Clinical trial NCT05056246
Conditions: Healthy Participants
Keywords: Maridebart Cafraglutide Japanese participants Caucasian participants AMG 133
Sponsor: Amgen
Start date: 2021-09-10; Completion date: 2022-04-08
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the pharmacokinetics (PK) of AMG 133 after single subcutaneous (SC) administration in healthy Japanese and Caucasian participants.

Detailed description:

Arms: arm 1: Healthy Japanese participants will receive the low dose of AMG 133 as a SC injection on Day 1 of the study. arm 2: Healthy Japanese participants will receive the medium dose of AMG 133 as a SC injection on Day 1 of the study. arm 3: Healthy Japanese participants will receive the high dose of AMG 133 as a SC injection on Day 1 of the study. arm 4: Healthy Caucasian participants will receive the medium dose of AMG 133 as a SC injection on Day 1 of the study. arm 5: Healthy Caucasian participants will receive the high dose of AMG 133 as a SC injection on Day 1 of the study.
Interventions: intervention 1: AMG 133
Intervention descriptions: intervention 1: Solution for SC injection

Protocol documents:
Prot_000.pdf: 
Protocol  
CONFIDENTIAL 
Labcorp Drug Development Study: 8473020 
Protocol Reference: 20200290 
Protocol Amendment 01, 24 August 2021 
Page 1 of 63 
 
 
Protocol 
A Phase I, Open-label, Randomized, Parallel-arm, Single-dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 133 
Administered Subcutaneously in Healthy Japanese and Caucasian Subjects 
Protocol Status: Final 
Protocol Date: 24 August 2021 
Protocol Version: 2.0 
Investigational Product: AMG 133 
Amgen Protocol Reference Number: 20200290 
Labcorp Drug Development Study Number: 8473020 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320, USA 
This protocol was developed, reviewed, and approved in accordance with Labcorp 
Drug Development’s standard operating procedures. This format and content of this 
protocol is aligned with Good Clinical Practice: Consolidated Guidance (ICH E6). 
NCT Number: NCT05056246
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


Protocol  
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Protocol Amendment 01, 24 August 2021 
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Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staffs and 
members of the Institutional Review Board/Independent Ethics Committee/Institutional 
Scientific Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Protocol  
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Protocol Amendment 01, 24 August 2021 
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INVESTIGATOR AGREEMENT 
I have read the protocol entitled “A Phase I, Open-label, Randomized, Parallel-arm, Single-dose 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 133 Administered 
Subcutaneously in Healthy Japanese and Caucasian Subjects” and agree to conduct the study as 
described herein. 
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) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 


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STUDY IDENTIFICATION 
Sponsor 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320, USA 
Sponsor’s Study 
Contact 
Director, Clinical Pharmacology 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320, USA 
Tel:
Email:
Medical Monitor 
 
 MD 
Medical Director 
Labcorp Drug Development Clinical Pharmacology Services 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704, USA 
Tel: (Office):
Email:
Sponsor’s Study 
Manager 
Global Early Clinical Development Manager 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320, USA 
Tel:
Email:
Labcorp Drug 
Development PM 
 MBA 
Project Manager  
Labcorp Drug Development Clinical Pharmacology Services  
3301 Kinsman Boulevard  
Madison, Wisconsin 53704, USA  
Tel:
Email:
Statistician 
MS 
Labcorp Drug Development Clinical Pharmacology Services 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704, USA 
Tel
Email:
 
 


Protocol  
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Protocol Reference: 20200290 
Protocol Amendment 01, 24 August 2021 
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SYNOPSIS 
Title of study: A Phase I, Open-label, Randomized, Parallel-arm, Single-dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 133 Administered 
Subcutaneously in Healthy Japanese and Caucasian Subjects 
Objectives:  
The primary objective of the study is: 
• 
to evaluate the pharmacokinetics (PK) of AMG 133 after single subcutaneous (SC) 
administration in healthy Japanese and Caucasian subjects. 
The secondary objectives of the study are: 
• 
to evaluate the safety and tolerability of AMG 133 after single SC administration in 
healthy Japanese and Caucasian subjects. 
• 
to evaluate the incidence of anti-AMG 133 antibodies in healthy Japanese and 
Caucasian subjects. 
Study design: 
This will be a Phase I, single-center, open-label, randomized, parallel-arm study to investigate 
the PK, safety, and tolerability of a single SC dose of AMG 133 in 3 groups of healthy 
Japanese subjects and 2 groups of healthy Caucasian subjects. Potential subjects will be 
screened to assess their eligibility to enter the study within 28 days prior to dose 
administration. Eligible subjects will be admitted into the clinical research unit (CRU) for 
Check-in on Day -1 and be confined to the CRU until clinic discharge on Day 8. On Day 1, 21 
Japanese subjects will be randomly assigned in a 1:1:1 ratio to Group 1, 2, or 3, and 14 
Caucasian subjects will be randomly assigned in a 1:1 ratio to either Group 4 or 5. Each 
subject will participate in 1 treatment group only. 
Number of subjects: 
Approximately 35 subjects will be enrolled in total, with 7 subjects in each of the 5 groups. 
Diagnosis and main criteria for inclusion: 
Healthy Japanese and Caucasian male or female subjects, 18 to 65 years of age (inclusive), and 
body mass index of 18 to 30 kg/m2. 
Investigational products, dose, and mode of administration: 
Investigational Medicinal Product: 
 mg/mL solution AMG 133 administered via 
subcutaneous injection.  
On Day 1, AMG 133 will be administered as a SC dose to the following groups: 
• 
Group 1:
mg (Japanese subjects) 
• 
Group 2:
mg (Japanese subjects) 
• 
Group 3:
mg (Japanese subjects) 
• 
Group 4:
mg (Caucasian subjects) 
• 
Group 5:
mg (Caucasian subjects) 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to End of Study visit): approximately 21 weeks.  


Protocol  
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Protocol Reference: 20200290 
Protocol Amendment 01, 24 August 2021 
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Primary endpoints: 
The primary endpoints for this study are AMG 133 PK parameters: maximum observed plasma 
concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to 
time of last quantifiable concentration (AUClast), and area under the plasma concentration-time 
curve from time zero to infinity (AUCinf).  
Secondary endpoints: 
Secondary endpoints for this study are: adverse events, clinical laboratory tests, 12-lead 
electrocardiograms (ECGs), vital signs, and incidence of anti-AMG 133 antibody formation. 
Statistical methods: 
The primary PK parameters will include Cmax, AUClast, and AUCinf for AMG 133. All other PK 
parameters will be regarded as secondary and will not be subject to inferential statistical 
analysis.  
The incidence and percentage of subjects who develop anti-AMG 133 antibodies (binding and 
if positive, neutralizing, when available) at any time will be tabulated by treatment group. 
Tables of fatal adverse events, serious adverse events, adverse events leading to withdrawal 
from investigational product or other protocol-required therapies, and significant treatment-
emergent adverse events will also be provided. Subject-level data may be provided instead of 
tables if the subject incidence is low. Endpoints for clinical laboratory tests, ECG, and vital 
signs will be summarized. 
Additional details will be included in the Statistical Analysis Plan. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS ...........................................................................................................7 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................13 
1.1. 
Background ............................................................................................................13 
1.1.1. 
Investigational Drug Product: AMG 133 .....................................................13 
1.1.2. 
Pharmacology ..............................................................................................13 
1.2. 
Nonclinical Pharmacokinetics ...............................................................................13 
1.3. 
Nonclinical Toxicology .........................................................................................14 
1.4. 
Preliminary Clinical Data ......................................................................................14 
1.5. 
Study Rationale ......................................................................................................14 
1.6. 
Benefit-risk Assessment.........................................................................................15 
1.6.1. 
Therapeutic Context .....................................................................................15 
1.6.1.1. 
Key Benefits.......................................................................................15 
1.6.1.2. 
Key Potential Risks ............................................................................15 
1.6.1.2.1. 
Gastrointestinal Tolerability Issues..........................................15 
1.6.1.2.2. 
Hypersensitivity Reactions ......................................................15 
1.6.1.2.3. 
Injection Site Reactions ...........................................................16 
1.6.1.2.4. 
Immunogenicity .......................................................................16 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................16 
2.1. 
Objectives ..............................................................................................................16 
2.2. 
Endpoints ...............................................................................................................17 
2.2.1. 
Primary Endpoints .......................................................................................17 
2.2.2. 
Secondary Endpoints ...................................................................................17 
3. 
INVESTIGATIONAL PLAN ..........................................................................................17 
3.1. 
Overall Study Design and Plan ..............................................................................17 
3.2. 
Discussion of Study Design ...................................................................................18 
3.3. 
Selection of Doses in the Study .............................................................................18 
4. 
SELECTION OF STUDY POPULATION .....................................................................19 
4.1. 
Inclusion Criteria ...................................................................................................19 
4.2. 
Exclusion Criteria ..................................................................................................19 
4.3. 
Screen Failures and Rescreening ...........................................................................22 


