Clinical trial NCT03757130
Conditions: Obesity
Sponsor: Amgen
Start date: 2018-11-26; Completion date: 2019-12-16
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main objective of this study is to assess the safety and tolerability of multiple doses of AMG 598 administered alone or in combination with liraglutide in adults with obesity.

Detailed description:

Arms: arm 1: Participants received placebo subcutaneous injection once every 4 weeks (Q4W) for a total of 3 doses. arm 2: Participants received placebo subcutaneous injection once every 4 weeks for a total of 3 doses in addition to liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5. arm 3: Participants received 70 mg AMG 598 by subcutaneous injection once every 4 weeks (Q4W) for a total of 3 doses. arm 4: Participants received 70 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses in addition liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5. arm 5: Participants received 210 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses. arm 6: Participants received 210 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses in addition to liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5. arm 7: Participants received 420 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses. arm 8: Participants received 420 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses in addition to liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5.
Interventions: intervention 1: AMG 598 intervention 2: Placebo intervention 3: Liraglutide
Intervention descriptions: intervention 1: AMG 598 administered by subcutaneous injection intervention 2: Placebo matching to AMG 598 administered by subcutaneous injection intervention 3: Liraglutide administered by subcutaneous injection. The starting dose is 0.6 mg/day, and increased by 0.6 mg/day dose increment every 7 days, up to the full dosage of 3.0 mg/day by week 5.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 1 of 111
CONFIDENTIAL
Title Page
Protocol Title:
A Phase 1b, Randomized, Double-blind, 
Placebo-controlled, Multiple Ascending Dose 
Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of 
AMG 598 in Subjects With Obesity
Short Protocol Title:
Multiple Ascending Dose Study of AMG 598 in 
Subjects with Obesity
Protocol Number:
20170139
Investigational Product:
AMG 598
Trade Name:
NA
Sponsor
Name of Sponsor:
Amgen, Inc.
Address:
One Amgen Center Drive
Telephone Number:
805-447-1000
Protocol 
Approver
Name:
Function:
Medical Director, Translational Medicine
Key 
Sponsor 
Contact
Name:
Address:
One Amgen Center Drive
Telephone Number:
Email Address:
EudraCT Number:
Enter EudraCT Number
NCT Number:
NCT03757130
Protocol Date:
Document Version
Date
Original
20 September 2018
Amendment 1
07 November 2018
Amendment 2
15 February 2019
Amendment 3
25 June 2019
Version/Date:
Data Element Standards Version
6.1
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 2 of 111
CONFIDENTIAL
Confidentiality Notice
This document contains confidential information of Amgen Inc.
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent.
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc.
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 3 of 111
CONFIDENTIAL
Investigator’s Agreement:
I have read the attached protocol entitled A Phase 1b, Randomized, Double-blind, 
Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 598 in Subjects 
With Obesity, dated 25 June 2019, and agree to abide by all provisions set forth 
therein.  
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status.
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.
_______________________________
Signature
_______________________________
____________________________
Name of Investigator
Date (DD Month YYYY)
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 4 of 111
CONFIDENTIAL
Table of Contents
Table of Contents ...................................................................................................4
1.
Protocol Synopsis...................................................................................................9
2.
Study Schema and Schedule of Activities.............................................................16
2.1
Study Schema...........................................................................................16
2.2
Schedule of Activities................................................................................17
3.
Introduction...........................................................................................................23
3.1
Study Rationale.........................................................................................23
3.2
Background...............................................................................................23
3.2.1
Disease .....................................................................................23
3.2.2
Amgen Investigational Product Background:  
AMG 598...................................................................................25
3.2.2.1
Pharmacology .........................................................25
3.2.2.2
Pharmacokinetics....................................................26
3.2.2.3
Toxicology...............................................................26
3.2.2.4
Reproductive and Developmental Toxicity...............28
3.2.2.5
Clinical Experience..................................................29
3.2.3
Non-Amgen Non-investigational Product Background:  
Liraglutide (Saxenda®)...............................................................29
3.3
Benefit/Risk Assessment...........................................................................30
3.3.1
Therapeutic Context ..................................................................30
3.3.2
Key Benefits ..............................................................................30
3.3.3
Key Risks ..................................................................................30
3.3.3.1
Risks .......................................................................31
4.
Objectives, Endpoints and Hypotheses.................................................................33
4.1
Objectives and Endpoints..........................................................................33
4.2
Hypotheses...............................................................................................34
5.
Study Design ........................................................................................................34
5.1
Overall Design ..........................................................................................34
5.2
Number of Subjects...................................................................................35
5.2.1
Replacement of Subjects...........................................................35
5.2.2
Number of Sites.........................................................................35
5.3
End of Study .............................................................................................35
5.3.1
End of Study Definition..............................................................35
5.3.2
Study Duration for Subjects.......................................................36
5.4
Justification for Investigational Product Dose ............................................36
5.5
Patient Input on Study Design...................................................................37
6.
Study Population...................................................................................................37
6.1
Inclusion Criteria:  Part 1...........................................................................37
6.2
Exclusion Criteria:  Part 1..........................................................................38
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 5 of 111
CONFIDENTIAL
6.3
Inclusion Criteria Part 2 (Cohort 7 only).....................................................42
6.4
Exclusion Criteria Part 2 (Cohort 7 only)....................................................42
6.5
Lifestyle Restrictions .................................................................................42
6.5.1
Meals and Dietary Restrictions ..................................................42
6.5.1.1
Mixed Meal Tolerance Test (MMTT)........................42
6.5.2
Caffeine, Alcohol, and Tobacco.................................................43
6.5.3
Activity.......................................................................................43
6.6
Subject Enrollment....................................................................................43
6.7
Screen Failures.........................................................................................44
7.
Treatments ...........................................................................................................44
7.1
Treatment Procedures...............................................................................45
7.1.1
Investigational Products ............................................................45
7.1.2
Non-investigational Products.....................................................45
7.1.3
Medical Devices ........................................................................46
7.1.4
Other Protocol-required Therapies ............................................46
7.1.5
Other Treatment Procedures.....................................................46
7.1.6
Product Complaints ...................................................................46
7.1.7
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ...............................................47
7.2
Method of Treatment Assignment .............................................................47
7.3
Blinding.....................................................................................................48
7.3.1
Site Personnel Access to Individual Treatment 
Assignments..............................................................................48
7.3.2
Access to Individual Subject Treatment Assignments 
by Amgen or Designees............................................................48
7.4
Dose Modification......................................................................................49
7.4.1
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules..........................................................................49
7.4.2
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation .....................................50
7.4.2.1
Amgen Investigational Product:  AMG 598..............50
7.4.2.2
Non-Amgen Non-investigational Product:  
Liraglutide (Saxenda®).............................................51
7.4.3
Hepatotoxicity Stopping and Rechallenge Rules .......................52
7.5
Preparation/Handling/Storage/Accountability ............................................52
7.6
Treatment Compliance..............................................................................52
7.7
Treatment of Overdose .............................................................................52
7.8
Prior and Concomitant Treatment .............................................................52
7.8.1
Prior Treatment .........................................................................52
7.8.2
Concomitant Treatment.............................................................52
8.
Discontinuation Criteria.........................................................................................53
8.1
Discontinuation of Study Treatment...........................................................53
8.2
Discontinuation From the Study ................................................................54
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 6 of 111
CONFIDENTIAL
8.2.1
Reasons for Removal From Run In ...........................................54
8.2.2
Reasons for Removal From Study.............................................55
8.3
Lost to Follow-up.......................................................................................55
9.
Study Assessments and Procedures ....................................................................55
9.1
General Study Periods ..............................................................................56
9.1.1
Screening, Enrollment and/or Randomization............................56
9.1.2
Treatment Period and Follow up................................................57
9.1.3
End of Study..............................................................................57
9.2
Description of General Study Assessments and Procedures.....................57
9.2.1
General Assessments ...............................................................57
9.2.1.1
Informed Consent....................................................57
9.2.1.2
Demographics.........................................................57
9.2.1.3
Medical History........................................................58
9.2.1.4
Physical Examination ..............................................58
9.2.1.5
Physical Measurements ..........................................58
9.2.1.6
Substance Abuse History ........................................58
9.2.2
Efficacy Assessments................................................................58
9.2.3
Safety Assessments..................................................................58
9.2.3.1
Adverse Events.......................................................59
9.2.3.2
Pregnancy and Lactation.........................................61
9.2.3.3
Vital Signs...............................................................61
9.2.3.4
Electrocardiograms (ECGs).....................................61
9.2.3.5
Vital Status..............................................................62
9.2.3.6
Suicidal Risk Monitoring..........................................62
9.2.4
Clinical Laboratory Assessments...............................................62
9.2.4.1
Pregnancy Testing ..................................................63
9.2.5
Biomarker Assessments............................................................63
9.2.6
Pharmacokinetic Assessments..................................................63
9.2.7
Pharmacodynamic Assessments...............................................64
9.2.8
Pharmacogenetic Assessments.................................................64
9.2.9
Antibody Testing Procedures.....................................................64
9.2.10
Biomarker Development............................................................65
9.2.11
Health Economics......................................................................65
9.2.12
Optional Substudies ..................................................................65
9.2.13
Other Assessments ...................................................................65
10.
Statistical Considerations......................................................................................66
10.1
Sample Size Determination.......................................................................66
10.2
Analysis Sets, Subgroups, and Covariates................................................66
10.2.1
Analysis Sets.............................................................................66
10.2.1.1
Safety Analysis Set .................................................66
10.2.1.2
Pharmacokinetic (PK) Analysis Set .........................66
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 7 of 111
CONFIDENTIAL
10.2.1.3
Pharmacodynamic (PD) Analysis Set......................66
10.2.2
Covariates.................................................................................66
10.2.3
Subgroups.................................................................................66
10.2.4
Handling of Missing and Incomplete Data..................................66
10.3
Statistical Analyses ...................................................................................67
10.3.1
Planned Analyses......................................................................67
10.3.1.1
Interim Analysis and Early Stopping
Guidelines...............................................................67
10.3.1.2
Primary Analysis .....................................................67
10.3.1.3
Final Analysis..........................................................67
10.3.2
Methods of Analyses .................................................................67
10.3.2.1
General Considerations...........................................67
10.3.2.2
Efficacy Analyses....................................................67
10.3.2.3
Safety Analyses ......................................................68
10.3.2.4
Other Analyses........................................................69
11.
References ...........................................................................................................71
12.
Appendices...........................................................................................................74
12.1
Appendix 1.  List of Abbreviations and Definitions of Terms......................75
12.2
Appendix 2.  Clinical Laboratory Tests ......................................................77
12.3
Appendix 3.  Study Governance Considerations .......................................79
12.4
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting.......................................87
12.5
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information........................................................95
12.6
Appendix 6.  Sample Storage and Destruction........................................101
12.7
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments....................................................................103
12.7.1
Drug-induced Liver Injury Reporting and Additional 
Assessments...........................................................................104
12.8
Appendix 8.  Mental Health Criteria Stopping Rules: Suggested
Actions and Follow-up Assessments.......................................................107
12.9
Appendix 9.  Columbia Suicide Severity Rating Scale.............................108
12.10 Appendix 10.  Patient Health Questionnaire 9 (PHQ-9)...........................111
List of Tables
Table 2-1.  Schedule of Activities for Cohorts 1, 3 and 5 ...............................................17
Table 2-2.  Schedule of Activities for Cohorts 2, 4 and 6 ...............................................20
Table 2-3.  Schedule of Activities for Cohort 7...............................................................22
Table 3-1.  Liraglutide (Saxenda®) Dose Escalation Schedule.......................................29
Table 5-1.  Estimated Exposure Margins of AMG 598 for Multiple Doses 
(Q4W).....................................................................................................37
Table 7-1.  Study Treatments ........................................................................................45
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 8 of 111
CONFIDENTIAL
Table 7-2.  Cohort Dose Stopping Rules .......................................................................51
Table 12-1.  Analyte Listing ...........................................................................................77
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................104
Table 12-3.  Conditions for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies 
Due to Changes in Mental Health Scores .............................................107
List of Figures
Figure 2-1.  Study Schema............................................................................................16
Figure 12-1.  Sample Serious Adverse Event Report Form ...........................................92
Figure 12-2.  Pregnancy and Lactation Notification Worksheet......................................99
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 9 of 111
CONFIDENTIAL
1.
Protocol Synopsis
Protocol Title:  A Phase 1b, Randomized, Double-blind, Placebo-controlled, 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 598 in Subjects With Obesity
Short Protocol Title:  Multiple Ascending Dose Study of AMG 598 in Subjects with 
Obesity
Study Phase:  1
Indication:  Obesity
Rationale
The current study evaluates the safety, tolerability, pharmacokinetics (PK), and
pharmacodynamics (PD) of multiple ascending doses of AMG 598 alone, and in 
combination with liraglutide, as a potential weight loss therapy.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To assess the safety and tolerability of multiple 
subcutaneous (SC) doses of AMG 598 
administered alone or in combination with 
liraglutide in subjects with obesity

Subject incidence of 
treatment-emergent adverse events

Safety laboratory data, vital signs, and 
electrocardiograms (ECGs)
Secondary

To characterize the PK of multiple SC doses of 
AMG 598 administered alone or in combination 
with liraglutide in subjects with obesity

AMG 598 PK parameters may include, but are 
not limited to, maximum observed 
concentration (Cmax), time of maximum 
observed concentration (tmax), and area under 
the concentration time curve (AUC) 
Exploratory

To characterize the PD effects of AMG 598 
PD parameters: 
o
Concentrations of fasting glucose, insulin, 
c-peptide, glucose dependent 
insulinotropic polypeptide (GIP), 
glucagon-like polypeptide type 1 (GLP-1), 
glucagon, and free fatty acid (FFA)
o
Concentration-time profiles and AUC for 
metabolic parameters following a mixed 
meal tolerance test (MMTT)
o
Lipid levels, including but not limited to,
total cholesterol, low density lipoprotein
cholesterol (LDL-C), high density 
lipoprotein cholesterol 
(HDL-C), and triglycerides
o
Hemoglobin A1c (HbA1c)
o
Potential biomarkers including, but not 
limited to inflammatory and adipose tissue 
markers
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 10 of 111
CONFIDENTIAL
Objectives
Endpoints
Exploratory (continued)

To assess the effects of AMG 598 on body 
weight, waist circumference and body mass 
index (BMI)

Change in body weight, waist circumference, 
and BMI

To assess the effect of AMG 598 on bone 
mineral density by dual energy x-ray 
absorptiometry (DXA) (cohorts 1-6)

Changes in bone mineral density as measured 
by DXA (cohorts 1-6)

To assess the effect of AMG 598 on body 
composition (cohort 7)

Changes in body composition as measured by 
whole body DXA (cohort 7)

To evaluate the immunogenicity of AMG 598

Incidence of anti-AMG 598 antibody formation
Hypotheses

AMG 598 will be safe and well tolerated following multiple SC dose administrations in 
subjects with obesity across the dose range evaluated

AMG 598 in combination with liraglutide will be safe and well tolerated following 
multiple SC dose administrations in subjects with obesity across the dose range 
evaluated

AMG 598 PK profile following multiple SC dose administrations will support selection 
of dose and frequency of administration in future multi-dose trials of AMG 598
Overall Design
This is a randomized, placebo-controlled, double-blind, multiple ascending dose study in 
subjects with obesity. The study consists of a total of 7 cohorts; 3 cohorts (1, 3 and 5) 
with administration of AMG 598 or matching placebo SC every 4 weeks (Q4W) x3,
3 cohorts (2, 4 and 6) with Q4W x3 SC administration of AMG 598 or matching placebo 
in combination with liraglutide SC once daily (QD) ascending doses, and 1 cohort 
(cohort 7) with SC administration of AMG 598 or matching placebo SC Q4W x3 in 
addition to liraglutide (3.0 mg SC QD) in subjects who have been on a stable dose of 
liraglutide (3.0 mg SC QD) for at least 6 months or more. In cohorts 1-6, 
eight (8) subjects will be randomized to receive AMG 598 or placebo SC in a 3:1 ratio as 
described in the table below. In cohort 7, sixty (60) subjects will be randomized in a 
1:1 ratio to receive AMG 598 or placebo SC as described in the table below.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 11 of 111
CONFIDENTIAL
Planned Dose Levels by Cohort
Cohort
# 
Subjects
Product
Dose/ Frequency
Route
N (active:
placebo)
1
8
AMG 598/Placebo
70 mg Q4W x 3
SC
6:2
2
8
AMG 598/Placebo 
+
Liraglutide
70 mg Q4W x 3
+
0.6, 1.2, 1.8, 2.4, 3.0 mg 
QDa
SC
SC
6:2
3
8
AMG 598/Placebo
210 mg Q4W x 3
SC
6:2
4
8
AMG 598/Placebo
+ 
Liraglutide
210 mg Q4W x 3
+
0.6, 1.2, 1.8, 2.4, 3.0 mg 
QDa
SC
SC
6:2
5
8
AMG 598/Placebo
420 mg Q4W x 3
SC
6:2
6
8
AMG 598/Placebo
+ 
Liraglutide
420 mg Q4W x 3
+
0.6, 1.2, 1.8, 2.4, 3.0 mg 
QDa
SC
SC
6:2
7
60
AMG 598/Placebo
+
Liraglutide
420 mg Q4W x 3
+
3.0 mg QDb
SC
30:30
a Subjects will start the first dose of liraglutide (0.6 mg, SC QD) on day 1, and increase the dose of liraglutide 
by 0.6 mg dose increment every 7 days, up to the full dosage of 3.0 mg by week 5 and remain on 3.0 mg 
until day 84, inclusive
b Subjects eligible for the study will have been on a stable dose of liraglutide 3.0 mg SC QD for at least 
6 months and will continue liraglutide 3.0 mg SC QD throughout the screening and study period from study 
days -56 to end of study (EOS) (day 207) 
A dose level review meeting (DLRM) will be held to review the data and monitor safety 
before escalation to the next higher dose or expansion to the liraglutide combination 
cohort. The DLRM members will be composed of, at minimum, the investigator(s) 
actively enrolling subjects (whether in screening or enrolled) at the time of the meeting, 
the Amgen Medical Monitor, and Amgen Global Safety Officer or designee, and 
Amgen Study Manager or designee. Additional members may be added as needed 
(eg, PK/biomarker scientist, Biostatistician, or others providing expanded expertise).  
The DLRM voting members include the principal investigator(s) or designee, Amgen 
Medical Monitor and Amgen Global Safety Officer or designee. 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
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CONFIDENTIAL
Escalation to a higher dose cohort or expansion to liraglutide combination cohorts will 
only proceed when the previous dose regimen has been found to be safe and 
reasonably tolerated based on available safety and laboratory data through day 36 for a
minimum of 6 of the 8 subjects dosed, and upon unanimous recommendation at the 
Dose Level Review Meeting (DLRM). The planned dose escalation schedule may be 
modified based on treatment-emergent data (safety and/or PK). Dose adjustments (if 
any) will be made on a treatment cohort and not on an individual subject basis and will 
be agreed upon by Amgen in conjunction with the Principal Investigator. Clear stopping 
rules will be followed, and ad hoc DLRMs will be held, if necessary.
Enrollment can be initiated in the subsequent cohorts after the planned DLRMs. The 
DLRMs will take place at the following time points:
DLRM #1: After a minimum of 6 out of 8 subjects dosed in cohort 1 complete study
day 36.  Enrollment in cohorts 2 and 3 can be initiated after DLRM #1.
DLRM #2: After a minimum of 6 out of 8 subjects dosed in each cohort 2 and 3 complete
study day 36.  Enrollment in cohorts 4 and 5 can be initiated after DLRM #2.
DLRM #3: After a minimum of 6 out of 8 subjects dosed in each cohort 4 and 5 complete
study day 36.  Enrollment in cohort 6 can be initiated after DLRM #3.
DLRM #4: After a minimum of 6 out of 8 subjects dosed in cohort 6 complete study 
day 36.  Enrollment in cohort 7 can be initiated after DLRM #4.
Number of Subjects
Approximately 108 subjects (8 per cohort, cohorts 1-6; 60 in cohort 7) will be enrolled.
Summary of Subject Eligibility Criteria
Males and females aged 18 to 65 years (inclusive) at the time of randomization with a 
BMI of ≥ 30.0 and ≤ 40.0 kg/m2.  Females enrolled in cohorts 1-6 must be of 
non-reproductive potential. 
For cohort 7, subjects must additionally have been receiving liraglutide at 3.0 mg QD, 
SC for at least 6 months before screening, with liraglutide being generally well tolerated 
per the investigator’s discretion (and subjects plan to continue liraglutide 3.0 mg QD, 
SC). 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.4.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 13 of 111
CONFIDENTIAL
Treatments
Cohorts 1, 3, and 5: After completion of all pre-dose procedures on the day of dosing,
subjects will receive AMG 598 (70, 210, or 420 mg) or placebo SC on days 1, 29, and 
57.
Cohorts 2, 4, and 6: After completion of all pre-dose procedures on the day of dosing, 
subjects will receive AMG 598 (70, 210, or 420 mg) or placebo SC Q4W x3 on days 1, 
29 and 57 in addition to liraglutide SC QD. Subjects will start the first dose of liraglutide 
(0.6 mg SC QD) on day 1 and increase the dose of liraglutide by 0.6 mg dose increment 
every 7 days, up to the full dosage of 3.0 mg by week 5 and remain on 3.0 mg until 
day 84, inclusive (See Table 3-1).
Cohort 7: Subjects that have been on a stable dose of liraglutide (3.0 mg SC QD) for at 
least 6 months will continue to receive liraglutide (3.0 mg SC QD) and receive one dose 
of placebo SC on day -28, as part of a 4-week run-in. After completion of all pre-dose 
procedures on the day of dosing, subjects will then receive AMG 598 420 mg or placebo 
SC Q4W on days 1, 29, 57 in addition to the liraglutide (3.0 mg SC QD).
Procedures
Screening:
For cohorts 1-6, after informed consent is obtained, all screening procedures and tests 
establishing eligibility will be performed within 28 days before first dose of AMG 598 or 
placebo (day 1).
Subjects in cohort 7 will be screened between days -56 and -29 from first dose of 
AMG 598 or placebo (day 1).  Subjects who meet all the screening inclusion/exclusion 
criteria will be eligible to report to the research facility on day -28, subjects enrolled will
receive a dose of placebo.
Day -2: 
Cohorts 1, 3, and 5:  Subjects who meet all the screening inclusion/exclusion criteria will 
be eligible to report to the research facility on day -2, at which time assessments will be 
performed to confirm eligibility.  If subjects are eligible after the completion of all day -2
study assessments, subjects will be randomized to receive either AMG 598 or placebo.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 14 of 111
CONFIDENTIAL
Day -1:
Cohorts 1, 3, and 5: A mixed meal tolerance test (MMTT) will be performed.
Cohorts 2, 4, and 6: Subjects who meet all the screening inclusion/exclusion criteria will 
be eligible to report to the research facility on day -1, at which time assessments will be 
performed to confirm eligibility.  If subjects are eligible after the completion of all day -1 
assessments, subjects will be randomized to receive either AMG 598 or placebo.
Treatment and Follow-up (day 1 to day 206):
AMG 598 or placebo will be administered SC Q4W x3 on days 1, 29 and 57 after 
pre-dose procedures.  All procedures on day of dosing as outlined in the Schedule of 
Activities should occur prior to dosing of AMG 598 or placebo. 
Cohorts 1, 3, and 5:  Subjects will be admitted for overnight stays prior to MMTTs. An 
MMTT will occur on day -1, day 6 (+/- 1 day), and day 64 (+/- 1 day).
Cohorts 2, 4, and 6: Subjects may be admitted for optional overnight stays on day -1, 
day 6 (+/- 1 day), and day 62 (+/- 1 day).
Subjects will return to the research facility as outlined in the Schedule of Activities and 
will undergo the following assessments at specified time points throughout the study:  
clinical laboratory evaluations, adverse event (AE) and serious adverse event (SAE) 
collection, vital sign measurements, 12-lead ECGs, physical examinations, MMTTs, 
Patient Health Questionnaire (PHQ-9), Columbia Suicide Severity Rating Scale 
(C-SSRS), dual-energy x-ray absorptiometry (DXA) bone density measurements 
(cohorts 1-6) and body composition assessments (cohort 7), PK, and PD assessments.
Subjects will remain in the research facility until completion of all study procedures on 
each visit day.  
Day 207/End of Study (EOS):
Subjects will be followed through the completion of EOS procedures on day 207.
All adverse events and use of concomitant medication will be collected for the duration 
of the study, up to and including the EOS visit.  All treatment-emergent AEs or laboratory 
abnormalities will be followed until either: a) resolution of the abnormality, b) it is 
considered stable in the opinion of the Principal Investigator, or c) subject is lost to follow 
up.
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1 to Table 2-3.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 15 of 111
CONFIDENTIAL
Statistical Considerations
Descriptive statistics will be provided for selected demographics, safety, PK and PD 
data.  Data for subjects receiving placebo will be combined across the monotherapy 
cohorts and across the combination therapy cohorts.
Descriptive statistics on continuous measurements will include means, medians, 25th 
and 75th percentiles, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages. PK, PD and clinical laboratory 
data will be summarized at each time point when samples are collected.
The number and percentage of subjects reporting any treatment-emergent adverse 
events will be tabulated by system organ class and preferred term and will be further 
classified by relationship to treatment. SAEs and clinically significant changes in clinical 
laboratory test values, ECG, or vital signs will be noted.  Both exploratory graphical and 
model-based PK/PD analyses may be conducted with selected PD markers.
The sample size for the study is based on practical considerations. For safety 
considerations, with up to 66 subjects receiving AMG 598, there is a 96.6% chance of 
detecting an adverse event with a true incidence rate of 5% or greater and a 
99.9% chance of detecting an adverse event with a true incidence rate of 10%.
Cohort 7 with 30:30 randomization will allow for 80% probability of observing a mean 
treatment difference in percent change from baseline in body weight between AMG 598 
and placebo of > 3%, assuming a true treatment difference of 5%
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor Name:
Amgen, Inc.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 16 of 111
CONFIDENTIAL
2.
Study Schema and Schedule of Activities
2.1
Study Schema
Figure 2-1.  Study Schema
 
Approved 
 
 
t 
! 
OLRM •t 
Cohort 1 
I 
I I._ 
62, At.tG598.'Pl'tCetl0 
Screen 
Treannert 
70mgSC04W:c J 
..,, 
., 
.,. 
Cohort2 
6•2. At-10598/pl;,.oebo 70mg SC04Wll 3 
~" 
D• 
' 
AMG 598/pliac:ebo 
,. lJrt10UJ:de-
Cf8En 
Cohort3 
..,, ., 
62. M.tGS98,'pla;cebo210rno 
SC04Wll3 
screet1 
Cohort4 
6 2 N.IG59afplaoeb0 210 mg SC04W,: 3 
• Uragu:i<1e-
Cohorts 
6 2, At/G 598.'PbCetl0 420 mg SC 
04\V,:3 
t 
FUPernxl 
.. 
.,. 
"' 
reaunem ! 
.,. 
L 
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EOS 
FUPenod 
EOS 
FUPenod 
I DLRMO I 
-·- -•+ 
"" 
"' 
T ,........,. 
RIPerlOO 
! 
! 
• 
"' 
Treatmelll 
RIPerlOO 
EDS 
EDS 
! l.rcll!,hAide~CE"l'ldi<lgdose$(¥t 
-
l irllpl1idedoWIS-
i-
' OLRM:J. 
-- ... 
Cohort&; 62. At..0598,'pQcebo 
420 mg SC04W:c 3• UragUide- ~" 
Cohort7 
D• 
.,. 
Trea1rnen1 
.. ,. 
"' 
i:UPetlOd 
! 
! 
~" 
D• 
·c 
;;,Uraglutide dosing: Subject$ in cohorts 2, 
4, and 6 will receive liraglutide at a 
starting dose of 0.6 mg subcutaneously 
(SC) once-<iaily (QD) on Dav 1, and will be 
instructed to increase the dose of 
liraglutide by 0.6 mg dose increment 
every 7 days (0.6 mg, 1.2 mg, 1.8 mg, 2.4 
mg, 3.0 mg), vp to the full do,age of 3.0 
mg SC QD by week 5, and remain on full 
dosage until day 84. 
°Cohort 7 Uraglutide: Subjects eligible for 
the study will have been on a stable dose 
of liraglutide 3.0 mg SC QD for at least 6 
months and will continue liraglutide 3.0 
mg SC QD throughout the K reening and 
study period from study days -S6 to end 
of ,tvdy (EOS) (day 207) 
EDS 
! 
'" 
EDS 
30 30. At.lG 598,'pli:lcebo 
420mg SCO.Wll 3 
I Saoon I 
Run ,n I 
Treamiett 
I 
RIPerlOO I .. 
• SIIICle Uf&gUld~ 
S1.Mle ot1 3..0mc ll1•1lutWe > 6mo 
. -
AMrar 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 17 of 111
CONFIDENTIAL
2.2
Schedule of Activities
Table 2-1.  Schedule of Activities for Cohorts 1, 3 and 5
Page 1 of 2
Footnotes defined on last page of the table
 
Approved 
 
 
Screening 
Treatment 
Follow up 
EOS 
Study Oay 
-28 to -3 -2 
-1 
1 
6 
8 15 22 29 
36 
57 62 
64 
71 
85 
99 113 127 169 207 
Visit Windows 
:!: 1 day 
:!: 1 day 
:!: 1 days 
:!: 2 days 
:!: 3 days 
:!: 7 days 
Tim e (in minutes)b 
-15 
0 
30 
60 120 240 
-15 
0 
30 
60 120 240 
-15 
0 
30 
60 120 240 
Tim e (in hours)b 
Pre 
0 
0.5 
1 
2 
4 
Pre 
0 
0.5 
1 
2 
4 
Pre 
0 
0.5 
1 
2 
4 
General and l aboratory Assessments 
In house residencv'" 
Informed Consent 
X 
Medical History 
X 
Demographics 
X 
Phvsical Examination° 
X 
X° 
x• 
x• 
X° 
X 
X° 
CSSRS +PHQ9 
X 
X 
x• 
x• 
X 
X 
Boc!y Weight 
X 
X 
x• 
X X X x• 
X x• 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Boc!y Mass Index 
X 
Waist Circumference 
x• 
x• 
x• 
X 
X 
X 
X 
Vital Signs (BP, HR, RR, 
X 
X 
x• X 
X X X x• 
X x• 
X 
X 
X 
X 
X 
X 
X 
TEMP) 
12-Lead ECG· ·· 
X 
X 
xe X 
X 
X x• 
X x• 
X 
X 
X 
X 
X 
Concomitant Medications 
Actverse Event Recording 
' 
Serious Actverse Event 
Recording 
Clinical Chemistrv'·• 
X 
X 
X 
x• 
X x• 
X 
X 
X 
X 
X 
Clinical Hematoloav'·• 
X 
X 
X 
x• 
X x• 
X 
X 
X 
X 
X 
Coagulation Tests' 
X 
eGFR1·' 
X 
X 
X 
Serum CTX and P1NP9·' 
X 
X 
x• 
X x• 
X 
X 
X 
X 
Serum Amylase and 
X 
X 
x• 
X x• 
X 
X 
X 
X 
Lipase'·• 
Urinalvsis1 
X 
X 
X 
X 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 18 of 111
CONFIDENTIAL
Table 2-1.  Schedule of Activities for Cohorts 1, 3 and 5
Page 2 of 2
Footnotes defined on next page
 
Approved 
 
 
Screening 
Treatment 
Follow up 
EOS 
Study Day 
-28to-3 -2 
-1 
1 
6 
8 
15 22 29 
36 
57 
62 
64 
71 
85 
99 
113 127 169 207 
Visit Windows 
±1 day 
t1 day 
±1 days 
± .2d1y1 ± 3 d1y1 
± 7days 
Time {in mlnutes)b 
-15 
0 
30 
60 
120 240 
-15 
0 
30 
60 
120 240 
-15 
0 
30 
60 
120 240 
Time (In hours)b 
Pre 
0 
0.5 
1 
2 
4 
Pre 
0 
0.5 , 
2 
4 
Pre 
0 
0.5 
1 
2 
4 
General and Laboratory Asaeasmenta 
Urtnalvsls1 
X 
X 
X 
X 
Alcohol, ConUnlne and Drug 
X 
X 
Screen' 
HIV, HBcAb, HBsAg, and 
X 
HeoCAbth 
Preanancv TesiJ 
"X! 
xi 
Serum FSH Test (Females 
Xk 
Onllll" 
MMTT 
X 
X 
X 
Dosing 
Study Drug Administration 
X 
X 
X 
ISC) 
Blood Samples (:!: window) 
:!: 2mln 
:!: 2mln 
:!: 2mln 
Serum PK9 
x• X 
X X X X' 
X x· X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (lns,,lln, C-pei,bde, 
G!Ucose, GIP, GLP, 1, and 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x• 
x• 
X 
X 
X 
X 
X 
X 
X 
Glucagon) gJ, 
Serum PD IFFA19 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x• 
x• 
X 
X X 
X X 
X 
X 
Lipid Panel (total cllolestero!, 
LDL-C, HDL-C and 
X 
x• 
x• 
lngl)'cefldes{h 
x• 
X 
X 
X 
HbA1c1J, 
X 
X 
X 
X 
Pharmacooenellc" 
X 
X 
Biomarker Davelooment• 
X 
X 
X 
X 
X 
X 
Anti-AMG 598 AnUbody 
x• 
X' 
X 
X 
X 
Imaging 
DXA Scan• 
X 
X 
X 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 19 of 111
CONFIDENTIAL
ECG = electrocardiogram; DXA= Dual-Energy X-ray absorptiometry; Mixed Meal Tolerance Test (MMTT)
a Pre-dose assessments
b Time in minutes/hours relative to the start time of standardized meal during MMT test and start of each investigational product dose administration during Treatment 
and Follow-up periods.
c Physical exam to include neurological assessment 
d Single ECG at screening and triplicate (30 seconds apart) at other timepoints
e 3 sets of triplicate ECGs at least 30 min apart (-90, -60, and -30 minutes prior to dosing)
f Analyzed at the local laboratory
g Analyzed at the central laboratory
h 10-hour fasting is required at all timepoints
i Serum pregnancy test at screening and EOS
j Urine pregnancy test
k Serum FSH Test (female only) for postmenopausal status confirmation
l Local laboratory at screening, then central lab at other timepoints
m In house residency day -2 to 1 (2 nights; second overnight, day -1 to 1, is optional), days 5 to 6 (1 night with +/- 1 day start window), day 62 to 64 (2 nights with +/-
1 day start window; first overnight, day 62 to 63, is optional)
n DXA scan may be performed within 3 days prior to day 1 or within ±3 days of day 85 and 169 visits
 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 20 of 111
CONFIDENTIAL
Table 2-2.  Schedule of Activities for Cohorts 2, 4 and 6
Page 1 of 2
Footnotes defined on next page of the table
 
Approved 
 
 
ACuvlLJ 
~creenmn 
re~en• 
I 
i;o11owun 
I c , 
Study Day 
-28to -2 I -1 
1 I 6 
8 I 15 I 22 
29 
36 
I 57 I 62 I 64 I 71 
857 997 113 127 1697 207 
Visit Windows 
I 
•1 dav 
I • 1 dav I 
I • 1 dav I • 2 da•s •3 da•s 1 
• 7 da•s 
General and Laboratorv Assessments 
In house residencv-
Informed Consent 
X 
Medical Historv 
X 
Demoaraohics 
X 
Phvsical Examination• 
X 
)(' 
't: 
't: 
)(' 
X 
)(' 
CSSRS•PHQ9 
X 
X 
't: 
't: 
X 
X 
BodvWeiaht 
X 
X 
X' 
X 
X 
X 
X' 
X 
't: 
X 
X 
X 
X 
X 
X 
X 
X 
Heiahl 
X 
Bodv Mass Index 
X 
Waisl Cirrumference 
't: 
X' 
X' 
X 
X 
X 
X 
Vital Sians (BP, HR. RR TEMP) 
X 
X 
't: 
X 
X 
X 
't: 
X 
't: 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG-
X 
X 
X 
X 
X 
't: 
X 
't: 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
Adverse Event Recordina 
I 
Serious Adverse Event Recordina 
Clinical Chemis,_ 
X 
X 
X 
't: 
X 
't: 
X 
X 
X 
X 
X 
X 
Clinical Hemalolonv-
X 
X 
X 
't: 
X 
't: 
X 
X 
X 
X 
X 
X 
Coaaulation Tests-
X 
eGFR"' 
X 
X 
X 
Serum CTX and P1NPg.o 
X 
X 
't: 
X 
't: 
X 
X 
X 
X 
X 
Serum Amvlase and lioase"' 
X 
X 
't: 
X 
't: 
X 
X 
X 
X 
X 
Urinalvsis' 
X 
X 
X 
X 
Alcohol, Continine and Drua Screen' 
X 
X 
HIV HBcAb, HBsAa. and HeoCAb"' 
X 
Preanancv Tesl" 
X' 
x! 
Serum FSH Test /Females Onlvl' 
X' 
Dosina 
stuc!y Drug Administration (SC) 
I 
I 
I X 
I 
I 
X I 
I X 
I 
I 
' 
7 
7 
' 
Liranlutide Administration 1sc,0 
I 
I 
I 
X' 
I 
I 
I 
I 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 21 of 111
CONFIDENTIAL
Table 2-2.  Schedule of Activities for Cohorts 2, 4 and 6
Page 2 of 2
ECG = electrocardiogram; DXA= Dual-Energy X-ray absorptiometry
a Pre-dose assessments
b Liraglutide dose escalation; starting dose 0.6 mg SC QD on Day 1, increase by 0.6 mg dose increment Q1W up to the full dose of 3.0 mg SC QD at week 5. Remain 
  at 3.0 mg SC QD from week 5 until Day 84, inclusive. 
c Physical exam to include neurological assessment  
d Single ECG at screening and triplicate (30 seconds apart) at other timepoints
e 3 sets of triplicates at least 30 min apart (-90, -60, and -30 minutes prior to dosing)
f Analyzed at the local laboratory
g Analyzed at the central laboratory
h 10-hour fasting is required at all timepoints
I Serum pregnancy test at screening and EOS
j Urine pregnancy test
k Serum FSH Test (female only) for postmenopausal status confirmation
l Local laboratory at screening, then central lab at other timepoints
mOptional in-house residency day -1 to 1 (1 night), days 6 to 8 (2 nights with +/- 1 day start window), day 62 to 64 (2 nights with +/- 1 day start window)
n DXA scan may be performed within 3 days prior to day 1 or within ±3 days of day 85 and 169 visits
 
Approved 
 
 
Activity 
Screening 
Treatment 
Follow up 
EOS 
Study Day 
•28 to •2 
·1 
1 
6 
8 
15 
22 
29 
36 
57 
62 
64 
71 
85 
99 
113 127 169 207 
Visit Windows 
± 1 day 
t 1 dav 
t 1 day 
± 2 days 
t 3 days 
± 7 days 
PK and Other Blood Samples 
Serum PK (AMG 598\9 
x• 
X 
X 
X 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PK /liraalutide lg 
x• 
x• 
x• 
X 
X 
Plasma PD (Insulin, C•peptide, Glucose, GIP, 
x• 
X 
x• 
x• 
X 
X 
X 
X 
GLP· 1, and Glucagon)V" 
Serum PD IFFA\11" 
x• 
X 
x• 
x• 
X 
X 
X 
X 
Lipid Panel (total cholesterol. LOL-C, HDL·C 
X 
x• 
x• 
x• 
X 
X 
X 
X 
and triglycerides )1" 
HbA1ct.h 
X 
X 
X 
X 
Pharmacooenetic" 
X 
X 
Biomarker Develooment" 
X 
X 
X 
X 
X 
X 
X 
Anti-AMG 598 Antibody 
xa 
x• 
X 
X 
X 
Imaging 
DXA Scan" 
X 
X 
X 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 22 of 111
CONFIDENTIAL
Table 2-3.  Schedule of Activities for Cohort 7
ECG = electrocardiogram; DXA= Dual-Energy X-ray absorptiometry
a Pre-dose assessments
b Subjects to remain on liraglutide 3mg SC QD throughout duration of the study
c Physical exam to include neurological assessment
d Single ECG 
e Analyzed at the central laboratory
f 10-hour fasting is required at all timepoints
g Serum pregnancy test at screening and EOS for all female subjects
h Urine pregnancy test for female subjects of reproductive potential
i Serum FSH Test (female only) for postmenopausal status confirmation
j All subjects receive placebo injection
k Whole body DXA scan may be performed within 3 days prior to day 1 or within ±3 days of day 85 visit
Approved 
 
 
Activitv 
Screenina 
Run-in 
Treatment 
Follow uo 
I EOS 
Studv Dav 
-56 to-29 
-28 
1 
15 
29 
57 
71 
85 
I 
145 I 
207 
Visit Windows 
!2 daus 
!2 daus 
!ldau 
!ldau 
!3 daus 
! 7 daus 
General and Laboratorv Assessments 
Informed Consent 
X 
Medical Historv 
X 
Demoarahics 
X 
Phvsical Examination 
X 
X"' 
X' 
X' 
X' 
X' 
CSSRS + PHQ9 
X 
X 
X' 
X' 
X' 
X 
X 
BodvWeiaht 
X 
X 
X' 
X 
X' 
X' 
X 
X 
X 
X 
Heiaht 
X 
Bodv Mass Index 
X 
Waist Circumference 
X' 
X' 
X' 
X 
X 
X 
V ttal Sians !BP HR RR TEMP\ 
X 
X 
X' 
X 
X' 
X' 
X 
X 
X 
X 
12-Lead ECG4 
X 
X 
X' 
X' 
X' 
X 
X 
Concomitant Medications 
Adverse Event Recordino 
I 
Serious Adverse Event Recordino 
Clinical Chemist .... ,o., 
X 
X' 
X' 
X' 
X 
X 
X 
Clinical HematolO"'",o., 
X 
X' 
X' 
X' 
X 
X 
X 
Coaaulation Tests01 
X 
eGFR"' 
X 
X' 
X 
Serum CTX and P1 NP°' 
X' 
X 
X' 
X' 
X 
X 
X 
X 
Serum Arm.1Iase and Unase01 
X' 
X 
X' 
X' 
X 
X 
X 
X 
Urinatvsis0 
X 
Alcohol Continine and Druo Screen° 
X 
HIV HBcAb HBsAa and HeoCAb0 
X 
Preanan"""' Test°1' 
X" 
)('-' 
)('-' 
)('-' 
)(' 
)(' 
X' 
Serum FSH Test (Females Qnh.,\1 
x! 
Dosino 
Studv Druo Administration (SC\ 
I 
I 
x! 
X 
X 
X 
I 
I 
I 
Liraalutide !SC\• 
I 
X" 
PK and Other Blood Samples 
Serum PK° 
X' 
X 
X' 
X' 
X 
X 
X 
X 
Plasma PK° 
X' 
X 
X' 
X' 
X 
X 
X 
X 
Plasma PD (Insulin, C-peptide, Glucose, GIP, 
GLP-1, and Glucagon)01 
X' 
X 
X' 
X' 
X 
X 
X 
Serum PD (FFA )-
X " 
X 
X " 
X " 
X 
X 
X 
Lipid Panel (total cholesterol, LDL-C, HDL-C 
and trigtycerides)01 
X 
X' 
X' 
X' 
X 
X 
HbA1c-
X 
X " 
X 
Pharmacogenetic 
X " 
Biomarker Development 
X " 
X 
A nti-AMG 598 A ntibody 
X " 
)(:' 
X 
X 
X 
Imaging 
Whole bodv DXA scan" 
I 
I 
X' 
I 
X' 
I 
I 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 23 of 111
CONFIDENTIAL
3.
Introduction
3.1
Study Rationale
Obesity is a growing global health crisis that is in critical need of safe and effective 
therapies. Currently approved products provide modest weight loss from baseline with 
issues of discontinuation due to the side effects of nausea and GI intolerability, as well 
as lack of continued efficacy. The current study evaluates the safety and tolerability, PK, 
and PD of multiple ascending doses of AMG 598 alone, and in combination with 
liraglutide, as a potential weight loss therapy for subjects with obesity. AMG 598, a 
human monoclonal antibody, binds the glucose dependent insulinotropic polypeptide 
receptor (GIPR), and blocks the binding of its endogenous ligand (glucose-dependent 
insulinotropic polypeptide [GIP]) preventing activation of the receptor and downstream 
pathways. Nonclinical animal studies demonstrated that GIPR antagonism resulted in 
significant (5-8%) weight loss compared to vehicle control.  When combined with 
commercially available glucagon-like peptide-1 (GLP-1) receptor agonists, AMG 598 
lead to a > 20% weight reduction in overweight and obese animals. Thus, in addition to 
evaluating AMG 598 safety and tolerability, PK and PD alone or in combination with 
liraglutide (a GLP-1 receptor agonist), the current study also examines the safety and 
preliminary weight loss efficacy of AMG 598 in a cohort of subjects who have been 
maintained on a stable dose of liraglutide. The sample size for this specific 
cohort (30:30 subjects in cohort 7) is based on practical considerations and statistical 
analysis for the detection of meaningful weight loss. The rationale for dose selection was 
based on PK and safety analysis of preliminary data collected in the first-in-human (FIH)
single ascending dose study of AMG 598 in subjects with obesity. The blinded safety 
data from the AMG 598 FIH study suggests single doses of AMG 598 have been 
generally well tolerated up to 560 mg SC, with no serious adverse events (SAE), deaths, 
or withdrawals related to adverse events reported. 
3.2
Background
3.2.1
Disease
Obesity represents a major threat to public health and the accompanying health-care 
costs pose an enormous financial burden (Terranova et al, 2012; Wang et al, 2011).  
The prevalence of obesity has more than doubled worldwide over the last decades and 
currently, 600 million adults are obese, defined as having a body mass index (BMI) of 
>30 kg/m2 (World Health Organization [WHO], 2016).  Obesity is a major risk factor for 
type 2 diabetes and cardiovascular disease (CVD) and is associated with increased risk 
of all-cause and CVD-related mortality (Jensen et al, 2014). Additional comorbidities 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 24 of 111
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include nonalcoholic steatohepatitis (NASH), polycystic ovary syndrome, obstructive 
sleep apnea, osteoarthritis, gallbladder and skin diseases, and several forms of cancer 
(Jensen et al, 2014).  In addition, persons with obesity frequently encounter 
psychological and social problems such as low self-esteem, prejudice, and 
discrimination (Kolotkin et al, 2001).
Achieving clinically significant weight loss (> 5%) through lifestyle changes focuses on 
reduced energy intake and increased physical activity, and can improve risk factors for 
CVD, delay or prevent the development of type 2 diabetes, and contribute to better 
quality of life (Jensen 2014, Look AHEAD Research Group, 2013).  Exercise and 
nutritional counseling can be effective in the short term, but many patients will sustain 
less than 5% weight loss in the long term (Look AHEAD Research Group, 2014).
Currently approved weight loss products belong to the following therapeutic classes: 
GLP-1R agonists (liraglutide [Saxenda®]), 5-HTR agonists (lorcaserin [Belviq®]), 
noradrenergic agents (phentermine [Adipex-P®]), lipase inhibitors (orlistat 
[Xenical/ Alli®]), in addition to fixed combination products (phentermine + topiramate 
[Qsymia®], and bupropion + naltrexone [Contrave®]).  With the currently approved 
pharmacotherapy for weight management, a modest incremental average weight loss of 
2–9 kg can be achieved over and above lifestyle measures.  Across phase 3 studies of 
currently approved products, a greater proportion of individuals with obesity on active 
medication (44-75%) achieve a reduction in bodyweight > 5% from baseline over 
52 weeks than among those assigned to placebo (23%) (Khera et al, 2016).  Side effects 
of currently approved weight loss products vary depending upon their mechanism and 
include increased blood pressure, tachycardia, restlessness (stimulants like 
phentermine), flatulence, and diarrhea (medicines that affect fat absorption, such as 
orlistat), nausea, vomiting, constipation, dry mouth, and dizziness (molecules that 
directly interfere with neurotransmitter signaling in the brain, such as lorcaserin, 
bupropion and naltrexone) (Heymsfield and Wadden, 2017). The majority of persons 
with obesity are generally dissatisfied with weight loss of less than 10 kg, and as a 
consequence may discontinue pharmacological treatment to avoid the both the costs 
and side effects accompanying the potential life-long medication 
(Dalle Grave et al, 2005).  Consequently, new pharmacological agents for the treatment 
of obesity are needed to improve efficacy and reduce side effects.
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3.2.2
Amgen Investigational Product Background:  AMG 598
3.2.2.1
Pharmacology
AMG 598 is a fully human monoclonal antagonistic antibody that binds the extracellular 
domain of human GIPR.  AMG 598 blocks the binding of the endogenous ligand, GIP,
preventing activation of the receptor and accumulation of cyclic adenosine 
monophosphate (cAMP). GIP and GLP-1 are gut-derived incretin hormones, known for 
their ability to augment glucose stimulated insulin secretion, and in the case of GLP-1
also recognized to promote satiety (Baggio et al, 2014).  As such, GLP-1 analogs are 
marketed for treatment of type 2 diabetes (T2D), and for weight management in obesity 
(liraglutide [Saxenda®]). In addition to ingested carbohydrate, dietary fat is a potent 
stimulant of GIP secretion in humans (Falko et al, 1975), and meal size is positively 
correlated with postprandial GIP secretion (Vilsboll et al, 2003).  The exposure of 
rodents to a high-fat diet (HFD) leads to increased GIP secretion from K cells in the 
proximal small intestine (Suzuki, 2013; Tseng 1994).  Similarly, acute high fat-feeding in 
humans also results in a 42% increase in circulating GIP levels before any noticeable 
body weight increase (Brons et al, 2009).
GIPR has been reproducibly identified in human genetic association studies of BMI 
measurements (Berndt et al, 2013; Okada et al, 2012; Wen et al, 2012;
Speliotes et al, 2010; Yip et al, 1998;).  Of the four SNPs (rs2287019, rs10423928, 
rs1800437, rs1167664) which have been described, only one SNP (rs1800437) results 
in a non-synonymous change at residue 354 (E354Q) with the obesity risk allele (E354) 
leading to an obesity odds ratio of 1.1.  Reciprocally, Q354 is associated with reduced 
incretin effect (Almind et al, 1998) and delayed GIPR membrane recycling 
(Mohammad et al, 2014) suggesting that Q354 exhibits lower GIPR activity than that of 
E354, allowing speculation that higher GIPR activity is obesity promoting. GIP, K-cell 
and GIPR null mice are all resistant to high fat diet induced obesity
(Nasteska et al, 2014; Althage et al, 2008; Miyawaki et al, 2002).  Notably these 
changes in adiposity were not associated with profound changes in appetite.
Additionally, GIP vaccination (Fulurija et al, 2008) or neutralization (Boylan et al, 2015) 
lead to reductions in fat mass accumulation. Administration of a mouse specific GIPR 
antibody (mAb 2.63.1) alone resulted in significant lower weights than placebo (> 5%) in 
diet induced obese (DIO) mice, and greater than 20% weight reduction when combined 
with a GLP-1 agonist in DIO mice. Obese cynomolgus monkeys exhibited an 8% weight 
loss with AMG 598 alone as compared to placebo, and over 20% weight reduction with 
AMG 598 and a GLP-1 agonist combined. 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
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The mouse, cynomolgus monkey, and human genetic evidence supports the therapeutic 
concept of developing a GIPR antagonist either alone or in combination with a GLP-1R 
agonist for the treatment of obesity.
Refer to the AMG 598 Investigator’s Brochure (IB) for additional information related to 
the pharmacology, physical, chemical, and pharmaceutical properties and formulations 
of AMG 598.
3.2.2.2
Pharmacokinetics
AMG 598 PK was evaluated in single dose-studies in mice and monkeys over the dose 
ranges of 1 to 10 mg/kg and 0.1 to 3 mg/kg, respectively. Following a single dose, 
AMG 598 exposure as assessed by maximum observed concentration (Cmax) and area
under the concentration time curve (AUC) was approximately dose-proportional. 
AMG 598 was absorbed upon SC administration with absolute bioavailability of 80% and 
127% in mice and monkeys, respectively, although the estimate for monkeys was not 
considered reliable due to sampling limitations. AMG 598 demonstrated a long terminal
half-life (t1/2,z) ranging from 13.6 to 19.3 days and from 10.3 to 20.1 days in mice and 
monkeys, respectively.
The toxicokinetics (TK) of AMG 598 was characterized in a Good Laboratory Practice 
study after weekly subcutaneous (SC) doses of 50, 150, and 700 mg/kg administered for 
4 weeks in mice. AMG 598 TK was also characterized in a GLP study after weekly 
SC doses of 6, 30, and 200 mg/kg administered for 4 weeks in cynomolgus monkeys 
and in a GLP study after weekly SC doses of 30 and 200 mg/kg administered for 
13 weeks in cynomolgus monkeys. Following multiple doses, AMG 598 exposure 
increased approximately dose proportionally over a dose range from 50 to 700 mg/kg 
and from 6 to 200 mg/kg in mice and monkeys, respectively. AMG 598 exposures were 
similar (within 2-fold) between male and female animals in both species.
For summary information on preliminary PK in humans, please refer to Section 5.4
3.2.2.3
Toxicology
In compliance with the International Council for Harmonisation (ICH) S6 (R1) and ICH 
M3 (R2) guidelines, a comprehensive nonclinical toxicology program was conducted to 
support the proposed clinical study with AMG 598 (ICH S6 (R1), 2011; 
ICH M3(R2), 2009). The Good Laboratory Practice studies included 4-week SC 
repeat-dose toxicology studies conducted in cynomolgus monkeys and in mice (for 
additional information, refer to Investigator’s Brochure), one 13-week SC repeat-dose 
toxicology study in cynomolgus monkeys and a tissue cross reactivity study in a full 
Approved 
 
 


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panel of human tissues with biotin conjugated AMG 598. AMG 598 binds with 
equivalent high affinity to human, cynomolgus monkey, and mouse GIPR; however, in 
regard to inhibition of GIP signaling through GIPR, AMG 598 demonstrates 
approximately 50-fold decreased potency for mouse GIPR in comparison to human or 
cynomolgus monkey GIPR. 
In the 13-week study in cynomolgus monkeys, AMG 598 (30 or 200 mg/kg administered 
weekly by SC injection in the subscapular region), liraglutide (1.8 mg administered daily 
by SC injection in the thigh), and corresponding placebos were administered to 
3 monkeys/sex/group.  Combinations administered were placebo/placebo, 
placebo/Liraglutide, AMG 598 (30 or 200 mg/kg)/placebo, and AMG 598 
(30 or 200 mg/kg)/Liraglutide.  Liraglutide, AMG 598, and AMG 598/Liraglutide were well 
tolerated at all doses with no effects on mortality, food consumption, coagulation, 
urinalysis, biomechanical markers of bone turnover, respiration, electrocardiographic 
(qualitative and quantitative) or ophthalmic assessments.  Administration of both 
AMG 598 and liraglutide did not affect the pharmacokinetic parameters of either drug. 
Transient decreases in body weights observed in some animals administered liraglutide
or 30 mg/kg AMG 598/Liraglutide is an anticipated pharmacologic effect.  AMG 598 and 
AMG 598/Liraglutide-related hematology changes included minimally decreased red 
blood cell mass in males only at 200 mg/kg AMG 598 and ≥ 30 mg/kg 
AMG 598/Liraglutide which was associated with minimally to moderately increased 
reticulocytes and mildly increased red cell distribution width in males at 200 mg/kg 
AMG 598.  
AMG 598/Liraglutide-related clinical chemistry changes included transient minimal 
increases in total bilirubin, mild decreases in glucose, and moderately to marked 
decreases in insulin at doses ≥ 30 mg/kg that recovered by day 92, except for decreased 
insulin at 30 mg/kg. Liraglutide-related changes included transient minimal to mild 
increases in total bilirubin and mild decreases in glucose and insulin that recovered by 
day 92.  
AMG 598 is immunogenic in the cynomolgus monkey and 16 of the 24 monkeys 
administered AMG 598 developed anti-drug antibodies (ADA) by end of study. Clinical 
signs were limited to one male at 200 mg/kg AMG 598 and consisted of skin lesions 
which correlated to scab formation and a light microscopic finding of ulceration.  The skin 
lesions were related to cutaneous vasculitis which was considered secondary to 
AMG 598/ADA immune complex (IC) formation.  AMG 598 and 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
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AMG 598/Liraglutide-related light microscopic changes of (peri-) vascular mononuclear 
and mixed cell infiltrates in various tissues were suggestive of ADA/IC-related pathology 
(Rojko et al 2014, Mease et al, 2017). Two animals (200 mg/kg AMG 598) with
(peri)vascular mononuclear and mixed cell infiltrates in multiple organs (including the 
skin lesions described above) had changes in clinical chemistry parameters that 
included minimally decreased albumin and mildly increased globulins on day 92 
suggestive of an acute phase response.  One of these animals also had mild to 
moderate increases in aspartate aminotransferase, alkaline phosphatase, gamma 
glutamyltransferase, and total bilirubin on day 92.  Because the induction of antibody 
formation to a human protein in animals is not predictive of potential immunogenicity in 
human subjects (ICH S6(R1) 2011; Ponce et al, 2009), the light microscopic changes 
are not predictive for the development of similar changes in human subjects. 
Decreases in absolute and relative thymus weights were observed in females 
administered liraglutide, AMG 598 at 200 mg/kg, or AMG 598/Liraglutide. Light 
microscopic changes due to the stress of transient body weight loss and ADA/IC 
formation were observed in the thymus (atrophy), in the pancreas (decreased secretory 
content), and in the salivary glands (decreased secretory content) in some females at 
≥30 mg/kg AMG 598/Liraglutide.  The no-observed-adverse-effect level (NOAEL) for 
AMG 598 was determined to be 200 mg/kg either as a monotherapy or in combination 
with 1.8 mg liraglutide.  The NOAEL of 200 mg/kg AMG 598 when administered with 
1.8 mg liraglutide corresponded to a mean Cmax of 4670 µg/mL and an AUClast of 
662000 hr∙µg/mL on day 85, with anticipated 62X and 61X AUC and Cmax exposure 
multiples, respectively, when compared to the highest proposed monthly clinical dose of 
420 mg (Table 5-1).  The 1.8 mg dose of liraglutide when administered with 200 mg 
AMG 598 corresponded to a mean Cmax of 6.75 µg/mL and an AUClast of 75.0 hr∙µg/mL 
on day 91 which corresponds to an approximately 25X exposure multiple above the 
average steady state concentration (AUCτ/24 hr) of 116 ng/mL for a 3.0 mg dose of 
liraglutide in obese patients (Saxenda® Label).
3.2.2.4
Reproductive and Developmental Toxicity
No nonclinical toxicity studies of the effects of AMG 598 on reproduction and 
development have been conducted. Females of child-bearing potential may participate in 
cohort 7 of the study if they are willing to use highly effective method of contraception 
during treatment and for an additional 5 months after the last dose of AMG 598.
AMG 598 is a monoclonal antibody. The embryo-fetal exposure of monoclonal 
antibodies during organogenesis is understood to be low in humans based on current 
Approved 
 
 


Product:  AMG 598
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scientific evidence, and therefore the developmental toxicity study with AMG 598 will be 
conducted later in drug development (ICH M3 R2, 2009). Male subjects with partners of 
childbearing potential must practice a highly effective method of birth control for the 
duration of the study and continuing for 5 months after the last dose of investigational 
product. Refer to Section 12.5 for additional contraceptive information.
3.2.2.5
Clinical Experience
As of August 2018, in the ongoing FIH single ascending dose trial of AMG 598 in 
subjects with obesity, 56 subjects have received a single dose of AMG 598 or placebo. 
The blinded safety data through day 15 of the 560 mg SC dose cohort supports the dose 
range to be evaluated in this study.  In addition, a cohort where subjects received a
single dose of AMG 598 560 mg SC in combination with liraglutide 0.6 mg SC QD for 
7 days has completed dosing.  Single ascending doses of AMG 598 have been safe and 
generally well tolerated.  No SAEs or deaths have been reported, and most AEs 
reported were mild, with one moderate adverse event associated with gastroenteritis.
3.2.3
Non-Amgen Non-investigational Product Background:  Liraglutide
(Saxenda®)
Liraglutide, a GLP-1 receptor agonist, is indicated as an adjunct to a 
reduced-calorie diet and increased physical activity for chronic weight management in 
adult patients with an initial BMI of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater 
(overweight) in the presence of at least one weight-related comorbid condition 
(eg hypertension, type 2 diabetes mellitus, or dyslipidemia).
Cohorts 2, 4, and 6: Subjects will begin receiving liraglutide (0.6 mg SC QD) on day 1, 
and increased doses of liraglutide (0.6 mg dose increment every 7 days), up to the full 
dosage of 3.0 mg by week 5, and continue to receive 3.0 mg SC, QD until Day 84, 
inclusive.  If subjects do not tolerate an increased dose during dose escalation, dose 
escalation may be delayed for approximately one additional week. See Table 3-1.
Table 3-1.  Liraglutide (Saxenda®) Dose Escalation Schedule
Week
1
2
3
4
5
Daily Dose (mg)
0.6
1.2
1.8
2.4
3
Cohort 7: Subjects that have been on liraglutide (3.0 mg SC QD) for 6 months will 
continue to be administered liraglutide (3.0 mg SC QD) for the duration of the study.
Liraglutide is manufactured by Novo Nordisk Inc. and is provided as an injection-ready, 
pre-filled, multi-dose pen containing 3 mL (6 mg/mL).  Doses of liraglutide will be 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
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self-administered with the pre-filled multi-dose pen.  Details will be provided in the 
Investigational Product Instruction Manual (IPIM) and the subject will be trained on the
Instructions for Use (IFU).  A dosing diary will be used to track self-administered dosing.
Refer to the regional manufacturer package insert for additional information.
3.3
Benefit/Risk Assessment
The potential benefits of AMG 598 alone, or in combination with liraglutide, include the
anticipated weight loss, and improved cardiovascular risk factors associated with weight 
loss.  Potential risks of AMG 598, as anticipated from animal data and the literature, are 
described below in Section 3.3.3.
The following benefit risk assessment supports the conduct of this clinical trial. Please 
refer to the Investigator’s Brochure for further data on AMG 598.
3.3.1
Therapeutic Context
Obesity, with its increasing incidence, associated comorbidities and negative impact on 
well-being, constitutes a growing crisis and critical unmet need in healthcare. Internal 
non-clinical studies have established a wealth of evidence that AMG 598 targets a 
pathway that both genetically and physiologically is associated with weight loss. 
AMG 598 was well tolerated in the FIH single ascending dose study. The current 
multi-dose study examines the safety and preliminary efficacy of AMG 598 as a weight 
loss therapy.
3.3.2
Key Benefits
The key anticipated benefits of AMG 598 include clinically meaningful weight loss and its 
associated benefits of improved cardiovascular health, glucose metabolism, and overall 
well-being, as well as potential reduced cancer risk.
3.3.3
Key Risks
Potential risks of AMG 598, as anticipated by evidence from animal data and the 
literature, include those commonly associated with therapeutic antibody administration 
including local (eg, injection site) reactions, systemic (eg, hypersensitivity) reactions and 
immunogenicity (ie, the development of anti-AMG 598 antibodies). 
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Key potential risks detailed below:
1. Injection or allergic reaction – Injection or allergic reactions are potential human 
risks with AMG 598 based on clinical experience with other biologic agents. 
Subjects will be monitored during and after administration of AMG 598 for 
infusion or allergic reactions, such as fever, chills, shaking, hypotension, 
wheezing, itching, nausea, and/or rash. Following SC administration, subjects will 
be monitored for injection site reactions, which may include redness, 
tenderness/pain, bruising, warmth, swelling, itching, and/or infection.
2. Immunogenicity – As a biologic, AMG 598 poses a potential risk of anti-drug 
antibodies (ADA). Antidrug antibodies have been observed in GLP studies 
involving cynomolgus monkeys. However, induction of antibodies against human 
proteins in animals are not predictive of immunogenicity in humans. Subjects will 
be monitored for potential effects of ADA that may include antibody mediated 
AEs, altered drug exposure, or loss of efficacy. Pharmacokinetic and 
immunogenicity samples from subjects in this Phase 1 study will be sent to 
central laboratories for storage and ADA analysis will be performed.
3. Impaired Glucose Tolerance - Given the role of the GIP-GIPR axis in the 
production of insulin in response to food ingestion, there is a theoretical risk that 
GIPR antagonism with administration of AMG 598 could negatively affect glucose 
homeostasis, resulting in impaired glucose tolerance due to decreased insulin 
release following food consumption. Pharmacology studies in diet-induced 
obese mice with a murine surrogate antibody to GIPR, and pharmacology and 
toxicology studies in normal weight and obese mice and cynomolgus monkeys 
with AMG 598, showed no negative impact on glucose homeostasis with GIPR 
antagonism as measured by either fasting serum glucose and insulin levels or as 
serum glucose and insulin responses to glucose tolerance tests. The MMTT to 
be conducted in cohorts 1, 3, and 5 will assess the potential of AMG 598 to 
decrease insulin and increase blood glucose levels after a standardized
carbohydrate load.
Please refer to the Investigator’s Brochure for further data on AMG 598.
3.3.3.1
Risks
Other potential risks identified by evidence from animal data, the literature, or the first in 
human study (FIH) include the following: 
1. Increased Bilirubin – Animal studies have demonstrated minimal transient 
increases in total bilirubin that are considered non-adverse. Subjects will be 
monitored for changes in bilirubin.
2. Gastrointestinal effects - Reduced food intake is expected with AMG 598 
administration due to the mechanism of action of AMG 598 and nonclinical 
observations in DIO mice and overweight cynomolgus monkeys. While food 
intake was not directly measured, subjects did report a mild loss of appetite in the 
FIH study after a single dose of AMG 598.  In the current study, subjects who 
receive AMG 598 in combination with liraglutide may experience more severe or 
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prolonged gastrointestinal side effects, such as nausea and vomiting, in greater 
magnitude than the known side effects of liraglutide alone. Blinded safety data of 
the FIH single ascending dose study reported 12 (21%) of 56 subjects reported 
one or more AEs in the GI disorder organ class, most of mild severity, with one 
moderate severity event of gastroenteritis. Clinical signs and symptoms will be 
monitored during the study.
Based only on review of the literature, the following assessments have been 
incorporated into this study: 
1. Bone turnover assessments
As nonclinical evidence in the literature indicates that GIPR signaling may play 
an anabolic role in the maintenance of bone quality and/or bone mineral density 
(Hansen et al, 2017; Holst et al, 2016; Torekov et al, 2014), a series of animal 
studies were conducted where no differences in bone turnover markers, bone 
mass, bone density, or microarchitecture in the bones were observed in animals 
receiving mouse GIPR antibody (mAb 2.63.1) indicating that in a
hormonally-deficient state, GIPR antagonism does not enhance bone loss. In 
addition, no changes in bone turnover markers were observed in the 13-week 
toxicology study of AMG 598 in the cynomolgus monkey.  However, to monitor 
for bone loss in the current multiple dose human study, bone turnover serum 
markers and bone density scans (by DXA) are included as assessments.
2. Neurologic assessments
There exists a limited data set in the literature that indicates that impairment of 
GIPR signaling may decrease sensory and motor neuron function 
(Yu et al, 2016; Okawa et al, 2014; Buhren et al, 2009). While the nonclinical 
animal studies conducted do not support this evidence, neurological exams are 
incorporated as part of the safety assessments in the current study. The 
neurological exam will include peripheral sensory and motor evaluation, and 
assessment of gait, pain, position, strength and reflexes.
3. Suicidal ideation assessments
It is unknown whether AMG 598 may be a central nervous system (CNS)-active 
study treatment or associated with an increased risk of suicidal ideation or 
behavior. Liraglutide is a CNS-active study treatment.  In addition, there have 
been some reports of suicidal ideation and behavior when liraglutide has been 
given to some subjects with obesity. To characterize and mitigate risk, eligibility 
and monitoring criteria including PHQ-9 and CSSR-S are included in the study 
assessments. 
For full description please refer to Table 2-1 to Table 2-3 Schedule of Activities.
Refer to the AMG 598 IB, Section 7 for additional information related to potential side 
effects.
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4.
Objectives, Endpoints and Hypotheses
4.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the safety and tolerability 
of multiple SC doses of AMG 598 
administered alone or in 
combination with liraglutide in 
subjects with obesity

Subject incidence of treatment-emergent AEs

Safety laboratory data, vital signs, and ECGs
Secondary

To characterize the PK of multiple 
SC doses of AMG 598 administered 
alone or in combination with 
liraglutide in subjects with obesity

AMG 598 PK parameters may include, but are 
not limited to, maximum observed concentration 
(Cmax), time of maximum observed 
concentration (tmax), and area under the 
concentration time curve (AUC) 
Exploratory

To characterize the PD effects of 
AMG 598 
PD parameters: 
o
Concentrations of fasting glucose, insulin, 
c-peptide, glucose dependent insulinotropic 
polypeptide (GIP), glucagon-like polypeptide 
type 1 (GLP-1), glucagon, and free fatty 
acid (FFA)
o
Concentration-time profiles and AUC for 
metabolic parameters following a mixed 
meal tolerance test
o
Lipid levels, including but not limited to, total 
cholesterol, low density lipoprotein 
cholesterol (LDL-C), high density lipoprotein 
cholesterol (HDL-C), and triglycerides
o
Hemoglobin A1c (HbA1c)
o
Potential biomarkers including, but not 
limited to, inflammatory and adipose tissue 
markers

To assess the effects of AMG 598 
on body weight, waist circumference 
and BMI

Change in body weight, waist circumference, 
and BMI

To assess the effect of AMG 598 on 
bone mineral density by dual energy 
x-ray absorptiometry (DXA) (cohorts 
1-6)

Changes in bone mineral density as measured 
by DXA (cohorts 1-6)

To assess the effect of AMG 598 on 
body composition (cohort 7)

Changes in body composition as measured by 
whole body DXA (cohort 7)

To evaluate the immunogenicity of 
AMG 598

Incidence of anti-AMG 598 antibody formation
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4.2
Hypotheses

AMG 598 will be safe and well tolerated following multiple SC dose administrations in 
subjects with obesity across the dose range evaluated

AMG 598 in combination with liraglutide will be safe and well tolerated following 
multiple SC dose administrations in subjects with obesity across the dose range 
evaluated

AMG 598 PK profile following multiple SC dose administrations will support selection 
of dose and frequency of administration in future multi-dose trials of AMG 598
5.
Study Design
5.1
Overall Design
This is a randomized, placebo-controlled, double-blind, multiple ascending dose study in 
subjects with obesity.  The study consists of 7 cohorts with SC administration of 
AMG 598 or matching placebo with and without liraglutide.
Approximately 108 subjects (8 per cohort for cohorts 1-6, 60 for cohort 7) will be 
enrolled.  This study will be conducted at approximately 30 sites in the US.
For cohorts 1 to 6, eight subjects will be randomized to receive AMG 598 or placebo SC
every 4 weeks (Q4W) x 3 in a 3:1 ratio at the proposed dose levels of 70, 210, and
420 mg on days 1, 29, and 57.  All subjects in cohorts 1, 3, and 5 will undergo MMTT on 
day -1, 6 (+/- 1 day), and day 64 (+/- 1 day). Subjects in cohorts 2, 4, 6 and 7 will also 
receive liraglutide at up to 3.0 mg SC QD per the treatment schedule.
For cohort 7, sixty subjects that have been on a stable dose of liraglutide (3.0 mg SC 
QD) for at least 6 months will be randomized in a 1:1 ratio to receive AMG 598 or 
placebo. Subjects will continue to receive liraglutide (3.0 mg SC QD) and receive 
one dose of placebo on day -28, as part of a 4-week run-in. Subjects will then receive 
AMG 598 420 mg or placebo SC Q4W on days 1, 29, 57 in addition to stable liraglutide 
(3.0 mg SC QD).
Escalation to a higher dose cohort (cohorts 1 to 6) will only proceed when the previous 
dose regimen has been found to be safe and reasonably tolerated based on available 
safety and laboratory data through study day 36 for at least 6 out of 8 subjects dosed
and upon unanimous recommendation at the DLRM.  The planned dose escalation 
schedule may be modified based on treatment-emergent data (eg, safety and/or PK).
Subsequent dosing will be guided by tolerability and safety. Dose adjustments for 
AMG 598, if any, will be made on a treatment cohort and not on an individual subject 
basis, and will be agreed upon by Amgen in conjunction with the Principal Investigator. 
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The overall study design is described by a study schema in Section 2.1. The endpoints 
are defined in Section 4.1.
5.2
Number of Subjects
Approximately 108 subjects will be enrolled in the study, with 8 subjects per cohort 
(cohort 1-6) and 60 subjects in cohort 7. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1.
5.2.1
Replacement of Subjects
Subjects who withdraw from the study or who discontinue study drug administration 
prematurely may be replaced at the discretion of Amgen in consultation with the 
investigator. The replacement subject will be assigned to receive the identical treatment 
as the replaced subject.
5.2.2
Number of Sites
Approximately 1-4 investigative sites in the United States will enroll into cohorts 1-6 and 
approximately 30 investigative sites in the United States will enroll into cohort 7.
5.3
End of Study
5.3.1
End of Study Definition
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early.
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit).
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up), as 
applicable.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 36 of 111
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5.3.2
Study Duration for Subjects
Cohorts 1 to 6
Subject participation will last up to approximately 235 days. This includes a 28-day 
screening period, a period of up to 2 days prior to investigational product (IP) 
administration and an on-study period lasting up to 207 days.
Cohort 7
Subject participation will last up to approximately 263 days. This includes a 28-day 
screening period, a 28-day run-in period, and an on-study period lasting up to 207 days.
5.4
Justification for Investigational Product Dose
The rationale for the dose selection and frequency (Q4W) in the current study is based 
on PK/PD analysis of animal data, as well as PK data from the ongoing FIH single 
ascending dose study of AMG 598 (20170138). In the FIH study, all 7 cohorts, totaling 
56 subjects, have received a single dose of AMG 598 or placebo (AMG 598 dose ranges 
from 21 mg to 560 mg). Preliminary review of the PK data in the FIH single ascending 
dose study demonstrated linear PK and dose proportional Cmax (AUC data pending), with
a half-life of approximately 27 days (through 560 mg SC). The median peak serum 
concentrations after SC administration were observed in approximately 7 days. The 
anticipated exposure margins for the highest planned AMG 598 dose in the current study 
(420 mg SC Q4W) for Cmax and AUC are 61 and 62, respectively calculated from the 
Cmax and AUC at the NOAEL (200 mg/kg) of AMG 598 in combination with liraglutide in 
the 13-week toxicology study in monkeys (Table 5-1). The blinded safety data from the 
AMG 598 FIH single ascending dose study through day 15 of the 560 mg SC dose 
cohort supports the dose range to be evaluated in this study.  In addition, a cohort where 
subjects received a single dose of AMG 598 560 mg SC in combination with liraglutide 
0.6 mg SC QD for 7 days has completed dosing.  Single ascending doses of AMG 598 
have been safe and generally well tolerated.  No SAEs or deaths have been reported, 
and most AEs reported were mild, with one moderate adverse event associated with 
gastroenteritis.
Based on the available PK and safety data from cohorts 1 to 6 reviewed at the DLRM #4 
(Figure 2-1 Study Schema), the dose regimen for cohort 7 will be AMG 598 420 mg or 
placebo SC Q4W x 3.  AMG 598 420 mg or placebo Q4W SC x 2 (safety data evaluated 
through study day 36) dosed concomitantly with liraglutide escalation was safe and 
generally well tolerated.  
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 37 of 111
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Table 5-1.  Estimated Exposure Margins of AMG 598 for Multiple Doses (Q4W)
Estimated Exposure Margins of AMG 598 for Multiple Doses (NOAEL=200 mg/kg)
Cohorts
Dose
Route
Predicted AUC0-28day,last 
dosea
Predicted Cmax, last 
dosea
Exposure 
Marginsb
(mg)
(µg·day/mL)
(µg/mL)
AUCc
Cmaxd
1 and 2
70
SC
298
12.8
370
365
3 and 4
210
SC
893
38.3
124
122
5 and 6
420
SC
1790
76.6
62
61
a PK data (up to 280 mg cohort) from AMG 598 FIH study is used for PK prediction
b Based on NOAEL of 200 mg/kg AMG 598 as a monotherapy or in combination with liraglutide in 
cynomolgus monkeys; AUC0-7day (study days 85 to 92) = 27600 µg·day/mL (662000 hr*µg/mL divided by 
24 hr/day) and Cmax (study day 86) = 4670 µg/mL from 6 animals that were administered both 200 mg/kg 
AMG 598 SC weekly and 1.8 mg Liraglutide SC daily for 13 weeks. 
c AUC margin = [AUC0-7day,last dose,cyno]×4/[AUC0-28day, last dose human] 
d Cmax margin = [Cmax,last dose,cyno]/[Cmax,last dose human]
5.5
Patient Input on Study Design
No patient input was obtained for the study design.
6.
Study Population
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).
For Cohorts 1-6, eligibility criteria will be evaluated during screening period.
For Cohort 7, eligibility criteria will be evaluated during the screening period.  Subjects 
will not be randomized into a treatment group until after successful completion of the 
run-in period. Subjects who do not complete the run-in or Part 2 criteria at Day 1 will be 
removed from study and may be replaced.
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 12.3).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided.
6.1
Inclusion Criteria: Part 1
Subjects are eligible to be included in the study only if all of the following criteria apply:
101
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures
102
Males and females ≥18 to ≤65 years of age, at the time of signing the informed 
consent
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 38 of 111
CONFIDENTIAL
103
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in the protocol
104
Except for obesity, otherwise healthy (or for cohort 7, medically stable as 
described below) as determined by the investigator or medically qualified 
designee based on a medical evaluation including medical history, physical 
examination, laboratory tests, and ECGs on day -2 (cohorts 1, 3, and 5), or day -
1 (cohorts 2, 4, and 6), and at screening (cohorts 1-7)
For cohort 7, chronic stable medical conditions that are not otherwise 
excluded are permitted if in the opinion of the investigator, and the Amgen 
Medical Monitor if consulted, do not pose a risk to subject safety or 
interfere with the study evaluation, procedures or completion.
105
Body mass index (BMI) between ≥30.0 kg/m2 and ≤ 40.0 kg/m2
106
Have a stable body weight (less than 5 kg self-reported change during the 
previous 8 weeks) prior to screening
107
Willing to maintain current general diet and physical activity regimen, except for 
the physical activity in the 72 hours before each blood sample collection for the 
clinical laboratory analysis, which should not be strenuous
108
Female subjects must be of non-reproductive potential (cohorts1-6)
Postmenopausal as defined as:

Age of ≥ 55 years with no menses for at least 12 months; OR

Age < 55 with no menses within the past 12 months AND with a 
follicle-stimulating hormone level > 40 IU/L or according to the definition 
of “postmenopausal range” for the laboratory involved; OR

History of hysterectomy; OR

History of bilateral oophorectomy
109
Male subjects must agree to practice an acceptable method of effective birth 
control while on study through 5 months after receiving study drug.  Acceptable 
methods of effective birth control include sexual abstinence; vasectomy; or a 
condom with spermicide (males) in combination with barrier methods 
(diaphragm, cervical cap or cervical sponge), hormonal birth control or IUD 
(females) 
110
Male subjects must be willing to abstain from sperm donation while on study 
through 5 months after receiving study drug
111
For cohort 7, currently on liraglutide 3.0 mg SC QD with history of taking 
liraglutide 3.0 mg SC QD continuously for ≥ 6 months and liraglutide being 
generally well tolerated per the investigator’s discretion (and subjects plan to 
continue liraglutide 3.0 mg SC QD) 
6.2
Exclusion Criteria: Part 1
Subjects are excluded from the study if any of the following criteria apply:
Other Medical Conditions
201
History or clinical evidence of diabetes mellitus, including a fasting glucose 
≥ 125 mg/dl (6.9 mmol/L) and/or HbA1c > 6.5% at screening
202
Triglycerides ≥ 5.65 mmol/L (ie, 500 mg/dL) at screening 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 39 of 111
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203
Hepatic liver enzymes ALT, AST, alkaline phosphatase (ALP), or total bilirubin 
(TBIL) levels > 1.5 (cohorts 1-6) or > 2 (cohort 7) times the upper limit of normal 
(ULN) at screening
204
History or clinical evidence of bleeding diathesis or any coagulation disorder, 
including prothrombin time (PT), activated partial thromboplastin time (APTT), 
International normalized ratio (INR) or platelet count outside of the laboratory’s 
normal reference range at screening
205
Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as 
thyroid-stimulating hormone > 6 mIU/L or <0.4 mIU/L
206
A corrected QT interval (QTc) at screening of > 450 msec in males or 
> 470 msec in females or history of long QT syndrome.
207
For cohorts 2, 4, 6, and 7, screening calcitonin ≥ 50 ng/L
208
For cohorts 2, 4, 6, and 7 subjects with a family or personal history of medullary 
thyroid carcinoma or multiple endocrine neoplasia type 2; a personal history of 
non-familial medullary thyroid carcinoma; confirmed chronic pancreatitis or 
idiopathic acute pancreatitis, or gallbladder disease (ie, cholelithiasis or 
cholecystitis) not treated with cholecystectomy
209
Subjects with a history of renal impairment or renal disease and/or estimated 
glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2
210
Obesity induced by other endocrinologic disorders (eg Cushing’s Syndrome)
211
Previous surgical treatment for obesity (excluding liposuction if performed 
>1 year before trial entry)
212
History of major depressive disorder
213
History of other severe psychiatric disorders, eg schizophrenia, bipolar disorder
214
A patient health questionnaire (PHQ-9) score of ≥ 10
215
Any lifetime history of a suicidal attempt or of any suicidal behavior 
216
Any suicidal ideation as identified by endorsement of (answered yes to) any of 
the items numbered 1-5 on the Columbia Suicide Severity Rating Scale 
(C-SSRS) 
217
Surgery scheduled for the trial duration period, except for minor surgical 
procedures, at the discretion of the investigator
218
History of malignancy of any type, other than in situ cervical cancer or surgically 
excised non-melanomatous skin cancers occurring more than 5 years prior to 
randomization
219
Positive results for human immunodeficiency virus (HIV) antibodies, hepatitis B 
surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus 
ribonucleic acid (RNA).  For hepatitis C, hepatitis C antibody (HepCAb) testing is 
done at screening, followed by hepatitis C virus RNA by polymerase chain 
reaction (PCR) if hepatitis C antibody is positive
Approved 
 
 


Product:  AMG 598  
Protocol Number:  20170139 
Date:  25 June 2019 
Page 40 of 111 
CONFIDENTIAL 
 
 
220 
Subject has systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure  
≥ 90 mm Hg (cohorts 1-6) or ≥ 95 mm Hg (cohort 7) at screening, or on day -2 
(cohorts 1, 3, 5) or day -1 (cohorts 2, 4, 6) or on day -28 (cohort 7).  For each 
visit, if the initial blood pressure is elevated, the reading may be repeated once 
at least 15 minutes later and the lower of the 2 readings may be used.  
221 
History of myocardial infarction or stroke, or hospitalization for cardiovascular 
disease in the 6 months prior to screening 
Prior/Concomitant Therapy 
222 
Cohorts 1 to 6:  Use of the following agents are excluded unless there is a prior 
consultation between the Principal Investigator and Amgen Medical Monitor: 
• 
Prescription and nonprescription drugs within 14 days or 5 half-lives, 
whichever is longer, before the first dose of investigational product, with 
exception to acetaminophen up to 2 g per day for analgesia, and hormone 
replacement therapy (eg, estrogen, thyroid)  
• 
All herbal medicines, vitamins, and supplements consumed by the subject 
within the 30 days prior to receiving the first dose of investigational 
product. Exceptions must be reviewed and approved by the investigator 
and Amgen Medical Monitor 
• 
Current or history of treatment with medications that may cause significant 
weight gain, within 3 months prior to screening, including systemic 
corticosteroids (except for a short course of treatment, ie, 7−10 days),  
tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers  
(eg, imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, 
chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its 
derivatives, and lithium) 
• 
Current participation (or within the last 3 months) in an organized weight 
reduction program or currently using or used within 3 months before 
screening: pramlintide, sibutramine, orlistat, zonisamide, topiramate, 
phentermine, naltrexone, bupropion, lorcaserin, or metformin (either by 
prescription or as part of a clinical trial) 
Cohort 7:  Use of the following agents are excluded unless there is a prior 
consultation between the Principal Investigator and Amgen Medical Monitor: 
• 
Current or history of treatment with medications that may cause significant 
weight gain, within 3 months prior to screening, including systemic 
corticosteroids (except for a short course of treatment, ie, 7−10 days), 
tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (eg, 
imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, 
chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its 
derivatives, and lithium)  
• 
Currently using or used within 3 months before screening including, but not 
limited to: pramlintide, sibutramine, orlistat, zonisamide, topiramate, 
phentermine, naltrexone, bupropion, lorcaserin, or metformin (either by 
prescription or as part of a clinical trial).  
• 
Current participation in diets that include extreme calorie restriction or 
other activity or dietary practices that cannot be maintained for the duration 
of trial.  
Approved 
 
 
AMGEN® 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 41 of 111
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Prior/Concurrent Clinical Study Experience
223
Prior exposure to AMG 598, or currently receiving treatment in another 
investigational device or drug study, or less than 30 days, or 5 half-lives 
(whichever is longer), since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded
Other Exclusions
224
Female subjects who are lactating/breastfeeding or who plan to breastfeed while 
on study through 5 months after receiving the last dose of investigational product
225
Male subjects with partners who are pregnant or planning to become pregnant 
while the subject is on study through 5 months after receiving the last dose of 
investigational product
226
Female subjects of childbearing potential with a positive pregnancy test 
assessed at screening (cohort 7) and/or day -1 (cohorts 2, 4, 6) or day -2 
(cohorts 1, 3, 5) by a serum pregnancy test and/or urine pregnancy test
227
Female subjects (cohort 7) of childbearing potential unwilling to use highly 
effective method of contraception during treatment and for an additional 
5 months after the last dose of AMG598. Refer to Section 12.5 for additional 
contraceptive information.
228
Subject has known sensitivity to AMG 598 or components thereof or a history of 
drug or other allergy that is in the opinion of the investigator or medical monitor 
(if appropriate), contraindicates their participation
229
Subject has known sensitivity to mammalian derived products
230
For cohorts 2, 4, 6 and 7, subject has a known sensitivity to liraglutide or any 
product components
231
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge
232
Subject has a history or evidence of any other clinically significant disorder, 
condition or disease (with the exception of those outlined above) that, in the 
opinion of the investigator or Amgen Medical Monitor, if consulted, would pose a 
risk to subject safety or interfere with the study evaluation, procedures or 
completion
233
Subject is unwilling or unable to limit alcohol consumption throughout the course 
of the study.  Alcohol is prohibited 48 hours prior to day -2 (cohorts 1, 3, and 5) or 
day -1 (cohorts 2, 4, 6), day -28 (cohort 7) and is limited to no more than to 2 
drinks per day for males and 1 drink per day for females for the duration of the 
study (1 drink being equivalent to 12 ounces of regular beer, 8 to 9 ounces of 
malt liquor, 5 ounces of wine, or 1.5 ounces of 80 proof distilled spirits)
234
Subject uses nicotine or tobacco containing products (including but not limited to: 
snuff, chewing tobacco, cigars, cigarettes, e-cigarettes, pipes, or nicotine 
patches) within 6 months before screening. Subject is unwilling or unable to 
abstain from nicotine or tobacco, cigars, cigarettes, pipes, or nicotine patches
throughout the course of the study
235
Subject is tested positive for alcohol and/or drugs of abuse at screening.
Approved 
 
 


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Protocol Number:  20170139
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CONFIDENTIAL
236
History of substance abuse (ie, alcohol, licit or illicit drugs) within 12 months 
before screening
237
Subject is unwilling to refrain from strenuous exercise (eg, heavy lifting, weight 
training, and aerobics) for 72 hours prior to each blood collection for clinical 
laboratory tests
238
Subject has donated or lost ≥ 500 mL of blood or plasma within 60 days of day -1
6.3
Inclusion Criteria Part 2 (Cohort 7 only)
112
No change in eligibility since screening as determined by the investigator or 
medically qualified designee based on a medical evaluation including medical 
history, physical examination, vital signs and ECGs on day 1
113
Compliant in taking liraglutide 3.0 mg SC QD and liraglutide being generally well 
tolerated per the investigator’s discretion 
6.4
Exclusion Criteria Part 2 (Cohort 7 only)
239
A patient health questionnaire (PHQ-9) score of ≥ 10 up to day 1
240
Any suicidal ideation as identified by endorsement of (answered yes to) any of 
the items numbered 1-5 on the Columbia Suicide Severity Rating Scale 
(C-SSRS) up to day 1
241
Subject has systolic blood pressure ≥150 mm Hg or diastolic blood pressure 
≥ 95 mm Hg on day 1.  For each visit, if the initial blood pressure is elevated, the 
reading may be repeated once at least 15 minutes later and the lower of the 
2 readings may be used
242
A corrected QT interval (QTc) of > 450 msec in males or > 470 msec in females
up to day 1
6.5
Lifestyle Restrictions
6.5.1
Meals and Dietary Restrictions
Subjects will be required to fast overnight for at least 10 hours prior to all blood draws for
routine clinical laboratory, lipid profile and PD assessments per Schedule of Activities.
After dosing, no water is allowed for 2 hours, after which water is allowed ad libitum.
6.5.1.1
Mixed Meal Tolerance Test (MMTT)
Subject in cohorts 1, 3 and 5 will receive a mixed meal on day -1, day 6 (+/- 1 day), and 
64 (+/- 1 day). A mixed meal tolerance test (to be initiated early in the morning) will be 
performed after an overnight fast for at least 10 hours. The meal will be a standardized 
meal (ie, 2 bottles or cans of Ensure Plus®) for all subjects and will be provided by the
site. Subjects can take up to 10 minutes to consume the 2 bottles or cans of Ensure 
Plus®. As part of the MMTT, multiple blood samples will be collected per the Schedule of 
Activities.
Please refer to the central laboratory manual for instructions on the collection of these
samples.
Approved 
 
 


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Protocol Number:  20170139
Date:  25 June 2019
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6.5.2
Caffeine, Alcohol, and Tobacco
Subjects must limit alcohol consumption throughout the course of the study. Alcohol is
prohibited 48 hours prior to admission to the research facility on day -2 (cohorts 1, 3 and 
5), day -1 (cohorts 2, 4, 6), day -28 (cohort 7). Additionally, for cohorts 2, 4 and 6, 
alcohol is prohibited 48 hours prior to day 6 +/- 1 day and day 64 +/- 1 day. For all 
subjects, alcohol consumption is limited to no more than 2 drinks per day for males, 
1 drink per day for females, for the duration of the study (1 drink is equivalent to 
12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine or 1.5 ounces 
of 80 proof distilled spirits).
Only non-nicotine or non-tobacco using subjects should be enrolled. Subjects should not
have used any nicotine or tobacco containing products within the last 6 months prior to
screening. Subjects must abstain from nicotine or tobacco containing products (including 
but not limited to: snuff, chewing tobacco, cigars, cigarettes, e-cigarettes, pipes, or 
nicotine patches) throughout the screening period and for the duration of the study. 
6.5.3
Activity
Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, and 
aerobics) for 72 hours before each blood collection for clinical laboratory tests.  Subjects 
may participate in light recreational activities during the 72-hour period prior to blood 
collection (eg, walking, watching television, reading).
6.6
Subject Enrollment
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 12.3).
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures.
For cohorts 1-6, a subject is considered enrolled when the investigator decides that the 
subject has met all (Part 1) eligibility criteria.  The investigator is to document this 
recommendation and date, in the subject’s medical record and in/on the enrollment case 
report form (CRF).
For cohort 7, the subject will be enrolled after meeting Part 1 eligibility criteria at 
screening.  The subject will be randomized into a treatment regimen if they complete all 
run-in procedures and meet Part 2 eligibility prior to dosing on day 1. Subjects who do 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 44 of 111
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not complete all run-in procedures, do not meet Part 2 criteria, or meet any other study 
discontinuation criteria, will complete an early termination run-in visit and will be 
removed from study. Subjects who are terminated prior to receiving AMG 598/placebo 
may be replaced.
Each subject who enters into the screening period for the study (defined as the time
when the subject signs the informed consent) receives a unique subject identification 
number before any study-related activities/procedures are performed.  Subjects enrolled 
into cohorts 1-6 will be randomized manually.  The subject identification number will be 
assigned via IVRS/IWRS for Cohort 7.  This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject.
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. Re-screening of subjects is acceptable upon discussion with and 
approval by the Amgen Medical Monitor.
6.7
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled.  A minimal set of screen failure information will be 
collected that includes demography, screen failure details, eligibility criteria, medical 
history, prior therapies, and any serious adverse events.
Individuals who do not meet the criteria for participation in this study (screen failure) may
be rescreened with approval by the Amgen Medical Monitor. Refer to Section 9.1.1.
7.
Treatments
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol.
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively.
Approved 
 
 


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The IPIM, a document external to this protocol, contains detailed information regarding 
the storage, preparation, destruction, and administration of each treatment shown in 
Table 7-1 below.
7.1
Treatment Procedures
7.1.1
Investigational Products
Table 7-1.  Study Treatments
Study Treatment 
Name
Amgen Investigational Product:a
AMG 598
Placebo
Dosage Formulation
Colorless to slightly yellow liquid 
drug product in a 5 mL glass vial 
(12 vials per box) filled with a 1 mL 
deliverable volume of 70 mg/mL.  
The specific packaging dimensions 
are 8.9 x 6.7 x 4.5 cm.
Placebo will be presented in 
identical containers, and 
stored/packaged the same as 
AMG 598
Unit Dose 
Strength(s)/
Dosage Level(s) and 
Dosage Frequency
Varies per treatment cohort
Route of 
Administration
SC injection
Accountability
The unblinded pharmacist must 
provide AMG 598 or placebo from 
the Amgen supplied stock 
according to the unblinded 
randomization log. The 
concentration of preparation, 
quantity, dose, start date/time, and 
lot number of AMG 598 is to be 
recorded on each subject's 
CRF(s).
Dosing Instructions
Administration of AMG 598 or 
placebo requires specific training 
which must be completed and 
documented prior to undertaking 
any administration related 
activities. AMG 598 will be 
delivered as 1+ injections to the 
abdomen. Dosing instructions are 
provided in the IPIM. 
SC = subcutaneous
a AMG 598 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures.
7.1.2
Non-investigational Products
Liraglutide (Saxenda®) is manufactured by Novo Nordisk Inc. and is provided as an 
injection-ready, pre-filled, multi-dose pen containing 3 mL (6 mg/mL).
Approved 
 
 


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Liraglutide is sourced and provided by the site and is not manufactured, packaged or 
distributed using Amgen clinical study drug distribution procedures
Cohorts 2, 4, and 6: Subjects will start the first dose of liraglutide (0.6 mg SC QD) on 
day 1 and increase the dose of liraglutide by 0.6 mg dose increment every 7 days, up to 
the full dosage of 3.0 mg by week 5 and remain on 3.0 mg through Day 84. If subjects 
do not tolerate an increased dose during dose escalation, dose escalation may be 
delayed for approximately one additional week.
Cohort 7: Subjects that have been on liraglutide (3 mg SC QD) for 6 months will 
continue to receive liraglutide (3 mg SC QD) for the duration of the study.
For Cohorts 2, 4, 6 and 7, liraglutide administration should occur 30 – 60 mins after 
AMG 598 administration on days 1, 29 and 57 when both products are administered. 
Liraglutide must be to be stored, prepared and dosed according to the package insert 
and IPIM. 
7.1.3
Medical Devices
This section is not applicable for the Amgen investigational product. There are no 
Amgen medical devices or Amgen combination products in this study.
Other non-investigational medical devices may be used in the conduct of this study, 
including the liraglutide administration pen, or as part of standard care.
Non-investigational, non-Amgen, medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.
7.1.4
Other Protocol-required Therapies
Other than Liraglutide (Saxenda®), there are no other protocol-required therapies.  
7.1.5
Other Treatment Procedures
This section is not applicable.
7.1.6
Product Complaints
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.
Approved 
 
 


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This includes drug(s), device(s), or combination product(s) provisioned and/or 
repackaged/modified by Amgen (ie, investigational product: AMG 598/placebo).
Any product complaint(s) associated with investigational product (AMG 598/placebo) 
supplied by Amgen are to be reported according to the instructions provided in the IPIM.
Any product complaint(s) associated with non-investigational product (ie, liraglutide) not 
supplied by Amgen are to be reported to the manufacturer and outcome of any inquiry 
should be reported to Amgen according to the instructions provided in the IPIM.
7.1.7
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period
Cohorts 1-6: With exception to acetaminophen up to 2 g per day for analgesia and 
hormone replacement therapy (eg, estrogen, thyroid), use of any over-the-counter or 
prescription medications within the 14 days or 5 half-lives (whichever is longer) prior to 
dosing on day 1, and for the duration of the study, is not permitted unless to treat a 
medical emergency. In addition, it is recommended that subjects avoid starting new or 
changing herbal medicines, vitamins and supplements unless reviewed and approved by 
the Principal Investigator and Amgen Medical Monitor within 30 days prior to dosing on 
day 1 and for the duration of the study. Any changes regarding concomitant medications 
should be recorded on the subject’s source documents and the CRF along with the 
reason for the change.
Cohort 7: Any over-the-counter or prescription medication that is known or suspected to 
have activity on metabolism or weight will not be allowed during the study, including but 
not limited to:

Medications that may cause significant weight gain, including systemic 
corticosteroids (except for a short course of treatment, ie, 7−10 days), tri-cyclic 
antidepressants, atypical antipsychotic and mood stabilizers (eg, imipramine, 
amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, 
clozapine, olanzapine, valproic acid and its derivatives, and lithium).

Medications that may cause significant weight loss, including, pramlintide, 
sibutramine, orlistat, zonisamide, topiramate, phentermine, naltrexone, 
bupropion, lorcaserin, or metformin.  

Diets that include extreme calorie restriction or other activity or dietary practices 
that cannot be maintained for the duration of trial will not be permitted.
7.2
Method of Treatment Assignment
On day -2 (cohorts 1, 3 and 5) or day -1 (cohorts 2, 4 and 6), or day 1 (cohort 7) eligible 
subjects will be randomized to a treatment assignment in a double-blind fashion. Within 
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each cohort, subjects will be randomly assigned in a 3:1 ratio (or 1:1 ratio in cohort 7) to 
receive either AMG 598 or placebo.
The randomization will be performed manually for cohorts 1-6 and, for cohort 7, by 
IVRS/IWRS. Subjects will be assigned a randomization number based in sequential 
order in which they qualified to be randomized. Subjects will be considered randomized 
once a unique subject randomization number has been assigned. Dosing should occur 
within 2 days of randomization for cohorts 1, 3 and 5, and 1 day of randomization for 
cohorts 2, 4, 6 and 7. The randomization date is to be documented in the subject’s 
medical records and on the enrollment case report form (CRF).
A randomization schedule, based on a computer-generated randomization list prepared
by Amgen, will be provided to the unblinded pharmacist at the site. The unblinded 
pharmacist will prepare all treatments accordingly and will randomize all subjects based
on the randomization schedule.
7.3
Blinding
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below.
7.3.1
Site Personnel Access to Individual Treatment Assignments
A subject’s treatment assignment is to only be unblinded by the investigator when 
knowledge of the treatment is essential for the further management of the subject on this 
study or may potentially impact the safety of the subject.  Unblinding at the study site for 
any other reason will be considered a protocol deviation.  It is encouraged that the 
Amgen Trial Manager be notified before the blind is broken unless the investigator 
believes that identification of the study treatment is required for a medical emergency.  If 
this is not possible, the Amgen Trial Manager must be notified within 24 hours after 
breaking the blind.  The date and reason that the blind was broken must be recorded in 
the source documentation and CRF, as applicable.
7.3.2
Access to Individual Subject Treatment Assignments by Amgen or 
Designees
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded. Amgen staff and their designees involved in the study will not be 
blinded but will only be given treatment assignments when there is a need to use the 
information for analysis, discussion, and internal decision making. Access to treatment 
assignments and other restricted data are described in Amgen standard documents. 
Unblinded individuals are to ensure unblinding and potentially unblinding information 
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should not be distributed to the investigators or subjects prior to the study being formally 
unblinded.
7.4
Dose Modification
7.4.1
Dose-cohort Study Escalation/De-escalation and Stopping Rules
Dose Level Review Meetings (DLRM) will be held to review data, monitor safety and 
make dose change recommendations. The DLRM members will be composed of the 
Principal Investigator or designee, the Amgen Medical Monitor, Amgen Global Safety 
Officer or designee, Amgen Clinical Research Study Manager or designee, and 
biostatistics representative or designee. Additional members may be added as needed 
(eg, clinical pharmacology scientist). The DLRM voting members include the Principal 
Investigator or designee, Amgen Medical Monitor and Amgen Global Safety Officer or 
designee.
The DLRM members are responsible for dose modification recommendations, which 
may include escalation to the next planned dose; escalation to an intermediate dose 
(a dose lower than the next planned dose); de-escalation to a lower dose; continuation, 
delay, or termination of dosing; or repetition or expansion of a cohort. Study data, 
including demographics, investigational product administration, medical history, 
concomitant medications, AEs (including SAEs), ECGs, vital signs, and safety laboratory 
results will be reviewed. If available, emerging PK and PD data may also be reviewed in 
a manner that does not unblind individual treatment assignments. The data to be 
reviewed may not have been source data verified or queried.
Data will be reviewed by DLRM members in a blinded manner (ie, treatment assignment
will not be revealed) unless unblinding of all subjects in a given cohort is deemed
necessary for the review team to make dosing recommendations. Unblinding of 
individual subjects can be performed at any time by the investigator or Amgen if deemed
necessary for subject safety. If deemed necessary, unblinding will be performed
according to Amgen standard procedures.
Escalation to a higher dose or combination cohort will only proceed when the previous
dose regimen has been found to be safe and reasonably tolerated based on available
safety and laboratory data through study day 36 for at least 6 out of 8 subjects dosed in 
a given cohort and upon unanimous recommendation at the DLRM. Available data from 
previous cohorts will also be considered. The next cohort will be open for dosing
immediately following the DLRM recommendation.
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The planned dose escalation schedule may be modified based on treatment-emergent
data (safety and/or PK). Dose adjustments, if any, will be made on a treatment cohort
and not on an individual basis, and will be agreed upon by Amgen in coordination with
the Principal Investigator.
The review of available safety data and dosing change recommendations will be 
documented in meeting minutes. Amgen will issue a written notification of the dose 
change recommendation to investigators.
7.4.2
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation
7.4.2.1
Amgen Investigational Product:  AMG 598
The reason for dose change of AMG 598 is to be recorded on each subject’s CRF(s).
Adverse event severity grading scale (12.4 Appendix 4) grading will be used to inform 
the cohort dose stopping rules as shown in Table 7-2.
For cohorts 1 to 6, dosing will be stopped or modified by the DLRM members if 
suspected adverse drug reactions and/or changes in safety data (including but not 
limited to vital signs, ECGs, or clinical laboratory results) are observed and these 
changes pose a significant health risk. The Amgen Medical Monitor will review data on 
an ongoing basis, and for cohorts 1 to 6 may suspend dosing and convene a DLRM at 
any time based on emerging safety data. In addition, for cohorts 1 to 6 dose escalation 
will be stopped or modified as shown in Table 7-2.
Cohort 7 safety data will be monitored on an ongoing basis by the unblinded medical 
monitor. In addition, a Safety Surveillance Team (SST) will be convened quarterly at a 
minimum to review cumulative available study data from cohort 7 to assess risk. An 
ad-hoc SST may also be convened at any time for reasons such as a significant and 
unanticipated safety finding. The SST will be comprised of the following study team 
members, or their delegates: the unblinded Medical Monitor, Clinical Research Study 
Manager, Global Safety Officer, and Biostatistician. Additional members may be added 
as needed (eg, clinical pharmacology scientist). Study data, including demographics, 
investigational product administration, medical history, concomitant medications, AEs 
(including SAEs), ECGs, vital signs, and safety laboratory results will be reviewed. If 
available, emerging PK and PD data may also be reviewed.
The data to be reviewed 
may not have been source data verified or queried. Study data will be reviewed by the 
SST in a blinded manner, unless unblinding is necessary to further evaluate a potential 
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safety signal. The SST may recommend alteration or termination of enrollment and/or 
dosing in cohort 7 at any time based on emerging safety information.
Clinically or medically significant suspected adverse drug reactions, and serious adverse
events considered to be related to study procedures will be followed until resolved or
considered stable.
Table 7-2. Cohort Dose Stopping Rules
Scenario
Action
Any occurrence of a moderate
suspected adverse drug reaction in 
2 or more subjects in the same 
cohort

Stop dosing additional subjects and convene DLRM 
(if event occurs outside of the regularly scheduled DLRM)

Review adverse event and all relevant safety data for 
evidence of relationship to treatment and clinical or medical 
significance

Consider unblinding as appropriate1

Upon unanimous decision by the DLRM members, one of the 
following decisions may be made:
o
stop enrollment of the cohort (if applicable)
o
resume enrollment of the cohort as planned
o
resume enrollment of the cohort at a lower dose
o
expand the cohort at the same dose
o
add a lower dose cohort to the study
o
escalate to an intermediate dose (a dose lower than 
the next planned dose)
o
escalate to the next planned dose
Any occurrence of a severe or 
greater suspected adverse drug 
reaction

Stop dosing additional subjects and convene DLRM (if event
occurs outside of the regularly scheduled DLRM)

Review adverse event and all relevant safety data for 
evidence of relationship to treatment and clinical or medical 
significance

Consider unblinding as appropriate1

If the adverse event is determined by unanimous decision of 
the DLRM members to be related to study drug (ie, AMG 598, 
after breaking of the study blind) and clinically or medically 
significant, no further doses should be administered at this 
dose and no dose escalation should proceed. Enrollment of 
the study may continue at a lower dose or a lower dose 
cohort may be added to the study.

Otherwise (ie, if considered not related to AMG 598 or not
clinically relevant), upon unanimous decision of the DLRM
members, one of the following decisions may be made:
o
resume enrollment of the cohort as planned
o
resume enrollment of the cohort at a lower dose
o
expand the cohort at the same dose
o
add a lower dose cohort to the study
o
escalate to an intermediate dose (a dose lower than 
the next planned dose)
o
escalate to the next planned dose
1 A subject’s treatment assignment should only be unblinded when knowledge of the treatment is essential 
for the further management of the subject, or may impact the safety of subjects currently enrolled, or 
subjects in subsequent cohorts.
7.4.2.2
Non-Amgen Non-investigational Product:  Liraglutide (Saxenda®)
The reason for dose change of liraglutide is to be recorded on each subject’s CRF(s).
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7.4.3
Hepatotoxicity Stopping and Rechallenge Rules
Refer to Section 12.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009. 
7.5
Preparation/Handling/Storage/Accountability
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product AMG 598 and liraglutide during the study are 
provided in the IPIM.
7.6
Treatment Compliance
Subjects are to follow the guidance provided by the managing physician / investigator.
Noncompliance with the treatment protocol is defined by subjects not taking the 
complete/correct dose(s), missed doses, failure to meet lifestyle restrictions, failure to 
adhere to visit schedule as defined in the Schedule of Activities, or any other deviation 
outlined in the protocol.
As noncompliance may impact subject safety or data integrity, treatment compliance of 
AMG 598 and/or liraglutide will be monitored via drug accountability records, drug 
concentration measurements, and medication event monitoring.
Please consult the investigator and Amgen Medical Monitor immediately if a dose has 
been missed or delayed or if an overdose is suspected.
7.7
Treatment of Overdose
The effects of overdose of AMG 598 are not known. Consult the investigator and Amgen 
Medical Monitor immediately if an overdose is suspected, or subject experiences signs 
or symptoms of an adverse event related to a potential overdose.
For liraglutide, refer to the approved product label for advice on overdose and report to 
Amgen Medical Monitor.
7.8
Prior and Concomitant Treatment
7.8.1
Prior Treatment
Prior therapies that were being taken/used prior to enrollment will be collected per the 
timeframes defined in Sections 6.1 and 6.2.
7.8.2
Concomitant Treatment
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7.
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Concomitant therapies are to be collected from enrollment through the end of study. For 
all concomitant therapies, collect therapy name, indication, dose, unit, frequency, route, 
start date and stop date.
8.
Discontinuation Criteria
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution.
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion for the reasons listed in Sections 8.1, 8.2.1, 
and 8.2.2.
8.1
Discontinuation of Study Treatment
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see
Section 2.2) including different options of follow-up (eg, in person, by phone/mail, 
through family/friends, in correspondence/communication with other treating physicians, 
from the review of medical records) and collection of data, including endpoints, adverse 
events, as applicable and must document this recommendation in the subject’s medical 
records.  Subjects who have discontinued investigational product and/or other protocol-
required therapies or procedures should not be automatically removed from the study.  
Whenever safe and feasible, it is imperative that subjects remain on-study to ensure 
safety surveillance and/or collection of outcome data.
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with
Section 12.3
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Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following:

Decision by Sponsor

Lost to follow-up

Death

Ineligibility determined

Protocol deviation

Non-compliance 

Adverse event

Subject request

Pregnancy

Protocol-specified criteria (Hepatotoxicity Stopping Rules and Mental Health Criteria 
Stopping Rules); see Section 7.4 and Section 12.8
8.2
Discontinuation From the Study
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study and must document the 
subject’s recommendation to withdraw in the subject’s medical records.  
Whenever safe and feasible it is imperative that subjects remain on-study to ensure 
safety surveillance and/or collection of outcome data. The investigator must document 
the level of follow-up that is agreed to by the subject.
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly 
(see Section 12.6 for further details). 
8.2.1
Reasons for Removal From Run In
Reasons for removal of a subject from the run-in period are:

Decision by Sponsor

Lost to follow-up

Death

Ineligibility determined

Protocol deviation
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
Non-compliance 

Adverse event

Subject request

Pregnancy

Protocol-specified criteria (Part 2 inclusion/exclusion criteria);
see Section 6.3 and 6.4
Subjects removed from run-in will be removed from study.
8.2.2
Reasons for Removal From Study
Reasons for removal of a subject from the study are:

Decision by Sponsor

Withdrawal of consent from study

Death

Lost to Follow up

Protocol-specified criteria (Part 2 inclusion/exclusion criteria);
see Section 6.3 and 6.4
8.3
Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study.

In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record.

If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible.
9.
Study Assessments and Procedures
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1 to Table 2-3). 
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As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment.
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct.
9.1
General Study Periods
9.1.1
Screening, Enrollment and/or Randomization
Informed consent must be obtained before completing any study specific screening 
procedure or discontinuation of standard therapy for any disallowed therapy.  For 
subjects consenting to participate in cohorts 1-6, after the subject has signed the 
informed consent form, they will be assigned a subject ID. For subjects consenting to 
participate in Cohort 7, after the subject has signed the informed consent form, the site 
will register the subject in the IVRS/IWRS and screen the subject in order to assess 
eligibility for participation. The screening window is up to 28 days prior to first dose of 
AMG 598/placebo or, for cohort 7, the placebo at the start of the run-in.
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 6.6) as applicable.
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 1 time, after Sponsor approval.
If the subject meets eligibility criteria but is not enrolled within the 28 day screening 
period, a new 28-day screening window may begin for an open cohort and all screening 
procedures should be repeated. This subject is not registered as a screen fail.
Once the subject is registered as rescreened, a new 28-day screening window will 
begin.  Subjects will retain the same subject identification number assigned at the 
original screening.  If the rescreening period begins more than 28 days after the original 
signing of the informed consent form, all screening procedures, including informed 
consent, must be repeated.
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9.1.2
Treatment Period and Follow up
Visits will occur per the Schedule of Activities (Section 2.2).  On-study visits may be 
completed within 207 days of day 1.  The date of the first dose of protocol-required 
therapies is defined as day 1 for cohorts 1-6, and the first dose of AMG 598/placebo 
after randomization for cohort 7.  All subsequent doses and study visits will be scheduled 
based on the day 1 date.  The final investigational product dose occurs on day 57.  
For Cohorts 2, 4, and 6, liraglutide dosing begins on day 1 and continues through day 
84. For Cohort 7, subjects will remain on 3 mg liraglutide SC QD for the duration of the 
study (6 months prior to screening through EOS).
Upon permanent discontinuation from the study treatment for any reason, a safety 
follow-up visit will be performed approximately 30 (+3) days after the end of the last 
dosing interval of AMG 598/placebo.  End of Study visit procedures should be performed 
at the safety follow-up visit.
9.1.3
End of Study
End of Study (EOS) visit procedures will be performed per the Schedule of Activities 
(Section 2.2).  For subject completing the study, this visit occurs on day 207. If feasible, 
all EOS procedures should be performed at the final visit for subjects who are removed 
from study prior to day 207.
9.2
Description of General Study Assessments and Procedures
The sections below provide a description of the individual study procedures for required 
time points.
9.2.1
General Assessments
9.2.1.1
Informed Consent
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed.
9.2.1.2
Demographics
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data may be used to study the impact on biomarkers 
variability and pharmacokinetics of the protocol-required therapies.
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9.2.1.3
Medical History
A complete medical history will be obtained at screening by the investigator or
designated site physician. Medical history will include information on the subject’s 
current health, psychiatric, and surgical history. Relevant medical history findings will be 
recorded in the subject’s source notes and on the appropriate pages of the CRF. Any 
unresolved medical history will be graded according to Clinical Adverse Event Severity 
Grading Scale and is described in Section 12.4.
9.2.1.4
Physical Examination 
Physical examination, including periodic neurologic examinations, will be performed as 
per standard of care.  Physical examination findings should be recorded on the 
appropriate CRF (eg, medical history, event). The neurological exam will include 
peripheral sensory and motor evaluation, and assessment of gait, pain, position, 
strength and reflexes.
9.2.1.5
Physical Measurements
Height [in centimeters] should be measured without shoes. Subjects should be in a 
clinic gown and without shoes each time body weight [in kilograms] is measured. Body 
Mass Index should be calculated using the following formula: 
BMI (kg/m2) = weight (kg)/[height (cm)/100]^2.
Waist circumference will also be measured (cm) per the Schedule of Activities. Subjects 
should be standing and relaxed, with restrictive clothing removed from the abdomen. 
Waist circumference measurements should be taken directly on the skin with a 
tension-sensitive, non-elastic tape. The tape should be placed in a horizontal line 
around the abdomen at the level of the iliac crest. The measurement should be read at 
the end of a normal respiratory expiration.
9.2.1.6
Substance Abuse History 
Obtain a detailed history of prior and/or concurrent use of alcohol, drugs of abuse and 
tobacco.
9.2.2
Efficacy Assessments
This section is not applicable.
9.2.3
Safety Assessments
Planned time points for all safety assessments are listed in the Schedule of Activities
see (Section 2.2).
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9.2.3.1
Adverse Events
9.2.3.1.1
Time Period and Frequency for Collecting and Reporting Safety 
Event Information
9.2.3.1.1.1
Adverse Events
The adverse event grading scale to be used for this study will be the Clinical Adverse 
Event Severity Grading Scale and is described in Section 12.4.
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of AMG 598/placebo
through the end of study are reported using the Event CRF.
9.2.3.1.1.2
Serious Adverse Events
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after the informed consent through 
end of study are reported using the Event CRF. All serious adverse events will be 
collected, recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Section 12.4.  The investigator will submit any updated serious adverse 
event data to the sponsor within 24 hours of it being available.
9.2.3.1.1.3
Serious Adverse Events After the Protocol-required Reporting 
Period
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after end of study.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge of the event.
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product. 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 12.4.
9.2.3.1.2
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence.
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9.2.3.1.3
Follow-up of Adverse Events and Serious Adverse Events
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Section 12.4.
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information. If specifically 
requested, the investigator may need to provide additional follow up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF.
9.2.3.1.4
Regulatory Reporting Requirements for Serious Adverse Events
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment 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 treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary.
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements.
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team as appropriate.  
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Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements.
9.2.3.2
Pregnancy and Lactation
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until 
5 months after receiving study drug.
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 12.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events.
Further details regarding pregnancy and lactation are provided in Section 12.5
9.2.3.3
Vital Signs
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature. Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible. The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF. The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF. Record all measurements on the vital 
signs CRF.
9.2.3.4
Electrocardiograms (ECGs)
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted. If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible. ECGs should be 
performed in a standardized method, in triplicate, and run consecutively 
(ie, < 30 seconds apart), prior to blood draws or other invasive procedures. Each ECG 
must include the following measurements: QRS, QT, QTc, RR, and PR intervals. 

Single ECG at Screening (cohorts 1-6) and at all time points for cohort 7 only

≥3 baseline ECGs collected ≥30 minutes apart, with each baseline ECG in triplicate 
run consecutively (ie, < 30 seconds apart) [ie, total ≥9 ECGs] (cohorts 1-6)

Triplicate ECGs at time points after dosing (cohorts 1-6)
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Baseline is defined as day 1 pre-dose for all cohorts. The PI or designated site physician
will review all ECGs. ECGs will be transferred electronically to an ECG central reader for 
analysis per Amgen instructions. Once signed, the original ECG tracing will be retained 
with the subject's source documents. At the request of the sponsor, a copy of the original 
ECG will be made available to Amgen. Standard ECG machines should be used for all 
study-related ECG requirements.
9.2.3.5
Vital Status
This section is not applicable.
9.2.3.6
Suicidal Risk Monitoring
Liraglutide is considered to be a central nervous system (CNS)-active study treatment.  
In addition, there have been some reports of suicidal ideation and behavior when it has 
been given to some subjects with obesity.  The sponsor considers it important to monitor 
for such events before and during this clinical study.
It is unknown whether AMG 598 may be associated with an increased risk of suicidal 
ideation or behavior.  
Subjects being treated with AMG 598 and/or liraglutide must be monitored appropriately 
and observed closely for suicidal ideation and behavior or any other unusual changes in 
behavior.  Consideration is to be given to discontinuing AMG 598 and/or liraglutide in 
subjects who experience signs of suicidal ideation or behavior. 
Families and caregivers of subjects being treated with AMG 598 and/or liraglutide are to 
be instructed to monitor subjects for the emergence of unusual changes in behavior, as 
well as the emergence of suicidal ideation and behavior, and to report such symptoms 
immediately to the study investigator.
Baseline assessment of suicidal ideation and behavior and treatment-emergent suicidal 
ideation and behavior will be assessed during the study using C-SSRS and Patient 
Health Questionnaire 9 (PHQ-9).  Refer to Section 12.9 and 12.10 for more information.
9.2.4
Clinical Laboratory Assessments
Refer to Section 12.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 2.2) for the timing and frequency.
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
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laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event.
All protocol-required laboratory assessments, as defined in Section 12.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities (see 
Section 2.2).
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
9.2.4.1
Pregnancy Testing
A high sensitive (urine or serum) pregnancy test should be completed at screening and 
within 7 days of initiation of investigational product for females of childbearing potential.
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see (Figure 12-2).  Refer to Section 12.5 for contraceptive requirements. 
Additional pregnancy testing should be performed at monthly intervals during treatment 
with protocol-required therapies and 30 days +/- 3days after discontinuing 
protocol-required therapies.
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations.
9.2.5
Biomarker Assessments
Longitudinal effects on lipid levels (eg, total cholesterol, low density lipoprotein 
cholesterol [LDL-C], high density lipoprotein cholesterol [HDL-C], and triglycerides) and 
potential effects on glycemic control (HbA1c) and bone metabolism (CTX and P1NP) will 
be assessed as detailed in the Schedule of Activities.
9.2.6
Pharmacokinetic Assessments
All subjects enrolled into the study will have pharmacokinetic samples assessed. Whole 
blood samples of approximately 5 mL will be collected for each measurement of serum
concentrations of AMG 598 and plasma concentration of liraglutide as specified in the 
Schedule of Activities (Section 2.2). Instructions for the collection and handling of 
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biological samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sample will be recorded.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.2.7
Pharmacodynamic Assessments
Venous blood samples of approximately 5 to 7.5 mL will be collected for measurement of 
AMG 598 treatment PD effects at each time point specified in the Schedule of Activities.
Concentration-time profiles and AUCs for metabolic parameters (glucose, insulin, 
c-peptide, GIP, GLP-1, glucagon, and FFAs) will be assessed.
9.2.8
Pharmacogenetic Assessments
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of obesity and/or to 
identify subjects who may have positive or negative response to AMG 598. Additional 
samples are collected for this part of the study. For subjects who consent to this/these 
analysis/analyses, DNA may be extracted from residual cell pellets retained from the first 
plasma PD blood draws.
The final disposition of samples will be described in Section 12.6. 
9.2.9
Antibody Testing Procedures
Blood samples for antibody testing are to be collected as outlined in the Schedule of 
Activities (Section 2.2).  Bioanalytical testing for anti-AMG 598 antibodies will be 
conducted on these samples. Subjects who test positive at the final scheduled study 
visit, defined as the end of study (EOS) visit, and have clinical sequelae that are 
considered potentially related to an anti-AMG 598 antibody response will be asked to 
return for additional follow-up testing.  Sample collection and testing will occur 
approximately every 3 months from EOS until: (1) the antibody response is negative or 
(2) the subject has been followed for a period of at least 1 year (± 4 weeks) post 
administration of AMG 598.  All follow up results, both positive and negative will be 
communicated to the sites.  More frequent testing or testing for a longer period of time 
may be requested in the event of safety-related concerns.  Follow-up testing will not be 
required where it is established that the subject did not receive AMG 598.
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9.2.10
Biomarker Development
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity.
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to AMG 598, to investigate the mechanism of action of 
AMG 598 and/ or further the biological understanding of obesity and related metabolic 
disorders.
Blood samples (approximately 11 mL per collection) are to be collected for biomarker 
development at the time points specified in the Schedule of Activities (Section 2.2). 
9.2.11
Health Economics 
Medical resource utilization and health economics data, associated with medical 
encounters, may be collected in the CRF by the investigator and study-site personnel for 
all subjects throughout the study.  Protocol-mandated procedures, tests, and encounters 
are excluded. 
The data collected may be used to conduct exploratory economic analyses and will 
include:

Number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient)

Duration of hospitalization (total days or length of stay, including duration by wards)

Number and type of diagnostic and therapeutic tests and procedures

Outpatient medical encounters and treatments (including physician or emergency 
room visits, tests and procedures, and medications).
9.2.12
Optional Substudies
The pharmacogenetic testing is optional in this study.
Obtain confirmation that the pharmacogenetic and future testing portions of the Informed 
Consent Form has been signed prior to performing optional substudy procedures.
9.2.13
Other Assessments
Dual-energy x-ray absorptiometry (DXA) scans will be conducted as outlined in the 
Schedule of Activities (Section 2.2). DXA scans for bone density measurements of the 
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spine and hip/femur will be performed in cohorts 1-6. DXA scans of body composition 
measurements will be performed in cohort 7.
10.
Statistical Considerations
10.1
Sample Size Determination
The sample size for the study is based on practical considerations.  For safety 
considerations, with up to 66 subjects receiving AMG 598 (6 subjects in each of cohorts 
1-6 and 30 subjects in cohort 7), there is a 96.6% chance of detecting an adverse event 
with a true incidence rate of 5% or greater and a 99.9% chance of detecting an adverse 
event with a true incidence rate of 10%.
In cohort 7, with a sample size of 30 subjects per group, there is approximately an 80% 
probability of observing a mean treatment difference in percent change from baseline in 
body weight between AMG 598 and placebo of > 3%, assuming a true treatment 
difference of 5%.  This assumes a standard deviation for percent change from baseline 
in body weight of 7% in each treatment group.
10.2
Analysis Sets, Subgroups, and Covariates
10.2.1
Analysis Sets
10.2.1.1
Safety Analysis Set
The safety analysis set will consist of all subjects who receive at least one dose of
investigational product on day 1.
10.2.1.2
Pharmacokinetic (PK) Analysis Set
The PK analysis set will consist of all subjects for whom at least one PK parameter or 
endpoint can be adequately estimated.
10.2.1.3
Pharmacodynamic (PD) Analysis Set
The PD analysis set will consist of all subjects for whom at least one PD parameter or 
endpoint can be adequately estimated.
10.2.2
Covariates
Baseline values may be used as a covariate in analyses.
10.2.3
Subgroups
No subgroup analyses are planned.
10.2.4
Handling of Missing and Incomplete Data
The frequency of missing and incomplete data is expected to be low in this study and 
therefore, missing data will not be imputed.  Methods for handling incomplete dates will 
be covered in the Statistical Analysis Plan.
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10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 5.3.1.
10.3.1
Planned Analyses
10.3.1.1
Interim Analysis and Early Stopping Guidelines
DLRM members will oversee progress of the study and make recommendations relating 
to early closure / extension or alteration of the study based on ongoing monitoring of the 
study data.  Refer to Section 7.4.2 for further details.
10.3.1.2
Primary Analysis
The primary analysis will occur after all subjects in cohorts 1-6 have completed the 
study.
10.3.1.3
Final Analysis
The final analysis will occur after all subjects in cohort 7 have completed the study.
10.3.2
Methods of Analyses
10.3.2.1
General Considerations
Descriptive statistics will be provided for selected demographics, safety, PK and PD 
endpoints.  Descriptive statistics on continuous measurements will include means, 
medians, standard deviations and ranges, while categorical data will be summarized 
using frequency counts and percentages.  Data will be presented and summarized by 
treatment and at each time point.  Graphical summaries of the data may also be 
presented.
Data for subjects receiving placebo will be combined across cohorts 1, 3 and 5 
(monotherapy cohorts) and separately across cohorts 2, 4 and 6 (combination therapy 
cohorts).  Placebo data for subjects in cohort 7 will not be combined with other cohorts.
Data for subjects receiving AMG598 will be presented separately by cohort.
When data are summarized by time, the values recorded against the scheduled time 
points listed in the protocol will be used.  When assessing minimum/maximum increases 
or decreases over the study, all assessments, including unscheduled assessments will 
be used.
10.3.2.2
Efficacy Analyses
This section is not applicable.
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10.3.2.3
Safety Analyses
10.3.2.3.1
Analyses of Primary Safety Endpoint(s)
Endpoint
Statistical Analysis Methods
Primary

Subject incidence of treatment-emergent adverse events including fatal 
adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product or other protocol-required 
therapies, and significant treatment emergent adverse events.

Summary statistics of safety laboratory test results including summary 
statistics at each protocol scheduled visit by cohort / combined placebo 
cohort. 

Summary statistics of vital signs including summary statistics at each 
protocol scheduled visit by cohort / combined placebo cohort. 

Summaries over time and/or changes from baseline over time will be 
provided for all ECG parameters. 

Summary statistics from mental health questionnaires. 
10.3.2.3.2
Adverse Events
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term according to the medical dictionary for regulatory 
activities (MedDRA) terminology. Tables of fatal adverse events, serious adverse 
events, adverse events leading to withdrawal from IP or other protocol-required 
therapies, and treatment emergent adverse events will also be provided. The number 
and percentage of subjects reporting adverse events will be evaluated for each dose 
cohort, across dose cohorts, and will also be tabulated by relationship to study drug. 
Adverse events resulting in treatment discontinuation will be identified.
10.3.2.3.3
Laboratory Test Results
Hematology, chemistry and urinalysis data will be listed and reviewed for each subject. 
Values outside the normal laboratory reference range will be flagged as high or low on 
the listings. Depending on the size and scope of changes in laboratory data, summaries 
of laboratory data over time and/or changes from baseline over time may be provided.
10.3.2.3.4
Vital Signs
Vital signs will be listed and reviewed for each subject. Summaries of heart rate and 
blood pressure data over time and change from baseline will be provided.
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10.3.2.3.5
Physical Measurements
The analyses of physical measurements will include summary statistics at each protocol 
scheduled visit by cohort / combined placebo cohort.
10.3.2.3.6
Electrocardiogram
Summaries over time and/or changes from baseline over time will be provided for all
ECG parameters. Subjects’ maximum change from baseline in QT interval corrected for
heart rate using Fridericia's formula (QTcF) will be categorized, and the number and
percentage of subjects in each group will be summarized. Subjects’ maximum
post-baseline values will also be categorized, and the number and percentage of
subjects in each group will be summarized. All on-study ECG data will be listed and
select parameters of interest plotted. 
10.3.2.3.7
Antibody Formation
The incidence and percentage of subjects who develop anti-AMG 598 antibodies at any 
time will be tabulated by treatment group.
10.3.2.3.8
Exposure to Investigational Product
The number of doses of IP and the proportion of subjects receiving each dose level will 
be summarized using descriptive statistics. Subject-level data may be provided instead 
of the summary if the subject incidence is low or single dose is given.
10.3.2.3.9
Exposure to Other Protocol-required Therapy
Descriptive statistics of the number of doses of liraglutide received by each subject will 
be produced to describe the exposure to liraglutide in Cohorts 2, 4, 6 and 7 (eg, from 
baseline to end of study).
10.3.2.3.10
Exposure to Concomitant Medication
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category for each cohort /combined placebo cohort as coded by the 
World Health Organization Drug dictionary.
10.3.2.4
Other Analyses
10.3.2.4.1
Secondary Endpoint – Pharmacokinetics Analysis
Serum AMG 598 concentrations will be determined using a validated assay.  Individual 
serum concentration-time plots for AMG 598 will be presented for each subject as well 
as mean concentration-time plots for each dose cohort.  PK parameters that may 
include, but are not limited to AUC, Cmax and tmax will be estimated using either 
compartmental (eg, PK modeling) or non-compartmental methods.  Actual dosing and 
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sampling times will be used for calculation of PK parameters.  Summary statistics will be
generated for each PK parameter for each dose cohort.
10.3.2.4.2
Exploratory Endpoints 
The statistical analyses in this section are considered exploratory in nature and will be
performed only when deemed appropriate.  The safety analysis set will be used for all 
exploratory endpoint analysis performed.
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12.
Appendices
Approved 
 
 


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12.1
Appendix 1.  List of Abbreviations and Definitions of Terms
Abbreviation or Term
Definition/Explanation
CFR
U.S. Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
COA
clinical outcomes assessment
CRF
case report form
CRO
contract research organization
CSSR-S
Columbia Suicide Severity Rating Scale
DES
Amgen data element standard
DILI
drug induced liver injury
DLRT
dose level review team
DMC
data monitoring committee
DRT
data review team
ECG
electrocardiogram
Echo
echocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EDC
electronic data capture
Electronic Source Data 
(eSource) 
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial.
Enrollment
Subject randomized to treatment group
Exposure-Response 
Analysis
mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic (PK) exposure 
(eg, population pharmacokinetic modeling) and response, which 
may include biomarkers, pharmacodynamic (PD) effects, 
efficacy and safety endpoints.
End of Follow-up
defined as when the last subject completes the last 
protocol-specified assessment in the study  
End of Study for Individual 
Subject
defined as the last day that protocol-specified procedures are 
conducted for an individual subject
End of Study (primary 
completion)
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early 
End of Study (end of trial)
defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable
End of Treatment
defined as the last assessment for the protocol specified 
treatment phase of the study for an individual subject
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GOG PS
Gynecological Oncology Group (GOG) Performance Status
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Abbreviation or Term
Definition/Explanation
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormone replacement therapy
IBG
Independent Biostatistics Group
ICF
informed consent form
ICH
International Conference on Harmonisation
ICJME
International Committee of Medical Journal Editors
IEC
IFU
Independent Ethics Committee
Instructions for Use
IPIM
Investigational Product Instruction Manual
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormonal-releasing system
Interactive Voice Response 
System (IVRS)
telecommunication technology that is linked to a central 
computer in real time as an interface to collect and process 
information
Interactive Web Response 
System (IWRS)
web based technology that is linked to a central computer in real 
time as an interface to collect and process information
KPS
Karnofsky Performance Status
Lansky PFS
Lansky Play-Performance Scale
LVEF
left ventricular ejection fraction
MUGA scan
multigated acquisition scan
NCT
National Clinical Trials
PHQ-9
Patient Health Questionnaire 9 
SAT
safety assessment team
Source Data
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research. The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value.
Study Day 1
defined as the first day that protocol-required therapies are 
administered to the subject
TBL
total bilirubin
SUSAR
suspected unexpected serious adverse reaction
TMF
trial master file
ULN
upper limit of normal
Approved 
 
 


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12.2
Appendix 2.  Clinical Laboratory Tests
The tests detailed in Table 12-1 will be performed by the central laboratory and/or by the 
local laboratory as described in the Schedule of Activities.
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.4 of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 12-1.  Analyte Listing
Local Laboratory: 
Chemistry
Local Laboratory: 
Local
Laboratory: 
Urinalysis
Local Laboratory: 
Hematology
Central Laboratory: 
Other 
Sodium
Potassium
Chloride
Bicarbonate/CO2
Total protein
Albumin
Calcium
Glucose
BUN or Urea
Creatinine
Total bilirubin
Direct bilirubin
ALP
AST (SGOT)
ALT (SGPT)
TSH – screening 
only
Calcitonin –
screening only
Tryptase (in the 
event of a 
suspected 
anaphylactic 
reaction)
Amylase
Lipase
Drug Screen
Benzodiazepines
Barbiturates
Opiates
Tetrahydrocannabi
nol
Cocaine
Amphetamines
Ethanol (may be 
performed by a 
breath test)
Viral Panel
Hep B surface 
antigen
HBcAb
HepCAb
HCV RNA PCR(as 
necessary)
HIVa
Reproductive
Serum or Urine 
Pregnancy
FSH
Specific gravity
pH
Blood
Protein Glucose
Bilirubin
WBC
RBC
Epithelial cells
Bacteria
Casts
Crystals
RBC
Hemoglobin
Hematocrit
MCV 
MCH
MCHC
Platelets
WBC
Differential
• Total Neutrophils -
or- seg. Neutrophils 
and Bands/Stabs
• Eosinophils
• Basophils
• Lymphocytes
• Monocytes 
Coagulation
PT/INR
PTT/APTT
PD assessments
Insulin
Glucose
c-peptide
free fatty acids
GIP
GLP-1
Glucagon
HbA1c (local at 
screening)
Safety 
assessments
P1NP
CTX-1
Lipid Panel
Cholesterol (total)
LDL-C
HDL-C
Triglycerides
a HIV assessment is recommended.
ALP = alkaline phosphatase; ALT  alanine aminotransferase; AST = aspartate aminotransferase;
BUN = blood urea nitrogen; CTX-1 = C-terminal telopeptides of Type I collagen; GIP = Glucose dependent 
insulinotropic peptide; GLP-1 = Glucagon-like peptide-1; HbA1c = ; hemoglobin A1c; HDL = high density 
lipoprotein; Hep = hepatitis; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; 
INR = international normalized ratio; LDH = lactate dehydrogenase; LDL = low density lipoprotein; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; P1NP = Procollagen Type 1 N-Terminal Peptide; PT = prothrombin time; 
PTT/APTT = activated partial thromboplastin time;  RBC = red blood cell count; RDW = Red cell distribution 
width; SGOT = serum glutamic-oxaloacetic transaminase; SGPT - serum glutamic-pyruvic transaminase; 
WBC = white blood cell count
Approved 
 
 


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Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
Approved 
 
 


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12.3
Appendix 3.  Study Governance Considerations
Safety Monitoring Committee
A safety monitoring committee was not established for this study.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable ICH laws and regulations
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product.
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen

Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures

Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations
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Informed Consent Process
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population.
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol specific screening procedures or any 
investigational product(s) is/are administered and answer all questions regarding the 
study.  
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site.
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form.
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the
subject or a legally acceptable representative and by the person who conducted the 
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informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 8.
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study. 
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.)
Subjects who are rescreened are required to sign a new informed consent form.
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 
signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature.
Data Protection/Subject Confidentiality
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment.
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations).
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Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below.
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study. 
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study related records, including personal 
information.
Publication Policy
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication.
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4.
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
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persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.   Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications.
Investigator Signatory Obligations
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator.
The coordinating investigator, identified by Amgen, will be any or all of the following:

A recognized expert in the therapeutic area

An Investigator who provided significant contributions to either the design or 
interpretation of the study

An Investigator contributing a high number of eligible subjects
Data Quality Assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Clinical 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 subjects 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 per 
the sponsor’s monitoring plan. 
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The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved.
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities 
(eg, pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study related- records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements.
Retention of study documents will be governed by the Clinical Trial Agreement.
Amgen (or designee) will perform Self-Evident Corrections to obvious data errors in the 
clinical trial database.  Self-Evident Corrections will be documented in the CRF Standard 
Instructions and the CRF Specific Instructions, both of these will be available through the 
electronic data capture (EDC) system.  Examples of obvious data errors that may be 
corrected by Amgen (or designee) include deletion of obvious duplicate data (ie, the 
same results sent twice with the same date with different visit) and updating a specific 
response if the confirming datum is provided in the “other, specify” field (eg, for race, 
reason for ending study).
Source Documents
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form.
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. Source documents may also include data captured in the 
Interactive Voice Response System (IVRS) / Interactive Web Response System (IWRS) 
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system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment).
Data reported on the CRF or entered in the electronic CRF 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 previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available.
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.
Elements to include:

Subject files containing completed CRFs, informed consent forms, and subject 
identification list

Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation, and all correspondence to and from the IRB/IEC
and Amgen

Investigational product-related correspondence including Investigational Product 
Accountability Record(s) and Final Investigational Product Reconciliation Statement, 
as applicable

Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable (eg, for liraglutide and administration pen).
Retention of study documents will be governed by the Clinical Trial Agreement.
Study and Site Closure
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen.
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
Approved 
 
 


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whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially.
Compensation
Any arrangements for compensation to subjects for injury or illness that arises in the
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document.
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12.4
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting
Definition of Adverse Event
Adverse Event Definition

An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.  

Note:  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device or procedure.
Events Meeting the Adverse Event Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiological scans, vital signs measurements,
change in mental health questionnaire scores), including those that worsen from baseline, 
that are considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported regardless of 
sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an adverse event or serious adverse event.  Such instances will be captured in the 
efficacy assessments.  However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as adverse event or serious adverse event if they fulfill 
the definition of an adverse event or serious adverse event. 
Events NOT Meeting the Adverse Event Definition

Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to 
the procedure is the adverse event.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
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Definition of Serious Adverse Event
A Serious Adverse Event is defined as any untoward medical occurrence that, meets 
at least 1 of the following serious criteria:
Results in death (fatal)
Immediately life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
Requires in-patient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are an adverse event.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious.  Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an adverse event.
Results in persistent or significant disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other medically important serious event
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition.  These events are typically to be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
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Recording Adverse Events and Serious Adverse Events
Adverse Event and Serious Adverse Event Recording

When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory, and 
diagnostics reports) related to the event.

The investigator will then record all relevant adverse event serious adverse event 
information in the Event case report form (CRF).

The investigator must assign the following adverse event attributes:
o
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms);
o
Dates of onset and resolution (if resolved);
o
Severity (or toxicity defined below);
o
Assessment of relatedness to Investigational product: (AMG 598/placebo), and/or 
non-Amgen non-investigational other protocol-required therapy (liraglutide) and/or any 
study-mandated activity/procedure
o
Action taken.

It is not acceptable for the investigator to send photocopies of the subject’s medical records 
to Amgen in lieu of completion of the Event CRF page.

If the severity of an adverse event worsens from the date of onset to the date of resolution, 
record a single event for each increased level of severity on the Event CRF

If specifically requested, the investigator may need to provide additional follow-up
information, such as discharge summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to Amgen.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse 
event.
Evaluating Adverse Events and Serious Adverse Events
Assessment of Severity
The investigator will make an assessment of severity for each adverse event and serious 
adverse event reported during the study.  The assessment of severity will be based on: 
The Amgen Standard Grading Scale as show below:
Grade
Definition
MILD
Aware of sign or symptom, but easily tolerated
MODERATE
Discomfort enough to cause interference with usual activity
SEVEREa
Incapacitating with inability to work or do usual activity
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of a serious adverse event, NOT when it is rated as severe.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 90 of 111
CONFIDENTIAL
Assessment of Causality

The investigator is obligated to assess the relationship between investigational product, 
protocol-required therapies, and/or study-mandated procedure and each occurrence 
of each adverse event/serious adverse event.

Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment.

For each adverse event/serious adverse event, the investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and has 
provided an assessment of causality.

There may be situations in which a serious adverse event has occurred, and the 
investigator has minimal information to include in the initial report.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the serious adverse event data.

The investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of Adverse Event and Serious Adverse Event

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Amgen to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully 
as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a subject is permanently withdrawn from protocol-required therapies because of a serious 
adverse event, this information must be submitted to Amgen.

If a subject dies during participation in the study or during a recognized follow-up period,
the investigator will provide Amgen with a copy of any post-mortem findings including 
histopathology.

New or updated information will be recorded in the originally completed Event CRF.

The investigator will submit any updated serious adverse event data to Amgen within 
24 hours of receipt of the information.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 91 of 111
CONFIDENTIAL
Reporting of Serious Adverse Event
Serious Adverse Event Reporting via Paper CRF

Facsimile transmission of the Serious Adverse Event Report Form 
(see Figure 12-1 is the preferred method to transmit this information.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the Serious Adverse Event Report Form sent 
by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting time frames.
Approved 
 
 
I 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 92 of 111
CONFIDENTIAL
Figure 12-1.  Sample Serious Adverse Event Report Form
Approved 
 
 
20170139 
Clinical Trial Serious Adverse Event Report- Phase 1-4 
AMG 598 
1. SITE INFORMATION 
2. SUBJECT INFORMATIO N 
S,.,1bject ID Nl.irrber 
Ho6fy Amgen "fthu, 24 Hours ol-wfedge of the ..... t 
AMGEN US SAFETY FAX# : +888 814 8653 
Age al e\ent ol'6e! 
Su 
OF 
fax~rrb:r 
Dale of"""" 
Day 
Mor.th 
Ye,ar 
If applicable, provide Er1d of 
5"'dyd.t., 
3. SERIOUS ADVERSE EVENT - Information in this section must also be entered on the Serious Adverse Event Summa 
CRF 
Provide the date the Investigator became aware of this Serious Adverse Event Information: Day __ f.lontll_
Year __ 
s«ioutACP/8fM EVent oia!JI08ia or synarome 
If diagnosis is unknOwn. enter Signs/ 
Symptom& 
When Final Diagnosis is mown. enter -aa 
Aavenie Event 
Lisi Oll'ee)M per Me. Jt e1Mi.s rM.ai, ffi$"1!ie 
c.wse ot DH!II. Emry o< "Oeard' i.s rt« acce,crie\' 
a.smisis ~I)-~ 
Date Enoea 
O:i:-:l 
&as 
en'yi Sc,i:t.s 
e~titl Cil:iiia ... 
~"' 
(see 
d'o..o.ecri v;,du 
I? 
&effj 
1:: U\Ef'e ; rea:«iac:epoosb'li';y!Nl!IM e\efl! 
ma1 nave Deen caused tiy l?or ¥1Jl.m}en aeYU 
'-1$1:(1 f.O almristel 
I?'? 
Outeo,r.,c ~
crfy 
of~ h-.~i! 
111 
*.df 
IJ2N,t 
pwetbre 
rc::o\d 
«1,!:iepsr 
ll3 fr/Al 
ll4U:~11 
Serious 01 Fatal 
03 Required hospitalization 
Criteria: 02 lrrrnediatefy life- threatening 04 Prolonged ho.spitslization 
05 Persistent or signi6cant disabifi.ty /incapacity 
06 Congenital anomaty I birth defect 
07 Other medically 
important serious event 
4, HOSPITALIZATION 
AMG 598 
Blinded 
Date Admitted 
Date Discharged 
M onth 
Year 
Os 
Month 
Year 
es. please ~lete date(s): 
,..,., .. 
,_ ____ ..,._P~ri•~•~•~"=••~--=~of"E~ven=I ~~~---<Action Tat.en with Proctoct 
lot I and Seri.al tf 
Date of Doee 
Ooee 
RotM 
Frequency 
01 Stil Deing Mmirislere<J 
D;,y 
Month 
02 Pem'l3Mntl)'cisoon:'"nle0 
Vear 
03 Winnetl 
I.('!; __ 
_ 
0U1.~1o.n 
~ 1~1; __ 
0U1.~1o.n 
FORM-lH5"'82 Clinicaf Trial SAE Reporl- Phase 1-4 V10.0 Effective date: 23-Ap,il-2018 
Page 1 of3 
S4ERCreated:. 09-August-2018 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 93 of 111
CONFIDENTIAL
Figure 12-1.  Sample Serious Adverse Event Report Form
Approved 
 
 
.. 
20170139 
Clinical Trial Serious Adverse Event Report- Phase 1-4 
AMG 598 
Holify Amgen -.tthin 24 Hours of knowledge of th<, ..,.,,t 
Site Number 
I 
SUbject I) Number 
I I I I 
I I I I I I I I I I 
6. CONCOMITANT MEDICATIONS (eg, chemotherapy) 
Any Concomitant Medications? Cl No O Yes. If yes. please COl'l1)1ete: 
Medication Name(s) 
Slaff Date 
Stop Date 
C1»11;91)8C( 
Continuing 
Oooe 
Root, 
Freq. 
Treatment I.led 
,ti~· ,,.,. 
Ye~f 
•~ )' ... 
Ye:1 
fb,I' 
M:,.l'I 
tt,-.1' 1 Y,-.1' 
7. RELEVANT MEDICAL HISTORY finclude dates alle~ies and anv relevant nrior theJ'anu, 
8. RELEVANT LABORATORY VALUES (include baseline values) AAyRelevsnt Laboratory values? •::::! No 
Yes. If yes. please complete: 
Teat 
Unit -
o=r 
.., . Ye:1 
9. OTHER RELEVANT TESTS (diagnostics and procedures) 
Any Other Relevant tests? 
,., 
Da<e 
Additional Tests 
l.b:l'I 
Y~III 
FORM-lH5"'82CJinicaf Trial SAEReporl- Phase 
V10.0 Effective date: 23-April-2018 
Page2of3 
0 No O Yes. If yes, pleaseoomplete: 
Results 
Unrts 
SAERCreated:. 09-August-2018 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 94 of 111
CONFIDENTIAL
Figure 12-1.  Sample Serious Adverse Event Report Form
Approved 
 
 
. 
. . 
20170139 
Clinical Trial Serious Adverse Event Report- Phase 1-4 
AMG 598 
Ho6fy Amgen "fthu, 24 Hours ol-wfedge of the ..... t 
Site Number 
SUbject I) Number 
CASE DESCRIPTION (Provide narrative details of events listed in section 3) For each event in section 3, where relationship=Yes., 
ease 
ovide rationale. 
Signature of Investigator or Oesignee 
I confirm by signing this nporr. that the information on this form, ind!Jding 
seriousn~s and covsa!iry assessments_, is being provided to Amgen by the 
Investigator for this st.udy, or U'f o Quofi[fN Medical Person ovthorized U'f the 
Investigator for this st.udy. 
Title 
FORM-lH5"'82Clinicaf Trial SAEReporl- Phase 1-4 V10.0 Effective date: 23-April-2018 
Page3of3 
Dste 
S4ERCreated:. 09-August-2018 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 95 of 111
CONFIDENTIAL
12.5
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information
Study-specific contraception requirements for males and females of childbearing 
potential are outlined below.
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant or father a 
child during treatment and for 5 months after the last dose of protocol-required therapies.
Definition of Females of Childbearing Potential
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy.
Females in the following categories are not considered female of childbearing potential:

Premenopausal female with 1 of the following:
o
Documented hysterectomy;
o
Documented bilateral salpingectomy; or
o
Documented bilateral oophorectomy.
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview.

Premenarchal female

Postmenopausal female
o
A postmenopausal state is 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 
females not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
o
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 96 of 111
CONFIDENTIAL
Contraception Methods for Female Subjects
Highly Effective Contraceptive Methods
Note: Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal)

Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable)

Intrauterine device 

Intrauterine hormonal-releasing system 

Bilateral tubal ligation/occlusion

Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success)

Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject)
Contraception Methods for Male Subjects 

Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject) 

Use a condom during treatment and for an additional 5 months after the last dose of 
protocol-required therapies
The female partner should consider using an acceptable method of effective 
contraception such as: hormonal, IUD, IUS, female barrier method (diaphragm, cap, 
sponge [a female condom is not an option because there is a risk of tearing when both 
partners use a condom]).
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study.
Unacceptable Methods of Birth Control for Male and Female Subjects
Birth control methods that are considered unacceptable in clinical trials include:

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus)

Spermicides only

Lactational amenorrhea method
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 97 of 111
CONFIDENTIAL
Collection of Pregnancy Information
Female Subjects Who Become Pregnant

Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 5 months after last dose of 
investigational product.

Information will be recorded on the Pregnancy Notification Worksheet 
(see Figure 12-2).  The worksheet must be submitted to Amgen Global Patient 
Safety within 24 hours of learning of a subject’s pregnancy.  (Note: Sites are not 
required to provide any information on the Pregnancy Notification Worksheet that 
violates the country or regions local privacy laws).

After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 5 months after 
last dose of the investigational product.  This information will be forwarded to Amgen 
Global Patient Safety.  Generally, infant follow-up will be conducted up to 12 months 
after the birth of the child (if applicable).

Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 

While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case.

If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event.

Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 12.4.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting. 

Any female subject who becomes pregnant while participating will no longer be 
eligible to continue in the study and study treatment will be discontinued
(see Section 8.1 for details).
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 98 of 111
CONFIDENTIAL
Male Subjects With Partners Who Become Pregnant

In the event a male subject fathers a child during treatment, and for an additional 
5 months after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet
(see Figure 12-2) must be submitted to Amgen Global Patient Safety within 24 hours 
of the site’s awareness of the pregnancy.  (Note: Sites are not required to provide 
any information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws).

The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information.

After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety.

Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 

Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.
Collection of Lactation Information

Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 5 months after last dose of 
investigational product.

Information will be recorded on the Lactation Notification Worksheet (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event.

Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 223.

With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 5 months after last dose of investigational 
product after discontinuing protocol-required therapies.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 99 of 111
CONFIDENTIAL
Figure 12-2.  Pregnancy and Lactation Notification Worksheet
Approved 
 
 
AIIICJEN• Pregnancy Notification Worksheet 
Fax Comptered Form ro rile Coumry-respecrive Safery Fax Line 
us:-"8 au s,n 
Study Design: .!!I lnterventional D Obseivational (If Obseivational: D Prospective D Retrospective) 
2. Contact Information 
Investigator Name____________________ 
Site # ___________ _ 
Phone ~ - ~ --------
Fax L__) ________ _ 
Email ____________ _ 
lnstitution ______________________________________ _ 
Address ----------------------------------------
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
Frequency 
Route 
Start Date 
conception 
mm ...:J,dd :::Jlyyyy_ 
Was the Amgen product (or study drug) discontinued? D Yes D No 
If yes, provide product (or sb.Jdy drug) stop date: mm 
...:.ltdd ...:J1yyyy __ 
Did lhe subject withdraw from the study? 0 Yes D No 
5. Pregnancy Information 
Pregnantremale's LMP 
mm 
...:J,1 dd 
..:Ji yyyy___ D Unknown 
Estimated date of delivery mm 
...:J / J ...:J, yyyy__ 0 Unknown O NIA 
If NIA, date of tennination (actual or planned) mm 
...:J / dd 
...:J, YYY"J __ 
_ 
Has the pregnant remale already delivered? D Yes D No D Unknown D NIA 
1r yes, provide date of delivery: mm _____.;J, dd_____.;J, yyyy __ 
_ 
Was the infant healthy? D Yes D No 
O Unknown D NIA 
If any Adverse Event was expe-rienced by the infant. provide brief details:. _______________ _ 
Form Completed by: 
Print Name:-==---------------
Signature: _ 
~ ---------------
Effective Date: March 27. 2011 
Title: _______________ _ 
Date: _______________ _ 
Page 1of1 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 100 of 111
CONFIDENTIAL
Figure 12-2.  Pregnancy and Lactation Notification Worksheet
Approved 
 
 
AIVmt" 
Lactation Notification Worksheet 
Fax Completed Form to the Country-respective Safety Fax Line 
SELECT OR TYPE IN A FAX# Qs: +888 814 8653 
1. Case Administrative Information 
Protocol/Study Number: _20_1_7_0_13_9 ____________ 
_ 
Study Design: 0 lnterventional O aiservational (If Observational: 0 Prospective O Retrospective) 
2. Contact Information 
Investigator Name ___________________ _ 
Site# ___________ _ 
Phone~-
~ --------
FaxL__) ________ _ 
Email ___________ _ 
lnstiMion ______________________________________ _ 
4. Amgen Product Exposure 
Amgen Product 
Dose at t ime of 
Frequency 
Route 
Start Date 
breast feeding 
mm __ 
/dd __ 
lyyyy _
_ 
Was the Amgen product (or study drug) discontinued? O Yes 
If yes, provide product (or study drug) stop date: mm __ 
/dd __ 
lyyyy __ 
Did the subject withdraw from the study? 0 Yes 
No 
5. Breast Feeding Information 
Did the mother breastfeed or provide the infant with pumped breast rrilk while actively taking an Amgen product? D Yes 
D No 
If No. prollide stop date: mm ___ 
/dd ___ lyyyy ___ _ 
Infant date of birth: mm ___ 
/dd ___ 
lyyyy __ 
_ 
Infant gender. 0 Female O Male 
Is the infant healthy? D Yes 
O No O Unknovm O NIA 
If any Adverse Event was experienced by the molher or the infant. provide brief details=~--------------
Form Completed by: 
Print Name: _______________ _ 
Tnle: ______________ _ 
Signature: _______________ _ 
Date: _______________ _ 
Effective Date: 03 April 2012, version 2. 
Page 1 of 1 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 101 of 111
CONFIDENTIAL
12.6
Appendix 6.  Sample Storage and Destruction
Any blood sample collected according to the Schedule of Activities (Table 2-1 to 
Table 2-3) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
obesity and related metabolic disorders, the dose response and/or prediction of 
response to AMG 598, and characterize aspects of the molecule (eg, mechanism of 
action/target, metabolites).  Results from this analysis are to be documented and 
maintained but are not necessarily reported as part of this study.  Samples can be 
retained for up to 20 years.  
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent.
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the blood cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen.
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 102 of 111
CONFIDENTIAL
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 103 of 111
CONFIDENTIAL
12.7
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis 
(as described below) may meet the criteria for withholding or permanent discontinuation 
of Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009.
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified. 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to:

Hepatobiliary tract disease

Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus)

Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia

Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms

Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir)

Alpha-one antitrypsin deficiency

Alcoholic hepatitis

Autoimmune hepatitis

Wilson’s disease and hemochromatosis

Nonalcoholic fatty liver disease including steatohepatitis

Non-hepatic causes (eg, rhabdomyolysis, hemolysis)
If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix. 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 104 of 111
CONFIDENTIAL
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix).
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity
Analyte
Temporary Withholding
Permanent Discontinuation
TBL
> 3x ULN 
at any time
> 2x ULN
OR
INR
--
> 1.5 (for subjects not on 
anticoagulation therapy)
OR
AND
AST/ALT
> 8x ULN at any time
> 5x ULN but < 8x ULN for ≥ 2 weeks
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice)
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values
> 3x ULN (when baseline was < ULN)
OR
ALP
> 8x ULN at any time
--
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, Principal Investigator, and Amgen.   
If signs or symptoms recur with rechallenge, then the study drug should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 12-2) are never to be rechallenged.
12.7.1
Drug-induced Liver Injury Reporting and Additional Assessments
Reporting
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following:
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 105 of 111
CONFIDENTIAL

The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded)

The appropriate Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 12.4.
Additional Clinical Assessments and Observation
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 12-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.  
Assessments that are to be performed during this period include: 

Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours 

In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic.
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation:

Complete blood count with differential to assess for eosinophilia

Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis

Serum acetaminophen (paracetamol) levels

A more detailed history of: 
o
Prior and/or concurrent diseases or illness
o
Exposure to environmental and/or industrial chemical agents 
o
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever
o
Prior and/or concurrent use of alcohol, recreational drugs and special diets
o
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 106 of 111
CONFIDENTIAL

Viral serologies

Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear

Appropriate liver imaging if clinically indicated

Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected

Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist)
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies.
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs. 
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 107 of 111
CONFIDENTIAL
12.8
Appendix 8.  Mental Health Criteria Stopping Rules: Suggested 
Actions and Follow-up Assessments
Subjects with an increase in score on either the PHQ-9 and/or CSSR-S assessments
may meet the criteria for permanent discontinuation of Amgen investigational product or 
other protocol-required therapies.
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Mental Health Changes
The following stopping rules apply to subjects for whom an increase in their PHQ-9 
and/or CSSR-S sores have been identified.
Table 12-3.  Conditions for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Changes in Mental Health 
Scores 
Mental Health Assessment
Permanent Discontinuation
PHQ-9
≥ 10
OR
CSSR-S
Answers yes to any items #1-5
PHQ-9 = Patient Health Questionnaire 9 ; CSSR-S = Columbia Suicide Severity Rating Scale
Reporting
To facilitate appropriate monitoring for signals of mental health changes according to the 
criteria specified in the above, require the following:

The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded)

The appropriate Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen 
Additional Clinical Assessments and Observation
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld permanently due to potential mental health changes as specified in Table 12-3
are to undergo a period of “close observation” until the subject’s care can be transferred 
to an appropriate mental health professional.
Approved 
 
 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 108 of 111
CONFIDENTIAL
12.9
Appendix 9.  Columbia Suicide Severity Rating Scale
Baseline Form (shown below) at screening visit and Since Last Visit Form at all 
subsequent visits.
Approved 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
f'/ 
Version 1/14/09 
Pos11er, K.; Brem, D.; Lucas, C.; Gould, J1.; Sta11/ey, B.; Bro.,.11, G.; Fisher, P.; Zelaz11y, J.; 
Burke, A.; Oque11do, 111.; Jl1mm, J. 
Disdaimer. 
This scale is intended to be used by individuals ~10 have received training in its administration. The questions contained 
in the u,/umbi~Suicide Severity Rating Scale are suggested probes. Uhimate/y, the detennination of the presence of 
suicidal ideation or behavior depends on the judgment of the inaNidual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
.furm. developed by john Mann, MD and Maria Oquendo, MD, Conte c.enter (or die Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, I 051 Riverside Drive, New Yori<. NY, I 0032. (Oquendo M A, 
Halberstam B. & Mann J. }., Risk (actors (or suicidal behavior: utility and limitations of research instruments. In Ma First 
[Ed.] Standardized Evaluation in O inical Practice, pp. I 03 -130, 2003.) 
For reprints of the C-SSRS contaa Kelly Posner, 1'11.D., New Yark State Psychiatric Institute, I 051 Riverside Drive, New 
Yori<. New Yori<. I 003 2; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Fo undation for Mental Hygiene, Inc. 
AttGEN. 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 109 of 111
CONFIDENTIAL
Approved 
 
 
SC.'ICIDAL IDEATION 
• -!sk questions 1 and 2. Q both are nc,-gari\ie, proc:,r;.l'!d to "Suk-id al Behtn•ior .. section. lf the answu to question 2 is ",l't'.lS ", 
lifetime: 
Time Hf/Silt 
ask qurun·ons 3, 4 and 5. lfthe a,1swu to qururion 1 mid/or 2 fa ') •es", c:ompl61e "Jmensi(V of ld,r;.at;o,i" s« 1;0,i b.;low. 
Felt Most 
SUXiclal 
l. Wish to be Dead 
Su~ K1 endorses th.oughts aboUI a wi.b to be &ad or 001 a?i\1e tn)lllote. or wish to fall asleep an.d not v.'Ue up. 
Yes 
.No 
H(J'.Y. Jl)# wllht.d you wtrt. iea4 or wislt.t.dJYJM coll.lit" to sleep ad not 1'4.ll up? 
D 
C 
Ifyes.de.cn"be: 
l , Non-Specifi( .-\din Sui.tidal Thoughts 
Genml. ooo-;:pedfic th.oug,bls of waorlng to end ooe·s li:fe/colllD'lil S'iOCide (e.g .• 'Tw OIO!lg.N OOO!lt J:iiling my!#j/') witho-ilt tho-ilght; o: 'i'-ay; to kill 
Yes 
No 
onesili'tisociated lUth.od... 11!.tmt or plan. 
Hinv. Jo• ortuolly lt.oi airy {}to Melt.IS of kiJlhtg JYJtnsdf! 
D 
C 
Ii yes. descn"be: 
3, :\ctin· Stll<'id.-tl Ideation nitb Any ~Ietbods (Not PL'Ul) nitbout Intent to .-\ct 
Yes 
No 
Su~ K1 endorses th.oughts of 9.licide and ha. thougl!.1 of at least ooe method during the as;es,;meo1 period. Thh is d.iffmt!.I thao a specific plan v.itb time. 
place or memodd.!taili waited O'ilt (e.g .. thought of method to kill -self but noi a ;pedfic plan). lrichldes per..ot. who v.-O'll)d -say. "/ rho~hr about toking an 
D 
C 
<A·,rdos, bur / nf\·,r modfla sp«Vk plan as ro 'lfiutJt. tdtm or hO'll-' 1,ro11lel amul,'Y do it .•. tmd l t.rOUidnf\·,r go rh:rot.git v izi, iL" 
Hin-,. Jo• bun thiJtkiJtt do11t /Jqw yo• Inieltl 4o /Aft'! 
f, 
Ifyes.de.cn"be: 
4, :\ctin· Stllcid.-tl Ideation nitb So CM lnte-ut to .:\ct, without Specific Plan 
Yes 
No 
Active -suicidal tho-il.plt> of kil!il!.g oneself and subject repon.; bnll!g scm:e inlmt 10 act on sitth lboog:ht>. as opposed to "! har4' rhf UIOl;g)tts bur I 
d¢nirfl,'Y 'lliU Mt do 01\l~ 
OOow riltm..,, 
D 
C 
Hin-,. Jo• hod Ot.nt. t/JOllt/Jtr 11.nd lt.o4 $(11'Jt in«lllion of 11.t.ting on t/Jnn? 
If yes. de.cn"be: 
!,, :\ctin· Suicid.-tl Ideation nitb Specific Pfan and Intent 
ThO'ilghu ofJtllling on.eself \\itb detaili ofphn f,tlly orp.uiiilly wocked. out and silbject ha. some inlet!! to cany it O'ill. 
Yes 
No 
HinY. Jo• start ti u, ~•ork ow or MYN'ud 011t tht. 4ttl1ils o/lt.ow 10 kill yoursdf! D")"'" inltn4 u, tfl.try 0111 this plon? 
D 
C 
Ii yes. descn"be: 
l1''TENSITYOF IDEATION 
The,fol/oking,f«stuN.s should~ rar«i 'lliih ~.spur to ille mcm :~·wet>~ qfid«1ti011 (i.e., J .5 from aboi:e. with 1 luing rhe least :n ·we 
and 5 bei71g ille mcm ;qr~re) . • ct about time heJslie was/Hling the mos; sui<:idaL 
Mo~t 
Most Sh•tre ldration: 
--
Se\·ere 
T,-.e #(I-5) 
Desmnn·on of ldean·on 
frequenc-r 
How many rimes have J'Oll had these thoughts? 
--
(l)Lmchari oncea \l'ffk (l) Oo::ea,nek (3) 2-5tinmiD'ilwl. (•) Daily or alir,oo d,lJy (5) Mm)' times eath day 
Duration 
1"1tm you have the thoughts, how long do the,, last? 
(1) P.tffll!.g • few second; or mil!ute; 
(2) Less WD 1 hour/some of die tiD:.e 
(3) l-4 hours/a Joi of time 
(4) 4-S boun.'DlO>t of day 
(5) More thao S hours.lpersistm1 orcol!.rirru.OU> 
--
CoutroUabili~· 
Could/can J'Oll stop thinking about killing J'Oll.rself or wanDng to die if sou M·ant to? 
(})Easily abletoconttol d:loughu 
(2) Can control ch~s v.i.lb litti)e difficulty 
(3) Can control ch~s v.i.lb ;ome difficu.by 
(4) Cm control cho-aghts wilb a kit of &ffirully 
(5) Unable1oconttol d:lcmght; 
(O)Does noi atta:npt to control tho-il.plts 
--
Deterre-ut,; 
Are there things - anyone or anJ'lhing (,.g., fmni/J', rdigi.on, pa.in of demh) - thm stopped J'Oll from MYJ.nn·ng to die or ae-ling on 
thoughts of commim·ng suic-ide? 
(l) Detemou definit!ly stopped. )Vil from a.ttm.pting -suicide 
(4) Delant!.ts DlO>t likely did nOI stop )Vil 
--
(2) Detemou ptOOably-stopped you 
(3) U ncenain tbl detemots stopped )'Oil 
(5) Deterrent. definrtely did 00< stop yoo 
(0) Doe; "'' 'PPIY 
Reasons for Ideation 
1"1tm sort of reasom did J'OU haw for thinking about wo.nri.ng to die or killing J·ourself! Was it to ,ttd the pa.in or stop the MYI.Y 
J-OU M·erefeeling (in other M·ords J'OU couldn>, go on li,>ing wi.th this pa.in or h<M• J-OU M·erefe,ling) or was it to ze,tanmtion, 
reivnze. or a reacrionfrom others? Or both? 
0 ) CoD:pleteiy to p-t anmtion. m~e or a reacrioi. from others: 
(2) Mo>tly 10 
atta:ition. m:-mg.e or a reactioo from others 
(4) Mostiy to end or ;i:op die pain (you co-itldD 'I g.o oo 
U\it!.g 'ilith tile pain or how you 'il-ert feelil!.g) 
--
(3) Equally to p-t atl!l!.tion. m~ or a reacriot. from others: 
and to end/stop th.epalll 
(5) C.Ompl!tely 10 end or stoptbe J),UD (you <ooldn'1 goon 
thing rib die pain or how )'Oil v.-ere fee~ g) 
(0) Does l!.Ot am:lv 
~
l oi'l 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 110 of 111
CONFIDENTIAL
Approved 
 
 
SllICTD.'ILBEK~HOR 
(Ch«k. all t!wt a,. .. ,.~ ::::o Jomr as tlws~ an-scnarare. A@ts; must ask.about oJl n:ne_;l 
Lifefimt 
Actual Attempt: 
y., No 
A pot-emially self-injunou>a<:1 cocmm.tt~ v.i.mar le.is. s.o~ w-.;b to di~ as a ro:uh o/aa. Belmtor was in pan tboog!:n of., method 10 kill ones!li U!£m1 
does cot lal.•e tobe 1~4. Ifd!.m is Oft\' mtmlde;.i::e co die ~..odated with lb! w. tt:m ?I cm be coru.i.dered an .terual SJ!cide anempi. Tbrre does no1 
Jun-e co be an.v i,,ji•ry• or ha,11t,jllll the potmw.1 forfnjury or h.>Jm. If pmol!.puDs. trig..-r \\bile gm is. in moorh but g-JD i; broken so c<i itjwy P.su?is. 
tltis.iscocmdmd.an~p1. 
D 
D 
lnfmfug inem: Et'!!l if ari illlil\id'.W d..-mes iru:em,'wim 10 die. i! lll.lY be illfmed c:liniaiiy from the 'belll\tor or drcu:imtat1ces. F<ir ~pie. a hipl.,'y !efhal 
m th.u ii cleuiy £ot anacdderu -.o no ow.£ ime!::.1 bui iU:itide car: be infetnd (e.g., gw:.;.hot to held. j;,:im;iitl.g from witdow of a high floor,'mny). .%a. if 
someone dmies. inwu ro di~ buJ they l00Ugh1 tha! v,t;u r.hey did co--illd b! !~..11. Went Ir.l}' be mferred.. 
HtNe J->ou made a suicide one.mpt? 
Hal•e .J'OU don~ any1ln·na to Jwnn yourulf! 
HtNe .vou done OlfJ'tlring dangerous .,.,hrre yoJ1 c:,,uld h0'e di~d? 
TocaUof 
J1t1tat di.d J'Clf do? 
Anempu. 
Did you ___ c.s a way to md J'Our life? 
DidJ'OU l<l'Ollrto di~ (ei•ttn a liale) w htn}VJll __ ? 
--
R-n"e )' OU ,,.,.;,,g Ji, e11d your life "'hnt you __ ? 
Or iJid you d,.i,,k ir•·a.s possible sou rould /w,e dird /ro1't __ ? 
Or did you do itpun.Jyfor 01hn· re<0.:W11SI -.i1hou1 AJ\T inu,uion of killing J'Oll.rsrlf(like to r,lirnsuess~f«J bener, ga sympalltj', 
or g<'t something ,tse 10 happen)? (Self•!l!juno°JS Seh.lvio! v.ithout >ilk.idal imml) 
Ii ye;., d.e;c.nl!e: 
v .. No 
Has subie<"t eune:ed in Non-Suicidal ~elf-Iniutioas Beha,'lor~ 
D 
D 
lnterrupte-d .-\ttempt: 
. 
y., No 
\\:tw:i tbe persoc: is in!em;ipt!d (by a:i ouoidi! c:irrum.;iwi!) from -swtin.g the potmfully self-injwious act tr 1101 /qr Wt. anuai ammpt ·•;;rrJ!d ka\'f' 
OCCW'Tfld).. 
D 
D 
O\:erdos.e: Per.on has pilh iD lm!dbm is. siopped frocl ~ _exi.ng. Ot:c.e lbeyinges1 .m}' ¢1h. this bee~ ao anempi ra1h<:,1 tr.all .ui interr.ipied attempt. 
Sbootlq : :Per.on has rm poim..d toward .e-'.f. g:im h Wen .t'inyby someone C.e. or is ;o:nelxr"' p!,?\:mted from~ trig.gs. O!l.ce Ibey pull the Inger. 
e\·en iftb gim faili 10 !ire. i! ii ui .tnetnp1. Jtu:!pl!lg: ?moo is po~ed ro jump. U. grabbed aod tuen dcr.re: from 
~g: Pmoo h:a; noose around oKk 
b\a lui 001 }~l SW1ed t'1 bac: · is ttopped from do:Ilg $0, 
Total~ o: 
Has there bun a rime when }·o.t, started w do somerhing to end your 6/e but someone or .somnhing stoppd J--OU before J'OU 
int~ 
actua.ll)' did any tlJ:UJ.g? 
li _ya;., Ce.cn"be: 
--
Aborted .-\nemp1: 
y., No 
\\,'heo p.r.on cegm:s ;o tlle S'lep; rov..'ani c:aldng,a i'UU:!de a..-i:a:::pt. ~.n s1ep; lhwse.'I\.~ before they .tu:.nliy b~ en:aged tn a.oyself-deswctive bel-~\for. 
E1QJnPl~ <k""e sfmim to Ulteaupte.:! attempt;. e:s::ept that the m.d.'\,idu.u ':itopi hilt.•h.r;~ llmead ofbem;~ StOJ)?ed b}' .otnethiJli elie. 
0 
D 
Ilas r.hm be.en a rime wrfren .rou staned m do somerhfog co ,:ry to end j'OUr life. but you. stopped. rounelf before J'Oll ac'lually did 
OltJ'thing? 
Total#o: 
1€ yes.. .de.cnl)e-; 
•bortol 
--
Preparntory .-\~.u or Beh3,ior: 
Am OJ' ~antion towards ilru:ililen-tly making II mdde ar:tempt. Toll can includ.~ .lll)"dlirig beyottd a vo!balizatiooor i.bo'lptt. ;rJCh 11;aose.!1!'.tl!ingi ;pedfu 
y., N& 
IJ'.ed!od (e.g .. buying pills.. ptlf"J-.aililg II gim).or preparing foro~·s death b)·suicide (e.g., gh,illg lhing;: away. \1ritin_g .,_ suidd!. l:!Ote). 
D 
D 
Ho,~ you rol--e11 OltJ' stqn JOM•ards· moku1g a suicide onempt or preytml1g 10 kill J'Ollrself(sueh as collrca'ngpilJ.s, gelling a gi,n., 
P,in.g w1luabl~ a_.~,, or writing a suicide no1ej? 
Iiye;., de;cn"b!: 
Sufoidal Beh:nior: 
y., N& 
Suicll21 beh.wiot 'i\'a.i pll'sent dtlJllls the a.>ses;mzi1 period? 
D 
D 
A11s\ver for .4cfual Aftempti 011(•· 
!d<Xt"Recem 
Monl.edw 
mriwtirst 
An.empt 
Attempt 
Attempt 
Date: 
Date: 
Date: 
.-\ctu:tl Le-thaliry;M,dic:tl Dama;,: 
0. No pb};.kal damag,e, or very l!U1Jot pbys:iul &mag:(e.g., ;U%UCe .aa?Wi). 
En:wCcd, 
En:wCcd, 
En:wCcd, 
l. Mm.or pCy;.it11}~
e (~ .• ~git: speech; fio.1-&gm bums: miid blffdm~ s.pccUllS). 
2. Moderate Jmy-...ic.tl ~
g,e,: medx.al anenlioo need!d(e..g.. collic~but dff'py. som.e•:dw re;poru.i\-e: second-degree 
bwn.s: b~ 
ofau:jor \~~). 
3. Mo&r.:11elystten pltysiu.l damage:: m,diralbrupiuhzarioo ilt.d likely ilutt.ii\'e ca.rt r~ (e.g.. com.111Y..e nith. 
re:fli?Ms. ft.tact:~ b:um less tl-..a!: 10% of body: exi:e;i;:e blood tos.. but cao rec.onr-. major frJlC!W'~;.~ 
---
---
---
4. Sa-ere phyTIC.U ctam.lge:. m«iical hospimliution v.ith iata:i;iwcaP. telfllled (e.g.. comit1ose ribOUI te.fle-.,;e,;: mild-
b°lllllS,owt 20¼ofbody; e:g.msiwb»oil io>s. wi:th ttl!..table. viral sign;: mAjorruml11g,! 10 11 \iw.u~a). 
;, Dead! 
Potenrial LethaHi,.·: Only .-\nm -er if .-\c,n13J Leth.-i.tity-=0 
Likely l~:hllil)' of 11n:.Wa1tempc if no medical dlina~ (W follooa'll?'g e:wnple;. 'ililile having oo .tcr.-i.tJ mtdical ~e. 
£ncncoa, 
£ncncoa, 
£ncncoa, 
had poieolial fo: ;·ery .,afou.. lewli~-: pm g;.m iD mO'itth ~d p..tl!ed the aig_ge.r bur~ tail; ro fire ;o l:!Oll:edical damage: 
hying on. m.in mW ;,.itb oc.toming cr.t.m bw. 
i 1,1,-ay before run ow). 
0 = Beha\i CG' c.o1 l:l.elyto re;u!t minjury 
I = S.,.....h.wior likely 10 muh in iejwy tu..n not likely oo ca·JSe Wlh 
---
---
---
l = Behnior l!k'?lv 10 re;u!J indE.ul!. deS"C:ie avail4b!e tr.edica1 can 
, . 
~
1o!2 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 111 of 111
CONFIDENTIAL
12.10
Appendix 10.  Patient Health Questionnaire 9 (PHQ-9)
Approved 
 
 
Over the last 2 weeks. how often have you been bothered 
More 
Near-fy 
by any ol the following problems? 
Sewral 
than ha 
e¥erf 
(l.ke -,,,- ' indica e your answer} 
Nata 
days 
the days 
my 
or 
in d · g things 
0 
2 
3 
2. eeling 
depressed. or hopeless 
0 
2 
3 
3. rou 
ng or staying asleep, or sleeping i:.oo much 
0 
2 
3 
4. eeling ·rec1 or having · e energy 
0 
2 
3 
5.Poorap 
·;e or overea!i 
0 
2 
3 
6. 
ing 
d abo 
you 
af 
re or 
0 
2 
3 
have et yourself or 
eading 
e 
0 
2 
3 
other people COdd ae 
no1iced? Or the opposite -
· g so fidge1y or res:Jess 
0 
2 
3 
you a. e been moving around a 
9. Thoughts tha: you wou d be 
er 
g 
0 
2 
3 
yo 
SOffleW3f'/ 
FOR OFFlCE COOl'fG ...JL_ + ___ + ___ + __ _ 
= otal Score: 
If you checked off~ problems, how difficult h~ these problems made it for you to do your 
work, ta e care ol tt,-ngs at home, or get 
ong with othef" people? 
Not difficult 
tall 
Somewhat 
difficult 
Ver, 
<ifficult 
Extremely 
difficult 


Product:  AMG 598
Protocol Number:  20170139
Date:  25 June 2019
Page 1 of 11
CONFIDENTIAL
Amendment 3
Protocol Title:  A Phase 1b, Randomized, Double-blind, Placebo-controlled, 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 598 in Subjects With Obesity
Amgen Protocol Number: AMG 598 20170139
Amendment Date:
25 June 2019
Rationale:
The following updates were made to the protocol, dated 15 February 2019:

The dose regimen for Cohort 7 was added following the review of available 
safety and PK data from cohorts 1 through 6

Inclusion and exclusion criteria were modified for cohort 7 to allow chronic stable 
medical conditions, including updates to laboratory reference ranges, and 
allowed concomitant medications

A Safety Surveillance Team (SST) was added for ongoing safety review of 
Cohort 7 emergent data

Criteria for rechallenge of Amgen investigational product after potential 
hepatotoxicity were added

Visit windows were added to the cohort 7 Schedule of Assessments

Bone mineral density (BMD) measurement clarified to state specifically in spine 
and hip/femur in cohort 1-6 DXA description

Mental health questionnaire appendices updated to include the specific forms to 
be used at the sites
Approved 
 
 
AMGEN® 


Product:  AMG 598
Protocol Number:  20170139
Date:  15 February 2019
Page 1 of 9
CONFIDENTIAL
Amendment 2
Protocol Title:  A Phase 1b, Randomized, Double-blind, Placebo-controlled, 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 598 in Subjects With Obesity
Amgen Protocol Number: AMG 598 20170139
Amendment Date:
15 Feb 2019
Rationale:
The following updates were made to the protocol, dated 07 November 2018:

Cohort 7 visits and procedures were streamlined to reduce complexity and 
burden on subjects completing the study.

Primary analysis of data from escalation cohorts 1-6 was added in additional to 
final analysis of all subjects in cohorts 1-7.

Objective and endpoint language was updated to clarify that potential 
biomarkers, including but not limited to inflammatory and adipose tissue markers,
are one of the PD effects of AMG 598 that will be evaluated in this study.

Protocol language was updated to reflect that spine and femur bone mineral 
density will be evaluated by dual energy x-ray absorptiometry (DXA) in subjects 
in cohorts 1-6, while total body composition, including bone mineral content, will 
be evaluated by DXA in subjects in cohort 7.

DXA visit windows added.

Typographical and formatting errors throughout the protocol were fixed.
Approved 
 
 
AMGEN® 


Product:  AMG 598 
Protocol Number:  20170139 
Date:  07 November 2018 
Page 1 of 4 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 1b, Randomized, Double-blind, Placebo-controlled, 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 598 in Subjects With Obesity 
 
Amgen Protocol Number: AMG 598 20170139 
 
Amendment Date: 
07 November 2018 
 
Rationale: 
In response to an FDA request, analysis of AMG 598 anti-drug antibody (ADA) samples 
will be conducted.  In addition, the exclusion criteria were updated to exclude previous 
exposure to AMG 598. 
Typographical errors and inconsistencies throughout the protocol were fixed. 
Approved 
 
 
AMGEN® 

SAP_001.pdf: 
Product:  AMG 598 
Protocol Number:  20170139 
Date:  22 July 2019 
Page 1 of 28 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1b, Randomized, Double-blind, 
Placebo-controlled, Multiple Ascending Dose 
Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of 
AMG 598 in Obese Subjects 
Short Protocol Title: 
Multiple Ascending Dose Study of AMG 598 in 
Obese Subjects  
Protocol Number: 
20170139 
NCT Number: 
NCT03757130 
Authors: 
 
Sponsor: 
 
Amgen, Inc. 
One Amgen Center Drive 
SAP Date: 
Document Version 
Date 
Original (v[1.0]) 
22 July 2019 
AMGEN~ 


Product:  AMG 598 
Protocol Number:  20170139 
Date:  22 July 2019 
Page 2 of 28 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents .............................................................................................................. 2 
1. 
Introduction .............................................................................................................. 6 
2. 
Objectives, Endpoints and Hypotheses .................................................................... 6 
2.1 
Objectives and Endpoints ............................................................................. 6 
2.2 
Hypotheses and/or Estimations .................................................................... 7 
3. 
Study Overview ........................................................................................................ 7 
3.1 
Study Design ................................................................................................ 7 
3.2 
Sample Size ................................................................................................. 9 
3.3 
Adaptive Design ......................................................................................... 10 
4. 
Covariates and Subgroups ..................................................................................... 10 
4.1 
Planned Covariates .................................................................................... 10 
4.2 
Subgroups .................................................................................................. 10 
5. 
Definitions .............................................................................................................. 10 
6. 
Analysis Sets .......................................................................................................... 12 
6.1 
Safety Analysis Set ..................................................................................... 12 
6.2 
Pharmacokinetic (PK) Analysis Set ............................................................ 12 
6.3 
Pharmacodynamic (PD) Analysis Set ......................................................... 12 
6.4 
Primary Analysis set ................................................................................... 12 
6.5 
Final Analysis set ........................................................................................ 12 
7. 
Planned Analyses .................................................................................................. 12 
7.1 
Interim Analysis and Early Stopping Guidelines ......................................... 12 
7.2 
Primary Analysis ......................................................................................... 13 
7.3 
Final Analysis ............................................................................................. 13 
8. 
Data Screening and Acceptance ............................................................................ 13 
8.1 
General Principles ...................................................................................... 13 
8.2 
Data Handling and Electronic Transfer of Data .......................................... 13 
8.3 
Handling of Missing and Incomplete Data .................................................. 13 
8.4 
Detection of Bias ........................................................................................ 14 
8.5 
Outliers ....................................................................................................... 14 
8.6 
Distributional Characteristics ...................................................................... 14 
8.7 
Validation of Statistical Analyses ................................................................ 14 
9. 
Statistical Methods of Analysis ............................................................................... 14 
9.1 
General Considerations .............................................................................. 14 
9.2 
Subject Accountability ................................................................................ 15 
9.3 
Important Protocol Deviations .................................................................... 15 
9.4 
Demographic and Baseline Characteristics ................................................ 15 
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Product:  AMG 598 
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Date:  22 July 2019 
Page 3 of 28 
CONFIDENTIAL  
 
 
9.5 
Efficacy Analyses ....................................................................................... 16 
9.6 
Safety Analyses .......................................................................................... 16 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 16 
9.6.2 
Adverse Events  ......................................................................... 16 
9.6.3 
Laboratory Test Results ............................................................. 17 
9.6.4 
Vital Signs ................................................................................... 18 
9.6.5 
Physical Measurements ............................................................. 18 
9.6.6 
Electrocardiogram ...................................................................... 18 
9.6.7 
Antibody Formation .................................................................... 19 
9.6.8 
Exposure to Investigational Product ........................................... 19 
9.6.9 
Exposure to non investigational product ..................................... 19 
9.6.10 
Exposure to Concomitant Medication ......................................... 19 
9.7 
Analyses of secondary and exploratory endpoints ..................................... 19 
9.7.1 
Analyses of Pharmacokinetic Endpoints .................................... 19 
9.7.2 
Exploratory Endpoints ................................................................ 20 
9.7.2.1 
Pharmacodynamic Parameters: ............................... 20 
9.7.2.2 
Bone Mineral Density by DXA .................................. 20 
9.7.2.3 
Whole Body Composition by DXA ........................... 21 
9.7.2.4 
Weight, Waist Circumference and BMI: ................... 21 
10. 
Changes From Protocol-specified Analyses .......................................................... 21 
11. 
Literature Citations / References ............................................................................ 22 
12. 
Prioritization of Analyses ........................................................................................ 25 
13. 
Data Not Covered by This Plan .............................................................................. 25 
14. 
Appendices ............................................................................................................ 26 
Appendix A.  Handling of Missing or Incomplete Dates for Adverse 
Events and Concomitant Medications ........................................................ 27 
14.1.1 
Imputation Rules for Partial or Missing Stop Dates: ................... 27 
14.1.2 
Imputation Rules for Partial or Missing Start Dates: ................... 27 
Appendix B.  Reference Values/Clinical Severity grading ...................................... 28 
 
AMGEN® 


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Protocol Number:  20170139 
Date:  22 July 2019 
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CONFIDENTIAL 
List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event(s) 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum serum concentration 
DLRM 
DXA 
Dose level review meeting 
Dual-energy x ray absorptiometry 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
12-lead electrocardiogram
eCRF 
electronic case report form
EOS 
FFA 
GIP 
GLP-1 
End of Study 
Free fatty acid 
Glucose-dependent insulinotropic polypeptide 
Glucagone-like peptide-1   
HbA1c 
HDL-C 
HR 
Hemoglobin A1c 
High density lipoprotein cholesterol 
heart rate 
IP 
IPD 
investigational product 
important protocol deviation 
LDL-C 
low-density lipoprotein cholesterol 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMTT 
Mixed meal tolerance test 
PD 
pharmacodynamic(s) 
PI 
Principle investigator 
PK 
pharmacokinetic(s) 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
QRS interval 
QRS interval the interval between the Q wave and the S wave in 
the heart's electrical cycle as measured by ECG; represents the 
time it takes for the depolarization of the ventricles 
QT interval 
QT interval is a measure of the time between the start of the 
Q wave and the end of the T wave in the heart's electrical cycle 
as measured by ECG 
QTc interval 
QT interval corrected for heart rate using accepted methodology 
RR 
respiratory rate 
SAE 
serious adverse event 
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Product:  AMG 598 
Protocol Number:  20170139 
Date:  22 July 2019 
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CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
SC 
TEAE            
Subcutaneous 
Treatment emergent adverse event 
tmax 
time to maximum serum concentration 
 
AMGEN® 


Product:  AMG 598 
Protocol Number:  20170139 
Date:  22 July 2019 
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CONFIDENTIAL 
1.
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical
analyses that have been outlined within the protocol amendment 3 for study 20170139,
AMG 598 dated 25 June 2019. The scope of this plan includes the primary analysis and
the final analysis that are  planned and will be executed by the Amgen Global
Biostatistical Science department unless otherwise specified.
2.
Objectives, Endpoints and Hypotheses
2.1 
Objectives and Endpoints
Objectives 
Endpoints 
Primary 
•
To assess the safety and tolerability
of multiple subcutaneous (SC)
doses of AMG 598 administered
alone or in combination with
liraglutide in subjects with obesity
•
Subject incidence of
treatment-emergent adverse events
•
Safety laboratory data, vital signs, and
electrocardiograms (ECGs)
Secondary 
•
To characterize the PK of multiple
SC doses of AMG 598 administered
alone or in combination with
liraglutide in subjects with obesity
•
AMG 598 PK parameters may include, but are
not limited to, maximum observed concentration
(Cmax), time of maximum observed
concentration (tmax), and area under the
concentration time curve (AUC)
Exploratory 
•
To characterize the PD effects of
AMG 598
PD parameters: 
o
Concentrations of fasting glucose, insulin,
c-peptide, glucose dependent insulinotropic
polypeptide (GIP), glucagon-like polypeptide
type 1 (GLP-1), glucagon, and free fatty
acid (FFA)
o
Concentration-time profiles and AUC for
metabolic parameters following a mixed
meal tolerance test (MMTT)
o
Lipid levels, including but not limited to, total
cholesterol, low density lipoprotein
cholesterol (LDL-C), high density lipoprotein
cholesterol
(HDL-C), and triglycerides
o
Hemoglobin A1c (HbA1c)
o
Potential biomarkers including, but not
limited to inflammatory and adipose tissue
markers
AMGEN® 


Product:  AMG 598 
Protocol Number:  20170139 
Date:  22 July 2019 
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CONFIDENTIAL 
Objectives 
Endpoints 
•
To assess the effects of AMG 598
on body weight, waist circumference
and body mass index (BMI)
•
Change in body weight, waist circumference,
and BMI
•
To assess the effect of AMG 598 on
bone mineral density by dual energy
x-ray absorptiometry (DXA) (cohorts
1-6)
•
Changes in bone mineral density as measured
by DXA (cohorts 1-6)
•
To assess the effect of AMG 598 on
body composition (cohort 7)
•
Changes in body composition as measured by
whole body DXA (cohort 7)
•
To evaluate the immunogenicity of
AMG 598
•
Incidence of anti-AMG 598 antibody formation
2.2 
Hypotheses and/or Estimations 
•
AMG 598 will be safe and well tolerated following multiple SC dose administrations in
subjects with obesity across the dose range evaluated
•
AMG 598 in combination with liraglutide will be safe and well tolerated following
multiple SC dose administrations in subjects with obesity across the dose range
evaluated
•
AMG 598 PK profile following multiple SC dose administrations will support selection
of dose and frequency of administration in future multi-dose trials of AMG 598
3.
Study Overview
3.1 
Study Design
This is a randomized, placebo-controlled, double-blind, multiple ascending dose study in
subjects with obesity. The study consists of a total of 7 cohorts; 3 cohorts (1, 3 and 5)
with administration of AMG 598 or matching placebo SC every 4 weeks (Q4W) x3,
3 cohorts (2, 4 and 6) with Q4W x3 SC administration of AMG 598 or matching placebo
in combination with liraglutide SC once daily (QD) ascending doses, and 1 cohort
(cohort 7) with SC administration of AMG 598 or matching placebo SC Q4W x3 in
addition to liraglutide (3.0 mg SC QD) in subjects who have been on a stable dose of
liraglutide (3.0 mg SC QD) for at least 6 months. In cohorts 1-6,
eight (8) subjects will be randomized to receive AMG 598 or placebo SC in a 3:1 ratio as
described in the table below. In cohort 7, sixty (60) subjects will be randomized in a
1:1 ratio to receive AMG 598 or placebo SC as described in the table below.
AMGEN® 


Product:  AMG 598 
Protocol Number:  20170139 
Date:  22 July 2019 
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CONFIDENTIAL 
Planned Dose Levels by Cohort 
Cohort 
# 
Subjects 
Product 
Dose/ Frequency 
Route 
N (active: 
placebo) 
1 
8 
AMG 598/Placebo 
70 mg Q4W x 3 
SC 
6:2 
2 
8 
AMG 598/Placebo 
+ 
Liraglutide 
70 mg Q4W x 3 
+ 
0.6, 1.2, 1.8, 2.4, 3.0 mg 
QDa 
SC 
SC 
6:2 
3 
8 
AMG 598/Placebo 
210 mg Q4W x 3 
SC 
6:2 
4 
8 
AMG 598/Placebo 
+  
Liraglutide 
210 mg Q4W x 3 
+ 
0.6, 1.2, 1.8, 2.4, 3.0 mg 
QDa 
SC 
SC 
6:2 
5 
8 
AMG 598/Placebo 
420 mg Q4W x 3 
SC 
6:2 
6 
8 
AMG 598/Placebo 
+  
Liraglutide 
420 mg Q4W x 3 
+ 
0.6, 1.2, 1.8, 2.4, 3.0 mg 
QDa 
SC 
SC 
6:2 
7 
60 
AMG 598/Placebo 
+ 
Liraglutide 
420 mg SC Q4W x 3 
based on the safety, PK 
and PD from cohorts 1– 6 
+ 
3.0 mg QDb 
SC 
30:30 
a Subjects will start the first dose of liraglutide (0.6 mg, SC QD) on day 1, and increase the dose of liraglutide 
by 0.6 mg dose increment every 7 days, up to the full dosage of 3.0 mg by week 5 and remain on 3.0 mg 
until day 84, inclusive 
b Subjects eligible for the study will have been on a stable dose of liraglutide 3.0 mg SC QD for at least 
6 months and will continue liraglutide 3.0 mg SC QD throughout the screening and study period from study 
days -56 to end of study (EOS) (day 207)  
A dose level review meeting (DLRM) will be held to review the data and monitor safety 
before escalation to the next higher dose or expansion to the liraglutide combination 
cohort. The DLRM members will be composed of, at minimum, the investigator(s) 
actively enrolling subjects (whether in screening or enrolled) at the time of the meeting, 
the Amgen Medical Monitor, and Amgen Global Safety Officer or designee, and  
Amgen Study Manager or designee. Additional members may be added as needed  
(eg, PK/biomarker scientist, Biostatistician, or others providing expanded expertise).   
The DLRM voting members include the principal investigator(s) or designee, Amgen 
Medical Monitor and Amgen Global Safety Officer or designee.  
Escalation to a higher dose cohort or expansion to liraglutide combination cohorts will 
only proceed when the previous dose regimen has been found to be safe and 
reasonably tolerated based on available safety and laboratory data through day 36 for a 
AMGEN® 


Product:  AMG 598 
Protocol Number:  20170139 
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CONFIDENTIAL  
 
 
minimum of 6 of the 8 subjects dosed, and upon unanimous recommendation at the 
Dose Level Review Meeting (DLRM).  The dose level for cohort 7 will be chosen based 
on the preceding cohorts’ safety and PK data. The dose level for cohort 7 will not exceed 
the highest dose evaluated in cohorts 1-6.  The planned dose escalation schedule may 
be modified based on treatment-emergent data (safety and/or PK). Dose adjustments  
(if any) will be made on a treatment cohort and not on an individual subject basis and will 
be agreed upon by Amgen in conjunction with the Principal Investigator.  Clear stopping 
rules will be followed, and ad hoc DLRMs will be held, if necessary. 
Enrollment can be initiated in the subsequent cohorts after the planned DLRMs.  The 
DLRMs will take place at the following time points: 
DLRM #1: After a minimum of 6 out of 8 subjects dosed in cohort 1 complete study  
day 36.  Enrollment in cohorts 2 and 3 can be initiated after DLRM #1. 
DLRM #2: After a minimum of 6 out of 8 subjects dosed in each cohort 2 and 3 complete 
study day 36.  Enrollment in cohorts 4 and 5 can be initiated after DLRM #2. 
DLRM #3: After a minimum of 6 out of 8 subjects dosed in each cohort 4 and 5 complete 
study day 36.  Enrollment in cohort 6 can be initiated after DLRM #3. 
DLRM #4: After a minimum of 6 out of 8 subjects dosed in cohort 6 complete study  
day 36.  Enrollment in cohort 7 can be initiated after DLRM #4. 
3.2 
Sample Size 
Approximately 108 subjects (8 per cohort, cohorts 1-6; 60 in cohort 7) will be enrolled. 
The sample size for the study is based on practical considerations.  For safety 
considerations, with up to 66 subjects receiving AMG 598 (6 subjects in each of cohorts 
1-6 and 30 subjects in cohort 7), there is a 96.6% chance of detecting an adverse event 
with a true incidence rate of 5% or greater and a 99.9% chance of detecting an adverse 
event with a true incidence rate of 10%. 
In cohort 7, with a sample size of 30 subjects per group, there is approximately an 80% 
probability of observing a mean treatment difference in percent change from baseline in 
body weight between AMG 598 and placebo of > 3%, assuming a true treatment 
difference of 5%.  This assumes a standard deviation for percent change from baseline 
in body weight of 7% in each treatment group. 
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Product:  AMG 598 
Protocol Number:  20170139 
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CONFIDENTIAL  
 
 
Replacement of subjects: 
Subjects who withdraw from the study or who discontinue study drug administration 
prematurely may be replaced at the discretion of Amgen in consultation with the 
investigator. The replacement subject will be assigned to receive the identical treatment 
as the replaced subject. 
3.3 
Adaptive Design 
Not applicable 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Baseline values may be used as a covariate in analyses.  
4.2 
Subgroups 
No subgroup analyses are planned.  
5. 
Definitions 
Age 
Subject age at randomization will be determined using the age in years reported in the 
clinical database. 
Treatment-Emergent Adverse Event: 
A treatment-emergent adverse event (TEAE) is any adverse event that begins or 
worsens after the initial dose of investigational product as determined by the flag 
indicating the adverse event started after the first dose on the Events case report form 
(CRF) and ends prior to or at end of the study.  
Baseline: 
For any variable, unless otherwise defined, baseline is the last assessment taken prior  
to the first dose of investigational product. 
Baseline ECG: 
Baseline for ECG data is defined as the pre-dose assessments on day 1. 
As per protocol, predose ECGs will be performed on 3 occasions separated by at least 
30 minutes all in triplicate for a total of 9 ECGs (3 sets of triplicate ECGs) at -90, -60 and 
-30 minutes before investigational product administration. 
Baseline will be calculated by calculating the means of each of the triplicate predose 
observations separately and finally establishing the mean of those 3 separate means of 
triplicates. 
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CONFIDENTIAL  
 
 
Change from Baseline: 
Change from Baseline is the arithmetic difference between Post-baseline and Baseline. 
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value) 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value) / 
Baseline Value] x 100 
Enrollment Date: 
The enrollment date is defined as the randomization date.  This is scheduled to be  
Day -2 for Cohorts 1, 3 and 5, and Day -1 for Cohorts 2, 4 and 6 and day -28 for 
cohort 7. 
Investigational Product: 
The term investigational product is used in reference to AMG 598 or placebo. 
Non-investigational Product: 
Liraglutide is the non-investigational product used in this study. 
Primary Completion:  
The primary completion date is defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the primary endpoint(s), for the 
purposes of conducting the primary analysis, whether the study concluded as planned in 
the protocol or was terminated early. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  
The end of study date is defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up), as applicable. 
Screening Date: 
The screening date is defined as the date the informed consent is signed. 
Study Day 1: 
Day 1 is defined as the first day that investigational product is administered to the 
subject.  
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CONFIDENTIAL  
 
 
Study Day: 
Post study day 1: study day = (study date - date of Study Day 1) + 1 
Pre study day 1 = (study date – date of Study Day 1) 
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  QTcF=QT/(RR/1000)1/3 
Bazett-corrected QT Interval (QTcB) 
The Bazett’s correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  QTcB=QT/(RR/1000)1/2 
 
6. 
Analysis Sets 
6.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects who receive at least one dose of 
investigational product. 
6.2 
Pharmacokinetic (PK) Analysis Set  
The PK analysis set will consist of all subjects for whom at least one PK parameter or 
endpoint can be adequately estimated. 
6.3 
Pharmacodynamic (PD) Analysis Set 
The PD analysis set will consist of all subjects for whom at least one PD parameter or 
endpoint can be adequately estimated.  
6.4 
Primary Analysis set 
The primary analysis set will consist of all subjects from cohort 1 to 6 who receive at 
least one dose of investigational product. 
6.5 
Final Analysis set 
The final analysis set will consist of all subjects from cohort 7 who receive at least one 
dose of investigational product. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
DLRM members will oversee progress of the study and make recommendations relating 
to early closure / extension or alteration of the study based on ongoing monitoring of the 
study data.  Refer to Section 7.4.1 and 7.4.2 of the protocol amendment 3 for further 
details. 
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7.2 
Primary Analysis 
The primary analysis will occur after all subjects from cohorts 1 to 6 have completed the 
study and it will include all subjects from cohorts 1 to 6. 
Data from cohort 1 to 6 will be locked prior to primary analysis is carried out and clean 
snapshot data from cohort 1 to 6 will be used for primary analysis. 
7.3 
Final Analysis 
The final analysis will occur after all subjects in cohort 7 have completed the study and it 
will include all subjects from cohort 7. 
Data from cohort 7 will be locked prior to final analysis and clean snapshot data from 
cohort 7 will be used for final analysis. 
8.
Data Screening and Acceptance
8.1 
General Principles
The objective of the data screening is to assess the quantity, quality, and statistical
characteristics of the data relative to the requirements of the planned analyses.
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the 
RAVE database. 
8.3 
Handling of Missing and Incomplete Data 
The frequency of missing and incomplete data is expected to be low in this study and 
therefore, missing data will not be imputed.  
Laboratory measurements that are below the quantification limits will be considered 
equal to the lower limit of quantification (LLQ) for the calculation of population averages 
as a part of the summary tables. There will be no imputation of clinical laboratory values 
below LLQ for individual subject level data in line listings.  
Biomarker data that are below the quantification limits will be considered equal to half of 
the LLQ for all analyses unless specified otherwise. 
PK concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PK parameters. 
For partial dates (such as treatment emergent AE, concomitant medication, drug 
administration etc.), imputation of dates will be carried out as per Appendix A. 
I 
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8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by listing important protocol deviations (IPD) by cohort and site. The clinical 
study team will identify and document the criteria for important protocol deviations. 
 
8.5 
Outliers 
Details of detecting outliers can be found in the Data Management Plan (DMP) or other 
data management document. In addition, outliers may be identified via the use of 
descriptive statistics. All confirmed outlier data will be included in the analyses presented 
in this statistical analysis plan unless there is sufficient scientific justification to exclude 
them. 
Pharmacokinetic (PK) plasma concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed.  
 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version [9.4] or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK and PD 
endpoints.  Descriptive statistics on continuous measurements will include means, 
medians, standard deviations and ranges, while categorical data will be summarized 
using frequency counts and percentages.  Data will be presented and summarized by 
treatment at each time point, as applicable.  Graphical summaries of the data may also 
be presented. 
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Data for subjects receiving placebo will be combined across cohorts 1, 3 and 5 
(monotherapy cohorts) and separately across cohorts 2, 4 and 6 (combination therapy 
cohorts).  Placebo data for subjects in cohort 7 will not be combined with other cohorts. 
Data for subjects receiving AMG 598 will be presented separately by cohort. 
When data are summarized by time, the values recorded against the scheduled time 
points listed in the protocol will be used.  When assessing minimum/maximum increases 
or decreases over the study, all assessments, including unscheduled assessments will 
be used.  
9.2 
Subject Accountability 
A summary of subject disposition and investigational and non-investigational product 
administration will be provided for all subjects enrolled in the study along with a 
summary of sites. 
A summary of study reporting and analysis set dispositions will also be prepared. A 
subject disposition listing, noting inclusion in each analysis subset, will be provided for all 
subjects enrolled.  
A subject listing noting duration of investigational product administration, reason for 
discontinuation of treatment, and reason for discontinuing study will be provided. A list of 
subjects screened but not enrolled (screen failures) will be provided. 
A subject listing will be provided for randomization information, randomized treatment 
and actual treatments, including usage of liraglutide, as applicable.  
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. Listings of subjects with IPDs as well as those with inclusion and 
exclusion deviations will be provided separately. 
9.4 
Demographic and Baseline Characteristics 
Demographic (ie. age, age groups [< 40, >= 40], sex, race, ethnicity) and baseline 
characteristics (height, weight, body mass index, medical history) will be summarized by 
cohort and treatment received and overall (i.e. total from all the cohorts involved in the 
analysis and irrespective of treatment received) using descriptive statistics.  If multiple 
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races have been reported for a subject, the subject will be categorized as multiple race 
as well as by the combination of race. 
9.5 
Efficacy Analyses 
This section is not applicable.  
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
The primary objective of this phase 1b study is to evaluate the safety and tolerability of 
AMG 598 administered alone or in combination with liraglutide in subjects with obesity.  
The safety analyses will include the descriptive summary of treatment emergent adverse 
events, laboratory data, vital signs, physical measurements and ECG data. 
9.6.2 
Adverse Events  
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. The severity of each adverse event will be graded using the clinical 
severity grading system provided in Appendix B. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events (SAE), adverse events leading to withdrawal of 
investigational product (AMG598 or Placebo)  and/or non-investigational product 
(Liraglutide), fatal adverse events and adverse events of interest (EOI) .   
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of investigational product (AMG598 or Placebo)  
and/or non-investigational product (Liraglutide), fatal adverse events and adverse events 
of interest (EOI) will be tabulated by system organ class and preferred term (in which 
system organ class will be ordered alphabetically and the preferred terms within each 
system organ class will appear in descending order of frequency). 
In addition, summaries of treatment-emergent and serious adverse events by preferred 
term in any treatment arm will be provided in descending order of frequency.   
Summaries of treatment-emergent and serious adverse events will also be tabulated by 
system organ class, preferred term, and grade. 
The subject incidence of treatment-emergent adverse events will be summarized by 
actual treatment received. 
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Treatment related treatment emergent adverse events will be further summarized (by 
system organ class and preferred term) for AMG 598 and liraglutide separately.  
Subject incidence of events of interest will also be summarized according to their 
categories and preferred term. Events of interest of hypersensitivity will be identified 
using a narrow search/scope in standardized MedDRA query (SMQ). Events of interest 
of osteoporosis/osteopenia, gastrointestinal nonspecific inflammation and dysfunctional 
conditions, hyperglycaemia/new onset diabetes mellitus, depression and 
suicide/self-injury, and peripheral neuropathy will be identified using a broad 
search/scope in SMQ. Immunogenicity and Injection site reactions will be identified using 
Amgen-defined MedDRA search strategies. 
9.6.3 
Laboratory Test Results 
Individual chemistry, hematology and urinalysis laboratory data listings will be reviewed. 
Parameters that will be collected are presented in table A below.  
Values outside the normal laboratory reference range will be flagged as high or low at 
baseline and each post-baseline time point on the listings. 
For the parameters that are bolded in below Table A, summary statistics including actual 
value, change from baseline and percent change from baseline at protocol defined visits 
will be summarized. 
Table A: 
Local 
Laboratory: 
Chemistry 
Local Laboratory: 
Local 
Laboratory: 
Urinalysis 
Local Laboratory: 
Hematology 
Central 
Laboratory: 
Other 
Sodium 
Potassium 
Chloride 
Bicarbonate/CO
2  
Total protein 
Albumin 
Calcium 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
TSH – screening 
only 
Calcitonin – 
Drug Screen 
Benzodiazepines 
Barbiturates 
Opiates 
Tetrahydrocanna
binol 
Cocaine 
Amphetamines 
Ethanol (may be 
performed by a 
breath test) 
Viral Panel 
Hep B surface 
antigen 
HBcAb 
HepCAb 
HCV RNA 
PCR(as 
Specific 
gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
Platelets 
WBC 
Differential 
• Total
Neutrophils -or- 
seg. Neutrophils
and Bands/Stabs
• Eosinophils
• Basophils
• Lymphocytes
• Monocytes
Safety 
assessments 
P1NP 
CTX-1 
Lipid Panel 
Cholesterol 
(total) 
LDL-C 
HDL-C 
Triglycerides 
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Local 
Laboratory: 
Chemistry 
Local Laboratory: 
Local 
Laboratory: 
Urinalysis 
Local Laboratory: 
Hematology 
Central 
Laboratory: 
Other 
screening only 
Tryptase (in the 
event of a 
suspected 
anaphylactic 
reaction) 
Amylase 
Lipase 
necessary) 
HIVa 
Reproductive 
Serum or Urine 
Pregnancy 
FSH 
Coagulation 
PT/INR 
PTT/APTT 
a HIV assessment is recommended. 
ALP = alkaline phosphatase; ALT  alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CTX-1 = C-terminal telopeptides of Type I collagen; GIP = Glucose dependent 
insulinotropic peptide; GLP-1 = Glucagon-like peptide-1; HbA1c = ; hemoglobin A1c; HDL = high density 
lipoprotein; Hep = hepatitis; HIV = human immunodeficiency virus; HLA = human leukocyte antigen;  
INR = international normalized ratio; LDH = lactate dehydrogenase; LDL = low density lipoprotein;  
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; P1NP = Procollagen Type 1 N-Terminal Peptide; PT = prothrombin 
time; PTT/APTT = activated partial thromboplastin time;  RBC = red blood cell count; RDW = Red cell 
distribution width; SGOT = serum glutamic-oxaloacetic transaminase; SGPT - serum glutamic-pyruvic 
transaminase; WBC = white blood cell count 
9.6.4 
Vital Signs 
Vital signs data listings will be reviewed for each subject. Summaries of heart rate and 
blood pressure data over time and change from baseline will be provided.  
9.6.5 
Physical Measurements 
The analyses of physical measurements (weight, BMI and waist circumference) will 
include summary statistics at each protocol scheduled visit by cohort and by treatment. 
9.6.6 
Electrocardiogram 
All on-study ECG data listings will be reviewed. 
Each ECG will include the following measurements: QRS, QT, QTc, RR, and PR 
intervals. The Fridericia’s (QTcF) QT correction and Bazett’s (QTcB) QT correction will 
be computed as specified in section 5. All ECG parameters will be summarized over 
time and change from baseline over time will be provided.  
Further, subjects’ maximum change from baseline in QTcF and QTcB will be categorized 
in following categories and the number and percentage of subjects in each group will be 
summarized. Unscheduled assessments will be included in the determination of the 
maximum change. 
•
≤ 30 msec
•
> 30 – 60 msec
•
> 60 msec
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Subjects’ maximum post baseline values in QTcF and QTcB will also be categorized in 
the following categories and the number and percentage of subjects in each group will 
be summarized. 
•
≤ 450 msec
•
> 450 – 480 msec
•
> 480 – 500 msec
•
> 500 msec
9.6.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 598 antibodies 
(binding and if positive, neutralizing) at any time will be tabulated by cohort and by 
treatment.  
Antibody data will be listed for each subject. 
9.6.8 
Exposure to Investigational Product 
The number of doses of IP and the proportion of subjects receiving each dose level will 
be summarized using descriptive statistics.  
9.6.9 
Exposure to non investigational product 
Descriptive statistics of the number of doses of liraglutide received by each subject will 
be produced for cohorts 2, 4, 6 and 7.  
9.6.10 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving concomitant medication will be summarized 
by preferred term for each cohort and treatment as coded by the World Health 
Organization Drug dictionary.  
9.7 
Analyses of secondary and exploratory endpoints  
9.7.1 
Analyses of Pharmacokinetic Endpoints 
The Clinical Pharmacology Modeling and Simulation (CPMS) group at Amgen will 
perform this part of the analysis. The analysis will be performed using the PK analysis 
set. 
Serum AMG 598 concentrations will be determined using a validated assay.  
Individual serum concentration-time plots for AMG 598 will be presented for each subject 
as well as mean concentration-time plots for each dose cohort.  PK parameters including 
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but not limited to AUC, Cmax and tmax will be estimated using either compartmental 
(eg, PK modeling) or non-compartmental methods.   
Actual dosing and sampling times will be used for calculation of PK parameters.  
Summary statistics will be generated for each PK parameter for each dose cohort. 
Liraglutide PK concentrations will be summarized. 
9.7.2 
Exploratory Endpoints  
9.7.2.1 
Pharmacodynamic Parameters: 
Absolute values, change values and percent change from baseline values will be 
summarized in a table for following parameters:  
•
fasting glucose, insulin, c-peptide, glucose dependent insulinotropic
polypeptide (GIP), glucagon-like polypeptide type 1 (GLP-1), glucagon,
and free fatty acid (FFA)
•
Concentration-time profiles and AUC for metabolic parameters following a
MMTT
•
Lipid levels, including but not limited to, total cholesterol, low density
lipoprotein cholesterol, high density lipoprotein cholesterol, and
triglycerides
•
Hemoglobin A1c
Graph of mean percent change from baseline by visit for all treatment groups will be 
provided for all PD parameters. 
Additionally, a subset of these parameters (glucose, insulin, C-peptide, GIP, GLP-1, 
glucagon, and free fatty acids) will be measured on Day -1 and Day 6 postdose (ie. post 
IP administration) and day 64 postdose after meals during a MMTT and for these 
parameters, absolute values and percent change from baseline values will be 
summarized by cohort and treatment. 
Graph of grometric mean (+/- SE) vs. time (in minutes) for days -1, 6 and 64  will be 
plotted for glucose, insulin, C-peptide, GIP, GLP-1, glucagon, and free fatty acids 
following MMTT. 
9.7.2.2 
Bone Mineral Density by DXA 
Summary of absolute and percent changes in bone mineral density at the lumbar spine, 
femoral neck and total hip, as measured by DXA, will be summarized for subjects 
enrolled in cohorts 1-6. 
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9.7.2.3 
Whole Body Composition by DXA  
Summary of absolute and percent change from baseline values in body composition, 
including measures of total bone mineral context (BMC), total fat mass, total lean mass 
and visceral adipose tissue (VAT), as measured by whole body DXA will be summarized 
for subjects in cohort 7. 
9.7.2.4 
Weight, Waist Circumference and BMI: 
Summary of absolute and percent change from baseline values in body weight, weight 
circumference and BMI will be summarized. 
Mean percent change from baseline in weight by visit for all treatment groups will also be 
graphed. 
10.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses.
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11.
Literature Citations / References
Almind K, Ambye L, Urhammer SA, Hansen T, et al. Discovery of amino acid variants in 
the human glucose-dependent insulinotropic polypeptide (GIP) receptor: the impact on 
the pancreatic beta cell responses and functional expression studies in Chinese hamster 
fibroblast cells.  Diabetologia.  1998;41:1194-1198. 
Althage MC, Ford EL, Wang S, Tso P, et al.  Targeted ablation of glucose-dependent 
insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin 
resistance induced by a high fat diet.  J Biol Chem. 2008;283:18365-18376. 
Amgen.  AMG 598 Investigator’s Brochure, Edition 1. 
Baggio L, Drucker D. Glucagon-like peptide-1 receptors in the brain: controlling food 
intake and body weight. J Clin Invest. 2014;124:4223–4226. 
Beck B, Max JP. Direct metabolic effects of gastric inhibitory polypeptide (GIP): 
dissociation at physiological levels of effects on insulin-stimulated fatty acid and glucose 
incorporation in rat adipose tissue.  Diabetologia.  1986;29:68.  
Berndt SI, Gustafsson S, Magi R, Ganna A, et al.  Genome-wide meta-analysis identifies 
11 new loci for anthropometric traits and provides insights into genetic architecture. Nat 
Genet.  2013;45:501 to 512. 
Boylan MO, Glazebrook PA, Tatalovic M, Wolfe MM.  Gastric inhibitory polypeptide 
immunoneutralization attenuates development of obesity in mice.  Am J Physiol 
Endocrinol Metab.  2015;309:E1008-1018. 
Brons C, Jensen CB, Storgaard H, Hiscock NJ, et al.  Impact of short-term high-fat 
feeding on glucose and insulin metabolism in young healthy men.  J Physiol. 
2009;587:2387-2397. 
Dalle Grave R, Calugi S, Molinari E, et al.  Weight loss expectations in obese patients 
and treatment attrition: an observational multicenter study.  Obes Res. 2005;13:1961–
1969. 
Falko JN, Crockett SE, Cataland S, Mazzaferri EL.  Gastric inhibitory poly peptide (GIP) 
stimulated by fat ingestion in man.  J Clin Endocrinol Metab.  1975;41:260-265. 
Fulurija A, Lutz TA, Sladko K, Osto M, et al.  Vaccination against GIP for the treatment of 
obesity.  PLoS One.  2008;3:e3163. 
Heymsfield SB, Wadden TA.  Mechanisms, pathophysiology and management of 
obesity.  N Engl J Med.  2017;376:254-266. 
International Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use;  ICH Harmonised Tripartite Guideline: 
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals S6 (R1), 2011. 
International Committee of Medical Journal Editors Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals:  
http://www.icmje.org/icmje-recommendations.pdf 
Jensen MD, Ryan DH, Apovian CM, et al.  2013 AHA/ACC/TOS guideline for the 
management of overweight and obesity in adults:  a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines and The 
Obesity Society.  Circulation.  2014;129(Suppl 2):S102–38. 
Khera R, Murad MH, Chandar AK, et al.  Association of pharmacological treatments for 
obesity with weight loss and adverse events.  JAMA.  2016;315:2424. 
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Kim SJ, Nian C, McIntosh CH.  Activation of lipoprotein lipase by glucose-dependent 
insulinotropic polypeptide in adipocytes.  A role for a protein kinase B, LKB1, and AMP-
activated protein kinase cascade.  J Biol Chem.  2007;282:8557-8567. 
Kolotkin RL, Meter K, Williams GR.  Quality of life and obesity.  Obes Rev.  
2001;2:219-229. 
Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, et al.  Cardiovascular 
effects of intensive lifestyle intervention in type 2 diabetes.  N Engl J Med. 
2013;369:145–154. 
Look AHEAD Research Group.  Eight-year weight losses with an intensive lifestyle 
intervention: the look AHEAD study.  Obesity (Silver Spring).  2014;22:5–13. 
Marti A, Moreno-Aliaga MJ, Hebebrand J, Martínez JA. Genes, lifestyles, and obesity.  
Int J Obes Relat Metab Disord.  2004;28:S29-36. 
Miyawaki K, Yamada Y, Ban N, Ihara Y, et al.  Inhibition of gastric inhibitory polypeptide 
signaling prevents obesity.  Nat Med.  2002;8:738-742. 
Miyawaki K, Yamada Y, Yano H, Niwa H, et al.  Glucose intolerance caused by a defect 
in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout 
mice.  Proc Natl Acad Sci U S A.  1999;96:14843-14847.  
Mohammad S, Patel RT, Bruno J, Panhwar MS, et al.  A naturally occurring GIP 
receptor variant undergoes enhanced agonist-induced desensitization, which impairs 
GIP control of adipose insulin sensitivity.  Mol Cell Biol.  2014;34:3618-3629. 
Murphy KG, Bloom SR.  Gut hormones and the regulation of energy homeostasis. 
Nature.  2006;444:854–859. 
Murphy MC, Isherwood SG, Sethi S, Gould BJ, et al.  Postprandial lipid and hormone 
responses to meals of varying fat contents: modulatory role of lipoprotein lipase? Eur J 
Clin Nutr.  1995;49:578-588. 
Nasteska D, Harada N, Suzuki K, Yamane S, et al.  Chronic reduction of GIP secretion 
alleviates obesity and insulin resistance under high-fat diet conditions.  Diabetes. 
2014;63:2332-2343. 
Okada Y, Kubo M, Ohmiya H, Takahashi A, et al.  Common variants at CDKAL1 and 
KLF9 are associated with body mass index in east Asian populations.  Nat Genet. 
2012;44:302-306. 
Ponce R, Abad L, Amaravadi L, et al. Immunogenicity of biologically-derived 
therapeutics: assessment and interpretation of nonclinical safety studies. Regul Toxicol 
Pharmacol. 2009;54:164-182. 
Saxena R, Hivert MF, Langenberg C, Tanaka T, et al. Genetic variation in GIPR 
influences the glucose and insulin responses to an oral glucose challenge.  Nat Genet. 
2010;42:142-148. 
Simpson KA, Martin NM, Bloom SR. Hypothalamic regulation of appetite.  Expert Rev 
Endocrinol Metab.  2008;3:577–592. 
Speliotes EK, Willer CJ, Berndt SI, Monda KL, et al.  Association analyses of 249,796 
individuals reveal 18 new loci associated with body mass index.  Nat Genet. 
2010;42:937-948. 
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Suzuki K, Harada N, Yamane S, Nakamura Y, et al.  Transcriptional regulatory factor X6 
(Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K-
cells and is involved in GIP hypersecretion in high fat diet-induced obesity. J Biol Chem. 
2013;288:1929-1938. 
Terranova L, Busetto L, Vestri A, et al. Bariatric surgery: cost-effectiveness and budget 
impact.  Obes Surg.  2012;22:646–653. 
Tseng CC, Jarboe LA, Wolfe MM. Regulation of glucose-dependent insulinotropic 
peptide gene expression by a glucose meal.  Am J Physiol.  1994;266:G887-891. 
Tseng CC, Zhang XY. Role of G protein-coupled receptor kinases in glucose-dependent 
insulinotropic polypeptide receptor signaling. Endocrinology. 2000;141:947-52. 
Vilsboll T, Krarup T, Sonne J, Madsbad S, et al. Incretin secretion in relation to meal size 
and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. 
J Clin Endocrinol Metab.  2003;88:2706-2713 
Wang YC, McPherson K, Marsh T, et al.  Health and economic burden of the projected 
obesity trends in the USA and the UK.  Lancet (London, England). 2011;378:815–825. 
Wen W, Cho YS, Zheng W, Dorajoo R, et al.  Meta-analysis identifies common variants 
associated with body mass index in east Asians.  Nat Genet.  2012;44:307-311. 
WHO (World Health Organization).  Obesity and overweight.  2016 [cited 2017 Aug 22]. 
http://www.who.int/mediacentre/factsheets/fs311/en/ 
Yip RG, Boylan MO, Kieffer TJ, Wolfe MM.  Functional GIP receptors are present on 
adipocytes.  Endocrinology.  1998;139:4004-4007. 
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12. 
Prioritization of Analyses 
 There is no prioritization of analyses. 
 
13. 
Data Not Covered by This Plan 
Not applicable 
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14. 
Appendices 
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Appendix A.  Handling of Missing or Incomplete Dates for Adverse Events and 
Concomitant Medications 
 
14.1.1 
Imputation Rules for Partial or Missing Stop Dates: 
If the month and year are present, impute to the last day of the month.  
If only the year is present, impute December 31 of that year. 
If the stop date is entirely missing, assume the event or medication is ongoing. If a 
partial or complete stop date is present and the ‘ongoing’ or ‘continuing’ box is checked, 
then it will be assumed that the AE or conmed stopped and the stop date will be 
imputed, if partial. 
14.1.2 
Imputation Rules for Partial or Missing Start Dates:  
 
  
Stop Date 
Complete:  
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start 
Date 
<1st 
Dose 
≥1st 
Dose 
<1st 
Dose 
yyyymm 
≥1st 
Dose 
yyyymm 
<1st 
Dose 
yyyy 
≥1st 
Dose 
yyyy 
Partial: 
yyyymm 
Equal to 
1st Dose 
yyyymm 
2 
1 
2 
1 
N/A 
1 
1 
Not 
equal to 
1st Dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
Equal to 
1st Dose 
yyyymm 
3 
1 
3 
1 
N/A 
1 
1 
Not 
equal to 
1st Dose 
yyyymm 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
 
 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month.  
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date.  
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Appendix B.  Reference Values/Clinical Severity grading 
 The clinical severity grading scale is as follows: 
• 
grade 1 = mild (e.g., asymptomatic or mild symptoms, clinical or diagnostic 
observations only, intervention not indicated, or does not interfere with 
activity) 
• 
grade 2 = moderate (e.g., minimal intervention indicated or interferes with 
activity) 
• 
grade 3 = severe (e.g., medically significant but not immediately life-
threatening, prevents daily activity, or requires treatment) 
• 
grade 4 = life-threatening (i.e., refers to an event in which the subject was, in 
the view of the investigator, at risk of death at the time of the event) 
• 
grade 5 = fatal 
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