A Phase 1, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 133 in Subjects With Obesity
Phase: PHASE1
Conditions: Obesity
Sponsor: Amgen

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 1 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Title Page 
Protocol Title: 
A Phase 1, Randomized, Double-blind, 
Placebo-controlled, Single Ascending Dose and 
Multiple Ascending Dose Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 133 in Subjects 
With Obesity 
Short Protocol Title: 
Single and Multiple Ascending Dose Study of 
AMG 133 in Subjects with Obesity 
Protocol Number: 
20180048 
Investigational Product: 
AMG 133 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
+1 (805) 447-1000 
Protocol 
Approver 
Name: 
 
Function: 
Executive Medical Director, Translational 
Medicine 
 
Key 
Sponsor 
Contact 
Name: 
 MD, PhD 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
Email Address: 
 
NCT Number: 
NCT04478708 
Protocol Version Date: 
Document Version 
Date 
Original 
13 May 2020 
Amendment 1 (v1.0) 
19 November 2020 
Amendment 2 (v2.0) 
Amendment 3 (v3.0) 
08 February 2021 
14 May 2021 
Amendment 4 (v4.0) 
03 February 2022 
Data Elements Standards 
Version: 
6.4 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  The format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6).   
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 2 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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. 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 3 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1, Randomized, Double-blind, 
Placebo-controlled, Single Ascending Dose and Multiple Ascending Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 
133 in Subjects With Obesity, dated 03 February 2022, 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 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) 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 4 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary .................................................................................................. 9 
1.1 
Synopsis ..................................................................................................... 9 
1.2 
Study Schema ........................................................................................... 19 
1.3 
Schedule of Activities (SoA) ...................................................................... 22 
2. 
Introduction ........................................................................................................... 41 
2.1 
Study Rationale ......................................................................................... 41 
2.2 
Background ............................................................................................... 41 
2.2.1 
Disease ..................................................................................... 41 
2.2.2 
Amgen Investigational Product Background:  
AMG 133 ................................................................................... 42 
2.2.2.1 
Pharmacology ......................................................... 42 
2.2.2.2 
Pharmacokinetics .................................................... 44 
2.2.2.3 
Toxicology ............................................................... 45 
2.2.2.4 
Clinical Experience .................................................. 46 
2.3 
Benefit/Risk Assessment ........................................................................... 47 
2.3.1 
Key Benefits .............................................................................. 47 
2.3.2 
Key Risks .................................................................................. 47 
3. 
Objectives and Endpoints ..................................................................................... 50 
3.1 
Hypotheses ............................................................................................... 51 
4. 
Study Design ........................................................................................................ 51 
4.1 
Overall Design .......................................................................................... 51 
4.2 
Number of Subjects ................................................................................... 54 
4.2.1 
Replacement of Subjects ........................................................... 55 
4.2.2 
Number of Sites ......................................................................... 55 
4.3 
Justification for Investigational Product Dose ............................................ 55 
4.4 
End of Study ............................................................................................. 58 
4.4.1 
End of Study Definition .............................................................. 58 
4.4.2 
Study Duration for Subjects ....................................................... 58 
4.5 
Patient Input on Study Design ................................................................... 58 
5. 
Study Population .................................................................................................. 58 
5.1 
Inclusion Criteria ....................................................................................... 60 
5.2 
Exclusion Criteria ...................................................................................... 60 
5.3 
Lifestyle Considerations ............................................................................ 63 
5.3.1 
Meals and Dietary Restrictions .................................................. 63 
5.3.2 
Caffeine, Alcohol, and Tobacco ................................................. 64 
5.3.3 
Activity ....................................................................................... 64 
5.4 
Subject Enrollment .................................................................................... 64 
5.5 
Screen Failures ......................................................................................... 65 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 5 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
5.6 
Washout Period/Run-in Period/Invasive Procedures ................................. 65 
6. 
Treatments ........................................................................................................... 65 
6.1 
Treatment(s) Administered ........................................................................ 65 
6.1.1 
Investigational Products ............................................................ 65 
6.1.2 
Noninvestigational Products ...................................................... 68 
6.1.3 
Medical Devices ........................................................................ 68 
6.1.4 
Other Protocol-required Therapies ............................................ 68 
6.1.5 
Other Treatment Procedures ..................................................... 68 
6.1.6 
Product Complaints ................................................................... 69 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 69 
6.2 
Dose Modification ...................................................................................... 70 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 70 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 72 
6.2.2.1 
Amgen Investigational Product:  AMG 133 .............. 72 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 72 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 72 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 72 
6.4.1 
Method of Treatment Assignment .............................................. 72 
6.4.2 
Blinding ..................................................................................... 72 
6.4.2.1 
Site Personnel Access to Individual 
Treatment Assignments .......................................... 72 
6.4.2.2 
Access to Individual Subject Treatment 
Assignments by Amgen or Designees ..................... 73 
6.5 
Treatment Compliance .............................................................................. 73 
6.6 
Treatment of Overdose ............................................................................. 73 
6.7 
Prior and Concomitant Treatment ............................................................. 74 
6.7.1 
Prior Treatment ......................................................................... 74 
6.7.2 
Concomitant Treatment ............................................................. 74 
7. 
Discontinuation Criteria ......................................................................................... 74 
7.1 
Discontinuation of Study Treatment........................................................... 74 
7.2 
Discontinuation From the Study ................................................................ 75 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 75 
7.2.2 
Reasons for Removal From Study ............................................. 76 
7.3 
Lost to Follow-up ....................................................................................... 76 
8. 
Study Assessments and Procedures .................................................................... 76 
8.1 
General Study Periods .............................................................................. 77 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 77 
8.1.2 
Treatment Period ....................................................................... 77 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 6 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
8.1.3 
Safety Follow-up ........................................................................ 77 
8.1.4 
End of Study .............................................................................. 78 
8.2 
Description of General Study Assessments and Procedures ..................... 78 
8.2.1 
General Assessments ............................................................... 79 
8.2.1.1 
Informed Consent .................................................... 79 
8.2.1.2 
Demographics ......................................................... 79 
8.2.1.3 
Medical History ........................................................ 79 
8.2.1.4 
Physical Examination .............................................. 79 
8.2.1.5 
Physical Measurements .......................................... 79 
8.2.1.6 
Substance Abuse History ........................................ 80 
8.2.2 
Safety Assessments .................................................................. 80 
8.2.2.1 
Vital Signs ............................................................... 80 
8.2.2.2 
Suicidal Risk Monitoring .......................................... 80 
8.2.2.3 
Electrocardiograms ................................................. 81 
8.2.2.5 
Neurologic assessments ......................................... 82 
8.2.3 
Adverse Events and Serious Adverse Events ............................ 82 
8.2.3.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 82 
8.2.3.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 83 
8.2.3.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 83 
8.2.3.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 84 
8.2.3.5 
Safety Monitoring Plan ............................................ 84 
8.2.3.6 
Pregnancy and Lactation ......................................... 85 
8.2.4 
Clinical Laboratory Assessments ............................................... 85 
8.2.5 
Pharmacokinetic Assessments .................................................. 86 
8.2.6 
Pharmacodynamic Assessments ............................................... 86 
8.2.7 
Pharmacogenetic Assessments................................................. 86 
8.2.8 
Antibody Testing Procedures ..................................................... 87 
8.2.9 
Biomarkers ................................................................................ 87 
9. 
Statistical Considerations ...................................................................................... 90 
9.1 
Statistical Hypotheses ............................................................................... 90 
9.2 
Sample Size Determination ....................................................................... 90 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 90 
9.3.1 
Analysis Sets ............................................................................. 90 
9.3.1.1 
Full analysis Set ...................................................... 90 
9.3.1.2 
Safety Analysis Set ................................................. 91 
9.3.1.3 
Pharmacokinetic Analysis Set ................................. 91 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 7 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
9.3.2 
Covariates ................................................................................. 91 
9.3.3 
Subgroups ................................................................................. 91 
9.3.4 
Handling of Missing and Incomplete Data .................................. 91 
9.4 
Statistical Analyses ................................................................................... 91 
9.4.1 
Planned Analyses ...................................................................... 91 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 91 
9.4.1.2 
Primary Analysis ..................................................... 92 
9.4.1.3 
Final Analysis .......................................................... 92 
9.4.2 
Methods of Analyses ................................................................. 92 
9.4.2.1 
General Considerations ........................................... 92 
9.4.2.2 
Efficacy Analyses .................................................... 93 
9.4.2.3 
Safety Analyses ...................................................... 94 
9.4.2.4 
Other Analyses ........................................................ 95 
10. 
References ........................................................................................................... 97 
11. 
Appendices ........................................................................................................... 99 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 100 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 103 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 105 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 114 
Definition of Adverse Event ..................................................................... 114 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 122 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 128 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 130 
11.8 
Appendix 8.  Mental Health Criteria Stopping Rules: Suggested 
Actions and Follow-up Assessments ....................................................... 134 
11.9 
Appendix 9.  Columbia Suicide Severity Rating Scale (C-SSRS) ............ 135 
11.10 Appendix 10.  Patient Health Questionnaire 9 (PHQ-9) ........................... 138 
11.11 Appendix 11.  Subject Educational Material for Managing 
Nausea ................................................................................................... 139 
 
List of Tables 
Table 1.  Schedule of Activities — Cohorts 1 to 5 and Cohort 11 ................................... 22 
Table 2.  Schedule of Activities — Cohort 6 ................................................................... 25 
Table 3.  Schedule of Activities – Cohorts 7 to 9 ............................................................ 29 
Table 4.  Schedule of Activities – Cohort 10 .................................................................. 32 
Table 5.  Schedule of Activities – Part C Cohort 12 ....................................................... 35 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 8 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 6.  Schedule of Activities - Part C Cohort 13 ........................................................ 38 
Table 7.  Planned Dose Levels by Cohort ...................................................................... 54 
Table 8.  Estimated Exposure Margins of Intact AMG 133 Following Repeat 
Doses (Q4W) .......................................................................................... 57 
Table 9.  Estimated Exposure Margins of Total AMG 133 Following Repeat 
Doses (Q4W) .......................................................................................... 57 
Table 10.  Study Treatments ......................................................................................... 66 
Table 11.  Dose Cohort Stopping Rules ......................................................................... 71 
Table 12.  Analyte Listing ............................................................................................ 103 
Table 13.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ............................................. 131 
Table 14.  Conditions for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies 
Due to Changes in Mental Health Scores ............................................. 134 
List of Figures 
Figure 1-1.  Dose Selection for Cohort 9 and 10 ............................................................ 12 
Figure 1-2.  Study Schema ............................................................................................ 19 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form ................ 119 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 126 
Figure 11-3.  Sample C-SSRS Form ........................................................................... 135 
Figure 11-4.  Sample PHQ-9 Form .............................................................................. 138 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 9 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1, Randomized, Double-blind, Placebo-controlled, Single 
Ascending Dose and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 133 in Subjects With Obesity 
Short Protocol Title:  Single and Multiple Ascending Dose Study of AMG 133 in 
Subjects with Obesity 
Study Phase:  1 
Indication:  Obesity 
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 with side effects that 
include gastrointestinal intolerability.  AMG 133 is a peptide conjugated antibody 
composed of a human monoclonal antibody (mAb) that binds to and blocks the glucose 
dependent insulinotropic polypeptide receptor (GIPR) conjugated to 2 identical peptides.  
The conjugated peptides are glucagon-like peptide 1 receptor agonists.  In preclinical 
studies in obese cynomolgus monkeys, AMG 133 administration resulted in an 
approximate weight reduction of 17% compared with vehicle, with concomitant 
decreases in food intake, insulin, and triglyceride levels.  The current study evaluates the 
safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) of single ascending 
doses (SADs) and multiple ascending doses (MADs) of AMG 133 as a potential therapy 
for the treatment of obesity. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To assess the safety and tolerability 
of AMG 133 as single and multiple 
doses in subjects with obesity 
 
Subject incidence of 
treatment-emergent adverse events. 
 
Changes in laboratory safety tests, 
vital signs, and 12-lead 
electrocardiograms (ECGs) 
Secondary 
 
To characterize the pharmacokinetics 
of AMG 133 as single or multiple 
doses in subjects with obesity 
 
AMG 133 pharmacokinetic 
parameters including, but not limited 
to, maximum observed drug 
concentration during a dosing interval 
(Cmax), the time of maximum observed 
concentration (tmax), and area under 
the concentration-time curve (AUC) 
 
To evaluate the immunogenicity of 
AMG 133 
 
Incidence of anti-AMG 133 antibody 
formation 
 
Overall Design 
Part A (cohorts 1 to 6 and cohort 11) is a phase 1, randomized, double-blind, 
placebo-controlled, SAD study in adult subjects with obesity.  AMG 133 will be 
administered by subcutaneous (SC) injection for cohorts 1 to 5 and cohort 11, and 
intravenous (IV) injection for cohort 6.  Part A consists of a total of 7 cohorts. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 10 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Subjects will be confined at the Clinical Research Unit from check-in (morning of day -2) 
through the morning of day 8 for cohorts 1 to 5 and cohort 11 and day 6 for cohort 6. 
Approximately 56 subjects will enroll into 1 of 7 cohorts.  In each cohort, 8 subjects will 
be randomized to receive AMG 133 or placebo SC (cohorts 1 to 5 and cohort 11) or IV 
(cohort 6) in a 3:1 ratio as described below.  For cohort 1, the first 2 subjects (sentinel 
pair) will be randomized such that 1 subject will receive AMG 133 and 1 subject will 
receive placebo.  The sentinel pair will be observed for at least 48 hours before the 
remaining subjects in the cohort are dosed, provided there are no safety or tolerability 
concerns as assessed by the investigator.  Enrollment into the SAD cohorts will be 
sequential.  Subsequent cohorts will be dosed after the dosing regimen in the preceding 
cohort has been recommended by the Dose Level Review Team (DLRT) to be safe and 
well tolerated based on the safety and laboratory data through at least day 15 for at least 
7 out of 8 subjects dosed.  Subjects in cohorts 1 to 5 and cohort 11 will also participate 
in
 tests at day -1 and day 7. 
Part B (cohorts 7 to 10) is a randomized, placebo-controlled, double-blind, MAD study in 
adult subjects with obesity.  In each cohort, subjects will be randomized to receive 
AMG 133 or placebo SC in a 3:1 ratio as described in Table 7. 
Approximately 24 subjects will enroll into cohorts 7 to 9 (8 subjects per cohort).  
Cohorts 7 to 9 will include assessments of 
 
.  Enrollment into Part B cohort 7 will occur with a starting 
MAD dose that is at least 2 SAD dose levels below what was recommended by the 
DLRT to be safe and reasonably tolerated in Part A.  Enrollment into the MAD cohorts 8 
and 9 will be sequential.   
Subjects in cohorts 8 and 9 will be dosed after the dose regimen in the preceding MAD 
cohort has been recommended by the DLRT to be safe and reasonably tolerated based 
on safety and laboratory data through at least study day 36 for 6 out of 8 subjects dosed. 
The DLRT for SAD cohort 11 will also make dosing recommendations for cohort 9 
(Figure 1-1 [A]).  
 
 
Cohort 10 will enroll up to 20 subjects and will include the use of 
 
  Therefore, the dose recommended for cohort 10 should be the 
same as a dose studied in a previous MAD cohort. 
The dose recommended for cohort 10 will depend on the final dose recommended for 
cohort 9 and the safety and tolerability profiles for MAD cohorts 7 and 8 (Figure 1-1 [B]).  

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 11 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
In all dose escalation process between cohorts, DRLM will make a recommendation 
and Amgen will make the final decision on dose level. 
Part C (cohort 12 to 13) is an open-label modified dose-escalation MAD study in 
subjects with obesity.  Doses selected for these cohorts have been doses 
previously studied in Part A and Part B and have been shown to have an 
acceptable safety and tolerability profile.  Doses selected in Part C will not exceed 
the dose levels previously studied in the MAD cohorts ( 420 mg SC Q4Wx 3).  
Cohort 12 will receive
mg SC on days
followed by 
mg SC on 
days 
.  Cohort 13 will receive
mg SC on days 
followed 
by 
mg SC on days
.  Up to 6 subjects per cohort will receive 
AMG 133 as described in Section 1.3.  Cohort 12 and cohort 13 will enroll in 
parallel.  The DLRT will review the safety and laboratory data through at least 
day 36. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 12 of 138 
CONFIDENTIAL  
 
FORM-001520, v.24, 21 May 2019 
 
 
Figure 1-1.  Dose Selection for Cohort 9 and 10 
 
 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 13 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
MAD cohorts 7 to 9: Study drug will be administered every 4 weeks for a total of 
3 SC doses.  The dose levels will be defined after evaluation of the available PK and 
PD data from preceding cohorts in the SAD phase (Part A).  Three different dose 
levels will be evaluated with the lowest dose administered to cohort 7, and 2 higher 
ascending doses administered to cohorts 8 and 9.  The dose level for cohorts 
7 to 9 will not exceed the highest dose evaluated in cohorts 1 to 6 and cohort 
11 (Part A).  Subjects enrolled in cohorts 7 to 9 will also be asked to 
 
 
 
MAD cohort 10:  Up to twenty subjects will be randomized in a 3:1 ratio to receive 
AMG 133 or placebo SC.  All subjects will be asked to use
  