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4.4. 
Subject Number and Identification ........................................................................22 
4.5. 
Subject Withdrawal and Replacement ...................................................................22 
4.6. 
Study Termination .................................................................................................23 
5. 
STUDY TREATMENTS .................................................................................................23 
5.1. 
Investigational Product ..........................................................................................23 
5.2. 
Investigational Product Administration .................................................................24 
5.3. 
Treatment of Overdose ..........................................................................................25 
5.3.1. 
Medical Devices...........................................................................................25 
5.3.2. 
Product Complaints ......................................................................................25 
5.4. 
Randomization .......................................................................................................25 
5.5. 
Blinding..................................................................................................................25 
5.6. 
Treatment Compliance ...........................................................................................25 
5.7. 
Drug Accountability...............................................................................................26 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................26 
6.1. 
Concomitant Therapies ..........................................................................................26 
6.2. 
Diet .........................................................................................................................26 
6.3. 
Smoking .................................................................................................................27 
6.4. 
Exercise ..................................................................................................................27 
6.5. 
Blood Donation ......................................................................................................27 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................27 
7.1. 
Pharmacokinetic Assessments ...............................................................................28 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................28 
7.1.2. 
Analytical Methodology ..............................................................................28 
7.2. 
Antidrug Antibody Assessments............................................................................28 
7.3. 
Safety and Tolerability Assessments .....................................................................29 
7.3.1. 
Adverse Events and Serious Adverse Events: Time Period and Frequency 
for Collecting and Reporting Safety Event Information ..............................29 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................31 
7.3.3. 
Vital Signs ....................................................................................................32 
7.3.4. 
12-lead Electrocardiogram ...........................................................................32 
7.3.5. 
Physical Examination...................................................................................32 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................32 
8.1. 
Determination of Sample Size ...............................................................................32 
8.2. 
Analysis Populations ..............................................................................................33 
8.2.1. 
Pharmacokinetic Population ........................................................................33 
8.2.2. 
Safety Population .........................................................................................33 


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8.3. 
Pharmacokinetic Analyses .....................................................................................33 
8.4. 
Antidrug Antibody Analysis ..................................................................................33 
8.5. 
Safety Analysis ......................................................................................................33 
8.6. 
Interim Analysis .....................................................................................................33 
9. 
REFERENCES ................................................................................................................34 
10. APPENDICES .................................................................................................................35 
Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Adverse Events, Serious Adverse Events ...............36 
Appendix 2: Clinical Laboratory Evaluations ...................................................................44 
Appendix 3: Total Blood Volume......................................................................................46 
Appendix 4: Contraception Requirements .........................................................................47 
Appendix 5: Collection of Pregnancy and Lactation Information .....................................49 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations ............................53 
Appendix 7: Hepatotoxicity: Suggested Actions and Follow-up Assessments .................58 
Appendix 8: Schedule of Assessments ..............................................................................61 
 


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LIST OF TABLES AND FIGURES 
Table 1: 
Investigational Product ..............................................................................24 
  
Figure 1:  
Study Design ..............................................................................................18 
Figure 2:  
Sample Serious Adverse Event Report Form ............................................41 
Figure 3:  
Pregnancy Notification Form .....................................................................51 
Figure 4:  
Lactation Notification Form ......................................................................52 
 


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Protocol Amendment 01, 24 August 2021 
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LIST OF ABBREVIATIONS 
Abbreviation Definition 
ADA 
antidrug antibodies 
ALT 
alanine aminotransferase 
AST 
asparatate aminotransferase 
AUCinf 
area under the plasma concentration-time curve from time zero to 
infinity 
AUClast 
area under the plasma concentration-time curve from time zero to time 
of last quantifiable concentration 
AV 
atrioventricular 
cAMP 
cyclic adenosine monophosphate 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed plasma concentration 
CRU 
clinical research unit 
DILI 
drug-induced liver injury  
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOS 
end of study 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GIP 
glucose-dependent insulinotropic polypeptide 
GIPR 
glucose-dependent insulinotropic polypeptide receptor 
GLP-1 
glucagon-like peptide 1 
GLP-1R 
GLP-1 receptor 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
INR 
International normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IV 
intravenous 


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mAb 
monoclonal antibody 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SC 
subcutaneous 
TBL 
total bilirubin 
ULN 
upper limit of normal 
 
 
 


Protocol  
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1. INTRODUCTION 
Refer to the Investigator’s Brochure (IB)1 for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational medicinal product (IMP). 
1.1. 
Background 
Obesity (defined as body mass index of ≥ 30 kg/m2)2 is a major risk factor for type 2 diabetes 
mellitus and cardiovascular disease. Glucose-dependent insulinotropic polypeptide (GIP) and 
glucagon-like peptide 1 (GLP-1) are gut-derived incretin hormones, known for their ability to 
augment glucose-stimulated insulin secretion through the GIP receptor (GIPR) and GLP-1 
receptor (GLP-1R), respectively. In addition, GLP-1 is also known to promote satiety3, while 
GIP has been shown to promote adiposity.4,5  
1.1.1. 
Investigational Drug Product: AMG 133 
AMG 133 is engineered by conjugation of a human monoclonal antihuman GIPR antagonist 
antibody (mAb) with 2 identical GLP-1 analog peptides, and therefore, exhibits both GIPR 
antagonism and GLP-1R agonism activities. 
1.1.2. 
Pharmacology  
In human embryonic kidney 293T cells stably expressing human GIPR, AMG 133 binds with a 
dissociation constant (Kd) of 37 pM and inhibits GIP-induced accumulation of cyclic adenosine 
monophosphate (cAMP), with a half-maximal inhibitory concentration (IC50) of 42.4 nM. In 
addition, using a GLP-1 radioligand competition binding assay, AMG 133 binds to human 
GLP-1R with an IC50 of 55.2 nM. In Chinese hamster ovary K1 cells stably expressing human 
GLP-1R, AMG 133 binds to the GLP-1R and activates GLP-1 increasing cAMP levels with half-
maximal effective concentration (EC50) of 24.4 pM. 
In preclinical studies in obese cynomolgus monkeys, AMG 133 administration resulted in an 
approximate weight reduction of 17%, compared with vehicle, with concomitant decreases in 
food intake, insulin, and triglyceride levels. 
1.2. 
Nonclinical Pharmacokinetics 
AMG 133 pharmacokinetics (PK) is defined based on intact AMG 133 molecule (anti-GIPR 
mAb with at least 1 GLP-1 analog peptide) or total AMG 133 (anti-GIPR mAb with or without 
GLP-1 analog peptide).  
The PK of AMG 133 has been evaluated in single-dose studies in the mouse and cynomolgus 
monkeys with a dose of 5 mg/kg intravenous (IV) and 3 mg/kg subcutaneous (SC), respectively.  
Exposure of intact and total AMG 133 were also evaluated in the mouse and cynomolgus 
monkey in repeat-dose toxicology studies including a 4-week exploratory study and a pivotal 


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Good Laboratory Practices-compliant 13-week SC repeat-dose. The doses evaluated in the 13-
week GLP toxicology studies in mice ranged from 25 to 150 mg/kg and in cynomolgus monkeys 
from 20 to 120 mg/kg. In both the total and intact forms, AMG 133 exhibited linear 
pharmacokinetics in both mice and cynomolgus monkeys, regardless of the regimens (single or 
repeat) at all dose levels evaluated. Terminal half-life estimates in the obese cynomolgus 
monkeys ranged from 231 to 284 hours for total AMG 133, and from 189 to 222 hours for intact 
AMG 133. Some loss of the GLP-1 moiety of AMG 133 was observed in repeat-dose GLP 
mouse and cynomolgus monkey toxicology studies, but significant exposure of intact AMG 133 
was maintained throughout the study.1  
1.3. 
Nonclinical Toxicology 
The cynomolgus monkey and the mouse were selected as the nonclinical toxicology species. In 
in vitro studies, AMG 133 binds with similar affinity to human, cynomolgus monkey, and mouse 
GIPR. Whereas AMG 133 functionally inhibits GIP signaling through human and cynomolgus 
monkey GIPR in vitro with equivalent potency, it has more than 20-fold lower potency for 
inhibition of GIP signaling through mouse GIPR. AMG 133 shows equivalent potency for 
human, cynomolgus monkey, and mouse GLP-1R. Despite the lower potency of AMG 133 for 
mouse GIPR, the high exposures obtained in the repeat-dose toxicology studies in the mouse 
likely achieved at least partial GIPR antagonism. 
The studies conducted in the safety assessment of AMG 133 included exploratory 4-week SC 
repeat-dose and Good Laboratory Practice-compliant 13-week SC repeat-dose toxicology studies 
conducted in the mouse and the cynomolgus monkey. AMG 133-associated changes were 
limited to the anticipated pharmacological action of the molecule (eg, decreases in body weight, 
decreases in food consumption, atrophy of adipose tissue, decreased serum triglyceride in ≥ 1 
studies) and minimal to moderate changes in red blood cell parameters and/or some clinical 
chemistry parameters, which are clinically monitorable. The no-observed-adverse-effect level for 
the 13-week SC repeat-dose toxicology studies in the mouse and the cynomolgus monkey was 
the highest tested doses of 150 and 120 mg/kg, respectively. 
1.4. 
Preliminary Clinical Data 
As of July 2021, a total of 49 subjects received a single dose of AMG 133 or placebo across 
doses ranging from 21 to 840 mg administered SC in the ongoing first-in-human (FIH) single-
ascending-dose trial and eight subjects have received repeat-doses of AMG 133 
 mg 
administered every 4 weeks or placebo in the ongoing multiple-dose trial.  So far, AMG 133 (in 
SAD and MAD cohorts) has been generally well tolerated across the doses evaluated. No serious 
adverse events or deaths have been reported, and most adverse events reported were mild 
consisting of nausea, vomiting, and dyspepsia.   
1.5. 
Study Rationale 
AMG 133 has not been previously studied in healthy Japanese or healthy Caucasian subjects 
without obesity. The objective of this study is to evaluate the PK, safety, and tolerability of a 


