Clinical trial NCT04199351
Conditions: Obesity
Keywords: Obesity
Sponsor: Amgen
Start date: 2019-12-13; Completion date: 2021-09-10
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To assess the safety and tolerability of AMG 171 as single or multiple doses in subjects with obesity

Detailed description:

Arms: arm 1: AMG 171 or placebo, 2 SAD cohorts arm 2: AMG 171 or placebo, 1 MAD cohort arm 3: AMG 171 or placebo, 3 titration cohorts
Interventions: intervention 1: AMG 171 intervention 2: Placebo
Intervention descriptions: intervention 1: 2 SAD cohorts of 8 subjects per cohort randomized 3:1 in Part A; 1 cohort of 8 subjects 3:1 ratio in Part B; and 24 subjects enrolled into 1 of 3 cohorts with 8 subjects randomized to receive 2 to 3 consecutive doses (titration) 3:1 ratio in Part C. intervention 2: AMG 171 placebo

Protocol documents:
Prot_000.pdf: 
Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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 and Multiple 
Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 171 in Subjects 
With Obesity 
Short Protocol Title: 
Single and Multiple Ascending Dose Study of 
AMG 171 in Subjects With Obesity 
Protocol Number: 
20180224 
Investigational Product: 
AMG 171  
Sponsor 
Name of Sponsor: 
Amgen, Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
+ 1 (805) 447-1000 
Key 
Sponsor 
Contact 
Name: 
, Medical Director 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
Email Address: 
Sponsor 
Contact 
Name: 
Address: 
1120 Veterans Blvd, Bld 3 
South San Francisco, CA  94080 
Telephone Number: 
Email Address: 
NCT Number: 
04199351 
Protocol Version Date: 
Document Version 
Date 
Original  
14 October 2019 
Protocol Amendment 1 
07 February 2020 
Protocol Amendment 2 
28 October 2020 
Protocol Amendment 3 
18 August 2021 
Data Elements Standards 
Version: 
6.2 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures. 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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; Amgen’s general 
number in the US, 1-805-447-1000. 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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 and Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 171 in Subjects With 
Obesity, dated 18 August 2021, 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 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 4 of 138 
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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) ...................................................................... 20 
2. 
Introduction ........................................................................................................... 50 
2.1 
Study Rationale ......................................................................................... 50 
2.2 
Background ............................................................................................... 50 
2.2.1 
Disease ..................................................................................... 50 
2.2.2 
Amgen Investigational Product Background:  
AMG 171 ................................................................................... 51 
2.2.2.1 
Pharmacology ......................................................... 51 
2.2.2.2 
Pharmacokinetics .................................................... 53 
2.2.2.3 
Toxicology ............................................................... 54 
2.3 
Benefit/Risk Assessment ........................................................................... 55 
2.3.1 
Key Benefits .............................................................................. 55 
2.3.2 
Key Risks .................................................................................. 55 
3. 
Objectives and Endpoints ..................................................................................... 57 
4. 
Study Design ........................................................................................................ 60 
4.1 
Overall Design .......................................................................................... 60 
4.2 
Number of Subjects ................................................................................... 62 
4.2.1 
Replacement of Subjects ........................................................... 63 
4.2.2 
Number of Sites ......................................................................... 63 
4.3 
Justification for Investigational Product Dose ............................................ 63 
4.4 
End of Study ............................................................................................. 65 
4.4.1 
End of Study Definition .............................................................. 65 
4.4.2 
Study Duration for Subjects ....................................................... 66 
4.5 
Patient Input on Study Design ................................................................... 66 
5. 
Study Population .................................................................................................. 66 
5.1 
Inclusion Criteria ....................................................................................... 66 
5.2 
Exclusion Criteria ...................................................................................... 67 
5.3 
Lifestyle Considerations ............................................................................ 70 
5.3.1 
Meals and Dietary Restrictions .................................................. 70 
5.3.2 
Caffeine, Alcohol, and Tobacco ................................................. 70 
5.3.3 
Activity ....................................................................................... 70 
5.4 
Subject Enrollment .................................................................................... 70 
5.5 
Screen Failures ......................................................................................... 71 
5.6 
Washout Period/Run-in Period/Invasive Procedure(s) ............................... 71 
6. 
Treatments ........................................................................................................... 71 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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6.1 
Treatment(s) Administered ........................................................................ 72 
6.1.1 
Investigational Products ............................................................ 72 
6.1.2 
Medical Devices ........................................................................ 72 
6.1.3 
Other Protocol-required Therapies ............................................ 72 
6.1.4 
Other Treatment Procedures ..................................................... 73 
6.1.5 
Product Complaints ................................................................... 73 
6.1.6 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 73 
6.2 
Dose Modification  ..................................................................................... 74 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 74 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 76 
6.2.2.1 
Amgen Investigational Product:  AMG 171 .............. 76 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 76 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 76 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 76 
6.4.1 
Method of Treatment Assignment .............................................. 76 
6.4.2 
Blinding ..................................................................................... 77 
6.4.2.1 
Site Personnel Access to Individual 
Treatment Assignments .......................................... 77 
6.4.2.2 
Access to Individual Subject Treatment 
Assignments by Amgen or Designees ..................... 77 
6.5 
Treatment Compliance .............................................................................. 77 
6.6 
Treatment of Overdose ............................................................................. 77 
6.7 
Prior and Concomitant Treatment ............................................................. 78 
6.7.1 
Prior Treatment ......................................................................... 78 
6.7.2 
Concomitant Treatment ............................................................. 78 
7. 
Discontinuation Criteria ......................................................................................... 78 
7.1 
Discontinuation of Study Treatment........................................................... 78 
7.2 
Discontinuation From the Study ................................................................ 79 
7.2.1 
Reasons for Removal From Study ............................................. 80 
7.3 
Lost to Follow-up ....................................................................................... 80 
8. 
Study Assessments and Procedures .................................................................... 80 
8.1 
General Study Periods .............................................................................. 81 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 81 
8.1.2 
Treatment Period and Follow-up ................................................ 81 
8.1.3 
End of Study .............................................................................. 82 
8.2 
Description of General Study Assessments and Procedures ..................... 82 
8.2.1 
General Assessments ............................................................... 82 
8.2.1.1 
Informed Consent .................................................... 83 
8.2.1.2 
Demographics ......................................................... 83 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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8.2.1.3 
Medical History ........................................................ 83 
8.2.1.4 
Physical Examination .............................................. 83 
8.2.1.5 
Physical Measurements .......................................... 83 
8.2.1.6 
Substance Abuse History ........................................ 84 
8.2.2 
Safety Assessments .................................................................. 84 
8.2.2.1 
Vital Signs ............................................................... 84 
8.2.2.2 
Electrocardiograms (ECGs) ..................................... 84 
8.2.2.3 
Vital Status .............................................................. 85 
8.2.2.4 
Suicidal Risk Monitoring .......................................... 85 
8.2.3 
Adverse Events and Serious Adverse Events ............................ 86 
8.2.3.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 86 
8.2.3.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 87 
8.2.3.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 87 
8.2.3.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 88 
8.2.3.5 
Safety Monitoring Plan ............................................ 89 
8.2.3.6 
Pregnancy and Lactation ......................................... 89 
8.2.3.7 
Adverse Device Effects ........................................... 89 
8.2.4 
Clinical Laboratory Assessments ............................................... 89 
8.2.5 
Pharmacokinetic Assessments .................................................. 90 
8.2.6 
Pharmacodynamic Assessments ............................................... 90 
8.2.7 
Pharmacogenetic Assessments................................................. 90 
8.2.8 
Antibody Testing Procedures ..................................................... 91 
8.2.9 
Biomarker Discovery ................................................................. 92 
8.2.9.1 
Biomarker Development/Future Research ............... 92 
8.2.10 
Health Economics ..................................................................... 92 
8.2.11 
Other Assessments ................................................................... 92 
9. 
Statistical Considerations ...................................................................................... 93 
9.1 
Statistical Hypotheses ............................................................................... 93 
9.2 
Sample Size Determination ....................................................................... 93 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 93 
9.3.1 
Analysis Sets ............................................................................. 93 
9.3.1.1 
Safety Analysis Set ................................................. 93 
9.3.1.2 
Pharmacokinetic (PK) Analysis Set ......................... 93 
9.3.1.3 
Pharmacodynamic (PD) Analysis Set ...................... 93 
9.3.2 
Covariates ................................................................................. 93 
9.3.3 
Subgroups ................................................................................. 94 
9.3.4 
Handling of Missing and Incomplete Data .................................. 94 
9.4 
Statistical Analyses ................................................................................... 94 
9.4.1 
Planned Analyses ...................................................................... 94 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 7 of 138 
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9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 94 
9.4.1.2 
Primary Analysis ..................................................... 94 
9.4.1.3 
Final Analysis .......................................................... 94 
9.4.2 
Methods of Analyses ................................................................. 94 
9.4.2.1 
General Considerations ........................................... 94 
9.4.2.2 
Efficacy Analyses .................................................... 95 
9.4.2.3 
Safety Analyses ...................................................... 95 
9.4.2.4 
Other Analyses ........................................................ 96 
10. 
References ........................................................................................................... 98 
11. 
Appendices ......................................................................................................... 100 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 101 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 104 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 106 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 115 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 123 
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 
11.7.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies Due to Potential 
Hepatotoxicity.......................................................................... 130 
11.7.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ........................................................... 131 
11.7.3 
Drug-induced Liver Injury Reporting and Additional 
Assessments Reporting .......................................................... 132 
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 
 
List of Tables 
Table 1-1.  Planned Dose Levels by Cohort in Parts A, B, and C................................... 14 
Table 1-2.  Schedule of Activities Cohorts 1 and 1b (SAD) ............................................ 21 
Table 1-3.  Schedule of Activities Cohort 2 .................................................................... 24 
Table 1-4.  Schedule of Activities for Q2W Dose Titration – Cohort 3 ............................ 26 
Table 1-5.  Schedule of Activities for Q2W Dose Titration – Cohort 4 ............................ 28 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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Table 1-6.  Schedule of Activities for Q1W Dose Titration – Cohort 5 ............................ 30 
Table 1-7.  Schedule of Activities for Q2W Dose Titration – Cohort 6a .......................... 32 
Table 1-8.  Schedule of Activities for Q2W Dose Titration – Cohort 6b .......................... 35 
Table 1-9.  Schedule of Activities for Q2W Dose Titration – Cohort 6c .......................... 38 
Table 1-10.  Schedule of Activities for Q1W Dose Titration – Cohort 7a ........................ 41 
Table 1-11.  Schedule of Activities for Q1W Dose Titration – Cohort 7b ........................ 44 
Table 1-12.  Schedule of Activities for Q1W Dose Titration – Cohort 7c ........................ 47 
Table 4-1.  Predicted Human Exposures and Associated Exposure Multiples 
Following the Last Proposed AMG 171 Doses – Cohorts 6a, 
6b, and 6c ............................................................................................... 65 
Table 4-2.  Predicted Human Exposures and Associated Exposure Multiples 
Following the Last Proposed AMG 171 Doses – Cohorts 7a, 
7b, and 7c ............................................................................................... 65 
Table 6-1.  Study Treatments ........................................................................................ 72 
Table 6-2.  Dose Cohort Stopping Rules ....................................................................... 75 
Table 11-1.  Analyte Listing ......................................................................................... 105 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 131 
Table 11-3.  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.  Study Schema ............................................................................................ 19 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form ................ 120 
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 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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 and Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 171 in Subjects With 
Obesity 
Short Protocol Title:  Single and Multiple Ascending Dose Study of AMG 171 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 significant side 
effects.  AMG 171 is a long acting Fc fusion protein of Growth Differentiation Factor 
15 (GDF15).  In preclinical studies AMG 171 administration in obese cynomolgus 
monkeys resulted in an approximate 12% reduction in weight as compared to 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 and multiple ascending doses of AMG 171 as a potential therapy for the 
treatment of obesity. 
Objective(s)/Endpoint(s) 
 
 
Objectives 
Endpoints 
Primary 
 To assess the safety and tolerability 
of AMG 171 as single or 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 PK of AMG 
171 as single or multiple doses in 
subjects with obesity 
 
AMG 171 PK parameters including, but 
not limited to, maximum observed 
concentration (Cmax), the time of 
maximum observed concentration 
(Tmax), and area under the 
concentration time curve (AUC) 
 To evaluate the immunogenicity of 
AMG 171 
 
Incidence of anti-AMG 171 antibody 
formation 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 10 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Objectives 
Endpoints 
Exploratory 
 To characterize the PD effects of 
AMG 171 as single or multiple doses 
in subjects with obesity 
o To assess the effect of 
AMG 171 on fasting and 
post-prandial (Part A) 
metabolic parameters 
 
o To assess the effect of 
AMG 171 on gastric 
emptying in the single 
ascending dose cohorts 
(Part A) 
 
o To assess the effect of 
AMG 171 on fasting lipid 
levels 
 
 
 
 
o To assess the effect of 
AMG 171 on hemoglobin A1c 
(HbA1c) in the multiple dose 
cohorts (Part B) 
 
o To assess the effect of 
AMG 171 on potential 
biomarkers 
 
 
o To assess the effect of 
AMG 171 on endogenous 
GDF15 levels 
 
o To assess the effects of 
AMG 171 on body weight, 
waist circumference and 
body mass index (BMI) 
 
o To assess the effect of 
AMG 171 on body 
composition in the multiple 
dose cohorts (Part B) 
 
Changes in PD parameters: 
 
 
o Changes in the fasting and 
post-mixed meal challenge 
glucose, insulin, c-peptide, 
glucagon, and free fatty acid 
(FFA) concentrations 
o Gastric emptying as assessed 
by acetaminophen absorption 
kinetics (Cmax and AUC)  
 
 
 
o Changes in fasting lipid levels, 
including, but not limited to, total 
cholesterol, low density 
lipoprotein cholesterol (LDL-C), 
high density lipoprotein 
cholesterol (HDL-C), and 
triglycerides 
 
o Changes in HbA1c levels  
 
 
 
o Changes in potential biomarkers 
including, but not limited to, 
inflammatory and adipose tissue 
markers 
 
o Changes in endogenous GDF15 
levels 
 
 
o Changes in body weight, waist 
circumference, and BMI 
 
 
o Changes in body composition as 
measured by whole body 
dual-energy x-ray 
absorptiometry (DXA)  
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 11 of 138 
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FORM-001520, v.24, 21 May 2019 
 
Overall Design 
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple 
ascending dose study in adult subjects with obesity.  The study will be conducted at 
approximately 3 - 4 sites in the United States.  Additional sites may be added.  
AMG 171 will be administered subcutaneously (SC).  Part A is comprised of 2 single 
ascending dose (SAD) cohorts; Part B is a multiple dose cohort.  Part C will be a titration 
phase with step dosing ranging from 2 to 3 ascending doses.  Part D will be a multiple 
ascending dose titration phase with step dosing ranging from 6 to 8 ascending 
doses.  The study consists of a total of 12 cohorts:  2 cohorts (Part A), 1 cohort (Part B), 
3 cohorts (Part C), and 6 cohorts (Part D).  
Potential subjects will be screened within 28 days before day 1 to assess their eligibility 
to enter the study.  Subjects will be confined at the Clinical Research Unit (CRU) from 
Check-in (morning of day 1) through the morning of day 6 in Part A (SAD phase), from 
1 day prior to each dose through the morning of day 6 for the first 2 doses in Part B, for 
each dose (2 to 3 doses) in Part C (titration phase), and for the first 3 days (2 nights) 
in Part D (multiple ascending dose titration phase).   
Part A (SAD) 
Seventeen subjects were enrolled into 2 cohorts (1 subject was replaced).  No additional 
cohorts are planned for Part A.  In each cohort, 8 subjects were randomized to receive 
AMG 171 or placebo SC (cohorts 1, 1b) in a 3:1 ratio as described in Table 1-1.  For 
each cohort, the first 2 subjects (sentinel pair) were randomized such that 1 subject 
received AMG 171 and 1 subject received placebo.  The sentinel pair was observed for 
at least 24 hours before the remaining subjects in the cohort were dosed after 
confirmation that there were no safety or tolerability concerns as assessed by the 
Principal Investigator.  Enrollment into the SAD cohorts was sequential.  Cohort 1b was 
dosed after the dose regimen in cohort 1 was deemed by the Dose Level Review Team 
(DLRT) to have no safety signals observed and be reasonably tolerated based on the 
safety and laboratory data through at least study day 15 for at least 7 out of 8 subjects 
dosed.  The 2 SAD cohorts have completed dosing.  Cohort 1 has reached study 
completion and cohort 1b has completed 3 months of follow-up.  In Part A cohorts 1 and 
1b tolerability was noted to worsen with the dose increase from
mg (cohort 1) to 
 mg (cohort 1b) with adverse events of nausea and vomiting (mild to moderate 
severity). 
Part B (Multiple Ascending Dose [MAD]) 
Approximately 8 subjects will enroll into 1 cohort (cohort 2) where 8 subjects will be 
randomized to receive a total of 6 doses of
mg AMG 171 or placebo SC in a 3:1 ratio 
as described in Table 1-1.  No additional cohorts are planned for Part B.  
 
Cohort 2:  Study drug will be administered SC every 2 weeks (Q2W) for a total of 
six
 mg doses.  
Part C (Titration) 
Approximately 24 subjects will enroll into 1 of 3 cohorts (cohorts 3 to 5).  In each cohort, 
8 subjects will be randomized to receive 2 to 3 consecutive doses of
 mg 
AMG 171 or placebo SC in a 3:1 ratio as described in Table 1-1.  Enrollment into 
cohort 3 will occur after DLRT recommendation based on safety and laboratory data 
through at least study day 22 of cohort 2 (Part B).  Subsequently, cohorts 4 and 5 will be 
dosed in parallel after the dose regimen in cohort 3 has been recommended by the 
DLRT to have no safety signals observed and be reasonably tolerated based on 
safety and laboratory data through at least study day 22 for at least 6 out of 8 subjects 
dosed and cumulative data of all prior cohorts.  Enrollment of dose cohorts is 
depicted in Figure 1-1.  No additional cohorts are planned for Part C. 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 12 of 138 
CONFIDENTIAL  
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 
Cohort 3:  Two doses of study drug will be administered SC Q2W apart with the 
first dose of
mg and second dose of
mg.  
 
Cohort 4: Three doses of study drug will be administered SC Q2W apart with the 
first dose of
mg, second dose of 
mg, and third dose of
mg.  
 
Cohort 5: Two doses of study drug will be administered SC Q1W apart with the 
first dose of 
 mg and second dose of
mg.  
Part D (MAD Titration) 
Approximately 48 subjects will enroll into 1 of 6 cohorts (cohorts 6a-c and 7a-c). In 
each cohort, 8 subjects will be randomized to receive 6 to 8 consecutive doses of 
AMG 171 or placebo SC in a 3:1 ratio as described in Section 1.3.  The cohorts in 
group 6 will begin with
 mg with dose escalation every 2 weeks while those in 
group 7 will begin with
mg with dose escalation weekly until the fourth dose 
(
 mg) and then every other week thereafter.  Enrollment into cohorts 6a and 
7a will begin contemporaneously after a Dose Level Review Meeting (DLRM) of 
cohorts 4 and 5, which include review of cumulative data of all prior cohorts.  
Enrollment in cohorts 6b and 7b will occur after DLRT recommendation based on 
all safety and laboratory data through at least study day 43 of cohort 6a (Part D) 
and cumulative data of all prior cohorts.  Subsequently, cohorts 6c and 7c will be 
dosed in parallel after the dose regimen in cohort 6b has been recommended by 
the DLRT to have no safety signals observed and be reasonably tolerated based 
on all safety and laboratory data through at least study day 57 for at least 6 out of 
8 subjects dosed and cumulative data of all prior cohorts.  Enrollment of dose 
cohorts is depicted in Figure 1-1.  
 
Cohort 6a:  Study drug will be administered SC Q2W for a total of 7 doses 
   
 
Cohort 6b:  Study drug will be administered SC Q2W for a total of 7 doses 
.  
 
Cohort 6c:  Study drug will be administered SC Q2W for a total of 7 doses 
.   
 
Cohort 7a:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional doses 
).   
 
Cohort 7b:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional doses 
.   
 
Cohort 7c:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional doses 
.   
Dose Level Review Meetings (DLRM) 
A DLRM will be held to review subject data and monitor safety before escalation to the 
next cohort.  Escalation to a higher dose titration cohort will only proceed when the 
previous dose regimen and cumulative data from previous cohorts have been reviewed 
and found to have no safety signals observed and be reasonably tolerated based on 
available safety and laboratory data upon unanimous recommendation at the DLRM. 
Safety and laboratory data will be reviewed after 7 of 8 subjects have reached day 15 
or 8 of 8 subjects have reached day 22 for each respective cohort in Part A, B and 
C.  Safety and laboratory data will be reviewed through at least study day 43 of 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 13 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
cohort 6a (Part D).  Subsequently, cohorts 6c and 7c will be dosed in parallel after 
the dose regimen in cohort 6b has been recommended by the DLRT to have no 
safety signals observed and be reasonably tolerated based on all safety and 
laboratory data through at least study day 57 for at least 6 out of 8 subjects dosed 
and cumulative data of all prior cohorts.  
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.     
Number of Subjects 
Approximately 96 subjects (8 subjects per cohort, cohorts 1, 1b, 2 to 5, 6a-c, and 7a-c) 
will be enrolled.  Additional subjects may be enrolled if a DLRT recommendation is made 
to expand, repeat or add cohorts to the study. 
Summary of Subject Eligibility Criteria 
Subjects in the study will be males and females aged 18 to 65 years (inclusive) at the 
time of randomization with a BMI of ≥ 30.0 kg/m2 and ≤ 40.0 kg/m2.  Females enrolled 
must be of non-reproductive potential. 
For a full list of eligibility criteria, please refer to Section 5.1 to 5.2. 
Treatments 
Cohorts 1-1b (Part A):  After completion of all pre-dose procedures on the day of 
dosing, subjects in cohorts 1 and 1b received AMG 171 (
mg, respectively) or 
placebo SC on day 1.  No additional cohorts are planned for Part A. 
Cohort 2 (Part B):  After completion of all pre-dose procedures on the day of dosing, 
subjects in cohort 2 will receive AMG 171 
mg) or placebo SC Q2W x 6 on days 1, 
15, 29, 43, 57, and 71.  
Cohort 3 (Part C):  After completion of all pre-dose procedures on the day of dosing, 
subjects in cohort 3 will receive AMG 171 (
mg) or placebo SC on day 1, and 
AMG 171 
mg) or placebo SC on day 15. 
Cohort 4 (Part C):  After completion of all pre-dose procedures on the day of dosing, 
subjects in cohort 4 will receive AMG 171 
 mg) or placebo SC on day 1, and AMG 
171 
mg) or placebo SC on day 15, and AMG 171 
mg) or placebo SC on day 29. 
Cohort 5 (Part C):  After completion of all pre-dose procedures on the day of dosing, 
subjects in cohort 3 will receive AMG 171 
 mg) or placebo SC on day 1, and AMG 
171 
mg) or placebo SC on day 8. 
The 2 cohorts in Part C (cohorts 4 and 5) will enroll in parallel. 
Cohort 6a (Part D):  After completion of all pre-dose procedures on the day of 
dosing, subjects in cohort 6a will receive AMG 171 (
mg) or placebo SC on 
day 1; AMG 171 (
mg) or placebo SC on day 15; AMG 171 
mg) or placebo SC 
on day 29; and AMG 171 (
mg) or placebo SC on days 43, 57, 71, and 85. 
Cohort 6b (Part D):  After completion of all pre-dose procedures on the day of 
dosing, subjects in cohort 6b will receive AMG 171 
mg) or placebo SC on 
day 1; AMG 171 (
mg) or placebo SC on day 15; AMG 171 
mg) or placebo SC 
on day 29; AMG 171 (
mg) or placebo SC on day 43; and AMG 171 
mg) or 
placebo on days 57, 71, and 85. 
Cohort 6c (Part D):  After completion of all pre-dose procedures on the day of 
dosing, subjects in cohort 6c will receive AMG 171 
mg) or placebo SC on 
day 1; and AMG 171 
mg) or placebo SC on day 15; AMG 171 
mg) or 
placebo SC on day 29; AMG 171 
 mg) or placebo SC on day 43; AMG 171 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 14 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
(
mg) or placebo on day 57; and AMG 171 
mg) or placebo on days 71 and 
85. 
Cohort 7a (Part D):  After completion of all pre-dose procedures on the day of 
dosing, subjects in cohort 7a will receive AMG 171 
mg) or placebo SC on day 1; 
AMG 171 (
mg) or placebo SC on day 8; AMG 171 
 mg) or placebo on day 15; 
AMG 171 (
mg) or placebo on day 22; AMG 171 
mg) or placebo on day 36; 
and AMG 171 (
 mg) or placebo on days 50, 64, and 78. 
Cohort 7b (Part D):  After completion of all pre-dose procedures on the day of 
dosing, subjects in cohort 7b will receive AMG 171 
mg) or placebo SC on day 1; 
AMG 171 
mg) or placebo SC on day 8; AMG 171 
mg) or placebo on day 15; 
AMG 171 
mg) or placebo on day 22; AMG 171 
mg) or placebo on day 36; 
AMG 171 
mg) or placebo on day 50; and AMG 171 
mg) or placebo on 
days 64 and 78. 
Cohort 7c (Part D):  After completion of all pre-dose procedures on the day of 
dosing, subjects in cohort 7c will receive AMG 171 
mg) or placebo SC on day 1; 
AMG 171 
mg) or placebo SC on day 8; AMG 171 
mg) or placebo on day 15; 
AMG 171 
g) or placebo on day 22; AMG 171 
mg) or placebo on day 36; 
AMG 171 
 mg) or placebo on day 50; AMG 171 
mg) or placebo on day 64; 
and AMG 171 
mg) or placebo on day 78. 
Table 1-1.  Planned Dose Levels by Cohort in Parts A, B, and C 
 