The dose level will be defined after evaluation of the available PK and PD data from 
preceding MAD cohorts.  The dose level will not exceed the highest dose evaluated 
in cohorts 7 to 9 (Part B). 
Dose Level Review Meetings 
A DLRM will be held to review subject data and monitor safety before escalation to the 
next cohort.  Escalation to a higher dose cohort will only proceed when the previous 
dose regimen and cumulative data from previous cohorts have been reviewed and found 
to be safe and reasonably tolerated based on available safety and laboratory data 
through day 15 for at least 7 out of 8 subjects dosed in Part A and day 36 for Part B for 
at least 6 out of 8 subjects dosed and upon unanimous agreement of the DLRT 
members. 
The planned dose escalation schedule may be modified based on treatment-emergent 
data (safety and/or PD).  Dose adjustments (if any) will be made by Amgen on a 
treatment cohort and not on an individual basis. 
The doses selected for Part C cohorts are those that have already been shown to 
have an acceptable safety and tolerability profile.  The DLRT will meet to review 
the safety and tolerability through at least day 36. 
Number of Subjects 
A total of approximately 112 subjects will be enrolled in the study.  Approximately 
56 subjects will be enrolled in Part A of the study, with 8 subjects in each of the 
7 cohorts.  Approximately 44 subjects will be enrolled in Part B of the study, with 
8 subjects in cohorts 7 to 9 and up to 20 subjects in cohort 10.  Up to 6 subjects per 
cohort will be enrolled in cohorts 12 and 13.  Additional subjects may be enrolled if a 
DLRT recommendation is made to expand, repeat, or add cohorts to the study or if 
replacement subjects are added. 
Summary of Subject Eligibility Criteria 
Subjects in the study will be males and females  18 to  65 years of age at the time of 
randomization with a body mass index (BMI) of  30.0 kg/m2 and  40.0 kg/m2.  Females 
enrolled must be of nonreproductive potential. 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 14 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Treatments 
Cohorts 1 to 6 and cohort 11 (Part A):  After completion of all predose procedures on 
the day of dosing, subjects in cohorts 1 to 5 and cohort 11 will receive AMG 133 (21 mg 
or a dose based on available data from previous cohorts, not exceeding 70, 140, 280, 
560, or 840 mg), or placebo SC on day 1.  For cohort 6, subjects will receive AMG 
133 at a dose based on available data from previous cohorts, not exceeding 70 mg or 
placebo IV on day 1. 
Cohorts 7 to 9 (Part B):  After completion of all predose procedures on the day of 
dosing, subjects will receive AMG 133 (a dose based on available data from previous 
cohorts, not exceeding 140, 280, and 560 mg for cohorts 7, 8, and 9 respectively), or 
placebo SC on days 1, 29, and 57. 
Cohort 10 (Part B):  After completion of all predose procedures on the day of dosing, 
subjects will then receive placebo or AMG 133 at a dose level not exceeding 560 mg or 
placebo SC Q4W on days 1, 29, 57 in addition to the
  The dose level 
of cohort 10 will be determined based on the emerging safety and PK data of the 
preceding cohorts and will not exceed the highest dose evaluated in cohorts 7 to 9. 
Cohorts 12 to 13 (Part C):  After completion of all predose procedures on the day 
of dosing, subjects will receive AMG 133
mg SC on day 
  Subjects enrolled in 
cohort 12 will also receive 
mg SC on day 
followed by a dose of 
 mg SC 
on days 
  Subjects enrolled into cohort 13 will also receive
mg SC on 
days 
followed by a dose of 
mg on days
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 15 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Planned Dose Levels by Cohort 
 
Cohort 
No.  
Subjects 
AMG 133/Placebo 
Dose/ Frequency 
Route 
N 
(active: 
placebo) 
Part A 
1 
8 
21 mg day 1 
SC 
6:2 
2 
8 
Not exceeding 70 mg day 1a 
SC 
6:2 
3 
8 
Not exceeding 140 mg day 1a 
SC 
6:2 
4 
8 
Not exceeding 280 mg day 1a 
SC 
6:2 
5 
8 
Not exceeding 560 mg day 1a 
SC 
6:2 
11 
8 
Not exceeding 840 mg day 1a 
SC 
6:2 
6 
8 
Not exceeding 70 mg day 1a 
IV 
6:2 
Part B 
7 
8 
Not exceeding 140 mgb 
Q4W x 3 
SC 
6:2 
8 
8 
Not exceeding 280 mgb 
Q4W x 3 
SC 
6:2 
9 
8 
Not exceeding 560 mgb 
Q4W x 3 
SC 
6:2 
10 
 20 
Not exceeding 560 mgc 
Q4W x 3 
+  
SC 
 15:5 
Part C 
12 
 6 
SC 
N/A 
13 
 6
SC 
N/A 
QW  every week; Q4W = every four weeks; SC = subcutaneous; IV = intravenous. 
a Actual dose levels will be based on available data from previous cohorts. 
b Dose will not exceed the highest dose evaluated in cohorts 1 to 5 and cohort 11 (Part A) 
c Dose will not exceed the highest dose evaluated in cohorts 7 to 9 (Part B) 
Procedures 
Screening  
For all subjects, after informed consent is obtained, all screening procedures and tests 
establishing eligibility will be performed within 28 days before the first dose of 
AMG 133 or placebo (day 1). 
Study procedures are summarized in the Schedule of Activities (Section 1.3). 
Serious adverse events will be collected from the time the informed consent form is 
signed. 
Day -28 to -14 (Part B) 
Cohort 10: Subjects who meet all the screening inclusion/exclusion criteria will be 
eligible to report to the research facility prior to day -14. 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 16 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Day -28 to -4 (Part B):  
Cohorts 7 to 9:  Subjects who meet all the screening inclusion/exclusion criteria will be 
eligible to report to the research facility on or prior to day -4 depending on scheduling 
allowances,
 
In-House Residency  
Subjects in cohorts 1 to 5 and cohort 11 (Part A) will be admitted after confirmed 
eligibility on day -2 for a 10-day (9-night) residency period.  Subjects in cohort 6 (Part A) 
will be admitted after confirmed eligibility on day -2 for an 8-day (7-night) residency 
period. 
Subjects in cohorts 7 to 10 (Part B) will be admitted after confirmed eligibility on 
day -1 for a 3 day (2 night) residency.  Subjects will be dosed on day 1, the second day 
of residency.  Subjects will be admitted on days 28 – 30 and days 56 – 58 for a 3 day 
(2 night) residency.  Subjects will receive AMG 133 or placebo on days 29 and 57, 
respectively.   
Subjects in cohorts 12 and 13 (Part C) will have an optional overnight in-house 
residency period after the scheduled 
mg SC AMG 133 administration on days
for cohort 12 and on days 
for cohort 13.  Subjects may 
remain in-house for continued observation based on changes in the vital signs 
and/or the subject reports adverse events that interfere with daily activities and/or 
per clinical judgement of the site Principal Investigator if the subject is anticipated 
to require supportive management of adverse events.  Subjects in cohorts 12 and 
13 will be admitted for a required overnight observation on either Day 15 
(cohort 12) or Day 29 (cohort 13) after receiving the first dose of 
mg SC AMG 133. 
Day -2 Part A; Part C 
Part A:  Cohorts 1 to 6 and cohort 11:  Subjects who meet all the screening inclusion 
criteria and none of the 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 assessments, subjects will be randomized 
to receive either AMG 133 or placebo on day 1. 
Part C:  Cohorts 12 - 13:  Subjects who meet all the screening inclusion criteria 
and none of the exclusion criteria will be eligible to report to the research facility 
once on day -2 (up to day -4), at which time assessments will be performed to 
confirm eligibility.  If subjects are eligible after the completion of all day -2 
assessments, subjects will receive AMG 133 on day 1. 
Day -1 
Part A:  Cohorts 1 to 5 and cohort 11:  A
test will be performed on 
day -1 along with additional procedures as outlined in the Schedule of Activities in 
Section 1.3.  As part of the

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 17 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
summarized in the Schedule of Activities in Section 1.3. 
tests will not 
be performed in cohort 6. 
Part B: cohorts 7 to 10: Subjects who meet all the screening inclusion criteria and none 
of the 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 133 or placebo on day 1. 
Day 1: 
Part A: After completion of all predose procedures on the day of dosing (day 1), subjects 
will receive investigational product (SC for cohorts 1 to 5 and cohort 11 and IV for 
cohort 6, only).  Subjects will undergo vital signs and pharmacokinetics blood draws 
postdose as outlined in the Schedule of Activities in Section 1.3. 
Part B: After completion of all predose procedures on the day of dosing (day 1), subjects 
will receive investigational product (SC for cohorts 7 to10).  Subjects should undergo 
additional vital sign assessments 3 hours after dosing but are not scheduled to get 
postdose blood draws on day 1 (see Schedule of Activities in Section 1.3). 
Part C:  After completion of all predose procedures on the day of dosing (day 1), 
subjects will receive AMG 133 (SC).  Subjects are scheduled to get postdose 
blood draws on day 1 but should undergo additional monitoring (per clinical site 
standard operating procedures) and vital sign assessments approximately 
4 to 5 hours after dosing.  The subjects can be discharged from the clinical facility 
based upon a stable vital signs and assessment per clinical site standard 
operating procedures. 
Day 7 
Cohorts 1 to 5 and cohort 11:  A 
 test will be repeated on day 7 along 
with additional procedures as outlined in the Schedule of Activities in Section 1.3.  
tests will not be performed in cohort 6. 
Treatment and Follow-Up 
Part A: AMG 133 or placebo will be administered SC on day 1 after predose 
procedures.   
Part B: AMG 133 or placebo will be administered SC Q4W x3 on days 1, 29, and 
57 after predose procedures.   
Part C:  After predose procedures for cohort 12,
mg AMG 133 will be 
administered SC on days
 and
mg will be administered SC on days 
 
  After predose procedures for cohort 13,
mg AMG 133 will be 
administered SC on days
mg will be administered SC on days 
  
All procedures on day of dosing as outlined in the Schedule of Activities (Section 1.3) 
should occur prior to dosing of AMG 133 or placebo unless otherwise specified. 
Subjects will return to the research facility as outlined in the Schedule of Activities in 
Section 1.3 and will undergo the following assessments at specified time points 
throughout the study:   physical examinations, physical measurements, 12-lead ECGs, 
vital sign measurements, adverse event and serious adverse event collection, 
concomitant therapies review, clinical laboratory evaluations,
pharmacokinetic and other pharmacodynamic assessments.  Specific assessments for 
Part A cohorts 1 to 5 and cohort 11 include the 
 test and specific 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 18 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
assessments for Part B and Part C (cohorts 7 to 13) include the Patient Health 
Questionnaire-9 (PHQ-9), Columbia Suicide Severity Rating Scale (C-SSRS), 
  Subjects will 
remain in the research facility until completion of all study procedures on each visit day. 
End of Study (EOS): 
Subjects will be followed through the completion of end of study (EOS) procedures on 
day 150 ± 7 (Part A), day 207 ± 7 (Part B), and up to day 207 ± 7 (Part C). 
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 adverse events 
or laboratory abnormalities will be followed until either: a) resolution of the abnormality, 
b) it is considered stable in the opinion of the 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 8.2 and the Schedule of Activities in Section 1.3. 
Statistical Considerations 
Descriptive statistics will be provided for selected demographics, safety, 
pharmacokinetic, and pharmacodynamic endpoints.  Accumulating pharmacodynamic 
data might be reviewed throughout the study by treatment periodically. 
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.  Pharmacokinetic, 
pharmacodynamic, and clinical laboratory data will be summarized by treatment group 
and at each time point when samples are collected.  Graphical summaries of the data 
may also be presented.  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 investigational product. 
The sample size for the study is based on practical considerations.  No statistical 
hypotheses will be tested.  For safety considerations, with up to 87 subjects (42 subjects 
from cohorts 1 to 6 and cohort 11 of Part A, 18 subjects from cohorts 7 to 9 of Part B, up 
to 15 subjects from cohort 10 of Part B, and up to 12 subjects in Part C) receiving 
AMG 133, there is at least 92.9% chance of detecting an adverse event with a true 
incidence rate of 3% or greater and at least 98.8%  chance of detecting an adverse 
event with a true incidence rate of 5% or greater. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
No statistical hypotheses will be tested in this study. 
Sponsor Name: 
 Amgen Inc. 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 19 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
1.2 
Study Schema 
Figure 1-2.  Study Schema 
Part A:  Single Ascending Dose in Obese Subjects (n = 56) 
D-28        D1 single dose                     EOS           
Screen
FU Period
D-28        D1 single dose                     EOS            
Cohort 1
6:2, 21mg SC
Screen
FU Period
D-28         D1 single dose                     EOS            
D-28           D1 single dose                     EOS            
Cohort 3
6:2, ≤ 140 mg SC
Cohort 4
6:2, ≤ 280 mg SC
Cohort 5
6:2, ≤ 560 mg SC
Screen
FU Period
Screen
FU Period
Screen
FU Period
D-28        D1 single dose                     EOS            
Cohort 2
6:2, ≤ 70 mg SC
D-28        D1 single dose                      EOS            
IV cohort for 
Bioavailability
Cohort 6
6:2, 70 mg IV
Screen
FU Period
Cohort 11
6:2, ≤ 840 mg SC
D-28           D1 single dose                        EOS            
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 20 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Part B:  Multiple Ascending Dose in Obese Subjects (n = 44) 
Screen
Treatment
FU Period
D-28                   D1                                                                  EOS            
Cohort 8
6:2, 280 mg SC Q4Wx3
Screen
Treatment
FU Period
D-28                   D1                                                                  EOS            
Cohort 9
6:2, 420 mg SC Q4Wx3
Treatment
Screen
FU Period
D-28                   D1                                                                   EOS            
Cohort 7
6:2, 140 mg SC Q4W x3
Screen
Treatment
FU Period
D-28                   D1                                                                 EOS            
Cohort 10
≤15:5, 280 mg SC Q4Wx3 +
 
D = day; EOS = end of study; FU = follow-up; IV = intravenous; Q4W = every 4 weeks; SC = subcutaneous. 
 
Part C:  Modified Dose-escalation in Obese Subjects (n  12) 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 21 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Cohort 12
Cohort 13
Screen
FU Period
D-28             D1                                                                                        EOS            
Treatment
Screen
FU Period
D-28                D1                                                                                        EOS           
Treatment
 
D = day; FU = follow-up; SC = subcutaneous. 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 22 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
1.3 
Schedule of Activities (SoA) 
Table 1.  Schedule of Activities — Cohorts 1 to 5 and Cohort 11 
PROCEDURE 
Screening 
(Days) 
Treatment Period (Days) 
EOS/ 
SFUa 
Notes 
-28 -2 -1 
1 
2 
3 
4 
5 
6 
7 
8 
15  
1 
22  
1 
29  
1 
43  
3 
57  
3 
71  
3 
92  
7 
120   
7 
150  
 7 
In-house residency 
day -2 to 8 
GENERAL AND SAFETY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Physical measurements 
X 
 
 
Xb,c 
 
 
 
 
Xb 
 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate measurementd 
Xe Xe 
 
Xc,f 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
Vital signs 
X 
X 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and/or Urine pregnancy 
test (females only)g,h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum pregnancy test at 
day -28 and EOS, urine 
pregnancy test at day -2  
Serum FSH testh 
(postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For postmenopausal 
status confirmation 
Coagulationh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
Chemistryh,j 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Calcitonin and TSH at 
day -28 only.  Serum 
amylase and lipase on 
days -2, 8, 15, 29, and 
EOS only. 
Page 1 of 3 
Footnotes defined on last page of the table. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 23 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 1.  Schedule of Activities — Cohorts 1 to 5 and Cohort 11 
PROCEDURE 
Screening 
(Days) 
Treatment Period (Days) 
EOS/ 
SFUa 
Notes 
-28 -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
15  
1 
22  
1 
29  
1 
43  
3 
57  
3 
71  
3 
92  
7 
120   
7 
150   
7 
In-house residency 
day -2 to 8 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B and C 
screeningh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysish 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Alcohol, cotinine, and drug 
screenh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 133-antibodyi 
 
 
 
Xc 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Creatine Kinase 
X 
X 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
STUDY-SPECIFIC 
ASSESSMENTS (eg, DISEASE-
SPECIFIC ASSESSMENTS, 
RADIOLOGICAL 
ASSESSMENTS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma AMG 133 
pharmacokineticsi 
 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sampling time points on 
day 1 to include predose, 
and at 1, 2, 4, and 
8 hours postdose. 
Page 2 of 3 
Footnotes defined on last page of the table. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 24 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 1.  Schedule of Activities — Cohorts 1 to 5 and Cohort 11 
PROCEDURE 
Screening 
(Days) 
Treatment Period (Days) 
EOS/ 
SFUa 
Notes 
-28 -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
15  
1 
22  
1 
29  
1 
43  
3 
57  
3 
71  
3 
92  
7 
120   
7 
150   
7 
In-house residency 
day -2 to 8 
PHARMACODYNAMIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOGENETIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic studiesl 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amgen investigational product 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 3 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study;FSH = follicle stimulating hormone;
 HIV = human 
immunodeficiency virus; SFU = safety follow-up. 
a 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 investigational product. 
b Body weight (kg) only. 
c Predose assessment. 
d 12-lead ECGs to be performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs should be completed within a total of 5 minutes from start of 
the first to the completion of the third). 
e Single 12-lead ECG. 
f 3 sets of triplicate 12-lead ECGs at baseline (day 1 predose). 
g Additional on-treatment pregnancy testing may be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and 
regulations. 
h Analyzed at the local laboratory, additional samples may be collected for safety reasons, at the investigator’s discretion. 
i Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons, at the investigator’s discretion. 
j 10-hour fasting is required at all time points
 
k Local laboratory at screening, then central laboratory at other time points. 
l For subjects who provided informed consent for the pharmacogenetic studies. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 25 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 2.  Schedule of Activities — Cohort 6 
PROCEDURE 
Screening 
(Days)  
Treatment Period (Days) 
EOS/ 
SFUa Notes 
-28 -2 -1 
1 
2 
3 
4 
5 
6 15  1 22  1 29  1 43  3 57  3 71  3 92  7 
120   
7 
150   
7 
In-house residency 
day -2 to 6 
GENERAL AND SAFETY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Physical measurements 
X 
 
 Xb,c 
 
 
 
 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate measurementd 
Xe Xe 
 
Xc,f X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
ECG on day 1 should be 
performed predose and at 
10 minutes and 2 hours 
postdose. 
Vital signs 
X 
X X Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs on day 1 to be 
measured predose, and at 
2, 4, and 8 hours 
postdose. 
Adverse events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serious adverse events 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant therapies review 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and/or Urine pregnancy 
test (females only)g,h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum pregnancy test at 
day -28 and EOS, urine 
pregnancy test at day -2  
Serum FSH testh 
(postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For postmenopausal 
status confirmation 
Coagulationh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 3 
Footnotes defined on last page of the table. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 26 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 2.  Schedule of Activities — Cohort 6 
PROCEDURE 
Screening 
(Days)  
Treatment Period (Days) 
EOS/ 
SFU Notes 
-28 -2 -1 
1 
2 
3 
4 
5 
6 15  1 22  1 29  1 43  3 57  3 71  3 92  7 
120   
7 
150   
7 
In-house residency 
day -2 to 6 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Hematology at day 
1 should be collected 
2 hours postdose. 
Chemistryh,j 
X 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Chemistry at day 1 should 
be collected 2 hours 
postdose.  Calcitonin and 
TSH at day -28 only.  
Serum amylase and lipase 
on days -2, 6, 15, 29 and 
EOS only. 
HIV, Hepatitis B and C screeningh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysish 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Alcohol, cotinine, and drug 
screenh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 133-antibodyi 
 
 
 
Xc 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Creatine Kinase 
X 
X 
 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
STUDY-SPECIFIC 
ASSESSMENTS (eg, DISEASE-
SPECIFIC ASSESSMENTS, 
RADIOLOGICAL 
ASSESSMENTS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 3 
Footnotes defined on last page of the table. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 27 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 2.  Schedule of Activities — Cohort 6 
PROCEDURE 
Screening 
(Days)  
Treatment Period (Days) 
 