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single SC dose of AMG 133 at 3 dose levels (
, and 
 mg) in Japanese subjects and at 
2 dose levels (
 and 
 mg) in Caucasian subjects. This study will inform about any possible 
ethnic differences in PK between Japanese and Caucasian subjects. 
1.6. 
Benefit-risk Assessment 
The following benefit-risk assessment supports the conduct of this clinical study. Refer to the IB1 
for more information. 
1.6.1. 
Therapeutic Context 
1.6.1.1. 
Key Benefits 
Healthy subjects in the current study will not receive any health benefit (beyond that of an 
assessment of their medical status) from participating in the study.  
1.6.1.2. 
Key Potential Risks 
To limit the risk of excessive exposure to healthy subjects in the current study, subjects will be 
administered as a single SC dose of AMG 133 at 3 dose levels (
, and 
 mg) in 
Japanese subjects and at 2 dose levels (
 and 
 mg) in Caucasian subjects (details provided 
in Section 3.3). 
1.6.1.2.1. 
Gastrointestinal Tolerability Issues 
Gastrointestinal tolerability issues including nausea, vomiting, and diarrhea are common adverse 
reactions for molecules targeting the obesity pathways. Gastrointestinal tolerability issues in 
humans are expected based on experience with marketed GLP-1R agonists. Subjects will be 
monitored for signs and symptoms of adverse events of nausea, vomiting, and diarrhea 
throughout the study.  
1.6.1.2.2. 
Hypersensitivity Reactions 
As with any biologic, administration of AMG 133 may result in systemic reactions including 
immune-mediated hypersensitivity. Drug hypersensitivity reactions typically occur during or 
within several hours after drug administration, but they may be delayed. Severe reactions may 
occur, including anaphylaxis, angioedema, and serum-like sickness. Potential anaphylactic 
reactions will be assessed by Sampson criteria. If Sampson criteria are positive, the potential 
anaphylactic reaction will be confirmed by measuring tryptase in blood plasma within 30 
minutes of symptoms, and at any other time points as warranted and if feasible. AMG 133 will 
be administered by SC injection by a qualified clinical research staff member. Subjects will be 
monitored for signs and symptoms of hypersensitivity reactions during and after AMG 133 
administration, such as fever, chills, shaking, hypotension, wheezing, itching, nausea, and/or 
rash.  


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1.6.1.2.3. 
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). After 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.  
1.6.1.2.4. 
Immunogenicity  
As with all biological products, there is a potential for the development of anti-AMG 133 
antibodies. The potential effects of anti-AMG 133 antibodies on subjects who might develop 
them are not known, but reduced efficacy of AMG 133 is a possibility. Subjects will be 
monitored for potential effects of antidrug antibodies (ADA) that may include antibody-mediated 
adverse events, altered drug exposure, or loss of efficacy. Pharmacokinetic and immunogenicity 
samples from subjects in this Phase I study will be collected from study subjects at 
protocol-defined intervals and analyzed to monitor the development of anti-AMG 133 
antibodies. Positive samples will be titrated and evaluated for neutralizing antibodies. Additional 
blood samples may be obtained to evaluate any ADA-mediated effects on safety during the 
study.  
The above benefit risk assessment supports the conduct of this clinical trial. Reference should be 
made to the IB for further data on potential side effects of AMG 133. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
• to evaluate the PK of AMG 133 after single SC administration in healthy Japanese and 
Caucasian subjects. 
The secondary objectives of the study are: 
• to evaluate the safety and tolerability of AMG 133 after single SC administration in 
healthy Japanese and Caucasian subjects. 
• to evaluate the incidence of anti-AMG 133 antibodies in healthy Japanese and Caucasian 
subjects. 


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2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints of the study are: 
• maximum observed plasma concentration (Cmax) 
• area under the plasma concentration‑time curve from time zero to time of last 
quantifiable concentration (AUClast) 
• area under the plasma concentration‑time curve from time zero to infinity (AUCinf). 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
• adverse events 
• clinical laboratory tests 
• 12-lead electrocardiograms (ECGs) 
• vital signs  
• incidence of anti-AMG 133 antibodies. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a Phase I, single-center, open-label, randomized, parallel-arm study to investigate 
the PK, safety, and tolerability of a single SC dose of AMG 133 in 3 groups of healthy Japanese 
subjects and 2 groups of healthy Caucasian subjects.  
Approximately 35 subjects will be enrolled in total, with 7 subjects in each of the 5 groups.  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to dose administration. Eligible subjects will be admitted into the clinical research unit 
(CRU) for Check-in on Day -1 and be confined to the CRU until clinic discharge on Day 8. On 
Day 1, 21 Japanese subjects will be randomly assigned in a 1:1:1 ratio to Group 1, 2, or 3, and 
14 Caucasian subjects will be randomly assigned in a 1:1 ratio to either Group 4 or 5. Each 
subject will participate in 1 treatment group only. 
On Day 1, AMG 133 will be administered as a single SC dose to the following groups: 
• Group 1: 
 mg (Japanese subjects) 




Protocol  
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Labcorp Drug Development Study: 8473020 
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preliminary PK data from this study demonstrate that intact AMG 133 and total AMG 133 
plasma exposures increase in a dose-proportional manner.  
The doses 
, and 
 mg are selected for evaluation in Japanese subjects and will enable 
an assessment of pharmacokinetic linearity within the AMG 133 dose range that is anticipated to 
be clinically relevant. The highest dose of 
 mg is selected as this is the highest dose planned 
for the ongoing multiple-ascending-dose study 
 mg administered every 4 weeks) and is the 
highest anticipated dose to be tested in a Phase 2 study.  
4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria prior to enrollment unless otherwise stated: 
1. Subject has provided informed consent before initiation of any study-specific 
activities/procedures. 
2. Japanese subjects must be first-generation Japanese (4 grandparents, biological parents, 
and subject born in Japan). 
3. Healthy male or female subjects between 18 and 65 years of age (inclusive) at the time of 
Screening. 
4. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory 
evaluations (congenital nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s 
syndrome based on total and direct bilirubin] is not acceptable) as assessed by the 
Investigator (or designee). 
5. Body mass index between 18 and 30 kg/m2 at the time of Screening. 
6. Females of nonchildbearing potential defined as permanently sterile (ie, due to 
hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) or postmenopausal 
(defined as at least 45 years of age with amenorrhea for 12 months without an alternative 
medical cause and follicle-stimulating hormone [FSH] level ≥ 40 mIU/mL). 
4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria prior to 
enrollment unless otherwise stated: 
1. History or evidence, at Screening or Check-in, of clinically significant disorder, 
condition, or disease not otherwise excluded that, in the opinion of the Investigator (or 
designee), would pose a risk to subject safety or interfere with the study evaluation, 
procedures, or completion. 


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2. History or current signs or symptoms of cardiovascular disease, including, but not limited 
to, myocardial infarction, congenital heart disease, valvular heart disease, coronary 
revascularization, or angina. 
3. History or evidence of clinically significant arrhythmia at Screening, including any 
clinically significant findings on the ECG taken at Check-in. 
4. A QT interval corrected for heart rate (HR) based on the Fridericia method (QTcF) 
interval >450 ms in male subjects or >470 msec in female subjects or history/evidence of 
long QT syndrome (confirmed by calculating the mean of the original value and 2 
repeats) at Screening or Check-in. 
5. PR interval >200 ms, second-degree atrioventricular (AV) block, or third-degree AV 
block at Screening or Check-in. 
6. Systolic blood pressure >140 mmHg or < 90 mmHg, or diastolic blood pressure >90 
mmHg, or HR >100 bpm at Screening or Check-in. 
7. History of hypersensitivity, intolerance, or allergy to any drug compound, food, or other 
substance, unless approved by the Investigator (or designee) and in consultation with the 
Sponsor. 
8. Poor peripheral venous access. 
9. Estimated glomerular filtration rate less than ≤ 80 mL/min/1.73 m2 as calculated by the 
Modification of Diet in Renal Disease equation at Screening or Check-in. 
10. Alanine aminotransferase or aspartate aminotransferase > the upper limit of normal at 
Screening or Check-in.  
11. Positive hepatitis B or hepatitis C panel and/or positive human immunodeficiency virus 
test at Screening. Subjects whose results are compatible with prior immunity (vaccination 
or prior infection) may be included. 
12. Use of any over-the-counter or prescription medications within 30 days or 5 half-lives 
(whichever is longer) before Check-in. 
a. Acetaminophen (paracetamol; up to 2 g per day) for analgesia will be allowed. 
b. Hormone replacement therapy (eg, estrogen) will be allowed. 
13. All herbal medicines (eg, St. John’s wort), vitamins, and supplements consumed by the 
subject within the 30 days prior to enrollment, unless deemed acceptable by the 
Investigator (or designee) and in consultation with the Sponsor. 
14. Consumption of foods and beverages containing poppy seeds within 7 days prior to 
Check-in. 
15. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 


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16. Alcohol consumption from 48 hours prior to Check-in and prior to each clinic visit and 
agrees to limit alcohol intake to a maximum of 1 unit/day on all other days, while not in 
the CRU, from Screening through the EOS visit. 
17. Regular alcohol consumption of >14 units per week for males and >7 units for females. 
One unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL) 
wine. 
18. Use of tobacco- or nicotine-containing products within 6 months prior to Check-in. 
19. Unwilling to maintain normal level of physical activity from 7 days before Check-in until 
the EOS visit (ie, will not begin a new exercise program nor participate in any unusually 
strenuous physical exertion). 
20. Positive test for illicit drugs, cotinine (tobacco or nicotine use), and/or alcohol use at 
Screening or Check-in. 
21. Consumption of caffeine-containing foods and beverages within 48 hours prior to 
Check-in. 
22. Female subjects with a positive pregnancy test at Screening or Check-in.  
23. Female subjects lactating/breastfeeding or who plans to breastfeed during the study 
through 90 days after the EOS visit. 
24. Unwilling to adhere to contraceptive requirements through 90 days after the EOS visit 
(see Appendix 4).  
25. Unwilling to abstain from sperm donation through 90 days after the EOS visit (see 
Appendix 4). 
26. Male subjects with a female partner of childbearing potential and not willing to inform 
his partner of his participation in this clinical study. 
27. Male subjects with a pregnant partner or partner planning to become pregnant who are 
unwilling to practice abstinence (refrain from heterosexual intercourse) or use 
contraception while the subject is on study through 90 days after the EOS visit. 
28. Subject has received a dose of an investigational drug within the past 90 days or 
5 half-lives, whichever is longer, prior to Check-in. 
29. Have previously completed or withdrawn from this study or any other study investigating 
AMG 133 or have previously received the investigational product.  
30. Donation of blood from 3 months prior to Check-in, plasma from 2 weeks prior to 
Check-in, or platelets from 6 weeks prior to Check-in. 
31. Unwilling to abide with study restrictions. 
32. Subjects who, in the opinion of the Investigator (or designee), should not participate in 
this study. 