Cohort 
# 
Subjects 
AMG 171/Placebo 
Dose/Frequency 
Route 
N (active: 
placebo) 
PART A 
1 
8 
mg day 1 x 1 
SC 
6:2 
1ba 
8 
mg day 1 x 1 
SC 
6:2 
PART B 
(MAD) 
2 
8 
 mg Q2W x 6 
SC 
6:2 
PART C 
(titration) 
3 
8 
mg day 1 x 1 
mg day 15 x 1 
SC 
6:2 
4 
8 
mg day 1 x 1 
mg day 15 x 1 
mg day 29 x 1 
SC 
6:2 
5 
8 
mg day 1 x 1 
mg day 8 x 1 
SC 
6:2 
PART D 
(MAD 
titration) 
6a 
8 
mg day 1 x 1 
mg day 15 x 1 
mg day 29 x 1 
mg day 43 x 1 
mg day 57 x 1 
mg day 71 x 1 
mg day 85 x 1 
SC 
6:2 
6b 
8 
mg day 1 x 1 
mg day 15 x 1 
mg day 29 x 1 
mg day 43 x 1 
SC 
6:2 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 15 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Cohort 
# 
Subjects 
AMG 171/Placebo 
Dose/Frequency 
Route 
N (active: 
placebo) 
mg day 57 x 1 
mg day 71 x 1 
mg day 85 x 1 
6c 
8 
mg day 1 x 1 
mg day 15 x 1 
mg day 29 x 1 
mg day 43 x 1 
mg day 57 x 1 
mg day 71 x 1 
mg day 85 x 1 
SC 
6:2 
7a 
8 
mg day 1 x 1 
mg day 8 x 1 
mg day 15 x 1 
mg day 22 x 1 
mg day 36 x 1 
mg day 50 x 1 
mg day 64 x 1 
mg day 78 x 1 
SC 
6:2 
7b 
8 
mg day 1 x 1 
mg day 8 x 1 
mg day 15 x 1 
mg day 22 x 1 
mg day 36 x 1 
mg day 50 x 1 
mg day 64 x 1 
mg day 78 x 1 
SC 
6:2 
7c 
8 
mg day 1 x 1 
mg day 8 x 1 
mg day 15 x 1 
mg day 22 x 1 
mg day 36 x 1 
mg day 50 x 1 
mg day 64 x 1 
mg day 78 x 1 
SC 
6:2 
MAD = multiple ascending dose; Q2W = every 2 weeks; SC = subcutaneous. 
a Cohort 1b added during protocol Amendment 1. 
Procedures 
Screening: 
For all subjects, after informed consent is obtained, all screening procedures and tests 
establishing eligibility will be performed within 28 days before first dose of AMG 171 or 
placebo (day 1).   
Study procedures are summarized in the Schedule of Activities in Section 1.3.   


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 16 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Serious Adverse Events (SAEs) will be collected from the time the Informed Consent 
Form (ICF) is signed. 
In-House Residency  
Subjects in Part A (cohorts 1 and 1b) were admitted after confirmed eligibility on  
day -2 for an 8-day (7-night) residency period.  
Subjects in Part B (cohort 2) will be admitted after confirmed eligibility on day -1 for a 
7-day (6-night) residency period and re-admitted on day 14 for a second 7-day (6-night) 
residency period. 
Subjects in Part C (cohorts 3 to 5) will be admitted after confirmed eligibility on day -1. 
Cohort 3 subjects will be admitted after confirmed eligibility on day -1 for a 7-day 
(6-night) residency period and re-admitted on day 14 for a second 7-day (6-night) 
residency period. 
Cohort 4 subjects will be admitted after confirmed eligibility on day -1 for a 7-day 
(6-night) residency period, re-admitted on day 14 for a second 7-day (6-night) residency 
period, and re-admitted on day 28 for a third 7-day (6-night) residency period. 
Cohort 5 subjects will be admitted after confirmed eligibility on day -1 for a 14-day 
(13-night) residency period. 
Cohort 6 subjects will be admitted after confirmed eligibility on day -1 for a 2-day 
(1-night) residency period, re-admitted on days 14 and 28 for a 3-day (2-night) 
residency period, re-admitted on day 42 for a 7-day (6-night) residency period, and 
re-admitted on days 56, 70, and 84 for a 2-day (1-night) residency period.   
Cohort 7 subjects will be admitted after confirmed eligibility on day -1 for a 3-day 
(2-night) residency period, and re-admitted on days 35, 49, 63, and 77 for a 3-day 
(2-night) residency period. 
Day -2 
Part A: Subjects who met all the screening inclusion criteria and none of the exclusion 
criteria were eligible to report to the research facility on day -2, at which time 
assessments were performed to confirm eligibility.  Subjects that were deemed eligible 
after the completion of all day -2 assessments, were randomized to receive either 
AMG 171 or placebo on day 1.  
Day -1 
Part A:  A Gastric Emptying test was performed on day -1 along with additional 
procedures as outlined in the Schedule of Activities in Section 1.3.  As part of the 
Gastric Emptying test, subjects underwent an overnight fast of a minimum of 10 hours.  
Oral liquid acetaminophen 1000 mg (acetaminophen Extra Strength) was administered 
followed immediately by a standardized liquid meal (ie, 2 bottles or cans of Ensure 
Plus®). Timing of PK samples of acetaminophen after the standardized meal are 
summarized in the Schedule of Activities in Section 1.3.   
Parts B, C, and D:  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 171 or placebo on day 1.  


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 17 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Day 1  
After completion of all pre-dose procedures on the day of dosing (day 1), subjects will 
receive study drug (SC).  Subjects will undergo vital signs and PK blood draws 
post-dose as outlined in the Schedule of Activities in Section 1.3. 
Day 5  
Part A:  A Gastric Emptying test was repeated on day 5 along with additional procedures 
as outlined in the Schedule of Activities in Section 1.3.  
Treatment and Follow-up 
Subjects will return to the research facility as outlined in the Schedule of Activities and 
will undergo the following assessments at specified time points throughout the study:  
clinical laboratory evaluations, adverse event and serious adverse event collection, vital 
sign measurements, 12-lead ECGs, physical examinations, Gastric Emptying test  
(Part A only), Patient Health Questionnaire (PHQ-9), Columbia Suicide Severity Rating 
Scale (C-SSRS, Parts B, C, and D), DXA whole body composition assessments (Part 
B), PK, and other PD assessments.  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 EOS procedures on day 
120 (Part A), day 207 (Part B), and a minimum of 70 days or 60 days after the last 
scheduled dose (Parts C and D, respectively). 
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 Principal Investigator, or c) subject is lost 
to follow up. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Section 1.3. 
Statistical Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK and PD 
endpoints.  Accumulating PD data might be reviewed throughout the trial 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, PD, 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 treatment.   
The sample size for the study is based on practical considerations.  No statistical 
hypothesis will be tested.  For safety considerations, with up to 72 subjects (12 subjects 
from Part A, 6 subjects from Part B, 18 subjects from Part C, and 36 subjects from 
Part D) receiving AMG 171, the chance of detecting an adverse event with a true 
incidence rate of 2% or greater is larger than 77% and the chance of detecting an 
adverse event with a true incidence rate of 4% or greater is larger than 95%.  


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 18 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
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 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 19 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
1
Cohort 6b
6:2, Dose titration Q2W;
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 3
Cohort 6c
6:2, Dose titration Q2W;
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 2
Cohort 7b
6:2, Dose titration Q1W;
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 1
6:2, Dose titration Q2W;
mg SC x 1
mg SC x 1
mg SC x 2
Cohort 7c
6:2, Dose titration Q1W;
mg SC x 1
 mg SC x 1
 mg SC x 1
 mg SC x 1
6:2, Dose titration Q2W;
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 1
Cohort 6a
6:2, Dose titration Q2W;
mg SC x 1
mg SC x 1
mg SC x 1
 mg SC x 4
Cohort 7a
6:2, Dose titration Q1W;
mg SC x 1
mg SC x 1
mg SC x 1
mg SC x 1
6:2, Dose titration Q2W;
mg SC x 1
 mg SC x 3
 
EOS = end of study; FU = follow-up; Q1W = weekly; Q2W = every 2 weeks; SC = subcutaneous. 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 20 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
1.3 
Schedule of Activities (SoA) 
 
Table 1-2 
Schedule of Activities Cohorts 1 and 1b (SAD) 
Table 1-3 
Schedule of Activities Cohort 2 
Table 1-4 
Schedule of Activities for Q2W Dose Titration – Cohort 3 
Table 1-5 
Schedule of Activities for Q2W Dose Titration – Cohort 4 
Table 1-6 
Schedule of Activities for Q1W Dose Titration – Cohort 5 
Table 1-7 
Schedule of Activities for Q2W Dose Titration – Cohort 6a 
Table 1-8 
Schedule of Activities for Q2W Dose Titration – Cohort 6b 
Table 1-9 
Schedule of Activities for Q2W Dose Titration – Cohort 6c 
Table 1-10 
Schedule of Activities for Q1W Dose Titration – Cohort 7a 
Table 1-11 
Schedule of Activities for Q1W Dose Titration – Cohort 7b 
Table 1-12 
Schedule of Activities for Q1W Dose Titration – Cohort 7c 
 
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 21 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 1-2.  Schedule of Activities Cohorts 1 and 1b (SAD) 
Period 
Screening  
Treatment  
EOS/ 
FU 
Study Day 
-28 
-2 
-1 
1 
2 
3 
4 
5 
6 
15 
22 
29 
43 
57 
71 
92 
120 
Visit Windows 
 
 
 
 
 
 
 
 
 
 1 day 
 3 day 
 7 days 
Time (in minutes) 
 
 
0 
30 
60 
90 120 180 300 
0 
10 
60 120 
240 
480 
 
 
 
0 
30 
60 
90 120 180 300 
 
 
 
 
 
 
 
 
 
Time (in hours)a 
 
 
0 
0.5 
1 
1.5 
2 
2.5 
5 
0 
 
0.1
6 
1 
2 
4 
8 
 
 
 
0 
0.5 
1 
1.5 
2 
2.5 
5 
 
 
 
 
 
 
 
 
 
In-house residencym 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
C-SSRS + PHQ-9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, 
RR, TEMP) 
X 
X 
X 
 
 
 
 
 
 
Xb 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGc 
X 
X 
 
 
 
 
 
 
 
Xb, d 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
Concomitant 
Medications 
 
Adverse Event 
Recording  
 
 
Serious Adverse 
Event Recording 
 
Clinical Chemistrye,g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Clinical Hematologye 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Page 1 of 3 
Footnotes defined on last page of the table.  


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 22 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 1-2.  Schedule of Activities Cohorts 1 and 1b (SAD) 
Period 
Screening  
Treatment  
EOS/ 
FU 
Study Day 
-28 
-2 
-1 
1 
2 
3 
4 
5 
6 
15 
22 
29 
43 
57 
71 
92 
120 
Visit Windows 
 
 
 
 
 
 
 
 
 
 1 day 
 3 day 
 7 days 
Time (in minutes) 
 
 
0 
30 
60 
90 120 180 300 
0 
10 60 120 
240 
480 
 
 
 
0 
30 
60 
90 120 180 300 
 
 
 
 
 
 
 
 
 
Time (in hours)a 
 
 
0 
0.5 
1 
1.5 
2 
2.5 
5 
0 
0.1
6 
1 
2 
4 
8 
 
 
 
0 
0.5 
1 
1.5 
2 
2.5 
5 
 
 
 
 
 
 
 
 
 
Coagulation Testse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Alcohol, Cotinine and 
Drug Screene 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, 
and HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Teste,h,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH Test 
(Females Only)e,k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gastric Emptying 
Testo 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BLOOD SAMPLES (± WINDOW) 
Serum PKf 
 
 
 
 
 
 
 
 
 
Xb 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma 
Acetaminophen PKf,g 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
X  
X 
X 
 
X 
 
X 
Xb 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Serum PD (FFA)f,g 
 
 
X  
X 
X 
 
X 
 
X 
Xb 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Serum endogenous 
GDF15f,g 
 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, 
HDL-C and 
triglycerides)g,l 
X 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Page 2 of 3 
Footnotes defined on last page of the table.  


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 23 of 138 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 1-2.  Schedule of Activities Cohorts 1 and 1b (SAD) 
Period 
Screening  
Treatment 
EOS/ 
FU 
Study Day 
-28 
-2 
-1 
1 
2 
3 
4 
5 
6 
15 
22 
29 
43 
57 
71 
92 
120 
Visit Windows 
 
 
 
 
 
 
 
 
 
 1 day 
 3 day 
 7 days 
Time (in minutes) 
 
 
0 
30 
60 
90 120 180 
300 
0 
10 60 120 
240 
480 
 
 
 
0 
30 
60 
90 120 180 300 
 
 
 
 
 
 
 
 
 
Time (in hours)a 
 
 
0 
0.5 
1 
1.5 
2 
2.5 
5 
0 
0.1
6 
1 
2 
4 
8 
 
 
 
0 
0.5 
1 
1.5 
2 
2.5 
5 
 
 
 
 
 
 
 
 
 
HbA1ce 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Anti-AMG 
171 antibody 
 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
Page 3 of 3 
EOS = end of study; HIV = human immunodeficiency virus. 
a Time in minutes/hours relative to the start time of standardized meal during Gastric Emptying test and start of each investigational product dose administration during 
Treatment and Follow-up periods 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 pre-dose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons, as defined by the principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons, as defined by the principal investigator 
g 10-hour fasting is required at all timepoints with the exception of timepoints following the standardized meal as part of the gastric emptying study  
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints  
m In-house residency day -2 to 6  
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 24 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-3.  Schedule of Activities Cohort 2 
Period 
Screening 
Treatment 
Follow-up 
EOS/FU 
Study Day 
-28 
-1 
1 
5 
8 
14 15 19 22 29 
36 
43 
50 57 64 
71 
74 
78 
85 
127 169 
207 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 3 days 
In-house 
residencya 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
X 
 
 
 
 
 
 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
 
X 
X 
 
X 
C-SSRS + 
PHQ-9 
X 
X 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
Xb 
 
 
X 
X 
 
X 
Body weight 
X 
 
Xb 
X 
X 
 
Xb 
X 
X 
Xb 
X 
Xb 
X 
Xb 
X 
Xb 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist 
Circumference 
 
 
Xb 
 
 
 
 
 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
 
X 
 
 
X 
Vital Signs (BP, 
HR, RR, TEMP) 
X 
X 
Xb 
X 
X 
X 
Xb 
X 
X 
Xb 
X 
Xb 
X 
Xb 
X 
Xb 
X 
X 
X 
X 
X 
X 
12-Lead ECGc 
X 
X 
Xb,d 
 
X 
 
Xb 
 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
 
X 
 
 
X 
Concomitant 
Medications 
 
Adverse Event 
Recording 
 
 
 
Serious Adverse 
Event Recording 
 
Clinical 
Chemistrye,g 
X 
X 
Xb 
X 
 
 
Xb 
 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
 
X 
X 
X 
X 
Clinical 
Hematologye 
X 
X 
Xb 
X 
 
 
Xb 
 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
 
X 
X 
X 
X 
Coagulation 
Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine 
and Drug 
Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, 
HBsAg, and 
HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration 
(SC) 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 25 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-3.  Schedule of Activities Cohort 2 
Period 
Screening 
Treatment   
Follow-up 
EOS/FU 
Study Day 
-28 
-1 
1 
5 
8 
14 15 19 22 29 
36 
43 
50 57 64 
71 
74 
78 
85 
127 169 
207 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 3 days 
BLOOD SAMPLES (± WINDOW) 
Serum PKg 
 
 
Xb 
X 
X 
X 
Xb X 
X 
Xb 
X 
Xb 
X 
Xb 
X 
Xb 
X 
X 
X 
X 
X 
X 
Plasma PD 
(Insulin, 
C-peptide, 
Glucose, and 
Glucagon)f,g 
 
 
Xb 
X 
 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
X 
 
 
X 
Serum PD 
(FFA)f,g 
 
 
Xb 
X 
 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
X 
 
 
X 
Serum 
endogenous 
GDF15f,g 
 
 
Xb 
X 
 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, 
LDL-C, HDL-C 
and 
triglyceridesg,l 
X 
 
Xb 
 
 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
X 
 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Pharmacogenetic 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 
Xb 
X 
 
 
 
 
 
 
 
 
 
 
 
Xb 
 
 
X 
 
 
X 
Anti-AMG 
171 antibodym 
 
 
Xb 
 
 
 
X 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
X 
 
 
X 
IMAGING 
Whole body 
composition DXA 
Scann 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Page 2 of 2 
ECG = electrocardiogram; HIV = human immunodeficiency virus; DXA = Dual-Energy X-ray absorptiometry 
a In-house residency day -1 to 6, and day 14 to day 20 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise 
specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 pre-dose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by the 
principal investigator 
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons 
as defined by the principal investigator 
g 10-hour fasting is required at all timepoints 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration  
n DXA scan may be performed within 3 days prior to day 1 and within ±3 days of day 85 and 169 visits  


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 26 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-4.  Schedule of Activities for Q2W Dose Titration – Cohort 3 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 
1 
2 
3 
4 
5 6 
9 
14 15 16 17 18 19 
20 
24 
29 
43 
57 
71 
85 
Visit Windows 
 
 
 
 
 
 
 
  1 
day 
 
 
 
 
 
 
 
 
1 day 
 
 1 
day 
 3 days 
In house residencya 
 
X 
X 
X X 
X 
X X 
 
X 
X X 
X 
X 
X 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X Xb 
 
 
 
X 
 
 
 
Xb 
 
 
 
X 
 
 
X 
X 
 
 
X 
C-SSRS + PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Body weight 
X 
 
Xb 
 
X 
 
 
X 
X 
 
Xb 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
 
 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
X 
X 
 
 
X 
Vital Signs (BP, HR, RR, 
TEMP) 
X 
X Xb X 
 
X 
 
X 
X 
X 
Xb X 
 
X 
 
X 
 
X 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d 
 
 
 
 
X 
 
 
Xb 
 
 
X 
 
 
 
X 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X X 
X 
X X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
X 
X 
X X 
X 
X X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
Recording 
X 
X 
X 
X X 
X 
X X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistrye,g 
X 
X Xb 
 
 
 
X 
 
 
 
Xb 
 
 
 
X 
 
 
X 
 
X 
 
X 
Clinical Hematologye 
X 
X Xb 
 
 
 
X 
 
 
 
Xb 
 
 
 
X 
 
 
X 
 
X 
 
X 
Coagulation Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine and 
Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, 
and HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 27 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-4.  Schedule of Activities for Q2W Dose Titration – Cohort 3 
 
Screening 
Treatment 
Follow Up 
EOS 
Study Day 
-28 
-1 1 
2 
3 
4 
5 
6 
9 
14 15 16 17 18 19 20 
24 
29 
43 
57 
 
71 
 
85 
Visit Windows 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
1 day 
 
 
1 day 
 3 days 
BLOOD SAMPLES (± WINDOW) 
Serum PKf 
 
 
Xb X X 
X 
X X 
X 
X Xb X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
Xb   
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
Serum PD (FFA) f,g 
 
 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
Serum endogenous 
GDF15f,g 
 
 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, HDL-C 
and triglyceridesg,l 
X 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Pharmacogenetic 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Developmentg 
 
 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
Anti-AMG 171 antibodym 
 
 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
X 
 
X 
 
X 
Page 2 of 2 
ECG = electrocardiogram; HIV = human immunodeficiency virus; Q2W = every 2 weeks 
a In-house residency day -1 to 6, and day 14 to day 20 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise 
specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by the 
principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons 
as defined by the principal investigator 
g 10-hour fasting is required at all timepoints 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration 
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 28 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-5.  Schedule of Activities for Q2W Dose Titration – Cohort 4 
 
 
Screening 
 
Treatment 
 
Follow 
up 
 
EOS 
Study Day 
-28 
-1 1 2 3 4 5 6 
9 
14 15 16 17 18 19 20 
24 
28 
 
29 30 31 32 33 34 
37 
43 57 85 
113 
Visit Windows 
 
 
 
 
  
 
  
1 day   
  
  
 
 
1 day  
 
 
 
 
 
 
 
1 day 
 3 days 
 
5 days 
In house 
residencya 
 
X 
X X X X X X 
 
X X X X X X X 
 
X X X X X X X 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
X Xb 
 
 
 X 
 
 
 Xb  
 
 
X 
 
 
 
Xb  
 
 
X 
 
 
X 
 
 
X 
C-SSRS  
PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
Body weight 
X 
 
Xb 
 X   
X 
X 
 Xb  
X 
 
 
X 
X 
 
Xb X 
 
 
X X 
X 
X X X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass 
Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist 
Circumference 
 
 
Xb 
 
 
 
 
 
 
 Xb  
  
 
 
 
 
Xb  
 
 
 
 
 
X X 
 
X 
Vital Signs (BP, 
HR, RR, 
TEMP) 
X 
X Xb X  X  X 
X 
X Xb X 
 
X 
 
X 
X 
 
Xb X 
 
X 
 
X 
 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d  
 X  X 
 
X Xb  
 
 
 
 
X 
 
Xb  
 
 
 
 
 
X 
 
 
X 
Concomitant 
Medications 
X 
X 
X X X X X X 
X 
X X X X X X X 
X 
X X X X X X X 
X 
X X X X 
Adverse Event 
Recording 
 
X 
X X X X X X 
X 
X X X X X X X 
X 
X X X X X X X 
X 
X X X 
X 
Serious 
Adverse Event 
Recording 
X 
X 
X X X X X X 
X 
X X X X X X X 
X 
X X X X X X X 
X 
X X X 
X 
Clinical 
Chemistrye,g 
X 
X Xb 
 
 
 X 
 
 
 Xb  
 
 
X 
 
 
 
Xb  
 
 
X 
 
 
X 
 
 
X 
Clinical 
Hematologye 
X 
X Xb 
 
 
 X 
 
 
 Xb  
 
 
X 
 
 
 
Xb  
 
 
X 
 
 
X 
 
 
X 
Coagulation 
Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, 
Cotinine and 
Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, 
HBsAg, and 
HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH 
Test (Females 
Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration 
(SC) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 29 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-5.  Schedule of Activities for Q2W Dose Titration – Cohort 4 
 
Screening 
Treatment 
Follow 
Up 
EOS 
Study Day 
-28 
-
1 1 2 3 4 5 6 
9 
14 15 16 17 18 19 20 
24 
28 29 30 31 32 33 34 
37 
43 57 85 
113 
Visit Windows 
 
 
 
 
 
 
 
 
 
1 day  
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
1 day 
 3 days 
 
5 days 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 Xb X X X X X 
X 
X Xb X X X X X 
X 
X Xb X X X X X 
X 
X X X 
X 
Plasma PD (Insulin, 
C-peptide, 
Glucose, 
Glucagon)f,g 
 
 Xb  
 
 
 
 
 
 Xb  
 
 
 
 
 
 
Xb  
 
 
 
 
 
X 
 
 
 
Serum PD (FFA)f,g 
 
 Xb  
 
 
 
 
 
 Xb  
 
 
 
 
 
 
Xb  
 
 
 
 
 
X 
 
 
 
Serum endogenous 
GDF15f,g 
 
 Xb  
 
 
 
 
 
 Xb  
 
 
 
 
 
 
Xb  
 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, 
HDL-C and 
triglyceridesg,l 
X 
 Xb  
 
 
 
 
 
 Xb  
 
 
 
 
 
 
Xb  
 
 
 
 
 
X 
 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Pharmacogenetic 
 
 Xb  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 Xb  
 
 
 
 
 
 Xb  
 
 
 
 
 
 
Xb  
 
 
 
 
 
