month, and year 
x The first dose date will be used. 
Missing data imputation for stop dates: 
If the start date is non-missing and the imputed stop date is before the start date, the start date 
will be used. If the death date is available and the imputed stop date is after the death date, the 
death date will be used. 
(1) Missing day only 
x The last day of the month will be assigned as the missing day. 
(2) Missing day and month 
x December 31st will be assigned to the missing fields. 
(3) Missing day, month, and year 
x Th event will be regarded as ongoing. 
 
 
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Statistical Analysis Plan 
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CONFIDENTIAL 
8.4 
Appendix C – Criteria for Clinically Significant Values 
Table 7.4.a 
Hematology - Criteria for Clinically Significant Values 
Parameter 
Unit 
Low Abnormal 
High Abnormal 
Hemoglobin 
Both 
<0.8 × LLN 
>1.2 × ULN 
Hematocrit 
Both 
<0.8 × LLN 
>1.2 × ULN 
RBC count 
Both 
<0.8 × LLN 
>1.2 × ULN 
WBC count 
Both 
<0.5 × LLN 
>1.5 × ULN 
Platelet count 
Conventional 
SI 
<75 × 103/μL 
<75 × 109/L 
>600 × 103/μL 
>600 × 109/L 
LLN=lower limit of normal, ULN=upper limit of normal, RBC=red blood cell, WBC=white blood cell. 
 
Table 7.4.b 
Clinical Chemistry - Criteria for Clinically Significant Values 
Parameter 
Unit 
Low Abnormal 
High Abnormal 
ALT 
Both 
-- 
>3 × ULN 
AST 
Both 
-- 
>3 × ULN 
GGT 
Both 
-- 
>3 × ULN if baseline 
is normal; >2 × 
baseline if baseline is 
high abnormal 
Alkaline phosphatase 
Both 
-- 
>3 × ULN if baseline 
is normal; >2 × 
baseline if baseline is 
high abnormal 
Calcium  
Conventional 
SI 
<7.0 mg/dL 
<1.75 mmol/L 
>11.5 mg/dL 
>2.88 mmol/L 
Chloride 
Conventional 
SI 
< 75 mEq/L 
<75 mmol/L 
>126 mEq/L 
>126 mmol/L 
Total bilirubin 
Both 
-- 
>1.5 × ULN if 
baseline is 
normal, >1.5 × 
baseline if baseline is 
high abnormal 
Albumin 
Conventional 
SI 
<2.5 g/dL 
<25 g/L 
-- 
-- 
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Statistical Analysis Plan 
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CONFIDENTIAL 
Total protein 
Both 
<0.8 × LLN 
>1.2 × ULN 
Creatinine 
Conventional 
SI 
-- 
-- 
>2.0 mg/dL 
>177 μmol/L 
Blood urea nitrogen 
Conventional 
SI 
-- 
-- 
>30 mg/dL 
>10.7 mmol/L 
Sodium 
Conventional 
SI 
<130 mEq/L 
<130 mmol/L 
>150 mEq/L 
>150 mmol/L 
Potassium 
Conventional 
SI 
<3.0 mEq/L 
<3.0 mmol/L 
>5.5 mEq/L 
>5.5 mmol/L 
Glucose 
Conventional 
SI 
<50 mg/dL 
<2.8 mmol/L 
>180 mg/dL 
>10 mmol/L 
Bicarbonate 
Conventional 
SI 
<8.0 mEq/L 
<8.0 mmol/L 
-- 
-- 
Creatine kinase 
Both 
-- 
>ULN – 2.5 × ULN 
Total cholesterol 
Conventional 
SI 
-- 
-- 
>300 mg/dL 
>7.72 mmol/L 
INR 
Both 
-- 
>1.5 × ULN 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=γ-glutamyl transferase, 
LLN=lower limit of normal, ULN=upper limit of normal. 
 
Table 7.4.c 
Vital Signs and Body Weight - Criteria for Clinically Significant Values 
Parameter 
Unit 
Lower Criteria 
Upper Criteria 
Respiratory rate 
breaths/min 
<12 
>25 
Pulse 
bpm 
<50 
>120 
Systolic blood 
pressure 
mmHg 
<85 
>180 
Diastolic blood 
pressure 
mmHg 
<50 
>110 
Body temperature 
°C 
<35.6 
>37.7 
Body weight 
kg 
Change of ≥7% body weight 
 
 
 
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