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4.3. 
Screen Failures and Rescreening 
Screen failures are defined as subjects who consent to participate in the clinical study, but are not 
subsequently enrolled in the study because they do not meet eligibility requirements. 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 only once.  
4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be assigned a 
subject number prior to the first dosing occasion. Assignment of subject numbers will be in 
ascending order and no numbers will be omitted (eg, Subjects 0101, 0102, 0103). Replacement 
subjects will be assigned a subject number corresponding to the number of the subject he/she is 
replacing plus 1000 (eg, Subject 1101 replaces Subject 0101). 
Subjects will be identified by subject number only on all study documentation. A list identifying 
the subjects by subject number will be kept in the Site Master File. 
4.5. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be withdrawn 
from dosing if any of the following criteria are met: 
• change in compliance with any inclusion/exclusion criterion that is clinically relevant and 
affects subject safety as determined by the Investigator (or designee) 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn from dosing, the Sponsor (or designee) will be notified and the date and 
reason(s) for the withdrawal will be documented in the subject’s electronic Case Report Form 
(eCRF). If a subject is withdrawn, efforts will be made to perform all EOS assessments, if 
possible (Appendix 8). Other procedures may be performed at the Investigator’s (or designee’s) 
and/or Sponsor’s discretion. If the subject is in-house, these procedures should be performed 
before the subject is discharged from the clinic. The Investigator (or designee) may also request 
that the subject return for an additional follow-up visit. All withdrawn subjects will be followed 
until resolution of all their adverse events, serious adverse events, or until the unresolved adverse 
events, serious adverse events are judged by the Investigator (or designee) to have stabilized. 


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Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of adverse 
events/serious adverse events thought to be related to the study drug will generally not be 
replaced. 
4.6. 
Study Termination 
The Sponsor 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 
Good Clinical Practice. Both the Sponsor 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 Institutional Review Board (IRB) in writing of the study's completion 
or early termination and send a copy of the notification to the Sponsor. The Sponsor reserves the 
unilateral right, at its sole discretion, to determine whether to supply investigational product and 
by what mechanism, after termination of the study. 
In addition, the study may be terminated by the Sponsor at any time and for any reason. If the 
Sponsor decides to terminate the study, they will inform the Investigator as soon as possible.  
5. STUDY TREATMENTS 
Study treatment is defined as any investigational product, non-investigational product, placebo, 
or medical device 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 IMP and non-IMP, respectively. 
5.1. 
Investigational Product 
The IMP will be supplied by the Sponsor. The Investigational Product Instruction Manual 
(IPIM), a document external to this protocol, contains detailed information regarding the storage, 
preparation, destruction, and administration of the IMP shown in Table 1. 
All supplies of investigational product, both bulk and subject-specific, will be stored in 
accordance with the manufacturer’s instructions or pharmacy instructions. Until dispensed to the 
subjects, the investigational and non-investigational products will be stored at the study site in a 
location that is locked with restricted access. 
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5.3. 
Treatment of Overdose 
The effects of overdose of AMG 133 are not known. In case of overdose, consultation with the 
medical monitor is recommended for prompt reporting of clinically apparent or laboratory 
adverse events possibly related to overdose, and to discuss further management of the subject. 
5.3.1. 
Medical Devices  
No investigational medical device(s) will be used in this study. 
Other non-investigational medical devices may be used in the conduct of this study as part of 
standard care. Non-Amgen non-investigational medical devices (eg, syringes, sterile needles) 
that are commercially available are not usually provided or reimbursed by the Sponsor (except, 
for example, if required by local regulation). The Investigator will be responsible for obtaining 
supplies of these devices.  
5.3.2. 
Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
drug(s) or device(s) after it is released for distribution to market or clinic by either the Sponsor or 
by distributors and partners for whom the Sponsor manufactures the material. This includes any 
investigational product (AMG 133) provisioned and/or repackaged/modified by the Sponsor. 
Any product complaint(s) associated with an investigational product (AMG 133) supplied by the 
Sponsor are to be reported according to the instructions provided in the Amgen IPIM. 
5.4. 
Randomization 
This is a randomized, parallel-arm study. Japanese subjects will be randomized (1:1:1) to 1 of the 
3 treatment groups, and Caucasian subjects will be randomized (1:1) to 1 of the 2 treatment 
groups. Randomization scheme will be provided by a biostatistician.  
5.5. 
Blinding 
This is an open-label study. 
5.6. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of the Investigator or designee. 
• At each dosing occasion, a predose and postdose inventory of AMG 133 will be 
performed.  


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5.7. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of AMG 133 
received. In addition, an accurate drug disposition record will be kept, specifying the amount 
dispensed to each subject and the date of dispensing. This drug accountability record will be 
available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused assembled 
unit doses will be retained until completion of the study. 
At the completion of the study, all unused AMG 133 will be returned to the Sponsor, retained at 
the study site, or disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or nonprescription medications/products during 
the study until the EOS visit, unless the Investigator (or designee) and/or Sponsor have given 
their prior consent.  
Acetaminophen (paracetamol; 2 g/day) or hormone replacement therapy are acceptable 
concomitant medications. The administration of any other concomitant medications during the 
study is prohibited without prior approval of the Investigator (or designee), unless its use is 
deemed necessary for treatment of an adverse event/serious adverse event. Any medication taken 
by a subject during the course of the study and the reason for its use will be documented in the 
source data.  
6.2. 
Diet 
Subjects will be fasted overnight (at least 8 hours) before collection of blood samples for clinical 
laboratory evaluations. While confined at the study site, subjects will receive a standardized diet 
at scheduled times that do not conflict with other study-related activities.  
Refer to Section 5 and Table 1 for diet requirements/restrictions on applicable days of study 
treatment and/or PK assessments. 
Foods and beverages containing poppy seeds will not be allowed from 7 days prior to Check-in 
until EOS visit.  
Caffeine-containing foods and beverages will not be allowed from 48 hours before each study 
visit through the EOS visit.  


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Consumption of alcohol will not be permitted from 48 hours prior to each clinic visit, and 
alcohol intake will be limited to a maximum of 1 unit/day on all other days, while not in the 
CRU, from Screening through the EOS visit. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 6 months 
prior to Check-in until the EOS visit.  
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in until the 
EOS visit. Subjects will otherwise maintain their normal level of physical activity during this 
time (ie, will not begin a new exercise program nor participate in any unusually strenuous 
physical exertion).  
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to Check-in, plasma 
from 2 weeks prior to Check-in, and platelets from 6 weeks prior to Check-in until 3 months 
after the EOS visit.  
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
• dosing 
• safety assessments (ECGs will be scheduled before vital signs measurements) 
• PK blood samples 
• antidrug antibody samples 
• any other procedures. 
Where activities at a given timepoint coincide, consideration must be given to ensure that the 
following order of activities is maintained: ECGs, vital signs, and clinical laboratory 
assessments. 


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7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments in Appendix 8. Procedures for collection, processing, and shipping of 
PK blood samples will be detailed in a separate document.  
Any blood sample collected according to the Schedule of Assessments (Appendix 8) 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.  
7.1.2. 
Analytical Methodology 
Plasma concentrations of AMG 133 will be determined using validated analytical procedures. 
Specifics of the analytical method will be provided in a separate document (ie, Statistical 
Analysis Plan).  
7.2. 
Antidrug Antibody Assessments 
Serum samples for antibody testing are to be collected as outlined in the Schedule of 
Assessments in Appendix 8. 
Bioanalytical testing for anti-AMG 133 antibodies will be conducted on these samples using a 
fully validated, electrochemiluminescence-based immunoassay. All samples that test positive for 
ADA will be titered and evaluated for neutralizing antibodies against human GLP-1 using a 
cell-based assay. All neutralizing antibody positive subjects and subjects who tested positive for 
binding ADAs at the final scheduled study visit, defined as the EOS visit, and have clinical 
sequelae that are considered potentially related to an anti-AMG 133 antibody response will be 
asked to return for additional follow-up testing until the ADA responses have returned to (1) 
baseline, (2) a low titer, or (3) the subject has been followed for a period of at least 1 year (±4 
weeks) post-administration of AMG 133. All follow-up results, both positive and negative will 
be communicated to the sites. More frequent testing or testing for a longer period of time may be 
requested in the event of safety-related concerns. Follow-up testing will not be required where it 
is established that the subject did not receive AMG 133. 