X 
 
X 
 
Anti-AMG 
171 antibodym 
 
 Xb  
 
 
 
  
 Xb   
 
 
 
 
 
Xb  
 
 
 
 
 
X 
 
X 
X 
Page 2 of 2 
ECG  electrocardiogram; HIV  human immunodeficiency virus; Q2W = every 2 weeks 
a Optional in-house residency day -1 to 6, day 14 to day 20, and day 28 to day 34 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise 
specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 pre-dose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by the 
principal investigator 
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons 
as defined by the principal investigator 
g 10-hour fasting is required at all timepoints  
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration 
 
 
 
 
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 30 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-6.  Schedule of Activities for Q1W Dose Titration – Cohort 5 
 
Screening 
Treatment 
Follow up 
EOS 
Study Day 
-28 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 
13 
17 
22 
29 43 57 
71 
85 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 3 days 
In house residencya 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
Xb 
 
 
 
X 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
C-SSRS  PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Body weight 
X 
 
Xb 
 
 
 
X 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
 
 
Xb 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Vital Signs (BP, HR, RR, 
TEMP) 
X 
X 
Xb 
X 
 
X 
X 
X 
 
Xb 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
12-Lead ECGc 
X 
X Xb,d 
 
 
 
X 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistrye,g 
X 
X 
Xb 
 
 
 
X 
 
 
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical Hematologye 
X 
X 
Xb 
 
 
 
X 
 
 
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Coagulation Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine and 
Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, and 
HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 
 
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 31 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table 1-6.  Schedule of Activities for Q1W Dose Titration – Cohort 5 
 
Screening 
Treatment 
Follow up 
EOS 
Study Day 
-28 
-1 1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 17 
22 
29 
43 
57 71 
85 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 3 days 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 
Xb X X X X X 
X 
Xb X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
Xb 
 
 
 
 
 
 
Xb  
 
 
 
 
 
 
X 
 
X 
 
X 
Serum PD (FFA)f,g 
 
 
Xb 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Serum endogenous 
GDF15f,g 
 
 
Xb 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, HDL-C 
and triglyceridesg,l 
X 
 
Xb 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Pharmacogenetic 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Developmentg 
 
 
Xb 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Anti-AMG 171 antibodym 
 
 
Xb 
 
 
 
 
  
Xb 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Page 2 of 2 
ECG  electrocardiogram; HIV  human immunodeficiency virus 
a In house residency day -1 to day 14 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise 
specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by 
principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons 
as defined by principal investigator 
g 10-hour fasting is required at all timepoints. 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 32 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-7.  Schedule of Activities for Q2W Dose Titration – Cohort 6a 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 
1 
2 
4 12 13 15 17 
19 
22 
29 33 43 
45 
47 
49 
52 
57 
71 
85 
86 
88 
90 
93 
99 
113 
127 
141 
155 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
In house residencya 
 
X 
X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
C-SSRS  PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Body weight 
X 
 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
 
 
Xb 
 
  
 
Xb 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
Vital Signs (BP, HR, 
RR, TEMP) 
X 
X 
Xb X X 
X 
X 
Xb 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse 
Event Recording 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistrye,g 
X 
X 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
Clinical Hematologye 
X 
X 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
Coagulation Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 33 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-7.  Schedule of Activities for Q2W Dose Titration – Cohort 6a 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 
1 
2 4 12 13 15 17 
19 
22 
29 33 43 
45 
47 
49 
52 
57 
71 
85 
86 
88 
90 
93 
99 
113 
127 
141 
155 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine, and 
Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, 
and HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 
Xb 
 
X 
 
 
Xb 
 
X 
 
Xb 
X 
Xb 
X 
X 
X 
X 
Xb 
Xb 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum PD (FFA)f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum endogenous 
GDF15f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, 
HDL-C and 
triglyceridesg,l 
X 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
Pharmacogenetic 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 
Xb 
 
 
 
 
Xb 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-AMG 171 antibodym 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Page 2 of 2 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 34 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
ADA = anti-drug antibody; BP = blood pressure; CSSR-S = Columbia Suicide Severity Rating Scale; ECG  electrocardiogram; eGFR = epidermal growth 
factor receptor; EOS = end of study; FFA = free fatty acid; FSH = follicle stimulating hormone; HbA1c = hemoglobin A1C; HBcAb = hepatitis B core 
antibody; HBsAg = hepatitis B surface antigen; HDL-C = high-density lipoprotein cholesterol; HepCAb = hepatitis C antibody; HIV  human 
immunodeficiency virus; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; PD = pharmacodynamic(s); PHQ-9 = 9 question Patient Health 
Questionnaire; PK = pharmacokinetic(s); Q2W = every 2 weeks; SC = subcutaneous; TEMP = temperature. 
a In house residency day -1 to day 2 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons as defined by principal investigator 
g 10-hour fasting is required at all timepoints. 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 35 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-8.  Schedule of Activities for Q2W Dose Titration – Cohort 6b 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 
1 
2 4 12 13 15 17 
19 
22 
29 33 43 47 
57 
59 
61 
63 
66 
71 
85 
86 
88 
90 
93 
99 
113 
127 
142 
155 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
In house residencya 
 
X 
X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
X 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
C-SSRS  PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Body weight 
X 
 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
 
 
Xb 
 
  
 
Xb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Vital Signs (BP, HR, 
RR, TEMP) 
X 
X 
Xb X X X 
X 
Xb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d  
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse 
Event Recording 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistrye,g 
X 
X 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Clinical Hematologye 
X 
X 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Coagulation Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 36 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-8.  Schedule of Activities for Q2W Dose Titration – Cohort 6b 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 
1 
2 4 12 13 15 17 
19 
22 
29 33 43 47 
57 
59 
61 
63 
66 
71 
85 
86 
88 
90 
93 
99 
113 
127 
142 
155 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine, and 
Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, 
and HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 
Xb 
 
X 
 
 
Xb 
 
X 
 
Xb X 
Xb 
X 
Xb 
X 
X 
X 
X 
Xb 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum PD (FFA)f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum endogenous 
GDF15f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, 
HDL-C and 
triglyceridesg,l 
X 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Pharmacogenetic 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 
Xb 
 
 
 
 
Xb 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-AMG 171 antibodym 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Page 2 of 2 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 37 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
ADA = anti-drug antibody; BP = blood pressure; CSSR-S = Columbia Suicide Severity Rating Scale; ECG  electrocardiogram; eGFR = epidermal growth 
factor receptor; EOS = end of study; FFA = free fatty acid; FSH = follicle stimulating hormone; HbA1c = hemoglobin A1C; HBcAb = hepatitis B core 
antibody; HBsAg = hepatitis B surface antigen; HDL-C = high-density lipoprotein cholesterol; HepCAb = hepatitis C antibody; HIV  human 
immunodeficiency virus; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; PD = pharmacodynamic(s); PHQ-9 = 9 question Patient Health 
Questionnaire; PK = pharmacokinetic(s); Q2W = every 2 weeks; SC = subcutaneous; TEMP = temperature. 
a In house residency day -1 to day 2 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons as defined by principal investigator 
g 10-hour fasting is required at all timepoints. 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 38 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-9.  Schedule of Activities for Q2W Dose Titration – Cohort 6c 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 
1 
2 4 12 13 15 17 19 
22 
29 33 43 47 57 
61 
71 
73 
75 
77 
80 
85 
86 
88 
90 
93 
99 
113 
127 
142 
155 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
In house residencya 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
X Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
C-SSRS  PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Body weight 
X 
 
Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist 
Circumference 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Vital Signs (BP, HR, 
RR, TEMP) 
X 
X Xb X X X 
X Xb 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d  
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse 
Event Recording 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistrye,g 
X 
X Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Clinical 
Hematologye 
X 
X Xb 
 
 
X 
 
Xb 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Coagulation Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 39 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-9.  Schedule of Activities for Q2W Dose Titration – Cohort 6c 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 
1 
2 4 12 13 15 17 19 
22 
29 33 43 47 57 
61 
71 
73 
75 
77 
80 
85 
86 
88 
90 
93 
99 
113 
127 
142 
155 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
1 day  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine, and 
Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, 
and HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 
Xb 
 X 
 
 
Xb 
 
X 
 
Xb X Xb 
X 
Xb 
X 
Xb 
X 
X 
X 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum PD (FFA)f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum endogenous 
GDF15f,g 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, 
HDL-C and 
triglyceridesg,l 
X 
 
Xb 
 
 
 
 
Xb 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Pharmacogenetic 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 
Xb 
 
 
 
 
Xb 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-AMG 171 antibodym 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Page 2 of 2 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 40 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
ADA = anti-drug antibody; BP = blood pressure; CSSR-S = Columbia Suicide Severity Rating Scale; ECG  electrocardiogram; eGFR = epidermal growth 
factor receptor; EOS = end of study; FFA = free fatty acid; FSH = follicle stimulating hormone; HbA1c = hemoglobin A1C; HBcAb = hepatitis B core 
antibody; HBsAg = hepatitis B surface antigen; HDL-C = high-density lipoprotein cholesterol; HepCAb = hepatitis C antibody; HIV  human 
immunodeficiency virus; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; PD = pharmacodynamic(s); PHQ-9 = 9 question Patient Health 
Questionnaire; PK = pharmacokinetic(s); Q2W = every 2 weeks; SC = subcutaneous; TEMP = temperature. 
a In house residency day -1 to day 2 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons as defined by principal investigator 
g 10-hour fasting is required at all timepoints. 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 41 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-10.  Schedule of Activities for Q1W Dose Titration – Cohort 7a 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 1 
2 4 5 6 7 8 9 10 11 12 14 15 17 18 
22 
24 25 29 30 36 40 44 50 51 
54 
56 
59 
64 
78 
79 
81 
83 
86 
92 
106 
120 134 148 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
In house 
residencya 
 
X X X  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
X Xb 
 
 X  
 Xb  
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
C-SSRS  PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body weight 
X 
 
Xb 
 
 X  
 Xb  
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist 
Circumference 
 
 
Xb 
 
 
 
 
 Xb  
 
 
 
 
X 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Vital Signs (BP, 
HR, RR, TEMP) 
X 
X Xb X X X X  Xb X  
X X X X 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d  
 X  
 Xb  
 
 
X 
 
X 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X X X X X X X X X X X X X X X 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
 
X X X X X X X X X X X X X X 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse 
Event Recording 
X 
X X X X X X X X X X X X X X X 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Chemistrye,g 
X 
X Xb 
 
 X  
 Xb  
 
 
 
 
X 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Clinical 
Hematologye 
X 
X Xb 
 
 X  
 Xb  
 
 
 
 
X 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Coagulation 
Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 3 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 42 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-10.  Schedule of Activities for Q1W Dose Titration – Cohort 7a 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-1 1 
2 4 5 6 7 8 9 10 11 12 14 15 17 18 
22 
24 25 29 30 36 40 44 50 51 
54 
56 
59 
64 
78 
79 
81 
83 
86 
92 
106 
120 134 148 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine, 
and Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, 
HBsAg, and 
HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration 
(SC) 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 
Xb 
 X     Xb  
 
X     Xb   
X 
Xb 
  X     Xb X   Xb 
X 
X 
  
X 
Xb 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD 
(Insulin, 
C-peptide, 
Glucose, 
Glucagon)f,g 
 
 
Xb 
 
 
 
 
 Xb  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum PD (FFA)f,g 
 
 
Xb 
 
 
 
 
 Xb  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum 
endogenous 
GDF15f,g 
 
 
Xb 
 
 
 
 
 Xb  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, 
LDL-C, HDL-C, 
and triglyceridesg,l 
X 
 
Xb 
 
 
 
 
 Xb  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Page 2 of 3 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 43 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-10.  Schedule of Activities for Q1W Dose Titration – Cohort 7a 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-
1 
1 2 4 5 6 7 8 9 10 11 12 14 15 17 18 
22 
24 25 29 30 36 40 44 50 51 
54 
56 
59 
64 
78 
79 
81 
83 
86 
92 
106 
120 134 148 
Visit Windows 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
1 day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
HbA1cl 
X 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Pharmacogenetic 
 
 
Xb   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 
Xb   
  
 Xb  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Anti-AMG 171 antibodym 
 
 
Xb   
  
 
 
 
 
 
 
 Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Page 3 of 3 
ADA = anti-drug antibody; BP = blood pressure; CSSR-S = Columbia Suicide Severity Rating Scale; ECG  electrocardiogram; eGFR = epidermal growth 
factor receptor; EOS = end of study; FFA = free fatty acid; FSH = follicle stimulating hormone; HbA1c = hemoglobin A1C; HBcAb = hepatitis B core 
antibody; HBsAg = hepatitis B surface antigen; HDL-C = high-density lipoprotein cholesterol; HepCAb = hepatitis C antibody; HIV  human 
immunodeficiency virus; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; PD = pharmacodynamic(s); PHQ-9 = 9 question Patient Health 
Questionnaire; PK = pharmacokinetic(s); Q1W = weekly; SC = subcutaneous; TEMP = temperature. 
a In house residency day -1 to day 2 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons as defined by principal investigator 
g 10-hour fasting is required at all timepoints. 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 44 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-11.  Schedule of Activities for Q1W Dose Titration – Cohort 7b 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-
1 
1 2 4 5 6 7 8 9 10 11 12 14 15 18 19 21 
22 
25 26 28 30 36 40 44 50 54 58 64 67 68 70 73 78 
79 
81 
83 
86 
92 
106 120 134 148 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
In house residencya 
 
X X X  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X Xb  
 X  
 Xb  
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
C-SSRS  PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body weight 
X 
 
Xb  
 X  
 Xb  
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
 
 
Xb  
 
 
 
 Xb  
 
 
 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Vital Signs (BP, HR, RR, 
TEMP) 
X 
X Xb X X X X  Xb X  
X X X X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d  
 X  
 Xb  
 
 
X 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X X X X X X X X X X X X X X X X 
X 
X 
X X X X X X X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
 
X X X X X X X X X X X X X X X 
X 
X 
X X X X X X X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
Recording 
X 
X X X X X X X X X X X X X X X X 
X 
X 
X X X X X X X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistrye,g 
X 
X Xb  
 X  
 Xb  
 
 
 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Clinical Hematologye 
X 
X Xb  
 X  
 Xb  
 
 
 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Coagulation Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 45 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-11.  Schedule of Activities for Q1W Dose Titration – Cohort 7b 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-
1 
1 2 4 5 6 7 8 9 10 11 12 14 15 18 19 21 
22 
25 26 28 30 36 40 44 50 54 58 64 67 68 70 73 78 
79 
81 
83 
86 
92 
106 120 134 148 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
Urinalysise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine, and 
Drug Screene 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, and 
HepCAbe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH Test 
(Females Only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
X 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 
Xb  X     Xb  
 
  X   Xb   X 
  
Xb 
    X   Xb X   Xb X   Xb X X   X Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
Xb  
 
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum PD (FFA)f,g 
 
 
Xb  
 
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum endogenous 
GDF15f,g 
 
 
Xb  
 
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, 
HDL-C and 
triglyceridesg,l 
X 
 
Xb  
 
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
HbA1cl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Pharmacogenetic 
 
 
Xb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Developmentg 
 
 
Xb  
 
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Anti-AMG  171 antibodym 
 
 
Xb  
 
 
 
 
 
 
 
 
 
 Xb 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Page 2 of 2 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 46 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
ADA = anti-drug antibody; BP = blood pressure; CSSR-S = Columbia Suicide Severity Rating Scale; ECG  electrocardiogram; eGFR = epidermal growth 
factor receptor; EOS = end of study; FFA = free fatty acid; FSH = follicle stimulating hormone; HbA1c = hemoglobin A1C; HBcAb = hepatitis B core 
antibody; HBsAg = hepatitis B surface antigen; HDL-C = high-density lipoprotein cholesterol; HepCAb = hepatitis C antibody; HIV  human 
immunodeficiency virus; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; PD = pharmacodynamic(s); PHQ-9 = 9 question Patient Health 
Questionnaire; PK = pharmacokinetic(s); Q1W = weekly; SC = subcutaneous; TEMP = temperature. 
a In house residency day -1 to day 2 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons as defined by principal investigator 
g 10-hour fasting is required at all timepoints. 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 47 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-12.  Schedule of Activities for Q1W Dose Titration – Cohort 7c 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-
1 
1 2 4 5 6 7 8 9 10 11 12 14 15 18 19 
21 
22 
25 26 28 30 36 40 44 50 54 58 64 67 68 70 73 78 79 
81 
83 
86 
92 106 120 134 148 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
In house residencya 
 
X X X  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X Xb  
 X  
 Xb  
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
C-SSRS  PHQ-9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body weight 
X 
 
Xb  
 X  
 Xb  
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
 
 
Xb  
 
 
 
 Xb  
 
 
 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Vital Signs (BP, HR, RR, 
TEMP) 
X 
X Xb X X X X  Xb X  
X X X X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
12-Lead ECGc 
X 
X Xb,d  
 X  
 Xb  
 
 
X 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X X X X X X X X X X X X X X X X 
X 
X 
X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
 
X X X X X X X X X X X X X X X 
X 
X 
X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
Recording 
X 
X X X X X X X X X X X X X X X X 
X 
X 
X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistrye,g 
X 
X Xb  
 X  
 Xb  
 
 
 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Clinical Hematologye 
X 
X Xb  
 X  
 Xb  
 
 
 
 
X 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Coagulation Testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFRe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 48 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Table 1-12.  Schedule of Activities for Q1W Dose Titration – Cohort 7c 
 
Screening 
Treatment 
Follow-up 
EOS 
Study Day 
-28 
-
1 
1 2 4 5 6 7 8 9 10 11 12 14 15 18 19 
21 
22 
25 26 28 30 36 40 44 50 54 58 64 67 68 70 73 78 79 
81 
83 
86 
92 106 120 134 148 
Visit Windows 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 day  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 days 
Urinalysise 
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, Cotinine, and 
Drug Screene 
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBcAb, HBsAg, and 
HepCAbe 
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh,j 
X 
Xi 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH Test 
(Females Only)k 
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Study Drug 
Administration (SC) 
 
 
X 
  
 
 
 X  
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
BLOOD SAMPLES ( WINDOW) 
Serum PKf 
 
 
Xb  X     Xb  
 
  X   Xb   X 
  
Xb 
X       Xb X   Xb X   Xb         Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PD (Insulin, 
C-peptide, Glucose, 
Glucagon)f,g 
 
 
Xb   
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum PD (FFA)f,g 
 
 
Xb   
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum endogenous 
GDF15f,g 
 
 
Xb   
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Lipid Panel (total 
cholesterol, LDL-C, 
HDL-C and 
triglyceridesg,l 
X 
 
Xb   
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
HbA1cl 
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Pharmacogenetic 
 
 
Xb   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
Developmentg 
 
 
Xb   
 
 
 Xb  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Anti-AMG 171 antibodym 
 
 
Xb   
 
 
 
 
 
 
 
 
 Xb 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Page 2 of 2 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
 
Page 49 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
ADA = anti-drug antibody; BP = blood pressure; CSSR-S = Columbia Suicide Severity Rating Scale; ECG  electrocardiogram; eGFR = epidermal growth 
factor receptor; EOS = end of study; FFA = free fatty acid; FSH = follicle stimulating hormone; HbA1c = hemoglobin A1C; HBcAb = hepatitis B core 
antibody; HBsAg = hepatitis B surface antigen; HDL-C = high-density lipoprotein cholesterol; HepCAb = hepatitis C antibody; HIV  human 
immunodeficiency virus; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; PD = pharmacodynamic(s); PHQ-9 = 9 question Patient Health 
Questionnaire; PK = pharmacokinetic(s); Q1W = weekly; SC = subcutaneous; TEMP = temperature. 
a In house residency day -1 to day 2 
b Predose assessments 
c Single ECG during screening (day -28 to day -1) and triplicate at other timepoints unless otherwise specified. 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) 
d 3 sets of triplicate ECGs at baseline (day 1 predose) 
e Analyzed at the local laboratory, additional samples may be collected for safety reasons as defined by principal investigator  
f Analyzed at the central laboratory/sponsor facility, additional samples may be collected for safety reasons as defined by principal investigator 
g 10-hour fasting is required at all timepoints. 
h Serum pregnancy test at screening and EOS (females only) 
i Urine pregnancy test (females only) 
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 Serum FSH Test (female only) for postmenopausal status confirmation 
l Local laboratory at screening, then central laboratory at other timepoints 
m All ADA samples will be taken prior to dosing on days of dose administration 
 