EOS/ 
SFU Notes 
-28 -2 -1 
1 
2 
3 
4 
5 
6 15  1 22  1 29  1 43  3 57  3 71  3 92  7 
120   
7 
150   
7 
In-house residency 
day -2 to 6 
Plasma AMG 
133 pharmacokineticsi 
 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sampling time points on 
day 1 to include predose, 
and at 10 minutes and 1, 
2, 4, and 
8 hours postdose. 
PHARMACODYNAMIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOGENETIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic studiesl 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amgen investigational product 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 3 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; FSH = follicle stimulating hormone;
HIV = human immunodeficiency virus; SFU = safety follow-up. 
a 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 investigational product. 
b Body weight (kg) only. 
c Predose assessment. 
d 12-lead ECGs to be performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs should be completed within a total of 5 minutes from start of 
the first to the completion of the third). 
e Single 12-lead ECG. 
f 3 sets of triplicate 12-lead ECGs at baseline (day 1 predose) followed by triplicate 12-lead ECGs at 10 minutes and 2 hours postdose. 
g Additional on-treatment pregnancy testing may be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and 
regulations. 
h Analyzed at the local laboratory, additional samples may be collected for safety reasons, at the investigator’s discretion. 
i Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons, at the investigator’s discretion. 
j 10-hour fasting is required at all time points. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 28 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
k Local laboratory at screening, then central laboratory at other time points. 
l For subjects who provided informed consent for the pharmacogenetic studies. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 29 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 3.  Schedule of Activities – Cohorts 7 to 9 
PROCEDURE 
Screening 
Treatment Period 
EOS/SFUa 
Notes 
Study Day 
-28 -4 -1 1 4 5 7 15 22 29 36 43 50 57 60 61 63 71 78 84 85 87 127 169 207 
 
Visit Windows 
 
 
  
 
± 
1 da
y 
 
± 1 day 
 
 
± 1 day 
± 2 day 
± 7 day 
 
GENERAL AND SAFETY ASSESSMENTS 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
X 
 
   
 
 
Xc 
 
 
 
Xc 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Height and body mass index 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
X 
 
 
Xc   X X X Xc X X X Xc 
 
 
X X X 
 
X 
 
X 
X 
X 
 
Waist circumference (cm) 
 
 
 
Xc    
 
 
Xc 
 
 
 
Xc 
 
 
 
 
 
 
X 
 
X 
 
X 
 
C-SSRS + PHQ9 
X 
 
X 
 
   
 
 
Xc 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate measurementd 
Xe 
 Xe Xc,f    
 
 
Xc 
 
 
 
Xc 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital signs (BP, HR, RR, Temp) 
X 
X X Xc,g  X X X X Xc,g X X X Xc,g  
X X X X 
 
X 
 
X 
X 
X 
 
Adverse events 
 
 
 
X  X X X X X X X X X 
 
X X X X 
 
X 
 
X 
X 
X 
 
Serious adverse events 
X 
X X X  X X X X X X X X X 
 
X X X X 
 
X 
 
X 
X 
X 
 
Concomitant therapies review 
X 
X X X  X X X X X X X X X 
 
X X X X 
 
X 
 
X 
X 
X 
 
STUDY TREATMENT 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amgen investigational product 
 
 
 
X    
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationh 
X 
 
X 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
 
X 
 
   X 
 
Xc 
 
 
 
Xc 
 
X X 
 
 
 
X 
 
X 
X 
X 
 
Chemistryh,i 
X 
 
X 
 
   X 
 
Xc 
 
 
 
Xc 
 
X X 
 
 
 
X 
 
X 
X 
X 
 
HIV, Hepatitis B and C screeningh 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum amylase and lipasei 
 
 
X 
 
  X  
 
X X 
 
 
X 
 
X X 
 
 
 
 
 
X 
X 
X 
 
eGFRh 
X 
 
X 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysish 
X 
 
X 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Alcohol, cotinine, and drug screenh 
X 
 
X 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and/or Urine pregnancy test (females only)h,j 
X 
 
X 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum FSH testh (postmenopausal females only) 
X 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on last page of the table. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 30 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 3.  Schedule of Activities – Cohorts 7 to 9 
PROCEDURE 
Screening 
Treatment Period 
EOS/SFUa 
Notes 
Study Day 
-28 -4 -1 1 4 5 7 15 22 29 36 43 50 57 60 61 63 71 78 84 85 87 127 169 207 
 
Visit Windows 
 
 
   
± 
1 day  
± 1 day 
 
 
± 1 day 
± 2 day 
± 7 day 
 
STUDY-SPECIFIC ASSESSMENTS (eg, DISEASE-SPECIFIC 
ASSESSMENTS, RADIOLOGICAL ASSESSMENTS) 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 133-antibodyk 
 
 
 
Xc    X 
 Xc  
 
 
Xc 
 
 
 
 
 
 
X 
 
 
 
X 
 
PHARMACOKINETIC ASSESSMENTS 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma AMG 133 pharmacokineticsk 
 
 
 
Xc  X X X X Xc X X X Xc 
 
X X X X 
 
X 
 
X 
X 
X 
 
PHARMACODYNAMIC ASSESSMENTS 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOGENETIC ASSESSMENTS 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic studiesk,n  
 
 
X 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMAGING 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale;
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study;
FSH = follicle stimulating hormone;
HIV = human 
immunodeficiency virus; HR = heart rate;
 PD = pharmacodynamic; PHQ9 = Patient Health Questionnaire-9; 
RR = respiratory rate;
SFU = safety follow-up; Temp = temperature. 
Please note: Subjects will be admitted after confirmed eligibility on day -1 for a 3 day (2 night) residency.  Subjects will be dosed on day 1, the second day of residency.  
Subjects will be admitted on days 28 – 30 and days 56 – 58 for a 3 day (2 night) residency.  Subjects will receive AMG 133 or placebo on days 29 and 57, respectively.   
a 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 investigational product. 
b Physical exam to include neurologic assessment. 
c Predose assessment. 
d 12-lead ECGs to be performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs should be completed within a total of 5 minutes from start of 
the first to the completion of the third). 
e Single 12-lead ECG. 
f 3 sets of triplicate 12-lead ECGs at baseline (day 1 predose). 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 31 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
g Subjects should get vital signs 3 hours after dosing 
h Analyzed at the local laboratory, additional samples may be collected for safety reasons, at the investigator’s discretion. 
i 10-hour fasting is required at all time points. 
j Additional on-treatment pregnancy testing may be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and 
regulations. 
k Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons, at the investigator’s discretion. 
m Local laboratory at screening, then central laboratory at other time points. 
n For subjects who provided informed consent for the pharmacogenetic studies. 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 32 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 4.  Schedule of Activities – Cohort 10 
PROCEDURE 
Screening 
Treatment Period 
EOS/SFUa 
Notes 
Study Day 
-28 
-14 -1 
1 
5 7 15 22 29 36 43 50 57 63 71 78 85 127 155 169 207 
 
Visit Windows 
 
 
 
 
± 1 day 
 
± 1 day 
 
± 1 day ± 3 day 
± 7 day 
 
GENERAL AND SAFETY ASSESSMENTS 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
X 
 
  
 
 
Xc 
 
 
 
Xc 
 
 
 
X 
X 
 
 
X 
 
Height and body mass index 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
X 
 
 
Xc 
 X X X Xc X X X Xc X X X X 
X 
 
X 
X 
 
Waist circumference (cm) 
 
 
 
Xc 
  
 
 
Xc 
 
 
 
Xc 
 
 
 
X 
X 
 
 
X 
 
C-SSRS + PHQ9 
X 
 
X 
 
  
 
 
Xc 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
ECG triplicate measurementd 
Xe 
 
Xe Xc,f   
 
 
Xc 
 
 
 
Xc 
 
 
 
X 
 
 
 
X 
 
Vital signs (BP, HR, RR, Temp) 
X 
 
X Xc, p X X X X Xc,p X X X Xc,p X X X X 
X 
 
X 
X 
 
Adverse events 
 
 
 
X 
X X X X X X X X X X X X X 
X 
 
X 
X 
 
Serious adverse events 
X 
 
X 
X 
X X X X X X X X X X X X X 
X 
 
X 
X 
 
Concomitant therapies review 
X 
 
X 
X 
X X X X X X X X X X X X X 
X 
 
X 
X 
 
STUDY TREATMENT 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amgen investigational product 
 
 
 
X 
  
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationg 
X 
 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyg 
X 
 
X 
 
  X 
 
Xc 
 
 
 
Xc X 
 
 
X 
X 
 
X 
X 
 
Chemistryg,h 
X 
 
X 
 
  X 
 
Xc 
 
 
 
Xc X 
 
 
X 
X 
 
X 
X 
 
HIV, Hepatitis B and C screeningg 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum amylase and lipaseh 
 
 
X 
 
 X  
 
X X 
 
 
X X 
 
 
 
X 
 
X 
X 
 
eGFRg 
X 
 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysisg 
X 
 
X 
 
  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Alcohol, cotinine, and drug screeng 
X 
 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and/or Urine pregnancy test (females only)g,i 
X 
 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum FSH testg (postmenopausal females only) 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on last page of the table. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 33 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 4.  Schedule of Activities – Cohort 10 
PROCEDURE 
Screening 
Treatment Period 
EOS/SFUa 
Notes 
Study Day 
-28 
-14 -1 
1 
5 7 15 22 29 36 43 50 57 63 71 78 85 127 155 169 207 
 
Visit Windows 
 
 
 
 
± 1 day 
 
± 1 day 
 
± 1 day 
± 
3 day 
± 7 day 
 
Anti-AMG 133-antibodyj 
 
 
 
Xc 
 
 X 
 Xc  
 
 Xc 
 
 
 
X 
 
 
 
X 
 
STUDY-SPECIFIC ASSESSMENTS (eg, 
DISEASE-SPECIFIC ASSESSMENTS, RADIOLOGICAL 
ASSESSMENTS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma AMG 133 pharmacokineticsj 
 
 
 
Xc X X X X Xc X X X Xc X X X X 
 
 
X 
X 
 
PHARMACODYNAMIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOGENETIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic studiesj,n 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMAGING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
BP= blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale;
ECG = electrocardiogram; eGFR =estimated glomerular filtration rate; EOS = end of study; 
; FSH = follicle stimulating hormone; 
 
HIV = human 
immunodeficiency virus; HR = heart rate
PD = pharmacodynamic; PHQ9 = Patient Health Questionnaire-9; RR = respiratory rate; SFU = safety follow-up; Temp = temperature.  
Please note: Subjects will be admitted after confirmed eligibility on day -1 for a 3 day (2 night) residency.  Subjects will be dosed on day 1, the second day of residency.  
Subjects will be admitted on days 28 – 30 and days 56 – 58 for a 3 day (2 night) residency.  Subjects will receive AMG 133 or placebo on days 29 and 57, respectively.   
a 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 investigational product. 
b Physical exam to include neurologic assessment. 
c Predose assessment. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 34 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
d 12-lead ECGs to be performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs should be completed within a total of 5 minutes from start of 
the first to the completion of the third). 
e Single 12-lead ECG. 
f 3 sets of triplicate 12-lead ECGs at baseline (day 1 predose). 
g Analyzed at the local laboratory, additional samples may be collected for safety reasons, at the investigator’s discretion. 
h 10-hour fasting is required at all time points. 
i Additional on-treatment pregnancy testing may be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and 
regulations. 
j Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons, at the investigator’s discretion. 
m Local laboratory at screening, then central laboratory at other time points. 
n For subjects who provided informed consent for the pharmacogenetic studies. 
p Subjects should get vital signs 3 hours after dosing 
 
Table 5.  Schedule of Activities – Part C Cohort 12 
PROCEDURE 
SCREENING 
TREATMENT PERIOD 
SFU/EOSA 
Study Day 
-28 
-2b 
1 
8 
15 
20 
43 
57 
71 
132 
193 
Visit Windows 
 
 
 
 
 
 1 
day 
 
 3 days 
±7 days 
Visit type 
C 
C 
C 
C 
C 
C 
C 
P 
C 
P 
C 
GENERAL AND SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
X 
 
 
 
 
X 
 
X 
 
X 
Height and body mass index 
X 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
X 
 
Xd 
Xd 
Xd 
X 
Xd 
 
X 
 
X 
Waist circumference (measured in cm only) 
 
 
Xd 
 
 
 
Xd 
 
X 
 
X 
C-SSRS + PHQ9 
X 
 
Xd 
Xd 
Xd 
 
Xd 
 
X 
 
X 
ECG triplicate measurement 
Xe 
Xe 
Xd,f,g 
 
 
 
Xd,f 
 
Xf 
 
 
Vital signs (BP, HR, RR, Temp) 
X 
X  
Xd,h 
Xd,h 
Xd,h 
X 
Xd,h 
 
X 
 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 35 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
Amgen investigational product 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
Coagulationj 
X 
X 
 
 
 
 
 
 
 
 
 
Hematologyj 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
Chemistryj 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HS-CRPj 
 
 
X 
 
 
 
 
 
X 
 
X 
HIV, Hepatitis B and C screeningj 
X 
 
 
 
 
 
 
 
 
 
 
Serum amylase and lipasej 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
eGFRj 
X 
X 
 
 
 
 
 
 
 
 
X 
Urinalysisj 
X 
X 
 
 
 
 
 
 
X 
 
X 
Alcohol, cotinine, and drug screenj 
X 
X 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on last page of the table.  
Table 5.  Schedule of Activities – Part C Cohort 12 
PROCEDURE 
SCREENING 
TREATMENT PERIOD 
SFU/EOSA 
Study Day 
-28 
-2b 
1 
8 
15 
20 
43 
57 
71 
132 
193 
Visit Windows 
 
 
 
 
 
 1 
day 
 
 3 days 
 7 days 
Visit type 
C 
C 
C 
C 
C 
C 
C 
P 
C 
P 
C 
Serum and/or Urine pregnancy test (females only)j 
X 
X 
 
 
 
 
 
 
 
 
X 
Serum FSH testj (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 133-antibodyk,m 
 
 
Xd 
 
Xd 
 
Xd 
 
X 
 
X 
STUDY-SPECIFIC ASSESSMENTS (eg, DISEASE-SPECIFIC 
ASSESSMENTS, RADIOLOGICAL ASSESSMENTS) 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
Plasma AMG 133 pharmacokineticsk,m 
 
 
Xd 
Xd 
Xd 
 
Xd 
 
X 
 
X 
PHARMACODYNAMIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 36 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
PHARMACOGENETIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic studieso,m 
 
X 
 
 
 
 
 
 
 
 
 
IMAGING 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
BP = blood pressure; C  clinic visit; C-SSRS = Columbia Suicide Severity Rating Scale; cm = centimeters; 
; 
; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; 
 
FSH = follicle stimulating hormone;
 
 HIV = human immunodeficiency virus; HR = heart rate; HS-CRP = high-sensitivity C-reactive protein; 
P  phone visit; PD = pharmacodynamic; PHQ9 = Patient Health Questionnaire-9; RR = respiratory rate; 
; SFU = safety follow-up; Temp = temperature. 
Please note:  Subjects are eligible for an optional in-house residence period on Day 1 and 8 for an overnight observation period.  Subjects are eligible for a 
required in-house residency period for Day 15 and 43.  Subjects will receive AMG 133 on Days 1, 8, 15, and 43.   
a Upon permanent discontinuation from the study treatment for any reason, an SFU visit will be performed approximately 30 (+3) days after the end of the 
last dosing interval of investigational product. 
b Eligibility can be confirmed up to -4 days prior to Day 1 to allow for lab tests to result. 
c Physical exam to include neurologic assessment. 
d Predose assessment 
e Single 12-lead ECG 
f 12-lead ECGs to be performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs should be completed within a total of 5 minutes 
from start of the first to the completion of the third). 
g 3 sets of triplicate 12-lead ECGs at baseline (Day 1 predose) 
h Subjects should get vital signs 4 to 5 hours after dosing 
i Phone call follow up 
j Analyzed at the local laboratory, additional samples may be collected for safety reasons, at the investigator’s discretion. 
k 10-hour fasting is required at all time points. 
l Additional on-treatment pregnancy testing may be performed at the investigator’s discretion, if there is suspicion that a female subject is pregnant or per 
local laws and regulations. 
m Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons, at the investigator’s discretion. 
n Local laboratory at screening, then central laboratory at other time points. 
o For subjects who provided informed consent for the pharmacogenetic studies. 
 