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7.3. 
Safety and Tolerability Assessments 
7.3.1. 
Adverse Events and Serious Adverse Events: Time Period and Frequency for 
Collecting and Reporting Safety Event Information 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
adverse events and serious adverse events are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to EOS visit. 
Subjects will be observed for any signs or symptoms and asked about their condition by open 
questioning, such as “How have you been feeling since you were last asked?”, at least once each 
day while resident at the study site and at each study visit. Subjects will also be encouraged to 
spontaneously report adverse events and serious adverse events occurring at any other time 
during the study. 
Adverse Events 
The adverse event grading scale to be used in this study is described in Appendix 1. 
The Investigator is responsible for ensuring that all non-serious adverse events observed by the 
Investigator or reported by the subject (whether reported by the subject voluntarily or upon 
questioning, or noted on physical examination) from enrollment through the EOS visit are 
recorded/reported using the appropriate eCRF. 
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 ICF through 30 days after 
the last dose of study treatment or the EOS visit (whichever is later) are reported using the 
appropriate eCRF and reported on the paper-based Serious Adverse Event Report Form 
(described in Appendix 1). 
All serious adverse events will be collected, recorded, and reported to the Sponsor within 
24 hours of the Investigator’s knowledge of the event. The Investigator will submit any updated 
serious adverse event data to the Sponsor within 24 hours of it being available. 
Serious Adverse Events After the Protocol-required Reporting Period  
There is no requirement to monitor study subjects for serious adverse events following the 
protocol-required reporting period or after EOS. However, these serious adverse events should 
be reported to Amgen (regardless of causality) if the Investigator becomes aware of them. Per 
local requirements in some countries, Investigators are required to report serious adverse events 
that they become aware of after EOS. If serious adverse events are reported, the Investigator is to 
report them to the Sponsor within 24 hours following the Investigator’s knowledge/awareness of 
the event using the paper-based Serious Adverse Event Report Form.  


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Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the Sponsor’s safety database as clinical trial cases and handled accordingly 
based on relationship to investigational product.  
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. 
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, where possible, until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up. This will be completed at the 
Investigator’s (or designee’s) discretion. 
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 eCRF. 
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 the Sponsor. 
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 


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Sponsor will file it along with the IB and will notify the IRB, if appropriate according to local 
requirements. 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Sponsor’s safety surveillance and 
signal management processes. 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and pregnancies in female partners 
of male subjects will be collected. 
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 Appendix 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 Appendix 5. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including clinical 
chemistry, hematology, urinalysis, and serology) at the times indicated in the Schedule of 
Assessments in Appendix 8. Clinical laboratory evaluations are listed in Appendix 2. 
The Investigator is responsible for reviewing laboratory test results and recording any clinically 
relevant changes occurring during the study in CRF/eCRF. 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. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, and 
will undergo an alcohol breath or urine test at the times indicated in the Schedule of Assessments 
in Appendix 8. For all female subjects, a pregnancy test and FSH screen for postmenopausal 
women will be performed at the times indicated in the Schedule of Assessments in Appendix 8.  
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 


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7.3.3. 
Vital Signs 
Supine blood pressure, supine heart rate, respiratory rate, and oral body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 8. Vital signs may 
also be performed at other times if judged to be clinically appropriate or if the ongoing review of 
the data suggests a more detailed assessment of vital signs is required. 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. 
Subjects must be supine for at least 5 minutes before blood pressure and heart rate 
measurements. When vital signs are scheduled at the same time as blood draws, the blood draws 
will be obtained at the scheduled timepoint, and the vitals will be obtained as close to the 
scheduled blood draw as possible, but prior to the blood draw. 
7.3.4. 
12-lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at least 
5 minutes at the times indicated in the Schedule of Assessments in Appendix 8. Single 12-lead 
ECGs will be repeated twice, and an average taken of the 3 readings, if either of the following 
criteria apply: 
• QTcF is >500 ms 
• QTcF change from the baseline (predose) is >60 ms. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a more detailed assessment of ECGs is required. 
The Investigator (or designee) will perform a clinical assessment of each 12-lead ECG. 
7.3.5. 
Physical Examination 
A full physical examination or symptom-directed physical examination will be performed at the 
timepoints specified in the Schedule of Assessments in Appendix 8.  
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
The sample size for this study is based practical considerations. No statistical hypotheses will be 
tested. Approximately 35 subjects will be enrolled across 5 groups (7 subjects per group). The 
study design and sample size per dose group for this study is considered adequate for evaluation 
of the study objectives. 


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8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of AMG 133 and have 
evaluable PK data.  
8.2.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of AMG 133. 
8.3. 
Pharmacokinetic Analyses 
Plasma AMG 133 concentrations will be determined using a validated assay. Individual plasma 
concentration-time plots for AMG 133 will be presented for each subject as well as mean 
concentration-time plots for each dose group. Pharmacokinetics parameters of AMG 133 will be 
calculated using standard noncompartmental methods. 
The primary PK parameters will include Cmax, AUClast, and AUCinf for AMG 133. All other PK 
parameters will be regarded as secondary and will not be subject to inferential statistical analysis.  
Additional parameters may be calculated. Specific details will be presented in the Statistical 
Analysis Plan for this study. 
8.4. 
Antidrug Antibody Analysis 
The incidence and percentage of subjects who develop anti-AMG 133 antibodies (binding and if 
positive, neutralizing, when available) at any time will be tabulated by treatment group. 
8.5. 
Safety Analysis 
The number and percentage of subjects reporting any adverse events will be tabulated by 
Medical Dictionary for Regulatory Activities system organ class and preferred term. Tables of 
fatal adverse events, serious adverse events, adverse events leading to withdrawal from 
investigational product or other protocol-required therapies, and significant treatment-emergent 
adverse events will also be provided. Subject-level data may be provided instead of tables if the 
subject incidence is low. 
Endpoints for clinical laboratory tests, ECG, and vital signs will be summarized. 
8.6. 
Interim Analysis 
No interim analyses are planned for this study.  


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9. REFERENCES
1. Amgen Inc. AMG 133 – Investigator’s Brochure (Version 1.0). 01 June 2020.
2. World Health Organization. Obesity and overweight; 2018. Available from:
http://www.who.int/mediacentre/factsheets/fs311/en/.
3. Turton MD, O'shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central
regulation of feeding. Nature. 1996;379:69-72.
4. Yip RG, Boylan MO, Kieffer TJ, Wolfe MM. Functional GIP receptors are present on
adipocytes. Endocrinology. 1998;139:4004-4007
5. Beck B, Max JP. Hypersensitivity of adipose tissue to gastric inhibitory polypeptide action in
the obese Zucker rat. Cell Mol Biol. 1987;33:555-562.


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10. APPENDICES 












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Figure 2:  
Sample Serious Adverse Event Report Form 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Lipase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatinine Kinase 
Hemoglobin A1C 
High-density lipoprotein (HDL) 
Low-density lipoprotein (LDL) 
Lactate dehydrogenase (LDH) 
Direct bilirubina 
Gamma-glutamyl transferase 
Glucose 
Indirect bilirubina 
Inorganic phosphate 
Magnesium 
Phosphorus 
Potassium  
Sodium  
Total bilirubina 
Total creatine kinase  
Total protein 
Uric acid 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
Reticulocytes 
White blood cell (WBC) count 
WBC differential: 
  Basophils 
  Eosinophils 
  Lymphocytes 
  Monocytes 
  Neutrophils 
  Segmented Neutrophils 
  Bands/Stabs 
 
Bilirubin 
Blood 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination (if 
protein, leukocyte esterase, 
nitrite, or blood is positive) 
 
Serologyb: 
Drug screenc: 
Hormone panel - females only: 
Anti-hepatitis B surface antibody 
Anti-hepatitis B core antibody  
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
and p24 antigen 
Including but not limited to:  
Amphetamines/methamphetamin
es 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
Alcohol breath or urine test  
Follicle-stimulating hormone 
(postmenopausal females only) b 
Serum pregnancy test (human 
chorionic gonadotropin)d 
Urine pregnancy testd 
Other tests: 
Hepatotoxicity only: 
International normalized ratio 
(INR)e 
Estimated glomerular filtration 
rate (eGFR)f 
 
a Direct and indirect bilirubin will be analyzed if total bilirubin is elevated.  
b Only analyzed at Screening. 


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c Only analyzed at Screening and Check-in. Alcohol testing is not included at Screening. Cotinine testing at Screening, Check-in, 
and all outpatient visits. 
d Performed in serum at Screening and in urine at all other times for all females. A positive urine pregnancy test will be 
confirmed with a serum pregnancy test. 
e International normalized ratio will be tested if hepatotoxicity is suspected, per guidelines presented in Appendix 7. 
f Estimated glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease equation. 


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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations 
7.5 
8 
60 
Serology 
3.5 
1 
3.5 
Serum FSH 
4 
1 
4 
Serum pregnancy test 
4 
1 
4 
AMG 133 
pharmacokinetics 
4 
16 
64 
Anti-AMG 133 antibody 
4 
5 
20 
Total: 
155.5 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject will 
not exceed 500 mL. 