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 50 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 significant side 
effects.  AMG 171 is a long acting Fc fusion protein of Growth Differentiation Factor 
15 (GDF15).  In preclinical studies AMG 171 administration in obese cynomolgus 
monkeys resulted in an approximate 12% reduction in body weight as compared to 
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 and multiple ascending doses of AMG 171 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 health-care 
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 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 (NASH), polycystic ovary syndrome, obstructive sleep 
apnea, osteoarthritis, gallbladder and skin diseases, and several forms of cancer 
(Jensen et al, 2014).  In addition, persons with obesity frequently encounter 
psychological and social problems such as low self-esteem, prejudice, and 
discrimination (Kolotkin et al, 2001). 
Achieving clinically significant weight loss (> 5%) through lifestyle changes focuses on 
reduced energy intake and increased physical activity, and can improve risk factors for 
CVD, delay or prevent the development of type 2 diabetes, and contribute to better 
quality of life (Jensen 2014, Look AHEAD Research Group, 2013).  Exercise and 
nutritional counseling can be effective in the short term, but many patients will sustain 
less than 5% weight loss in the long term (Look AHEAD Research Group, 2014).  
Currently approved weight loss products belong to the following therapeutic classes:  
glucagon-like peptide (GLP)-1R agonists (liraglutide [Saxenda®]) and semaglutide 
[Wegovy®], 5-HTR agonists (lorcaserin [Belviq®]), noradrenergic agents (phentermine 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 51 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
[Adipex-P®]), lipase inhibitors (orlistat [Xenical/ Alli®]), in addition to fixed combination 
products (phentermine + topiramate [Qsymia®], and bupropion + naltrexone 
[Contrave®]).  With the currently approved pharmacotherapy for weight management, a 
modest incremental average weight loss of 2–9 kg can be achieved over and above 
lifestyle measures.  Across phase 3 studies of currently approved products, a greater 
proportion of individuals with obesity on active medication (44-75%) achieve a reduction 
in bodyweight > 5% from baseline over 52 weeks than among those assigned to placebo 
(23%) (Khera et al, 2016).  Side effects of currently approved weight loss products vary 
depending upon their mechanism and include increased blood pressure, tachycardia, 
restlessness (stimulants like phentermine), flatulence, and diarrhea (medicines that 
affect fat absorption, such as orlistat), nausea, vomiting, constipation, dry mouth, and 
dizziness (molecules that directly interfere with neurotransmitter signaling in the brain, 
such as lorcaserin, bupropion and naltrexone) (Heymsfield and Wadden, 2017).  The 
majority of persons with obesity are generally dissatisfied with weight loss of less than 
10 kg, and as a consequence, may discontinue pharmacological treatment to avoid 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 171 
2.2.2.1 
Pharmacology 
AMG 171 is a recombinant growth differentiation factor 15 (GDF15) fragment 
crystallizable (Fc) fusion protein intended for the treatment of obesity. GDF15 is a distant 
member of the transforming growth factor- (TGF) superfamily which has been 
associated with multiple disorders of metabolism such as obesity and insulin resistance 
(Breit et al, 2017).  It is found in the circulation as a 25 kilodalton (KD) homodimer 
protein.  Literature findings support GDF15 as a potential regulator of body weight and 
fat mass.  Genetically engineered mice which do not express GDF15 have increased 
body weight, where overexpression resulted in mice with lower body weight and fat 
mass (Tsai et al, 2013; Johnen et al, 2007).  Engineered GDF15 peptides administered 
to both mice and cynomolgus monkeys also resulted in lower body weight and fat mass 
(Xiong et al, 2017).  GDNF family receptor -like (GFRAL) has recently been identified 
as the hindbrain localized receptor that mediates GDF15 action (Yang et al, 2017; 
Emmerson et al, 2017; Mullican et al, 2017; Hsu et al, 2017).  GFRAL associates with a 
coreceptor, rearranged during transfection (RET), that results in downstream 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 52 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
phosphorylation of effectors such as extracellular signal -related kinase (ERK) and 
protein kinase B (AKT).  AMG 171 incorporates 1 Fc dimer per GDF15 subunit; this 
modification increases the half-life of GDF15 in the circulation.  Binding affinity of 
AMG 171 to human, cynomolgus monkey, and mouse GFRAL was determined by 
measuring the binding kinetics of AMG 171 to a soluble form of human, cynomolgus 
monkey, or mouse GFRAL and then calculating affinity. AMG 171 binds to human, 
cynomolgus monkey, and mouse GFRAL with affinities of 1.8  0.06 nM, 1.6  0.3 nM, 
and 5.6  0.4 nM, respectively. 
In human embryonic kidney cells (HEK) 293T transiently expressing human, mouse, or 
cynomolgus monkey GFRAL and RET, AMG 171 increased measurable phosphorylated 
ERK with a mean half maximal effective concentration (EC50) of 0.343 nM, 0.103 nM, 
and 0.356 nM respectively.   
The effects of AMG 171 were examined in leptin deficient (ob/ob) and diet-induced 
obese mice (DIO) as well as spontaneously obese cynomolgus monkeys.  In ob/ob mice 
AMG 171 dose-dependently reduced food intake with an average 50 effective dose 
(ED50) value of 11.3  3.1 g/kg and with maximum inhibition of 30.5  3.7.   
After 5 weeks of treatment of vehicle or AMG 171 in diet induced obese (DIO) mice, and 
after removal of animals that were suspected of anti-drug antibody (ADA) formation, 
body weight percent change from baseline for AMG 171 group was -21.6 and when 
compared to the vehicle group, AMG 171 group showed a 30.1 lower body weight.  
AMG 171 was evaluated in obese non-human primates using a chronic dosing regimen.  
AMG 171 reduced food intake, body weight, insulin and triglyceride levels in obese 
cynomolgus monkeys after 5 weeks of dosing with sustained effect on the weight loss 
during the washout phase, suggesting a strong potential as an anti-obesity therapeutic. 
The digestive tract is important for nutrient absorption following food intake.  It is also 
known that gastric motility mediated by smooth muscle peristalsis dictates the rate at 
which ingested food is emptied from the upper digestive tract.  Gastric emptying rates 
can be determined by using techniques such as time mediated retention of phenol red in 
the stomach or appearance of orally administered acetaminophen in blood 
(Clark and Williams, 1971; Clements et al, 1978; Paixao et al, 2018).  The latter can be 
used in the clinical setting to determine gastric emptying rates in humans 
(Paixao et al, 2018).  Changes in gastric emptying rates mediated by AMG 171 can 
provide insight into its mechanism of action on body weight and food intake.  The phenol 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 53 of 138 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
red data showed higher gastric retention of phenol red after GDF15 treatment, indicating 
delayed gastric emptying by GDF15.  When GDF15 was injected 30 minutes before oral 
gavage, acetaminophen levels were lower in GDF15 treated group.  Area under the 
curve (AUC) of the acetaminophen curve shows 21.7 reduction by GDF15 treatment. 
Refer to the AMG 171 Investigator’s Brochure (IB) for additional information related to 
the pharmacology, physical, chemical, and pharmaceutical properties and formulations 
of AMG 171. 
2.2.2.2 
Pharmacokinetics 
2.2.2.2.1 
Non-clinical Pharmacokinetics 
Single-dose PK of AMG 171 were characterized following intravenous (IV) and 
subcutaneous (SC) administration to cynomolgus monkeys.  Multiple dose toxicokinetics 
(TK) were characterized following SC dosing to mice and cynomolgus monkeys. 
AMG 171 single-dose PK was characterized after IV or SC administration of AMG 171 to 
lean (non-obese) male cynomolgus monkeys at 2 dose levels 
mg/kg) to 
cover a 10-fold range.  AMG 171 PK was linear based on dose-proportional increases in 
exposure (maximum observed concentration [Cmax] and area under the 
concentration-time curve from 0 to infinity [AUC0-inf]).  The terminal half-life (t1/2,z) in 
monkeys ranged between 6.1 to 7.1 days.  AMG 171 was absorbed upon SC 
administration to monkeys with absolute bioavailability of 79%.  
The multi-dose TK of AMG 171 was characterized in CD-1 mice in an exploratory study 
with weekly (QW) SC doses of
 mg/kg for 4 weeks.  Exposure was 
approximately dose-proportional during the week 1 dosing interval, with no evidence of 
drug accumulation over 4 weeks dosing.  There was no observed sex difference in 
AMG 171 TK exposure. 
The TK of AMG 171 in CD-1 mice was characterized study after SC doses of
 and 
mg/kg administered every 2 weeks (Q2W) for fourteen weeks.  AMG 171 exposure 
increased with dose.  There were no observed differences in TK parameters estimates 
(Cmax and AUClast) between males and females during the week 1 interval.  There was no 
AMG 171 accumulation observed at all dose levels after repeat administration. 
The multi-dose TK of AMG 171 was characterized in lean (non-obese) female 
cynomolgus monkeys in an exploratory study with SC doses of 
mg/kg 
QW over 4 weeks. Following multiple doses, exposure was dose-proportional up to 
mg/kg, but exposure was greater than dose proportional doses of 
mg/kg based 


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on Cmax and AUClast. AMG 171 drug accumulation was observed for individual monkeys 
in all groups (up to 1.8-fold) upon repeat administration. 
The TK of AMG 171 in cynomolgus monkeys was characterized after SC doses of 
mg/kg administered Q2W for fourteen weeks.  AMG 171 exposure increased 
approximately proportional to dose.  Moderate AMG 171 accumulation (up to 1.6-fold) 
was observed upon repeated administration.  No difference in exposure was observed 
between males and females. 
2.2.2.3 
Toxicology 
A comprehensive nonclinical toxicology program was conducted to support the SC 
administration of AMG 171 in the proposed clinical study for up to 3 months.  The 
nonclinical safety assessment of AMG 171 consisted of 4-week exploratory and 14-week 
Good Laboratory Practices (GLP)-compliant toxicology studies in the mouse and 
cynomolgus monkey.  In addition, a single dose GLP-compliant central nervous 
system/respiratory safety pharmacology study in the mouse found no AMG 171-related 
effects, and a single dose GLP-compliant cardiovascular safety pharmacology study in 
the telemetered cynomolgus monkey was conducted.     
In the 14-week studies, SC administration (Q2W) of doses up to
mg/kg and 
mg/kg were well tolerated in the mouse and cynomolgus monkey, respectively.  
Mice administered 
mg/kg had AMG 171-related decreases in body weight 
gain, the intended pharmacologic activity.  Decreased body weights, primarily because 
of widespread decreased body fat and decreased overall growth, were associated with 
secondary effects that are consistent with an adaptive response to decreased body 
weight gains due to food or caloric restriction in rodents (Levin et al, 1993).  All changes 
attributed to the intended pharmacologic activity of AMG 171 and secondary metabolic 
consequences showed signs of recovery by the end of the 4-month recovery phase, 
except for decreased serum lipid levels in females at
mg/kg. Additionally, insulin and 
glucose were lower than control for males at
 mg/kg at the end of the recovery 
phase, which was attributed to improved insulin sensitivity.  AMG 171-related changes 
that were not clearly secondary to body weight reductions included a mild increase in 
platelets and a minimal increase in alkaline phosphatase at all dose levels.  The minimal 
increase in alkaline phosphatase at
mg/kg persisted through the recovery period.  
The no observed adverse effect level (NOAEL) in mice was
mg/kg. 
Cynomolgus monkeys given
 mg/kg SC Q2W for 14 weeks had few changes 
attributed to AMG 171.  Two out of 16 animals, including the largest female on study 


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(administered
mg/kg) and a high dose male, lost weight which was attributed to the 
expected pharmacology of AMG 171.  Females at
mg/kg had minimal to mild 
decreases in globulins which fully reversed by the end of the 4-month recovery phase.  
Minimal to mild mononuclear cell infiltrates observed in several tissues at both dose 
levels were attributed to an immunogenic response to a foreign human biotherapeutic 
and not a direct AMG 171-related effect (Engelhardt, 2008, Naylor et al, 2019).  After the 
4-month recovery phase, this finding was considered fully or partially reversed in all 
tissues.  The NOAEL was 
mg/kg in cynomolgus monkeys. 
The effects of AMG 171 on the cardiovascular system were assessed in a dedicated 
cardiovascular safety pharmacology study in telemetered male cynomolgus monkeys 
(Study 150667).  Animals were administered
mg/kg AMG 171 on day 1 and 
evaluated for 24 hours on days 1 and 5.  There were no AMG 171-related effects on 
ECG parameters, heart rate, arterial pulse pressure, respiration rate, or body 
temperature.  At 
 mg/kg, there were slight, transient increases in systolic 
(up to +8 mmHg), diastolic (+4 mmHg) and mean arterial pressures (+6 mmHg) on 
day 1 (but not on day 5).  The change at this dose was associated with a Cmax value that 
is approximately 90X higher than the estimated Cmax for the highest dose in the clinical 
trial 
 mg).  
The highest planned dose in the clinical trial (
mg) is associated with predicted 
exposure multiples of 5- and 28-times relative to the AUC at NOAEL in mice and 
monkeys, respectively. 
2.3 
Benefit/Risk Assessment 
The potential benefits of AMG 171 include anticipated weight loss and improved 
cardiovascular risk factors associated with weight loss.  Potential risks of AMG 171, as 
anticipated from animal data and the literature, are described below in Section 2.3.2. 
2.3.1 
Key Benefits 
The key anticipated benefits of AMG 171 include clinically meaningful weight loss and its 
associated benefits of improved cardiovascular health, glucose metabolism, and overall 
well-being. 
2.3.2 
Key Risks 
Potential risks of AMG 171, 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 171 antibodies). Other potential risks include blood pressure 


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changes (as was observed in cynomolgus monkeys), and risks commonly associated 
with targeting obesity pathways.  
Key risks detailed below: 
1. 
Nausea/Vomiting 
Nausea and vomiting are common adverse reactions for molecules targeting the obesity 
pathways.  Mild to moderate, non-serious adverse events of nausea and vomiting have 
been observed in cohorts 1 through 5 approximately 1 to 4 days after receiving 
Investigational Product.  All events were self-resolved. Nausea and vomiting are 
considered identified risks with AMG 171. Subjects will be monitored for signs and 
symptoms of adverse events of nausea and vomiting throughout the study.  
2. 
Increased Blood Pressure 
In a cardiovascular safety pharmacology study in cynomolgus monkeys, there were 
higher systolic (up to  8 mm Hg), diastolic ( 4 mm Hg) and mean arterial pressures 
( 6 mm Hg) 24 hours post-dose at the highest dose tested 
mg/kg, which is 
associated with a 90X higher Cmax than estimated from the
mg dose) and was not 
observed at the low dose of
mg/kg.  The effect was transient and was not observed 
on day 5 in the presence of continued exposure.  Subjects will have their vital signs, 
including blood pressure, monitored throughout the study.  No abnormal trends in vital 
signs were observed in clinical cohorts 1 through 5 in blinded review of data 
available at the DLRMs. 
3. 
Hypersensitivity Reactions 
As with any biologic, administration of AMG 171 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 171 will be administered SC or IV by a 
qualified clinical research staff member.  Subjects will be monitored for signs and 
symptoms of hypersensitivity reactions during and after AMG 171 administration, such 
as fever, chills, shaking, hypotension, wheezing, itching, nausea, and/or rash. 


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4. 
Immunogenicity 
As with all biological products, there is a potential for the development of 
anti-AMG 171 antibodies.  Additionally, there is a theoretical possibility that anti-drug 
antibodies may inhibit native GDF15.  The potential effects of anti-AMG 171 antibodies 
on subjects who might develop them are not known, but reduced efficacy of AMG 171 is 
a possibility.  Subjects will be monitored for potential effects of ADA that may include 
antibody mediated adverse events (AEs), 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 171 antibodies.  Additional blood samples may be obtained to 
evaluate any ADA-mediated effects on safety, PK, and PD during the study. 
5. 
Injection Site Reactions 
Injection site reactions (eg, erythema, itching, hematoma, swelling, bruising and pain) 
are common side effects of drugs with SC administration.  These reactions can range 
from mild to severe (including injection site necrosis, which is an uncommon side effect).  
Following SC 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.  
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 AMG 171. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 To assess the safety and tolerability 
of AMG 171 as single or 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 PK of AMG 
171 as single or multiple doses in 
subjects with obesity 
 
AMG 171 PK parameters including, but 
not limited to, maximum observed 
concentration (Cmax), the time of 
maximum observed concentration 
(Tmax), and area under the 
concentration time curve (AUC) 


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 To evaluate the immunogenicity of 
AMG 171 
 
Incidence of anti-AMG 171 antibody 
formation 


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Objectives 
Endpoints 
Exploratory 
 To characterize the PD effects of 
AMG 171 as single or multiple doses 
in subjects with obesity 
o To assess the effect of 
AMG 171 on fasting and 
post-prandial (Part A) 
metabolic parameters 
 
o To assess the effect of 
AMG 171 on gastric 
emptying in the single 
ascending dose cohorts 
(Part A) 
 
o To assess the effect of 
AMG 171 on fasting lipid 
levels 
 
 
 
 
o To assess the effect of 
AMG 171 on hemoglobin A1c 
(HbA1c) in the multiple dose 
cohorts (Part B) 
 
o To assess the effect of 
AMG 171 on potential 
biomarkers 
 
 
o To assess the effect of 
AMG 171 on endogenous 
GDF15 levels 
 
o To assess the effects of 
AMG 171 on body weight, 
waist circumference and 
body mass index (BMI) 
 
o To assess the effect of 
AMG 171 on body 
composition in the multiple 
dose cohorts (Part B) 
 
Changes in PD parameters: 
 
 
o Changes in the fasting and 
post-mixed meal challenge 
glucose, insulin, c-peptide, 
glucagon, and free fatty acid 
(FFA) concentrations 
o Gastric emptying as assessed 
by acetaminophen absorption 
kinetics (Cmax and AUC)  
 
 
 
o Changes in fasting lipid levels, 
including, but not limited to, total 
cholesterol, low density 
lipoprotein cholesterol (LDL-C), 
high density lipoprotein 
cholesterol (HDL-C), and 
triglycerides 
 
o Changes in HbA1c levels  
 
 
 
o Changes in potential biomarkers 
including, but not limited to, 
inflammatory and adipose tissue 
markers 
 
o Changes in endogenous GDF15 
levels 
 
 
o Changes in body weight, waist 
circumference, and BMI 
 
 
o Changes in body composition as 
measured by whole body 
dual-energy x-ray 
absorptiometry (DXA)  
 


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4. 
Study Design 
4.1 
Overall Design 
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple 
ascending dose study in adult subjects with obesity.  The study will be conducted at 
approximately 3-4 sites in the United States.  Additional sites may be added.  
AMG 171 will be administered SC.  Part A (completed) was a single ascending dose 
(SAD) phase; Part B is a multiple dose phase in 1 cohort; and Part C is a titration phase 
with step dosing for 2 to 3 doses total.  Part D will be a multiple ascending dose 
titration phase with step dosing ranging from 6 to 8 ascending doses.  The study 
consists of a total of 12 cohorts:  2 cohorts (Part A; SAD), 1 cohort (Part B), 3 cohorts 
(Part C; titration), and 6 cohorts (Part D; multiple ascending dose titration).   
Potential subjects will be screened within 28 days before day 1 to assess their eligibility 
to enter the study.  Subjects will be confined at the Clinical Research Unit (CRU) from 
Check-in (morning of day -1) through the morning of day 6 in Part A (SAD phase), from 
day -1 for a 7-day (6-night) residency period and re-admitted on day -13 for a second 
7-day (6-night) residency period in Part B.  Subjects in Part C (cohorts 3 to 5) will be 
admitted after confirmed eligibility on day -1.  Cohort 3 subjects will be admitted after 
confirmed eligibility on day -1 for a 7-day (6-night) residency period and re-admitted on 
day 14 for a second 7-day (6-night) residency period.  Cohort 4 subjects will be admitted 
after confirmed eligibility on day -1 for a 7-day (6-night) residency period, re-admitted on 
day 14 for a second 7-day (6-night) residency period, and re-admitted on day 28 for a 
third 7-day (6-night) residency period.  Cohort 5 subjects will be admitted after confirmed 
eligibility on day -1 for a 14-day (13-night) residency period. 
Cohort 6 subjects will be admitted after confirmed eligibility on day -1 for a 2-day 
(1-night) residency period, re-admitted on days 14 and 28 for a 3-day (2-night) 
residency period, re-admitted on day 42 for a 7-day (6-night) residency period, and 
re-admitted on days 56, 70, and 84 for a 2-day (1-night) residency period.   
Cohort 7 subjects will be admitted after confirmed eligibility on day -1 for a 3-day 
(2-night) residency period, and re-admitted on days 35, 49, 63, and 77 for a 3-day 
(2-night) residency period. 
Part A (SAD; completed) 
Seventeen subjects were enrolled into 2 cohorts (1 subject was replaced).  No additional 
cohorts are planned for Part A.  In each cohort, 8 subjects were randomized to receive 
AMG 171 or placebo SC (cohorts 1 and 1b) in a 3:1 ratio as described in Table 1-1.  For 


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each cohort, the first 2 subjects (sentinel pair) were randomized such that 1 subject 
received AMG 171 and 1 subject received placebo.  The sentinel pair was observed for 
at least 24 hours before the remaining subjects in the cohort were dosed, as there were 
no safety or tolerability concerns as assessed by the Principal Investigator.  Enrollment 
into the SAD cohorts was sequential.  Subsequent cohorts were dosed after the dose 
regimen in the preceding cohort was recommended by the Dose Level Review Team 
(DLRT) to have no safety signals observed and be reasonably tolerated based on the 
safety and laboratory data through at least study day 15 for at least 7 out of 8 subjects 
dosed.  The 2 SAD cohorts have completed dosing.  Cohort 1 has reached study 
completion and cohort 1b has completed 3 months of follow-up.  As tolerability was 
noted to worsen with the dose increase from
 mg (cohort 1) to 
mg (cohort 1b) with 
adverse events of nausea and vomiting, titration to and above those dose levels will be 
evaluated in Part B. 
Part B (Multiple Ascending Dose [MAD]) 
Approximately 8 subjects will enroll into 1 cohort (cohort 2) where 8 subjects will be 
randomized to receive AMG 171 or placebo SC in a 3:1 ratio as described in Table 1-1.   
Cohort 2:  Study drug will be administered SC every Q2W for a total of six,
 mg 
doses.  
Part C (Titration) 
Approximately 24 subjects will enroll into 1 of 3 cohorts (cohorts 3 to 5).  In each cohort, 
8 subjects will be randomized to receive AMG 171 or placebo SC in a 3:1 ratio as 
described in Table 1-1.  Enrollment into cohort 3 will occur after DLRT recommendation 
based on safety and laboratory data through at least study day 22 of cohort 2 (Part B).  
Subsequently, both cohorts 4 and 5 will be dosed after the dose regimen in the 
cohort 3 has been recommended by the DLRT to have no safety signals observed 
and be reasonably tolerated based on safety and laboratory data through day 22 for at 
least 6 out of 8 subjects dosed and cumulative data of all prior cohorts.  
Enrollment of dose cohorts is depicted in Figure 1-1.  No additional cohorts are 
planned for Part C. 
Cohort 3:  Two doses of study drug will be administered SC Q2W apart with the first 
dose of
 mg and second dose of 
mg.  
Cohort 4: Three doses of study drug will be administered SC Q2W apart with the first 
dose of
mg, second dose of 
mg and third dose of 
 mg.  


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Cohort 5: Two doses of study drug will be administered SC weekly (Q1W) apart with 
the first dose of
mg and second dose of
mg.  
Part D (MAD Titration) 
Approximately 48 subjects will enroll into 1 of 6 cohorts (cohorts 6a-c and 7a-c). In 
each cohort, 8 subjects will be randomized to receive 6 to 8 consecutive doses of 
AMG 171 or placebo SC in a 3:1 ratio as described in Section 1.3.  The cohorts in 
group 6 will begin with
 mg with dose escalation every 2 weeks while those in 
group 7 will begin with
mg with dose escalation weekly until the fourth dose and 
then every other week thereafter.  Enrollment into cohorts 6a and 7a will begin 
contemporaneously after a Dose Level Review Meeting (DLRM) of cohorts 4 and 5, 
which include review of cumulative data of all prior cohorts.  Enrollment in 
cohorts 6b and 7b will occur after DLRT recommendation based on all safety and 
laboratory data through at least study day 43 of cohort 6a (Part D) and cumulative 
data of all prior cohorts.  Subsequently, cohorts 6c and 7c will be dosed in 
parallel after the dose regimen in cohort 6b has been recommended by the DLRT 
to have no safety signals observed and be reasonably tolerated based on all 
safety and laboratory data through at least study day 57 for at least 6 out of 
8 subjects dosed and cumulative data of all prior cohorts.  Enrollment of dose 
cohorts is depicted in Figure 1-1.  
 
Cohort 6a:  Study drug will be administered SC Q2W for a total of 7 doses 
.   
 
Cohort 6b:  Study drug will be administered SC Q2W for a total of 7 doses 
.  
 
Cohort 6c:  Study drug will be administered SC Q2W for a total of 7 doses 
.   
 
 Cohort 7a:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional doses 
.   
 
Cohort 7b:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional doses 
.   
 
Cohort 7c:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional doses 
.   
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 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 
Approximately 96 subjects (8 subjects per cohort, cohorts 1, 1b, 2 to 5, 6a-c, and 7a-c) 
will be enrolled.  Additional subjects may be enrolled if a DLRT recommendation is made 
to expand, repeat or add cohorts to the study. 


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Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 9.2. 
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 3 to 4 investigative sites in U.S. 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 starting dose and exposure multiples for the doses proposed for Part A, SAD were 
calculated based on the NOAELs determined in the 14-week GLP repeat-dose mouse 
and cynomolgus monkey toxicology studies (Q2W dosing, Section 2.2.2.3) and the 
observed reduction in body weight in the chronic efficacy study in cynomolgus monkeys. 
The planned cohorts in this amendment of the study consists of multiple-dose 
cohorts following a titration schema as presented in Figure 1-1.  
Previously, subjects in Part A received a single
mg SC dose (cohort 1) or 
mg SC 
(cohort 1b).  Events of nausea and vomiting were observed in the
mg SC single dose 
cohort, with fewer and milder events noted in the
mg SC single dose cohort.  All 
observed events were of mild to moderate intensity.  Nausea and vomiting are common 
adverse reactions for molecules targeting the obesity pathways that at times require 
titration to overcome tolerability, eg, GLP-1R agonists.   
Following this, a multiple dose cohort (Part B) consisting of multiple doses of 
 mg 
Q2W x 6 was evaluated (cohort 2).  This was followed by a series of titration cohorts 
(Part C) with dose escalation over 2 to 3 doses (cohorts 3, 4, and 5).  The objective of 
Part C was to evaluate titration to reach higher exposures and to use a dose 
escalation approach starting from a dose that was previously shown to be 
tolerable, that is,
mg and assessing if the events of nausea and/or vomiting 
were related to initial drug exposures and later decreases with increase in 
dose/exposures.  
Based on preclinical PK analysis, the predicted half-life is approximately 11 days 
and therefore a regimen administering AMG 171 doses every 2 weeks was 


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evaluated in cohorts 3 and 4 (Part C).  A weekly regimen was also evaluated in 
cohort 5 (Part C) as an alternative regimen approach.   
The rationale for dose and regimen selection for Part D is based on the available 
safety and tolerability data from cohorts 3, 4, and 5. The available PK data from 
the ongoing first-in-human (FIH) study cohorts 1 to 5 (Parts A, B, and C) and the 
NOAEL exposures established based on 14-week GLP repeat-dose toxicology 
studies in mouse and cynomolgus monkeys also support the selection of doses 
and regimen to be evaluated in Part D.  Preliminary review of the PK data in 
cohorts 1 to 5 demonstrated that AMG 171 serum exposures increase in an 
approximately dose-proportional manner based on Cmax (AUC data pending), with 
a half-life of approximately 12 days. 
In cohorts 1 to 5, adverse events of nausea and vomiting occurred at doses of 
AMG 171 ranging from
mg to
mg SC, though these events were generally 
mild and resolved over time, including with repeated doses.  The dosing schema 
proposed in cohorts 6a-c and 7a-c (Part D) will seek to define optimal dosing 
titration to minimize nausea and vomiting.  The proposed regimens to be 
evaluated in Part D are Q2W regimens in cohorts 6a, 6b, and 6c, and regimens 
with Q1W dose escalation followed by Q2W dose escalation in cohorts 7a, 7b, and 
7c.  These 2 distinct dose escalation approaches will allow us to identify the 
escalation strategy that minimizes nausea and vomiting. 
The proposed doses to be evaluated in Part D of amendment are not to exceed 
mg in cohort 6a and 7a,
mg in cohorts 6b and 7b, and
mg in 
cohorts 6c and 7c.  The predicted human exposure multiples for AMG 171 following 
the highest dose of
mg in cohort 6c (Q2W regimen) are approximately 169- and 
112-fold for Cmax and AUC, respectively, based on NOAEL established in cynomolgus 
monkeys, and 90- and 21-fold for Cmax and AUC, respectively, based on NOAEL 
established in mice (refer to Table 4-1).  
The predicted human exposure multiples for AMG 171 following the highest dose 
of 
mg in cohort 7c (regimen consisting of QW doses up to
mg and Q2W 
doses thereafter until the last dose) are approximately 217- and 149-fold for Cmax 
and AUC, respectively, based on NOAEL established in cynomolgus monkeys, 
and 116- and 28-fold for Cmax and AUC, respectively, based on NOAEL established 
in mice (refer to Table 4-2). 