Table 6.  Schedule of Activities - Part C Cohort 13 
PROCEDURE 
SCREENING 
TREATMENT PERIOD 
SFU/EOSA 
Study Day 
-28 
-2b 
1 
8 
15 
22 
29 
34 
57 
64 
85 
146 
207 
Visit Windows 
 
 
 
 
 
 
 
 1 day 
 
 3 days 
 7 days 
Visit type 
C 
C 
C 
C 
C 
C 
C 
C 
C 
P 
C 
P 
C 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 37 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
GENERAL AND SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Height and body mass index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
X 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
Xd 
 
X 
 
X 
Waist circumference (measured in cm only) 
 
 
Xd 
 
 
 
Xd 
 
Xd 
 
X 
 
X 
C-SSRS + PHQ9 
X 
 
Xd 
Xd 
Xd 
Xd 
Xd 
 
Xd 
 
X 
 
X 
ECG triplicate measurement 
Xe 
Xe 
Xd,f,g 
 
 
 
Xd,f 
 
Xd,f 
 
Xf 
 
 
Vital signs (BP, HR, RR, Temp) 
X 
X  
Xd,h 
Xd,h 
Xd,h 
Xd,h 
Xd,h 
X 
Xd,h 
 
X 
 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amgen investigational product 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematologyj 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Chemistryj 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
HS-CRPj 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
HIV, Hepatitis B and C screeningj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum amylase and lipasej 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
eGFRj 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysisj 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Alcohol, cotinine, and drug screenj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum and/or Urine pregnancy test 
(females only)j 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Page 1 of 2 
Footnotes defined on last page of the table. 
Table 6.  Schedule of Activities - Part C Cohort 13 
PROCEDURE 
SCREENING 
TREATMENT PERIOD 
SFU/EOSA 
Study Day 
-28 
-2b 
1 
8 
15 
22 
29 
34 
57 
64 
85 
146 
207 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 38 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Visit Windows 
 
 
 
 
 
 
 
 1 day 
 
 3 days 
 7 days 
Visit type 
C 
C 
C 
C 
C 
C 
C 
C 
C 
P 
C 
P 
C 
Serum FSH testj (postmenopausal females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 133-antibodyk,m 
 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
X 
 
X 
STUDY-SPECIFIC ASSESSMENTS (eg, 
DISEASE-SPECIFIC ASSESSMENTS, 
RADIOLOGICAL ASSESSMENTS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma AMG 133 pharmacokineticsk,m 
 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
Xd 
 
X 
 
X 
PHARMACODYNAMIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOGENETIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic studieso,m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IMAGING 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
BP = blood pressure; C = clinic visit; C-SSRS = Columbia Suicide Severity Rating Scale; cm = centimeters;
; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; 
 
FSH = follicle stimulating hormone; 
 HIV = human immunodeficiency virus; HR = heart rate; HS-CRP = high-sensitivity C-reactive protein; 
P = phone visit; PD = pharmacodynamic; PHQ9 = Patient Health Questionnaire-9; RR = respiratory rate; 
; SFU = safety follow-up; Temp = temperature. 
Please note:  Subjects are eligible for an optional in-house residence period on Day 1, 8, 15, and 22 for an overnight observation period.  Subjects are 
eligible for a required in-house residency period for Day 29 and 57.  Subjects will receive AMG 133 on Days 1, 8, 15, 22, 29, and 57.   
a Upon permanent discontinuation from the study treatment for any reason, a SFU visit will be performed approximately 30 (+3) days after the end of the 
last dosing interval of investigational product. 
b Eligibility can be confirmed up to -4 days prior to Day 1 to allow for lab tests to result. 
c Physical exam to include neurologic assessment. 
d Predose assessment 
e Single 12-lead ECG 
f 12-lead ECGs to be performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs should be completed within a total of 5 minutes 
from start of the first to the completion of the third). 
g 3 sets of triplicate 12-lead ECGs at baseline (day 1 predose) 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 39 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
h Subjects should get vital signs 4 to 5 hours after dosing 
i Phone call follow up 
j Analyzed at the local laboratory, additional samples may be collected for safety reasons, at the investigator’s discretion. 
k 10-hour fasting is required at all time points. 
l Additional on-treatment pregnancy testing may be performed at the investigator’s discretion, if there is suspicion that a female subject is pregnant or per 
local laws and regulations. 
m Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons, at the investigator’s discretion. 
n Local laboratory at screening, then central laboratory at other time points. 
o For subjects who provided informed consent for the pharmacogenetic studies. 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 40 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
2. 
Introduction 
2.1 
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 with side effects that 
include gastrointestinal intolerability.  AMG 133 is a peptide conjugated antibody 
composed of a human monoclonal antibody (mAb) that binds to and blocks the glucose 
dependent insulinotropic polypeptide receptor (GIPR) conjugated to 2 identical peptides.  
The conjugated peptides are glucagon-like peptide 1 (GLP-1) receptor (GLP1R) 
agonists.  In preclinical studies in obese cynomolgus monkeys, AMG 133 administration 
resulted in an approximate weight reduction of 17% compared with vehicle, with 
concomitant decreases in food intake, insulin, and triglyceride levels.  The current study 
evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD), 
of single ascending doses (SAD), and multiple ascending doses (MADs) of AMG 133 as 
a potential therapy for the treatment of obesity. 
2.2 
Background 
2.2.1 
Disease 
Obesity represents a major threat to public health and the accompanying healthcare 
costs pose an enormous financial burden (Terranova et al, 2012; Wang et al, 2011).  
The prevalence of obesity has nearly tripled since 1973 and currently, 650 million adults 
are obese, defined as having a body mass index (BMI) of 
≥30 kg/m2 (World Health Organization, 2018).  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 
include nonalcoholic steatohepatitis, 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 et al, 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).  

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 41 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Currently approved weight loss products belong to the following therapeutic classes:  
GLP-1R agonists (liraglutide [Saxenda®]), 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 to 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% to 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 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 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. 
2.2.2 
Amgen Investigational Product Background:  AMG 133 
The following sections provide an overview of the pharmacology, PK, nonclinical 
pharmacokinetics, and toxicology of AMG 133.  A detailed description of the 
pharmacology, physical, chemical, and pharmaceutical properties and formulations of 
AMG 133 is provided in the investigator’s brochure. 
2.2.2.1 
Pharmacology 
AMG 133 is a bispecific molecule with functional activities that antagonize GIPR and 
agonize GLP-1R.  AMG 133 is engineered by conjugation of a mAb GIPR antagonist 
antibody with 2 identical GLP-1 analog peptides, and therefore, exhibits both GIPR 
antagonism and GLP-1R agonism activities.  AMG 133 binds to human GIPR with a 
dissociation constant (Kd) of 37 pM and inhibits glucose dependent insulinotropic 
polypeptide (GIP)-induced accumulation of cyclic adenosine monophosphate (cAMP) in 
human embryonic kidney 293T cells stably expressing human GIPR, with a half-maximal 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 42 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
inhibitory concentration (IC50) of 42.4 nM.  In addition, AMG 133 binds to human GLP-1R 
as demonstrated by the GLP-1 radioligand competition binding assay with an IC50 of 
55.2 nM.  Upon receptor binding, AMG 133 activates GLP-1 and increases cAMP levels 
in Chinese hamster ovary (CHO) K1 (CHO-K1) cells stably expressing human GLP-1R 
with half-maximal effective concentration (EC50) of 24.4 pM. 
Glucose dependent insulinotropic polypeptide and GLP-1 are gut-derived incretin 
hormones, well known for their ability to augment glucose stimulated insulin secretion.  
In addition to the incretin effects, GLP-1 is recognized to promote satiety through the 
GLP-1R (Turton et al, 1996), and therefore has become an attractive approach to treat 
patients with type 2 diabetes and obesity (Drucker, 2006).  Glucose dependent 
insulinotropic polypeptide has been shown to promote adiposity (Yip et al, 1998; 
Beck and Max, 1987; Hauner et al, 1988; Knapper et al, 1995).  The GIPR is also 
recognized to contribute to adiposity as revealed from human and mouse genetic 
studies, in which genome-wide association studies identified the GIPR locus to 
contribute to measures of body weight (eg, BMI) (Berndt et al, 2013; Okada et al, 2012; 
Saxena et al, 2010; Speliotes et al, 2010; Wen et al, 2012).  In addition, Gip and Gipr 
knockout mice are protected from diet-induced obesity (Althage et al, 2008; 
Miyawaki et al, 2002; Nasteska et al, 2014).  Consistent with these data, 
pharmacological inhibition using anti-GIPR antibodies protected against body weight 
gain in diet-induced obese (DIO) mice and obese cynomolgus monkeys (Killion et al, 
2018).  In addition, GIPR antagonism synergistically reduced body weight in combination 
with GLP-1R agonism in preclinical models (Killion et al, 2018), offering the potential for 
a bispecific molecule with activities of both GIPR antagonism and GLP-1R agonism for 
the treatment of obesity. 
AMG 133 binds with similar affinity to human, cynomolgus monkey, and mouse GIPR 
(Kd of 37, 52, and 27 pM, respectively).  Whereas AMG 133 functionally inhibits GIP 
signaling through human and cynomolgus monkey GIPR with similar potency (IC50 of 
42.4 and 26.5 nM, respectively), it has more than 20-fold lower potency for inhibition of 
GIP signaling through rat and mouse GIPR.  Therefore, an antimouse GIPR surrogate 
antibody was used to conjugate the same GLP-1 analog peptide used for AMG 133 to 
generate a mouse surrogate molecule (1238) for pharmacology studies in mice.  
AMG 133 is a potent agonist on human, cynomolgus monkey, and mouse GLP-1R 
(EC50 of 24.4, 5.7 and 123 pM, respectively). 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 43 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
A murine surrogate,1238, with high potency for both murine GIPR and GLP-1R has been 
generated for use in mouse preclinical studies.  1238 fully blocks GIP-stimulated cAMP 
production in CHO AM-1D cells expressing mouse GIPR with an IC50 of 4.1 nM and 
stimulates cAMP production in CHO-K1 cells expressing mouse GLP-1R with an EC50 of 
90.6 pM. 
In PD studies in leptin receptor-deficient (db/db) mice, a single injection of 1238 showed 
a rapid and sustained effect on lowering blood glucose levels and body weight.  In a 
chronic study, administration of 1238 reduced body weight and food intake in DIO mice.  
In addition, significant reductions were observed in blood glucose and plasma insulin, 
cholesterol, triglycerides, aspartate aminotransferase, and alanine aminotransferase 
levels in mice treated with 1238 compared with the vehicle-treated group. 
The efficacy of AMG 133 was evaluated in lean mice and a spontaneously obese 
cynomolgus monkey model.  In lean mice, a single injection of AMG 133 prevented 
blood glucose elevation during a glucose tolerance test.  AMG 133 was evaluated in an 
obese cynomolgus monkey model using a weekly dosing regimen.  In this study, 
AMG 133 administration reduced body weight, food intake, cholesterol, insulin, and 
triglyceride levels after 6 weeks of dosing.  The weight loss effect was sustained during 
the dosing free washout period.  Taken together, these data suggest that AMG 
133 offers the potential to treat obesity in patients. 
2.2.2.2 
Pharmacokinetics 
2.2.2.2.1 
Nonclinical Pharmacokinetics 
AMG 133 pharmacokinetics is defined depending whether the intact (anti-GIPR 
monoclonal antibody [mAb] with at least 1 GLP-1 analog peptide) or total (anti-GIPR 
monoclonal antibodies with or without GLP-1 analog peptides) molecules are detected.  
AMG 133 exposure after repeat-dose administration over a dose range from 25 to 
150 mg/kg in the mouse and 20 to 120 mg/kg in the cynomolgus monkey increased 
approximately dose proportionally.  Exposure ratios of intact to total AMG 133 ranged 
from 0.81 to 0.85 on day 1 and 0.61 to 0.65 on day 85 in the mouse.  In the cynomolgus 
monkey the exposure ratio of intact to total AMG 133 ranged from 0.87 to 0.92 on day 1, 
0.69 to 0.77 on day 43, and 0.66 to 0.72 on day 85.  This indicates some clipping of the 
GLP-1 moiety, but significant exposures to intact AMG 133 were maintained throughout 
the study.  Exposures were similar between male and female animals in both species.  
In the chronic efficacy study in the cynomolgus monkey, trough plasma concentrations of 
both the intact and total forms of AMG 133 increased approximately dose proportionally 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 44 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
and were also increased after repeated dosing.  The terminal phase plasma 
concentration-time data implied reasonable stability of the intact form. 
For preliminary PK in humans see Section 4.3. 
2.2.2.3 
Toxicology 
Consistent with the International Council for Harmonisation (ICH) S6 (R1) guidance 
(ICH, 2011), the studies conducted in the nonclinical safety assessment of 
AMG 133 included in vitro genotoxicity studies, a tissue cross-reactivity study, and 
exploratory 4-week subcutaneous (SC) repeat-dose and pivotal Good Laboratory 
Practices-compliant 13-week SC repeat-dose toxicology studies conducted in the mouse 
and the cynomolgus monkey.  The GLP-1 analog peptide portions of AMG 133 contain a 
non-natural amino acid; the GLP-1 analog peptide was tested for genotoxicity in the 
bacterial reverse mutation and in vitro human peripheral blood lymphocyte micronucleus 
tests and did not show any evidence of genotoxic activity in either test.  The anti-GIPR 
mAb in AMG 133 has very high amino acid identity with AMG 598, Amgen’s anti-GIPR 
mAb (IND 135844).  Therefore, the results of the tissue cross-reactivity study in a full 
panel of human tissues with biotin-labeled AMG 598 is considered applicable to 
AMG 133; no potential AMG 598 cross reactivity in human tissues was identified. 
AMG 133 was administered to mice in a 4-week exploratory toxicology study and a 
13-week repeat-dose toxicology study.  Despite the lower potency of AMG 133 for 
mouse GIPR, the high exposures obtained in the repeat-dose toxicology studies in the 
mouse likely achieved at least partial GIPR antagonism.  In the 4-week exploratory 
toxicology study in the mouse, administration of AMG 133 by SC injection once weekly 
for a total of 4 doses was well tolerated up to 141 mg/kg.  The highest tested dose of 
658 mg/kg was not tolerated due to severe clinical signs of dehydration.  In the pivotal 
13-week repeat-dose toxicology study in mice, administration of 25, 75, and 150 mg/kg 
AMG 133 by SC injection once every 2 weeks for a total of 7 doses was well tolerated, 
with dose-dependent mild transient clinical observations of suspected dehydration.  
Exposure to AMG 133 induced anticipated pharmacologically-related changes in mice, 
including dose-independent body weight loss and, in the pivotal 13-week study, 
decreases in serum cholesterol and triglyceride levels.  There were no AMG 133-related 
changes in fasting blood glucose or insulin, hematology parameters, macroscopic 
observations, or light microscopic changes in the pancreas.  In the pivotal 13-week study 
in the mouse, body weight loss was associated with decreased organ weights and light 
microscopic observations of atrophy of adipose tissue and minimal to mild dilatation of 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 45 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Brunner’s glands in the submucosa of the proximal duodenum.  Light microscopic 
observations of minimal to mild SC inflammation at the injection site and skin in the 
mouse were considered to be an anticipated localized response to the SC administration 
of an exogenous protein and were associated with minimal increases in lymphoid 
cellularity in axillary lymph node and/or minimal or mild increases in extramedullary 
hematopoiesis in the spleen.  In the pivotal 13-week toxicology study in the mouse, the 
no observed adverse effect level (NOAEL) was the highest tested dose of 150 mg/kg. 
In the 4-week exploratory toxicology study in the monkey, weekly SC administration of 
11, 56, and 188 mg/kg AMG 133 was well tolerated, and dose-dependent body weight 
loss was observed.  In the pivotal 13-week toxicology study, once every 2 weeks SC 
administration of 20, 60, or 120 mg/kg AMG 133 for 13-weeks (7 total doses) induced 
dose-independent body weight loss, indicating maximum pharmacological activity at all 
tested doses.  In the pivotal 13-week study, there were no AMG 133-related effects on 
clinical observations, neurologic or ophthalmic examinations, quantitative and qualitative 
electrocardiography, vital signs, fasting blood glucose or insulin, coagulation and 
urinalysis parameters, biochemical biomarkers for bone metabolism, or organ weights.  
Nonadverse minimal to mild decreases in red blood cell parameters (hemoglobin, 
hematocrit, red blood cell counts) and reticulocyte counts were present in both studies in 
the monkey.  1 female at 120 mg/kg in the 13-week study also had changes in red blood 
cell morphology and a minimal increase in total bilirubin, suggestive of an increased red 
blood cell turnover; this change was considered nonadverse due to the small magnitude 
and lack of clinical observations or evidence of microscopic changes in the liver or gall 
bladder.  There were no macroscopic or microscopic changes in the monkey directly 
related to AMG 133, including in the pancreas; light microscopic observations of minimal 
to mild SC mononuclear cell infiltrates at the injection site were considered an 
anticipated localized response to the SC administration of an exogenous protein.  In the 
pivotal 13-week toxicology in the cynomolgus monkey, the NOAEL was the highest 
tested dose of 120 mg/kg. 
2.2.2.4 
Clinical Experience 
As of data entered by December 2021, in the ongoing first in human (FIH) SAD trial of 
AMG 133 in subjects with obesity, 57 subjects have received a single dose of 
AMG 133 or placebo (cohorts 1 to 6 and cohort 11).  The blinded safety data through 
day 15 of the 840 mg SC dose cohort supports the dose range to be evaluated in this 
study.  Single ascending doses of AMG 133 have been safe and generally well tolerated.  

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 46 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
No significant adverse events or deaths have been reported, and most adverse events 
reported were mild consisting of nausea, vomiting, and dyspepsia.  One subject in cohort 
3 (140 mg dose) reported moderate adverse events associated with nausea, abdominal 
discomfort, and dyspepsia. 
A total of 39 subjects have been enrolled in the MAD trial and have received 1 to 3 
doses of AMG 133 or placebo.  Most adverse events reported have been after the 
first dose of AMG 133 and were reported as mild consisting of headache, nausea, 
vomiting, and diarrhea.  There have been no serious adverse events or deaths 
reported after single or multiple doses.  Twenty-six percent of subjects did not 
receive the second or third dose of AMG 133 either due to adverse events or lost 
to follow up. 
2.3 
Benefit/Risk Assessment 
The potential long-term benefits of AMG 133 include anticipated weight loss and 
improved cardiovascular risk factors associated with weight loss.  Potential risks of 
AMG 133, as anticipated from animal data and the literature, are described below in 
Section 2.3.2. 
2.3.1 
Key Benefits 
There are no key anticipated benefits from short-term use of AMG 133. 
2.3.2 
Key Risks 
Potential risks of AMG 133, as anticipated by evidence from animal data and the 
literature, include those commonly associated with biologics, including local (eg, injection 
site) reactions, systemic (eg, hypersensitivity) reactions and immunogenicity (ie, the 
development of anti-AMG 133 antibodies).  Other potential risks include gastrointestinal 
tolerability issues and risks commonly associated with targeting obesity pathways. 
Key potential risks are detailed below. 
Gastrointestinal Tolerability Issues 
Gastrointestinal tolerability issues including nausea, vomiting, and diarrhea are common 
adverse reactions for molecules targeting the obesity pathways.  Gastrointestinal 
tolerability issues in humans are expected based on experience with marketed GLP-1R 
agonists.  Subjects will be monitored for signs and symptoms of adverse events of 
nausea, vomiting, and diarrhea throughout the study. 
Hypersensitivity Reactions 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 47 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
As with any biologic, administration of AMG 133 may result in systemic reactions 
including immune-mediated hypersensitivity.  Drug hypersensitivity reactions typically 
occur during or within several hours after drug administration, but they may be delayed.  
Severe reactions may occur, including anaphylaxis, angioedema and serum-like 
sickness.  Potential anaphylactic reactions will be assessed by Sampson criteria.  If 
Sampson criteria are positive, the potential anaphylactic reaction will be confirmed by 
measuring tryptase in blood plasma within 30 minutes of symptoms, and at any other 
time points as warranted and if feasible.  AMG 133 will be administered by SC or 
intravenous (IV) injection by a qualified clinical research staff member.  Subjects will be 
monitored for signs and symptoms of hypersensitivity reactions during and after 
AMG 133 administration, such as fever, chills, shaking, hypotension, wheezing, itching, 
nausea, and/or rash. 
Immunogenicity 
As with all biological products, there is a potential for the development of anti-
AMG 133 antibodies.  The potential effects of anti-AMG 133 antibodies on subjects who 
might develop them are not known, but reduced efficacy of AMG 133 is a possibility.  
Subjects will be monitored for potential effects of antidrug antibodies (ADA) that may 
include antibody-mediated adverse events, altered drug exposure, or loss of efficacy.  
Pharmacokinetic and immunogenicity samples from subjects in this phase 1 study will be 
collected from study subjects at protocol defined intervals and analyzed to monitor the 
development of anti-AMG 133 antibodies.  Positive samples will be titrated and 
evaluated for neutralizing antibodies.  Additional blood samples may be obtained to 
evaluate any ADA mediated effects on safety, pharmacokinetics, and 
pharmacodynamics during the study. 
Injection Site Reactions 
Injection site reactions (eg, erythema, itching, hematoma, swelling, bruising, and pain) 
are common side effects of drugs with SC/IV administration.  These reactions can range 
from mild to severe (including injection site necrosis, which is an uncommon side effect).  
After SC/IV administration, subjects will be monitored for injection site reactions, which 
may include redness, tenderness/pain, bruising, warmth, swelling, itching, and/or 
infection.  If appropriate, photographic documentation of injection site reactions will be 
obtained. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 48 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the investigator’s brochure for further data on potential side effects of 
AMG 133. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 49 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To assess the safety and tolerability 
of AMG 133 as single and multiple 
doses in subjects with obesity 
 
Subject incidence of 
treatment-emergent adverse events. 
 
Changes in laboratory safety tests, 
vital signs, and 12-lead 
electrocardiograms (ECGs) 
Secondary 
 
To characterize the pharmacokinetics 
of AMG 133 as single or multiple 
doses in subjects with obesity 
 
AMG 133 pharmacokinetic 
parameters including, but not limited 
to, maximum observed drug 
concentration during a dosing interval 
(Cmax), the time of maximum observed 
concentration (tmax), and area under 
the concentration-time curve (AUC) 
 
To evaluate the immunogenicity of 
AMG 133 
 
Incidence of anti-AMG 133 antibody 
formation 
 
 
Exploratory 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 50 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Exploratory 
3.1 
Hypotheses 
 
AMG 133 will be safe and well tolerated following single and/or multiple SC dose 
administrations in subjects with obesity across the dose range evaluated 
 
AMG 133 PK profile following multiple SC dose administrations will support selection 
of dose and frequency of administration in future multi-dose trials of AMG 133 
4. 
Study Design 
4.1 
Overall Design 
Part A (cohorts 1 to 6 and cohort 11) is a phase 1, randomized, double-blind, 
placebo-controlled, SAD study in adult subjects with obesity.  AMG 133 will be 
administered SC for cohorts 1 to 5 and cohort 11, and IV for cohort 6.  Part A consists of 
a total of 7 cohorts. 
Subjects will be confined at the Clinical Research Unit from check-in (morning of day -2) 
through the morning of day 8 for cohorts 1 to 5 and cohort 11 and, day 6 for cohort 6. 
Approximately 56 subjects will enroll into 1 of 7 cohorts.  In each cohort, 8 subjects will 
be randomized to receive AMG 133 or placebo SC (cohorts 1 to 5 and cohort 11) or IV 
(cohort 6) in a 3:1 ratio as described in Table 7.  For cohort 1, the first 2 subjects 
(sentinel pair) will be randomized such that 1 subject will receive AMG 133 and 1 subject 
will receive placebo.  The sentinel pair will be observed for at least 48 hours before the 
remaining subjects in the cohort are dosed, provided there are no safety or tolerability 
concerns as assessed by the investigator.  Enrollment into the SAD cohorts will be 
sequential.  Subsequent cohorts will be dosed after the dosing regimen in the preceding 
cohort has been recommended by the Dose Level Review Team (DLRT) to be safe and 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 51 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
well tolerated based on the safety and laboratory data through at least day 15 for at least 
7 out of 8 subjects dosed.  Subjects in cohorts 1 to 5 and cohort 11 will also participate 
in 
 tests at day -1 and day 7. 
Part B (cohorts 7 to 10) is a randomized, placebo-controlled, double-blind, MAD study in 
adult subjects with obesity.  In each cohort, subjects will be randomized to receive 
AMG 133 or placebo SC in a 3:1 ratio as described in Table 7.  Approximately 
24 subjects will enroll into cohorts 7 to 9.  Cohorts 7 to 9 will include assessments of 
  Enrollment 
into Part B cohort 7 will occur with a starting MAD dose that is at least 2 SAD dose levels 
below what was recommended by the DLRT to be safe and reasonably tolerated in 
Part A.  Enrollment into the MAD cohorts 8 and 9 will be sequential.   
Subjects in cohorts 8 and 9 will be dosed after the dose regimen in the preceding MAD 
cohort has been recommended by the DLRT to be safe and reasonably tolerated based 
on safety and laboratory data through at least study day 36 for 6 out of 8 subjects dosed.  
The DLRT for SAD cohort 11 will also make dosing recommendations for cohort 9 
(Figure 1-1 [A]).  
 
  All subjects in each Part B (MAD) cohort may be dosed on the same day.   
Cohort 10 will enroll up to 20 subjects and will include the 
 
.  Therefore, the dose recommended for cohort 10 should be the 
same as a dose studied in a previous cohort. 
The dose recommended for cohort 10 will depend on the final dose recommended for 
cohort 9 and the safety and tolerability profiles for MAD cohorts 7 and 8 (Figure 1-1 [B]).  

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 52 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
In all dose escalation process, DRLM will make a recommendation and Amgen will make 
the final decision on dose level. 
 
MAD cohorts 7 to 9:  Study drug will be administered every 4 weeks for a total of 
3 SC doses.  The dose levels will be defined after evaluation of the available PK and 
PD data from preceding cohorts in the SAD phase (Part A).  Three different dose 
levels will be evaluated with the lowest dose administered to cohort 7, and 2 higher 
ascending doses administered to cohorts 8 and 9.  The dose level for cohorts 
7 to 9 will not exceed the highest dose evaluated in cohorts 1 to 6 and cohort 
11 (Part A). Subjects enrolled in cohorts 7 to 9 will also be asked to 
 
 
 
MAD cohort 10:  Up to twenty subjects will be randomized in a 3:1 ratio to receive 
AMG 133 or placebo SC.  All subjects will be asked to use 
 
 The dose level will not exceed the highest dose evaluated in 
cohorts 7 to 9 (Part B). 
Part C (cohorts 12 to 13) is an open-label modified dose-escalation MAD study in 
subjects with obesity.  Approximately 12 subjects (up to 6 subjects per cohort) 
will enroll in Part C and receive AMG 133 (see Table 7).  Doses selected for these 
cohorts are known to have an acceptable safety and tolerability profile based on 
data reviewed by the DLRT from previous cohorts in Part A and Part B and will not 
exceed the dose levels previously studied in the MAD cohorts 7 to 9.  Cohort 12 
will receive
mg SC on days 
 followed by 
mg SC on days 
 
Cohort 13 will receive 
 mg on days 
 followed by 
 mg SC on 
days 
.  Cohorts 12 and 13 will enroll in parallel.  The DLRT will review the 
safety and laboratory data through at least day 36. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 53 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 7.  Planned Dose Levels by Cohort 
 
Cohort 
No.  Subjects 
AMG 133/Placebo 
Dose/ Frequency 
Route 
N (active: 
placebo) 
Part A 
1 
8 
21 mg day 1 
SC 
6:2 
2 
8 
Not exceeding 70 mg day 1a 
SC 
6:2 
3 
8 
Not exceeding 140 mg day 1a 
SC 
6:2 
4 
8 
Not exceeding 280 mg day 1a 
SC 
6:2 
5 
8 
Not exceeding 560 mg day 1a 
SC 
6:2 
11 
8 
Not exceeding 840 mg day 1a 
SC 
6:2 
6 
8 
Not exceeding 70 mg day 1a 
IV 
6:2 
Part B 
7 
8 
Not exceeding 140 mgb Q4W x 3 
SC 
6:2 
8 
8 
Not exceeding 280 mgb Q4W x 3 
SC 
6:2 
9 
8 
Not exceeding 560 mgb Q4W x 3 
SC 
6:2 
10 
 20 
Not exceeding 560 mgc Q4W x 3 
+  
SC 
 15:5 
Part C 
12 
 6 
SC 
N/A 
13 
 6 
SC 
N/A 
N/A = not applicable; Q4W = every four weeks; SC = subcutaneous; IV = intravenous. 
a Actual dose levels will be based on available data from previous cohorts. 
b Dose will not exceed the highest dose evaluated in cohorts 1 to 5 and cohort 11 (Part A) 
c Dose will not exceed the highest dose evaluated in cohorts 7 to 9 (Part B) 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.2 
Number of Subjects 
A total of approximately 112 subjects will be enrolled in the study.  Approximately 
56 subjects will be enrolled in Part A of the study, with 8 subjects in each of the 
7 cohorts.  Approximately 44 subjects will be enrolled in Part B of the study, with 
8 subjects in cohorts 7 to 9 and up to 20 subjects in cohort 10.  Up to 12 subjects will 
be enrolled in Part C cohorts 12 to 13.  Additional subjects may be enrolled if a DLRT 
recommendation is made to expand, repeat, or add cohorts to the study or if 
replacement subjects are needed.   
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 9.2. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 54 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
4.2.1 
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. 
4.2.2 
Number of Sites 
Approximately 1 to 3 investigative sites in United States will be included in the study.  
Sites that do not enroll subjects within 1 month of site initiation may be closed. 
4.3 
Justification for Investigational Product Dose 
The planned cohort in this amendment of the study consists of a multiple-dose 
cohort following a titration schema as presented in Figure 1-1. 
Previously, subjects in Part A received single doses of AMG 133 - 21, 70, 140, 280, 
560, and 840 mg administered SC.  This part also consisted of an IV cohort (cohort 6) at 
a dose of 70 mg administered IV; all SAD have been completed.  The starting dose and 
exposure multiples for the doses evaluated in SAD were calculated based on the 
NOAELs determined in the 13-week Good Laboratory Practices repeat-dose mouse and 
cynomolgus monkey nonhuman primate toxicology studies (every 2 weeks dosing, 
Section 2.2.2.3) and the observed reduction in body weight in the chronic efficacy study 
in obese cynomolgus monkeys.   
Part B consisted of evaluation of AMG 133 following repeat doses - 140, 280, and 
420 mg administered Q4W for a total of 3 doses per cohort. Preliminary review of 
the PK data in the FIH SAD and MAD part of the study demonstrated that AMG 
133 pharmacokinetics follow a linear, dose proportional kinetics based on Cmax (area 
under the curve [AUC] data pending), with a half-life of approximately 15 to 20 days.   
For SAD cohorts 1 to 6 and 11, no serious adverse events or deaths have been 
reported, and most adverse events reported were mild associated with nausea, 
vomiting, and dyspepsia.  One subject in cohort 3 (140 mg dose) had a moderate 
adverse event associated with gastroenteritis related to IP.  Approximately 90 of 
subjects enrolled in MAD cohorts 7 to 10 reported mild GI-related adverse events 
(mainly nausea, vomiting, and diarrhea) after the first dose of AMG 133 and less 
than 5% experienced GI-related adverse events after the second dose.  There were 
no serious adverse events or deaths reported after any of the doses.  
Approximately 26% of subjects in the MAD trial discontinued the study prior to 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 55 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
receiving the second dose which caused concerns regarding tolerability of the 
first dose; 50% of subjects in cohort 9 withdrew consent after receiving the 
420 mg dose on day 1 due to GI-related adverse events.  The doses were selected to 
allow for whole integer injection volumes to circumvent any potential dosing errors.   
Part C consists of two cohorts (cohorts 12 and 13), both open-label to evaluate 
dose-level escalation from  70 mg to  420 mg.  The objective of Part C is to 
evaluate first dose effects of AMG 133 on GI-related adverse events using a 
titration methodology.  Cohort 12 will start at a lower dose 
mg) of AMG 133 
given 
 
.   
Cohort 13 will start at a lower dose (
mg) of AMG 133 given 
 
 
.   
The rationale for dose selection for Part C is based on the available PK data from 
this ongoing FIH study cohorts 1 to 11 (Part A and Part B) and the NOAEL 
exposures established based on 13-week GLP repeat-dose studies in mouse and 
cynomolgus monkeys.  
Similarly, for cohort 12, the predicted human exposure multiples for intact 
AMG 133 following the second dose of 
 mg on Day 
 are approximately 
40.5-fold and 45-fold for Cmax and AUCss, respectively, based on NOAEL 
established in cynomolgus monkeys, and 43-fold and 42.4-fold for Cmax and AUCss, 
respectively, based on NOAEL established in mice.  The predicted human 
exposure multiples for total AMG 133 following the second dose of 
 mg on 
Day 
 are approximately 45-fold and 49-fold for Cmax and AUCss, respectively, 
based on NOAEL established in cynomolgus monkeys, and 54-fold and 42-fold for 
Cmax and AUCss, respectively, based on NOAEL established in mice (Table 8 and 
Table 9).  
For cohort 13, the predicted human exposure multiples for intact AMG 133 
following the second dose of 
 mg on Day 
 are approximately 39-fold and 
43.2-fold for Cmax and AUCss, respectively, based on NOAEL established in 
cynomolgus monkeys, and 41.3-fold and 40.6-fold for Cmax and AUCss, 
respectively, based on NOAEL established in mice.  The predicted human 
exposure multiples for total AMG 133 following the second dose of 
 mg on 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 56 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Day 
 are approximately 42.2-fold and 45.5-fold for Cmax and AUCss, respectively, 
based on NOAEL established in cynomolgus monkeys, and 50.9-fold and 47.5-fold 
for Cmax and AUCss, respectively, based on NOAEL established in mice (Table 8 
and Table 9).  
Table 8.  Estimated Exposure Margins of Intact AMG 133 Following Repeat Doses 
(Q4W) 
 
 
Predicted Human 
Exposure 
Predicted Exposure Multiplesa 
Mouseb 
Monkeyc 
Clinical 
Dose (mg) 
Route 
AUC0-28 
(ghr/mL) 
Cmax 
(g/mL) 
AUCd 
Cmaxe 
AUCd 
Cmaxe 
 
(cohort 12)f 
SC 
17 731 
37 
42.4 
43 
45.1 
40.5 
 
(cohort 13)f 
SC 
18 513.6 
38.5 
40.6 
41.3 
43.2 
39 
AUC = area under the concentration-time curve; AUClast = area under the concentration-time curve during a 
last dosing interval; AUC0-28 = area under the concentration-time curve during a dosing interval defined 
here from time 0 to 28 days after the 2nd dose; Cmax = maximum observed drug concentration during a 
dosing interval defined here after the 2nd dose; FIH = First in Human; NOAEL = no observed adverse 
effect level; PK = pharmacokinetic; SC = subcutaneous; Q4W = every 4 weeks. 
a PK data from AMG 133 FIH study is used for PK prediction 
b After the last dose after 13 weeks of treatment (7 total doses) at the NOAEL dose of 150 mg/kg in mice 
(Study 150238); mean AUClast (AUC0-168hrs) of 188 000 ghr/mL and mean Cmax of 1590 mg/mL of Intact 
AMG 133. 
c After the last dose after 13 weeks of treatment (7 total doses) at the NOAEL dose of 120 mg/kg in 
cynomolgus monkeys (Study 150239); mean AUClast (AUC0-168hrs) was 200 000 ghr/mL and mean Cmax 
of 1500 mg/mL of Intact AMG 133.   
d AUC exposure multiples = ratio of AUClast after 13 weeks (7 doses) of AMG 133 administration in the 
mouse or monkey x 4/predicted AUC0-28 in humans after the 2nd dose.   
e Cmax multiple = the ratio of Cmax after the last dose after 13 weeks (7 doses) of AMG 133 in the mouse or 
monkey to the predicted Cmax for each human single dose. 
f Actual dose levels will be based on available data from previous cohorts. 
Source:  Report 153788 
Table 9.  Estimated Exposure Margins of Total AMG 133 Following Repeat Doses 
(Q4W) 
 
 
Predicted Human Exposure 
Predicted Exposure Multiplesa 
Mouseb 
Monkeyc 
Clinical Dose 
(mg) 
Route 
AUCtau 
(ghr/mL) 
Cmax 
(g/mL) 
AUCd 
Cmaxe 
AUCd 
Cmaxe 
 (cohort 12)f 
SC 
22 831 
43.5 
51 
54.3 
48.9 
45.1 
 (cohort 13)f 
SC 
24 504 
46.4 
47.5 
50.9 
45.5 
42.2 
AUC = area under the concentration-time curve; AUC0-28 = area under the concentration-time curve during a 
dosing interval defined here from time 0 to 28 days after the 2nd dose; Cmax = maximum observed drug 
concentration during a dosing interval defined here after the 2nd dose; FIH = First in Human; NOAEL = no 
observed adverse effect level; PK = pharmacokinetic; SC = subcutaneous; Q4W = every 4 weeks. 
a PK data from AMG 133 FIH study is used for PK prediction 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 57 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
b After the last dose after 13 weeks of treatment (7 total doses) at the NOAEL dose of 150 mg/kg in mice 
(Study 150238); mean AUClast (AUC0-168hrs) of 291 000 g hr/mL and mean Cmax of 2360 mg/mL of Total 
AMG 133. 
c After the last dose after 13 weeks of treatment (7 total doses) at the NOAEL dose of 120 mg/kg in 
cynomolgus monkeys (Study 150239); mean AUClast (AUC0-168hrs) was 279 000 g hr/mL and mean Cmax 
of 1960 mg/mL of Total AMG 133.   
d AUC exposure multiples = ratio of AUClast after 13 weeks (7 doses) of AMG 133 administration in the 
mouse or monkey x 4/predicted (AUC0-28 days) in humans after the 2nd dose.   
e Cmax multiple = the ratio of Cmax after the last dose after 13 weeks (7 doses) of AMG 133 in the mouse or 
monkey to the predicted Cmax for each human single dose. 
f Actual dose levels will be based on available data from previous cohorts. 
4.4 
End of Study 
4.4.1 
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). 
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 (EOS) 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, 
additional antibody testing), as applicable. 
4.4.2 
Study Duration for Subjects 
The planned duration of participation in the study is approximately 178 days for Part A, 
235 days for Part B, and up to 235 days for Part C. 
4.5 
Patient Input on Study Design 
Patient input was not obtained in the design of this study. 
5. 
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).  This log may be completed and updated through an Interactive Response 
Technology (IRT). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 58 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 59 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent before initiation of any study-specific 
activities/procedures. 
102 
Age ≥ 18 years to ≤ 65 years, at the time of signing the informed consent. 
103 
Except for obesity, otherwise healthy 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 to 6, cohort 11 to 13) or day -1 (cohorts 7 to10) and screening. 
104 
BMI between ≥ 30.0 kg/m2 and ≤ 40.0 kg/m2.   
105 
Have a stable body weight (< 5 kg self-reported change during the previous 
8 weeks) before screening. 
106 
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. 
107 
Females must be of nonreproductive potential 
 
Postmenopausal as defined as: 
 
Age of ≥ 55 years with no menses for at least 12 months; OR 
 
Age < 55 years with no menses for at least 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. 
108 
For patients in cohorts 7 to 10 only, subjects must have a smartphone device 
with the capability of downloading apps or other digital tools required for this 
cohort. 
5.2 
Exclusion Criteria 
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 HbA1c > 6.5% and/or a 
fasting glucose ≥ 125 mg/dl (6.9 mmol/L) at screening. 
202 
Triglycerides ≥ 5.65 mmol/L (ie, 500 mg/dL) at screening. 
203 
Screening calcitonin ≥ 50 ng/L. 
204 
Hepatic liver enzymes aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, or total bilirubin levels > 1.5 times 
the upper limit of normal (ULN) at screening.  If ALT is  1.5 x the ULN at 
screening AND the AST, alkaline phosphatase, and total bilirubin levels are 
within normal limits, then subject may be eligible for enrollment after a 
discussion with the medical monitor. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 60 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
205 
History or clinical evidence of bleeding diathesis or any coagulation disorder, 
including prothrombin time (PT), activated partial thromboplastin time (PTT), 
international normalized ratio (INR), or platelet count outside of the laboratory’s 
normal reference range at screening.  If a single value (PT, PTT, INR, or 
platelet count) is outside the normal reference range at screening and the 
subject does not have evidence of any other bleeding or coagulation 
disorder, then the subject may be eligible for enrollment after a discussion 
with the medical monitor. 
206 
History of gastrointestinal abnormality that could affect gastrointestinal motility 
(including small bowel or colonic resection, inflammatory bowel disease, irritable 
bowel disease, and colon or gastrointestinal tract cancer). 
207 
Subjects with a family or personal history of medullary thyroid carcinoma or 
multiple endocrine neoplasia type 2 or a personal history of nonfamilial medullary 
thyroid carcinoma. 
208 
Subjects with a history of confirmed chronic pancreatitis or idiopathic acute 
pancreatitis. 
209 
Subjects with a history of gall bladder disease (ie, cholelithiasis or cholecystitis) 
not treated with cholecystectomy. 
210 
Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as 
thyroid-stimulating hormone > 6 mIU/L or < 0.4 mIU/L. 
211 
A corrected QT interval (QTc) at screening of > 450 msec in males or 
> 470 msec in females or history of long QT syndrome. 
212 
Subjects with a history of renal impairment or renal disease and/or estimated 
glomerular filtration rate ≤ 60 mL/min/1.73 m2. 
213 
Obesity induced by other endocrinologic disorders (eg, Cushing’s Syndrome). 
214 
Previous surgical treatment for obesity (excluding liposuction if performed 
>1 year before study entry) and/or subjects with recent (within 6 months) or 
planned endoscopic treatment for obesity. 
215 
History of major depressive disorder. 
216 
History of other severe psychiatric disorders, eg schizophrenia, bipolar disorder. 
217 
Any lifetime history of a suicidal attempt or of any suicidal behavior. 
218 
Surgery scheduled for the study duration period, except for minor surgical 
procedures, at the discretion of the investigator. 
219 
Positive results for human immunodeficiency virus antibodies, hepatitis B surface 
antigen, hepatitis B core antibody, or hepatitis C virus RNA.  For hepatitis C, 
hepatitis C antibody testing is done at screening, followed by hepatitis C virus 
RNA by polymerase chain reaction if hepatitis C antibody is positive. 
220 
Systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 90 mm Hg at 
screening, or on day -2.  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 malignancy of any type, other than in situ cervical cancer or surgically 
excised nonmelanomatous skin cancers occurring more than 5 years before 
randomization. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 61 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Prior/Concomitant Therapy 
222 
Use of the following agents are excluded unless there is a prior consultation 
between the 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 of hormone replacement therapy (eg, estrogen, thyroid). 
 
All herbal medicines, vitamins, and supplements within 30 days before 
receiving the first dose of investigational product. 
 
Exceptions must be reviewed and approved by the investigator and 
Amgen medical monitor.  Written documentation of this review and 
Amgen acknowledgment is required for subject participation. 
223 
Current or history of treatment with medications that may cause significant weight 
gain or loss, within 3 months before screening, including systemic corticosteroids 
(except for a short course of treatment, ie, 7 to 10 days), tricyclic 
antidepressants, atypical antipsychotic and mood stabilizers (eg, imipramine, 
amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, 
clozapine, olanzapine, valproic acid and its derivatives, and lithium). 
224 
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, metformin, or any GLP-1R agonists (either by 
prescription or as part of a clinical study). 
Prior/Concurrent Clinical Study Experience 
225 
Prior exposure to AMG 133 or AMG 598 or currently receiving treatment in 
another investigational device or drug study, or less than 5 half-lives since ending 
treatment on another investigational device or drug study(ies).  Other 
investigational procedures while participating in this study are excluded. 
Other Exclusions 
226 
Female subjects with a positive pregnancy test assessed at screening and/or 
day -2 by a serum pregnancy test and/or urine pregnancy test) or female 
subjects who are breastfeeding or planning to become pregnant or breastfeed 
during treatment and for an additional 5 months after the last dose of AMG 133. 
227 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use an 
acceptable method of contraception during treatment and for an additional 
5 months after the last dose of AMG 133.  Refer to Section 11.5 for additional 
contraceptive information. 
228 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 5 months after the last dose of AMG 133. 
230 
Subject has a known sensitivity to GLP-1R agonists. 
231 
Subject has known sensitivity to mammalian derived products. 
232 
Subject has an allergy or known sensitivity to acetaminophen. 
233 
Subject is unwilling or unable to limit alcohol consumption throughout the course 
of the study.  Alcohol is prohibited 48 hours before day -2 and is limited to no 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 62 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
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. 
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 before each blood collection for clinical 
laboratory tests. 
238 
Subject has donated or lost ≥ 500 mL of blood or plasma within 60 days of 
day -2. 
239 
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. 
240 
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 physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
241 
For subjects in cohorts 7 to 10 and cohorts 12 to 13 only, the Patient Health 
Questionnaire-9 (PHQ-9) score of ≥ 10 up to day 1 
242 
For subjects in cohorts 7 to 10 and cohorts 12 to 13 only, any suicidal ideation 
as identified by endorsement of (answered yes to) any of the items numbered 1 
to 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) up to day 1 
243 
For subjects in cohorts 7 to 10 and cohorts 12 to 13 only, 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 
244 
For subjects in cohorts 7 to 10 and cohorts 12 to 13 only, a QTc of > 450 msec 
in males or > 470 msec in females up to day 1 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Subjects will be required to fast overnight for at least 10 hours before all blood draws for 
routine clinical laboratory
 plasma pharmacokinetics, and 
pharmacodynamics assessments 
 
 per Schedule of Activities 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 63 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
(Section 1.3).  After dosing, no water is allowed for 2 hours, after which water is allowed 
ad libitum. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
Subjects must limit alcohol consumption throughout the course of the study.  Alcohol is 
prohibited 48 hours before admission to the research facility on day -2.  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 nontobacco using subjects should be enrolled.  Subjects should not 
have used any nicotine or tobacco containing products within the last 6 months before 
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. 
5.3.3 
Activity 
Subjects will abstain from strenuous exercise for 72 hours before each blood sample 
collection for clinical laboratory tests.  Subjects may participate in light recreational 
activities during studies (eg, watching television, reading). 
5.4 
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 11.3). 
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. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (after signing the 
consent form) receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 64 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
through IRT.  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. 
5.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  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.  Refer to Section 8.1.1. 
5.6 
Washout Period/Run-in Period/Invasive Procedures 
There will be no washout period, run-in period, or invasive procedures in this study. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), noninvestigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 10 below. 
6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 65 of 138 
CONFIDENTIAL  
FORM-001520, v 24, 21 May 2019 
 
Table 10.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
AMG 133 
Placebo 
Dosage Formulation 
Placebo will be presented in identical containers, 
and stored/packaged the same as AMG 133. 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage Frequency 
cohorts 1 to 5:  21 mg SC, or a dose based on 
available data from previous cohorts, not 
exceeding 70, 140, 280, or 560 mg SC 
cohort 6:  Dose based on available data from 
previous cohorts, not exceeding 70 mg IV 
cohorts 7 to 9:  a dose based on available data 
from previous cohorts, not exceeding 140, 280, or 
560 mg SC 
cohort 10:  Dose based on available data from 
cohorts 7, 8, or 9, not exceeding 560 mg SC.  
cohort 11:  Dose based on available data from 
cohorts 1 to 5, not exceeding 840 mg SC. 
cohorts 12 to 13:  Dose based on available 
data from cohorts 1 to 11, 
 
 
NA 
Route of Administration 
IV/SC injection 
Accountability 
The unblinded pharmacist must provide AMG 133 or placebo from the Amgen supplied stock 
according to the IRT assignment.  The volume of preparation, dose, start date/time, and lot number 
(after study is unblinded) of AMG 133 is to be recorded on each subject's CRF(s). 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 66 of 138 
CONFIDENTIAL  
FORM-001520, v 24, 21 May 2019 
 
Study Treatment Name 
Amgen Investigational Product:a 
AMG 133 
Placebo 
Dosing Instructions 
Administration of AMG 133 or placebo requires specific training, which must be completed and 
documented before undertaking any administration related activities.  AMG 133 will be delivered as 
1+ injections SC or IV.   
cohorts 1 to 5 and cohorts 7 to 13:  AMG 133 or placebo should be administered in the abdominal 
subcutaneous tissue by SC injection.  Where more than 1 injection is required to administer the full 
dose, the subject will receive the SC injections in different quadrants in the abdominal SC tissue in a 
consecutive fashion with the injections separated by no more than 1 minute.  Each injection should be 
separated by a minimum of 2 inches.  Each quadrant may be injected once with up to 2 mL of 
AMG 133 or placebo in the order described above. 
cohort 6:  AMG 133 or placebo should be administered by a short duration bolus injection over 3 to 
5 minutes in accordance with local policy. 
Additional dosing instructions are provided in the IPIM. 
CRF = case report form; IPIM = Investigational Product Instruction Manual; IRT = interactive response technology; IV = intravenous; NA = not applicable; 
SC = subcutaneous 
a AMG 133 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 67 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
6.1.2 
Noninvestigational Products 
No Amgen noninvestigational products will be used in this study. 
6.1.3 
Medical Devices 
No Amgen investigational medical devices will be used in this study. 
Investigational medical devices are not used in this study.  However, non-investigational 
devices such as an iPhone may be used with cohorts 7 to 9 and a 
 
  Amgen will be responsible for providing the 
devices to the investigators for use by subjects. 
Other noninvestigational medical devices may be used in the conduct of this study as 
part of standard care. 
Noninvestigational 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.   
Additional details are provided in the IPIM. 
6.1.4 
Other Protocol-required Therapies 
All other protocol-required therapies including, 
, that are commercially 
available are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
Subjects participating in cohorts 1 to 5 and cohort 11 will undergo a 
 
test after an overnight fast of a minimum of 10 hours.  
 
 are summarized in the Schedule of Activities in Section 1.3.  
 
tests will not be performed in cohorts 6 to 10 and cohort 12 to 13. 
6.1.5 
Other Treatment Procedures 
There will be no other treatment procedures in this study. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 68 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
6.1.6 
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, combination product, or device after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors or partners for 
whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts. 
This includes any investigational/non-investigational product(s), device(s) or 
combination product(s) provisioned and/or repackaged/modified by Amgen: 
AMG 133 
Any product complaint(s) associated with an investigational product(s), 
non-investigational products(s), devices(s), or combination product(s) supplied by 
Amgen are to be reported. 
As an industry-wide standard practice, the study site staff (whether experienced it 
him/herself or experienced/reported by a study participant) is advised to communicate 
an adverse event and/or a product complaint associated * with the non-Amgen wearable 
device to the legal manufacturer of that device as soon as possible. 
*Note:  By association means that an adverse event demonstrates temporal and/or 
spatial associations with the non-Amgen wearable device.  Please refrain from including 
further adjudication of such events in the communications to the device manufacturer 
and the expectedness of the event by investigators and by Amgen safety medical 
reviewers. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
With the exception of hormone replacement therapy (eg, estrogen, thyroid), use of any 
prescription or nonprescription drugs within the 14 days or 5 half-lives (whichever is 
longer) before the first dose of investigational product on day 1, and for the duration of 
the study, is not permitted unless to treat a medical emergency.  In addition, use of 
herbal medicines, vitamins and supplements within 30 days before dosing on day 1, and 
for the duration of the study, is not permitted unless reviewed and approved by the 
investigator and Amgen medical monitor.  Any changes regarding concomitant 
medications should be recorded on the subject’s source documents and the CRF along 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 69 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
with the reason for the change.  Use of any medication that may cause significant weight 
gain or loss, including systemic corticosteroids (except for a short course of treatment, 
ie, 7 to 10 days), tricyclic antidepressants, atypical antipsychotic, and mood stabilizers 
(eg, imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, 
thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium) within 
3 months before screening, and for the duration of the study is not permitted. 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
Dose Level Determination 
A recommendation to escalate to a higher dose cohort will only occur when the previous 
dose regimen(s) have been found to be reasonably well tolerated based on available 
study data through study day 15 for a minimum of 7 out of 8 dosed subjects 
(cohorts 1 to 6 and cohort 11) or through study day 36 for 6 of 8 dosed subjects (cohorts 
7 to 10) and upon unanimous agreement of the DLRT members.  Available data from 
previous cohorts will also be considered.  Dose level recommendations will be made on 
a treatment cohort basis (not on an individual basis).  After receiving the DLRT 
recommendation, Amgen will render a final decision and will issue a written notification 
of the dose change decision to investigators.  The DLRT will not make a dose level 
recommendation after reviewing the safety and tolerability data through study 
day 36 for subjects in cohorts 12 to 13 as these are terminal cohorts.  Further 
information on DLRMs is provided in Appendix 3 (Section 11.3). 
Dose Cohort Stopping Rules 
The DLRT will recommend stopping or modifying dosing if suspected adverse drug 
reactions, changes in vital signs, ECG, or clinical laboratory results are observed and 
these changes pose a significant health risk.  In addition, dosing will be stopped or 
modified if any of the stopping rules shown in Table 11 are met.  The Amgen medical 
monitor may suspend dosing and convene a DLRM at any time based on emerging 
safety data. 
Dosing will be stopped or modified as shown in Table 11. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 70 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 11.  Dose Cohort Stopping Rules 
Scenario 
Action 
Any 
occurrence 
of an Amgen 
Standard 
Grading 
Scale 
moderate 
adverse 
event of 
similar type 
in 2 or more 
subjects in 
the same 
cohort. 
Stop dosing and convene DLRM (if event occurs outside 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 appropriate.a 
Based on the DLRM vote, 1 of the following recommendations may be 
made: 
 
stop enrollment of the cohort (if applicable) 
 
resume enrollment of the cohort as planned 
 
expand the cohort at the same dose 
 
continue enrollment of the study at a lower dose 
 
upon a unanimous vote escalate to an intermediate dose (a dose 
lower than the next planned dose) 
 
upon a unanimous vote escalate to the next planned dose  
Any 
occurrence 
of an Amgen 
Standard 
Grading 
Scale severe 
adverse 
event.   
Stop dosing additional subjects in the cohort and convene DLRM (if 
the event occurs outside 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 to determine relatedness to investigational 
product.a 
If the adverse event is determined by a majority vote of the DLRT to be 
related to study drug and clinically or medically significant, recommend 
that no further doses should be administered at this dose and no dose 
escalation should proceed.  Recommend that enrollment of the study 
continue at a lower dose or a lower dose cohort may be added to the 
study. 
Otherwise, based on the majority vote of the DLRT, 1 of the following 
recommendations may be made: 
 
resume enrollment of the cohort as planned 
 
expand the cohort at the same dose 
 
continue enrollment of the study at a lower dose or add a lower 
dose cohort to the study. 
DLRM = dose level review meeting; DLRT = dose level review team 
a 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 of subjects in subsequent cohorts. 
Clinically or medically significant serious adverse events and suspected adverse drug 
reactions considered to be related to study procedures will be followed until resolved or 
considered stable. 
The study may be terminated at any point at the discretion of the sponsor. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 71 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Individual Stopping Rules 
No individual dose stopping rules will be implemented. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  AMG 133 
The reason for dose change of AMG 133/placebo is to be recorded on each subject’s 
CRF(s). 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009. 
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product and other protocol-required therapies during the 
study are provided in the IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects will be randomized in a 3:1 allocation ratio, to AMG 133 to placebo, 
respectively, in double-blind manner in Part A and Part B cohorts 1 to 11 only.  Part C 
cohorts 12 to 13 is an open-label study. 
The randomization will be performed by IRT. 
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. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
6.4.2 
Blinding 
This is a double-blind study for cohorts 1 to 11.  Treatment assignment will be blinded 
to all subjects, site personnel, and Amgen as described below. 
6.4.2.1 
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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 72 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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. 
6.4.2.2 
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 
should not be distributed to the investigators or subjects before the study is formally 
unblinded. 
6.5 
Treatment Compliance 
Investigational product will be administered at the clinic by qualified staff. 
6.6 
Treatment of Overdose 
The effects of overdose of AMG 133 are not known.  In case of dosing error, immediate 
consultation with the Amgen medical monitor is recommended to discuss subject 
management and prompt reporting of clinically apparent or laboratory adverse events 
possibly related to the dosing error. 
In case of overdose, subjects should be closely monitored for signs and symptoms of 
adverse events.  Pharmacokinetic assessments should be obtained if possible. 
Subjects should be monitored closely until any observed signs and/or symptoms revert 
to normal. 
Adverse events should be reported and documented according to instructions available 
in Section 8.2.3. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 73 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior therapies that were being taken/used from 14 days or 5 half-lives before enrollment 
through the first dose of investigational product will be collected.  For all prior therapies, 
collect therapy name, indication, dose, unit, frequency, route, start date and stop date.   
6.7.2 
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 6.1.7. 
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. 
7. 
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, device, 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 7.1, 7.2.1, and 7.2.2. 
7.1 
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 1.3) 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, and must document this decision in the subject’s medical records.  Subjects who 
have discontinued investigational product and/or other protocol-required therapies or 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 74 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 
 
Pregnancy 
7.2 
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 decision to withdraw in the subject’s medical records. 
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 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) for 
data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
There will be no washout period, run-in period, or invasive procedures during this study. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 75 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
7.2.2 
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 
7.3 
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. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 1.3). 
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 (Section 1.3), is essential and required for study conduct. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 76 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IRT and screen 
the subject to assess eligibility for participation.  The screening window is up to 28 days. 
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 5.5) 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 
rescreening 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. 
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  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. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Section 1.3).  On-study visits may be 
completed within the windows provided.  The date of the first dose of investigational 
product is defined as day 1.  All subsequent doses and study visits will be scheduled 
based on the day 1 date.  Administration of protocol-required therapies is to be 
administered after all predose assessments and/or procedures during each visit that it is 
required. 
8.1.3 
Safety Follow-up 
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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 77 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
dosing interval of investigational product.  End of Study visit procedures should be 
performed at this safety follow-up visit per the Schedule of Activities (Section 1.3). 
8.1.4 
End of Study 
End of study visit procedures will be performed per the Schedule of Activities 
(Section 1.3).  For subject completing the study, this visit occurs on day 150 ± 7 (Part A) 
and day 207 ± 7 (Part B), and up to day 207  7 days (Part C).  If feasible, all end of 
study procedures should be performed at the final visit for subjects who are removed 
from study before the defined end of study visit  
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
During the study, every effort should be made to perform the study procedures as 
indicated on the Schedule of Activities (Section 1.3).  Every effort should be taken to 
collect all laboratory, biomarker, and pharmacokinetic samples as described in the 
Schedule of Activities (Section 1.3).  If sample processing/shipment on a 
weekend/holiday is not logistically feasible for a site, this needs to be documented and 
will not be considered a protocol deviation. 
Subjects will be seen in the clinic for study evaluations.  When ECGs, vital signs, and 
blood sample collections occur at the same visit, ECGs and vital signs should be 
collected before blood samples.  The time of blood sample collection must be recorded 
with the exact time of collection (do not use the time that samples were frozen or at any 
other time point).  The study-specific manuals provide additional details regarding the 
requirements for these procedures. 
Acceptable deviation windows applicable to visits, ECG capture, dosing, and sample 
collections follow: 
 
± 5 minutes window around the target completion time for tests and samples through 
24 hours postdose (with the exception of the first 10-minute time point postdose in 
cohort 6) 
 
± 1 hour on subsequent days in-house 
 
per the visit windows through end of study 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 78 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
8.2.1 
General Assessments 
8.2.1.1 
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. 
8.2.1.2 
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 will be used to study the impact on biomarkers variability 
and pharmacokinetics of the protocol-required therapies.   
8.2.1.3 
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 11.4. 
8.2.1.4 
Physical Examination 
The investigator or designated site physician will perform a complete physical 
examination (excluding breast, genital, and rectal examination) at time points specified in 
the Schedule of Activities (Section 1.3).  The neurological exam is included as part of 
the physical exam in cohorts 7 to 10 and cohorts 12 to 13 (Section 1.3) and will 
include peripheral sensory and motor evaluation, and assessment of gait, pain, position, 
strength, and reflexes.   
Physical examination findings should be recorded on the appropriate CRF (eg, medical 
history, event). 
8.2.1.5 
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.  Weight is 
measured twice, with accepted values within 0.1 kg.  Body mass index should be 
calculated using the following formula:  
body mass index (kg/m2) = weight (kg)/[height (cm)/100]^2. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 79 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Waist circumference:  Subjects should wear minimal clothing to ensure that the 
measuring tape is correctly positioned.  Subjects should stand erect with the abdomen 
relaxed, arms at the sides, feet together and with their weight equally divided over both 
legs.  To perform the waist measurement, the lowest rib margin is first located and 
marked with a pen.  The iliac crest is then palpated in the midaxillary line, and also 
marked.  It is recommended to apply an elastic tape horizontally midway between the 
lowest rib margin and the iliac crest, and tie firmly so that it stays in position around the 
abdomen about the level of the umbilicus.  The elastic tape thus defines the level of the 
waist circumference, which can then be measured by positioning the measuring tape 
over the elastic tape.  Subjects are asked to breathe normally, and to breathe out gently 
at the time of the measurement to prevent them from contracting their muscles or from 
holding their breath.  Measurements should be performed using the same procedure 
throughout the study.  The reading is taken to the nearest centimeter and entered in the 
source document. 
8.2.1.6 
Substance Abuse History 
Obtain a detailed history of prior and/or concurrent use of alcohol, tobacco, drugs of 
abuse. 
8.2.2 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Section 1.3). 
8.2.2.1 
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.   
8.2.2.2 
Suicidal Risk Monitoring 
Baseline assessment of suicidal ideation and behavior, and treatment-emergent suicidal 
ideation and behavior will be monitored during the study using C-SSRS and Patient 
PHQ-9.  The C-SSRS is a clinician rating of suicidal behavior and ideation.  The 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 80 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
C-SSRS consists of a maximum of 20 items.  Columbia Suicide Severity Rating Scale 
will be administered in study subjects at each study visit to assess possible suicidal 
ideation and behavior.  Reports of suicidal ideation with intent to act (endorse item 4 or 
5) and reports of actual, aborted, or interrupted suicide attempts or a behavior 
preparatory for making an attempt indicate subjects at high risk for suicide.  If such 
reports are identified, the investigator is to appropriately manage the subject in 
accordance with standard of care. AMG 133 will be discontinued in subject who 
experience signs of suicidal ideation or behavior. Refer to Sections 11.8 through 
Section 11.10 for more information on mental health monitoring. 
8.2.2.3 
Electrocardiograms 
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.  The ECGs 
should be performed in a standardized method, in triplicate, and run consecutively (all 
3 ECGs should be completed within a total of 5 minutes from the start of the first to the 
completion of the third), before blood draws or other invasive procedures.  Each ECG 
must include the following measurements:  QRS, QT, QTc, RR, and PR intervals. 
As required per Section 1.3: 
 
Single ECG at Screening 
 
3 baseline ECGs collected ≥ 30 minutes apart, with each baseline ECG in 
triplicate run consecutively (all 3 ECGs should be completed within a total of 
5 minutes from the start of the first to the completion of the third) (total 9 ECGs) 
 
Triplicate ECGs at time points after dosing 
Baseline is defined as day 1 predose.  The primary investigator or (eg, designated site 
physician) will review all ECGs.  The ECGs will be transferred electronically to an ECG 
central vendor for storage and archiving 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, or designee.  
Standard ECG machines should be used for all study-related ECG requirements.  In 
certain circumstances Amgen may be able to provide a standard ECG machine if a site 
is unable to provide one. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 81 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
8.2.2.5 
Neurologic assessments 
Neurological exams are incorporated as part of the safety assessments in the multiple 
dose phase (Part B and Part C) of the current study.  The neurological exam will be 
conducted as part of the physical exam and will include peripheral sensory and motor 
evaluation, and assessment of gait, pain, position, strength, and reflexes. 
8.2.3 
Adverse Events and Serious Adverse Events  
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 11.4. 
8.2.3.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.3.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Amgen Standard 
Grading Scale and is described in Section 11.4. 
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 investigational 
product through the 30 (+3) days of last dose of investigational product or end of study, 
whichever is later are reported using the Event CRF. 
As an industry-wide standard practice, the study site staff (whether experienced it 
him/herself or experienced/reported by a study participant) is advised to communicate 
an adverse event and/or a product complaint associated * with the non-Amgen wearable 
device to the legal manufacturer of that device as soon as possible. 
*Note:  By association means that an adverse event demonstrates temporal and/or 
spatial associations with the non-Amgen wearable device.  Please refrain from including 
further adjudication of such events in the communications to the device manufacturer 
and the expectedness of the event by investigators and by Amgen safety medical 
reviewers. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 82 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
8.2.3.1.2 
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 signing of the informed 
consent through 30 (+3) days of last dose of investigational product or end of study, 
whichever is later are reported using the Events CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
8.2.3.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
After End of study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  
However, if the investigator becomes aware of serious adverse events suspected to 
be related to investigational product, then these serious adverse events will be 
reported to Amgen within 24 hours following the investigator’s awareness 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. 
If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study. 
8.2.3.2 
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. 
8.2.3.3 
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 7.3).  
Further information on follow-up procedures is given in Section 11.4. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 83 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness 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. 
8.2.3.4 
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.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
8.2.3.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 84 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
8.2.3.6 
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 the last dose of investigational product. 
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 11.5.  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 11.5. 
8.2.4 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) 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 Events 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 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 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Section 1.3). 
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. 
Pregnancy Testing 
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, 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 85 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
becomes pregnant it must be reported on the Pregnancy Notification Form, see 
Figure 11-2).  Refer to Section 11.5 for contraceptive requirements. 
A pregnancy test should be performed according to the Schedule of Activities 
(Section 1.3) including the end of study/safety follow-up visit 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. 
8.2.5 
Pharmacokinetic Assessments 
All subjects randomized to AMG 133 will have pharmacokinetic samples assessed. 
Whole blood samples of approximately 5 mL will be collected for measurement of 
plasma concentrations of AMG 133 as specified in the Schedule of Activities 
(Section 1.3).  A maximum of 3 samples may be collected at additional time points 
during the study if warranted and agreed upon between the investigator and the 
sponsor.  Instructions for the collection and handling of 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 would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Whole blood samples 
 
 will be collected by venipuncture or cannulation at the 
times indicated in the Schedule of Activities (Section 1.3). 
8.2.6 
Pharmacodynamic Assessments 
Venous blood samples of approximately 5 to 7.5 mL will be collected for measurement of 
AMG 133 treatment pharmacodynamic effects at each time point specified in the 
Schedule of Activities (Section 1.3).  
 
8.2.7 
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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 86 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 metabolic disorders, 
such as obesity, and/or to identify subjects who may have positive or negative response 
to AMG 133.  No additional samples are collected for this part of the study.  For subjects 
who consent to this/these analysis/analyses, DNA may be extracted from samples taken 
during the study. 
The final disposition of samples will be described in Section 11.6.   
8.2.8 
Antibody Testing Procedures 
Blood samples for antibody testing are to be collected as outlined in the Schedule of 
Activities (Section 1.3).  Bioanalytical testing for anti-AMG 133 antibodies will be 
conducted on these samples using a fully validated, electrochemiluminescence-based 
immunoassay.  All samples that test positive for ADA will be tittered and evaluated for 
neutralizing antibodies against human GLP-1 using a cell-based assay.  All neutralizing 
antibody positive subjects and subjects who tested positive for binding ADAs at the final 
scheduled study visit, defined as the end of study visit, and have clinical sequelae that 
are considered potentially related to an anti-AMG 133 antibody response will be asked to 
return for additional follow-up testing until the ADA responses have returned to 
(1) baseline, (2) a low titer, or (3) the subject has been followed for a period of at least 
1 year (± 4 weeks) post-administration of AMG 133.  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 133. 
8.2.9 
Biomarkers 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 87 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 88 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 89 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
No statistical hypotheses will be tested in this study. 
9.2 
Sample Size Determination 
The sample size for the study is based on practical considerations.  No statistical 
hypotheses will be tested.  Approximately 112 subjects will be enrolled in the study, with 
8 subjects per cohort (for cohorts 1 to 9 and cohort 11), up to 20 subjects in cohort 10, 
and up to 12 subjects from Part C with up to 6 subjects per cohort (for 
cohorts 12 to 13).  Additional subjects may be enrolled if a DLRT recommendation is 
made to expand, repeat, or add cohorts to the study or if replacement subjects are 
needed. 
For safety considerations, with up to 87 subjects (42 subjects from cohorts 1 to 6 and 
cohort 11 of Part A, 18 subjects from cohorts 7 to 9 of Part B, up to 15 subjects from 
cohort 10 of Part B, and up to 12 subjects from cohorts 12 and 13 in Part C) 
receiving AMG 133, there is at least 92.9% chance of detecting an adverse event with a 
true incidence rate of 3% or greater and at least 98.8% chance of detecting an adverse 
event with a true incidence rate of 5% or greater.   
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
9.3.1.1 
Full analysis Set 
The full analysis set will consist of all randomized subjects who receive at least 1 dose of 
AMG 133. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 90 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
9.3.1.2 
Safety Analysis Set 
The safety analysis set is the same as the full analysis set. 
9.3.1.3 
Pharmacokinetic Analysis Set 
The pharmacokinetics analysis set will consist of all subjects who received at least 
1 dose of AMG 133 for whom at least 1 pharmacokinetics parameter or endpoint can be 
adequately estimated. 
9.3.2 
Covariates 
Baseline values may be used as a covariate in analyses. 
9.3.3 
Subgroups 
No subgroup analyses are planned. 
9.3.4 
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. 
9.4 
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 after the end of 
study, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
The 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 11.3 for further details. 
The first administrative interim analysis will be conducted after the DLRM for cohort 9 
with no preplanned adaptive decisions.  This analysis will include data from 
cohorts 1 to 9.  If cohorts 10 and 11 have undergone DLRM prior to the DLRM for 
cohort 9, data from these cohorts should be included in the analysis as well.  For the 
first interim analysis, the data cutoff is 36 days after cohort 9 enrollment.  At that time, 
the database will be cleaned, processed, and a snapshot for cohorts 1 to 9 will be taken 
and an “as is” snapshot for cohorts 10 and 11.  The first interim analysis will assess the 
primary endpoints (subject incidence of treatment-emergent adverse events and 
changes in laboratory safety tests, vital signs, and 12-lead ECGs), secondary endpoints 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 91 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
(pharmacokinetic parameters and incidence of anti-AMG 133 antibody formation), and 
the following exploratory endpoints:  
 
  The study will be unblinded to 
sponsor staff conducting and reviewing the interim analysis and remain blinded to site 
personnel and site-facing staff of the sponsor.   
The second interim analysis will occur after all subjects in cohorts 1 to 11 have 
completed the study.  For the second interim analysis, the data cutoff is at EOS.  
At that time, the database will be cleaned, processed, and a snapshot for 
cohorts 1 to 11 will be taken.  The second interim analysis will include all time 
points and all planned analysis similar to the final analysis with the exception that 
the data generated 
 
 will not be included in the second 
interim analysis but will be included in the final analysis instead.  The study will 
be unblinded to sponsor staff conducting and reviewing the interim analysis and 
remain blinded to site personnel and site-facing staff of the sponsor.    
9.4.1.2 
Primary Analysis 
The primary analysis will occur at the final analysis and not be a separate analysis. 
9.4.1.3 
Final Analysis 
The final analysis will occur after all subjects in cohorts 1 to 13 have completed this 
study.  Data will be locked prior to conducting the final analysis based on a clean 
snapshot of data from cohorts 1 to 13. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, 
pharmacokinetic, and pharmacodynamic endpoints.  Accumulating pharmacodynamic 
data might be reviewed throughout the study by treatment, periodically.  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.  Pharmacokinetic, pharmacodynamic, and 
clinical laboratory data will be summarized by treatment group and at each time point 
when samples are collected.  Graphical summaries of the data may also be presented. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 92 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Data for subjects receiving placebo will be combined across cohorts 1 to 5 and 
cohort 11 (SC) and cohort 6 (IV), except for adverse events where the combined SC 
cohorts will be summarized separately from the IV cohort within Part A. 
Data for subjects receiving the placebo will be combined across cohorts 7 to 9 within 
Part B and data for subjects receiving placebo from cohort 10 will be summarized 
separately.  Part C is an open-label study, therefore, data for subjects from 
cohorts 12 to 13 will be summarized separately. 
Data for subjects receiving AMG 133 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. 
9.4.2.2 
Efficacy Analyses 
Efficacy will not be assessed in this study. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 93 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
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, and adverse events leading to 
withdrawal from investigational product or other protocol-required 
therapies. 
 
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. 
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product 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.   
9.4.2.3.3 
Laboratory Test Results 
Hematology, chemistry, and urinalysis data will be 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. 
9.4.2.3.4 
Vital Signs 
Vital signs will be reviewed for each subject.  Summaries of heart rate and blood 
pressure data over time and change from baseline will be provided. 
9.4.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at each protocol 
scheduled visit by cohort/combined placebo cohort. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 94 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
9.4.2.3.6 
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 will be categorized, and the number and percentage 
of subjects in each group will be summarized.  Subjects’ maximum postbaseline 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 
will be plotted. 
9.4.2.3.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 133 antibodies 
(binding and if positive, neutralizing to native GLP1, when available) at any time will be 
tabulated by treatment group. 
9.4.2.3.8 
Exposure to Investigational Product 
The number of doses of investigational product 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. 
9.4.2.3.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each cohort/combined placebo cohort as coded by the World Health 
Organization Drug dictionary. 
9.4.2.4 
Other Analyses 
9.4.2.4.1 
Secondary Endpoint — Pharmacokinetics Analysis 
Plasma AMG 133 concentrations will be determined using a validated assay.  Individual 
plasma concentration-time plots for AMG 133 will be presented for each subject as well 
as mean concentration-time plots for each dose cohort.  Pharmacokinetic parameters 
that may include, but are not limited to AUC, Cmax, and tmax will be estimated using either 
compartmental (eg, pharmacokinetic modeling) or noncompartmental methods.  Actual 
dosing and sampling times will be used for calculation of pharmacokinetic parameters.  
Summary statistics will be generated for each pharmacokinetic parameter for each dose 
cohort.   

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 95 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
A power model will be used to examine dose/concentration relationship over the SC 
cohorts.  The dependent variable will be ln(AUC) or loge(Cmax) and the independent 
variable will be loge(dose). 
 test will be 
determined using a validated assay.  Individual plasma concentration-time plots will be 
presented for each subject as well as mean concentration-time plot for each dose 
cohort.  Pharmacokinetic parameters that may include, but not limited to AUC from 0 to 
5 hours as well as Cmax and tmax. 
9.4.2.4.2 
Exploratory Endpoints 
The statistical analyses in this section are considered exploratory in nature and will be 
performed only when deemed appropriate.   

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 96 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
10. 
References 
Althage MC, Ford EL, Wang S, 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. 
AMG 133 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Beck, B Max, JP.  Hypersensitivity of adipose tissue to gastric inhibitory polypeptide 
action in the obese Zucker rat.  Cell Mol Biol.  1987;33:555-562. 
Berndt SI, Gustafsson S, Magi R, et al,  Genome-wide meta-analysis identifies 11 new 
loci for anthropometric traits and provides insights into genetic architecture.  Nat Genet.  
2013;45:501-512. 
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. 
Drucker, DJ.  (2006).  The biology of incretin hormones.  Cell Metab 3, 153-165. 
Hauner H, Glatting G, Kaminska D, Pfeiffer EF.  Effects of gastric inhibitory polypeptide 
on glucose and lipid metabolism of isolated rat adipocytes.  Ann Nutr Metab.  
1988;32:282-288. 
Heymsfield SB, Wadden TA.  Mechanisms, pathophysiology and management of 
obesity.  N Engl J Med.  2017;376:254-266. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
International Council for Harmonisation.  International Council for Harmonisation (ICH) 
Harmonised Tripartite Guideline:  Preclinical Safety Evaluation of Biotechnology-derived 
Pharmaceuticals S6 (R1), 2011. 
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–S138. 
Khera R, Murad MH, Chandar AK, et al,  Association of pharmacological treatments for 
obesity with weight loss and adverse events.  JAMA.  2016;315:2424. 
Killion EA, Wang J, Yie J, Shi SD, et al,  Anti-obesity effects of GIPR antagonists alone 
and in combination with GLP-1R agonists in preclinical models.  Sci Transl Med.  
2018;10:472. 
Knapper JM, Puddicombe SM, Morgan LM, Fletcher JM.  Investigations into the actions 
of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1(7-36)amide 
on lipoprotein lipase activity in explants of rat adipose tissue.  J Nutr.  1995;125:183-188. 
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.  8‑year weight losses with an intensive lifestyle 
intervention:  the look AHEAD study.  Obesity (Silver Spring).  2014;22:5-13.   

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 97 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Miyawaki K, Yamada Y, Ban N, et al,  Inhibition of gastric inhibitory polypeptide signaling 
prevents obesity.  Nat Med.  2002;8:738-742. 
Nasteska D, Harada N, Suzuki K, 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, et al,  Common variants at CDKAL1 and KLF9 are 
associated with body mass index in east Asian populations.  Nat Genet.  
2012;44:302-306. 
Saxena R, Hivert MF, Langenberg C, et al,  Genetic variation in GIPR influences the 
glucose and insulin responses to an oral glucose challenge.  Nat Genet.  
2010;42:142-148. 
Speliotes EK, Willer CJ, Berndt SI, et al,  Association analyses of 249,796 individuals 
reveal 18 new loci associated with body mass index.  Nat Genet.  2010;42:937-948. 
Terranova L, Busetto L, Vestri A, Zappa MA.  Bariatric surgery:  cost‑effectiveness and 
budget impact.  Obes Surg.  2012;22:646-653. 
Turton MD, O'shea D, Gunn I, Beak SA, Edwards CM, Meeran K, CHO-K1i SJ, et al,  A 
role for glucagon-like peptide-1 in the central regulation of feeding.  Nature.  
1996;379:69. 
United States Food and Drug Administration.  Guidance for Industry:  Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers, 2005. 
Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M.  Health and economic 
burden of the projected obesity trends in the USA and the UK.  Lancet.  
2011;378:815‑825. 
Wen W, Cho YS, Zheng W, et al, Meta-analysis identifies common variants associated 
with body mass index in east Asians  Nat Genet.  2012;44:307-311. 
World Health Organization.  Obesity and overweight; 2018 [cited 2019 September 18].  
Available from: 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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 98 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11. 
Appendices 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 99 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADA 
antidrug antibodies 
AUC 
area under the concentration-time curve 
AUCinf 
area under the plasma concentration time curve from time zero 
to infinity 
AUCtau 
area under the concentration-time curve during a dosing interval 
defined here from time after 3rd dose to day 57 
BIL 
bilirubin 
BMC 
body mineral content 
cAMP 
cyclic adenosine monophosphate 
CFR 
U.S.  Code of Federal Regulations 
CHO 
Chinese hamster ovary 
Cmax 
maximum observed drug concentration during a dosing interval 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CVD 
cardiovascular disease 
day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
DILI 
drug-induced liver injury 
DIO 
diet-induced obese 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
EC50 
half-maximal effective concentration 
ECG 
electrocardiogram 
EDC 
electronic data capture 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study (EOS) 
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, additional antibody testing), as 
applicable 
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  

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 100 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Enrollment 
defined as when the investigator decides that the subject has 
met all eligibility criteria and assigns a randomization number 
FIH 
first in human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GIP 
glucose dependent insulinotropic polypeptide 
GIPR 
glucose dependent insulinotropic polypeptide receptor 
GLP-1 
glucagon-like peptide 1 
GLP-1R 
glucagon-like peptide 1 receptor 
GSO 
global safety officer 
HbA1c 
hemoglobin A1c 
HRT 
hormone replacement therapy 
IC50 
half-maximal inhibitory concentration 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
IV 
intravenous 
Kd 
dissociation constant 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MRSD 
maximum recommended starting dose 
NCT 
National Clinical Trials 
NOAEL 
no observed adverse effect level 
PHQ-9 
Patient Health Questionnaire-9 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
QTc 
corrected QT interval 
QW 
every week 
Q4W 
every 4 weeks 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 101 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Randomization 
defined as once a unique subject randomization number has 
been assigned through IRT at enrollment 
SAD 
single ascending dose 
SC 
subcutaneous 
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 
study necessary for the reconstruction and evaluation of the 
study.  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. 
TBL 
total bilirubin 
tmax 
time of maximum observed concentration 
ULN 
upper limit of normal 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 102 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12 will be performed by the central laboratory and/or by the 
local laboratory. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 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.  Analyte Listing 
Local 
Laboratory:  
Chemistry 
Local Laboratory:   
Local 
Laboratory:  
Coagulation 
Local 
Laboratory:  
Urinalysis 
Local 
Laboratory:  
Hematologyc 
Central Laboratory: 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted 
calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
CRP 
(cohort 10), or 
CRP-HS 
(cohorts 7 to 9 
and 12 to 13) 
Calcitonin 
(screening only) 
Amylase 
Lipase Creatine 
kinase 
Tryptase (in the 
event of a 
suspected 
anaphylactic 
reaction) 
TSH (screening 
only) 
Drug Screen 
Benzodiazepines 
Barbiturates 
Opiates 
Tetrahydrocanna
binol 
Cocaine 
Amphetamines 
Ethanol (may be 
performed by a 
breath test) 
Cotinine 
Viral Panel 
Hep B surface 
antigen 
Hep B Core 
Antibody 
Hep C antibody 
HCV RNA PCR 
(as necessary) 
HIVa 
 
Reproductive 
Serum or Urine 
Pregnancy 
FSH 
 
APTT 
PT/INR  
 
 
Specific 
gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial 
cells 
Bacteria 
Casts 
Crystals 
RBC 
Nucleated RBC 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC total 
WBC Differential 
• Bands/stabs 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
• Segmented 
neutrophils 
• Total neutrophil 
count 
 
Antibodies 
Plasma PK 
• AMG 133 
Safety 
assessments 
 
a HIV assessment is recommended. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 103 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
c. Total neutrophils should be reported unless there are bands/stabs listed; then bands/stabs and 
segmented neutrophils should be reported. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; CRP = C-reactive protein; 
CRP-HS  C-reactive protein-high sensitivity; 
; 
CK  creatine kinase; FSH = follicle stimulating hormone;
 HCV = hepatitis C 
virus; 
; Hep = hepatitis; HIV = human immunodeficiency virus; 
 
INR = international normalized ratio; 
LDH = lactate dehydrogenase; 
; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PCR 
= polymerase chain reaction; PD = pharmacodynamics; PK = pharmacokinetics; PT = prothrombin time; 
; RBC = red blood cell count; RDW = Red cell 
distribution width; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic 
transaminase; TSH = thyroid stimulating hormone; WBC = white blood cell count 
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.   

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 104 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings (DLRM) 
A DLRM is conducted to review and interpret safety data for the purposes of making 
recommendations about dose-level escalation (either to the next planned dose or to an 
intermediate dose), dose level de-escalation, cohort continuation, or cohort expansion; 
making recommendations about non-dose escalation cohorts (eg, expanded, highest 
dose and/or final cohort); and evaluating safety signals for purposes of applying Dose 
Cohort Stopping Rules.  The required Dose Level Review Team (DLRT) members are 
the medical monitor, Global Safety Officer (GSO), and Site Investigators.  The DLRT will 
include actively screening and enrolling Site Investigators.  The medical monitor, GSO, 
and Site Investigators are the only voting DLRT members.  The following nonvoting 
Amgen representatives may also be part of the DLRT:  clinical study manager, 
biostatistician, or pharmacokinetics scientist. 
The medical monitor must be in attendance and cannot be represented by a voting 
designee or delegate.  Voting designees can be identified as appropriate by the GSO or 
site investigator(s).  A site investigator may identify a delegate (eg, sub-investigator) who 
is listed in the Delegation of Authority.  If a site investigator does this, the site 
investigator must provide written agreement with the designee or delegate’s vote. 
For a DLRM to occur, the medical monitor must attend, and the GSO or delegate must 
attend.  In addition, a quorum of Site Investigators must be present.  A quorum is defined 
as more than 50% of the participating investigators or their qualified designees.  The 
DLRM will be rescheduled if these requirements are not met. 
All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, electrocardiogram (ECG), 
vital signs, and laboratory results will be reviewed.  Data to be reviewed will be 
unqueried. 
Data will be reviewed blinded (ie, treatment assignment will not be revealed) unless 
unblinding is deemed necessary for the review team to make dosing recommendations.  
If deemed necessary, unblinding will be performed to assist dose change 
recommendations, in accordance with Amgen standard procedures. 
Dose Level Review Meeting voting will occur as follows:  there will be a total of 3 votes, 
1 for the medical monitor, 1 for the GSO or delegate, and 1 for all of the Site 
Investigators or delegates combined.  Regardless of how many Site Investigators there 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 105 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
are, all of the Site Investigators combined will have a total of 1 vote decided by a 
majority of the investigators (defined as greater than or equal to 50%). 
Dose Level Review Meeting recommendations to escalate to the next planned cohort, or 
to an intermediate cohort, must be by unanimous vote.  If the voting members of the 
DLRT are not able to reach a unanimous recommendation on whether to escalate to the 
next planned cohort or to an intermediate cohort, then this should be reflected in the 
DLRM Memo.  Other recommendations, such as expanding a cohort or lowering a dose 
will be made by a majority vote. 
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 Council for 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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 106 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 
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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 107 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 
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 7. 
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.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 28 days from the previous informed consent form signature 
date. 
The informed consent form 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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 108 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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). 
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, the investigator will obtain input and 
assistance from Amgen staff as appropriate. 
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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 109 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 
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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 110 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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. 
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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 111 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 response technology (IRT) system (if used, such as subject identification 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 prestudy documentation, and all correspondence to and from the (IRB/IEC) 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Noninvestigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 112 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 
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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 113 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.4 
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. 
 
Note:  Treatment-emergent adverse events will be defined in the statistical analysis plan. 
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), 
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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 114 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 115 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 
Did the event start prior to first dose of investigational product, other protocol-required 
therapies;  
o 
Assessment of seriousness;  
o 
Severity (or toxicity defined below); 
o 
Assessment of relatedness to investigational product, study-mandated procedures, and 
protocol-provided therapies; and/or study-mandated activity and/or procedures;  
o 
Action taken; and  
o 
Outcome of event. 
 
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. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical records 
to sponsor/responsible contact research organization in lieu of completion of the Event 
CRF page. 
 
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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 116 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational product, 
study-mandated procedure, and/or protocol-mandated therapies 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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 117 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic data 
capture (EDC) system via the Safety Report Form. 
 
If the EDC system is unavailable for more than 24 hours, then the site will report the 
information to Amgen using an electronic Serious Adverse Contingency Report Form (see 
Figure 11-1) within 24 hours of the investigator’s knowledge of the event. 
 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to prevent 
the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been taken 
off-line, then the site can report this information on a paper Serious Adverse Event Report 
Form. 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen if the investigator becomes aware 
of a serious adverse event.  The investigator should use the paper-based Serious 
Adverse Event Report Form to report the event. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 118 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 119 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 120 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 121 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for male and female of childbearing potential 
are outlined in Section 5.2. 
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 postmenopausal 
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: 
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
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 
 
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 
women not using hormonal contraception or hormonal replacement 
therapy (HRT).  However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
 
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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 122 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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, intrauterine device, intrauterine hormonal-releasing 
system, 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, postovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
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 the last 
dose of investigational product. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form 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 Form 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 the last dose of 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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 123 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
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 poststudy 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 11.4.  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 discontinue study 
treatment (see Section 7.1 for details). 
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 Form.  The form (see Figure 11-2) 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 Form 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 the last dose of 
investigational product. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 124 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Information will be recorded on the Lactation Notification Form (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 226. 
 
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 discontinuing 
protocol-required therapies. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 125 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Figure 11-2.  Pregnancy and Lactation Notification Forms 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 126 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 127 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood biomarkers and pharmacokinetics sample collected according to the Schedule 
of Activities (Section 1.3) 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 the 
obesity and other metabolic conditions, the dose response and/or prediction of response 
to AMG 133, 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, 
 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 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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 128 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
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.  
See Section 11.3 for subject confidentiality. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 129 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
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 (BIL) glucuronidation (eg, 
indinavir, atazanavir) 
 
Alpha-1 antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, 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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 130 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 13.  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 
-- 
> 1.5x (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 
Permanent withholding criteria are met when AST/ALT > 3x ULN in the presence of no 
important alternative causes for elevated AST/ALT and/or TBL values AND 1 of the 
following 2 are met:  TBL > 2X ULN OR > 1.5x (for subjects not on anticoagulation 
therapy. 
Criteria for Rechallenge of Amgen Investigational Product and Other Protocol-required 
Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then AMG 133 is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 13) are never to be rechallenged. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 131 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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: 
 
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 11.4. 
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 13 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, 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 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 132 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
A more detailed history of: 
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents 
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including nonprescription medicines and herbal 
and dietary supplements), plants, and mushrooms 
 
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. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 133 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.8 
Appendix 8.  Mental Health Criteria Stopping Rules: Suggested 
Actions and Follow-up Assessments 
Subjects with an increase in score on either the Patient Health Questionnaire 9 (PHQ-9) 
and/or C-SSRS 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 C-SSRS scores have been identified. 
Table 14.  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 
C-SSRS 
Answers yes to any items #1-5 
PHQ-9 = Patient Health Questionnaire 9 ; C-SSRS = 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 14 
are to undergo a period of “close observation” until the subject’s care can be transferred 
to an appropriate mental health professional.   

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 134 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.9 
Appendix 9.  Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline Form (example shown below) is to be administered at screening visit and Since 
Last Visit Form at all subsequent visits by trained staff.   
Figure 11-3.  Sample C-SSRS Form 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 135 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 136 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 137 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.10 
Appendix 10.  Patient Health Questionnaire 9 (PHQ-9) 
Figure 11-4.  Sample PHQ-9 Form 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 138 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Phase 1, Randomized, Double-blind, Placebo-controlled, Single 
Ascending Dose and Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 133 in Subjects 
With Obesity 
 
 
Amgen Protocol Number 20180048 
 
Amendment Date: 
03 February 2022 
 
Rationale: 
This protocol is being amended to:   
 
Update justification for investigational product dose, including estimated exposure. 
 
Add language to add flexibility to cohort 10 enrollment and change “20 subjects” to 
“up to 20 subjects.” 
 
Include 
 for cohort 10 
 
Add Part C (Cohorts 12 and 13) an open-label modified dose-escalation multiple 
ascending dose (MAD) cohorts in subjects with obesity. 
 
Update AMG 133 clinical experience. 
 
Add flexible language to allow for 
. 
 
Update inclusion and exclusion criteria to specify inclusion of cohorts 12 and 13, 
where applicable. 
 
Revise exclusion criterion #204 to include, “If ALT is  1.5 x the ULN at screening 
AND the AST, alkaline phosphatase, and total bilirubin levels are within normal limits, 
then subject may be eligible for enrollment after a discussion with the medical 
monitor.” 
 
Revise exclusion criterion #205 to include, “If a single value (PT, PTT, INR, or 
platelet count) is outside the normal reference range at screening and the subject 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  03 February 2022 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
does not have evidence of any other bleeding or coagulation disorder, then the 
subject may be eligible for enrollment after a discussion with the medical monitor.” 
 
Update investigational medical device language to allow use of an iPhone with 
cohorts 7 to 9. 
 
Update adverse event and serious adverse event reporting and product complaint 
language throughout protocol to align with current Amgen protocol template. 
 
Update language around interim analyses. 
 
Provide clarifying language surrounding laboratory tests in Table 12 Analyte Listing. 
 
Update “
.” 
 
Provide clarifying language throughout for better site adherence and understanding. 
 
Make typographical, formatting, and editorial changes throughout the protocol. 
 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  14 May 2021 
Page 1 of 37 
Amgen Proprietary - Confidential 
FORM-492529, Effective Date:  02 Mar 2020, Version: 6.0 
Amendment 3 
Protocol Title:  A Phase 1, Randomized, Double-blind, Placebo-controlled, Single 
Ascending Dose and Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 133 in Subjects 
With Obesity 
 
Amgen Protocol Number (AMG 133) 20180048 
 
Amendment Date: 
14 May 2021 
 
Rationale: 
The following changes were made to the protocol, dated 14 May 2021 to add cohort 11 
to further investigate the highest tolerable dose of AMG 133, to modify cohort 10 for 
added flexibility with dose selection, to add an interim analysis to assist with dose 
selection in phase 2 studies, and to clarify/correct other items in the protocol. 
Cohort 11 changes include: 
 
Updated overall design (Section 1.1 and Section 4.1) and throughout the protocol 
to include cohort 11. 
 
Updated number of subjects (Section 4.2) to include cohort 11. 
 
Updated study Schema (Section 1.2) to include cohort 11. 
 
Updated justification for investigational product dose (Section 4.3) to include data 
currently available.  
 
Updated study treatments (Section 6.1.1), Table 8 to include cohort 11. 
 
Updated pharmacodynamic assessments (Section 8.2.6) to include cohort 11 
and clarify parameters for the cohorts. 
Cohort 10 changes include: 
 
Updated overall design (Section 1.1 and Section 4.1) to modify cohort 10 dose 
selection for flexibility. 
 
Updated justification for investigational product dose (Section 4.3) to include data 
currently available.  

Product:  AMG 133 
Protocol Number:  20180048 
Date:  14 May 2021 
Page 2 of 37 
Amgen Proprietary - Confidential 
FORM-492529, Effective Date:  02 Mar 2020, Version: 6.0 
Interim analysis changes include: 
 
Updated Section 9.4.1.1 to include an interim analysis following the dose level 
review meeting for cohort 9. 
 
Updated Section 9.4.1.2 to indicate that the primary analysis will occur at the final 
analysis and not be a separate analysis. 
Other changes include:  
 
Updated the clinical experience (Section 2.2.2.4) to include the data currently 
available. 
 
Modified inclusion criterion 103 to clarify ECG testing for cohorts prior to 
enrollment. 
 
Updated safety language with current template language. 
 
Administrative, typographical and formatting changes were made throughout the 
protocol. 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  08 February 2021 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 1, Randomized, Double-blind, Placebo-controlled, Single 
Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 133 in Subjects With Obesity 
 
Amgen Protocol Number 20180048 
 
Amendment Date: 
08 February 2021 
 
Rationale: 
This amendment is being made to add MAD study cohorts 7 to 10 to this ongoing study.  This 
involves the following: 
 
Addition of cohorts 7-10 
 
The addition of the following
 
cohort 10 only 
 
Updated objectives and endpoints 
 
Administrative and editorial edits 
 

Product:  AMG 133 
Protocol Number:  20180048 
Date:  19 November 2020 
Page 1 of 25 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 1 
Protocol Title:  A Phase 1, Randomized, Double-blind, Placebo-controlled, Single 
Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 133 in Subjects With Obesity 
 
Amgen Protocol Number 20180048 
 
Amendment Date: 
19 November 2020 
 
Rationale: 
This amendment is being made as a result of a response to the Food and Drug Administration 
(FDA) review of the investigational new drug application (IND) in addition to some omissions of 
lab collection that have been subsequently discovered and corrected. As such, the following 
changes have been made: 
 
Add creatine kinase as part of the serial clinical chemistry testing in screening and all other 
time points where clinical chemistry will be performed 
 
Extend end of study follow-up visits from 120 days to 150 days 
 
Update study duration 
 
Add that permanent withholding criteria are met when aspartate transaminase (AST)/alanine 
transaminase (ALT)  3x upper limit of normal (ULN) in the presence of no important 
alternative causes for elevated AST/ALT and/or TBL values and 1 of the following 2 are met:  
Total bilirubin (TBL)  2X ULN OR  1.5x (for subjects not on anticoagulation therapy) 
 
Add amylase and lipase to day 15 
 
Add thyroid stimulating hormone (TSH) to screening