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Appendix 4: Contraception Requirements 
All subjects must receive pregnancy prevention counseling and be advised of the risk to the fetus 
if they conceive a child during treatment and for 90 days after the end of study (EOS) visit. 
Additional medications given during the study may alter the contraceptive requirements. The 
Investigator must discuss these contraceptive changes with the subject. 
Definition of Women of Childbearing Potential: premenopausal females who are anatomically 
and physiologically capable of becoming pregnant following menarche.  
Women of Nonchildbearing Potential: 
1. Surgically sterile: females who are permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or medical 
records. Surgical sterilization to have occurred a minimum of 6 weeks, or at the 
Investigator’s discretion, prior to Screening.  
2. Postmenopausal: females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating hormone 
levels of ≥40 mIU/mL. The amenorrhea should not be induced by a medical condition 
such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, or by 
extreme exercise. It should not be due to concomitant medications that may have induced 
the amenorrhea such as oral contraceptives, hormones, gonadotropin-releasing hormones, 
anti-estrogens, or selective estrogen receptor modulators.  
Fertile male: a male that is considered fertile after puberty.  
Infertile male: permanently sterile male via bilateral orchiectomy.  
Contraception Requirements 
Female Subjects  
Female subjects who are of nonchildbearing potential will not be required to use contraception.  
Male Subjects:  
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to a 
second method of acceptable contraception by female partner from Check-in until 90 days after 
the EOS visit. Acceptable methods of contraception for female partners include:  
• hormonal injection  
• combined oral contraceptive pill or progestin/progestogen-only pill  
• combined hormonal patch  
• combined hormonal vaginal ring  


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• surgical method (bilateral tubal ligation or regulatory approved method of hysteroscopic 
bilateral tubal occlusion)  
• hormonal implant  
• hormonal or non-hormonal intrauterine device  
• over-the-counter sponge with spermicide  
• cervical cap with spermicide  
• diaphragm with spermicide.  
Male subjects are required to refrain from donation of sperm from Check-in until 90 days after 
the EOS visit.  
Sexual Abstinence  
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months prior 
to Screening and must agree to remain abstinent from the time of signing the ICF until 90 days 
after the EOS visit.  
Same-sex Relationships 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after the 
EOS visit. 


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Appendix 5: Collection of Pregnancy and Lactation Information 
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 90 days after EOS.
•
Information will be recorded on the Pregnancy Notification Form (see
Figure 3: Pregnancy Notification Form). 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 region’s local privacy laws).
•
After obtaining the female subject’s signed consent 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 90 days after EOS. This information
will be forwarded to Amgen Global Patient Safety. Generally, infant follow-up will be
conducted up to 12 months after the birth of the child (if applicable).
•
Any termination of pregnancy will be reported to Amgen Global Patient Safety,
regardless of fetal status (presence or absence of anomalies) or indication for procedure.
•
While pregnancy itself is not considered to be an adverse event or serious adverse event,
any pregnancy complication or report of a congenital anomaly or developmental delay,
fetal death, or suspected adverse reactions in the neonate will be reported as an adverse
event or serious adverse event. Note that an elective termination with no information on a
fetal congenital malformation or maternal complication is generally not considered an
adverse event, but still must be reported to the Sponsor 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 Appendix 1. 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 5.6 for details).
Male Subjects with Partners Who Become Pregnant or Were Pregnant at the Time of Enrollment 
•
In the event a male subject fathers a child during treatment, and for an additional 90 days
after EOS, the information will be recorded on the Pregnancy Notification Form. The


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form (see Figure 3: Pregnancy Notification Form) 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 region’s local privacy laws). 
• The Investigator will attempt to obtain a signed consent 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 consent 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 90 days after EOS. 
• Information will be recorded on the Lactation Notification Form (Figure 4) and submitted 
to Amgen Global Patient Safety within 24 hours of the Investigator’s knowledge of event. 
• Study treatment will be discontinued if the female subject breastfeeds during the study. 
With the female subject’s signed consent 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 90 days after discontinuing protocol-required therapies.


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Figure 3:  
Pregnancy Notification Form 


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Figure 4:  
Lactation Notification Form 
 
 


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Appendix 6: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 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 laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator’s Brochure, and 
other relevant documents (eg, advertisements) must be submitted to an Institutional Review 
Board (IRB) by the Investigator and reviewed and approved by the IRB before the study is 
initiated.  
Any amendments to the protocol will require IRB and regulatory authority (as locally required) 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB. 
• Notifying the IRB of serious adverse events or other significant safety findings as 
required by IRB procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
An initial sample ICF will be provided for the Investigator (or designee) to prepare the informed 
consent document to be used at his or her site. Updates to the sample ICF are to be 
communicated formally in writing from the Study Manager to the Investigator. The written ICF 
is to be prepared in the language(s) of the potential study participant population. 


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The Investigator or his/her delegated representative will explain to the subject, or his/her legally 
authorized representative, the aims, methods, anticipated benefits, and potential hazards of the 
study before any protocol-specific screening procedures or any investigational product(s) is/are 
administered and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative (defined as an individual or other body authorized under applicable law 
to consent, on behalf of a prospective subject, to the subject’s participation in the clinical study) 
will then be required to sign a statement of informed consent that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, and the IRB 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 ICF. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her notification 
of the primary care physician is to be documented in the subject’s medical records, and the ICF 
is to be signed and personally dated by the subject or a legally acceptable representative and by 
the person who conducted the informed consent discussion. Subject withdrawal of consent or 
discontinuation from study treatment and/or procedures must also be documented in the subject’s 
medical records. 
Subjects must be re-consented to the most current version of the ICF during their participation in 
the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a copy of 
the ICF must be provided to the subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the ICF to the subject 
and must allow for questions. Thereafter, both the subject and the witness must sign the ICF to 
attest that informed consent was freely given and understood. (Refer to ICH GCP guideline, 
Section 4.8.9.) 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 
28 days from the previous ICF signature date and the same version of the ICF is in use at the 
time of rescreening. 
Subject Data Protection 
The Investigator must ensure that the subject’s confidentiality is maintained for documents 
submitted to the Sponsor. 
Subjects will be assigned a unique identifier by the Sponsor (or designee). 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.  


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On the electronic Case Report Form (eCRF) demographics page, in addition to the unique 
subject identification number (Section 4.4), include the age at time of enrollment. 
For serious adverse events reported to the Sponsor (or designee), subjects are to be identified by 
their unique subject identification number (Section 4.4) (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 the Sponsor (eg, signed ICFs) are to be kept in confidence 
by the Investigator, except as described below. 
In compliance with 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 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. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential information of the 
Sponsor, Amgen Inc. The Investigator (or designee) agrees not to disclose such information in 
any way without prior written permission from the Sponsor. 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 permission from the Sponsor. 
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 (or designee). 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 CRF demographics page, in addition to the unique subject identification number 
(Section 4.4), include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their unique 
subject identification number (Section 4.4), 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 ICFs) are to be kept in confidence by the 
Investigator, except as described below. 


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Data Quality Assurance 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, IRB 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. Predefined agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the data 
may be included in a Data Management Plan.  
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF 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. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c), unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and transmitted 
to the Sponsor or designee electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled subject who undergoes any screening procedures, 
according to the eCRF completion instructions. The Sponsor, or Contract Research Organization, 
will review the supporting source documentation against the data entered into the eCRFs to 


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verify the accuracy of the electronic data. The Investigator will ensure that corrections are made 
to the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the data on 
the eCRF, data queries, and site notifications. 
Publications 
The policy for publication of data obtained during this study will be documented in the Clinical 
Study Agreement. 


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Appendix 7: Hepatotoxicity: Suggested Actions and Follow-up Assessments  
Subjects with normal hepatic function at Screening who experience aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) elevations >3 x upper limit of normal (ULN) or 
subjects with elevated values before drug exposure who have a 2-fold increase above baseline 
values (as specified in the Guidance for Industry Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation, July 2009) are to undergo clinical assessments and a period of “close 
observation” until abnormalities return to normal or to the subject’s baseline level as described 
below. 
 
Clinical Assessments and Observation 
Assessments that are to be performed during this period include:  
• Repeat AST, ALT, alkaline phosphatase, bilirubin (total and direct), and international 
normalized ratio (INR) within 24 hours  
• In cases of total bilirubin (TBL) >2 x ULN or INR >1.5, retesting of liver tests, bilirubin 
(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.  
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 G, anti-nuclear antibody anti-smooth muscle antibody, and 
liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
• Serum acetaminophen (paracetamol) levels 
• A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 
o Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
o Concomitant use of medications (including nonprescription medicines and herbal 
and dietary supplements), plants, and mushrooms 
• Viral serologies 
• Creatine phosphokinase, haptoglobin, lactate dehydrogenase, and peripheral blood smear 
• Appropriate liver imaging if clinically indicated 


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• 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 are 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 drug-induced liver injury (DILI) event and additional information such as medical 
history, concomitant medications, and laboratory results must be captured in the corresponding 
electronic Case Report Form (eCRF). 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are not 
limited to: 
• Hepatobiliary tract disease 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
• Right sided heart failure, hypotension, or any cause of hypoxia to the liver causing 
ischemia 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms 
• Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
• Alpha-one antitrypsin deficiency 
• Alcoholic hepatitis 
• Autoimmune hepatitis 
• Wilson’s disease and hemochromatosis 
• Nonalcoholic fatty liver disease including steatohepatitis 
• Non-hepatic causes (eg, rhabdomylosis, hemolysis). 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, ie, cases of AST or ALT >3 x ULN and 
concurrent TBL >2 x ULN or INR >1.5 (for subjects not on anticoagulation therapy) without 
evidence of alternative cause of the elevations, require the following: 


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• The event is to be reported to the Sponsor 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 eCRF captures information necessary to facilitate the evaluation of 
treatment-emergent liver abnormalities is to be completed and sent to the Sponsor. 
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 Appendix 1. 
 


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Appendix 8: Schedule of Assessments 




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f Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 
30 days or 5 half-lives (whichever is longer) before Check-in for over-the-counter or prescription medications, and 30 days prior to enrollment for herbal medicines (eg, St. 
John’s wort), vitamins, and supplements, will be recorded on the subject’s electronic Case Report Form. 
g Performed in serum at Screening and in urine at all other times for all females. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
h Performed in postmenopausal females only. 
i Electrocardiograms will be collected after the subject has rested in a supine position for at least 5 minutes, and will be obtained prior to the scheduled blood draws. 
j Supine blood pressure, supine heart rate, respiratory rate, and oral body temperature will be measured after the subject has been resting in the supine position for at least 
5 minutes. 
k Clinical chemistry fasted at least 8 hours. 
l eGFR will be calculated using the Modified Renal Disease equation. 
m A full physical examination at Screening and Check-in and a symptom-directed physical examination at other timepoints. 
n The PK sample collected from predose through 48 hours postdose will have a sampling window of ± 30 minutes, samples collected at outpatient visits will have a sampling 
window of ± 48 hours. Times of all PK samples will be recorded to the nearest minute. 
o Dose administration of AMG 133 is to occur during the morning of Day 1 after an overnight fast of at least 10 hours.  
 