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Table 4-1.  Predicted Human Exposures and Associated Exposure Multiples 
Following the Last Proposed AMG 171 Doses – Cohorts 6a, 6b, and 6c 
Exposure Multiples 
Exposure Multiples 
Based on AUCss at the 
NOAELa 
Based on Cmax at the 
NOAELa 
Clinical 
Dose 
Anticipated 
Human Cmax 
(g/mL) 
Anticipated 
Human 
AUC 
(ghr/mL)b 
Mouse 
Monkey 
Mouse 
Monkey 
(mg) 
14-week 
14-week 
14-week 
14-week 
SC 
68 
368 
300 
563 
39 
208 
177 
331 
21 
112 
90 
169 
AUC = area under the curve; AUCss = area under the curve at steady state; Cmax = maximum concentration; 
GLP = glucagon-like peptide; NOAEL = no observed adverse effect level; Q2W = every 2 weeks; 
SC = subcutaneous.  
a Based on 14-week mouse GLP toxicology study NOAEL dose =
 mg/kg Q2W, Cmax =
µg/mL and 
AUCss = 
 µg-hr/mL; and based on 14-week GLP toxicology study in cynomolgus monkeys NOAEL 
dose =
mg/kg Q2W, Cmax =
µg/mL and AUCss = 
µg-hr/mL. 
b Predicted multiples rounded to integer. 
Table 4-2.  Predicted Human Exposures and Associated Exposure Multiples 
Following the Last Proposed AMG 171 Doses – Cohorts 7a, 7b, and 7c 
Exposure Multiples 
Exposure Multiples 
Based on AUCss at the 
NOAELa 
Based on Cmax at the 
NOAELa 
Clinical 
Dose 
Anticipated 
Human Cmax 
(g/mL) 
Anticipated 
Human 
AUC 
(ghr/mL)b 
Mouse 
Monkey 
Mouse 
Monkey 
(mg) 
14-week 
14-week 
14-week 
14-week 
SC 
81 
438   
323 
605 
43  
230 
193 
362 
28 
149 
116 
217 
AUC = area under the curve; AUCss = area under the curve at steady state; Cmax = maximum 
concentration; GLP = glucagon-like peptide; NOAEL = no observed adverse effect level; 
Q2W = every 2 weeks; SC = subcutaneous.  
a Based on 14-week mouse GLP toxicology study NOAEL dose =
mg/kg Q2W, Cmax =
µg/mL 
and AUCss = 
 µg-hr/mL; and based on 14-week GLP toxicology study in cynomolgus 
monkeys NOAEL dose =
mg/kg Q2W, Cmax =
µg/mL and AUCss =
 µg-hr/mL. 
b Predicted multiples rounded to integer. 
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4.4 
End of Study 
4.4.1 
End of Study Definition 
Primary Completion:  The primary completion date is the date when the last subject 
has completed the assessments for EOS. 


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If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study  
(ie, last subject last visit), following any additional parts in the study (eg, long-term 
follow-up, additional antibody testing), as applicable. 
4.4.2 
Study Duration for Subjects 
The planned duration of participation in the study is approximately 120 days for Part A, 
207 days for Part B, 85 days for cohorts 3 and 5, 113 days for cohort 4 (Part C), 
155 days for cohort 6 (Part D), and 148 days for cohort 7 (Part D).  
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 after signing the informed consent including limited information about the 
potential candidate (eg, date of screening).  This log may be completed and updated via 
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). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
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 prior to initiation of any study specific 
activities/procedures 
102 
Males and females age ≥ 18 to ≤ 65 years of age, 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 (Part A) and 
day -1 (Parts B and C) and screening  


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104 
Body mass index (BMI) between ≥ 30.0 kg/m2 and ≤ 40.0 kg/m2 
105 
Have a stable body weight (less than 5 kg self-reported change during the 
previous 8 weeks) prior to 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 non-reproductive potential  
o 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 
o History of hysterectomy; OR 
o History of bilateral oophorectomy 
108 
Males must agree to practice an acceptable method of effective birth control 
while on study through 2 and half months after receiving the last dose of study 
drug.  Acceptable methods of effective birth control include sexual abstinence; 
vasectomy and testing that shows there are no sperm in the semen; or a condom 
with spermicide (males) in combination with barrier methods (diaphragm, cervical 
cap or cervical sponge), hormonal birth control or IUD (females). 
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 
Hepatic liver enzymes ALT, AST, alkaline phosphatase (ALP), or total bilirubin 
(TBIL) levels > 1.5 times the upper limit of normal (ULN) at screening 
204 
History or clinical evidence of bleeding diathesis or any coagulation disorder, 
including prothrombin time (PT), activated partial thromboplastin time (APTT), 
International normalized ratio (INR) or platelet count outside of the laboratory’s 
normal reference range at screening 
205 
History of GI abnormality that could affect GI motility (including small bowel or 
colonic resection, inflammatory bowel disease, irritable bowel disease, and colon 
or GI tract cancer) 
206 
Allergy or sensitivity to acetaminophen (for subjects in Part A) 
207 
Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as 
thyroid-stimulating hormone > 6 mIU/L or < 0.4 mIU/L 
208 
A corrected QT interval (QTc) at screening of > 450 msec in males or  
> 470 msec in females or history of long QT syndrome 
209 
Subjects with a history of renal impairment or renal disease and/or estimated 
glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 


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210 
Obesity induced by other endocrinologic disorders (eg Cushing’s Syndrome) 
211 
Previous surgical treatment for obesity (excluding liposuction if performed  
>1 year before trial entry) and/or subjects with recent (within 6 months) or 
planned endoscopic treatment for obesity. 
212 
History of major depressive disorder 
213 
History of other severe psychiatric disorders, eg schizophrenia, bipolar disorder 
214 
A patient health questionnaire (PHQ-9) score of ≥ 10 
216 
Any suicidal ideation as identified by endorsement of (answered yes to) any of 
the items numbered 1-5 on the Columbia Suicide Severity Rating Scale  
(C-SSRS)  
217 
Surgery scheduled for the trial duration period, except for minor surgical 
procedures, at the discretion of the investigator 
218 
Positive results for human immunodeficiency virus (HIV) antibodies, hepatitis B 
surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus 
ribonucleic acid (RNA).  For hepatitis C, hepatitis C antibody (HepCAb) testing is 
done at screening, followed by hepatitis C virus RNA by polymerase chain 
reaction (PCR) if hepatitis C antibody is positive. 
219 
Subject has systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure  
≥ 90 mm Hg at screening, or on day -2 (Part A) or day -1 (Parts B and C).  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. 
220 
History of malignancy of any type, other than in situ cervical cancer or surgically 
excised non-melanomatous skin cancers occurring more than 5 years prior to 
randomization 
Prior/Concomitant Therapy 
221 
Use of the following agents are excluded unless there is a prior consultation 
between the Principal Investigator and Amgen Medical Monitor: 
 
Prescription and nonprescription drugs within 14 days or 5 half-lives, 
whichever is longer, before the first dose of investigational product, with 
exception to acetaminophen up to 2 g per day for analgesia, and hormone 
replacement therapy (eg, estrogen, thyroid)  
 
All herbal medicines, vitamins, and supplements within 30 days prior to 
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. 
222 
Current or history of treatment with medications that may cause significant weight 
gain, within 3 months prior to screening, including systemic corticosteroids 
(except for a short course of treatment, ie, 7−10 days), tri-cyclic antidepressants, 
atypical antipsychotic and mood stabilizers (eg, imipramine, amitriptyline, 
mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, 
olanzapine, valproic acid and its derivatives, and lithium) 
223 
Current participation (or within the last 3 months) in an organized weight 
reduction program or currently using or used within 3 months before screening: 


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pramlintide, sibutramine, orlistat, zonisamide, topiramate, phentermine, 
naltrexone, bupropion, lorcaserin, metformin, or any GLP-1R agonists (either by 
prescription or as part of a clinical trial) 
Prior/Concurrent Clinical Study Experience 
224 
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 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use 
contraception during treatment and for an additional 2 and half a months after the 
last dose of AMG 171  
227 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 2 and a half months after the last dose of AMG 171   
228 
Subject has known sensitivity to AMG 171 or components thereof or a history of 
drug or other allergy that is in the opinion of the investigator or medical monitor  
(if appropriate), contraindicates their participation 
229 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge 
230 
Subject has known sensitivity to mammalian derived products 
231 
Subject has a history or evidence of any other clinically significant disorder, 
condition or disease (with the exception of those outlined above) that, in the 
opinion of the investigator or Amgen Medical Monitor, if consulted, would pose a 
risk to subject safety or interfere with the study evaluation, procedures or 
completion 
232 
Subject is unwilling or unable to limit alcohol consumption throughout the course 
of the study.  Alcohol is prohibited 48 hours prior to day -2 (Part A) and day -1 
(Parts B and C) and is limited to no more than to 2 drinks per day for males and 
1 drink per day for females for the duration of the study (1 drink being equivalent 
to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine, or 
1.5 ounces of 80 proof distilled spirits). 
233 
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. 
234 
Subject is tested positive for alcohol and/or drugs of abuse at screening 
235 
History of substance abuse (ie, alcohol, licit or illicit drugs) within 12 months 
before screening 
236 
Subject is unwilling to refrain from strenuous exercise (eg, heavy lifting, weight 
training, and aerobics) for 72 hours prior to each blood collection for clinical 
laboratory tests 


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237 
Subject has donated or lost ≥ 500 mL of blood or plasma within 60 days of day -2 
(Part A) and day -1 (Parts B and C) 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Subjects will be required to fast overnight for at least 10 hours prior to all blood draws for 
routine clinical laboratory, lipid profile and PD assessments per Schedule of Activities 
(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 prior to admission to the research facility on day -2 (Part A) and 
day -1 (Parts B and C).  For all subjects, alcohol consumption is limited to no more than 
2 drinks per day for males, 1 drink per day for females, for the duration of the study 
(1 drink is equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces 
of wine or 1.5 ounces of 80 proof distilled spirits). 
Only non-nicotine or non-tobacco using subjects should be enrolled.  Subjects should 
not have used any nicotine or tobacco containing products within the last 6 months prior 
to screening.  Subjects must abstain from nicotine or tobacco containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, e-cigarettes, 
pipes, or nicotine patches) throughout the screening period and for the duration of the 
study.  
5.3.3 
Activity 
Subjects will abstain from strenuous exercise for 72 hours before each blood 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 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). 


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Each subject who enters into the screening period for the study (after signing the 
informed consent form) receives a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned via IRT (see Section 6.4).  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 1 time after discussion with Amgen Medical Monitor.  Refer to 
Section 8.1.1. 
5.6 
Washout Period/Run-in Period/Invasive Procedure(s) 
This section is not applicable. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The modular Investigational Product Instruction Manual (IPIM), a document external to 
this protocol, contains detailed information regarding the storage, preparation, 
destruction, and administration of each treatment. 


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6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
Table 6-1.  Study Treatments 
Study Treatment 
Name 
Amgen Investigational Product:a 
 AMG 171 
Placebo 
Dosage Formulation 
Colorless to slightly yellow liquid drug 
product in a
mL glass vial (12 vials 
per box) filled with a
mL deliverable 
volume of 
mg/mL.  The specific 
packaging dimensions are 8.9 x 6.7 x 
4.5 cm. 
Placebo will be 
presented in identical 
containers, and 
stored/packaged the 
same as AMG 171 
Unit Dose 
Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
Refer to Table 1-1 
 
Route of 
Administration 
SC injection 
 
Accountability 
The unblinded pharmacist must provide 
AMG 171 or placebo from the Amgen 
supplied stock according to the IRT 
assignment.  The, dose, start date/time, 
and lot number (after study is unblinded) of 
AMG 171 is to be recorded on each 
subject's CRF(s). 
 
Dosing Instructions 
Administration of AMG 171 or placebo 
requires specific training which must be 
completed and documented prior to 
undertaking any administration related 
activities. AMG 171 will be delivered as 
1+ injections SC.  Dosing instructions are 
provided in the modular IPIM. 
 
IV = intravenous; SC = subcutaneous 
a AMG 171 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
6.1.2 
Medical Devices 
This section is not applicable. 
6.1.3 
Other Protocol-required Therapies 
All other protocol-required therapies, including acetaminophen, 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 and 1b, will undergo a Gastric Emptying test after an 
overnight fast of a minimum of 10 hours.  For this assessment, oral liquid 
acetaminophen 1000 mg (acetaminophen Extra Strength) is administered followed 
immediately by administering a standardized liquid meal (ie, 16 fl oz, or 2 bottles or 


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cans, of Ensure Plus®). Timing of PK samples of acetaminophen after the standardized 
meal are summarized in the Schedule of Activities in Section 1.3. 
6.1.4 
Other Treatment Procedures 
This section is not applicable. 
6.1.5 
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 and 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 products provisioned and/or repackaged/modified by 
Amgen including AMG 171 and placebo. 
Any product complaint(s) associated with investigational products supplied by Amgen 
are to be reported according to the instructions provided in the modular IPIM. 
6.1.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
With exception to acetaminophen up to 2 g per day for analgesia and hormone 
replacement therapy (eg, estrogen, thyroid), use of any over-the-counter or prescription 
medications within the 14 days or 5 half-lives (whichever is longer) prior to dosing on day 
1, and for the duration of the study, is not permitted unless to treat a medical emergency.  
For subjects in Part A, acetaminophen should not be consumed within 72 hours of the 
Gastric Emptying test, otherwise the same guidance applies.  In addition, it is 
recommended that subjects avoid starting new or changing herbal medicines, vitamins 
and supplements unless reviewed and approved by the Principal Investigator and 
Amgen Medical Monitor within 30 days prior to dosing on day 1 and for the duration of 
the study.  Any changes regarding concomitant medications should be recorded on the 
subject’s source documents and the CRF along with the reason for the change. 


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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 tolerated based on available study 
data through study day 15 for all dosed subjects (cohorts 1 and 1b) or study day 22 for  
at least 6 of 8 dosed subjects (cohorts 2 and 3), as applicable and upon unanimous 
agreement of the DLRT members.  Enrollment into cohorts 6a and 7a will begin 
contemporaneously after a DLRM of cohorts 4 and 5, which include review of 
cumulative data of all prior cohorts.  Enrollment in cohorts 6b and 7b will 
occur after DLRT recommendation based on all safety and laboratory data 
through at least study day 43 of cohort 6a (Part D) and cumulative data of all prior 
cohorts.  Subsequently, cohorts 6c and 7c will be dosed in parallel after the dose 
regimen in cohort 6b has been recommended by the DLRT to have no safety 
signals observed and be reasonably tolerated based on all safety and laboratory 
data through at least study day 57 for at least 6 out of 8 subjects dosed and 
cumulative data of all prior cohorts.   
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.  Further 
information on DLRMs is provided in 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 6-2 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 6-2. 


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Table 6-2.  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 AE 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 AE 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. 
AE = adverse event; DLRM = dose level review meeting; DLRT = Dose Limiting Review Team; 
NIH = National Institutes of Health. 
Adverse drug reaction = adverse events with causal association to the study drug per the investigator.   
NIH nausea: grade 1 – transient (< 24 hours) or intermittent with no or minimal interference with normal 
intake; grade 2 – persistent nausea resulting in decreased oral intake for 24-48 hours; grade 3 – minimal 
oral intake for >48 hours or aggressive rehydration (intravenous fluids).  NIH vomiting: grade 1 – transient 
or intermittent vomiting with no or minimal interference with normal intake; grade 2 – frequent episodes of 
vomiting with no or mild dehydration; grade 3 – persistent vomiting resulting in orthostatic hypotension or 
aggressive rehydration indicated (eg, intravenous fluids) (Sibille et al, 2010). 
Please refer to Section 11.4 for additional information on adverse events and safety reporting. 


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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 suspected adverse drug reactions, and serious adverse 
events 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. 
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 171 
The reason for dose change of AMG 171/placebo is to be recorded on each subject’s 
CRF(s). Refer to Section 11.3 
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 and during 
the study are provided in the modular 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 of AMG 171 to placebo for 
cohorts 1, 1b, 2 to 5, 6a-c, and 7a-c, in a double-blind manner, respectively. 
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 records and on the enrollment case report form 
(CRF). 


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6.4.2 
Blinding 
This is a double-blind study.  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 
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 prior to the study being formally 
unblinded. 
6.5 
Treatment Compliance 
Study drug will be administered at the clinic by qualified staff. 
6.6 
Treatment of Overdose 
The effects of overdose of AMG 171 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. 


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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 8.2.4. 
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 prior to 
enrollment through the first dose of investigational product should 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 6.1.6. 
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 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 below in Sections 7.1, 
7.2, and 7.3. 
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 


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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 
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 
 
Protocol-specified criteria (eg meets hepatotoxicity stopping rules per Section 11.7 
and/or Mental Health Criteria Stopping Rules Section 11.8) 
 
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.   


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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).  Subject will be encouraged to attend a safety follow up 
visit to complete EOS assessment.  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 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 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 


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immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
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 in order to assess eligibility for participation.  The screening window is up to 
28 days/4 weeks. 
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 
re-screening 1 time after Sponsor approval.  
If the subject meets eligibility criteria but is not enrolled within the 28-day screening 
period, a new 28-day screening window may begin for an open cohort and all screening 
procedures should be repeated.  This subject is not registered as a screen fail. 
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/4 weeks 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 and Follow-up 
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 


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administered after all pre-dose assessments and/or procedures during each visit that it is 
required. 
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.  End of Study visit procedures should be 
performed at this safety follow-up visit per the Schedule of Activities (Section 1.3). 
8.1.3 
End of Study 
End of Study (EOS) visit procedures will be performed per the Schedule of Activities 
(Section 1.3).  For subject completing the study, this visit occurs on day 120 (Part A) or 
day 207 (Part B), a minimum of 70 days after the last scheduled dose (Part C), and a 
minimum of 60 days after the last scheduled dose (Part D).  If feasible, all EOS 
procedures should be performed at the final visit for subjects who are removed from 
study prior to the defined EOS 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. 
8.2.1 
General Assessments  
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 PK 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 electrocardiograms 
(ECGs), vital signs, 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: 


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For the SAD cohorts (Part A): 
 
 5 minutes window around the target completion time for tests and samples 
through 24 hours post-dose 
 
 1 hour on subsequent days in-house 
 
Per the visit windows through EOS 
For the multiple dose and titration cohorts (Parts B, C, and D): 
 
Per the visit windows through EOS 
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. 
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.  Pre-dose abnormal findings will be reported on the medical 
history page of the CRF. 
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:  BMI (kg/m2) = weight (kg)/[height (cm)/100]^2. 
Waist circumference: Subjects should wear minimal clothing to ensure that the 
measuring tape is correctly positioned.  Subjects should stand erect with the abdomen 


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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 or 1/2 inch 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, and drugs of 
abuse. 
8.2.2 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 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 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  ECGs should be 
performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs 
should be completed within a total of 5 minutes from the start of the first to the 


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completion of the third), prior to 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 pre-dose.  The PI or (eg, designated site physician) will 
review all ECGs. 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 1.  
8.2.2.3 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
8.2.2.4 
Suicidal Risk Monitoring 
AMG 171 is considered to be central nervous system (CNS)-active.   
Subjects being treated with multiple doses of AMG 171 (Parts B, C, and D) must be 
monitored appropriately and observed closely for suicidal ideation and behavior or any 
other unusual changes in behavior.  Consideration is to be given to discontinuing 
AMG 171 in subjects who experience signs of suicidal ideation or behavior.  
Families and caregivers of subjects being treated with multiple doses of AMG 171 are to 
be instructed to monitor subjects for the emergence of unusual changes in behavior, as 
well as the emergence of suicidal ideation and behavior, and to report such symptoms 
immediately to the study investigator. 


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For Parts B, C, and D, 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 Health Questionnaire 9 (PHQ-9).  The C-SSRS is a clinician 
rating of suicidal behavior and ideation.  The C-SSRS consists of a maximum of 
20 items.  C-SSRS 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.  Refer to Sections 11.8 through Section 11.10 for 
more information on mental health monitoring. 
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 end of study are reported using the Event CRF. 
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 end of study/safety follow-up visit are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s knowledge 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. 


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8.2.3.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events suspected to be 
related to investigational product after the protocol-required reporting period (as 
defined in Section 8.2.3.1.2) is complete, then these serious adverse events will be 
reported to Amgen within 24 hours following the investigator’s knowledge of the event 
on the Events CRF. 
If the study endpoint is overall survival, then the sites will also need to 
collect/report fatal serious adverse events (regardless of causality) to Amgen 
within 24 hours of awareness. 
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 if the subject ends the study. 
8.2.3.1.4 
Reporting a Safety Endpoint as a Study Endpoint 
Not applicable 
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 


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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. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
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. 


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8.2.3.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
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 
2 and half months after receiving last dose of study drug. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 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. 
8.2.3.7 
Adverse Device Effects 
This section is not applicable. 
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 Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
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).  


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Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening and 
within 7 days of initiation of investigational product for all female subjects.   
If a female subject, or the partner of a male subject, becomes pregnant it must be 
reported on the Pregnancy Notification Form, see Figure 11-2).  Refer to Section 11.5 for 
contraceptive requirements.  
For all female subjects, a serum pregnancy test should be performed according to the 
schedule of assessments including the EOS/safety follow up visit after discontinuing 
protocol-required therapies and 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 receive AMG 171 will have PK samples assessed. 
Whole blood samples of approximately 5 mL will be collected for measurement of serum 
concentrations of AMG 171 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. 
Blood samples (approximately 7 × 1 mL for acetaminophen PK, cohort 1 and 1b) 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 171 treatment PD effects at each time point specified in the Schedule of Activities.  
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 
inherited genetic variations to evaluate their possible correlation to the disease and/or 


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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 171.  Additional samples are collected for this part of the study.  For subjects 
who consent to this/these analysis/analyses, DNA may be extracted. 
The final disposition of samples will be described in Section 11.6.  
8.2.8 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Section 1.3) for the measurement of  
anti-AMG 171 binding antibodies.  Samples testing positive for binding antibodies will 
also be tested for neutralizing antibodies and may be further characterized.  Additional 
blood samples may be obtained to rule out anti-AMG 171 antibodies during the study. 
Sites will be notified of any positive neutralizing antibody results to AMG 171 for 
individual subjects at the end of the study for each subject.  If results are not provided, 
no neutralizing antibodies to AMG 171 have been detected. 
This notification is independent of and may be in advance of the time point when the 
entire study is planned to be unblinded.  Refer to Section 6.4.2 for additional information 
regarding unblinding. 
Subjects who test positive for neutralizing antibodies to AMG 171 at the final scheduled 
study visit defined as the end of study visit will be asked to return for additional follow-up 
testing.  This testing is to occur approximately every 3 months starting from when the 
site has been notified of the positive result until: (1) neutralizing antibodies are no longer 
detectable; or (2) the subject has been followed for a period of at least 1 year 
(± 4 weeks) post administration of AMG 171.  All follow-up results, both positive and 
negative will be communicated to the sites.  More frequent testing (eg, every month) or 
testing for a longer period of time may be requested in the event of safety-related 
concerns.  Follow-up testing is not required where it is established that the subject did 
not receive AMG 171. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-AMG 171 antibody response 
may also be asked to return for additional follow-up testing.  Refer to the Schedule of 
Activities (Section 1.3), as applicable, for specific time points, and the laboratory manual 
for detailed collection and handling instructions. 