 


Protocol  
CONFIDENTIAL 
Labcorp Drug Development Study: 8473020 
Protocol Reference: 20200290 
 
Protocol Amendment 01, 24 August 2021 
Page 1 of 2 
Summary of Amended Protocol Changes 
A Phase I, Open-label, Randomized, Parallel-arm, Single-dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of AMG 133 Administered Subcutaneously in 
Healthy Japanese and Caucasian Subjects 
Protocol Status: Final 
Original Protocol Date: 09 August 2021 
Protocol Date: 24 August 2021 
Investigational Drug: AMG 133 
 
Amgen Protocol Reference Number: 20200290 
Labcorp Drug Development Study: 8473020 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320, USA 
Study Site: 
Labcorp Drug Development 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704, USA 
 
 
Sponsor Signatory: 
Principal Investigator: 
MD, MPH, MBE 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
________________________________________ 
The primary change in this amendment is: 
1. to update the number of injections in the
 mg dose group from 
  
Minor changes: 
1. The version number and date were updated throughout the protocol. 



SAP_001.pdf: 
 
 
Statistical Analysis Plan 
 A Phase I, Open-label, Randomized, Parallel-arm, Single-dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 133 
Administered Subcutaneously in Healthy Japanese and Caucasian Subjects 
SAP Status: Final 
SAP Version: 1.0 
SAP Date: 18Nov2021 
Investigational Medicinal Product: AMG 133 
Protocol Reference: 20200290 
Labcorp Study: 8473020 
Sponsor: 
Amgen, Inc.  
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Study Sites: 
WCCT Global, LLC. 
5630 Cerritos Avenue 
Cypress, California 90630 
USA 
Principal Investigators: 
 MD MPH MBE 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
NCT Number: NCT05056246
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


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ST-AD-031 Version 02 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
4. STUDY DESIGN................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 8 
6. STUDY TREATMENTS ....................................................................................................... 8 
7. DEFINITIONS OF POPULATIONS .................................................................................... 9 
7.1. All Subjects Population ................................................................................................... 9 
7.2. Safety Population ............................................................................................................ 9 
7.3. Pharmacokinetic Population ........................................................................................... 9 
8. STATISTICAL METHODOLOGY ...................................................................................... 9 
8.1. General ............................................................................................................................ 9 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 10 
8.1.2. Calculation of the Summary Statistics ................................................................... 10 
8.1.3. Triplicate Readings................................................................................................. 11 
8.1.4. Repeat and Unscheduled Readings ........................................................................ 11 
8.2. Subject Disposition and Population Assignment .......................................................... 11 
8.3. Screening Demographics and Baseline Characteristics ................................................ 12 
8.4. Prior and Concomitant Medication ............................................................................... 12 
8.5. Pharmacokinetic Assessments ...................................................................................... 12 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 12 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 14 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 14 
8.6. Safety and Tolerability Assessments ............................................................................ 15 
8.6.1. Adverse Events ....................................................................................................... 15 
8.6.2. Clinical Laboratory Parameters .............................................................................. 16 
8.6.3. Vital Signs Parameters ........................................................................................... 17 


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8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 17 
8.6.5. Antibodies .............................................................................................................. 17 
8.6.6. Other Assessments ................................................................................................. 17 
8.6.7. Safety and Tolerability Statistical Methodology .................................................... 17 
9. INTERIM ANALYSES ....................................................................................................... 17 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 17 
11. REFERENCES .................................................................................................................. 18 
12. APPENDICES ................................................................................................................... 19 
Appendix 1: 
Document History ................................................................................ 19 
 
LIST OF IN-TEXT TABLES AND FIGURES 
  
Figure 1: 
Study Design ........................................................................................................... 8 
 


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ST-AD-031 Version 02 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
%AUCextrap 
percentage of area under the plasma concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
ADaM 
Analysis Data Model 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero 
extrapolated to infinity 
AUClast 
area under the plasma concentration-time curve from time zero to the 
last quantifiable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CDER 
Center for Drug Evaluation and Research 
CL/F 
apparent total clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CRU 
clinical research unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMP 
data management plan 
ECG 
electrocardiogram 
EOS 
end of study 
eCRF 
electronic case report form 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation 
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio 
time period over which λz was determined as a ratio of t1/2 
λz Upper 
end of exponential fit 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
not applicable 
PK 
pharmacokinetic(s) 
R2-adj 
adjusted coefficient for determination of exponential fit 
SAP 
statistical analysis plan 
SC 
subcutaneous 


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SD 
standard deviation 
SDV 
source document verification 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable concentration 
tmax 
time of the maximum observed plasma concentration 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  
 


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ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Amendment 1 dated 
24 August 2021) and electronic case report form (eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), safety, and tolerability 
data from this study. A detailed description of the planned TFLs to be presented in the 
clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Amgen Inc. A limited amount of information about this study 
(eg, objectives, study design) is given to help the reader’s interpretation.  
This SAP must be finalized prior to the lock of the clinical database. Additionally, the SAP 
and TFL shells should be finalized prior to any programming activities commencing.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Amgen Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, ICH E9 guideline 
Statistical Principles for Clinical Trials.1,2,3 
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
The primary objective of the study is: 
● to evaluate the PK of AMG 133 after single subcutaneous (SC) administration in 
healthy Japanese and Caucasian subjects.  
The secondary objectives of the study are:  
● to evaluate the safety and tolerability of AMG 133 after single SC administration in 
healthy Japanese and Caucasian subjects.  
● to evaluate the incidence of anti-AMG 133 antibodies in healthy Japanese and 
Caucasian subjects.   
3. STUDY ENDPOINTS  
The primary endpoints of the study are AMG 133 PK parameters:  
● maximum observed plasma concentration (Cmax)  


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● area under the plasma concentration-time curve (AUC) from time zero to the last 
quantifiable concentration (AUClast)  
● area under the plasma concentration-time curve from time zero extrapolated to 
infinity (AUCinf).  
The secondary endpoints of the study are:  
● adverse events (AE) 
● clinical laboratory tests  
● 12-lead electrocardiograms (ECGs) 
● vital signs  
● incidence of anti-AMG 133 antibodies.  
4. STUDY DESIGN  
This will be a Phase I, single-center, open-label, randomized, parallel-arm study to 
investigate the PK, safety, and tolerability of a single SC dose of AMG 133 in 3 groups of 
healthy Japanese subjects and 2 groups of healthy Caucasian subjects. 
Approximately 35 subjects will be enrolled in total, with 7 subjects in each of the 5 groups. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to dose administration. Eligible subjects will be admitted into the clinical research unit 
(CRU) for Check-in on Day -1 and be confined to the CRU until clinic discharge on Day 8. 
On Day 1, 21 Japanese subjects will be randomly assigned in a 1:1:1 ratio to Group 1, 2, or 3, 
and 14 Caucasian subjects will be randomly assigned in a 1:1 ratio to either Group 4 or 5. 
Each subject will participate in 1 treatment group only. 
On Day 1, AMG 133 will be administered as a single SC dose to the following groups: 
• Group 1: 
 mg (Japanese subjects) 
• Group 2: 
 mg (Japanese subjects) 
• Group 3: 
 mg (Japanese subjects) 
• Group 4: 
 mg (Caucasian subjects) 
• Group 5: 
 mg (Caucasian subjects) 
The total duration of study participation for each subject (from Screening through end of 
study [EOS] visit) is anticipated to be approximately 21 weeks. 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 


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The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
An overview of the study design is shown in Figure 1.  
Figure 1: Study Design  
  
 
 
5. SAMPLE SIZE JUSTIFICATION  
The sample size for this study is based practical considerations. No statistical hypotheses will 
be tested. Approximately 35 subjects will be enrolled across 5 groups (7 subjects per group). 
The study design and sample size per dose group for this study is considered adequate for 
evaluation of the study objectives.  
6. STUDY TREATMENTS  
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table . 
Table 1: Presentation of Study Treatments in TFLs  
Treatments 
Abbreviation 
Order in TFLs 
Group 1:
 mg (Japanese subjects) 
Japanese 
mg AMG 133 
1 
Group 2:
 mg (Japanese subjects) 
Japanese 
mg AMG 133 
2 
Group 3:
 mg (Japanese subjects) 
Japanese 
mg AMG 133 
3 
Group 4: 
mg (Caucasian subjects) 
Caucasian
 mg AMG 133 
4 
Group 5: 
mg (Caucasian subjects) 
Caucasian
 mg AMG 133 
5 
All TFLs will be based on actual treatments (eg, if subject was assigned to receive Group 1 
treatment but was wrongfully dosed with Group 3 treatment they would be summarized and 
listed under Group 3 treatment). 