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8.2.9 
Biomarker Discovery  
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
Samples will also be collected for biomarker analysis, eg, to evaluate potential 
biomarkers that may correlate with treatment response.   
Blood will be collected for biomarker discovery at the time points specified in the 
Schedule of Activities (Section 1.3).  Plasma and/or serum may also be used for DNA, 
RNA, and protein expression analysis including somatic mutations in order to correlate 
levels of expression with response. 
8.2.9.1 
Biomarker Development/Future Research 
Biomarker Development refers to using samples collected for Biomarker Discovery for 
future research after the study ends. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity.   
If consent is provided by subjects, biomarker discovery samples collected at the time 
points specified in the Schedule of Activities will be retained for future biomarker 
development as described in Section 11.6.  No additional samples will be collected for 
biomarker development/future research.  
Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to AMG 171 to investigate 
and further understand obesity and /or metabolic conditions. 
8.2.10 
Health Economics  
This section is not applicable. 
8.2.11 
Other Assessments  
Dual-energy x-ray absorptiometry (DXA) 
Dual-energy x-ray absorptiometry (DXA) scans of body composition [eg, fat, muscle and 
bone mineral content (BMC)] will be conducted in cohort 2 as outlined in the Schedule of 
Activities (Section 1.3). The central vendor will provide an instructional manual.   
Gastric Emptying Test 
Subject in cohorts 1 and 1b, underwent a Gastric Emptying test as measured by 
acetaminophen absorption and PK on day -1, and day 5.  The gastric emptying test 


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(initiated early in the morning) was performed after an overnight fast for at least 
10 hours.  Subjects received 1000 mg of oral liquid acetaminophen (Major®Extra 
Strength), followed immediately by a standardized meal (ie, bottles or cans, of Ensure 
Plus®).  Subjects were allowed to take up to 10 minutes to consume the standardized 
meal.  As part of this evaluation, multiple blood samples were collected for 
acetaminophen PK to measure gastric emptying, as well as PD measurements, per the 
Schedule of Activities (Section 1.3).  
Please refer to the central laboratory manual for instructions on the collection of these 
samples. 
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 
hypothesis will be tested.  For safety considerations, with up to 72 subjects (12 subjects 
from Part A, 6 subjects in Part B, 18 subjects from Part C, and 36 subjects from 
Part D) receiving AMG 171, the chance of detecting an adverse event with a true 
incidence rate of 2% or greater is larger than 77% and the chance of detecting an 
adverse event with a true incidence rate of 4% or greater is larger than 95%. 
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
9.3.1.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects who receive at least 1 dose of 
investigational product on day 1. 
9.3.1.2 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set will consist of all subjects who received at least 1 dose of 
AMG 171 for whom at least 1 PK parameter or endpoint can be adequately estimated. 
9.3.1.3 
Pharmacodynamic (PD) Analysis Set 
The PD analysis set will consist of all subjects who received 1 dose of investigational 
product for whom at least 1 PD parameter or endpoint can be adequately estimated. 
9.3.2 
Covariates 
Baseline values may be used as a covariate in analyses. 


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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 following 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 
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. 
9.4.1.2 
Primary Analysis 
The primary analysis will occur after all subjects have completed the study.  Data will be 
locked prior to the primary analysis and a clean snapshot of the data will be used for the 
primary analysis. 
9.4.1.3 
Final Analysis 
The primary analysis will be the final analysis for this study. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK and PD 
endpoints.  Descriptive statistics on continuous measurements will include means, 
medians, 25th and 75th percentiles, standard deviations and ranges, while categorical 
data will be summarized using frequency counts and percentages.  Data will be 
presented and summarized by treatment and at each time point.  Graphical summaries 
of the data may also be presented. 
Data for subjects receiving placebo may be combined across cohorts within Parts A, B, 
and C. 


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Data for subjects receiving AMG171 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 
This section is not applicable. 
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, 
and adverse events leading to withdrawal from investigational product or other 
protocol-required therapies.  The number and percentage of subjects reporting adverse 
events will be evaluated for each dose cohort, across dose cohorts.  Adverse events 
resulting in treatment discontinuation will be identified.  Subject incidence of 
device-related events, if applicable, will be tabulated by system organ class and 
preferred term. 
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. 


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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. 
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 (QTcF) will be categorized, and the number and 
percentage of subjects in each group will be summarized.  Subjects’ maximum 
post-baseline values will also be categorized, and the number and percentage of 
subjects in each group will be summarized.  All on-study ECG data will be listed and 
select parameters of interest plotted. 
9.4.2.3.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 171 antibodies 
(binding and if positive, neutralizing) at any time will be tabulated by treatment group. 
9.4.2.3.8 
Exposure to Investigational Product 
The number of doses of IP and the proportion of subjects receiving each dose level will 
be summarized using descriptive statistics.  Subject-level data may be provided instead 
of the summary if the subject incidence is low or single dose is given. 
9.4.2.3.9 
Exposure to Non-investigational Product 
Not applicable 
9.4.2.3.10 
Exposure to Other Protocol-required Therapy 
Not applicable. 
9.4.2.3.11 
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 
Serum AMG 171 concentrations will be determined using a validated assay.  Individual 
serum concentration-time plots for AMG 171 will be presented for each subject as well 
as mean concentration-time plots for each dose cohort.  PK parameters that may 
include, but are not limited to AUC, Cmax, and Tmax will be estimated using either 
compartmental (eg, PK modeling) or non-compartmental methods.  Actual dosing and 


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sampling times will be used for calculation of PK parameters.  Summary statistics will be 
generated for each PK parameter for each dose cohort. 
Plasma acetaminophen concentrations as part of the Gastric Emptying 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 AUC0-5h as well 
as maximum plasma acetaminophen concentrations (Cmax), and time of Cmax (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.  The safety analysis set will be used for all 
exploratory endpoint analysis performed. 


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10. 
References 
AMG 171 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Breit SN, Tsai VW, Brown DA. Targeting obesity and cachexia: identification of the 
GFRAL receptor–MIC-1/GDF15 pathway. Trends Mol Med. 2017;23:1065-1067 
Clarke RJ, Williams JA. The value of phenol red and chromic chloride as nonabsorbable 
gastric indicators. Gut. 1971;12:389-392. 
Clements JA, Heading RC, Nimmo WS, Prescott LF. Kinetics of acetaminophen 
absorption and gastric emptying in man. Clin Pharmacol Ther. 1978;24:420-431. 
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. 
Emmerson PJ, Wang F, Du Y, et al. The metabolic effects of GDF15 are mediated by 
the orphan receptor GFRAL. Nat Med. 2017;23:1215-1219. 
Engelhardt JA. Predictivity of animal studies for human injection site reactions with 
parenteral drug products. Exp Toxicol Pathol. 2008;60(4-5):323-7 
Heymsfield SB, Wadden TA. Mechanisms, pathophysiology and management of obesity. 
N Engl J Med. 2017;376:254-266. 
Hsu JY, Crawley S, Chen M, et al. Non-homeostatic body weight regulation through a 
brainstem-restricted receptor for GDF15. Nature. 2017;550:255-259. 
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):S102–138.  Cardiology/American 
Heart Association Task Force on Practice Guidelines and The Obesity Society. 
Circulation. 2014;129(Suppl 2):S102–38. 
Johnen H, Lin S, Kuffner T, et al. Tumor-induced anorexia and weight loss are mediated 
by the TGF-β superfamily cytokine MIC-1. Nat Med. 2007;13:1333-1340. 
Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for 
obesity with weight loss and adverse events. JAMA. 2016;315:2424. 
Kolotkin RL, Meter K, Williams GR. Quality of life and obesity. Obes Rev. 2001;2:219–
229. 
Levin S, Semler D, Rubin Z. Effects of two weeks of feed restriction on some common 
toxicologic parameters in Sprague Dawley rats. Tox Path. 1993;21(1):1-14. 
Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, et al.  Cardiovascular 
effects of intensive lifestyle intervention in type 2 diabetes.  N Engl J Med.  
2013;369:145‑154.   
Look AHEAD Research Group.  Eight‑year weight losses with an intensive lifestyle 
intervention:  the look AHEAD study.  Obesity (Silver Spring).  2014;22:5–13.  2013; 
288:1929-1938.  
Mullican SE, Lin-Schmidt X, Chin CN, et al. GFRAL is the receptor for GDF15 and the 
ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23:1150- 
1157. 


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Naylor SW, Czajkowski M, Harvey W, Smith M, Bradly AE, Cary M.  Histopathological 
findings in cynomolgus macaques (Macaca fascicularis) consistent with secondary 
immunological reaction to biotherapeutics with an emphasis on the CNS and eye. 
Toxicol Pathol. 2019; 47(2) 165-173. 
Paixão P, Bermejo M, Hens B, et al. Gastric emptying and intestinal appearance of 
nonabsorbable drugs phenol red and paromomycin in human subjects: A multi-
compartment stomach approach. Eur J Pharm Biopharm. 2018;129:162-74. 
Sibille M, Patat A, Caplain H, Donazzolo Y.  A safety grading scale to support dose 
escalation and define stopping rules for healthy subject first-entry-into-man studies. Br J 
Clin Pharmacol. 2010;70(5):736-748. 
Terranova L, Busetto L, Vestri A, Zappa MA.  Bariatric surgery:  cost‑effectiveness and 
budget impact.  Obes Surg.  2012;22:646–653.  
Tsai VW, Macia L, Johnen H, et al. TGF-b superfamily cytokine MIC-1/GDF15 is a 
physiological appetite and body weight regulator. PloS one. 2013;8:e55174. 
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.   
World Health Organization.  Obesity and overweight; 2018 [cited 2019 September 18].  
Available from: http://www.who.int/mediacentre/factsheets/fs311/en/ 
Xiong Y, Walker K, Min X, et al. Long-acting MIC-1/GDF15 molecules to treat obesity: 
Evidence from mice to monkeys. Sci Transl Med. 2017;9:eaan8732. 
Yang L, Chang CC, Sun Z, et al. GFRAL is the receptor for GDF15 and is required for 
the anti-obesity effects of the ligand. Nat Med. 2017;23:1158-1166. 


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11. 
Appendices 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADA 
anti-drug antibody 
AUC 
area under the curve 
CFR 
U.S. Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRF 
case report form 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DES 
Amgen data element standard 
DILI 
drug induced liver injury 
DLRM 
Dose level review meeting 
DLRT 
Dose Level Review Team 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
epidermal growth factor receptor 
Enrollment 
defined as when the investigator decides that the subject has 
met all eligibility criteria and assigns a randomization number   
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
EOS 
end of study 
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early  
End of Study (end of trial) 
defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
FFA 
free fatty acid 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GLP1R 
glucagon-like peptide-1 receptor 
HBcAb 
hepatitis B core antibody 


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Abbreviation or Term 
Definition/Explanation 
HBsAg 
hepatitis B surface antigen 
HDL-C 
high-density lipoprotein cholesterol 
HepCAb 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
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 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
LDL-C 
low-density lipoprotein cholesterol 
MAD 
multiple ascending dose 
NCT 
National Clinical Trials 
NOAEL 
no observed adverse effect level 
PHQ-9 
Patient Health Questionnaire 9 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
Q1W 
weekly 
Q2W 
every 2 weeks 
Randomization 
defined as once a unique subject randomization number has 
been assigned via IRT at enrollment 
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 trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
SUSAR 
suspected unexpected serious adverse reaction 


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Abbreviation or Term 
Definition/Explanation 
TMF 
trial master file 
ULN 
upper limit of normal 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory and/or by the 
local laboratory as described in Section 1.3.  Additional analyte test results may be 
reported by the local or central laboratory, in accordance with standard laboratory 
procedures (eg, components of a hematology panel). 
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. 


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Table 11-1.  Analyte Listing 
Local 
Laboratory: 
Chemistry 
Local 
Laboratory: 
Coagulation 
Local 
Laboratory: 
Urinalysis 
Local  
Laboratory: 
Hematology 
Other  
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or 
Urea 
Creatinine 
Uric acid 
Creatine 
kinase 
Total 
bilirubin 
Direct 
bilirubin 
ALP 
LDH 
AST 
(SGOT) 
ALT (SGPT) 
PT/INR 
APTT 
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 
Differential 
• Bands/stabs 
• Segmented 
     Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Total 
Neutrophil         
     Count 
Local Laboratory: 
Pregnancy (Serum or Urine)  
Hep B surface antigen 
Hep C antibody 
HIVa 
FSH 
TSH 
Lipid panelb 
• HDL 
• LDL 
• Triglycerides 
• Cholesterol 
HbA1cb 
Central Laboratory:  
Antibodies 
Serum PK 
Plasma PD: 
• Insulin 
• Glucose 
• c-peptide 
• Free fatty acids 
• Glucagon 
Serum PD 
Serum endogenous 
    GDF15 
Lipid Panelb 
• HDL 
• LDL 
• Triglycerides 
• Cholesterol 
HbA1cb 
Footnotes defined on next page of the table. 
a HIV assessment is recommended 
b Lipid panel and HbA1c are to be run by local lab at screening and central lab at all other time 
points  
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; FSH = follicle stimulating hormone; HbA1C = hemoglobin A1C; HDL = 
high density lipoprotein; Hep = hepatitis; HIV = human immunodeficiency virus; HLA = human leukocyte 
antigen; INR = international normalized ratio; LDH = lactate dehydrogenase; LDL = low density lipoprotein; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = 
mean corpuscular volume; PD = pharmacodynamic; PK = pharmacokinetic; PT = prothrombin time; 
PTT = partial thromboplastin time;  RBC = red blood cell count; RDW = Red cell distribution width; SGOT = 
serum glutamic-oxaloacetic transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC = white 
blood cell count 
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.  


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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 non-voting 
Amgen representatives may also be part of the DLRT:  clinical study manager, 
biostatistician, or pharmacokinetic (PK) 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, IP administration, medical history, 
concomitant medications, adverse events, ECG, vital signs, and laboratory results will be 
reviewed.  Data to be reviewed may 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. 
DLRM 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 the Site Investigators or delegates 
combined.  Regardless of how many Site Investigators there are, all the Site 


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Investigators combined will have a total of 1 vote decided by a majority of the 
investigators (defined as greater than or equal to 50%). 
DLRM 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 Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document that Amgen distributes to the site.  
The investigator must send a copy of the approval letter from the IRB/IEC and amended 
protocol Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
The investigator will be responsible for the following: 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 


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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 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 will then be 
required to sign a statement of informed consent that meets the requirements of  
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 


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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 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 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.  
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 (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 
signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 


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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 
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 


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submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
A recognized expert in the therapeutic area 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
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. 


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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. 
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 IRT 
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 


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inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation, and all correspondence to and from the IRB/IEC and 
Amgen 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product for 
Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
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. 


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Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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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 SAP. 
 
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. 
 
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. 
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) 


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Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 


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Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (CRF). 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product; 
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 (CRO) 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 shown below: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 


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


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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.  
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 the 
paper-based Serious Event Contingency Report Form. 


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
 


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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 Sections 5.1 and 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 2 and half months after the last dose of protocol-required 
therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:   
1) review of subject’s medical records; 2) subject’s medical examination; or  
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
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. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
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)  


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 
Use a condom during treatment and for an additional 2 and half months after the last 
dose of protocol-required therapies 
The female partner should consider using an acceptable method of effective 
contraception such as: hormonal, IUD, IUS, female barrier method (diaphragm, cap, 
sponge, a female condom is not an option because there is a risk of tearing when both 
partners use a condom). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Unacceptable Methods of Birth Control 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
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 2 and half months after 
last dosed of AMG 171/placebo. 
 
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 2 and half 
months of the study drug.  This information will be forwarded to Amgen Global 
Patient Safety.  Generally, infant follow-up will be conducted up to 12 months after 
the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 


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termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 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 
2 and half 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 2 and half month of receiving last 
dose of study drug. 
 
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 238. 


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 
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 2 and half months after discontinuing 
protocol-required therapies. 
Figure 11-2.  Pregnancy and Lactation Notification Forms 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood (biomarker, pharmacokinetics (PK) 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 
obesity and other metabolic conditions, the dose response and/or prediction of response 
to AMG 171 and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites).  Results from this analysis are to be documented and maintained but are 
not necessarily reported as part of this study.  Samples can be retained for up to 
20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the 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 


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request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
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. 


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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. 
11.7.1 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due 
to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-1 antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  


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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 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (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 
 
11.7.2 
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 study drug is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation  
(as described in Table 11-2) are never to be rechallenged. 


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11.7.3 
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 11-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


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 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
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.  
 


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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 Columbia-Suicide Severity Rating Scale (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 sores have been identified. 
Table 11-3.  Conditions for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Changes in Mental Health 
Scores  
Mental Health Assessment 
Permanent Discontinuation 
PHQ-9 
 10 
 
OR 
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 11-3 
are to undergo a period of “close observation” until the subject’s care can be transferred 
to an appropriate mental health professional. 


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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 
 


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Protocol Number:  20180224 
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Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
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Product:  AMG 171 
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11.10 
Appendix 10.  Patient Health Questionnaire 9 (PHQ-9) 
Figure 11-4.  Sample PHQ-9 Form 
 
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 1 of 2 
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 and Multiple Ascending Dose Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 171 in 
Subjects With Obesity 
Amgen Protocol Number AMG 171 20180224 
Amendment Date: 
18 August 2021 
 
Rationale: 
Additional dose cohorts are being added to explore higher exposures and dose titration 
regimens that will limit tolerability issues of nausea and vomiting. 
This protocol is being amended to: 
 
Update the study design:  AMG 171 or placebo will be administered 
subcutaneously (SC).  Part D is comprised of approximately 48 subjects enrolling 
into 1 of 6 cohorts.  Enrollment into cohorts 6a and 7a will begin 
contemporaneously after a Dose Level Review Meeting (DLRM) of cohorts 4 and 
5, respectively.  Enrollment in cohorts 6b and 7b will occur after Dose Level 
Review Team (DLRT) recommendation based on safety and laboratory data 
through at least study day 43 of cohort 6a (Part D).  Subsequently, cohorts 6c and 
7c will be dosed in parallel after the dose regimen in cohort 6b has been 
recommended by the DLRT to be safe and reasonably tolerated based on safety 
and laboratory data through at least study day 57 for at least 6 out of 8 subjects 
dosed.   
 
Update the AMG 171 dosing (Part D):  
o Cohort 6a:  Study drug will be administered SC every 2 weeks (Q2W) for 
a total of 7 doses 
   
o Cohort 6b:  Study drug will be administered SC Q2W for a total of 7 doses 
.  
o Cohort 6c:  Study drug will be administered SC Q2W for a total of 7 doses 
.   


Product:  AMG 171 
Protocol Number:  20180224 
Date:  18 August 2021 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
o Cohort 7a:  Study drug will be administered SC weekly (Q1W) for a total 
of 4 doses 
 and then Q2W for a total of 
4 additional doses 
.   
o Cohort 7b:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional 
doses
.   
o Cohort 7c:  Study drug will be administered SC Q1W for a total of 4 doses 
 and then Q2W for a total of 4 additional 
doses 
.   
 
Update the number of subjects planned to be enrolled for Part D 
 
Administrative, typographical, and formatting changes were made throughout all 
documents. 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  28 October 2020 
Page 1 of 2 
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 and Multiple Ascending Dose Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 171 in 
Subjects With Obesity 
 
 
Amgen Protocol Number AMG 171 20180224 
 
Amendment Date: 
28 October 2020 
 
Rationale: 
This protocol amendment addresses changes to study design after nausea and vomiting 
treatment-emergent adverse events (TEAEs) of moderate severity were reported in 
cohort 1b 
mg subcutaneous [SC]) and met protocol-specified stopping rule criteria.  
Adverse reactions of transient nausea and vomiting have been observed with other 
glucagon-like peptide 1R (GLP-1R) agonists drugs approved for chronic weight 
management in obese and overweight adults (eg, liraglutide) and have been associated 
with greater weight loss, suggesting an on-target pharmacodynamic effect.  In general, 
these reported side effects of other GLP-1 agonists were tolerable with the percentage 
of patients reporting nausea declining as treatment continued.  The observed TEAEs for 
AMG 171 may also reflect on-target pharmacodynamic activity.  This amendment 
incorporates adjustments to the dosing plan, to assess if dose titration and low fixed 
dose multiple dosing for AMG 171 help mitigate the side effects of nausea and vomiting. 
This protocol is being amended to: 
 
Update the study design:  AMG 171 will be administered SC.  Part A is 
comprised of 2 single ascending dose cohorts, Part B is a multiple dose cohort, 
and Part C is a titration phase with step dosing ranging from 2 to 3 ascending 
doses.  The study consists of a total of 6 cohorts: 2 cohorts (Part A), 1 cohort 
(Part B), and 3 cohorts (Part C). 
 
Update the AMG 171 dosing:  


Product:  AMG 171 
Protocol Number:  20180224 
Date:  28 October 2020 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
o Part A:  As tolerability was noted to worsen with the dose increase from 
 mg (cohort 1) to 
 mg (cohort 1b) with adverse events of nausea and 
vomiting (mild to moderate severity), multiple doses of the lower more 
tolerated dose 
 mg will be evaluated in Part B, and titration and Part  A 
dose levels will be evaluated in Part C. 
o Part B:  Approximately 8 subjects will enroll into 1 cohort 8 subjects will 
be randomized to receive AMG 171 or placebo SC in a 3:1 ratio.  
Enrollment of subsequent cohorts (Part C) will occur once recommended 
by the Dose Level Review Team (DLRT) after safety and laboratory data 
through at least study day 22 for at least 6 out of 8 subjects dosed in 
cohort 2 (Part B) is deemed to be safe and reasonably tolerated. 
o Part C:  Approximately 24 subjects will enroll into 1 of 3 cohorts.  In each 
cohort, 8 subjects will be randomized to receive AMG 171 or placebo SC 
in a 3:1 ratio.  Enrollment into cohort 3 will occur after DLRT 
recommendation based on safety and laboratory day through at least 
study day 22 of cohort 2 (Part B).  Subsequently, cohorts 4 and 5 will be 
dosed after the dose regimen in the cohort 3 has been recommended by 
the DLRT to be safe and reasonably tolerated based on safety and 
laboratory data through day 22 for at least 6 out of 8 subjects dosed.  
 
Update the number of subjects planned to be enrolled (approximately 48 subjects 
[8 subjects per cohort, cohorts 1, 1b, 2-5]). 
 
Additional study days were added to each cohort. 
 
Update the planned study duration: 
o Part A is approximately 120 days, Part B is 207 days, and Part C cohort 3 
is 85 days, cohort 4 is 113 days, and cohort 5 is 85 days. 
 
Update that the primary analysis will occur with the final analysis. 
 
Administrative, typographical, and formatting changes were made throughout all 
documents. 
 


Product:  AMG 171 
Protocol Number:  20180224 
Date:  07 February 2020 
Page 1 of 18 
CONFIDENTIAL 
 
 
Amendment #1 
 
Protocol Title:  A Phase 1, Randomized, Double-blind, 
Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 171 in 
Subjects With Obesity 
 
Amgen Protocol Number: AMG 171 20180224 
 
Amendment Date: 
07 February 2020 
Rationale: 
Protocol was amended to include an additional intermediate cohort (lower dose than 
planned) between cohort 1 and 2, and to revise dosing for future cohorts pending safety 
review of completed cohorts. Main changes to the protocol include: 
 
Addition of cohort 1b dosing at 
 mg (due to mild adverse events of nausea 
observed in cohort 1 suggesting a pharmacodynamic effect at initial low dose) 
 
Addition of ADA sample collection at Day 15 
 
Addition of ECG 10min post dose in cohort 6 IV dosing 
 
Removing Gastric emptying test in cohort 6 IV dosing 
 
Collection of photographs during local injection site reactions, if appropriate 
 
Collection of additional ADA samples within 30 min if subject experiences a 
hypersensitivity reaction 

SAP_001.pdf: 
Product:  AMG 171   
Protocol Number:  20180224 
Date:  01 February 2022 
Page 1 of 43 
 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 1, Randomized, Double-blind, 
Placebo-controlled, Single and Multiple Ascending 
Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 
171 in Subjects With Obesity 
Short Protocol Title: 
Single and Multiple Ascending Dose Study of AMG 
171 in Subjects with Obesity 
Protocol Number: 
20180224 
NCT Number: 
04199351 
Authors: 
 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
SAP Date: 
Document Version 
Date 
Amendment 1 (v[2.0]) 
01 February 2022 
  Original (v[1.0])                    09 April 2020 
 
 
 
 


Product:  AMG 171   
Protocol Number:  20180224 
Date:  01 February 2022 
Page 2 of 43 
 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
9 April 2020 
NA 
[Amendment 1 
(v2.0)] 
1st February 
2022 
1.0 Introduction 
Replace: 
The purpose of this Statistical Analysis 
Plan (SAP) is to provide details of the 
statistical analyses that have been 
outlined within the protocol amendment 1 
for study 20180224, AMG 171 dated 07 
February 2020. 
With: 
The purpose of this Statistical Analysis 
Plan (SAP) is to provide details of the 
statistical analyses that have been 
outlined within the protocol amendment 2 
for study dated 20180224, AMG 171 28 
October 2020. 
2.1 Objective and Endpoints 
Replace: 
 
To assess the effect of AMG 171 
on hemoglobin A1c (HbA1c) in the 
multiple dose cohorts (Parts B and 
C)  
 
 
To assess the effect of AMG 171 
on body composition in the 
multiple dose cohorts (Parts B and 
C)  
With: 
 
To assess the effect of 
AMG 171 on hemoglobin A1c 
(HbA1c) in the multiple dose 
cohorts (Parts B) 
 
To assess the effect of 
AMG 171 on body composition in 
the multiple dose cohorts (Parts 
B) 
 


Product:  AMG 171   
Protocol Number:  20180224 
Date:  01 February 2022 
Page 3 of 43 
 
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FORM-008180 v. 16.0, 15 May 2019 
 
3.1 Study Design 
Replace: 
This is a phase 1, randomized, double-
blind, placebo-controlled, single and 
multiple ascending dose study in adult 
subjects with obesity. The study will be 
conducted at approximately 3-4 sites in 
the United States. Additional sites may be 
added. AMG 171 will be administered 
subcutaneously (SC) or intravenously (IV) 
(Part A: cohort 6 only). Part A will be a 
single ascending dose (SAD) phase; Part 
B will be a multiple ascending dose  
phase; and Part C will be an expansion 
cohort. The study consists of a total of 12 
cohorts: 7 cohorts (Part A), 4 cohorts 
(Part B), and 1 cohort (Part C).  
Potential subjects will be screened within 
28 days before Day 1 to assess their 
eligibility to enter the study. Subjects will 
be confined at the Clinical Research Unit 
(CRU) from Check-in (morning of Day -2) 
through the morning of Day 6 in Part A 
(SAD phase), from Day -1 to Day 1 in 
Part B, or optionally from Day -1 to Day 1 
(Part C). 
Part A  
Approximately 56 subjects will enroll into 
one of 7 cohorts. In each cohort, eight (8) 
subjects will be randomized to receive 
AMG 171 or placebo SC (cohorts 1, 1b, 
2-5) or IV (cohort 6) in a 3:1 ratio as 
described in Table 3-1. For each cohort, 


Product:  AMG 171   
Protocol Number:  20180224 
Date:  01 February 2022 
Page 4 of 43 
 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
the first 2 subjects (sentinel pair) will be 
randomized such that 1 subject will 
receive AMG 171 and 1 subject will 
receive placebo. The sentinel pair will be 
observed for at least 24 hours before the 
remaining subjects in the cohort are 
dosed, provided there are no safety or 
tolerability concerns as assessed by the 
Principal Investigator (PI). Enrollment into 
the SAD cohorts will be sequential. 
Subsequent cohorts will be dosed after 
the dose regimen in the preceding cohort 
has been recommended by the Dose 
Level Review Team (DLRT) to be safe 
and reasonably tolerated based on the 
safety and laboratory data through at 
least study day 15 for at least 7 out of 8 
subjects dosed.  
Part B  
Approximately 32 subjects will enroll into 
one of 4 cohorts. In each cohort, eight (8) 
subjects will be randomized to receive 
AMG 171 or placebo SC in a 3:1 ratio as 
described in Table 3-1. Enrollment into 
Part B will occur with a starting 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. 
DLRT recommendations will be based on 
safety and laboratory data through at 
least study day 15 for at least 7 out of 8 
subjects dosed in each SAD cohort (Part 
A). Enrollment into the remaining cohorts 


Product:  AMG 171   
Protocol Number:  20180224 
Date:  01 February 2022 
Page 5 of 43 
 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
will be sequential. Subsequent cohorts 
will be dosed after the dose regimen in 
the preceding 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 a minimum of 6 out of the 8 
subjects dosed. All subjects in each Part 
B  cohort may be dosed on the same day. 
 
Cohorts 7-9: Study drug will be 
administered every 4 weeks 
(Q4W) 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 Part A (SAD). Three 
different dose levels will be 
evaluated with the lowest dose 
administered to cohort 7, and two 
higher ascending doses 
administered to cohorts 8 and 9. 
The dose level for cohorts 7-9 will 
not exceed the highest dose 
evaluated in cohorts 1-6 (Part A), 
including cohort 1b. 
 
Cohort 10: Study drug will be 
administered every 2 weeks 
(Q2W) for a total of 6 SC doses. 
The dose level will be defined 
after evaluation of the available 
PK and PD data from proceeding 
cohorts. The dose level will not 


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exceed half the highest dose 
evaluated in cohorts 7-9 (Part B).  
Part C  
Up to 60 subjects will enroll into cohort 
11. All subjects will be randomized in a 
1:1 ratio to receive AMG 171 or placebo 
SC as described in Table 3-1. Enrollment 
into cohort 11 (Part C) will occur after the 
dose regimen in previous cohorts (Part B) 
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 a minimum of 6 of 
the 8 subjects dosed. The dose regimen 
for cohort 11 will be chosen based on the 
preceding cohorts’ available safety and 
PK data and will not exceed the highest 
dose evaluated in cohorts 7-9. 
Dose Level Review Meetings (DLRM) 
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 has been 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 each cohort in Part A, 
and day 36 for a minimum of 6 of the 8 
subjects dosed in each cohort in Part B, 
and upon unanimous recommendation at 
the DLRM. 
 


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With: 
This is a phase 1, randomized, double-
blind, placebo-controlled, single and 
multiple ascending dose study in adult 
subjects with obesity.  The study will be 
conducted at approximately 3-4 sites in 
the United States.  Additional sites may 
be added.  AMG 171 will be administered 
SC.  Part A (completed) was a single 
ascending dose (SAD) phase; Part B is a 
multiple dose phase in 1 cohort; and Part 
C is a titration phase with step dosing 
for 2 to 3 doses total.  The study 
consists of a total of 6 cohorts: 2 cohorts 
(Part A; SAD), 1 cohort (Part B), and 
3 cohorts (Part C; titration). 
Potential subjects will be screened within 
28 days before day 1 to assess their 
eligibility to enter the study.  Subjects will 
be confined at the Clinical Research Unit 
(CRU) from Check-in (morning of Day -1) 
through the morning of day 6 in Part A 
(SAD phase), from day -1 for a 7-day 
(6-night) residency period and re-
admitted on day -14 for a second 7-day 


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(6-night) residency period in Part B.  
Subjects in Part C (cohorts 3 to 5) will 
be admitted after confirmed eligibility 
on day -1.  Cohort 3 subjects will be 
admitted after confirmed eligibility on 
day -1 for a 7-day (6-night) residency 
period and re-admitted on day 14 for a 
second 7-day (6-night) residency 
period.  Cohort 4 subjects will be 
admitted after confirmed eligibility on 
day -1 for a 7-day (6-night) residency 
period, re-admitted on day 14 for a 
second 7-day (6-night) residency 
period, and re-admitted on day 28 for a 
third 7-day (6-night) residency period.  
Cohort 5 subjects will be admitted 
after confirmed eligibility on day -1 for 
a 14-day (13-night) residency period. 
Part B 
Approximately 8 subjects will enroll 
into 1 cohort (cohort 2) where 8 
subjects will be randomized to receive 
AMG 171 or placebo SC in a 3:1 ratio 
as described in Table 3.1. 
Part C (Titration) 
Approximately 24 subjects will enroll into 
1 of 3 cohorts (cohorts 3 to 5).  In each 
cohort, 8 subjects will be randomized to 
receive AMG 171 or placebo SC in a 
3:1 ratio as described in Table 3.1.  
Enrollment into cohort 3 will occur after 
DLRT recommendation based on safety 
and laboratory data through at least study 


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day 22 of cohort 2 (Part B).  
Subsequently, both cohort 4 and 5 will 
be dosed after the dose regimen in cohort 
3 has been recommended by the DLRT to 
be safe and reasonably tolerated based 
on safety and laboratory data through at 
least study day 22 for at least 6 out of 
8 subjects dosed.  Enrollment of dose 
cohorts is depicted in Figure 3.1. 
 
 
Dose Level Review Meetings (DLRM) 
A DLRM will be held to review subject 
data and monitor safety before escalation 
to the next cohort.  Escalation to a higher 
dose titration 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 upon 
unanimous recommendation at the 
DLRM. 
Safety and laboratory data was 
reviewed through day 15 for at least 7 
out of 8 subjects dosed in Part A and 


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through day 22 for at least 6 of 8 
subjects dosed in Part B and Part C. 
 
 
3.2 Sample Size 
Replace: 
Approximately 148 subjects (8 subjects 
per cohort, cohorts 1, 1b, 2-10; up to 60 
subjects in cohort 11) will be enrolled. 
Additional subjects may be enrolled if a 
DLRT recommendation is made to 
expand, repeat or add cohorts to the 
study. The sample size for the study is 
based on practical considerations. No 
statistical hypothesis will be tested. For 
safety considerations, with up to 96 
subjects (66 subjects from Part A and B, 
30 subjects from Part C) receiving AMG 
171, the chance of detecting an adverse 
event with a true incidence rate of 2 or 
greater is more than 85 and the chance 
of detecting an adverse event with a true 
incidence rate of 4 or greater is more 
than 98.  
Cohort 11 (Part C) with 1:1 randomization 
will allow for 80 probability of observing 
a mean treatment difference in percent 


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change from baseline in body weight 
between AMG 171 and placebo of  3, 
assuming a true treatment difference of 
5 at week 12 which represents clinically 
meaningful weight loss. This assumes a 
standard deviation for percent change 
from baseline in body weight of 7 in 
each treatment group. 
With: 
Approximately 48 subjects (8 subjects per 
cohort, cohorts 1, 1b, 2 to 5) will be 
enrolled.  Additional subjects may be 
enrolled if a DLRT recommendation is 
made to expand, repeat or add cohorts to 
the study. The sample size for the study 
is based on practical considerations.  No 
statistical hypothesis will be tested.  For 
safety considerations, with up to 36 
subjects (12 subjects from Part A, 
6 subjects in Part B, and 18 subjects 
from Part C) receiving AMG 171, the 
chance of detecting an adverse event 
with a true incidence rate of 3% or greater 
is larger than 67% and the chance of 
detecting an adverse event with a true 
incidence rate of 5% or greater is larger 
than 84%. 
5.0 Defintions 
Replace: 
Treatment-Emergent Adverse Event:  
A treatment-emergent adverse event 
(TEAE) is any adverse event that is 
categorized as an Adverse Event (AE) 


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starting on or after first dose of 
investigational product as determined by 
the flag indicating if the adverse event 
started prior to the first dose on the 
Events eCRF and up to the End of Study 
date. 
With: 
Treatment-Emergent Adverse Event: 
Events categorized as Adverse Events 
(AEs) starting on or after first dose of 
investigational product as determined by 
"Did event start before first dose of 
investigational product" equal to "No" or 
missing on the Events eCRF and up to 
the End of Study date. 
Definition Added: 
Treatment-Emergent Serious Adverse 
Event: 
Treatment-emergent adverse events 
indicated as serious on the Events eCRF. 
Replace: 
 
Baseline ECG:  
For cohort 1 to 10 subjects, baseline ECG 
will be calculated as the average of the 
available pre-dose observations (9 
observations) taken on Day 1. If any of 
the observations are missing, the mean 
will be calculated by taking the available 
observations. If all Day 1 pre-dose 
observations are missing, the baseline 
will be calculated in the same way using 


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the last assessment before first dose of 
IP.  
For cohort 11 subjects, baseline ECG is 
defined as the single pre-dose 
observation taken on Day 1. If the Day 1 
pre-dose observation is missing, the last 
assessment taken before investigational 
product will be used. 
With: 
Baseline and Post-baseline ECG: 
Where multiple 12-lead ECG 
measurements are taken at the same 
assessment time point (they are planned 
to be recorded in triplicate 30 seconds 
apart) the mean value will be calculated 
and used in the analysis.  The baseline 
ECG is defined as the mean of all the pre-
dose assessments measured on Study 
Day 1; the mean of values in a triplicate 
should be calculated before taking the 
mean of the triplicate averages.  For pre 
and post dose ECG measurements, 
unscheduled ECG measurements taken 
up to 5 minutes after the last assessment 
of a triplicate will be included in the 
averages for a time point.  Where an ECG 
is missing within a triplicate, all available 
data will be averaged for that time point. 
Replace:  
End of Study:  
The end of study date is defined as the 
date when the last subject across all sites 
is assessed or receives an intervention 


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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. 
With: 
Subject-level End of Study (EOS) Date: 
End of study for each subject is defined 
as the date the subject last completed a 
protocol-specified procedure.  The date 
will be recorded on the End of Study CRF 
page. 
Definition Added: 
Baseline and Post-baseline BMI: 
Baseline and Post-baseline BMI is to 
derive by Baseline height and respective 
visit of the weight measurement.  
BMI (kg/m2)  weight (kg)/[height 
(cm)/100]^2. 
End of IP (EOIP) Date: 
End of IP Admin for each subject is 
defined as the date the decision was 
made to end IP as recorded on the End 
of IP CRF page. 
Last IP Dose Date: 
Last IP Dose Date for each subject is 
defined as the latest date IP is 
administered. 
Duration of IP Exposure in Weeks 
Duration of IP exposure (weeks)  (Last 
Dose IP Date – Study Day 1 1) / 7 


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Duration of Study Exposure in Weeks 
Duration of Study exposure (weeks)  
(EOS Date - Study Day 1  1) / 7 
Definition Removed: 
Bazett-corrected QT Interval (QTcB)  
The Bazett’s correction will be calculated 
from the investigator reported QT (msec) 
and RR interval (msec), as follows: 
QTcBQT/ (RR/1000)1/2 
6.0 Analysis Sets 
Replace: 
The following analysis sets may be 
separately defined for SAD (cohort 1-6), 
cohort 7-10 and extension cohort 11. 
With: 
The following analysis sets may be 
separately defined for part A (SAD cohort 
1 and 1b), part B (cohort 2) and part C 
(titration cohort 3-5). 
Definition Added: 
6.1  Full Analysis Set (FAS) 
The full analysis set will consist of all 
subjects who receive at least one dose 
of investigational product. 
6.2  Safety Analysis Set (SAS) 
Replace: 
The safety analysis set will consist of all 
subjects who receive at least one dose of 
investigational product. 
With: 


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The safety analysis set is defined as 
same to the FAS. 
6.3 Pharmacodynamic (PD) Analysis Set 
Removed 
7.2 Priimary Analysis 
Replace: 
The primary analysis will occur after all 
subjects in cohort 1 to 10 (including 
cohort 1b) have completed the study.  
Data will be locked prior to conducting the 
primary analysis based on a clean 
snapshot of data from cohort 1 to 10. 
With: 
The primary analysis will occur after all 
subjects have completed the study. 
Data will be locked prior to the primary 
analysis and a clean snapshot of data 
will be used for the primary analysis. 
7.3 Final Analysis 
Replace: 
The final analysis will occur after all 
subjects in cohort 11 have completed the 
study.  
Data will be locked prior to conducting the 
final analysis based on a clean snapshot 
of data from cohort 11. 
With: 
The primary analysis will be the final 
analysis for this study. 
9.0 General Considerations 
Replace: 


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Data for subjects receiving placebo may 
be combined across cohorts within Part A 
and Part B, separately. 
With: 
Data for subjects receiving placebo may 
be combined across cohorts within Parts 
A, B, and C. 
9.4 Demographic and Baseline 
Characteristics 
Replace: 
Demographic (ie. age, age groups [< 40, 
>= 40], sex, race, ethnicity) and baseline 
characteristics (height, weight, body mass 
index, medical history) will be 
summarized by cohort and actual 
treatment group and overall (i.e. total from 
all the cohorts involved in the analysis 
and irrespective of treatment received) 
using descriptive statistics. 
With: 
Demographic (ie. age, age groups [< 40, 
>= 40, <18, 18-64, ≥65],], sex, race, 
ethnicity) and baseline characteristics 
(height, weight, body mass index, medical 
history) will be summarized by cohort and 
actual treatment group and overall (i.e. 
total from all the cohorts involved in the 
analysis and irrespective of treatment 
received) using descriptive statistics. 
9.6.1 Analysis of Primary Safety 
Endpoint(s) 
Replace: 


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With: 
 
 
9.6.2 Adverse Events 
Replace: 
The subject incidence of adverse events 
will be summarized for all TEAEs, SAEs, 
TEAEs leading to withdraw of IP, fatal 
adverse events, treatment related TEAEs 
and adverse events of interest (EOIs).  
Subject incidence of all TEAEs, SAEs, 
TEAEs leading to withdrawal of IP, fatal 
adverse events, and treatment related 
TEAEs will be tabulated by SOC and PT 
in descending order of frequency. 
Immunogenicity, Injection site reactions 
and Nausea/vomiting will be identified 
using Amgen-defined MedDRA search 
strategies. 
With: 


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The subject incidence of adverse events 
will be summarized for all TEAEs, SAEs, 
TEAEs leading to withdraw of IP, fatal 
adverse events, and adverse events of 
interest (EOIs). 
Subject incidence of all TEAEs leading to 
withdrawal of IP, fatal adverse events, 
and will be tabulated by SOC and PT in 
descending order of frequency. 
Immunogenicity, Injection site reactions 
and Nausea/vomiting will be identified 
using a broad search/scope in Amgen-
defined MedDRA search strategies. 
 
9.6.3 Laboratory Test Results 
Replace: 
For key laboratory parameters which are 
given in Table A below, summary 
statistics will be provided for actual value, 
change from baseline and percent 
change from baseline by study part (Part 
A, B and C), actual treatment group at 
each protocol-specified scheduled visit.  
 
With: 
For key laboratory parameters which are 
given in Table 9.2 below, summary 
statistics will be provided for actual value, 
change from baseline and percent 
change from baseline by study part (Part 


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A, B and C), actual treatment group at 
each protocol-specified scheduled visit.  
 
 
9.6.6 Electrocardiogram 
Replace: 
Summary statistics for all ECG 
parameters (QRS, QT, QTc, RR, PR, 
QTcF and QTcB) will be provided for 
actual value, change from baseline and 
percent change from baseline by study 
parts (Part A, B and C) and actual 
treatment group at each specified 
protocol scheduled visit. Further, subjects’ 
maximum change from baseline in QTcF 
and QTcB will be categorized in following 
categories and the number and 
percentage of subjects in each group will 
summarized by study parts (Part A, B and 
C) and actual treatment group. 
Unscheduled assessments will be 
included in the determination of the 
maximum change.  
 
 30 msec 
 
 30 – 60 msec 
 
 60 msec 
Subjects’ maximum post baseline values 
in QTcF and QTcB will also be 
categorized in the following categories 
and the number and percentage of 
subjects in each group will be 
summarized.  


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 
 450 msec 
 
 450 – 480 msec 
 
 480 – 500 msec 
 
 500 msec 
Listings of all on-study ECG 
measurements may be generated and 
reviewed but may not be included in the 
CSR. 
With: 
Summaries over time and changes from 
baseline over time will be provided for all 
12-lead ECG parameters (QRS, QT, RR, 
PR, and QTcF) by study parts (Part A, B 
and C) and actual treatment group at 
each specified protocol scheduled visit.  
The analysis Fridericia’s (QTcF) QT 
correction will be performed using the 
derived results as specified in Section 5.  
Subjects will be categorized into the 
following groups per their maximum 
change from baseline in QTcF.  
Unscheduled assessments will be 
included in the determination of the 
maximum change. 
 
≤ 30 msec 
 
> 30 – 60 msec 
 
> 60 msec 
Subjects will also be categorized into the 
following groups per their maximum post 
baseline QTcF.  Unscheduled 
assessments will be included in the 
determination of the maximum post 
baseline value. 
 
≤ 450 msec 


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 
> 450 – 480 msec 
 
> 480 – 500 msec 
 
> 500 msec 
All on-study electrocardiogram (ECG) 
data will be listed and reviewed but may 
not be included in the CSR. 
9.7.1 Secondary Endpoint - 
Pharmacokinetics Analysis 
Removed: 
Plasma acetaminophen concentrations as 
part of the Gastric Emptying 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 AUC0-5h as well as maximum 
plasma acetaminophen concentrations 
(Cmax), and time of Cmax (Tmax). 
  
9.7.2.1 Pharmacodynamic Parameters 
Replace: 
 
HbA1c levels (Part B and C only). 
 
Body composition parameters (eg. 
Fat, muscle and bone mineral 
content) measured by Dual-
energy x-ray absorptiometry (Part 
B and C only). 
With: 
 
HbA1c levels (Part B only). 
 
Body composition parameters (eg. 
Fat, muscle and bone mineral 
content) measured by Dual-


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energy x-ray absorptiometry (Part 
B only). 
9.7.2.1 Pharmacodynamic Parameters 
Removed 
 
Gastric emptying as assessed by 
acetaminophen absorption 
kinetics (Cmax and AUC) (Part A 
only). 
 
Potential biomarkers including, but 
not limited to, inflammatory and 
adipose tissue markers  
 
Endogenous GDF15 levels  
10. Changes From Protocol-specified 
Analyses 
Replace: 
There are no changes to the protocol-
specified analyses 
With: 
No PK and pharmacodynamic (PD) 
analysis will be performed for gastric 
emptying test. PD analysis set will also 
not be created. 
 
 


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Table of Contents 
1. 
Introduction .......................................................................................................... 28 
2. 
Objectives, Endpoints and Hypotheses ................................................................ 28 
2.1 
Objectives and Endpoints ......................................................................... 28 
2.2 
Hypotheses and/or Estimations ................................................................. 30 
3. 
Study Overview .................................................................................................... 30 
3.1 
Study Design ............................................................................................ 30 
3.2 
Sample Size .............................................................................................. 32 
3.3 
Adaptive Design ........................................................................................ 32 
4. 
Covariates and Subgroups ................................................................................... 32 
4.1 
Planned Covariates ................................................................................... 32 
4.2 
Subgroups ................................................................................................ 32 
5. 
Definitions ............................................................................................................ 32 
6. 
Analysis Sets ........................................................................................................ 35 
6.1 
Full Analysis Set (FAS) ............................................................................. 35 
6.2 
Safety Analysis Set (SAS) ......................................................................... 35 
6.3 
Pharmacokinetic (PK) Analysis Set ........................................................... 35 
7. 
Planned Analyses ................................................................................................. 35 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 35 
7.2 
Primary Analysis ....................................................................................... 35 
7.3 
Final Analysis ............................................................................................ 35 
8. 
Data Screening and Acceptance .......................................................................... 35 
8.1 
General Principles ..................................................................................... 35 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 36 
8.3 
Handling of Missing and Incomplete Data ................................................. 36 
8.4 
Detection of Bias ....................................................................................... 36 
8.5 
Outliers ..................................................................................................... 36 
8.6 
Distributional Characteristics ..................................................................... 36 
8.7 
Validation of Statistical Analyses ............................................................... 37 
9. 
Statistical Methods of Analysis ............................................................................. 37 
9.1 
General Considerations ............................................................................ 37 
9.2 
Subject Accountability ............................................................................... 37 
9.3 
Important Protocol Deviations ................................................................... 38 
9.4 
Demographic and Baseline Characteristics ............................................... 38 
9.5 
Efficacy Analyses ...................................................................................... 38 
9.6 
Safety Analyses ........................................................................................ 38 
9.6.1 
Analyses of Primary Safety Endpoint(s) .................................... 38 


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9.6.2 
Adverse Events ......................................................................... 39 
9.6.3 
Laboratory Test Results ............................................................ 39 
9.6.4 
Vital Signs ................................................................................. 40 
9.6.5 
Physical Measurements ............................................................ 40 
9.6.6 
Electrocardiogram ..................................................................... 40 
9.6.7 
Antibody Formation ................................................................... 41 
9.6.8 
Exposure to Investigational Product .......................................... 41 
9.6.9 
Exposure to Concomitant Medication ........................................ 41 
9.7 
Other Analyses ......................................................................................... 41 
9.7.1 
Secondary Endpoint – Pharmacokinetics Analysis .................... 41 
9.7.2 
Exploratory Endpoints ............................................................... 42 
9.7.2.1 
Pharmacodynamic Parameters ............................... 42 
10. 
Changes From Protocol-specified Analyses ......................................................... 42 
11. 
Literature Citations / References .......................................................................... 42 
12. 
Prioritization of Analyses ...................................................................................... 42 
13. 
Data Not Covered by This Plan ............................................................................ 42 
14. 
Appendices .......................................................................................................... 43 
 
List of Table 
Table 3.1.  Planned Dose Levels by Cohort in Parts A, B and C ................................... 29 
Table 9.1.  Safety Endpoint Summary Table ................................................................. 36 
Table 9.2.  Laboratory parameters ................................................................................ 38 
 
List of Figures 
Figure 3.1.  Planned Dose Levels by Cohort in Parts A, B and C .................................. 29 
 
 


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List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event(s) 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
Cmax 
maximum serum concentration 
DLRM 
DLRT 
DXA  
Dose level review meeting 
Dose level review team 
Dual-energy x ray absorptiometry 
ECG 
12-lead electrocardiogram 
eCRF 
FFA 
electronic case report form 
Free Fatty Acid 
IP 
IPD 
Investigational product 
Important protocol deviation 
LDL-C 
LLQ 
Low-density lipoprotein cholesterol 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamic(s) 
PI 
Principle investigator 
PK 
PT 
Pharmacokinetic(s) 
Preferred term 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
QRS interval 
QRS interval the interval between the Q wave and the S wave in 
the heart's electrical cycle as measured by ECG; represents the 
time it takes for the depolarization of the ventricles 
QT interval 
QT interval is a measure of the time between the start of the Q 
wave and the end of the T wave in the heart's electrical cycle as 
measured by ECG 


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QTc interval 
QTcF 
Q2W 
Q4W 
QT interval corrected for heart rate using accepted methodology 
Fridericia-corrected QT Interval 
every 2 weeks 
every 4 weeks 
RR 
respiratory rate 
SAD 
SAE 
Single ascending dose 
Serious adverse event 
SC 
SAP 
SOC 
TEAE    
Subcutaneous 
Statistical analysis plan 
System organ class 
Treatment emergent adverse event 
Tmax 
time to maximum serum concentration 
EOS 
End of Study 
Safety FU 
Safety Follow-Up 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 2 for study 20180224, 
AMG 171 dated 28 October 2020.  The scope of this plan includes the primary analysis 
and the final analysis that are planned and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 To assess the safety and tolerability 
of AMG 171 as single or 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 PK of AMG 171 
as single or multiple doses in 
subjects with obesity 
 
AMG 171 PK parameters including, but 
not limited to, maximum observed 
concentration (Cmax), the time of 
maximum observed concentration 
(Tmax), and area under the 
concentration time curve (AUC) 
 To evaluate the immunogenicity of 
AMG 171 
 
Incidence of anti-AMG 171 antibody 
formation 
 


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Objectives 
Endpoints 
Exploratory 
 To characterize the PD effects of 
AMG 171 as single or multiple doses 
in subjects with obesity 
o To assess the effect of 
AMG 171 on fasting and 
post-prandial (Part A) 
metabolic parameters 
 
o To assess the effect of 
AMG 171 on gastric 
emptying in the single 
ascending dose cohorts 
(Part A) 
 
o To assess the effect of 
AMG 171 on fasting lipid 
levels 
 
 
o To assess the effect of 
AMG 171 on hemoglobin A1c 
(HbA1c) in the multiple dose 
cohorts (Part B) 
 
o To assess the effect of 
AMG 171 on potential 
biomarkers 
 
 
o To assess the effect of 
AMG 171 on endogenous 
GDF15 levels 
 
o To assess the effects of 
AMG 171 on body weight, 
waist circumference and 
body mass index (BMI) 
 
o To assess the effect of 
AMG 171 on body 
composition in the multiple 
dose cohorts (Part B) 
 
Changes in pharmacodynamic 
parameters: 
 
o Changes in the fasting and 
post-mixed meal challenge 
glucose, insulin, c-peptide, 
glucagon, and free fatty acid 
(FFA) concentrations 
o Gastric emptying as assessed 
by acetaminophen absorption 
kinetics (Cmax and AUC)  
 
o Changes in fasting lipid levels, 
including, but not limited to, total 
cholesterol, low density 
lipoprotein cholesterol (LDL-C), 
high density lipoprotein 
cholesterol (HDL-C), and 
triglycerides 
 
o Changes in HbA1c levels  
 
o Changes in potential biomarkers 
including, but not limited to, 
inflammatory and adipose tissue 
markers 
 
 
o Changes in endogenous GDF15 
levels 
 
 
o Changes in body weight, waist 
circumference, and BMI 
 
 
o Changes in body composition as 
measured by whole body 
dual-energy x-ray 
absorptiometry (DXA)  
 


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2.2 
Hypotheses and/or Estimations 
No statistical hypotheses will be tested in this study.  
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple 
ascending dose study in adult subjects with obesity.  The study will be conducted at 
approximately 3-4 sites in the United States.  Additional sites may be added.  AMG 
171 will be administered SC.  Part A (completed) was a single ascending dose (SAD) 
phase; Part B is a multiple dose phase in 1 cohort; and Part C is a titration phase with 
step dosing for 2 to 3 doses total.  The study consists of a total of 6 cohorts: 2 cohorts 
(Part A; SAD), 1 cohort (Part B), and 3 cohorts (Part C; titration). 
Potential subjects will be screened within 28 days before day 1 to assess their eligibility 
to enter the study.  Subjects will be confined at the Clinical Research Unit (CRU) from 
Check-in (morning of Day -1) through the morning of day 6 in Part A (SAD phase), 
from day -1 for a 7-day (6-night) residency period and re-admitted on day -14 for a 
second 7-day (6-night) residency period in Part B.  Subjects in Part C (cohorts 3 to 
5) will be admitted after confirmed eligibility on day -1.  Cohort 3 subjects will be 
admitted after confirmed eligibility on day -1 for a 7-day (6-night) residency period 
and re-admitted on day 14 for a second 7-day (6-night) residency period.  
Cohort 4 subjects will be admitted after confirmed eligibility on day -1 for a 7-day 
(6-night) residency period, re-admitted on day 14 for a second 7-day (6-night) 
residency period, and re-admitted on day 28 for a third 7-day (6-night) residency 
period.  Cohort 5 subjects will be admitted after confirmed eligibility on day -1 for a 
14-day (13-night) residency period. 
Part B 
Approximately 8 subjects will enroll into 1 cohort (cohort 2) where 8 subjects will 
be randomized to receive AMG 171 or placebo SC in a 3:1 ratio as described in 
Table 3.1. 
Part C (Titration) 
Approximately 24 subjects will enroll into 1 of 3 cohorts (cohorts 3 to 5).  In each cohort, 
8 subjects will be randomized to receive AMG 171 or placebo SC in a 3:1 ratio as 
described in Table 3.1.  Enrollment into cohort 3 will occur after DLRT recommendation 


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based on safety and laboratory data through at least study day 22 of cohort 2 (Part B).  
Subsequently, both cohort 4 and 5 will be dosed after the dose regimen in cohort 3 has 
been recommended by the DLRT to be safe and reasonably tolerated based on safety 
and laboratory data through at least study day 22 for at least 6 out of 8 subjects dosed.  
Enrollment of dose cohorts is depicted in Figure 3.1. 
Figure 3.1.  Planned Dose Levels by Cohort in Parts A, B and C 
 
Dose Level Review Meetings (DLRM) 
A DLRM will be held to review subject data and monitor safety before escalation to the 
next cohort.  Escalation to a higher dose titration 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 upon unanimous recommendation at the DLRM. 
Safety and laboratory data was reviewed through day 15 for at least 7 out of 8 
subjects dosed in Part A and through day 22 for at least 6 of 8 subjects dosed in 
Part B and Part C. 
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. 
Cohort 2
6:2,
 mg SC Q2W x 6
Cohort 3
6:2, Dose titration Q2W:
mg SC x 1 
mg SC x 1
Cohort 4
6:2, Dose titration Q2W:
mg SC x 1
mg SC x 1
mg SC x 1
Cohort 5
6:2, Dose titration Q1W:
mg SC x 1 
mg SC x 1
Screen
FU Period
D-28           D1 single dose                        EOS            
Cohort 1 6:2,
mg SC
Cohort 1B 6:2
mg SC
Screen
FU Period
D-28           D1 single dose                        EOS            
completed
Treatment
Screen
FU Period
D-28          D1                                                                                       EOS            
Treatment
Screen
FU Period
D-28          D1                                                                                       EOS            
Treatment
Screen
FU Period
D-28          D1                                                                                       EOS            
Treatment
Screen
FU Period
D-28          D1                                                                                       EOS            


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Table 3.1.  Planned Dose Levels by Cohort in Parts A, B and C 
 
Cohort 
 
Subjects 
AMG 171/Placebo 
Dose/Frequency 
Route 
N (active: 
placebo) 
PART A 
1 
8 
mg day 1 x 1 
SC 
6:2 
1ba 
8 
mg day 1 x 1 
SC 
6:2 
PART B 
2 
8 
 mg Q2W x 6 
SC 
6:2 
PART C 
(titration) 
3 
8 
mg day 1 x 1 
mg day 15 x 1 
SC 
6:2 
4 
8 
mg day 1 x 1 
mg day 15 x 1 
mg day 29 x 1 
SC 
6:2 
5 
8 
mg day 1 x 1 
mg day 8 x 1 
SC 
6:2 
Q2W  every 2 weeks; SC  subcutaneous. 
a Cohort 1b added during protocol Amendment 1. 
3.2 
Sample Size 
Approximately 48 subjects (8 subjects per cohort, cohorts 1, 1b, 2 to 5) will be enrolled.  
Additional subjects may be enrolled if a DLRT recommendation is made to expand, 
repeat or add cohorts to the study. The sample size for the study is based on practical 
considerations.  No statistical hypothesis will be tested.  For safety considerations, with 
up to 36 subjects (12 subjects from Part A, 6 subjects in Part B, and 18 subjects from 
Part C) receiving AMG 171, the chance of detecting an adverse event with a true 
incidence rate of 3% or greater is larger than 67% and the chance of detecting an 
adverse event with a true incidence rate of 5% or greater is larger than 84%. 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Baseline values may be used as a covariate in analyses. 
4.2 
Subgroups 
No subgroup analyses are planned. 


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5. 
Definitions 
Actual Treatment Group: 
A subject’s actual treatment group is defined as the treatment received, where subjects 
who received ≥ 1 dose of AMG 171 will be analyzed in the AMG 171 treatment group 
regardless of the randomized treatment. 
Age: 
Subject age at randomization will be determined using the age in years reported in the 
clinical database. 
Treatment-Emergent Adverse Event: 
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by "Did event start before first dose of 
investigational product" equal to "No" or missing on the Events eCRF and up to the End 
of Study date. 
Treatment-Emergent Serious Adverse Event: 
Treatment-emergent adverse events indicated as serious on the Events eCRF. 
Baseline: 
For any variable, unless otherwise defined, baseline is the last non-missing assessment 
taken prior to the first dose of investigational product. 
Baseline and Post-baseline BMI: 
Baseline and Post-baseline BMI is to derive by Baseline height and respective visit of the 
weight measurement.  
BMI (kg/m2) = weight (kg)/[height (cm)/100]^2. 
Baseline and Post-baseline ECG: 
Where multiple 12-lead ECG measurements are taken at the same assessment time 
point (they are planned to be recorded in triplicate 30 seconds apart) the mean value will 
be calculated and used in the analysis.  The baseline ECG is defined as the mean of all 
the pre-dose assessments measured on Study Day 1; the mean of values in a triplicate 
should be calculated before taking the mean of the triplicate averages.  For pre and post 
dose ECG measurements, unscheduled ECG measurements taken up to 5 minutes after 
the last assessment of a triplicate will be included in the averages for a time point.  
Where an ECG is missing within a triplicate, all available data will be averaged for that 
time point. 


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Change from Baseline: 
The change from baseline is defined as the arithmetic difference between a post-
baseline value and baseline for a given time point: 
Change from Baseline = (post-baseline value – baseline value) 
Percent Change from Baseline: 
The percent change from baseline for a given variable at a given time point is defined as:  
Percent Change from Baseline =  
[(post-baseline Value – baseline Value) / baseline Value] x 100 
Investigational Product (IP): 
The investigational products are defined as AMG 171 and placebo. 
Subject-level End of Study (EOS) Date: 
End of study for each subject is defined as the date the subject last completed a 
protocol-specified procedure.  The date will be recorded on the End of Study CRF page. 
End of IP (EOIP) Date: 
End of IP Admin for each subject is defined as the date the decision was made to 
end IP as recorded on the End of IP CRF page. 
Last IP Dose Date: 
Last IP Dose Date for each subject is defined as the latest date IP is administered. 
Study Day 1: 
Day 1 is defined as the date that the first dose of investigational product is administered. 
Study Day: 
For study date later than Study Day 1:  
Study Day = (study date - date of Study Day 1) + 1 
For study date earlier than Study Day 1: 
Study Day = (study date – date of Study Day 1) 
Duration of IP Exposure in Weeks 
Duration of IP exposure (weeks) = (Last Dose IP Date – Study Day 1+ 1) / 7 
Duration of Study Exposure in Weeks 
Duration of Study exposure (weeks) = (EOS Date - Study Day 1 + 1) / 7 


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Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  QTcF=QT/ (RR/1000) ^0.33. 
6. 
Analysis Sets 
The following analysis sets may be separately defined for part A (SAD cohort 1 and 1b), 
part B (cohort 2) and part C (titration cohort 3-5). 
6.1 
Full Analysis Set (FAS) 
The full analysis set will consist of all subjects who receive at least one dose of 
investigational product. 
6.2 
Safety Analysis Set (SAS) 
The safety analysis set is defined as same to the FAS. 
6.3 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set will consist of all subjects who receive at least one dose of AMG 171 
for whom at least one concentration post-dose or PK parameter or endpoint can be 
adequately estimated.  The subjects in cohort 4 who received expired IP are not included 
in the PK analysis set. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Members of DLRT 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 of 11.3 of the protocol for further details. 
7.2 
Primary Analysis 
The primary analysis will occur after all subjects have completed the study. 
Data will be locked prior to the primary analysis and a clean snapshot of data will 
be used for the primary analysis. 
7.3 
Final Analysis 
The primary analysis will be the final analysis for this study. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 


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8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
In the event that data is not available for a subject, no imputations will be done for the 
missing data. 
Laboratory measurements that are below the quantification limits will be considered 
equal to the lower limit of quantification (LLQ) for the calculation of population averages 
in summary tables. There will be no imputation of clinical laboratory values below LLQ 
for individual subject level data in line listings, as applicable. 
Biomarker data that are below the quantification limits will be considered equal to half of 
the LLQ for all analyses unless specified otherwise. 
PK concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PK parameters. 
For partial dates (such as for adverse event and concomitant medication, etc.), 
imputation of dates will be carried out as per Appendix A. 
8.4 
Detection of Bias 
Protocol compliance will be examined by listing important protocol deviations (IPD) by 
cohort and site. 
8.5 
Outliers 
Outliers may be identified via the use of descriptive statistics. All data confirmed as an 
outlier will not be excluded in the analyses described in this statistical analysis plan. 
If outliers exist a sensitivity analysis eliminating or reducing the outlier effect may be 
performed and differences between their results may be reviewed, if required. 
Pharmacokinetic (PK) plasma concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed.  


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8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures. 
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs. 
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version [9.4] or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics 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.  Data will be presented and 
summarized by study part (Part A, B and C), actual treatment received and at each 
protocol-specified scheduled time point. Graphical summaries of the data may also be 
presented. 
Data for subjects receiving placebo may be combined across cohorts within Parts A, B, 
and C. Data for subjects receiving AMG171 will be presented separately by cohort. 
When data are summarized by time, the values recorded against the scheduled time 
points listed in the protocol will be used.  When assessing minimum/maximum increases 
or decreases over the study, all assessments, including unscheduled assessments will 
be used. 
9.2 
Subject Accountability 
A summary of study reporting period and analysis set dispositions will also be prepared. 
Key study dates for the first subject enrolled, last subject enrolled and last subject's end 
of study include any other key study dates that are relevant for the study design (eg, last 
subject's end of investigational product, data cut-off date) will be presented. 
The number and percent of subjects who were randomized, received investigational 
product, completed investigational product, discontinued investigational product and 
reasons for discontinuing, completed study, discontinued study and reasons for 
discontinuing will be summarized by treatment group and cohort and overall. 
The number and percent of subjects randomized will be tabulated by study site. 


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Listings may be generated and reviewed but may not be included in the CSR. 
9.3 
Important Protocol Deviations 
Important Protocol Deviation (IPD) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD review meetings throughout the 
study prior to database lock.  These definitions of IPD categories, subcategory codes, 
and descriptions will be used during the course of the study.  Eligibility deviations are 
defined in the protocol. 
9.4 
Demographic and Baseline Characteristics 
Demographic (ie. age, age groups [< 40, >= 40, <18, 18-64, ≥65], sex, race, ethnicity) 
and baseline characteristics (height, weight, body mass index, medical history) will be 
summarized by cohort and actual treatment group and overall (i.e. total from all the 
cohorts involved in the analysis and irrespective of treatment received) using descriptive 
statistics.  If multiple races have been reported for a subject, the subject will be 
categorized as multiple race as well as by the combination of race. 
9.5 
Efficacy Analyses 
Not applicable. 
 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Table 9.1.  Safety Endpoint Summary Table 
Endpoint 
Statistical Analysis Methods 
Sensitivity 
Analysis 
Subject incidence of 
treatment-emergent 
adverse events (TEAEs) 
Following analysis will be performed for safety 
analysis set by part (Part A, B and C) and actual 
treatment group. 
 Subject incidence of   
▪ Fatal events by SOC/PT 
▪ TEAEs leading to withdrawal from IP or other 
protocol-required therapies by SOC/PT 
▪ TEAEs by SOC, PT and grade 
▪ SAEs by SOC, PT and grade 
Not Applicable
 
Changes in 
laboratory safety 
tests, vital sings and 
12-lead ECGs 
Following analysis will be performed for SAS by part 
(Part A, B and C) and actual treatment group at 
protocol-specified scheduled visit. 
 
Summary statistics of 
▪ 
Change from baseline safety laboratory test 
results 
▪ 
Change from baseline vital signs 
▪ 
Changes from baseline ECG parameters
Not Applicable


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9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. All adverse event tables will be summarized by actual treatment group, 
cohort. 
The subject incidence of adverse events will be summarized for all TEAEs, SAEs, 
TEAEs leading to withdraw of IP, fatal adverse events, and adverse events of interest 
(EOIs). 
Subject incidence of all TEAEs leading to withdrawal of IP, fatal adverse events, and will 
be tabulated by SOC and PT in descending order of frequency. 
Subject incidence of TEAEs and SAEs will also be tabulated by SOC, PT, and grade. 
Subject incidence of events of interest (EOIs) will also be tabulated according to the EOI 
search categories and preferred term if applicable. Events of interest of hypersensitivity 
will be identified using a narrow search/scope in standardized MedDRA query (SMQ). 
Immunogenicity, Injection site reactions and Nausea/vomiting will be identified using a 
broad search/scope in Amgen-defined MedDRA search strategies. 
9.6.3 
Laboratory Test Results 
Listings of individual chemistry, hematology and urinalysis laboratory may be generated 
and reviewed but may not be included in the CSR.  Values outside the normal laboratory 
reference range will be flagged as high or low at baseline and each post-baseline time 
point on the listings. 
For key laboratory parameters which are given in Table 9.2 below, summary statistics 
will be provided for actual value, change from baseline and percent change from 
baseline by study part (Part A, B and C), actual treatment group at each protocol-
specified scheduled visit.  


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Table 9.2.  Laboratory parameters 
Local Laboratory (Chemistry): Sodium, Potassium, Chloride, Bicarbonate, Total protein, 
Albumin, Calcium, Magnesium, Phosphorus, Glucose, BUN or Urea, Creatinine, Uric acid, 
Creatine kinase, Total bilirubin, Direct bilirubin, ALP, LDH, AST (SGOT), ALT (SGPT) 
Local Laboratory (Urinalysis): Specific gravity, 
pH 
 
Local Laboratory (Hematology): RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHC, 
Reticulocytes, Platelets, WBC, Differential  Eosinophils  Basophils  Lymphocytes  
Monocytes  Total Neutrophil Count 
Central Laboratory: Antibodies, Serum PK, Plasma PD:  Insulin  Glucose  c-peptide  
Glucagon, Serum PD: Free fatty acids, Lipid Panela  HDL  LDL  Triglycerides Cholesterol, 
HbA1ca 
     a Lipid panel and HbA1c are to be run by local lab at screening and central lab at all other time 
points  
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
BUN  blood urea nitrogen; HDL  high density lipoprotein; LDH  lactate dehydrogenase; LDL  low 
density lipoprotein; MCH  mean corpuscular hemoglobin; MCHC  mean corpuscular hemoglobin 
concentration; MCV  mean corpuscular volume; RBC  red blood cell count;  SGOT  serum glutamic-
oxaloacetic transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC  white blood cell count 
9.6.4 
Vital Signs 
Summary statistics of heart rate and blood pressure will be provided for actual value, 
change from baseline and percent change from baseline by study part (Part A, B and C) 
and actual treatment group at each protocol-specified scheduled visit.  Listings of vital 
signs may be generated and reviewed but may not be included in the CSR. 
9.6.5 
Physical Measurements 
Summary statistics of physical measurements (weight, waist circumference and BMI) will 
be provided for actual value, change from baseline and percent change from baseline by 
study part (Part A, B and C) and actual treatment group at each protocol-specified 
scheduled visit. 
9.6.6 
Electrocardiogram 
Summaries over time and changes from baseline over time will be provided for all 12-
lead ECG parameters (QRS, QT, RR, PR, and QTcF) by study parts (Part A, B and C) 
and actual treatment group at each specified protocol scheduled visit.  
The analysis Fridericia’s (QTcF) QT correction will be performed using the derived 
results as specified in Section 5.  Subjects will be categorized into the following groups 
per their maximum change from baseline in QTcF.  Unscheduled assessments will be 
included in the determination of the maximum change. 
 
≤ 30 msec 


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 
> 30 – 60 msec 
 
> 60 msec 
Subjects will also be categorized into the following groups per their maximum post 
baseline QTcF.  Unscheduled assessments will be included in the determination of the 
maximum post baseline value. 
 
≤ 450 msec 
 
> 450 – 480 msec 
 
> 480 – 500 msec 
 
> 500 msec 
All on-study electrocardiogram (ECG) data will be listed and reviewed but may not be 
included in the CSR. 
9.6.7 
Antibody Formation 
Subject incidence of developing anti-AMG 171 antibodies (binding and if positive for 
binding antibodies, neutralizing) at any time will be tabulated by study part (Part A, B and 
C) and actual treatment group. 
Listings of antibody data may be generated and reviewed but may not be included in the 
CSR. 
9.6.8 
Exposure to Investigational Product 
Summary statistics of number of doses of IP, total amount of the IP and the proportion of 
subjects receiving each dose level will be provided by study part (Part A, B and C) and 
actual treatment group.  Subject-level data may be provided instead of the summary if 
the subject incidence of exposure to IP is low or single dose is given. 
9.6.9 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term for each study part (Part A, B and C) and actual treatment 
group at each protocol-specified scheduled visit as coded by the World Health 
Organization Drug dictionary version September 2017 or later. 
9.7 
Other Analyses 
9.7.1 
Secondary Endpoint – Pharmacokinetics Analysis 
The Clinical Pharmacology Modeling and Simulation (CPMS) group at Amgen will 
perform this part of the analysis. The analysis will be performed using the PK analysis 
set. 


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Serum AMG 171 concentrations will be determined using a validated assay. 
Individual serum concentration-time plots for AMG 171 will be presented for each subject 
as well as mean concentration-time plots for each dose cohort.  PK parameters that may 
include, but are not limited to AUC, Cmax and Tmax will be estimated using either 
compartmental (eg, PK modeling) or non-compartmental methods. 
Actual dosing and sampling times will be used for calculation of PK parameters.  
Summary statistics will be generated for each PK parameter for each dose cohort. 
9.7.2 
Exploratory Endpoints 
9.7.2.1 
Pharmacodynamic Parameters 
Summary statistics for actual values, change from baseline and percent change from 
baseline will be provided for the following parameters by study part (Part A, B and C), 
actual treatment group at each protocol-specified scheduled visit: 
 
The fasting and post-mixed meal challenge glucose, insulin, c-peptide, 
glucagon, and free fatty acid (FFA) concentrations (Part A only). 
 
Fasting lipid levels, including, but not limited to, total cholesterol, low density 
lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), 
and triglycerides 
 
HbA1c levels (Part B only). 
 
Body composition parameters (eg. Fat, muscle and bone mineral content) 
measured by Dual-energy x-ray absorptiometry (Part B only). 
Graphs of mean percent change from baseline by study part (Part A, B and C), actual 
treatment group at each protocol-specified scheduled visit will be provided for all 
pharmacodynamic parameters. 
10. 
Changes From Protocol-specified Analyses 
No PK and pharmacodynamic (PD) analysis will be performed for gastric emptying 
test. PD analysis set will also not be created. 
11. 
Literature Citations / References 
12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
Not applicable. 


Product:  AMG 171   
Protocol Number:  20180224 
Date:  01 February 2022 
Page 43 of 43 
 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
14. 
Appendices 
Appendix A.  Handling of Missing or Incomplete Dates 
Adverse event and concomitant medication records with completely or partially missing 
start dates will be imputed as described in Table below. 
  
Stop Date 
  
  
Complete:  
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start Date 
  
<1st 
Dose 
≥1st 
Dose 
<1st 
Dose 
yyyym
m 
≥1st 
Dose 
yyyym
m 
<1st 
Dose 
yyyy 
≥1st 
Dose 
yyyy 
Partial: 
yyyymm 
Equal to 
1st Dose 
yyyymm 
2 
1 
2 
1 
N/A 
1 
1 
Not 
equal to 
1st Dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
Equal to 
1st Dose 
yyyy 
3 
1 
3 
1 
N/A 
1 
1 
Not 
equal to 
1st Dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
 
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month.  
Note: If the start date imputation leads to a start date that is after the stop date, then do not 
impute the start date.