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7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 8.1.1), will be considered prior to database lock for their 
importance and taken into consideration when assigning subjects to populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of AMG 133.   
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of AMG 133 and 
have evaluable PK data.  
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects assigned to the all subjects population and include 
data up to the point of study completion or discontinuation. Subjects are generally considered 
to have completed the study if they complete the scheduled end of study visit (rather than 
early termination visit). Any subject who discontinues the study will be identified 
accordingly in the listings. Summaries and statistical analyses will include the subjects 
assigned to the relevant population based on data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if a new version is issued during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if a new 
version is issued during the study). Pinnacle 21 Enterprise Version 4.2.0 (or higher if a new 
version is issued during the study) will be utilized to ensure compliance with CDISC 
standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.   
Where reference is made to ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  


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Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, percentage changes 
from baseline, and any parameter derivations.  
All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognized potential for: 
● Missed visits, caused by, for example: 
o Subject unable to travel to site due to restrictions, the need to quarantine, or 
COVID-19 infection 
o Subject unwilling to go to site due to fear of COVID-19 infection 
o Site postponing subject’s visit due to investigator not being available (eg, if they 
have been dispatched to hospital handling COVID19 infections) 
● Site unable to replenish supply of investigational product 
● Incomplete data entry by sites due to limited resources to support study or no access 
to source documents or to eCRF 
● Outstanding source document verification (SDV) due to sponsor or country 
restrictions on remote SDV, or no or limited access to site(s) for on-site visits 
● Unanswered queries 
At the time of the reporting of the study results, all protocol deviations due to COVID-19 or 
related restriction will be assessed for their severity and impact on the analyses. If needed, 
appropriate statistical methods will be applied as a mitigating action (eg, data might be 
categorized into 2 analysis groups, with and without COVID-19 and related restrictions 
impact); however, this will exclude any imputations of the missing values. Any mitigating 
actions will be agreed with Amgen Inc. in advance and identified in the CSR.  
8.1.2. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  


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● If the number of subjects with valid observations (n) <3, summary statistics will not 
be calculated, with the exception of n, minimum, and maximum.  
● In general, as early termination data are not associated with any scheduled timepoint, 
they will be excluded from all calculations of summary statistics and statistical 
analyses. Exceptions may be made where justified.  
For categorical data the following rules will be applied:  
● For ordered categorical data (eg, AE severity), all categories between the possible 
minimum and maximum categories will be included, even if n = 0 for a given 
category.  
● For non-ordered categorical data (eg, race), only those categories for which there is at 
least 1 subject represented will be included; unless specifically stated otherwise.  
● Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This 
will ensure that the population size totals are consistent across different parameters.  
8.1.3. Triplicate Readings  
For 12-lead electrocardiogram (ECG) data only, where triplicate readings are taken, the mean 
of triplicate readings will replace the separate individual triplicate readings in all calculations.  
In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean and/or medians will be calculated, as appropriate, based on the number of readings 
available.  
8.1.4. Repeat and Unscheduled Readings  
For vital signs and 12-lead ECG data only, any predose value recorded in addition to the 
original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 
parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations.   
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment will be provided, based on the safety population.  


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8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including sex, age, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by treatment will be provided, based on the safety population.  
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to dosing. Concomitant 
medication will be defined as medication that starts during or after dosing or starts but does 
not end prior to dosing.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2020 (or later if a new 
version is issued during the study; see the data management plan [DMP] for more details). 
Prior and concomitant medications will be listed.  
8.5. Pharmacokinetic Assessments  
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of AMG 133 using noncompartmental methods in validated software program 
Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUClast 
h*μg/mL 
area under the plasma concentration-time curve from time 
zero to the time of last quantifiable concentrationb 
AUCinf 
h*μg/mL 
area under the plasma concentration-time curve from time 
zero extrapolated to infinityc 
%AUCextrap 
% 
percentage of area under the plasma concentration-time curve 
due to extrapolation from the last quantifiable concentration 
to infinity 
Cmax 
μg/mL 
maximum observed plasma concentration 
tmax 
h 
time of the maximum observed plasma concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance, calculated as Dose/AUCinf  
Vz/F 
L 
apparent volume of distribution during the terminal phase, 
calculated as Dose/(AUCinf* λz)  
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b The area under the concentration-time curve will be calculated using the linear trapezoidal (linear interpolation) rule. 
c Based on the last observed quantifiable concentration 
 
Additional PK parameters may be determined where appropriate. 


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Pharmacokinetic analysis will be carried out where possible using actual dose administered 
(mg) and actual postdose blood sampling times. If an actual time is missing, the sample 
concentration result will be treated as missing unless there is scientific justification to include 
the result using the nominal time.  
The parameters Cmax, tlast, and tmax will be obtained directly from the concentration-time 
profiles. If Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence 
of Cmax. 
8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.8. 
Parameters requiring λz for their calculation (eg, AUCinf, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.8. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie, the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR. 
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax.  
If the extrapolated area is >20%, AUCinf (and derived parameters, CL/F, and Vz/F) may be 
excluded from the summary statistics and statistical analysis at the discretion of the sponsor 
or pharmacokineticist.  


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If AUCinf cannot be determined reliably for all subjects and/or dose levels, an alternative 
AUC measure, such as AUC to a fixed timepoint or AUClast, may be calculated. 
8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated as 
missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
● If a predose plasma concentration is missing, it will be set to 0 by default within 
Phoenix WinNonlin 
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be flagged in data listings and 
documented in the CSR. 
Any quantifiable predose concentration value will be considered anomalous and set to 
missing for the PK analysis. This will be set to 0 by default in Phoenix WinNonlin. 
8.5.2. Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates from the nominal time by more than ±20%, 
the plasma concentration will be flagged and excluded from the summary statistics.  
For plasma concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
For PK parameters the following rule will apply: 
● Geometric mean and coefficient of variation will not be calculated for tlast or tmax.  
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed. 


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Summary tables, mean (+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by treatment and time postdose will be provided for plasma PK 
concentrations. All figures will be produced on both linear and semi-logarithmic scales. 
Summary tables by treatment will be provided for all PK parameters, with the exception of 
regression-related PK parameters.  
 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.0 (or higher if a new version is issued during the study; see the DMP for more 
details). 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after dosing, or starts prior to dosing and increases in severity after dosing. 
A treatment-related TEAE will be defined as a TEAE with a relationship related to the study 
treatment, as determined by the investigator.  
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of 
dosing for TEAEs only.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by 
treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  


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For the AE data the following rules will apply:  
● For the derivation of treatment-emergent status (applicable to all AEs): If the start 
date/time of an AE is incomplete or missing, an AE will be assumed to not be a 
TEAE, unless the incomplete start date/time or the end date/time indicates an AE 
started after dosing. 
● For the derivation of treatment-related status (applicable to TEAEs only): If the study 
treatment relationship for a TEAE is missing, a TEAE will be assumed to not be a 
treatment-related TEAE.  
● For the derivation of onset time (applicable to TEAEs only): If the start date/time of a 
TEAE is missing, onset time will not be calculated. If the start date/time of a TEAE is 
incomplete, where possible, the minimum possible onset time will be calculated and 
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of dosing is 
01MAY2019/08:00 and recorded start date/time of a TEAE is 03MAY2019, then the 
minimum possible onset time will be calculated by assuming a TEAE started at the 
first hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as 
onset time ≥01:16:00 in the listing). If the start date of a TEAE is the same as the date 
of dosing but the start time of a TEAE is missing, an onset time will be presented as 
‘≥00:00:01’. Any clock changes will be accounted for in the derivation.  
● For the derivation of duration (applicable to all AEs): If the end date/time of an AE is 
missing, duration will not be calculated. If the start or end date/time of an AE is 
incomplete, where possible, the maximum possible duration will be calculated and 
presented in ‘≤DD:HH:MM’ format (eg, if the start of an AE date/time is 
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the 
maximum possible duration will be calculated by assuming an AE ended at the last 
hour and minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as 
duration ≤02:15:59 in the listing). Any clock changes will be accounted for in the 
derivation.  
● For the calculation of TEAE summary statistics: If the severity of a TEAE is missing, 
that TEAE will be counted under the ‘missing’ category. 
● For the calculation of TEAE summary statistics: If a subject experienced multiple 
TEAEs with the same preferred term for the same treatment, this will be counted as 1 
TEAE for that treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters, will be listed, as applicable; any value outside the clinical 
reference range will be flagged. Separate listings will be provided for any parameter for 
which there is any individual subject value outside the respective clinical reference range. 
Summary tables by treatment and timepoint will be provided for clinical chemistry and 
hematology parameters. 


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Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, and presentation in the figures, <x and ≤x values 
will be set to 0, whereas >x and ≥x values will be set to x.  
8.6.3. Vital Signs Parameters  
All vital signs parameters will be listed, as applicable; any value outside the clinical reference 
range will be flagged.  
Summary tables by treatment and timepoint will be provided by treatment group for all vital 
signs parameters as applicable.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters will be listed; any value outside the clinical reference range will 
be flagged. 
Summary tables by treatment and timepoint will be provided for all 12-lead ECG parameters. 
8.6.5. Antibodies 
The formation of anti-AMG 133 antibodies will be summarized descriptively. The incidence 
and percentage of subjects who develop anti-AMG 133 antibodies (binding and if positive, 
neutralizing to native GLP-1) will be summarized by treatment group. Furthermore, the 
incidence and percentage of subjects with treatment boosted anti-AMG 133 antibodies will 
also be summarized. In addition, subjects with positive anti-AMG 133 binding antibody and 
anti-GLP-1 neutralizing antibody results will be listed individually with corresponding time 
points. 
8.6.6. Other Assessments  
Medical history will not be listed.   
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.7. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  
9. INTERIM ANALYSES  
No interim analyses are planned.   
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  


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11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8). 
17 July 1997.  
3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
4. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
5. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
6. Statistical Approaches to Establishing Bioequivalence. Rockville, MD: US Dept of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER); January 2001. 
7. Schuirmann DJ. A comparison of the two one sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm. 1987;15(6):657-680. 
 


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12. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable