Clinical trial NCT04987333
Conditions: Inflammatory Diseases
Keywords: Systemic lupus erythematosus (SLE) Steroid-refractory chronic graft-versus-host disease (GvHD) Ulcerative colitis Single-dose study Efavaleukin alfa Regulatory T Cells (Tregs) Inflammatory
Sponsor: Amgen
Start date: 2021-08-09; Completion date: 2022-10-03
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

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

Detailed description:

Arms: arm 1: Chinese participants will receive a single dose of efavaleukin alfa at dose level 1. arm 2: Chinese participants will receive a single dose of efavaleukin alfa at dose level 2. arm 3: Japanese participants will receive a single dose of efavaleukin alfa at dose level 2. arm 4: Caucasian participants will receive a single dose of efavaleukin alfa at dose level 2.
Interventions: intervention 1: Efavaleukin alfa
Intervention descriptions: intervention 1: Administered as a single dose SC injection.

Protocol documents:
Prot_000.pdf: 
Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 1 of 68 
 
Protocol 
A Phase 1, Open-label, Sequential-group, Single-dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 592 
Administered Subcutaneously in Healthy Chinese, Japanese, and 
Caucasian Subjects 
Protocol Status: Final 
 
Protocol Amendment 2 
Protocol Amendment 2 Date: 28 April 2022 
Protocol Amendment 1 Date: 08 December 2021 
Original Protocol Version 1.0 Date: 01 April 2021 
 
Investigational Product: AMG 592 (efavaleukin alfa) 
 
Amgen Protocol Reference Number: 20200102 
Labcorp Drug Development Study Number: 8448873 
IND Number: 131270 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
 
 
 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 2 of 68 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the Institutional Review Board/Independent Ethics 
Committee/Institutional Scientific Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent 
of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 3 of 68 
INVESTIGATOR AGREEMENT 
I have read the protocol entitled “A Phase 1, Open-label, Sequential-group, 
Single-dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
AMG 592 Administered Subcutaneously in Healthy Chinese, 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 
 
_______________________________________                   
 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 
PPD


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 4 of 68 
STUDY IDENTIFICATION 
Sponsor 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
Sponsor’s Study Contact 
 
 
 
 
 
Medical Monitor 
 
 
 
 
Sponsor’s Study Manager 
 
 
 
 
Labcorp Drug Development 
Program Manager 
 
 
 
 
Statistician 
 
 
 
 
 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 5 of 68 
SYNOPSIS 
Title of study: A Phase 1, Open-label, Sequential-group, Single-dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of AMG 592 Administered Subcutaneously in 
Healthy Chinese, Japanese, and Caucasian Subjects 
Objectives:  
The primary objective of the study is: 
 
to evaluate the pharmacokinetics (PK) of AMG 592 after single subcutaneous (SC) 
administration in healthy Chinese, Japanese, and Caucasian subjects. 
The secondary objectives of the study are: 
 
to evaluate the safety and tolerability of AMG 592 after single SC administration in 
healthy Chinese, Japanese, and Caucasian subjects. 
 
to evaluate the incidence of anti-AMG 592 and anti-interleukin (IL)2 antibodies in 
healthy Chinese, Japanese, and Caucasian subjects after single SC administration of 
AMG 592. 
 
 
Study design: 
This will be an open-label, single-dose, sequential-group study in 2 groups of healthy Chinese 
subjects and 1 group of Japanese subjects. In addition, a group of Caucasian subjects will be 
evaluated at the high dose for comparison. Potential subjects will be screened within 28 days 
prior to the dose. 
Under the initial study design and plan prior to Amendment 2 of the protocol, 
 subjects in 
Group 1 (Chinese cohort, 
 
) and all subjects in Groups 3 and 4 (Japanese and Caucasian 
cohorts, respectively, 
) had been enrolled, dosed, and had remained in the clinical 
research unit (CRU) up through the earliest discharge day on Day 3. Due to the occurrence of 
adverse events in subjects administered with AMG 592 reported thus far in the study after day 
4 and during the period after discharge from the CRU, enrollment of the remaining  subjects 
in Group 1 was placed on temporary hold. The intention of the hold was to allow a full 
evaluation of emerging safety data and to prepare Protocol Amendment 2. 
Under Protocol Amendment 2 (to be conducted for the remaining subjects in Group 1 
[Chinese cohort, 
] and all subjects in Group 2 [Chinese cohort, 
 
], eligible 
subjects will be admitted into the CRU on Day 1 and will be confined to the CRU until 
discharge on Day 7 (individual subjects may be required to stay longer than Day 7 [to a 
maximum of Day 11] at the request of the Investigator based on emergence and progression of 
adverse events or other signs and symptoms requiring monitoring). The clinical conduct for the 
2 groups of Chinese subjects will be done in a sequential manner, such that Group 1 will be 
enrolled and dosed first, with a postdose safety evaluation period of at least 14 days prior to 
initiation of dosing in Group 2. Chinese subjects (n  /group) will receive a single SC dose of 
AMG 592 at 
 (Group 1) or 
 
 (Group 2). Since Protocol Amendment 1, Japanese 
subjects (n  ) received a single SC dose of AMG 592 at 
 
 (Group 3), Caucasian 
subjects (n  ) received a single SC dose of AMG 592 at 
 
 (Group 4), and Chinese 
subjects (n) received a single SC dose of AMG 592 at 
 
 (Group 1). After discharge 
from the research facility on Day 7, subjects will return to the CRU for outpatient visits on 
Days 8, 11, 15, 22, 29, and at the end of study (EOS) visit on Day 43. (For subjects enrolled 
prior to Amendment 2 and discharged on Day 3, outpatient visits also included Days 4, 5, and 
6.) A subject’s participation in the study will conclude at the completion of the EOS visit; 
however, subjects who test positive at the EOS timepoint for neutralizing antibodies to IL2 or 
binding antibodies with potentially antibody-mediated clinical sequelae will be asked to return 
for additional follow-up testing every 3 months until antibodies are no longer detected or up to 
12 months from dosing (whichever is shorter). 
Number of subjects: 
Approximately 32 subjects ( per group) will be enrolled in this study. 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 6 of 68 
Diagnosis and main criteria for inclusion: 
Healthy male or female subjects of Chinese ancestry, first- or second-generation Japanese 
subjects, and Caucasian subjects, 18 to 55 years of age (inclusive), body mass index of 17 to 
30 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Investigational Medicinal Product: 
 
 AMG 592 given as a 
 SC 
injection, 
 
AMG 592 given as a 
 SC injection. 
Group 1  
 
 SC 
Group 2  
 
 SC 
Group 3  
 
 SC 
Group 4  
 
 SC 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to EOS): approximately 10 weeks.  
Primary endpoints: 
The primary endpoints for this study are PK parameters: maximum observed serum 
concentration (Cmax), the time of maximum observed serum concentration (tmax), area under the 
serum concentration-time curve (AUC) from time zero to time of last quantifiable 
concentration (AUClast), and AUC from time zero to infinity (AUCinf). 
Secondary endpoints: 
Secondary endpoints for this study are: treatment-emergent adverse events and serious adverse 
events (including clinically significant changes in physical examinations), clinical laboratory 
tests, vital signs, and anti-AMG 592 and anti-IL-2 antibody formation. 
 
 
Statistical methods: 
Data will be analyzed for all subjects who were enrolled and received a dose of AMG 592. 
Descriptive statistics by treatment arm will be provided for selected demographics, safety, PK 
parameters, and PD and immunogenicity data. Descriptive statistics on continuous 
measurements will include geometric and arithmetic means, medians, standard deviations, and 
ranges, while categorical data will be summarized using frequency counts and percentages. 
The PK, vital signs, and clinical laboratory data will be summarized for each timepoint when 
samples are collected.  
The final safety analysis for the study will be performed at the end of the study. Adverse 
events will be summarized using descriptive methodology. Each adverse event will be coded 
using the Medical Dictionary for Regulatory Activities. No imputation will be done for safety 
assessments, and endpoints for clinical laboratory tests and vital signs will be summarized. No 
inferential statistical analysis is planned.  
Additional details will be included in the Statistical Analysis Plan. 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 7 of 68 
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 
1.2. 
Pharmacokinetics ................................................................................. 14 
1.3. 
Study Rationale .................................................................................... 15 
1.4. 
Benefit-risk Assessment....................................................................... 15 
1.4.1. 
Therapeutic Context ................................................................... 15 
1.4.1.1. 
Benefits ............................................................................ 15 
1.4.1.2. 
Risks ................................................................................. 15 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 15 
2.1. 
Objectives ............................................................................................ 15 
2.2. 
Endpoints ............................................................................................. 16 
2.2.1. 
Primary Endpoints ..................................................................... 16 
2.2.2. 
Secondary Endpoints ................................................................. 16 
2.2.3. 
Exploratory Endpoints ............................................................... 16 
3. 
INVESTIGATIONAL PLAN ........................................................................ 16 
3.1. 
Overall Study Design and Plan ............................................................ 16 
3.2. 
Discussion of Study Design ................................................................. 19 
3.3. 
Selection of Doses in the Study ........................................................... 19 
4. 
SELECTION OF STUDY POPULATION ................................................... 20 
4.1. 
Inclusion Criteria ................................................................................. 20 
4.2. 
Exclusion Criteria ................................................................................ 20 
4.3. 
Screen Failures and Rescreening ......................................................... 23 
4.4. 
Subject Number and Identification ...................................................... 23 
4.5. 
Subject Withdrawal and Replacement ................................................. 23 
4.6. 
Study Termination ............................................................................... 24 
5. 
STUDY TREATMENTS ............................................................................... 24 
5.1. 
Investigational Product ........................................................................ 24 
5.2. 
Investigational Product Administration ............................................... 25 
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 ......................................................................... 26 
5.7. 
Drug Accountability............................................................................. 26 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 8 of 68 
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 
 
 
 
 
 
 
7.3. 
Anti-AMG 592 and Anti-IL-2 Assessments ........................................ 28 
7.4. 
Biomarker Development ...................................................................... 28 
7.4.1. 
Blood Samples for Biomarker Development ............................. 28 
7.4.2. 
Analytical Methodology ............................................................ 29 
7.5. 
Safety and Tolerability Assessments ................................................... 29 
7.5.1. 
Adverse Events and Serious Adverse Events: Time Period and 
Frequency for Collecting and Reporting Safety Event 
Information ................................................................................ 29 
7.5.2. 
Clinical Laboratory Evaluations ................................................ 31 
7.5.3. 
Vital Signs .................................................................................. 32 
7.5.4. 
12-lead Electrocardiogram ......................................................... 32 
7.5.5. 
Physical Examination................................................................. 33 
8. 
SAMPLE SIZE AND DATA ANALYSIS .................................................... 33 
8.1. 
Determination of Sample Size ............................................................. 33 
8.2. 
Analysis Populations ............................................................................ 33 
8.2.1. 
Pharmacokinetic Population ...................................................... 33 
8.2.2. 
Pharmacodynamic Population ................................................... 33 
8.2.3. 
Safety Population ....................................................................... 33 
8.3. 
Pharmacokinetic Analyses ................................................................... 33 
 
 
8.5. 
Anti-AMG 592 and Anti-IL-2 Analyses .............................................. 34 
8.6. 
Safety Analysis .................................................................................... 34 
8.7. 
Interim Analysis ................................................................................... 34 
9. 
REFERENCES .............................................................................................. 34 
10. APPENDICES ............................................................................................... 36 
Appendix 1: Safety Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting of Adverse Events .................. 37 
Definition of Adverse Event ...................................................................... 37 
Definition of Serious Adverse Event ......................................................... 38 
Recording Adverse Events and Serious Adverse Events ........................... 39 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 9 of 68 
Evaluating Adverse Events and Serious Adverse Events .......................... 41 
Reporting of Serious Adverse Event.......................................................... 43 
Appendix 2: Clinical Laboratory Evaluations ................................................. 47 
Appendix 3: Total Blood Volume.................................................................... 48 
Appendix 4: Contraception Requirements ....................................................... 49 
Appendix 5: Collection of Pregnancy and Lactation Information ................... 53 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations .......... 58 
Appendix 7: Hepatotoxicity: Suggested Actions and Follow-up Assessments
.............................................................................................................. 64 
Drug-induced Liver Injury Reporting and Additional Assessments .......... 66 
Appendix 8: Schedule of Assessments ............................................................ 67 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 10 of 68 
LIST OF TABLES AND FIGURES 
Table 1: 
Investigational Product ............................................................ 25 
 
Figure 1: 
Study Design ............................................................................ 19 
Figure 2: 
Sample Serious Adverse Event Report Form .......................... 44 
Figure 3: 
Pregnancy Notification Form ................................................... 56 
Figure 4: 
Lactation Notification Form .................................................... 57 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 11 of 68 
LIST OF ABBREVIATIONS 
Abbreviation Definition 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
AUCinf 
area under the serum concentration-time curve from time zero to 
infinity 
AUClast 
area under the serum concentration-time curve from time zero to 
time of last quantifiable concentration 
AV 
atrioventricular 
BP 
blood pressure 
CD4 
cluster of differentiation 4 
CD25 
alpha chain of the interleukin 2 receptor 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed serum concentration 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CRU 
clinical research unit 
DILI 
drug-induced liver injury 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
FIH 
first-in-human 
FOXP3 
forkhead box P3; an essential transcription factor of Treg function, 
upregulated by IL-2R signals 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GvHD 
graft-versus-host disease 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation 
IL 
interleukin 
IL-2R 
interleukin 2 receptor 
IL-2RA 
interleukin 2 receptor alpha chain 
IL-2RB 
interleukin 2 receptor beta chain 
ILC2 
innate lymphoid cells 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
institutional review board 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 12 of 68 
IUD 
intrauterine device 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic(s) 
Q2W 
every 2 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
QW 
once weekly 
RA 
rheumatoid arthritis 
SC 
subcutaneous 
SLE 
systemic lupus erythematosus 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TBL 
total bilirubin 
Tcon 
conventional T cells 
tmax 
time of the maximum observed serum concentration 
Tregs 
regulatory T cells 
ULN 
upper limit of normal 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 13 of 68 
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 
Investigational Medicinal Product 
Regulatory T cells (Tregs) are a subset of cluster of differentiation 4 (CD4) T cells 
that suppress inflammation and whose numbers and function are maintained by 
interleukin (IL)-2. In addition to Treg, IL-2-responsive lymphocytes include 
conventional CD4 and CD8 T (Tcon) cells, natural killer (NK) cells, and innate 
lymphoid cells (ILC2). A loss in the homeostatic balance between Tregs and other 
lymphocytes is considered a causative factor in many inflammatory conditions.  
AMG 592 (efavaleukin alfa) is an Fc-IL-2 mutein that contains 2 mutations in the 
IL-2 domain. To increase the Treg selectivity of IL-2, 1 mutation is in the region that 
binds the beta chain of the IL-2 receptor (IL-2RB). This mutation reduces its signaling 
potency and increases its dependence on expression of interleukin 2 receptor alpha 
chain (IL-2RA/CD25). It drives a positive feedback loop enforcing Treg phenotype, 
abundance, and IL-2 responsiveness over effects on other lymphocytes. The other 
mutation is in an internal region of IL-2 and improves manufacturability of AMG 592 
but does not alter its biological activity.2,3,4 
The IL-2R is composed of 3 chains: IL-2RB and IL-2R gamma, which together 
deliver the intracellular IL-2R signal, and IL-2RA (CD25), which stabilizes IL-2 
association with IL-2RBG but does not contain a signaling domain. The alpha chain 
of the IL-2 receptor (CD25) is highly expressed on Treg, and IL-2R signaling in Treg 
promotes expression of both CD25 and FOXP3, the essential transcription factor for 
Treg development and function. High FOXP3 expression promotes both full Treg 
suppressor activity and high CD25 expression, resulting in a positive feedback loop 
enforcing Treg phenotype, abundance, and IL-2 responsiveness.2,3,4 
The mutation in the IL-2RB-binding region of IL-2 results in increased dependence 
on CD25 for IL-2R signaling compared with wild-type IL-2. Thus, efavaleukin alfa 
preferentially drives this positive feedback loop in Treg over effects on other 
lymphocytes (ie, other T cells and ILC2 which may express CD25 but do not express 
FOXP3, and NK cells which express little or no CD25 and no FOXP3). Compared 
with aldesleukin, efavaleukin alfa exhibits greatly improved selectivity for Treg over 
Tcon and NK cells both in vitro and in vivo, potentially resulting in an improved 
therapeutic margin. In addition, the Fc domain of AMG 592 confers a prolonged half-
life compared with aldesleukin, thus reducing the dosing frequency required to 
maintain Treg enrichment  
Nonclinical in vitro and in vivo studies have demonstrated that AMG 592 exhibits 
greater selectivity for inducing Treg expansion over the expansion of CD4 and CD8 
T cells, and NK cells, relative to low dose, recombinant IL-2. This greater selectivity 
of AMG 592 has promise for greater efficacy and a wider therapeutic margin in 
inflammatory diseases relative to low-dose recombinant IL-2-based modalities. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 14 of 68 
Amgen is developing AMG 592 as a treatment for multiple inflammatory diseases 
including systemic lupus erythematosus (SLE), steroid-refractory chronic 
graft-versus-host disease (GvHD), and ulcerative colitis. This study is designed to 
evaluate whether pharmacokinetic (PK) and safety data in Chinese and Japanese 
subjects are similar to those from the global population. 
A summary of completed and ongoing clinical studies for AMG 592 is provided in the 
IB.1  
Changes to Study Protocol 20200102 (Amendment 1) 
Under the study design and planning in Amendment 1, subjects in Group 1, Group 3, 
and Group 4 had been enrolled, dosed, and had remained in the clinical research unit 
(CRU) up through the earliest discharge day on Day 3. Due to the occurrence of 
adverse events in subjects administered with AMG 592 thus far in the study after day 
4 and during the period after discharge from the CRU, enrollment of the remaining 
 subjects in Group 1 was placed on temporary hold. The intention of the hold was to 
allow a full evaluation of emerging safety data and to prepare Protocol Amendment 2. 
The remaining subjects in Group 1 (Chinese cohort, 
 
 and all subjects in 
Group 2 (Chinese cohort, 
 
 will be enrolled under the amended protocol 
(Protocol Amendment 2). 
1.2. 
Pharmacokinetics 
In a first-in-human (FIH) study (Study 20140324), PK results of AMG 592 in healthy 
subjects following single-dose subcutaneous (SC) administration of AMG 592 are 
available for doses of 
. Results show 
dose-related increases in AMG 592 serum exposure (as assessed by maximum 
observed concentration [Cmax] and area under the serum concentration-time curve 
[AUC] from time zero to infinity [AUCinf]) with approximately dose-proportional 
increase over the 
 
. Following SC administration, the 
median time to maximum observed serum concentration (tmax) ranged from 
approximately 0.5 to 1 day with terminal phase half-life (t1/2) about 11 to 13 hours 
postdose at doses 
. 
In a single-dose PK study in healthy Japanese subjects (Study 20180132), exposure of 
AMG 592, assessed by Cmax and AUCinf, increased approximately dose proportionally 
over the 
. Mean Cmax and AUCinf exhibited 
 
. The median tmax was 
14 hours in the AMG 592 
 cohort and 24 hours in the AMG 592 
 
cohort. For the 
 cohort, the mean half-life, apparent drug clearance, volume of 
distribution, and mean residence time was 11.7 hours, 1.29 L/hour, 21.9 L, and 
33.2 hours, respectively. For the 
 cohort, the mean half-life, apparent drug 
clearance, volume of distribution, and mean residence time was 9.68 hours, 
0.852 L/hour, 11.7 L, and 39.5 hours, respectively. 
In a multiple-dose study in patients with active rheumatoid arthritis (RA), exposure to 
AMG 592, as expressed in AUC and Cmax, increased with increasing dose from 
every 2 weeks (Q2W) to 
 once weekly (QW) to 
 Q2W. Peak 
concentrations were observed about 6 to 12 hours following dosing, with half-lives 
that ranged from about 10 to 40 hours. Moderate drug accumulation was observed for 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 15 of 68 
 Q2W and 
 QW. There were not enough data to determine the 
accumulation ratio for the 
 Q2W dose. 
1.3. 
Study Rationale 
The highest dose of AMG 592 previously evaluated in healthy Japanese and 
Caucasian subjects is 
 
 and a dose of 
 
 has demonstrated Treg 
selectivity and acceptable safety in subjects with SLE. As AMG 592 has not 
previously been studied in healthy Chinese subjects, 
 
 was chosen as the 
low-dose level to permit direct comparison with results from previous studies. 
Chinese, Japanese, and Caucasian subjects were selected in order to allow comparison 
to previous data and extrapolation to future studies, to look for possible ethnic 
variation in PK or PD parameters, and as part of the effort to ensure that proper dose 
regimens are recommended for the appropriate patient populations of different 
ethnicities. The current study should inform dose selection and design of future 
Phase 2 and 3 studies. 
1.4. 
Benefit-risk Assessment 
The following benefit-risk assessment supports the conduct of this clinical study. 
Refer to the IB1 for more information. 
1.4.1. 
Therapeutic Context 
1.4.1.1. 
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.  
1.4.1.2. 
Risks 
The safety of AMG 592 (efavaleukin alfa) has been studied in healthy volunteers and 
in SLE, chronic GvHD, and RA patients. Prior to the current study, approximately 
136 subjects have been exposed to efavaleukin alfa in Amgen clinical studies. Single 
SC doses of up to 
 
 of efavaleukin alfa have been studied in healthy 
volunteers. Repeated SC doses of up to 
 
 of efavaleukin alfa administered 
Q2W have been studied in subjects with chronic GvHD over the course of a 52-week 
period. Doses up to 
 
 Q2W have been studied in subjects with SLE and up to 
 
 in subjects with RA over the course of a 12-week period. The safety 
profile of efavaleukin alfa is based on these clinical studies. Current adverse drug 
reactions reported in efavaleukin alfa clinical studies are erythema and pruritus, 
hypersensitivity, and RA. Potential risks are described in the IB.1 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
 to evaluate the PK of AMG 592 after single SC administration in healthy 
Chinese, Japanese, and Caucasian subjects. 
The secondary objectives of the study are: 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
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 to evaluate the safety and tolerability of AMG 592 after single SC 
administration in healthy Chinese, Japanese, and Caucasian subjects. 
 to evaluate the incidence of anti-AMG 592 and anti-IL-2 antibodies in healthy 
Chinese, Japanese, and Caucasian subjects after single SC administration of 
AMG 592. 
 
 
 
 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints of the study are: 
 Cmax 
 tmax 
 AUC from time zero to time of last quantifiable concentration (AUClast) 
 AUCinf. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
 treatment-emergent adverse events and serious adverse events (including 
clinically significant changes in physical examinations [PE]) 
 clinical laboratory tests 
 vital signs 
 anti-AMG 592 and anti-IL-2 antibody formation. 
 
 
 
  
 
 
 
 
 
 
 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a Phase 1, single-center, open-label, sequential-group study to investigate 
the safety, tolerability, and PK of a single SC dose of AMG 592 in 2 groups of 
healthy Chinese subjects and 1 group of healthy Japanese subjects. In addition, 
a group of healthy Caucasian subjects will be evaluated at the high dose level for 
comparison. 
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Approximately 32 subjects will be enrolled in total, with  subjects in each of the 
following 4 groups: 
 Group 1: Chinese subjects (n) will receive 
 
 AMG 592 given as one 
) SC injection 
 Group 2: Chinese subjects (n) will receive 
 
 AMG 592 given as one 
) SC injection 
 Group 3: Japanese subjects (n) will receive 
 
 AMG 592 given as one 
) SC injection 
 Group 4: Caucasian subjects (n) will receive 
 
 AMG 592 given as 
one
) SC injection. 
Potential subjects will be screened to assess their eligibility to enter the study within 
28 days prior to dose administration. 
Under the initial study design and plan prior to Amendment 2 of the protocol, 
 
subjects in Group 1 and all subjects in Groups 3 and 4 had been enrolled, dosed, and 
had remained in the CRU up through the earliest discharge day on Day 3. Due to the 
occurrence of adverse events in subjects administered with AMG 592 reported thus 
far in the study after day 4 and during the period after discharge from the CRU, 
enrollment of the remaining subjects in Group 1 was placed on temporary hold. 
The intention of the hold was to allow a full evaluation of emerging safety data and to 
prepare protocol amendment 2. 
Under Protocol Amendment 2, the overall study design and plan will be conducted 
as follows, for the remaining  subjects in Group 1 (Chinese cohort, 
 
) and all 
subjects in Group 2 (Chinese cohort, 
 
): 
Eligible subjects will be admitted into the CRU for Check-in on Day -1 and be 
confined to the CRU until clinic discharge on Day 7. Individual subjects may be 
required to remain in the CRU for safety observations beyond Day 7 (to a maximum 
of Day 11) at the discretion of the Investigator, based on the emergence and 
progression of adverse events and other signs and symptoms requiring monitoring. 
Each subject will participate in 1 treatment group only. 
Chinese subjects will be assigned to Group 1 or Group 2 in a sequential manner. 
Group 1 will be enrolled and dosed first, and will have postdose safety observations 
performed for at least 14 days prior to initiation of dosing in Group 2 to allow 
sufficient time for an adequate safety review. 
A full review of all available safety and tolerability data from the study including 
Group 1 (Chinese cohort, 
 
) will be performed by the Investigator and Sponsor 
to ensure it is safe to proceed with the planned dose escalation in Group 2 (Chinese 
cohort, 
 
). 
Japanese and Caucasian subjects were assigned to Groups 3 and 4, respectively, 
according to the planned enrollment and study design prior to Amendment 2 of the 
protocol. Aside from the sequential conduct for Groups 1 and 2, there is no priority or 
required order for conduct of the different ethnic groups. 
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Serial blood samples will be collected for determination of AMG 592 serum 
concentrations, PK parameters, and PD markers. 
For subjects to be enrolled under Amendment 2, after discharge from the CRU on 
Day 7, subjects will return for outpatient visits on Days 8, 11, 15, 22, 29, and the end 
of study (EOS) visit on Day 43. (For subjects enrolled prior to Amendment 2 and 
discharged on Day 3, outpatient visits also included Days 4, 5, and 6.) It is anticipated 
that many subjects will be traveling a great distance to the CRU in order to participate 
in the study; therefore, to reduce unnecessary travel and ease the burden on subjects 
needing to find local accommodations for the frequent outpatient visits in the first 
2 weeks of the study, subjects may reside in the CRU after clinic discharge on Day 7 
through a maximum of Day 11. In addition to this elective option to remain in the 
CRU, individual subjects may be required to remain in the CRU beyond Day 7 (to a 
maximum of Day 11) at the discretion of the Investigator, based on the emergence 
and progression of adverse events or signs/symptoms of other adverse drug reactions. 
To summarize, a subject may leave the CRU after discharge procedures on Day 7, 
unless required to stay by the Investigator or, if not required to stay, may elect to stay 
voluntarily; in either case, residence in the CRU may be through a maximum of 
Day 11. Subjects who remain in the CRU beyond Day 7 will have the applicable 
scheduled outpatient procedures performed while resident. A subject’s participation in 
the study will conclude at the completion of the EOS visit; however, subjects who test 
positive at EOS for neutralizing antibodies to IL-2 or binding antibodies with 
potentially antibody-mediated clinical sequelae will be asked to return for additional 
follow-up testing every 3 months until antibodies are no longer detected or up to 
12 months ( 4 weeks) post administration of AMG 592 (whichever is shorter). 
The total duration of study participation for each subject (from screening through the 
EOS visit) is anticipated to be approximately 10 weeks. 
The start of the study is defined as the date the first subject signs an informed consent 
form (ICF). The point of enrollment occurs at the time of subject number allocation. 
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. A Schedule of Assessments is 
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Figure 1: 
Study Design 
 
Note: Dashed line indicates that subjects may remain in the CRU beyond scheduled discharge on Day 7, as noted 
in footnote a. Outpatient visit procedures will be performed on an inpatient basis for subjects who are resident at 
the CRU on the scheduled outpatient visit days. 
 
a The scheduled day of discharge is Day 7. Subjects may reside at the CRU after discharge on Day 7 until a 
maximum of Day 11, to reduce the travel and accommodation burden on subjects. In addition, the Investigator 
may require a subject to remain in the CRU after Day 7 (to a maximum of Day 11) based on the emergence and 
progression of adverse events or clinical signs and symptoms of adverse drug reaction. (For subjects enrolled prior 
to Amendment 2 of the protocol, the schedule day of discharge was Day 3.) 
b The maximum planned in-clinic residence for a given subject is 12 days (Day -1 to Day 11), whether by subject 
choice for lodging and accommodation purposes or as required by the Investigator based on adverse event/s or 
clinical signs and symptoms of adverse drug reaction. 
3.2. 
Discussion of Study Design 
This study is an open-label investigation because the study endpoints are not believed 
to be subject to bias. 
This study will not be randomized as all subjects within a group will receive the same 
study treatment, and because of the need to conduct the Chinese groups in sequential 
order. Because of the sequential nature, Chinese subjects cannot be randomized to 
dose level as the timing for each group will differ and may affect subject availability. 
Subcutaneous injection was chosen because this is the intended clinical route of 
administration. 
Conducting the study in healthy subjects mitigates the potential confounding effects 
of the disease state and concomitant medications. 
3.3. 
Selection of Doses in the Study 
AMG 592 doses were selected based on safety, PK, and PD results from the 
completed FIH study (20140324), PK study in Japanese healthy subjects (20180132), 
multiple-dose study in RA patients, ongoing multiple SC dose Phase 1b studies in 
patients with chronic GvHD and patients with SLE, as well as results from GLP 
toxicology studies in cynomolgus monkeys. The high dose of 
 
 was chosen to 
evaluate the PK/PD response and because it is within the anticipated upper range of 
doses that will be used in Phase 2 and 3 studies. Results from Studies 20140324 and 
20180132 as well as preliminary Phase 1b data indicate that AMG 592 is well 
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tolerated at doses up to 
 with acceptable safety and Treg selectivity. 
Exposures in the present study are anticipated to be lower than those at the NOAEL 
(exposure multiples of at least 16.3 and 3 for AUC and Cmax, respectively) in the 
6-month repeat-dose GLP toxicology study in the cynomolgus monkey 
(Study 122293). 
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. Healthy male or female subjects, between 18 and 55 years of age (inclusive) at 
the time of Screening. 
3. Chinese, Japanese, or Caucasian subject: 
 Chinese subjects must be of Chinese ancestry (4 grandparents and 
biological parents). 
 Japanese subjects must be first- or second-generation Japanese 
(4 grandparents and biological parents; subject or both of their parents 
must have been born in Japan). 
 Caucasian subjects are those who self-identify exclusively as such on 
the electronic case report form (eCRF) and also identify their 
biological parents as such. 
4. In good health, determined by no clinically significant findings from medical 
history, PE, 12-lead electrocardiogram (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 17 and 30 kg/m2 (inclusive) at the time of 
Screening. 
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 a 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. 
2. Evidence of scars, tattoos, or other skin lesions that may interfere with the 
injection site or injection site assessments. 
3. History or evidence of clinically significant arrhythmia at Screening, including 
any clinically significant findings on the ECG taken at Check-in. 
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4. A QT interval corrected for heart rate using Fridericia’s method (QTcF) 
interval  450 msec in male subjects or  470 msec in female subjects or 
history/evidence of long QT syndrome, at Screening or Check-in. 
5. PR interval  210 msec, at Screening or Check-in. 
6. Second- or third-degree atrioventricular (AV) block, at Screening or Check-in. 
7. Systolic blood pressure (BP)  140 mmHg or  90 mmHg, or diastolic BP 
 90 mmHg, or HR  100 bpm, at Screening or Check-in. 
8. 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. 
9. Poor peripheral venous access. 
10. Estimated glomerular filtration rate less than 60 mL/min/1.73 m2 as calculated 
by the Modification of Diet in Renal Disease equation, at Screening. 
11. Underlying condition that predisposes the subject to infections (eg, history of 
splenectomy). 
12. HbA1C  7, at Screening or Check-in. 
13. Active tuberculosis (TB) requiring treatment or documented latent TB within 
the previous 3 years. All subjects will be required to have a QuantiFERON-TB 
Gold test performed at Screening. Also excluded are participants with 
evidence of a past TB infection without documented adequate therapy. 
Participants with a positive QuantiFERON-TB Gold test at Screening will not 
be eligible for the study. A QuantiFERON-TB Gold test performed within 
4 weeks of dosing on Day 1 is acceptable as long as there is documentation of 
a negative result. 
14. Subjects who have received live vaccines within 5 weeks prior to Screening, 
or plan to receive live vaccines within 105 days after administration of an 
investigational product. 
15. Subjects who have received Coronavirus Disease 2019 (COVID-19) vaccine 
within 28 days prior to dosing, or plan to receive a COVID-19 vaccine within 
28 days postdose; from 29 days postdose through EOS, vaccination for 
COVID-19 may be deemed acceptable for a subject following discussion and 
agreement between the Sponsor and the Investigator. 
16. History of active infections (viral, bacterial, or fungal) within 21 days of 
receiving the investigational product. 
17. Positive hepatitis B or hepatitis C panel (ie, positive hepatitis B surface 
antigen, hepatitis B core antibody or hepatitis C antibody) at Screening, or a 
medical history for hepatitis B or C; and/or positive human immunodeficiency 
virus test, at Screening. Subjects whose results are compatible with prior 
vaccination may be included. Subjects with a history of hepatitis B vaccination 
without a history of hepatitis B or C are allowed to participate. 
18. Use of any over-the-counter or prescription medications within 30 days or 
5 half-lives (whichever is longer) of Check-in. Continued use, if applicable, 
will be reviewed by the Investigator (or designee) and in consultation with the 
Sponsor. Written documentation of this review and Sponsor acknowledgment 
is required for subject participation. Exceptions are listed below. 


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 Acetaminophen [paracetamol] up to 2 g per day for analgesia will be 
allowed.  
 Hormonal contraception listed in Appendix 4 will be allowed. 
 Hormone replacement therapy (eg, estrogen) will be allowed.  
19. Use of any herbal medicines, vitamins, or supplements consumed within the 
30 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee) and in consultation with the Sponsor. 
20. Consumption of foods and beverages containing poppy seeds within 7 days 
prior to Check-in. 
21. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 
22. Alcohol consumption from 48 hours prior to Check-in. 
23. Regular alcohol consumption of  14 units per week for males and  7 units 
for females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 
1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. 
24. Use of tobacco- or nicotine-containing products within 6 months prior to 
Check-in. 
25. Positive test for illicit drugs, cotinine (tobacco or nicotine use), and/or alcohol 
use at Screening or Check-in. 
26. Consumption of caffeine-containing foods and beverages within 24 hours 
prior to Check-in. 
27. Female subjects with a positive pregnancy test at Screening or Check-in.  
28. Female subjects who are lactating/breastfeeding or who plan to breastfeed 
during the study through 90 days after the EOS visit. 
29. Subjects who are unwilling to adhere to contraceptive requirements through 
90 days after the EOS visit (see Appendix 4).  
30. Subjects who are unwilling to abstain from sperm donation and ovum 
donation from Check-in until 90 days after the EOS visit (see Appendix 4). 
31. Male subject with a female partner of childbearing potential and not willing to 
inform his partner of his participation in this clinical study. 
32. Male subject with a pregnant partner or partner planning to become pregnant 
while the subject is on study through 90 days after the EOS visit. 
33. Subject has received a dose of an investigational drug within the past 90 days 
or 5 half-lives of the drug, whichever is longer, prior to Check-in. 
34. Subjects who have previously completed or withdrawn from this study or any 
other study investigating AMG 592 or have previously received the 
investigational product.  
35. Donation of blood from 90 days prior to Check-in, plasma from 2 weeks prior 
to Check-in, or platelets from 6 weeks prior to Check-in. 
36. Subjects who are unwilling to abide with study restrictions. 
37. Subjects who, in the opinion of the Investigator (or designee), should not 
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38. Subjects with abnormal laboratory results for alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) (ie,  upper limit of normal) and total 
bilirubin (ie,  upper limit of normal) at Screening and Checkin. 
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. 
Subjects who have a screening laboratory test result that is out of range may have the 
test repeated once, and the subject may be enrolled if the repeated value is within 
range. This can be applied to any or all of the laboratory tests included in the 
exclusion criteria, and it can be disallowed for any critical tests at the discretion of the 
Investigator or Sponsor. 
4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. 
 
 
 
 
 
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, the Sponsor will be notified and the date and reason(s) for 
the withdrawal will be documented in the subject’s eCRF, and 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 residing at the CRU, 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 additional follow-up visit(s). All withdrawn subjects will be 
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followed until resolution of all their adverse events or until the unresolved adverse 
events are judged by the Investigator (or designee) to have stabilized. 
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 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 Ethics Committee (EC) 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 IMP will be stored at the study site in a location that is 
locked with restricted access. 
The IMP (solution containing
 AMG 592) will be supplied by the Sponsor 
(or designee), along with the lot numbers and Certificates of Analysis. The IMP will 
be stored according to the instructions on the label. 
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Table 1: 
Investigational Product 
Study Treatment 
Name 
Investigational Medicinal Product: 
AMG 592 
Unit Strength and 
Formulation 
 
Dosage Level 
 
 
 
Route of 
Administration 
Subcutaneous injection 
Accountability 
The quantity administered, date administered, and lot number of the 
investigational medicinal product are to be recorded on each subject's 
electronic case report form.  
Dosing Instructions 
Treatment will be administered after the completion of all predose procedures. 
5.2. 
Investigational Product Administration 
Each SC injection will be administered by qualified and appropriately trained clinical 
staff to the lower abdomen. There are no posture requirements for dosing. 
5.3. 
Treatment of Overdose 
Neither the effects of overdose of AMG 592 nor an antidote to overdose are known. 
5.3.1. 
Medical Devices  
No investigational medical device 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-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 592) 
provisioned and/or repackaged/modified by the Sponsor. 
Any product complaint(s) associated with an investigational product (AMG 592) 
supplied by the Sponsor are to be reported according to the instructions provided in 
the Amgen IPIM. 
5.4. 
Randomization 
This study will not be randomized. 
5.5. 
Blinding 
This is an open-label study.   
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5.6. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
 All doses will be administered under the supervision of suitably qualified 
study site staff. 
 At each dosing occasion, a predose and postdose inventory of AMG 592 will 
be performed.  
5.7. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of 
AMG 592 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 592 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), hormone replacement therapy or oral, 
implantable, transdermal, injectable, or intrauterine contraceptives 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. 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 required to fast from food overnight (at least 8 hours) before 
collection of blood samples for clinical laboratory evaluations. Water may be 
consumed ad libitum throughout the study. 
While confined at the study site, subjects will receive a standardized diet at scheduled 
times that do not conflict with other study-related activities.  
Foods and beverages containing poppy seeds will not be allowed from 7 days prior to 
Check-in until after the EOS visit. 


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Caffeine-containing foods and beverages will not be allowed from 24 hours prior to 
each clinic visit and while at the CRU. 
Consumption of alcohol will not be permitted from 48 hours prior to each clinic visit. 
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 after the EOS visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in 
until after 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 90 days 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 
 PK blood samples 
 safety assessments (ECGs will be scheduled before vital signs measurements) 
 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, safety 
laboratory assessments, and assessment of adverse events and serious adverse events. 
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.  


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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.  
7.1.2. 
Analytical Methodology 
Serum concentrations of AMG 592 will be determined using validated analytical 
procedures. Specifics of the analytical method will be provided in a separate 
document. 
 
 
 
 
 
 
 
 
 
 
7.3. 
Anti-AMG 592 and Anti-IL-2 Assessments 
Blood samples for antibody testing are to be collected at the times listed in the 
Schedule of Assessments (Appendix 8). Samples testing positive for anti-AMG 592 
and/or anti-IL-2 antibodies will also be tested for neutralizing antibodies and may be 
further characterized. More frequent testing or testing for a longer period of time may 
be required in the event of a safety-related concern. 
Subjects who test positive at the EOS timepoint for neutralizing antibodies to IL-2 or 
binding antibodies with potentially antibody-mediated clinical sequelae will be asked 
to return for follow-up testing. This testing is to occur approximately every 3 months 
starting from the EOS visit and continue until: 1) antibodies are no longer detectable 
or 2) the subject has been followed for a period of at least 12 months ( 4 weeks) 
post administration of AMG 592 (whichever is shorter). All follow-up results, both 
positive and negative, will be communicated to the study site.  
7.4. 
Biomarker Development 
7.4.1. 
Blood Samples for Biomarker Development 
Blood samples for biomarker development will be collected at the times indicated in 
the Schedule of Assessments in Appendix 8. Procedures for collection, processing, 
and shipping of biomarker development samples will be detailed in a separate 
document.  
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7.4.2. 
Analytical Methodology 
Blood samples for biomarker development may be used to explore possible 
relationships between exposure to AMG 592 and physiological responses in 
individual subjects or in the general population, as part of the overall development 
program for AMG 592. Specifics of the analytical methods will be provided in a 
separate document. 
7.5. 
Safety and Tolerability Assessments 
7.5.1. 
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 serious adverse events are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to 
the EOS.  
If an event is reported as beginning prior to signing of the ICF or occurs prior to 
initiation of study treatment on Day 1 and is assessed as not related to study 
procedures by the Investigator (or designee), the event will be recorded as subject 
medical history. Any events prior to study drug administration but deemed by the 
Investigator to be related to study procedures will be reported as adverse events. Any 
events occurring after study drug administration on Day 1 through the EOS visit will 
be reported as adverse events. 
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 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 adverse events observed by the 
Investigator or reported by the subject (whether reported by the subject voluntarily or 
upon questioning, or noted on PE) 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 


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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. However, these serious adverse 
events can be reported to Amgen. Per local requirements in some countries, 
Investigators are required to report serious adverse events that they become aware of 
after the EOS visit. If serious adverse events are reported, the Investigator is to report 
them to the Sponsor within 24 hours following the Investigator’s knowledge of the 
event using the paper-based Serious Adverse Event Report Form.  
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 the 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 the 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, ECs, and Investigators. 


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Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
An Investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the Sponsor will file it along with the IB and will notify the EC, 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 after the start of study treatment and 
until 90 days after the dosing. 
If a pregnancy and/or lactation 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. 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening 
and within 7 days of initiation of investigational product for females of childbearing 
potential. 
Note: Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements. (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 3). Refer to Appendix 4 for contraceptive requirements. 
A pregnancy test should be performed (at the end of the period of relevant systemic 
exposure) after discontinuing protocol-required therapies. 
Additional on-treatment pregnancy testing may be performed at the Investigator’s 
discretion or as required per local laws and regulations. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
7.5.2. 
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. 


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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 test at the times indicated in the Schedule of 
Assessments in Appendix 8. For all female subjects, a pregnancy test and 
follicle-stimulating hormone screen for postmenopausal status 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. 
7.5.3. 
Vital Signs 
Supine BP, 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 BP 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. 
7.5.4. 
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 once if either of the following 
criteria apply: 
 QTcF 500 msec 
 QTcF change from the baseline (predose) is 60 msec. 
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. 


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7.5.5. 
Physical Examination 
A full PE or symptom-directed PE will be performed at the timepoints specified in the 
Schedule of Assessments in Appendix 8. The PE will also include a neurological 
exam. The neurological examination should include an assessment of mental status, 
level of consciousness, cranial nerve function, motor function, sensory function, 
reflexes, and coordination. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
Approximately 32 subjects will be enrolled in 4 groups (  subjects per group).  
With subjects in each group receiving AMG 592, there is an 
 chance of 
 
 experiencing an adverse event with a true incidence rate of 
 
 
chance of 
 experiencing an adverse event with 
 true incidence 
rate. With a total of 32 subjects expected to receive AMG 592 across 4 cohorts, there 
is a 
 chance of 
 experiencing an adverse event with a true 
incidence rate of 
 and the chance of 
 experiencing an adverse 
event increases to 
 
 with a true incidence rate of 
, 
respectively. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of AMG 592 
and have evaluable PK data.  
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of AMG 592 
and have evaluable PD data. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of 
AMG 592 and have at least 1 postdose safety assessment. 
8.3. 
Pharmacokinetic Analyses 
The serum PK parameters of AMG 592 will be calculated using standard 
noncompartmental methods. 
The primary PK parameters are Cmax, tmax, AUClast, and AUCinf for AMG 592. All 
other PK parameters will be regarded as secondary and will not be subject to 
inferential statistical analysis. 
Additional PK parameters may be calculated. Specific details will be presented in the 
Statistical Analysis Plan for this study. 
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8.5. 
Anti-AMG 592 and Anti-IL-2 Analyses 
The formation of anti-AMG 592 and anti-IL-2 antibodies will be summarized 
descriptively. The incidence and percentage of subjects who develop antidrug 
antibodies (binding and if positive, neutralizing) at any time will be tabulated by 
treatment group. 
8.6. 
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.  
No imputation will be done for safety assessments, and endpoints for clinical 
laboratory tests and vital signs will be summarized. 
8.7. 
Interim Analysis 
No interim analyses are planned for this study.  
9. REFERENCES 
1. Amgen, Inc. Efavaleukin Alfa (AMG 592; Inflammatory Diseases) – 
Investigator’s Brochure. (Version 5.0). 17 December 2020. 
2. Yu A, Snowhite I, Vendrame F, et al. Selective IL-2 responsiveness of regulatory 
T cells through multiple intrinsic mechanisms support the use of low-dose IL-2 
therapy in Type-1 diabetes. Diabetes. Published online: 09 January 2015 (doi: 
10.2337/db 14-1322). 
3. Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of 
regulatory T cell differentiation. Nature. 2007;445:771-775. 
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4. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function to 
interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 
2005;6:1142-1151. 
 


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10. APPENDICES 


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Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Adverse Events 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.  
 
Note: An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device, or procedure. 
 
Note: Treatment-emergent adverse event will be defined in the Statistical Analysis Plan. 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiological scans, vital signs measurements), 
including those that worsen from baseline, that are considered clinically significant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication. Overdose per se will not be reported as an adverse 
event/serious adverse event unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses are to be reported regardless of sequelae. 
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the adverse event. 


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 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. For instance, drug-induced 
hepatitis that resolved without evidence of hepatic failure would not be considered life-
threatening even though drug-induced hepatitis can be fatal. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are an adverse event. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious. Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term “disability” means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 


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Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition. These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
Investigator to review all documentation (eg, hospital progress notes, laboratory, and 
diagnostics reports) related to the event. 
 
The Investigator will then record all relevant adverse event/serious adverse event 
information in the event electronic case report form (eCRF). 
 
The Investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to the investigational product(s) and/or study-mandated 
procedures, and 
o Action taken. 
 
If the severity of an adverse event changes from the date of onset to the date of resolution, 
record as a single event with the worst severity on the appropriate eCRF.  
 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records 
to Sponsor in lieu of completion of the appropriate eCRF page. 


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 
If specifically requested, the Investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records. In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to the Sponsor. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse event. 


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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The Investigator will make an assessment of severity for each adverse event and serious adverse 
event reported during the study. The assessment of severity will use the following definitions: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated, usually transient and may 
require only minimal treatment or therapeutic intervention. The event does 
not generally interfere with usual activities of daily living. 
MODERATE 
Discomfort enough to cause interference with usual activity causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Usually alleviated with additional specific therapeutic intervention. 
SEVEREa 
Incapacitating with inability to work or interrupts usual activities of daily 
living, or significantly affects clinical status, or may require intensive 
therapeutic intervention. 
a An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of a serious adverse event, NOT when it is rated as severe. 
Assessment of Causality 
 
The Investigator is obligated to assess the relationship between investigational product(s), 
protocol-required therapy and/or study-mandated procedure and each occurrence of each 
adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
 
The Investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study treatment administration will be 
considered and investigated. 


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 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the Investigator must document in the medical 
notes that he/she has reviewed the adverse event/serious adverse event and has provided an 
assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the Investigator 
has minimal information to include in the initial report. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the serious adverse event data. 
 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of a serious 
adverse event, this information must be submitted to the Sponsor. 
 
If a subject dies during participation in the study, the Investigator will provide the 
Sponsor with a copy of any post-mortem findings including histopathology.  
 
New or updated information will be recorded in the originally completed eCRF. 
 
The Investigator will submit any updated serious adverse event data to the Sponsor within 24 
hours of receipt of the information. 


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Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Paper Serious Adverse Event Report Form 
 
Facsimile transmission of the Serious Adverse Event Report Form (see Figure 2) is the 
preferred method to transmit this information. 
 
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the Serious Adverse Event Report Form sent by overnight mail 
or courier service. 
 
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the Serious Adverse Event Report Form within the designated reporting time 
frames. 


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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 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Bilirubina 
Gamma-glutamyl transferase 
Glucose 
HbA1C 
Inorganic phosphate 
Potassium  
QuantiFERON-TB Gold test  
Sodium  
Total CO2 (measured as 
bicarbonate) 
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 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
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 virus 
(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 test  
Follicle-stimulating hormoneb 
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 
Creatine kinase MB fractionc  
a Includes total, direct, and indirect.  
b Only analyzed at Screening. 
c Only analyzed at Screening and Check-in.  
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 
9 
67.5 
Serology 
3.5 
1 
3.5 
AMG 592 
pharmacokinetics 
3.5 
15 
52.5 
Lymphocyte subsets 
9 
6 
54 
Biomarker development 
samples 
5 
8 
40 
Anti-AMG 592 and 
anti-IL-2 Antibodies 
3.5 
4 
14 
Total: 
231.5 
FSH  follicle-stimulating hormone; IL-2  interleukin 2 
If additional blood samples are required, the maximum blood volume to be withdrawn per 
subject will not exceed 500 mL. 
 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 49 of 68 
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. 
Definitions  
Women of Childbearing Potential: 
Premenopausal females who are anatomically and physiologically capable of becoming 
pregnant following menarche.  
Women of Non-Childbearing 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.  
 


Protocol 
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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 50 of 68 
Contraception Requirements 
Female Subjects  
Female subjects who are of non-childbearing potential will not be required to use contraception. 
Female subjects of childbearing potential must be willing to use 2 methods [1 primary (highly 
effective) and 1 secondary method] of birth control from the time of signing the informed 
consent form until 90 days after the EOS visit.  
Primary (highly effective) methods of contraception include:  
 hormonal injection (as prescribed)  
 combined oral contraceptive pill or progestin/progestogen-only pill associated with 
inhibition of ovulation (as prescribed) without supplementary iron (ie, Loestrin Fe, Junel 
Fe, and Lo Loestrin Fe are prohibited) 
 combined hormonal patch (as prescribed)  
 combined hormonal vaginal ring (as prescribed)  
 surgical method performed at least 3 months prior to the Screening visit:  
o Bilateral tubal ligation with confirmation of surgical success 
o Regulatory approved method of hysteroscopic bilateral tubal occlusion with 
confirmation of occlusion of the fallopian tubes 
 hormonal implant  
 hormonal or non-hormonal intrauterine device (IUD or IUS) 
 vasectomized male partner (sterilization performed at least 90 days prior to the Screening 
visit, with verbal confirmation of surgical success, and the sole partner for the female 
subject).  
Secondary (barrier) methods of contraception include:  
 male condom with spermicide  
 female condom with spermicide  
 over-the-counter sponge with spermicide  
 cervical cap with spermicide (as prescribed)  
 diaphragm with spermicide (as prescribed).  
Female subjects should refrain from donation of ova from Check-in (Day -1) until 90 days after 
the EOS visit. 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 51 of 68 
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  
 surgical method (bilateral tubal ligation or regulatory approved method of hysteroscopic 
bilateral tubal occlusion)  
 hormonal implant  
 hormonal or non-hormonal IUD  
 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 informed consent 
form (ICF) until 90 days after the EOS visit.  
 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 52 of 68 
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. 
 


Protocol 
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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 53 of 68 
Appendix 5: Collection of Pregnancy and Lactation Information 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 The 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). The 
form must be submitted to Amgen Global Patient Safety within 24 hours of learning of a 
subject’s pregnancy. (Note: Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
 After obtaining the female subject’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 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 
events 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. 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 54 of 68 
 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 4.5 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 
form (see Figure 3) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy. (Note: Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions local 
privacy laws). 
 The Investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 After obtaining the female partner’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the pregnancy 
questionnaires. This information will be forwarded to Amgen Global Patient Safety. 
 Generally, infant follow up will be conducted up to 12 months after the birth of the child 
(if applicable).  
 Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for procedure. 
Collection of Lactation Information 
 The Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 90 days after the EOS. 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 55 of 68 
 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 authorization for release of mother and infant health 
information, the Investigator will collect mother and infant health information and complete the 
lactation questionnaire on any female subject who breastfeeds while taking protocol-required 
therapies through 90 days after discontinuing protocol-required therapies. 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 56 of 68 
Figure 3: 
Pregnancy Notification Form 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 57 of 68 
Figure 4: 
Lactation Notification Form 
 
 


Protocol 
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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 58 of 68 
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 (CIOMS) 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 must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC 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 or any nonsubstantial changes, as defined by 
regulatory requirements.  
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the EC. 
 Notifying the EC of serious adverse events or other significant safety findings as 
required by EC 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 EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 


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Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 59 of 68 
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. 
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 Ethics Committee 
(EC) 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.  


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Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 60 of 68 
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 21 days from the previous ICF signature date. 
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. 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 electronic case report form (eCRF) demographics page, in addition to the unique 
subject identification number, include the age at time of enrollment. 
For serious adverse events reported to the Sponsor, subjects are to be identified by their 
unique subject identification number, (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 EC 
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. 


Protocol 
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Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 61 of 68 
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. 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 electronic CRF (eCRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their unique 
subject identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in confidence by 
the Investigator, except as described below. 
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.  


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Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
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 The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The contract research organization (CRO) 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 the study site archive for at least 5 years after 
the end of the study 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 CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 63 of 68 
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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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 64 of 68 
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:  
 Prior and/or concurrent diseases or illness 
 Exposure to environmental and/or industrial chemical agents  
 Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 65 of 68 
 Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
 Concomitant use of medications (including nonprescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 Viral serologies 
 Creatine phosphokinase, haptoglobin, lactate dehydrogenase, and peripheral blood 
smear 
 Appropriate liver imaging if clinically indicated 
 Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist). 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or 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 


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Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
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 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: 
 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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Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 67 of 68 
Appendix 8: Schedule of Assessments 
PROCEDURE 
Screening Check-in 
 
 
Treatment Period 
 
 
Resident at the Clinical Research Unit 
 
 
 
 
 
 
 
 
 
 
Study Day 
-28 to -2 
-1 
1 
1 
1 
1 
1 
2 
3 
4 
5 
6 
7 
8 
11 
15 
22 
29 
43a (EOS)/ET 
Relative to Dosing (Hours) 
 
 
Pre 
0 
6 
12 
16 
24 
48 
72 
96 
120 144 168 240 
336 
504 
672 
1008 
 
GENERAL AND SAFETY ASSESSMENTS 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-house Residencyb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Medical History 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsf 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsg 
 
 
Serious Adverse Eventsh 
X 
 
Concomitant Therapy Reviewi 
 
 
 
LABORATORY ASSESSMENTS 
 
Pregnancy Testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry and Hematologyk 
X 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Xk 
 
X 
 
X 
 
X 
eGFRl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIOMARKER AND IMMUNOLOGICAL ASSESSMENTS 
Lymphocyte Subsets 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Biomarker Development Samples 
 
X 
 
 
X 
X 
 
 
Xo 
 
 
 
 
X 
 
X 
X 
 
X 
Anti-AMG 592 and Anti-IL-2 Antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
PHARMACOKINETIC ASSESSMENTS 
 
AMG 592 Serum PK Collectionn 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
STUDY TREATMENT 
 
AMG 592 Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 2, 28 April 2022 
Page 68 of 68 
Abbreviations: CRU  clinical research unit; ECG  electrocardiogram; eGFR  estimated glomerular filtration rate; EOS  end of study; FSH  follicle-stimulating hormone; 
PE  physical examination; PK  pharmacokinetic 
a Subjects who test positive at the EOS timepoint for neutralizing antibodies to IL-2 or binding antibodies with potentially antibody-mediated clinical sequelae that are considered 
potentially related to an anti-AMG 592 antibody response will be asked to return for additional follow-up testing every 3 months until antibodies are no longer detectable or up to 
12 months’ post administration of AMG 592 (whichever is shorter). 
b Inhouse residency from Day 1 through the completion of all assessments on Day 7. Solid line indicates time that subjects are required to stay in the CRU. Dashed line indicates 
that subjects may stay in the CRU after Day 7 until a maximum of Day 11 if they choose (to reduce travel and accommodation burden on subjects); alternatively, the Investigator 
may require subjects to remain in-house for 1 or more days after Day 7 (up to Day 11) at their discretion, based on other signs and symptoms requiring monitoring. Only subjects 
enrolled after Amendment 2 will have discharge study procedures completed on Day 7 at the earliest. (All other subjects enrolled prior to Amendment 2 had discharge study 
procedures completed by Day 3 at the earliest.) The latest discharge day for all subjects is Day 11. 
c Physical examination to include a neurological examination. A full PE will be conducted at Screening and at discharge (Day 7 at the earliest). A symptom-directed PE will be 
conducted on Days -1, 3, 11, 22, 29, and 43/EOS. Only subjects enrolled after Amendment 2 will have discharge study procedures completed on Day 7 at the earliest. (All other 
subjects enrolled prior to Amendment 2 had discharge study procedures completed by Day 3 at the earliest.) The latest discharge day for all subjects is Day 11. 
d Interim medical history only. 
e Electrocardiogram (ECG) will be single 12-lead ECG, prior to blood draws or invasive procedures.  
f Supine blood pressure (BP), supine heart rate, respiratory rate, and oral body temperature. Heart rate and BP will be measured using the same arm for each reading after the 
subject has been resting in the supine position for at least 5 minutes. For subjects enrolled after Amendment 2, additional days for vital signs measurements will include 
Days 4, 5, 7, 15, and 29. 
g Adverse events will be recorded from initiation of study treatment on Day 1 until the EOS. Any events prior to study drug administration but deemed by the Investigator to be 
related to study procedures will be reported as adverse events. 
h Serious adverse events will be recorded from the time the subject signs the informed consent form until the EOS. 
i Prior and concomitant medication administration will be recorded beginning at informed consent. Also, all Investigator-approved medications taken by a subject within 30 days or 
5 half-lives (whichever is longer) before Day 1 for over-the-counter or prescription medications, and 30 days prior to Check-in for herbal medicines (eg, St. John’s wort), 
vitamins, or supplements will be recorded on the subject’s electronic case report form. 
j 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. 
k Subjects will be fasted overnight (at least 8 hours) before collection of blood samples for clinical laboratory evaluations. Only subjects enrolled after Amendment 2 will have 
additional chemistry and hematology laboratory evaluations on Days 2, 5, and 7 and will have the additional urinalysis procedure at discharge (Day 7 at the earliest). (All other 
subjects enrolled prior to Amendment 2 had urinalysis conducted at discharge on Day 3 at the earliest.) 
l The eGFR will be calculated using the Modification of Diet in Renal Disease equation. 
m Performed in females only. 
n Blood samples for determination of AMG 592 serum concentrations and PK parameters will be collected: Predose; 6, 12, and 16 hours postdose; and on Days 2 (24 hours 
postdose), 3, 4, 5, 6, 8, 11, 15, 22, 29, and 43 (EOS) following administration of AMG 592 on Day 1. The postdose samples collected on Days 1 and 2 (6, 12, 16, and 24 hour 
samples) will have a sampling window of  30 minutes, postdose samples collected on Days 3 and 4 will have a sampling window of  6 hours, postdose samples collected on 
Days 5 through Day 15 will have a sampling window of  1 day, postdose samples taken on Days 22 and 29 will have a sampling window of  2 days, and postdose samples 
taken on Day 43 (EOS) will have a sampling window of  4 days. Times of all PK samples will be recorded to the nearest minute. 
o Only subjects enrolled after Amendment 2 will have additional biomarker development sample assessment on Day 3. 
 


Approval Signatures
Document Name:
Protocol Amendment efavaleukin alfa 20200102 2
Document Description:
A Phase 1, Open-label, Sequential-group, Single-dose Study to Evaluate
the Safety, Tolerability, and Pharmacokinetics of AMG 592 Administered
Subcutaneously in Healthy Chinese, Japanese, and Caucasian Subjects
Document Number:
CLIN-000265267
Approval Date:
29 Apr 2022
Type of Study Protocol:
Amendment
Protocol Amendment No.: 2
Document Approvals
Reason for Signing: Management
Name: 
Date of Signature: 28-Apr-2022 19:32:03 GMT+0000
Reason for Signing: Functional Area
Name: 
Date of Signature: 29-Apr-2022 15:12:07 GMT+0000
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 1 of 66 
 
Protocol 
A Phase 1, Open-label, Sequential-group, Single-dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 592 
Administered Subcutaneously in Healthy Chinese, Japanese, and 
Caucasian Subjects 
Protocol Status: Final 
 
Protocol Amendment 1  
Protocol Amendment 1 Date: 08 December 2021 
Original Protocol Version 1.0 Date: 01 April 2021 
 
Investigational Product: AMG 592 (efavaleukin alfa) 
 
Amgen Protocol Reference Number: 20200102 
Labcorp Drug Development Study Number: 8448873 
IND Number: 131270 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
 
 
 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 2 of 66 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the Institutional Review Board/Independent Ethics 
Committee/Institutional Scientific Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent 
of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 3 of 66 
INVESTIGATOR AGREEMENT 
I have read the protocol entitled “A Phase 1, Open-label, Sequential-group, 
Single-dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
AMG 592 Administered Subcutaneously in Healthy Chinese, 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 
 
_______________________________________                   
 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 4 of 66 
STUDY IDENTIFICATION 
Sponsor 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
Sponsor’s Study Contact 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
Sponsor’s Study Manager 
 
 
 
 
Labcorp Drug Development 
Program Manager 
 
 
 
 
Statistician 
 
 
 
 
 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 5 of 66 
SYNOPSIS 
Title of study: A Phase 1, Open-label, Sequential-group, Single-dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of AMG 592 Administered Subcutaneously in 
Healthy Chinese, Japanese, and Caucasian Subjects 
Objectives:  
The primary objective of the study is: 
• 
to evaluate the pharmacokinetics (PK) of AMG 592 after single subcutaneous (SC) 
administration in healthy Chinese, Japanese, and Caucasian subjects. 
The secondary objectives of the study are: 
• 
to evaluate the safety and tolerability of AMG 592 after single SC administration in 
healthy Chinese, Japanese, and Caucasian subjects. 
• 
to evaluate the incidence of anti-AMG 592 and anti-interleukin (IL)2 antibodies in 
healthy Chinese, Japanese, and Caucasian subjects after single SC administration of 
AMG 592. 
 
 
Study design: 
This will be an open-label, single-dose, sequential-group study in 2 groups of healthy Chinese 
subjects and 1 group of Japanese subjects. In addition, a group of Caucasian subjects will be 
evaluated at the high dose for comparison. Potential subjects will be screened within 28 days 
prior to the dose. Subjects will be admitted into the clinical research unit (CRU) on Day -1 and 
will be confined to the CRU until discharge on Day 3 (individual subjects may be required to 
stay longer than Day 3 [to a maximum of Day 11] at the request of the Investigator based on 
emergence and progression of adverse events or other signs and symptoms requiring 
monitoring). The clinical conduct for the 2 groups of Chinese subjects will be done in a 
sequential manner, such that Group 1 will be enrolled and dosed first, with a postdose safety 
evaluation period of at least 14 days prior to initiation of dosing in Group 2. Chinese subjects 
(n = /group) will receive a single SC dose of AMG 592 at 
 (Group 1) or 
 
(Group 2). Japanese subjects (n = ) will receive a single SC dose of AMG 592 at 
 
(Group 3). Caucasian subjects (n = ) will receive a single SC dose of AMG 592 at 
 
(Group 4). After discharge from the research facility, subjects will return to the CRU for 
outpatient visits on Days 4, 5, 6, 8, 11, 15, 22, 29, and at the end of study (EOS) visit on 
Day 43. A subject’s participation in the study will conclude at the completion of the EOS visit; 
however, subjects who test positive at the EOS timepoint for neutralizing antibodies to IL2 or 
binding antibodies with potentially antibody-mediated clinical sequelae will be asked to return 
for additional follow-up testing every 3 months until antibodies are no longer detected or up to 
12 months from dosing (whichever is shorter). 
Number of subjects: 
Approximately 32 subjects (  per group) will be enrolled in this study. 
Diagnosis and main criteria for inclusion: 
Healthy male or female subjects of Chinese ancestry, first- or second-generation Japanese 
subjects, and Caucasian subjects, 18 to 55 years of age (inclusive), body mass index of 17 to 
30 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Investigational Medicinal Product: 
 AMG 592 given as a 
 SC 
injection, 
 AMG 592 given as a 
 SC injection. 
Group 1 = 
 SC 
Group 2 = 
 SC 
Group 3 = 
 SC 
Group 4 = 
 SC 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to EOS): approximately 10 weeks.  
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Protocol 
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Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 6 of 66 
Primary endpoints: 
The primary endpoints for this study are PK parameters: maximum observed serum 
concentration (Cmax), the time of maximum observed serum concentration (tmax), area under the 
serum concentration-time curve (AUC) from time zero to time of last quantifiable 
concentration (AUClast), and AUC from time zero to infinity (AUCinf). 
Secondary endpoints: 
Secondary endpoints for this study are: treatment-emergent adverse events and serious adverse 
events (including clinically significant changes in physical examinations), clinical laboratory 
tests, vital signs, and anti-AMG 592 and anti-IL-2 antibody formation. 
 
 
Statistical methods: 
Data will be analyzed for all subjects who were enrolled and received a dose of AMG 592. 
Descriptive statistics by treatment arm will be provided for selected demographics, safety, PK 
parameters, and PD and immunogenicity data. Descriptive statistics on continuous 
measurements will include geometric and arithmetic means, medians, standard deviations, and 
ranges, while categorical data will be summarized using frequency counts and percentages. 
The PK, vital signs, and clinical laboratory data will be summarized for each timepoint when 
samples are collected.  
The final safety analysis for the study will be performed at the end of the study. Adverse 
events will be summarized using descriptive methodology. Each adverse event will be coded 
using the Medical Dictionary for Regulatory Activities. No imputation will be done for safety 
assessments, and endpoints for clinical laboratory tests and vital signs will be summarized. No 
inferential statistical analysis is planned.  
Additional details will be included in the Statistical Analysis Plan. 
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 7 of 66 
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 
1.2. 
Pharmacokinetics ................................................................................. 14 
1.3. 
Study Rationale .................................................................................... 15 
1.4. 
Benefit-risk Assessment ....................................................................... 15 
1.4.1. 
Therapeutic Context ................................................................... 15 
1.4.1.1. 
Benefits ............................................................................ 15 
1.4.1.2. 
Risks ................................................................................. 15 
2.
OBJECTIVES AND ENDPOINTS ............................................................... 15 
2.1. 
Objectives ............................................................................................ 15 
2.2. 
Endpoints ............................................................................................. 16 
2.2.1. 
Primary Endpoints ..................................................................... 16 
2.2.2. 
Secondary Endpoints ................................................................. 16 
2.2.3. 
Exploratory Endpoints ............................................................... 16 
3.
INVESTIGATIONAL PLAN ........................................................................ 16 
3.1. 
Overall Study Design and Plan ............................................................ 16 
3.2. 
Discussion of Study Design ................................................................. 18 
3.3. 
Selection of Doses in the Study ........................................................... 19 
4.
SELECTION OF STUDY POPULATION ................................................... 19 
4.1. 
Inclusion Criteria ................................................................................. 19 
4.2. 
Exclusion Criteria ................................................................................ 19 
4.3. 
Screen Failures and Rescreening ......................................................... 22 
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 ........................................................................ 24 
5.3.1. 
Medical Devices ......................................................................... 24 
5.3.2. 
Product Complaints .................................................................... 24 
5.4. 
Randomization ..................................................................................... 24 
5.5. 
Blinding................................................................................................ 25 
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Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 8 of 66 
5.6. 
Treatment Compliance ......................................................................... 25 
5.7. 
Drug Accountability............................................................................. 25 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS .............. 25 
6.1. 
Concomitant Therapies ........................................................................ 25 
6.2. 
Diet ....................................................................................................... 25 
6.3. 
Smoking ............................................................................................... 26 
6.4. 
Exercise ................................................................................................ 26 
6.5. 
Blood Donation .................................................................................... 26 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................... 26 
7.1. 
Pharmacokinetic Assessments ............................................................. 27 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ...... 27 
7.1.2. 
Analytical Methodology ............................................................ 27 
 
 
 
 
 
 
7.3. 
Anti-AMG 592 and Anti-IL-2 Assessments ........................................ 27 
7.4. 
Biomarker Development ...................................................................... 28 
7.4.1. 
Blood Samples for Biomarker Development ............................. 28 
7.4.2. 
Analytical Methodology ............................................................ 28 
7.5. 
Safety and Tolerability Assessments ................................................... 28 
7.5.1. 
Adverse Events and Serious Adverse Events: Time Period and 
Frequency for Collecting and Reporting Safety Event 
Information ................................................................................ 28 
7.5.2. 
Clinical Laboratory Evaluations ................................................ 30 
7.5.3. 
Vital Signs .................................................................................. 31 
7.5.4. 
12-lead Electrocardiogram ......................................................... 31 
7.5.5. 
Physical Examination................................................................. 31 
8. 
SAMPLE SIZE AND DATA ANALYSIS .................................................... 32 
8.1. 
Determination of Sample Size ............................................................. 32 
8.2. 
Analysis Populations ............................................................................ 32 
8.2.1. 
Pharmacokinetic Population ...................................................... 32 
8.2.2. 
Pharmacodynamic Population ................................................... 32 
8.2.3. 
Safety Population ....................................................................... 32 
8.3. 
Pharmacokinetic Analyses ................................................................... 32 
 
 
8.5. 
Anti-AMG 592 and Anti-IL-2 Analyses .............................................. 33 
8.6. 
Safety Analysis .................................................................................... 33 
8.7. 
Interim Analysis ................................................................................... 33 
9. 
REFERENCES .............................................................................................. 33 
10. APPENDICES ............................................................................................... 34 
Appendix 1: Safety Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting of Adverse Events .................. 35 
Definition of Adverse Event ...................................................................... 35 
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Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 9 of 66 
Definition of Serious Adverse Event ......................................................... 36 
Recording Adverse Events and Serious Adverse Events ........................... 37 
Evaluating Adverse Events and Serious Adverse Events .......................... 39 
Reporting of Serious Adverse Event .......................................................... 41 
Appendix 2: Clinical Laboratory Evaluations ................................................. 45 
Appendix 3: Total Blood Volume .................................................................... 46 
Appendix 4: Contraception Requirements ....................................................... 47 
Appendix 5: Collection of Pregnancy and Lactation Information ................... 51 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations .......... 56 
Appendix 7: Hepatotoxicity: Suggested Actions and Follow-up Assessments
.............................................................................................................. 62 
Drug-induced Liver Injury Reporting and Additional Assessments .......... 64 
Appendix 8: Schedule of Assessments ............................................................ 65 
 


Protocol 
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Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 10 of 66 
LIST OF TABLES AND FIGURES 
Table 1: 
Investigational Product ............................................................ 24 
 
Figure 1: 
Study Design ............................................................................ 18 
Figure 2: 
Sample Serious Adverse Event Report Form .......................... 42 
Figure 3: 
Pregnancy Notification Form ................................................... 54 
Figure 4: 
Lactation Notification Form .................................................... 55 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 11 of 66 
LIST OF ABBREVIATIONS 
Abbreviation Definition 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
AUCinf 
area under the serum concentration-time curve from time zero to 
infinity 
AUClast 
area under the serum concentration-time curve from time zero to 
time of last quantifiable concentration 
AV 
atrioventricular 
BP 
blood pressure 
CD4 
cluster of differentiation 4 
CD25 
alpha chain of the interleukin 2 receptor 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed serum concentration 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CRU 
clinical research unit 
DILI 
drug-induced liver injury 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
FIH 
first-in-human 
FOXP3 
forkhead box P3; an essential transcription factor of Treg function, 
upregulated by IL-2R signals 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GvHD 
graft-versus-host disease 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation 
IL 
interleukin 
IL-2R 
interleukin 2 receptor 
IL-2RA 
interleukin 2 receptor alpha chain 
IL-2RB 
interleukin 2 receptor beta chain 
ILC2 
innate lymphoid cells 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
institutional review board 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 12 of 66 
IUD 
intrauterine device 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic(s) 
Q2W 
every 2 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
QW 
once weekly 
RA 
rheumatoid arthritis 
SC 
subcutaneous 
SLE 
systemic lupus erythematosus 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TBL 
total bilirubin 
Tcon 
conventional T cells 
tmax 
time of the maximum observed serum concentration 
Tregs 
regulatory T cells 
ULN 
upper limit of normal 
 


Protocol 
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Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 13 of 66 
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 
Investigational Medicinal Product 
Regulatory T cells (Tregs) are a subset of cluster of differentiation 4 (CD4) T cells 
that suppress inflammation and whose numbers and function are maintained by 
interleukin (IL)-2. In addition to Treg, IL-2-responsive lymphocytes include 
conventional CD4 and CD8 T (Tcon) cells, natural killer (NK) cells, and innate 
lymphoid cells (ILC2). A loss in the homeostatic balance between Tregs and other 
lymphocytes is considered a causative factor in many inflammatory conditions.  
AMG 592 (efavaleukin alfa) is an Fc-IL-2 mutein that contains 2 mutations in the 
IL-2 domain. To increase the Treg selectivity of IL-2, 1 mutation is in the region that 
binds the beta chain of the IL-2 receptor (IL-2RB). This mutation reduces its signaling 
potency and increases its dependence on expression of interleukin 2 receptor alpha 
chain (IL-2RA/CD25). It drives a positive feedback loop enforcing Treg phenotype, 
abundance, and IL-2 responsiveness over effects on other lymphocytes. The other 
mutation is in an internal region of IL-2 and improves manufacturability of AMG 592 
but does not alter its biological activity.2,3,4 
The IL-2R is composed of 3 chains: IL-2RB and IL-2R gamma, which together 
deliver the intracellular IL-2R signal, and IL-2RA (CD25), which stabilizes IL-2 
association with IL-2RBG but does not contain a signaling domain. The alpha chain 
of the IL-2 receptor (CD25) is highly expressed on Treg, and IL-2R signaling in Treg 
promotes expression of both CD25 and FOXP3, the essential transcription factor for 
Treg development and function. High FOXP3 expression promotes both full Treg 
suppressor activity and high CD25 expression, resulting in a positive feedback loop 
enforcing Treg phenotype, abundance, and IL-2 responsiveness.2,3,4 
The mutation in the IL-2RB-binding region of IL-2 results in increased dependence 
on CD25 for IL-2R signaling compared with wild-type IL-2. Thus, efavaleukin alfa 
preferentially drives this positive feedback loop in Treg over effects on other 
lymphocytes (ie, other T cells and ILC2 which may express CD25 but do not express 
FOXP3, and NK cells which express little or no CD25 and no FOXP3). Compared 
with aldesleukin, efavaleukin alfa exhibits greatly improved selectivity for Treg over 
Tcon and NK cells both in vitro and in vivo, potentially resulting in an improved 
therapeutic margin. In addition, the Fc domain of AMG 592 confers a prolonged half-
life compared with aldesleukin, thus reducing the dosing frequency required to 
maintain Treg enrichment  
Nonclinical in vitro and in vivo studies have demonstrated that AMG 592 exhibits 
greater selectivity for inducing Treg expansion over the expansion of CD4 and CD8 
T cells, and NK cells, relative to low dose, recombinant IL-2. This greater selectivity 
of AMG 592 has promise for greater efficacy and a wider therapeutic margin in 
inflammatory diseases relative to low-dose recombinant IL-2-based modalities. 


Protocol 
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Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 14 of 66 
Amgen is developing AMG 592 as a treatment for multiple inflammatory diseases 
including systemic lupus erythematosus (SLE), steroid-refractory chronic 
graft-versus-host disease (GvHD), and ulcerative colitis. This study is designed to 
evaluate whether pharmacokinetic (PK) and safety data in Chinese and Japanese 
subjects are similar to those from the global population. 
A summary of completed and ongoing clinical studies for AMG 592 is provided in the 
IB.1  
Changes to Study Protocol 20200102 
The current study (20200102) was placed on a temporary hold during recruitment of 
the Japanese 
 cohort due to the occurrence of delayed-onset AEs in the 
majority of subjects administered AMG 592 thus far in the study.  The intention of the 
hold was to prepare a protocol amendment which would allow for the PI to direct that 
subjects should remain in the CRU beyond Day 3 for longer observation for delayed-
onset AEs.   As of 27Sept2021,  subjects in the Caucasian cohort and  subjects in 
the Japanese cohort had been enrolled, dosed, and completed all scheduled study 
procedures. The remaining  Japanese subjects and all Chinese subjects will be 
enrolled under the amended protocol (Protocol Amendment 1). 
1.2. 
Pharmacokinetics 
In a first-in-human (FIH) study (Study 20140324), PK results of AMG 592 in healthy 
subjects following single-dose subcutaneous (SC) administration of AMG 592 are 
available for doses of 
. Results show 
dose-related increases in AMG 592 serum exposure (as assessed by maximum 
observed concentration [Cmax] and area under the serum concentration-time curve 
[AUC] from time zero to infinity [AUCinf]) with approximately dose-proportional 
increase over the 
. Following SC administration, the 
median time to maximum observed serum concentration (tmax) ranged from 
approximately 0.5 to 1 day with terminal phase half-life (t1/2) about 11 to 13 hours 
postdose at doses 
. 
In a single-dose PK study in healthy Japanese subjects (Study 20180132), exposure of 
AMG 592, assessed by Cmax and AUCinf, increased approximately dose proportionally 
over the 
. Mean Cmax and AUCinf exhibited 
 
. The median tmax was 
14 hours in the AMG 592 
 cohort and 24 hours in the AMG 592 
 
cohort. For the 
 cohort, the mean half-life, apparent drug clearance, volume of 
distribution, and mean residence time was 11.7 hours, 1.29 L/hour, 21.9 L, and 
33.2 hours, respectively. For the 
 cohort, the mean half-life, apparent drug 
clearance, volume of distribution, and mean residence time was 9.68 hours, 
0.852 L/hour, 11.7 L, and 39.5 hours, respectively. 
In a multiple-dose study in patients with active rheumatoid arthritis (RA), exposure to 
AMG 592, as expressed in AUC and Cmax, increased with increasing dose from 
 every 2 weeks (Q2W) to 
 once weekly (QW) to 
 Q2W. Peak 
concentrations were observed about 6 to 12 hours following dosing, with half-lives 
that ranged from about 10 to 40 hours. Moderate drug accumulation was observed for 
 Q2W and 
 QW. There were not enough data to determine the 
accumulation ratio for the 
 Q2W dose. 
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Protocol 
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Labcorp Drug Development Study: 8448873  
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 15 of 66 
1.3. 
Study Rationale 
The highest dose of AMG 592 previously evaluated in healthy Japanese and 
Caucasian subjects is 
, and a dose of 
 has demonstrated Treg 
selectivity and acceptable safety in subjects with SLE. As AMG 592 has not 
previously been studied in healthy Chinese subjects, 
 was chosen as the 
low-dose level to permit direct comparison with results from previous studies. 
Chinese, Japanese, and Caucasian subjects were selected in order to allow comparison 
to previous data and extrapolation to future studies, to look for possible ethnic 
variation in PK or PD parameters, and as part of the effort to ensure that proper dose 
regimens are recommended for the appropriate patient populations of different 
ethnicities. The current study should inform dose selection and design of future 
Phase 2 and 3 studies. 
1.4. 
Benefit-risk Assessment 
The following benefit-risk assessment supports the conduct of this clinical study. 
Refer to the IB1 for more information. 
1.4.1. 
Therapeutic Context 
1.4.1.1. 
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.  
1.4.1.2. 
Risks 
The safety of AMG 592 (efavaleukin alfa) has been studied in healthy volunteers and 
in SLE, chronic GvHD, and RA patients. Prior to the current study, approximately 
136 subjects have been exposed to efavaleukin alfa in Amgen clinical studies. Single 
SC doses of up to 
 of efavaleukin alfa have been studied in healthy 
volunteers. Repeated SC doses of up to 
 of efavaleukin alfa administered 
Q2W have been studied in subjects with chronic GvHD over the course of a 52-week 
period. Doses up to 
 Q2W have been studied in subjects with SLE and up to 
 Q2W in subjects with RA over the course of a 12-week period. The safety 
profile of efavaleukin alfa is based on these clinical studies. Current adverse drug 
reactions reported in efavaleukin alfa clinical studies are erythema and pruritus, 
hypersensitivity, and RA. Potential risks are described in the IB.1 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
• to evaluate the PK of AMG 592 after single SC administration in healthy 
Chinese, Japanese, and Caucasian subjects. 
The secondary objectives of the study are: 
• to evaluate the safety and tolerability of AMG 592 after single SC 
administration in healthy Chinese, Japanese, and Caucasian subjects. 
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• to evaluate the incidence of anti-AMG 592 and anti-IL-2 antibodies in healthy 
Chinese, Japanese, and Caucasian subjects after single SC administration of 
AMG 592. 
 
 
 
 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints of the study are: 
• Cmax 
• tmax 
• AUC from time zero to time of last quantifiable concentration (AUClast) 
• AUCinf. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
• treatment-emergent adverse events and serious adverse events (including 
clinically significant changes in physical examinations [PE]) 
• clinical laboratory tests 
• vital signs 
• anti-AMG 592 and anti-IL-2 antibody formation. 
 
 
 
  
 
 
 
 
 
 
 
 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a Phase 1, single-center, open-label, sequential-group study to investigate 
the safety, tolerability, and PK of a single SC dose of AMG 592 in 2 groups of 
healthy Chinese subjects and 1 group of healthy Japanese subjects. In addition, a 
group of healthy Caucasian subjects will be evaluated at the high dose level for 
comparison. 
Approximately 32 subjects will be enrolled in total, with  subjects in each of the 
4 groups. 
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Protocol Amendment 1, 08 December 2021 
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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 3.  Individual subjects may be required to remain in the CRU 
for safety observations beyond Day 3 (to a maximum of Day 11) at the discretion of 
the Investigator, based on the emergence and progression of adverse events and other 
signs and symptoms requiring monitoring. Each subject will participate in 1 treatment 
group only. 
Chinese subjects will be assigned to Group 1 or Group 2 in a sequential manner. 
Group 1 will be enrolled and dosed first, and will have postdose safety observations 
performed for at least 14 days prior to initiation of dosing in Group 2. Japanese and 
Caucasian subjects will be assigned to Groups 3 and 4, respectively. Aside from the 
sequential conduct for Groups 1 and 2, there is no priority or required order for 
conduct of the different ethnic groups. 
On Day 1, AMG 592 will be administered as a single SC injection. 
• Group 1: Chinese subjects (n= ) will receive 
 AMG 592 given as one 
 SC injection 
• Group 2: Chinese subjects (n= ) will receive 
 AMG 592 given as one 
 SC injection 
• Group 3: Japanese subjects (n= ) will receive 
 AMG 592 given as one 
 SC injection 
• Group 4: Caucasian subjects (n= ) will receive 
 AMG 592 given as 
one 
 SC injection 
Serial blood samples will be collected for determination of AMG 592 serum 
concentrations, PK parameters, and PD markers. 
After discharge from the CRU, subjects will return for outpatient visits on Days 4, 5, 
6, 8, 11, 15, 22, 29, and the end of study (EOS) visit on Day 43. It is anticipated that 
many subjects will be traveling a great distance to the CRU in order to participate in 
the study; therefore, to reduce unnecessary travel and ease the burden on subjects 
needing to find local accommodations for the frequent outpatient visits in the first 
2 weeks of the study, subjects may reside in the CRU after clinic discharge on Day 3 
through a maximum of Day 11. In addition to this elective option to remain in the 
CRU, individual subjects may be required to remain in the CRU beyond Day 3 (to a 
maximum of Day 11) at the discretion of the Investigator, based on the emergence 
and progression of adverse events or signs/symptoms of other adverse drug reactions. 
To summarize, a subject may leave the CRU after discharge procedures on Day 3, 
unless required to stay by the Investigator or, if not required to stay, may elect to stay 
voluntarily; in either case, residence in the CRU may be through a maximum of 
Day 11. Subjects who remain in the CRU beyond Day 3 will have the applicable 
scheduled outpatient procedures performed while resident. A subject’s participation in 
the study will conclude at the completion of the EOS visit; however, subjects who test 
positive at EOS for neutralizing antibodies to IL-2 or binding antibodies with 
potentially antibody-mediated clinical sequelae will be asked to return for additional 
follow-up testing every 3 months until antibodies are no longer detected or up to 
12 months (± 4 weeks) post administration of AMG 592 (whichever is shorter). 
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Protocol Amendment 1, 08 December 2021 
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The total duration of study participation for each subject (from screening through the 
EOS visit) is anticipated to be approximately 10 weeks. 
The start of the study is defined as the date the first subject signs an informed consent 
form (ICF). The point of enrollment occurs at the time of subject number allocation. 
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. A Schedule of Assessments is 
presented in Appendix 8. 
Figure 1: 
Study Design 
 
3.2. 
Discussion of Study Design 
This study is an open-label investigation because the study endpoints are not believed 
to be subject to bias. 
This study will not be randomized as all subjects within a group will receive the same 
study treatment, and because of the need to conduct the Chinese groups in sequential 
order. Because of the sequential nature, Chinese subjects cannot be randomized to 
dose level as the timing for each group will differ and may affect subject availability. 
Subcutaneous injection was chosen because this is the intended clinical route of 
administration. 
Conducting the study in healthy subjects mitigates the potential confounding effects 
of the disease state and concomitant medications. 
-1 1
Study 
Day
11b
2
5
22
Screening
End of Study 
(EOS) Visit
-28
-1 1
AMG 592
Administration
6
29
2
15
4
43
8
Check-in to the
Clinical Research Unit (CRU)
3
-2
Outpatient Visits
Clinic Dischargea
The scheduled day of discharge is Day 3. Subjects may reside at the CRU after discharge on Day 3 until a maximum of 
Day 11, to reduce the travel and accommodation burden on subjects. In addition, the Investigator may require a subject 
to remain in the CRU after Day 3 (to a maximum of Day 11) based on the emergence and progression of adverse 
events or clinical signs and symptoms of adverse drug reaction.
a
b The maximum planned in-clinic residence for a given subject is 12 days (Day -1 to Day 11), whether by subject choice 
for lodging and accommodation purposes or as required by the Investigator based on adverse event(s) or clinical signs 
and symptoms of adverse drug reactions.
Note: Dashed line indicates that subjects may remain in the CRU beyond scheduled discharge on Day 3, as noted in 
footnote a.  Outpatient visit procedures will be performed on an inpatient basis for subjects who are resident at the 
CRU on the scheduled outpatient visit days.


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3.3. 
Selection of Doses in the Study 
AMG 592 doses were selected based on safety, PK, and PD results from the 
completed FIH study (20140324), PK study in Japanese healthy subjects (20180132), 
multiple-dose study in RA patients, ongoing multiple SC dose Phase 1b studies in 
patients with chronic GvHD and patients with SLE, as well as results from GLP 
toxicology studies in cynomolgus monkeys. The high dose of 
 was chosen to 
evaluate the PK/PD response and because it is within the anticipated upper range of 
doses that will be used in Phase 2 and 3 studies. Results from Studies 20140324 and 
20180132 as well as preliminary Phase 1b data indicate that AMG 592 is well 
tolerated at doses up to 
 with acceptable safety and Treg selectivity. 
Exposures in the present study are anticipated to be lower than those at the NOAEL 
(exposure multiples of at least 16.3 and 3 for AUC and Cmax, respectively) in the 
6-month repeat-dose GLP toxicology study in the cynomolgus monkey 
(Study 122293). 
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. Healthy male or female subjects, between 18 and 55 years of age (inclusive) at 
the time of Screening. 
3. Chinese, Japanese, or Caucasian subject: 
• Chinese subjects must be of Chinese ancestry (4 grandparents and 
biological parents). 
• Japanese subjects must be first- or second-generation Japanese 
(4 grandparents and biological parents; subject or both of their parents 
must have been born in Japan). 
• Caucasian subjects are those who self-identify exclusively as such on 
the electronic case report form (eCRF) and also identify their 
biological parents as such. 
4. In good health, determined by no clinically significant findings from medical 
history, PE, 12-lead electrocardiogram (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 17 and 30 kg/m2 (inclusive) at the time of 
Screening. 
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: 
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1. History or evidence, at Screening or Check-in, of a 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. 
2. Evidence of scars, tattoos, or other skin lesions that may interfere with the 
injection site or injection site assessments. 
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 using Fridericia’s method (QTcF) 
interval > 450 msec in male subjects or > 470 msec in female subjects or 
history/evidence of long QT syndrome, at Screening or Check-in. 
5. PR interval > 210 msec, at Screening or Check-in. 
6. Second- or third-degree atrioventricular (AV) block, at Screening or Check-in. 
7. Systolic blood pressure (BP) > 140 mmHg or < 90 mmHg, or diastolic BP 
> 90 mmHg, or HR > 100 bpm, at Screening or Check-in. 
8. 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. 
9. Poor peripheral venous access. 
10. Estimated glomerular filtration rate less than 60 mL/min/1.73 m2 as calculated 
by the Modification of Diet in Renal Disease equation, at Screening or 
Check-in. 
11. Underlying condition that predisposes the subject to infections (eg, history of 
splenectomy). 
12. HbA1C ≥ 7%, at Screening or Check-in. 
13. Active tuberculosis (TB) requiring treatment or documented latent TB within 
the previous 3 years. All subjects will be required to have a QuantiFERON-TB 
Gold test performed at Screening. Also excluded are participants with 
evidence of a past TB infection without documented adequate therapy. 
Participants with a positive QuantiFERON-TB Gold test at Screening will not 
be eligible for the study. A QuantiFERON-TB Gold test performed within 
4 weeks of dosing on Day 1 is acceptable as long as there is documentation of 
a negative result. 
14. Subjects who have received live vaccines within 5 weeks prior to Screening, 
or plan to receive live vaccines within 105 days after administration of an 
investigational product. 
15. Subjects who have received Coronavirus Disease 2019 (COVID-19) vaccine 
within 28 days prior to dosing, or plan to receive a COVID-19 vaccine within 
28 days postdose; from 29 days postdose through EOS, vaccination for 
COVID-19 may be deemed acceptable for a subject following discussion and 
agreement between the sponsor and the investigator. 
16. History of active infections (viral, bacterial, or fungal) within 21 days of 
receiving the investigational product. 


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Protocol Amendment 1, 08 December 2021 
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17. Positive hepatitis B or hepatitis C panel and/or positive human 
immunodeficiency virus test, at Screening. Subjects whose results are 
compatible with prior vaccination may be included. 
18. Use of any over-the-counter or prescription medications within 30 days or 
5 half-lives (whichever is longer) of Check-in. Continued use, if applicable, 
will be reviewed by the Investigator (or designee) and in consultation with the 
Sponsor. Written documentation of this review and Sponsor acknowledgment 
is required for subject participation. Exceptions are listed below. 
• Acetaminophen [paracetamol] up to 2 g per day for analgesia will be 
allowed.  
• Hormonal contraception listed in Appendix 4 will be allowed. 
• Hormone replacement therapy (eg, estrogen) will be allowed.  
19. Use of any herbal medicines, vitamins, or supplements consumed within the 
30 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee) and in consultation with the Sponsor. 
20. Consumption of foods and beverages containing poppy seeds within 7 days 
prior to Check-in. 
21. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 
22. Alcohol consumption from 48 hours prior to Check-in. 
23. Regular alcohol consumption of > 14 units per week for males and > 7 units 
for females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 
1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. 
24. Use of tobacco- or nicotine-containing products within 6 months prior to 
Check-in. 
25. Positive test for illicit drugs, cotinine (tobacco or nicotine use), and/or alcohol 
use at Screening or Check-in. 
26. Consumption of caffeine-containing foods and beverages within 24 hours 
prior to Check-in. 
27. Female subjects with a positive pregnancy test at Screening or Check-in.  
28. Female subjects who are lactating/breastfeeding or who plan to breastfeed 
during the study through 90 days after the EOS visit. 
29. Subjects who are unwilling to adhere to contraceptive requirements through 
90 days after the EOS visit (see Appendix 4).  
30. Subjects who are unwilling to abstain from sperm donation and ovum 
donation from Check-in until 90 days after the EOS visit (see Appendix 4). 
31. Male subject with a female partner of childbearing potential and not willing to 
inform his partner of his participation in this clinical study. 
32. Male subject with a pregnant partner or partner planning to become pregnant 
while the subject is on study through 90 days after the EOS visit. 
33. Subject has received a dose of an investigational drug within the past 90 days 
or 5 half-lives of the drug, whichever is longer, prior to Check-in. 


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34. Subjects who have previously completed or withdrawn from this study or any 
other study investigating AMG 592 or have previously received the 
investigational product.  
35. Donation of blood from 90 days prior to Check-in, plasma from 2 weeks prior 
to Check-in, or platelets from 6 weeks prior to Check-in. 
36. Subjects who are unwilling to abide with study restrictions. 
37. Subjects who, in the opinion of the Investigator (or designee), should not 
participate in this study. 
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. 
Subjects who have a screening laboratory test result that is out of range may have the 
test repeated once, and the subject may be enrolled if the repeated value is within 
range. This can be applied to any or all of the laboratory tests included in the 
exclusion criteria, and it can be disallowed for any critical tests at the discretion of the 
Investigator or Sponsor. 
4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. 
 
 
 
 
 
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. 
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Protocol Amendment 1, 08 December 2021 
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If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for 
the withdrawal will be documented in the subject’s eCRF, and 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 residing at the CRU, 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 additional follow-up visit(s). All withdrawn subjects will be 
followed until resolution of all their adverse events or until the unresolved adverse 
events are judged by the Investigator (or designee) to have stabilized. 
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 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 Ethics Committee (EC) 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 IMP will be stored at the study site in a location that is 
locked with restricted access. 


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The IMP (solution containing 
 AMG 592) will be supplied by the Sponsor 
(or designee), along with the lot numbers and Certificates of Analysis. The IMP will 
be stored according to the instructions on the label. 
Table 1: 
Investigational Product 
Study Treatment 
Name 
Investigational Medicinal Product: 
AMG 592 
Unit Strength and 
Formulation 
 
Dosage Level 
 
Route of 
Administration 
Subcutaneous injection 
Accountability 
The quantity administered, date administered, and lot number of the 
investigational medicinal product are to be recorded on each subject's 
electronic case report form.  
Dosing Instructions 
Treatment will be administered after the completion of all predose procedures. 
5.2. 
Investigational Product Administration 
Each SC injection will be administered by qualified and appropriately trained clinical 
staff to the lower abdomen. There are no posture requirements for dosing. 
5.3. 
Treatment of Overdose 
Neither the effects of overdose of AMG 592 nor an antidote to overdose are known. 
5.3.1. 
Medical Devices  
No investigational medical device 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-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 592) 
provisioned and/or repackaged/modified by the Sponsor. 
Any product complaint(s) associated with an investigational product (AMG 592) 
supplied by the Sponsor are to be reported according to the instructions provided in 
the Amgen IPIM. 
5.4. 
Randomization 
This study will not be randomized. 
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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 suitably qualified 
study site staff. 
• At each dosing occasion, a predose and postdose inventory of AMG 592 will 
be performed.  
5.7. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of 
AMG 592 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 592 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), hormone replacement therapy or oral, 
implantable, transdermal, injectable, or intrauterine contraceptives 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. 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 required to fast from food overnight (at least 8 hours) before 
collection of blood samples for clinical laboratory evaluations. Water may be 
consumed ad libitum throughout the study. 


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While confined at the study site, subjects will receive a standardized diet at scheduled 
times that do not conflict with other study-related activities.  
Foods and beverages containing poppy seeds will not be allowed from 7 days prior to 
Check-in until after the EOS visit. 
Caffeine-containing foods and beverages will not be allowed from 24 hours prior to 
each clinic visit and while at the CRU. 
Consumption of alcohol will not be permitted from 48 hours prior to each clinic visit. 
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 after the EOS visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in 
until after 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 90 days 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 
• PK blood samples 
• safety assessments (ECGs will be scheduled before vital signs measurements) 
• 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, safety 
laboratory assessments, and assessment of adverse events and serious adverse events. 
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 


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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. 
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.  
7.1.2. 
Analytical Methodology 
Serum concentrations of AMG 592 will be determined using validated analytical 
procedures. Specifics of the analytical method will be provided in a separate 
document. 
 
 
 
 
 
 
 
 
 
 
7.3. 
Anti-AMG 592 and Anti-IL-2 Assessments 
Blood samples for antibody testing are to be collected at the times listed in the 
Schedule of Assessments (Appendix 8). Samples testing positive for anti-AMG 592 
and/or anti-IL-2 antibodies will also be tested for neutralizing antibodies and may be 
further characterized. More frequent testing or testing for a longer period of time may 
be required in the event of a safety-related concern. 
Subjects who test positive at the EOS timepoint for neutralizing antibodies to IL-2 or 
binding antibodies with potentially antibody-mediated clinical sequelae will be asked 
to return for follow-up testing. This testing is to occur approximately every 3 months 
starting from the EOS visit and continue until: 1) antibodies are no longer detectable 
or 2) the subject has been followed for a period of at least 12 months (± 4 weeks) 
post administration of AMG 592 (whichever is shorter). All follow-up results, both 
positive and negative, will be communicated to the study site.  
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7.4. 
Biomarker Development 
7.4.1. 
Blood Samples for Biomarker Development 
Blood samples for biomarker development will be collected at the times indicated in 
the Schedule of Assessments in Appendix 8. Procedures for collection, processing, 
and shipping of biomarker development samples will be detailed in a separate 
document.  
7.4.2. 
Analytical Methodology 
Blood samples for biomarker development may be used to explore possible 
relationships between exposure to AMG 592 and physiological responses in 
individual subjects or in the general population, as part of the overall development 
program for AMG 592. Specifics of the analytical methods will be provided in a 
separate document. 
7.5. 
Safety and Tolerability Assessments 
7.5.1. 
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 serious adverse events are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to 
the EOS.  
If an event is reported as beginning prior to signing of the ICF or occurs prior to 
initiation of study treatment on Day 1 and is assessed as not related to study 
procedures by the Investigator (or designee), the event will be recorded as subject 
medical history. Any events prior to study drug administration but deemed by the 
Investigator to be related to study procedures will be reported as adverse events. Any 
events occurring after study drug administration on Day 1 through the EOS visit will 
be reported as adverse events. 
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 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 PE) from enrollment through the 
EOS visit are recorded/reported using the appropriate eCRF. 


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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. However, these serious adverse 
events can be reported to Amgen. Per local requirements in some countries, 
Investigators are required to report serious adverse events that they become aware of 
after the EOS visit. If serious adverse events are reported, the Investigator is to report 
them to the Sponsor within 24 hours following the Investigator’s knowledge of the 
event using the paper-based Serious Adverse Event Report Form.  
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 the 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 the subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to the Sponsor. 


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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, ECs, and Investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
An Investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the Sponsor will file it along with the IB and will notify the EC, 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 after the start of study treatment and 
until 90 days after the dosing. 
If a pregnancy and/or lactation 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. 
7.5.2. 
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 


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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 test at the times indicated in the Schedule of 
Assessments in Appendix 8. For all female subjects, a pregnancy test and 
follicle-stimulating hormone screen for postmenopausal status 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. 
7.5.3. 
Vital Signs 
Supine BP, 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 BP 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. 
7.5.4. 
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 once if either of the following 
criteria apply: 
• QTcF >500 msec 
• QTcF change from the baseline (predose) is >60 msec. 
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. 
7.5.5. 
Physical Examination 
A full PE or symptom-directed PE will be performed at the timepoints specified in the 
Schedule of Assessments in Appendix 8. The PE will also include a neurological 
exam. The neurological examination should include an assessment of mental status, 
level of consciousness, cranial nerve function, motor function, sensory function, 
reflexes, and coordination. 


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8. SAMPLE SIZE AND DATA ANALYSIS 
 
8.1. 
Determination of Sample Size 
Approximately 32 subjects will be enrolled in 4 groups (  subjects per group).  
With  subjects in each group receiving AMG 592, there is an 
 chance of 
 
 experiencing an adverse event with a true incidence rate of 
 
chance of 
 experiencing an adverse event with 
 true incidence 
rate. With a total of 32 subjects expected to receive AMG 592 across 4 cohorts, there 
is a 
 chance of 
 experiencing an adverse event with a true 
incidence rate of 
 and the chance of 
 experiencing an adverse 
event increases to 
 with a true incidence rate of 
, 
respectively. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of AMG 592 
and have evaluable PK data.  
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of AMG 592 
and have evaluable PD data. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of 
AMG 592 and have at least 1 postdose safety assessment. 
8.3. 
Pharmacokinetic Analyses 
The serum PK parameters of AMG 592 will be calculated using standard 
noncompartmental methods. 
The primary PK parameters are Cmax, tmax, AUClast, and AUCinf for AMG 592. All 
other PK parameters will be regarded as secondary and will not be subject to 
inferential statistical analysis. 
Additional PK parameters may be calculated. Specific details will be presented in the 
Statistical Analysis Plan for this study. 
 
 
  
 
 
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8.5. 
Anti-AMG 592 and Anti-IL-2 Analyses 
The formation of anti-AMG 592 and anti-IL-2 antibodies will be summarized 
descriptively. The incidence and percentage of subjects who develop antidrug 
antibodies (binding and if positive, neutralizing) at any time will be tabulated by 
treatment group. 
8.6. 
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.  
No imputation will be done for safety assessments, and endpoints for clinical 
laboratory tests and vital signs will be summarized. 
8.7. 
Interim Analysis 
No interim analyses are planned for this study.  
9. REFERENCES 
1. Amgen, Inc. Efavaleukin Alfa (AMG 592; Inflammatory Diseases) – 
Investigator’s Brochure. (Version 5.0). 17 December 2020. 
2. Yu A, Snowhite I, Vendrame F, et al. Selective IL-2 responsiveness of regulatory 
T cells through multiple intrinsic mechanisms support the use of low-dose IL-2 
therapy in Type-1 diabetes. Diabetes. Published online: 09 January 2015 (doi: 
10.2337/db 14-1322). 
3. Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of 
regulatory T cell differentiation. Nature. 2007;445:771-775. 
4. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function to 
interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 
2005;6:1142-1151. 
 
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10. APPENDICES 


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Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Adverse Events 
Definition of Adverse Event 
Adverse Event Definition 
• 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.  
• 
Note: An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device, or procedure. 
• 
Note: Treatment-emergent adverse event will be defined in the Statistical Analysis Plan. 
Events Meeting the Adverse Event Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiological scans, vital signs measurements), 
including those that worsen from baseline, that are considered clinically significant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication. Overdose per se will not be reported as an adverse 
event/serious adverse event unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses are to be reported regardless of sequelae. 
Events NOT Meeting the Adverse Event Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the adverse event. 


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• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. For instance, drug-induced 
hepatitis that resolved without evidence of hepatic failure would not be considered life-
threatening even though drug-induced hepatitis can be fatal. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are an adverse event. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious. Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term “disability” means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 


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Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition. These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
• 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
Investigator to review all documentation (eg, hospital progress notes, laboratory, and 
diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant adverse event/serious adverse event 
information in the event electronic case report form (eCRF). 
• 
The Investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to the investigational product(s) and/or study-mandated 
procedures, and 
o Action taken. 
• 
If the severity of an adverse event changes from the date of onset to the date of resolution, 
record as a single event with the worst severity on the appropriate eCRF.  
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records 
to Sponsor in lieu of completion of the appropriate eCRF page. 


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• 
If specifically requested, the Investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records. In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse event. 


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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The Investigator will make an assessment of severity for each adverse event and serious adverse 
event reported during the study. The assessment of severity will use the following definitions: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated, usually transient and may 
require only minimal treatment or therapeutic intervention. The event does 
not generally interfere with usual activities of daily living. 
MODERATE 
Discomfort enough to cause interference with usual activity causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Usually alleviated with additional specific therapeutic intervention. 
SEVEREa 
Incapacitating with inability to work or interrupts usual activities of daily 
living, or significantly affects clinical status, or may require intensive 
therapeutic intervention. 
a An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of a serious adverse event, NOT when it is rated as severe. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between investigational product(s), 
protocol-required therapy and/or study-mandated procedure and each occurrence of each 
adverse event/serious adverse event. 
• 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study treatment administration will be 
considered and investigated. 


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• 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each adverse event/serious adverse event, the Investigator must document in the medical 
notes that he/she has reviewed the adverse event/serious adverse event and has provided an 
assessment of causality. 
• 
There may be situations in which a serious adverse event has occurred and the Investigator 
has minimal information to include in the initial report. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the serious adverse event data. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
• 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a subject is permanently withdrawn from protocol-required therapies because of a serious 
adverse event, this information must be submitted to the Sponsor. 
• 
If a subject dies during participation in the study, the Investigator will provide the 
Sponsor with a copy of any post-mortem findings including histopathology.  
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated serious adverse event data to the Sponsor within 24 
hours of receipt of the information. 


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Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Paper Serious Adverse Event Report Form 
• 
Facsimile transmission of the Serious Adverse Event Report Form (see Figure 2) is the 
preferred method to transmit this information. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the Serious Adverse Event Report Form sent by overnight mail 
or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the Serious Adverse Event Report Form within the designated reporting time 
frames. 


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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 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Bilirubina 
Gamma-glutamyl transferase 
Glucose 
HbA1C 
Inorganic phosphate 
Potassium  
QuantiFERON-TB Gold test  
Sodium  
Total CO2 (measured as 
bicarbonate) 
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 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
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 virus 
(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 test  
Follicle-stimulating hormoneb 
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 
Creatine kinase MB fractionc  
a Includes total, direct, and indirect.  
b Only analyzed at Screening. 
c Only analyzed at Screening and Check-in.  
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 
6 
45 
Serology 
3.5 
1 
3.5 
AMG 592 
pharmacokinetics 
3.5 
15 
52.5 
Lymphocyte subsets 
9 
6 
54 
Biomarker development 
samples 
5 
7 
35 
Anti-AMG 592 and 
anti-IL-2 Antibodies 
3.5 
4 
14 
Total: 
204 
FSH = follicle-stimulating hormone; IL-2 = interleukin 2 
If additional 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. 
Definitions  
Women of Childbearing Potential: 
Premenopausal females who are anatomically and physiologically capable of becoming 
pregnant following menarche.  
Women of Non-Childbearing 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.  
 


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Contraception Requirements 
Female Subjects  
Female subjects who are of non-childbearing potential will not be required to use contraception. 
Female subjects of childbearing potential must be willing to use 2 methods [1 primary (highly 
effective) and 1 secondary method] of birth control from the time of signing the informed 
consent form until 90 days after the EOS visit.  
Primary (highly effective) methods of contraception include:  
• hormonal injection (as prescribed)  
• combined oral contraceptive pill or progestin/progestogen-only pill associated with 
inhibition of ovulation (as prescribed) without supplementary iron (ie, Loestrin Fe, Junel 
Fe, and Lo Loestrin Fe are prohibited) 
• combined hormonal patch (as prescribed)  
• combined hormonal vaginal ring (as prescribed)  
• surgical method performed at least 3 months prior to the Screening visit:  
o Bilateral tubal ligation with confirmation of surgical success 
o Regulatory approved method of hysteroscopic bilateral tubal occlusion with 
confirmation of occlusion of the fallopian tubes 
• hormonal implant  
• hormonal or non-hormonal intrauterine device (IUD or IUS) 
• vasectomized male partner (sterilization performed at least 90 days prior to the Screening 
visit, with verbal confirmation of surgical success, and the sole partner for the female 
subject).  
Secondary (barrier) methods of contraception include:  
• male condom with spermicide  
• female condom with spermicide  
• over-the-counter sponge with spermicide  
• cervical cap with spermicide (as prescribed)  
• diaphragm with spermicide (as prescribed).  
Female subjects should refrain from donation of ova from Check-in (Day -1) until 90 days after 
the EOS visit. 


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Protocol Version 2.0, 08 December 2021 
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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  
• surgical method (bilateral tubal ligation or regulatory approved method of hysteroscopic 
bilateral tubal occlusion)  
• hormonal implant  
• hormonal or non-hormonal IUD  
• 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 informed consent 
form (ICF) until 90 days after the EOS visit.  
 


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Amgen Protocol: 20200102 
Protocol Version 2.0, 08 December 2021 
Page 50 of 66 
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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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Version 2.0, 08 December 2021 
Page 51 of 66 
Appendix 5: Collection of Pregnancy and Lactation Information 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
• The 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). The 
form must be submitted to Amgen Global Patient Safety within 24 hours of learning of a 
subject’s pregnancy. (Note: Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
• After obtaining the female subject’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 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 
events 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. 


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Amgen Protocol: 20200102 
Protocol Version 2.0, 08 December 2021 
Page 52 of 66 
• 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 4.5 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 
form (see Figure 3) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy. (Note: Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions local 
privacy laws). 
• The Investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
• After obtaining the female partner’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the pregnancy 
questionnaires. This information will be forwarded to Amgen Global Patient Safety. 
• Generally, infant follow up will be conducted up to 12 months after the birth of the child 
(if applicable).  
• Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for procedure. 
Collection of Lactation Information 
• The Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 90 days after the EOS. 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Version 2.0, 08 December 2021 
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• 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 authorization for release of mother and infant health 
information, the Investigator will collect mother and infant health information and complete the 
lactation questionnaire on any female subject who breastfeeds while taking protocol-required 
therapies through 90 days after discontinuing protocol-required therapies. 


Protocol 
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Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 54 of 66 
Figure 3: 
Pregnancy Notification Form 
 


Protocol 
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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 55 of 66 
Figure 4: 
Lactation Notification Form 
 
 


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Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 56 of 66 
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 (CIOMS) 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 must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC 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 or any nonsubstantial changes, as defined by 
regulatory requirements.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the EC. 
• Notifying the EC of serious adverse events or other significant safety findings as 
required by EC 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 EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 


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Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 57 of 66 
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. 
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 Ethics Committee 
(EC) 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.  


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 58 of 66 
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 21 days from the previous ICF signature date. 
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. 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 electronic case report form (eCRF) demographics page, in addition to the unique 
subject identification number, include the age at time of enrollment. 
For serious adverse events reported to the Sponsor, subjects are to be identified by their 
unique subject identification number, (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 EC 
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. 


Protocol 
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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 59 of 66 
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. 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 electronic CRF (eCRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their unique 
subject identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in confidence by 
the Investigator, except as described below. 
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.  


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 60 of 66 
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The contract research organization (CRO) 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 the study site archive for at least 5 years after 
the end of the study 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 CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 61 of 66 
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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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 62 of 66 
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:  
• Prior and/or concurrent diseases or illness 
• Exposure to environmental and/or industrial chemical agents  
• Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 


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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 63 of 66 
• Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
• Concomitant use of medications (including nonprescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
• Viral serologies 
• Creatine phosphokinase, haptoglobin, lactate dehydrogenase, and peripheral blood 
smear 
• Appropriate liver imaging if clinically indicated 
• Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
• Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist). 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or 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 


Protocol 
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Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 64 of 66 
• 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: 
• 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. 
 


Protocol 
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Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 65 of 66 
Appendix 8: Schedule of Assessments 
PROCEDURE 
Screening Check-in 
 
Treatment Period 
 
 
Resident at the Clinical Research Unit 
 
 
 
 
 
 
 
 
 
Study Day 
-28 to -2 
-1 
1 
1 
1 
1 
1 
2 
3 
4 
5 
6 
8 
11 
15 
22 
29 43a (EOS)/ET 
Relative to Dosing (Hours) 
 
 
Pre 
0 
6 
12 
16 
24 
48 
72 
96 
120 168 240 
336 
504 
672 
1008 
GENERAL AND SAFETY ASSESSMENTS 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-house Residencyb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
Medical History 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsf 
X 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
X 
 
X 
 
X 
Adverse Eventsg 
 
 
 
 
 
 
Serious Adverse Eventsh 
X 
 
Concomitant Therapy Reviewi 
 
 
LABORATORY ASSESSMENTS 
 
Pregnancy Testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry and Hematologyk 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
eGFRl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIOMARKER AND IMMUNOLOGICAL ASSESSMENTS 
Lymphocyte Subsets 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
Biomarker Development Samples 
 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Anti-AMG 592 and Anti-IL-2 Antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
PHARMACOKINETIC ASSESSMENTS 
 
AMG 592 Serum PK Collectionn 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STUDY TREATMENT 
 
AMG 592 Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8448873 
Amgen Protocol: 20200102 
Protocol Amendment 1, 08 December 2021 
Page 66 of 66 
Abbreviations: CRU = clinical research unit; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; FSH = follicle-stimulating hormone; 
PE = physical examination; PK = pharmacokinetic 
a Subjects who test positive at the EOS timepoint for neutralizing antibodies to IL-2 or binding antibodies with potentially antibody-mediated clinical sequelae that are considered 
potentially related to an anti-AMG 592 antibody response will be asked to return for additional follow-up testing every 3 months until antibodies are no longer detectable or up to 
12 months’ post administration of AMG 592 (whichever is shorter). 
b Inhouse residency from Day 1 through the completion of all assessments on Day 3. Solid line indicates time that subjects are required to stay in the CRU. Dashed line indicates 
that subjects may stay in the CRU after Day 3 until a maximum of Day 11 if they choose (to reduce travel and accommodation burden on subjects); alternatively, the Investigator 
may require subjects to remain in-house for 1 or more days after Day 3 (up to Day 11) at their discretion, based on other signs and symptoms requiring monitoring.  
c Physical examination to include a neurological examination. A full PE will be conducted at Screening. A symptom-directed PE will be conducted on Days -1, 3, 11, 22, 29, 
and 43/EOS. 
d Interim medical history only. 
e Electrocardiogram (ECG) will be single 12-lead ECG, prior to blood draws or invasive procedures.  
f Supine blood pressure (BP), supine heart rate, respiratory rate, and oral body temperature. Heart rate and BP will be measured using the same arm for each reading after the 
subject has been resting in the supine position for at least 5 minutes. 
g Adverse events will be recorded from initiation of study treatment on Day 1 until the EOS. Any events prior to study drug administration but deemed by the Investigator to be 
related to study procedures will be reported as adverse events. 
h Serious adverse events will be recorded from the time the subject signs the informed consent form until the EOS. 
i Prior and concomitant medication administration will be recorded beginning at informed consent. Also, all Investigator-approved medications taken by a subject within 30 days or 
5 half-lives (whichever is longer) before Day 1 for over-the-counter or prescription medications, and 30 days prior to Check-in for herbal medicines (eg, St. John’s wort), 
vitamins, or supplements will be recorded on the subject’s electronic case report form. 
j 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. 
k Subjects will be fasted overnight (at least 8 hours) before collection of blood samples for clinical laboratory evaluations. 
l The eGFR will be calculated using the Modification of Diet in Renal Disease equation. 
m Performed in females only. 
n Blood samples for determination of AMG 592 serum concentrations and PK parameters will be collected: Predose; 6, 12, and 16 hours postdose; and on Days 2 (24 hours 
postdose), 3, 4, 5, 6, 8, 11, 15, 22, 29, and 43 (EOS) following administration of AMG 592 on Day 1. The postdose samples collected on Days 1 and 2 (6, 12, 16, and 24 hour 
samples) will have a sampling window of ± 30 minutes, postdose samples collected on Days 3 and 4 will have a sampling window of ± 6 hours, postdose samples collected on 
Days 5 through Day 15 will have a sampling window of ± 1 day, postdose samples taken on Days 22 and 29 will have a sampling window of ± 2 days, and postdose samples 
taken on Day 43 (EOS) will have a sampling window of ± 4 days. Times of all PK samples will be recorded to the nearest minute. 


Protocol 
CONFIDENTIAL 
Covance Study: 8448873 
 
Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 1 of 65 
 
Protocol 
A Phase 1, Open-label, Randomized, Parallel-arm, Single-dose Study 
to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
AMG 592 Administered Subcutaneously in Healthy Chinese, 
Japanese, and Caucasian Subjects 
Protocol Status: Final  
Protocol Date: 01 April 2021 
Protocol Version: 1.0 
Investigational Product: AMG 592 (efavaleukin alfa) 
 
Amgen Protocol Reference Number: 20200102 
Covance Study Number: 8448873 
IND Number: 131270 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
 
 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the Institutional Review Board/Independent Ethics 
Committee/Institutional Scientific Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent 
of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Protocol 
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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 2 of 65 
INVESTIGATOR AGREEMENT 
I have read the protocol entitled “A Phase 1, Open-label, Randomized, Parallel-arm, 
Single-dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
AMG 592 Administered Subcutaneously in Healthy Chinese, 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 
 
_______________________________________                   
 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 
PPD


Protocol 
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Covance Study: 8448873 
 
Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
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STUDY IDENTIFICATION 
Sponsor 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
Sponsor’s Study Contact 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
Sponsor’s Study Manager 
 
 
 
 
Covance Program Manager 
 
 
 
 
Statistician 
 
 
 
 
 
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PPD
PPD
PPD
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Protocol 
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Covance Study: 8448873 
 
Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
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SYNOPSIS 
Title of study: A Phase 1, Open-label, Randomized, Parallel-arm, Single-dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 592 Administered 
Subcutaneously in Healthy Chinese, Japanese, and Caucasian Subjects 
Objectives:  
The primary objective of the study is: 
• 
to evaluate the pharmacokinetics (PK) of AMG 592 after single subcutaneous (SC) 
administration in healthy Chinese, Japanese, and Caucasian subjects. 
The secondary objectives of the study are: 
• 
to evaluate the safety and tolerability of AMG 592 after single SC administration in 
healthy Chinese, Japanese, and Caucasian subjects. 
• 
to evaluate the incidence of anti-AMG 592 and anti-interleukin (IL)2 antibodies in 
healthy Chinese, Japanese, and Caucasian subjects after single SC administration of 
AMG 592. 
 
 
Study design: 
This will be an open-label, partially randomized, single-dose, parallel-arm study in 2 groups of 
healthy Chinese subjects and 1 group of Japanese subjects. In addition, a group of Caucasian 
subjects will be evaluated at the high dose for comparison. Potential subjects will be screened 
within 28 days prior to the dose. Subjects will be admitted into the clinical research unit (CRU) 
on Day -1 and will be confined to the CRU until discharge on Day 3. Chinese subjects (n = 
) 
will be randomized in a 1:1 ratio to receive a single SC dose of AMG 592 at 
 
(Group 1) or 
 (Group 2). Japanese subjects (n = ) will receive a single SC dose of 
AMG 592 at 
 (Group 3). Caucasian subjects (n = ) will receive a single SC dose of 
AMG 592 at 
 (Group 4). After discharge from the research facility, subjects will return 
to the CRU for outpatient visits on Days 4, 5, 6, 8, 11, 15, 22, 29, and at the end of study 
(EOS) visit on Day 43. A subject’s participation in the study will conclude at the completion of 
the EOS visit; however, subjects who test positive at the EOS timepoint for neutralizing 
antibodies to IL-2 or binding antibodies with potentially antibody-mediated clinical sequelae 
will be asked to return for additional follow-up testing every 3 months until antibodies are no 
longer detected or up to 12 months from dosing (whichever is shorter). 
Number of subjects: 
Approximately 32 subjects (  per group) will be enrolled in this study. 
Diagnosis and main criteria for inclusion: 
Healthy male or female subjects of Chinese ancestry, first- or second-generation Japanese 
subjects, and Caucasian subjects, 18 to 55 years of age (inclusive), body mass index of 17 to 
30 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Investigational Medicinal Product: 
 AMG 592 given as a 
 SC 
injection, 
 AMG 592 given as a 
 SC injection. 
Group 1 = 
 SC 
Group 2 = 
 SC 
Group 3 = 
 SC 
Group 4 = 
 SC 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to EOS): approximately 10 weeks.  
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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 5 of 65 
Primary endpoints: 
The primary endpoints for this study are PK parameters: maximum observed serum 
concentration (Cmax), the time of maximum observed serum concentration (tmax), area under the 
serum concentration-time curve (AUC) from time zero to time of last quantifiable 
concentration (AUClast), and AUC from time zero to infinity (AUCinf). 
Secondary endpoints: 
Secondary endpoints for this study are: treatment-emergent adverse events and serious adverse 
events (including clinically significant changes in physical examinations), clinical laboratory 
tests, vital signs, and anti-AMG 592 and anti-IL-2 antibody formation. 
 
 
Statistical methods: 
Data will be analyzed for all subjects who were enrolled and received a dose of AMG 592. 
Descriptive statistics by treatment arm will be provided for selected demographics, safety, PK 
parameters, and PD and immunogenicity data. Descriptive statistics on continuous 
measurements will include geometric and arithmetic means, medians, standard deviations, and 
ranges, while categorical data will be summarized using frequency counts and percentages. 
The PK, vital signs, and clinical laboratory data will be summarized for each timepoint when 
samples are collected.  
The final safety analysis for the study will be performed at the end of the study. Adverse 
events will be summarized using descriptive methodology. Each adverse event will be coded 
using the Medical Dictionary for Regulatory Activities. No imputation will be done for safety 
assessments, and endpoints for clinical laboratory tests and vital signs will be summarized. No 
inferential statistical analysis is planned.  
Additional details will be included in the Statistical Analysis Plan. 
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Protocol Version 1.0, 01 April 2021 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT........................................................................... 2 
STUDY IDENTIFICATION ................................................................................... 3 
SYNOPSIS ............................................................................................................... 4 
TABLE OF CONTENTS ......................................................................................... 6 
LIST OF TABLES AND FIGURES........................................................................ 9 
LIST OF ABBREVIATIONS ................................................................................ 10 
1.
INTRODUCTION ......................................................................................... 12 
1.1. 
Background .......................................................................................... 12 
1.2. 
Pharmacokinetics ................................................................................. 13 
1.3. 
Study Rationale .................................................................................... 13 
1.4. 
Benefit-risk Assessment ....................................................................... 14 
1.4.1. 
Therapeutic Context ................................................................... 14 
1.4.1.1. 
Benefits ............................................................................ 14 
1.4.1.2. 
Risks ................................................................................. 14 
2.
OBJECTIVES AND ENDPOINTS ............................................................... 14 
2.1. 
Objectives ............................................................................................ 14 
2.2. 
Endpoints ............................................................................................. 15 
2.2.1. 
Primary Endpoints ..................................................................... 15 
2.2.2. 
Secondary Endpoints ................................................................. 15 
2.2.3. 
Exploratory Endpoints ............................................................... 15 
3.
INVESTIGATIONAL PLAN ........................................................................ 15 
3.1. 
Overall Study Design and Plan ............................................................ 15 
3.2. 
Discussion of Study Design ................................................................. 17 
3.3. 
Selection of Doses in the Study ........................................................... 17 
4.
SELECTION OF STUDY POPULATION ................................................... 18 
4.1. 
Inclusion Criteria ................................................................................. 18 
4.2. 
Exclusion Criteria ................................................................................ 18 
4.3. 
Screen Failures and Rescreening ......................................................... 20 
4.4. 
Subject Number and Identification ...................................................... 21 
4.5. 
Subject Withdrawal and Replacement ................................................. 21 
4.6. 
Study Termination ............................................................................... 22 
5.
STUDY TREATMENTS ............................................................................... 22 
5.1. 
Investigational Product ........................................................................ 22 
5.2. 
Investigational Product Administration ............................................... 23 
5.3. 
Treatment of Overdose ........................................................................ 23 
5.3.1. 
Medical Devices ......................................................................... 23 
5.3.2. 
Product Complaints .................................................................... 23 
5.4. 
Randomization ..................................................................................... 23 
5.5. 
Blinding................................................................................................ 23 
5.6. 
Treatment Compliance ......................................................................... 24 
5.7. 
Drug Accountability............................................................................. 24 


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6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS .............. 24 
6.1. 
Concomitant Therapies ........................................................................ 24 
6.2. 
Diet ....................................................................................................... 24 
6.3. 
Smoking ............................................................................................... 25 
6.4. 
Exercise ................................................................................................ 25 
6.5. 
Blood Donation .................................................................................... 25 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................... 25 
7.1. 
Pharmacokinetic Assessments ............................................................. 26 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ...... 26 
7.1.2. 
Analytical Methodology ............................................................ 26 
 
 
 
 
 
 
7.3. 
Anti-AMG 592 and Anti-IL-2 Assessments ........................................ 26 
7.4. 
Biomarker Development ...................................................................... 26 
7.4.1. 
Blood Samples for Biomarker Development ............................. 26 
7.4.2. 
Analytical Methodology ............................................................ 27 
7.5. 
Safety and Tolerability Assessments ................................................... 27 
7.5.1. 
Adverse Events and Serious Adverse Events: Time Period and 
Frequency for Collecting and Reporting Safety Event 
Information ................................................................................ 27 
7.5.2. 
Clinical Laboratory Evaluations ................................................ 29 
7.5.3. 
Vital Signs .................................................................................. 30 
7.5.4. 
12-lead Electrocardiogram ......................................................... 30 
7.5.5. 
Physical Examination................................................................. 30 
8. 
SAMPLE SIZE AND DATA ANALYSIS .................................................... 30 
8.1. 
Determination of Sample Size ............................................................. 30 
8.2. 
Analysis Populations ............................................................................ 31 
8.2.1. 
Pharmacokinetic Population ...................................................... 31 
8.2.2. 
Pharmacodynamic Population ................................................... 31 
8.2.3. 
Safety Population ....................................................................... 31 
8.3. 
Pharmacokinetic Analyses ................................................................... 31 
 
 
8.5. 
Anti-AMG 592 and Anti-IL-2 Analyses .............................................. 32 
8.6. 
Safety Analysis .................................................................................... 32 
8.7. 
Interim Analysis ................................................................................... 32 
9. 
REFERENCES .............................................................................................. 32 
10. APPENDICES ............................................................................................... 33 
Appendix 1: Safety Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting of Adverse Events .................. 34 
Definition of Adverse Event ...................................................................... 34 
Definition of Serious Adverse Event ......................................................... 35 
Recording Adverse Events and Serious Adverse Events ........................... 36 
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Evaluating Adverse Events and Serious Adverse Events .......................... 38 
Reporting of Serious Adverse Event .......................................................... 40 
Appendix 2: Clinical Laboratory Evaluations ................................................. 44 
Appendix 3: Total Blood Volume .................................................................... 45 
Appendix 4: Contraception Requirements ....................................................... 46 
Appendix 5: Collection of Pregnancy and Lactation Information ................... 50 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations .......... 55 
Appendix 7: Hepatotoxicity: Suggested Actions and Follow-up Assessments
.............................................................................................................. 61 
Drug-induced Liver Injury Reporting and Additional Assessments .......... 63 
Appendix 8: Schedule of Assessments ............................................................ 64 
 


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LIST OF TABLES AND FIGURES 
Table 1: 
Investigational Product ............................................................ 22 
 
Figure 1: 
Study Design ............................................................................ 17 
Figure 2: 
Sample Serious Adverse Event Report Form .......................... 41 
Figure 3: 
Pregnancy Notification Form ................................................... 53 
Figure 4: 
Lactation Notification Form .................................................... 54 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
AUCinf 
area under the serum concentration-time curve from time zero to 
infinity 
AUClast 
area under the serum concentration-time curve from time zero to 
time of last quantifiable concentration 
AV 
atrioventricular 
BP 
blood pressure 
CD4 
cluster of differentiation 4 
CD25 
alpha chain of the interleukin 2 receptor 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed serum concentration 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CRU 
clinical research unit 
DILI 
drug-induced liver injury 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
FIH 
first-in-human 
FOXP3 
forkhead box P3; an essential transcription factor of Treg function, 
upregulated by IL-2R signals 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GvHD 
graft-versus-host disease 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation 
IL 
interleukin 
IL-2R 
interleukin 2 receptor 
IL-2RA 
interleukin 2 receptor alpha chain 
IL-2RB 
interleukin 2 receptor beta chain 
ILC2 
innate lymphoid cells 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
institutional review board 


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IUD 
intrauterine device 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic(s) 
Q2W 
every 2 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
QW 
once weekly 
RA 
rheumatoid arthritis 
SC 
subcutaneous 
SLE 
systemic lupus erythematosus 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TBL 
total bilirubin 
Tcon 
conventional T cells 
tmax 
time of the maximum observed serum concentration 
Tregs 
regulatory T cells 
ULN 
upper limit of normal 
 


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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 
Investigational Medicinal Product 
Regulatory T cells (Tregs) are a subset of cluster of differentiation 4 (CD4) T cells 
that suppress inflammation and whose numbers and function are maintained by 
interleukin (IL)-2. In addition to Treg, IL-2-responsive lymphocytes include 
conventional CD4 and CD8 T (Tcon) cells, natural killer (NK) cells, and innate 
lymphoid cells (ILC2). A loss in the homeostatic balance between Tregs and other 
lymphocytes is considered a causative factor in many inflammatory conditions.  
AMG 592 (efavaleukin alfa) is an Fc-IL-2 mutein that contains 2 mutations in the 
IL-2 domain. To increase the Treg selectivity of IL-2, 1 mutation is in the region that 
binds the beta chain of the IL-2 receptor (IL-2RB). This mutation reduces its signaling 
potency and increases its dependence on expression of interleukin 2 receptor alpha 
chain (IL-2RA/CD25). It drives a positive feedback loop enforcing Treg phenotype, 
abundance, and IL-2 responsiveness over effects on other lymphocytes. The other 
mutation is in an internal region of IL-2 and improves manufacturability of AMG 592 
but does not alter its biological activity.2,3,4 
The IL-2R is composed of 3 chains: IL-2RB and IL-2R gamma, which together 
deliver the intracellular IL-2R signal, and IL-2RA (CD25), which stabilizes IL-2 
association with IL-2RBG but does not contain a signaling domain. The alpha chain 
of the IL-2 receptor (CD25) is highly expressed on Treg, and IL-2R signaling in Treg 
promotes expression of both CD25 and FOXP3, the essential transcription factor for 
Treg development and function. High FOXP3 expression promotes both full Treg 
suppressor activity and high CD25 expression, resulting in a positive feedback loop 
enforcing Treg phenotype, abundance, and IL-2 responsiveness.2,3,4 
The mutation in the IL-2RB-binding region of IL-2 results in increased dependence 
on CD25 for IL-2R signaling compared with wild-type IL-2. Thus, efavaleukin alfa 
preferentially drives this positive feedback loop in Treg over effects on other 
lymphocytes (ie, other T cells and ILC2 which may express CD25 but do not express 
FOXP3, and NK cells which express little or no CD25 and no FOXP3). Compared 
with aldesleukin, efavaleukin alfa exhibits greatly improved selectivity for Treg over 
Tcon and NK cells both in vitro and in vivo, potentially resulting in an improved 
therapeutic margin. In addition, the Fc domain of AMG 592 confers a prolonged half-
life compared with aldesleukin, thus reducing the dosing frequency required to 
maintain Treg enrichment  
Nonclinical in vitro and in vivo studies have demonstrated that AMG 592 exhibits 
greater selectivity for inducing Treg expansion over the expansion of CD4 and CD8 
T cells, and NK cells, relative to low dose, recombinant IL-2. This greater selectivity 
of AMG 592 has promise for greater efficacy and a wider therapeutic margin in 
inflammatory diseases relative to low-dose recombinant IL-2-based modalities. 


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Amgen is developing AMG 592 as a treatment for multiple inflammatory diseases 
including systemic lupus erythematosus (SLE), steroid-refractory chronic 
graft-versus-host disease (GvHD), and ulcerative colitis. This study is designed to 
evaluate whether pharmacokinetic (PK) and safety data in Chinese and Japanese 
subjects are similar to those from the global population. 
A summary of completed and ongoing clinical studies for AMG 592 is provided in the 
IB.1  
1.2. 
Pharmacokinetics 
In a first-in-human (FIH) study (Study 20140324), PK results of AMG 592 in healthy 
subjects following single-dose subcutaneous (SC) administration of AMG 592 are 
available for doses of 
. Results show 
dose-related increases in AMG 592 serum exposure (as assessed by maximum 
observed concentration [Cmax] and area under the serum concentration-time curve 
[AUC] from time zero to infinity [AUCinf]) with approximately dose-proportional 
increase over the 
 
. Following SC administration, the 
median time to maximum observed serum concentration (tmax) ranged from 
approximately 0.5 to 1 day with terminal phase half-life (t1/2) about 11 to 13 hours 
postdose at doses 
. 
In a single-dose PK study in healthy Japanese subjects (Study 20180132), exposure of 
AMG 592, assessed by Cmax and AUCinf, increased approximately dose proportionally 
over the 
. Mean Cmax and AUCinf exhibited 
 
. The median tmax was 
14 hours in the AMG 592 
 cohort and 24 hours in the AMG 592 
 
cohort. For the 
 cohort, the mean half-life, apparent drug clearance, volume of 
distribution, and mean residence time was 11.7 hours, 1.29 L/hour, 21.9 L, and 
33.2 hours, respectively. For the 
 cohort, the mean half-life, apparent drug 
clearance, volume of distribution, and mean residence time was 9.68 hours, 
0.852 L/hour, 11.7 L, and 39.5 hours, respectively. 
In a multiple-dose study in patients with active rheumatoid arthritis (RA), exposure to 
AMG 592, as expressed in AUC and Cmax, increased with increasing dose from 
 every 2 weeks (Q2W) to 
 once weekly (QW) to 
 Q2W. Peak 
concentrations were observed about 6 to 12 hours following dosing, with half-lives 
that ranged from about 10 to 40 hours. Moderate drug accumulation was observed for 
 Q2W and 
 QW. There were not enough data to determine the 
accumulation ratio for the 
 Q2W dose. 
1.3. 
Study Rationale 
The highest dose of AMG 592 previously evaluated in healthy Japanese and 
Caucasian subjects is 
, and a dose of 
 has demonstrated Treg 
selectivity and acceptable safety in subjects with SLE. As AMG 592 has not 
previously been studied in healthy Chinese subjects, 
 was chosen as the 
low-dose level to permit direct comparison with results from previous studies. 
Chinese, Japanese, and Caucasian subjects were selected in order to allow comparison 
to previous data and extrapolation to future studies, to look for possible ethnic 
variation in PK or PD parameters, and as part of the effort to ensure that proper dose 
regimens are recommended for the appropriate patient populations of different 
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ethnicities. The current study should inform dose selection and design of future Phase 
2 and 3 studies. 
1.4. 
Benefit-risk Assessment 
The following benefit-risk assessment supports the conduct of this clinical study. 
Refer to the IB1 for more information. 
1.4.1. 
Therapeutic Context 
1.4.1.1. 
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.  
1.4.1.2. 
Risks 
The safety of AMG 592 (efavaleukin alfa) has been studied in healthy volunteers and 
in SLE, chronic GvHD, and RA patients. Overall, approximately 143 subjects have 
been exposed to efavaleukin alfa in Amgen clinical studies. Single SC doses of up to 
 of efavaleukin alfa have been studied in healthy volunteers. Repeated SC 
doses of up to 
 of efavaleukin alfa administered Q2W have been studied in 
subjects with chronic GvHD over the course of a 52-week period. Doses up to 
 Q2W have been studied in subjects with SLE and up to 
 Q2W in 
subjects with RA over the course of a 12-week period. The safety profile of 
efavaleukin alfa is based on these clinical studies. Current adverse drug reactions 
reported in efavaleukin alfa clinical studies are erythema and pruritus, 
hypersensitivity, and RA. Potential risks are described in the IB.1 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
• to evaluate the PK of AMG 592 after single SC administration in healthy 
Chinese, Japanese, and Caucasian subjects. 
The secondary objectives of the study are: 
• to evaluate the safety and tolerability of AMG 592 after single SC 
administration in healthy Chinese, Japanese, and Caucasian subjects. 
• to evaluate the incidence of anti-AMG 592 and anti-IL-2 antibodies in healthy 
Chinese, Japanese, and Caucasian subjects after single SC administration of 
AMG 592. 
 
 
 
 
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2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints of the study are: 
• Cmax 
• tmax 
• AUC from time zero to time of last quantifiable concentration (AUClast) 
• AUCinf. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
• treatment-emergent adverse events and serious adverse events (including 
clinically significant changes in physical examinations [PE]) 
• clinical laboratory tests 
• vital signs 
• anti-AMG 592 and anti-IL-2 antibody formation. 
 
 
 
  
 
 
 
 
 
 
 
 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a Phase 1, single-center, open-label, partially randomized, parallel-arm 
study to investigate the safety, tolerability, and PK of a single SC dose of AMG 592 
in 2 groups of healthy Chinese subjects and 1 group of healthy Japanese subjects. In 
addition, a group of healthy Caucasian subjects will be evaluated at the high dose 
level for comparison. 
Approximately 32 subjects will be enrolled in total, with  subjects in each of the 
4 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 3. Each subject will participate in 1 treatment group only. 
On Day 1, Chinese subjects (n = 
) will be randomly assigned in a 1:1 ratio to either 
Group 1 or Group 2 by a Covance statistician. Japanese and Caucasian subjects will 
be assigned to Groups 3 and 4, respectively. 
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On Day 1, AMG 592 will be administered as a single SC injection. 
• Group 1: Chinese subjects (n= ) will receive 
 AMG 592 given as one 
 SC injection 
• Group 2: Chinese subjects (n= ) will receive 
 AMG 592 given as one 
 SC injection 
• Group 3: Japanese subjects (n= ) will receive 
 AMG 592 given as one 
 SC injection 
• Group 4: Caucasian subjects (n= ) will receive 
 AMG 592 given as 
one 
 SC injection 
Serial blood samples will be collected for determination of AMG 592 serum 
concentrations, PK parameters, and PD markers. 
After discharge from the CRU, subjects will return for outpatient visits on Days 4, 5, 
6, 8, 11, 15, 22, 29, and the end of study (EOS) visit on Day 43. It is anticipated that 
many subjects will be traveling a great distance to the CRU in order to participate in 
the study; therefore, to reduce unnecessary travel and ease the burden on subjects 
needing to find local accommodations for the frequent outpatient visits in the first 
2 weeks of the study, subjects may reside in the CRU after clinic discharge on Day 3 
through a maximum of Day 11. As this is for logistical purposes only, no additional 
study procedures are planned for subjects who decide to remain in the CRU, aside 
from the scheduled outpatient visit assessments on Days 4, 5, 6, 8, and 11. A subject’s 
participation in the study will conclude at the completion of the EOS visit; however, 
subjects who test positive at EOS for neutralizing antibodies to IL-2 or binding 
antibodies with potentially antibody-mediated clinical sequelae will be asked to return 
for additional follow-up testing every 3 months until antibodies are no longer detected 
or up to 12 months (+/- 4 weeks) post administration of AMG 592 (whichever is 
shorter). 
The total duration of study participation for each subject (from screening through the 
EOS visit) is anticipated to be approximately 10 weeks. 
The start of the study is defined as the date the first subject signs an informed consent 
form (ICF). The point of enrollment occurs at the time of subject number allocation. 
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. A Schedule of Assessments is 
presented in Appendix 8. 
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Figure 1: 
Study Design 
 
3.2. 
Discussion of Study Design 
This study is an open-label investigation because the study endpoints are not believed 
to be subject to bias. 
This study will be partially randomized (Chinese subjects will be randomized in a 
1:1 ratio to 1 of 2 dose levels) to ensure there is no bias when assigning subjects to 
each dose level. 
Subcutaneous injection was chosen because this is the intended clinical route of 
administration. 
Conducting the study in healthy subjects mitigates the potential confounding effects 
of the disease state and concomitant medications. 
3.3. 
Selection of Doses in the Study 
AMG 592 doses were selected based on safety, PK, and PD results from the 
completed FIH study (20140324), PK study in Japanese healthy subjects (20180132), 
multiple-dose study in RA patients, ongoing multiple SC dose Phase 1b studies in 
patients with chronic GvHD and patients with SLE, as well as results from GLP 
toxicology studies in cynomolgus monkeys. The high dose of 
 was chosen to 
evaluate the PK/PD response and because it is within the anticipated upper range of 
doses that will be used in Phase 2 and 3 studies. Results from Studies 20140324 and 
20180132 as well as preliminary Phase 1b data indicate that AMG 592 is well 
tolerated at doses up to 
 with acceptable safety and Treg selectivity. 
Exposures in the present study are anticipated to be lower than those at the NOAEL 
(exposure multiples of at least 16.3 and 3 for AUC and Cmax, respectively) in the 
6-month repeat-dose GLP toxicology study in the cynomolgus monkey 
(Study 122293). 
-1 1
Study 
Day
11
2
5
22
Screening
End of Study 
(EOS) Visit
-28
-1 1
Randomization 
& AMG 592
Administration
6
29
2
15
4
43
8
Check-in to the
Clinical Research Unit (CRU)
3
-2
Outpatient Visits
Clinic Dischargea
   Subjects may reside at the CRU after discharge on Day 3 until a maximum of Day 11, to reduce the travel and
   accommodation burden on subjects. For subjects who remain in the CRU after Day 3, no additional procedures are
a
   planned aside from the scheduled outpatient visit assessments on Days 4, 5, 6, 8, and 11.
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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. Healthy male or female subjects, between 18 and 55 years of age (inclusive) at 
the time of Screening. 
3. Chinese, Japanese, or Caucasian subject: 
• Chinese subjects must be of Chinese ancestry (4 grandparents and 
biological parents). 
• Japanese subjects must be first- or second-generation Japanese 
(4 grandparents and biological parents; subject or both of their parents 
must have been born in Japan). 
• Caucasian subjects are those who self-identify exclusively as such on 
the electronic case report form (eCRF) and also identify their 
biological parents as such. 
4. In good health, determined by no clinically significant findings from medical 
history, PE, 12-lead electrocardiogram (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 17 and 30 kg/m2 (inclusive) at the time of 
Screening. 
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 a 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. 
2. Evidence of scars, tattoos, or other skin lesions that may interfere with the 
injection site or injection site assessments. 
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 using Fridericia’s method (QTcF) 
interval > 450 msec in male subjects or > 470 msec in female subjects or 
history/evidence of long QT syndrome, at Screening or Check-in. 
5. PR interval > 210 msec, at Screening or Check-in. 
6. Second- or third-degree atrioventricular (AV) block , at Screening or Check-
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7. Systolic blood pressure (BP) > 140 mmHg or < 90 mmHg, or diastolic BP 
> 90 mmHg, or HR > 100 bpm, at Screening or Check-in. 
8. 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. 
9. Poor peripheral venous access. 
10. Estimated glomerular filtration rate less than 60 mL/min/1.73 m2 as calculated 
by the Modification of Diet in Renal Disease equation, at Screening or 
Check-in. 
11. Underlying condition that predisposes the subject to infections (eg, history of 
splenectomy). 
12. HbA1C ≥ 7%, at Screening or Check-in. 
13. Active tuberculosis (TB) requiring treatment or documented latent TB within 
the previous 3 years. All subjects will be required to have a QuantiFERON-TB 
Gold test performed at Screening. Also excluded are participants with 
evidence of a past TB infection without documented adequate therapy. 
Participants with a positive QuantiFERON-TB Gold test at Screening will not 
be eligible for the study. A QuantiFERON-TB Gold test performed within 
4 weeks of dosing on Day 1 is acceptable as long as there is documentation of 
a negative result. 
14. Subjects who have received live vaccines within 5 weeks prior to Screening, 
or plan to receive live vaccines within 105 days after administration of an 
investigational product. 
15. Subjects who have received Coronavirus Disease 2019 (COVID-19) vaccine 
within 28 days prior to dosing, or plan to receive a COVID-19 vaccine within 
28 days postdose; from 29 days postdose through EOS, vaccination for 
COVID-19 may be deemed acceptable for a subject following discussion and 
agreement between the sponsor and the investigator. 
16. History of active infections (viral, bacterial, or fungal) within 21 days of 
receiving the investigational product. 
17. Positive hepatitis B or hepatitis C panel and/or positive human 
immunodeficiency virus test, at Screening. Subjects whose results are 
compatible with prior vaccination may be included. 
18. Use of any over-the-counter or prescription medications within 30 days or 
5 half-lives (whichever is longer) of Check-in. Continued use, if applicable, 
will be reviewed by the Investigator (or designee) and in consultation with the 
Sponsor. Written documentation of this review and Sponsor acknowledgment 
is required for subject participation. Exceptions are listed below. 
• Acetaminophen [paracetamol] up to 2 g per day for analgesia will be 
allowed.  
• Hormonal contraception listed in Appendix 4 will be allowed. 
• Hormone replacement therapy (eg, estrogen) will be allowed.  


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19. Use of any herbal medicines, vitamins, or supplements consumed within the 
30 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee) and in consultation with the Sponsor. 
20. Consumption of foods and beverages containing poppy seeds within 7 days 
prior to Check-in. 
21. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 
22. Alcohol consumption from 48 hours prior to Check-in. 
23. Regular alcohol consumption of > 14 units per week for males and > 7 units 
for females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 
1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. 
24. Use of tobacco- or nicotine-containing products within 6 months prior to 
Check-in. 
25. Positive test for illicit drugs, cotinine (tobacco or nicotine use), and/or alcohol 
use at Screening or Check-in. 
26. Consumption of caffeine-containing foods and beverages within 24 hours 
prior to Check-in. 
27. Female subjects with a positive pregnancy test at Screening or Check-in.  
28. Female subjects who are lactating/breastfeeding or who plan to breastfeed 
during the study through 90 days after the EOS visit. 
29. Subjects who are unwilling to adhere to contraceptive requirements through 
90 days after the EOS visit (see Appendix 4).  
30. Subjects who are unwilling to abstain from sperm donation and ovum 
donation from Check-in until 90 days after the EOS visit (see Appendix 4). 
31. Male subject with a female partner of childbearing potential and not willing to 
inform his partner of his participation in this clinical study. 
32. Male subject with a pregnant partner or partner planning to become pregnant 
while the subject is on study through 90 days after the EOS visit. 
33. Subject has received a dose of an investigational drug within the past 90 days 
or 5 half-lives of the drug, whichever is longer, prior to Check-in. 
34. Subjects who have previously completed or withdrawn from this study or any 
other study investigating AMG 592 or have previously received the 
investigational product.  
35. Donation of blood from 90 days prior to Check-in, plasma from 2 weeks prior 
to Check-in, or platelets from 6 weeks prior to Check-in. 
36. Subjects who are unwilling to abide with study restrictions. 
37. Subjects who, in the opinion of the Investigator (or designee), should not 
participate in this study. 
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 


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includes demography, screen failure details, eligibility criteria, medical history, prior 
therapies, and any serious adverse events. 
Subjects who have a screening laboratory test result that is out of range may have the 
test repeated once, and the subject may be enrolled if the repeated value is within 
range. This can be applied to any or all of the laboratory tests included in the 
exclusion criteria, and it can be disallowed for any critical tests at the discretion of the 
Investigator or Sponsor. 
4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. 
 
 
 
 
 
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, the Sponsor will be notified and the date and reason(s) for 
the withdrawal will be documented in the subject’s eCRF, and 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 residing at the CRU, 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 additional follow-up visit(s). All withdrawn subjects will be 
followed until resolution of all their adverse events or until the unresolved adverse 
events are judged by the Investigator (or designee) to have stabilized. 
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 thought to be related to the study drug will generally not be 
replaced. 
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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 Ethics Committee (EC) 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 IMP will be stored at the study site in a location that is 
locked with restricted access. 
The IMP (solution containing 
 AMG 592) will be supplied by the Sponsor 
(or designee), along with the lot numbers and Certificates of Analysis. The IMP will 
be stored according to the instructions on the label. 
Table 1: 
Investigational Product 
Study Treatment 
Name 
Investigational Medicinal Product: 
AMG 592 
Unit Strength and 
Formulation 
 
Dosage Level 
 
Route of 
Administration 
Subcutaneous injection 
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Study Treatment 
Name 
Investigational Medicinal Product: 
AMG 592 
Accountability 
The quantity administered, date administered, and lot number of the 
investigational medicinal product are to be recorded on each subject's 
electronic case report form.  
Dosing Instructions 
Treatment will be administered after the completion of all predose procedures. 
5.2. 
Investigational Product Administration 
Each SC injection will be administered by qualified and appropriately trained clinical 
staff to the lower abdomen. There are no posture requirements for dosing. 
5.3. 
Treatment of Overdose 
Neither the effects of overdose of AMG 592 nor an antidote to overdose are known. 
5.3.1. 
Medical Devices  
No investigational medical device 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-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 592) 
provisioned and/or repackaged/modified by the Sponsor. 
Any product complaint(s) associated with an investigational product (AMG 592) 
supplied by the Sponsor are to be reported according to the instructions provided in 
the Amgen IPIM. 
5.4. 
Randomization 
This study will be partially randomized (only Chinese subjects will be randomized to 
1 of 2 dose levels) to ensure there is no bias when assigning subjects to each dose 
level. The randomization code will be produced by a Covance Statistician. 
Prior to the start of the study, a copy of the master randomization code will be 
supplied to the Covance CRU pharmacy staff. 
5.5. 
Blinding 
This is an open-label study.   


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5.6. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of suitably qualified 
study site staff. 
• At each dosing occasion, a predose and postdose inventory of AMG 592 will 
be performed.  
5.7. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of 
AMG 592 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 592 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), hormone replacement therapy or oral, 
implantable, transdermal, injectable, or intrauterine contraceptives 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. 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 required to fast from food overnight (at least 8 hours) before 
collection of blood samples for clinical laboratory evaluations. Water may be 
consumed ad libitum throughout the study. 
While confined at the study site, subjects will receive a standardized diet at scheduled 
times that do not conflict with other study-related activities.  
Foods and beverages containing poppy seeds will not be allowed from 7 days prior to 
Check-in until after the EOS visit. 


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Caffeine-containing foods and beverages will not be allowed from 24 hours prior to 
each clinic visit. 
Consumption of alcohol will not be permitted from 48 hours prior to each clinic visit. 
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 after the EOS visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in 
until after 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 90 days 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 
• PK blood samples 
• safety assessments (ECGs will be scheduled before vital signs measurements) 
• 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, safety 
laboratory assessments, and assessment of adverse events and serious adverse events. 
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.  


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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.  
7.1.2. 
Analytical Methodology 
Serum concentrations of AMG 592 will be determined using validated analytical 
procedures. Specifics of the analytical method will be provided in a separate 
document. 
 
 
 
 
 
 
 
 
 
 
7.3. 
Anti-AMG 592 and Anti-IL-2 Assessments 
Blood samples for antibody testing are to be collected at the times listed in the 
Schedule of Assessments (Appendix 8). Samples testing positive for anti-AMG 592 
and/or anti-IL-2 antibodies will also be tested for neutralizing antibodies and may be 
further characterized. More frequent testing or testing for a longer period of time may 
be required in the event of a safety-related concern. 
Subjects who test positive at the EOS timepoint for neutralizing antibodies to IL-2 or 
binding antibodies with potentially antibody-mediated clinical sequelae will be asked 
to return for follow-up testing. This testing is to occur approximately every 3 months 
starting from the EOS visit and continue until: 1) antibodies are no longer detectable 
or 2) the subject has been followed for a period of at least 12 months (+/- 4 weeks) 
post administration of AMG 592 (whichever is shorter). All follow-up results, both 
positive and negative, will be communicated to the study site.  
7.4. 
Biomarker Development 
7.4.1. 
Blood Samples for Biomarker Development 
Blood samples for biomarker development will be collected at the times indicated in 
the Schedule of Assessments in Appendix 8. Procedures for collection, processing, 
and shipping of biomarker development samples will be detailed in a separate 
document.  
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7.4.2. 
Analytical Methodology 
Blood samples for biomarker development may be used to explore possible 
relationships between exposure to AMG 592 and physiological responses in 
individual subjects or in the general population, as part of the overall development 
program for AMG 592. Specifics of the analytical methods will be provided in a 
separate document. 
7.5. 
Safety and Tolerability Assessments 
7.5.1. 
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 serious adverse events are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to 
the EOS.  
If an event is reported as beginning prior to signing of the ICF or occurs prior to 
initiation of study treatment on Day 1 and is assessed as not related to study 
procedures by the Investigator (or designee), the event will be recorded as subject 
medical history. Any events prior to study drug administration but deemed by the 
Investigator to be related to study procedures will be reported as adverse events. Any 
events occurring after study drug administration on Day 1 through the EOS visit will 
be reported as adverse events. 
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 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 PE) 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 


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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. However, these serious adverse 
events can be reported to Amgen. Per local requirements in some countries, 
Investigators are required to report serious adverse events that they become aware of 
after the EOS visit. If serious adverse events are reported, the Investigator is to report 
them to the Sponsor within 24 hours following the Investigator’s knowledge of the 
event using the paper-based Serious Adverse Event Report Form.  
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 the 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 the 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, ECs, and Investigators. 


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Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
An Investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the Sponsor will file it along with the IB and will notify the EC, 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 after the start of study treatment and 
until 90 days after the dosing. 
If a pregnancy and/or lactation 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. 
7.5.2. 
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 test at the times indicated in the Schedule of 
Assessments in Appendix 8. For all female subjects, a pregnancy test and 
follicle-stimulating hormone screen for postmenopausal status will be performed at 
the times indicated in the Schedule of Assessments in Appendix 8. 


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An Investigator (or designee) will perform a clinical assessment of all clinical 
laboratory data. 
7.5.3. 
Vital Signs 
Supine BP, 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 BP 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. 
7.5.4. 
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 once if either of the following 
criteria apply: 
• QTcF >500 msec 
• QTcF change from the baseline (predose) is >60 msec. 
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. 
7.5.5. 
Physical Examination 
A full PE or symptom-directed PE will be performed at the timepoints specified in the 
Schedule of Assessments in Appendix 8. The PE will also include a neurological 
exam. The neurological examination should include an assessment of mental status, 
level of consciousness, cranial nerve function, motor function, sensory function, 
reflexes, and coordination. 
8. SAMPLE SIZE AND DATA ANALYSIS 
  
8.1. 
Determination of Sample Size 
Approximately 32 subjects will be enrolled in 4 groups (  subjects per group).  
With  subjects in each group receiving AMG 592, there is an 
 chance of 
 
 experiencing an adverse event with a true incidence rate of 
 
chance of 
 experiencing an adverse event with 
 true incidence 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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rate. With a total of 32 subjects expected to receive AMG 592 across 4 cohorts, there 
is a 
 chance of 
 experiencing an adverse event with a true 
incidence rate of 
 and the chance of 
 experiencing an adverse 
event increases to 
 with a true incidence rate of 
, 
respectively. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of AMG 592 
and have evaluable PK data.  
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of AMG 592 
and have evaluable PD data. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of 
AMG 592 and have at least 1 postdose safety assessment. 
8.3. 
Pharmacokinetic Analyses 
The serum PK parameters of AMG 592 will be calculated using standard 
noncompartmental methods. 
The primary PK parameters are Cmax, tmax, AUClast, and AUCinf for AMG 592. All 
other PK parameters will be regarded as secondary and will not be subject to 
inferential statistical analysis. 
Additional PK parameters may be calculated. Specific details will be presented in the 
Statistical Analysis Plan for this study. 
 
 
  
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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8.5. 
Anti-AMG 592 and Anti-IL-2 Analyses 
The formation of anti-AMG 592 and anti-IL-2 antibodies will be summarized 
descriptively. The incidence and percentage of subjects who develop antidrug 
antibodies (binding and if positive, neutralizing) at any time will be tabulated by 
treatment group. 
8.6. 
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.  
No imputation will be done for safety assessments, and endpoints for clinical 
laboratory tests and vital signs will be summarized. 
8.7. 
Interim Analysis 
No interim analyses are planned for this study.  
9. REFERENCES 
1. Amgen, Inc. Efavaleukin Alfa (AMG 592; Inflammatory Diseases) – 
Investigator’s Brochure. (Version 5.0). 17 December 2020. 
2. Yu A, Snowhite I, Vendrame F, et al. Selective IL-2 responsiveness of regulatory 
T cells through multiple intrinsic mechanisms support the use of low-dose IL-2 
therapy in Type-1 diabetes. Diabetes. Published online: 09 January 2015 (doi: 
10.2337/db 14-1322). 
3. Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of 
regulatory T cell differentiation. Nature. 2007;445:771-775. 
4. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function to 
interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 
2005;6:1142-1151. 
 


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10. APPENDICES 


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Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Adverse Events 
Definition of Adverse Event 
Adverse Event Definition 
• 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.  
• 
Note: An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device, or procedure. 
• 
Note: Treatment-emergent adverse event will be defined in the Statistical Analysis Plan. 
Events Meeting the Adverse Event Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiological scans, vital signs measurements), 
including those that worsen from baseline, that are considered clinically significant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication. Overdose per se will not be reported as an adverse 
event/serious adverse event unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses are to be reported regardless of sequelae. 
Events NOT Meeting the Adverse Event Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the adverse event. 


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• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. For instance, drug-induced 
hepatitis that resolved without evidence of hepatic failure would not be considered life-
threatening even though drug-induced hepatitis can be fatal. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are an adverse event. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious. Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term “disability” means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 


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Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition. These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
• 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
Investigator to review all documentation (eg, hospital progress notes, laboratory, and 
diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant adverse event/serious adverse event 
information in the event electronic case report form (eCRF). 
• 
The Investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to the investigational product(s) and/or study-mandated 
procedures, and 
o Action taken. 
• 
If the severity of an adverse event changes from the date of onset to the date of resolution, 
record as a single event with the worst severity on the appropriate eCRF.  
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records 
to Sponsor in lieu of completion of the appropriate eCRF page. 


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• 
If specifically requested, the Investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records. In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse event. 


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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The Investigator will make an assessment of severity for each adverse event and serious adverse 
event reported during the study. The assessment of severity will use the following definitions: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated, usually transient and may 
require only minimal treatment or therapeutic intervention. The event does 
not generally interfere with usual activities of daily living. 
MODERATE 
Discomfort enough to cause interference with usual activity causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Usually alleviated with additional specific therapeutic intervention. 
SEVEREa 
Incapacitating with inability to work or interrupts usual activities of daily 
living, or significantly affects clinical status, or may require intensive 
therapeutic intervention. 
a An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of a serious adverse event, NOT when it is rated as severe. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between investigational product(s), 
protocol-required therapy and/or study-mandated procedure and each occurrence of each 
adverse event/serious adverse event. 
• 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study treatment administration will be 
considered and investigated. 


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• 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each adverse event/serious adverse event, the Investigator must document in the medical 
notes that he/she has reviewed the adverse event/serious adverse event and has provided an 
assessment of causality. 
• 
There may be situations in which a serious adverse event has occurred and the Investigator 
has minimal information to include in the initial report. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the serious adverse event data. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
• 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a subject is permanently withdrawn from protocol-required therapies because of a serious 
adverse event, this information must be submitted to the Sponsor. 
• 
If a subject dies during participation in the study, the Investigator will provide the 
Sponsor with a copy of any post-mortem findings including histopathology.  
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated serious adverse event data to the Sponsor within 24 
hours of receipt of the information. 


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Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Paper Serious Adverse Event Report Form 
• 
Facsimile transmission of the Serious Adverse Event Report Form (see Figure 2) is the 
preferred method to transmit this information. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the Serious Adverse Event Report Form sent by overnight mail 
or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the Serious Adverse Event Report Form within the designated reporting time 
frames. 


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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 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Bilirubina 
Gamma-glutamyl transferase 
Glucose 
HbA1C 
Inorganic phosphate 
Potassium  
QuantiFERON-TB Gold test  
Sodium  
Total CO2 (measured as 
bicarbonate) 
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 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
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 virus 
(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 test  
Follicle-stimulating hormoneb 
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 
Creatine kinase MB fractionc  
a Includes total, direct, and indirect.  
b Only analyzed at Screening. 
c Only analyzed at Screening and Check-in.  
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 
6 
45 
Serology 
3.5 
1 
3.5 
Serum FSH 
4 
1 
4 
Serum pregnancy test 
4 
1 
4 
AMG 592 
pharmacokinetics 
4 
15 
60 
Lymphocyte subsets 
4 
5 
20 
Biomarker development 
samples 
4 
7 
28 
Anti-AMG 592 and 
anti-IL-2 Antibodies 
4 
4 
16 
Total: 
180.5 
FSH = follicle-stimulating hormone; IL-2 = interleukin 2 
If additional 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. 
Definitions  
Women of Childbearing Potential: 
Premenopausal females who are anatomically and physiologically capable of becoming 
pregnant following menarche.  
Women of Non-Childbearing 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.  
 


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Contraception Requirements 
Female Subjects  
Female subjects who are of non-childbearing potential will not be required to use contraception. 
Female subjects of childbearing potential must be willing to use 2 methods [1 primary (highly 
effective) and 1 secondary method] of birth control from the time of signing the informed 
consent form until 90 days after the EOS visit.  
Primary (highly effective) methods of contraception include:  
• hormonal injection (as prescribed)  
• combined oral contraceptive pill or progestin/progestogen-only pill associated with 
inhibition of ovulation (as prescribed) without supplementary iron (ie, Loestrin Fe, Junel 
Fe, and Lo Loestrin Fe are prohibited) 
• combined hormonal patch (as prescribed)  
• combined hormonal vaginal ring (as prescribed)  
• surgical method performed at least 3 months prior to the Screening visit:  
o Bilateral tubal ligation with confirmation of surgical success 
o Regulatory approved method of hysteroscopic bilateral tubal occlusion with 
confirmation of occlusion of the fallopian tubes 
• hormonal implant  
• hormonal or non-hormonal intrauterine device (IUD or IUS) 
• vasectomized male partner (sterilization performed at least 90 days prior to the Screening 
visit, with verbal confirmation of surgical success, and the sole partner for the female 
subject).  
Secondary (barrier) methods of contraception include:  
• male condom with spermicide  
• female condom with spermicide  
• over-the-counter sponge with spermicide  
• cervical cap with spermicide (as prescribed)  
• diaphragm with spermicide (as prescribed).  
Female subjects should refrain from donation of ova from Check-in (Day -1) until 90 days after 
the EOS visit. 


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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  
• surgical method (bilateral tubal ligation or regulatory approved method of hysteroscopic 
bilateral tubal occlusion)  
• hormonal implant  
• hormonal or non-hormonal IUD  
• 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 informed consent 
form (ICF) until 90 days after the EOS visit.  
 


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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 
• The 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). The 
form must be submitted to Amgen Global Patient Safety within 24 hours of learning of a 
subject’s pregnancy. (Note: Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
• After obtaining the female subject’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 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 
events 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. 


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• 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 4.5 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 
form (see Figure 3) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy. (Note: Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions local 
privacy laws). 
• The Investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
• After obtaining the female partner’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the pregnancy 
questionnaires. This information will be forwarded to Amgen Global Patient Safety. 
• Generally, infant follow up will be conducted up to 12 months after the birth of the child 
(if applicable).  
• Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for procedure. 
Collection of Lactation Information 
• The Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 90 days after the EOS. 


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Protocol Version 1.0, 01 April 2021 
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• 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 authorization for release of mother and infant health 
information, the Investigator will collect mother and infant health information and complete the 
lactation questionnaire on any female subject who breastfeeds while taking protocol-required 
therapies through 90 days after discontinuing protocol-required therapies. 


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
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Figure 3: 
Pregnancy Notification Form 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8448873 
Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
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Figure 4: 
Lactation Notification Form 
 
 


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Protocol Version 1.0, 01 April 2021 
Page 55 of 65 
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 (CIOMS) 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 must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC 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 or any nonsubstantial changes, as defined by 
regulatory requirements.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the EC. 
• Notifying the EC of serious adverse events or other significant safety findings as 
required by EC 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 EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 56 of 65 
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. 
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 Ethics Committee 
(EC) 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.  


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 57 of 65 
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 21 days from the previous ICF signature date. 
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. 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 electronic case report form (eCRF) demographics page, in addition to the unique 
subject identification number, include the age at time of enrollment. 
For serious adverse events reported to the Sponsor, subjects are to be identified by their 
unique subject identification number, (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 EC 
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. 


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
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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. 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 electronic CRF (eCRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their unique 
subject identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in confidence by 
the Investigator, except as described below. 
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.  


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
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• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The contract research organization (CRO) 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 the study site archive for at least 5 years after 
the end of the study 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 CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 60 of 65 
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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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 61 of 65 
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:  
• Prior and/or concurrent diseases or illness 
• Exposure to environmental and/or industrial chemical agents  
• Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
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• Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
• Concomitant use of medications (including nonprescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
• Viral serologies 
• Creatine phosphokinase, haptoglobin, lactate dehydrogenase, and peripheral blood 
smear 
• Appropriate liver imaging if clinically indicated 
• Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
• Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist). 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or 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 


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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 63 of 65 
• 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: 
• 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. 
 


Protocol 
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Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 64 of 65 
Appendix 8: Schedule of Assessments 
PROCEDURE 
Screening Check-in 
 
Treatment Period 
 
 
Resident at the Clinical Research Unit 
 
 
 
 
 
 
 
 
 
Study Day 
-28 to -2 
-1 
1 
1 
1 
1 
1 
2 
3 
4 
5 
6 
8 
11 
15 
22 
29 43a (EOS)/ET 
Relative to Dosing (Hours) 
 
 
Pre 
0 
6 
12 
16 
24 
48 
72 
96 
120 168 240 
336 
504 
672 
1008 
GENERAL AND SAFETY ASSESSMENTS 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-house Residencyb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
Medical History 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsf 
X 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
X 
 
X 
 
X 
Adverse Eventsg 
 
 
 
 
 
 
Serious Adverse Eventsh 
X 
 
Concomitant Therapy Reviewi 
 
 
LABORATORY ASSESSMENTS 
 
Pregnancy Testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry and Hematologyk 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
eGFRl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIOMARKER AND IMMUNOLOGICAL ASSESSMENTS 
Lymphocyte Subsets 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Biomarker Development Samples 
 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Anti-AMG 592 and Anti-IL-2 Antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
PHARMACOKINETIC ASSESSMENTS 
 
AMG 592 Serum PK Collectionn 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STUDY TREATMENT 
 
AMG 592 Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 
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Covance Study: 8448873 
Amgen Protocol: 20200102 
Protocol Version 1.0, 01 April 2021 
Page 65 of 65 
Abbreviations: CRU = clinical research unit; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; FSH = follicle-stimulating hormone; 
PE = physical examination; PK = pharmacokinetic 
a Subjects who test positive at the EOS timepoint for neutralizing antibodies to IL-2 or binding antibodies with potentially antibody-mediated clinical sequelae that are considered 
potentially related to an anti-AMG 592 antibody response will be asked to return for additional follow-up testing every 3 months until antibodies are no longer detectable or up to 
12 months’ post administration of AMG 592 (whichever is shorter). 
b In-house residency from Day -1 through the completion of all assessments on Day 3. Solid line indicates time that subjects are required to stay in the CRU. Dashed line indicates 
that subjects may stay in the CRU after Day 3 until a maximum of Day 11 if they choose (to reduce travel and accommodation burden on subjects). 
c Physical examination to include a neurological examination. A full PE will be conducted at Screening. A symptom-directed PE will be conducted on Days -1, 3, 11, 22, 29, 
and 43/EOS. 
d Interim medical history only. 
e Electrocardiogram (ECG) will be single 12-lead ECG, prior to blood draws or invasive procedures.  
f Supine blood pressure (BP), supine heart rate, respiratory rate, and oral body temperature. Heart rate and BP will be measured using the same arm for each reading after the 
subject has been resting in the supine position for at least 5 minutes. 
g Adverse events will be recorded from initiation of study treatment on Day 1 until the EOS. Any events prior to study drug administration but deemed by the Investigator to be 
related to study procedures will be reported as adverse events. 
h Serious adverse events will be recorded from the time the subject signs the informed consent form until the EOS. 
i Prior and concomitant medication administration will be recorded beginning at informed consent. Also, all Investigator-approved medications taken by a subject within 30 days or 
5 half-lives (whichever is longer) before Day 1 for over-the-counter or prescription medications, and 30 days prior to Check-in for herbal medicines (eg, St. John’s wort), 
vitamins, or supplements will be recorded on the subject’s electronic case report form. 
j 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. 
k Subjects will be fasted overnight (at least 8 hours) before collection of blood samples for clinical laboratory evaluations. 
l The eGFR will be calculated using the Modification of Diet in Renal Disease equation.
m Performed in females only.
n Blood samples for determination of AMG 592 serum concentrations and PK parameters will be collected: Predose; 6, 12, and 16 hours postdose; and on Days 2 (24 hours
postdose), 3, 4, 5, 6, 8, 11, 15, 22, 29, and 43 (EOS) following administration of AMG 592 on Day 1. The postdose samples collected on Days 1 and 2 (6, 12, 16, and 24 hour
samples) will have a sampling window of ± 30 minutes, postdose samples collected on Days 3 and 4 will have a sampling window of ± 6 hours, postdose samples collected on
Days 5 through Day 15 will have a sampling window of ± 1 day, postdose samples taken on Days 22 and 29 will have a sampling window of ± 2 days, and postdose samples
taken on Day 43 (EOS) will have a sampling window of ± 4 days. Times of all PK samples will be recorded to the nearest minute.

SAP_001.pdf: 
 
 
TITLE PAGE 
Statistical Analysis Plan 
 A Phase 1, Open-label, Sequential-group, Single-dose Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of AMG 592 Administered 
Subcutaneously in Healthy Chinese, Japanese, and Caucasian Subjects 
SAP Status: Final 
SAP Version: 3.0 
SAP Date: 20May2022 
Investigational Medicinal Product: AMG 592 (efavaleukin alfa) 
Protocol Reference: 20200102 
Covance Study: 8448873 
Sponsor: 
Amgen, Inc.  
One Amgen Center Drive 
Thousand Oaks, California 91320 USA 
Study Site: 
Covance Leeds Clinical Research Unit 
Springfield House, Hyde Street,  
Leeds, LS2 9LH, 
UK 
 
 
 
 
Principal Investigators: 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 
PPD


SAP 
CONFIDENTIAL 
Covance Study: 8448873 
Protocol Reference: 20200102 
Final Version 3.0, 20May2022 
Page 2 of 22 
 
 
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 .................................................................................................... 7 
4. STUDY DESIGN ........................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION .................................................................................10 
6. STUDY TREATMENTS ...............................................................................................10 
7. DEFINITIONS OF POPULATIONS..............................................................................10 
7.1. All Subjects Population ...........................................................................................11 
7.2. Safety Population ....................................................................................................11 
7.3. Pharmacokinetic Population.....................................................................................11 
7.4. Pharmacodynamic Population ..................................................................................11 
8. STATISTICAL METHODOLOGY................................................................................11 
8.1. General ...................................................................................................................11 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ................................................................................................................12 
8.1.2. Calculation of the Summary Statistics ................................................................12 
8.1.3. Repeat and Unscheduled Readings.....................................................................13 
8.1.4. Definitions of Baseline, Change from Baseline, Percent Change from Baseline and 
Fold Change from Baseline .........................................................................................13 
8.2. Subject Disposition and Population Assignment .......................................................14 
8.3. Screening Demographics and Baseline Characteristics ..............................................14 
8.4. Prior and Concomitant Medication ...........................................................................14 
8.5. Pharmacokinetic Assessments ..................................................................................14 
8.5.1. Pharmacokinetic Analysis .................................................................................14 
8.5.2. Presentation of Pharmacokinetic Data ................................................................16 
8.5.3. Pharmacokinetic Statistical Methodology...........................................................17 
 
 
CCI


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Covance Study: 8448873 
Protocol Reference: 20200102 
Final Version 3.0, 20May2022 
Page 3 of 22 
 
 
ST-AD-031 Version 02 
 
 
8.7. Safety and Tolerability Assessments ........................................................................18 
8.7.1. Adverse Events .................................................................................................18 
8.7.2. Clinical Laboratory Parameters..........................................................................20 
8.7.3. Vital Signs Parameters ......................................................................................20 
8.7.4. 12-lead Electrocardiogram Parameters ...............................................................20 
8.7.5. Antibodies ........................................................................................................20 
8.7.6. Other Assessments ............................................................................................20 
8.7.7. Safety and Tolerability Statistical Methodology .................................................20 
9. INTERIM ANALYSES .................................................................................................21 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........21 
11. REFERENCES ............................................................................................................21 
12. APPENDICES .............................................................................................................22 
Appendix 1: 
Document History............................................................................22 
 
LIST OF IN-TEXT TABLES AND FIGURES 
  
Figure 1: 
Study Design .................................................................................................... 9 
 
CCI


SAP 
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Covance Study: 8448873 
Protocol Reference: 20200102 
Final Version 3.0, 20May2022 
Page 4 of 22 
 
 
ST-AD-031 Version 02 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
ADaM 
Analysis Data Model 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the serum concentration-time curve 
AUCinf 
area under the serum concentration-time curve from time zero to 
infinity 
AUClast 
AUC from time zero to the last quantifiable concentration 
BLQ 
below the limit of quantification 
CD4 
cluster of differentiation 4 
CD8 
cluster of differentiation 8 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent total serum clearance 
Cmax 
maximum observed serum concentration 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
Foxp3 
forkhead box P3 
GLSM 
geometric least squares mean 
ICF 
informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
LLOQ 
lower limit of quantification 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRTinf 
mean residence time observed from time zero to infinity 
NK 
natural killer 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PK 
pharmacokinetic(s) 


SAP 
CONFIDENTIAL 
Covance Study: 8448873 
Protocol Reference: 20200102 
Final Version 3.0, 20May2022 
Page 5 of 22 
 
 
ST-AD-031 Version 02 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SEM 
standard error of the mean 
SD 
standard deviation 
SDV 
source document verification 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time of the maximum observed concentration 
Tcon 
Conventional T Cells 
Treg 
Regulatory T Cells 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  


SAP 
CONFIDENTIAL 
Covance Study: 8448873 
Protocol Reference: 20200102 
Final Version 3.0, 20May2022 
Page 6 of 22 
 
 
ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP is to provide details of statistical analysis that have been outlined within the clinical 
study protocol for study 20200102 (Final Version dated 01 April 2021, Amendment 1 dated 
08 December 2021, Amendment 2 dated 28 April 2022) and electronic case report form 
(eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), pharmacodynamic 
(PD), 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 592 after single subcutaneous (SC) administration in healthy 
Chinese, Japanese, and Caucasian subjects.  
The secondary objectives of the study are:  
• 
to evaluate the safety and tolerability of AMG 592 after single SC administration in 
healthy Chinese, Japanese, and Caucasian subjects.  
• 
to evaluate the incidence of anti-AMG 592 and anti-IL-2 antibodies in healthy Chinese, 
Japanese, and Caucasian subjects after single SC administration of AMG 592.  
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3. STUDY ENDPOINTS  
The primary endpoints of the study are PK parameters for AMG 592:  
• 
maximum observed serum concentration (Cmax)  
• 
area under the serum concentration-time curve (AUC) from time zero to the last 
quantifiable concentration (AUClast)  
• 
area under the serum concentration-time curve from time zero to infinity (AUCinf).  
• 
time of the maximum observed concentration (tmax)  
The secondary endpoints of the study are:  
• 
treatment-emergent adverse events (AE) and serious adverse events (including clinical 
significant changes in physical examination [PE]) 
• 
clinical laboratory tests  
• 
vital signs  
• 
anti-AMG 592 and anti-IL-2 antibody formation 
 
 
 
 
 
4. STUDY DESIGN  
This will be a Phase 1, single-center, open-label, sequential-group study to investigate the 
safety, tolerability, and PK of a single SC dose of AMG 592 in 2 groups of healthy Chinese 
subjects and 1 group of healthy Japanese subjects. In addition, a group of healthy Caucasian 
subjects will be evaluated at the high dose level for comparison. 
Approximately 32 subjects will be enrolled in total, with  subjects in each of the following 
4 groups: 
 Group 1: Chinese subjects (n) will receive 
 AMG 592 
 
 SC injection 
 Group 2: Chinese subjects (n) will receive 
 AMG 592 
 
 SC injection 
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 Group 3: Japanese subjects (n) will receive 
 
) SC injection 
 Group 4: Caucasian subjects (n) will receive 
 
) SC injection. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to dose administration. 
Under the initial study design and plan prior to Amendment 2 of the protocol, 
 subjects 
in Group 1 and all subjects in Groups 3 and 4 had been enrolled, dosed, and had remained in 
the CRU up through the earliest discharge day on Day 3. Due to the occurrence of adverse 
events in subjects administered with AMG 592 reported thus far in the study after day 4 and 
during the period after discharge from the CRU, enrollment of the remaining 
subjects in 
Group 1 was placed on temporary hold. The intention of the hold was to allow a full 
evaluation of emerging safety data and to prepare protocol amendment 2. 
Under Protocol Amendment 2, the overall study design and plan will be conducted as 
follows, for the remaining  subjects in Group 1 (Chinese cohort, 
 and all subjects in 
Group 2 (Chinese cohort, 
): 
Eligible subjects will be admitted into the CRU for Check-in on Day -1 and be confined to 
the CRU until clinic discharge on Day 7. Individual subjects may be required to remain in the 
CRU for safety observations beyond Day 7 (to a maximum of Day 11) at the discretion of the 
Investigator, based on the emergence and progression of adverse events and other signs and 
symptoms requiring monitoring. Each subject will participate in 1 treatment group only. 
Chinese subjects will be assigned to Group 1 or Group 2 in a sequential manner. Group 1 will 
be enrolled and dosed first, and will have postdose safety observations performed for at least 
14 days prior to initiation of dosing in Group 2 to allow sufficient time for an adequate safety 
review. 
A full review of all available safety and tolerability data from the study including Group 1 
(Chinese cohort, 
) will be performed by the Investigator and Sponsor to ensure it is 
safe to proceed with the planned dose escalation in Group 2 (Chinese cohort, 
 
Japanese and Caucasian subjects were assigned to Groups 3 and 4, respectively, according to 
the planned enrollment and study design prior to Amendment 2 of the protocol. Aside from 
the sequential conduct for Groups 1 and 2, there is no priority or required order for conduct of 
the different ethnic groups. 
Serial blood samples will be collected for determination of AMG 592 serum concentrations, 
PK parameters, and PD markers. 
For subjects to be enrolled under Amendment 2, after discharge from the CRU on Day 7, 
subjects will return for outpatient visits on Days 8, 11, 15, 22, 29, and the end of study (EOS) 
visit on Day 43. (For subjects enrolled prior to Amendment 2 and discharged on Day 3, 
outpatient visits also included Days 4, 5, and 6.) It is anticipated that many subjects will be 
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traveling a great distance to the CRU in order to participate in the study; therefore, to reduce 
unnecessary travel and ease the burden on subjects needing to find local accommodations for 
the frequent outpatient visits in the first 2 weeks of the study, subjects may reside in the CRU 
after clinic discharge on Day 7 through a maximum of Day 11. In addition to this elective 
option to remain in the CRU, individual subjects may be required to remain in the CRU 
beyond Day 7 (to a maximum of Day 11) at the discretion of the Investigator, based on the 
emergence and progression of adverse events or signs/symptoms of other adverse drug 
reactions. To summarize, a subject may leave the CRU after discharge procedures on Day 7, 
unless required to stay by the Investigator or, if not required to stay, may elect to stay 
voluntarily; in either case, residence in the CRU may be through a maximum of Day 11. 
Subjects who remain in the CRU beyond Day 7 will have the applicable scheduled outpatient 
procedures performed while resident. A subject’s participation in the study will conclude at 
the completion of the EOS visit; however, subjects who test positive at EOS for neutralizing 
antibodies to IL-2 or binding antibodies with potentially antibody-mediated clinical sequelae 
will be asked to return for additional follow-up testing every 3 months until antibodies are no 
longer detected or up to 12 months ( 4 weeks) post administration of AMG 592 (whichever 
is shorter). 
The total duration of study participation for each subject (from screening through the EOS 
visit) is anticipated to be approximately 10 weeks. 
The start of the study is defined as the date the first subject signs an informed consent form 
(ICF). The point of enrollment occurs at the time of subject number allocation. 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  
 
 


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Note: Dashed line indicates that subjects may remain in the CRU beyond scheduled discharge on Day 7, as noted in footnote 
a. Outpatient visit procedures will be performed on an inpatient basis for subjects who are resident at the CRU on the 
scheduled outpatient visit days. 
 
a The scheduled day of discharge is Day 7. Subjects may reside at the CRU after discharge on Day 7 until a maximum of 
Day 11, to reduce the travel and accommodation burden on subjects. In addition, the Investigator may require a subject to 
remain in the CRU after Day 7 (to a maximum of Day 11) based on the emergence and progression of adverse events or 
clinical signs and symptoms of adverse drug reaction. (For subjects enrolled prior to Amendment 2 of the protocol, the 
schedule day of discharge was Day 3.) 
b The maximum planned in-clinic residence for a given subject is 12 days (Day -1 to Day 11), whether by subject choice for 
lodging and accommodation purposes or as required by the Investigator based on adverse event/s or clinical signs and 
symptoms of adverse drug reaction. 
5. SAMPLE SIZE JUSTIFICATION  
Approximately 32 subjects will be enrolled in 4 groups (  subjects per group).  
With 
subjects in each group receiving AMG 592, there is an 
chance of 
 
experiencing an adverse event with a true incidence rate of 
 chance 
of 
 experiencing an adverse event with 
true incidence rate. With a total 
of 32 subjects expected to receive AMG 592 across 4 cohorts, there is a 
 chance of  
 experiencing an adverse event with a true incidence rate of 
 and the chance 
of 
 experiencing an adverse event increases to 
 with a true 
incidence rate of 
, respectively.  
6. STUDY TREATMENTS  
In addition to the 4 planned study treatments, an overall for 
 AMG 592 will also be 
presented in the TFLs. The study treatment names, abbreviations, and ordering to be used in 
the TFLs are presented in Table 1. 
Table 1: 
Presentation of Study Treatment Groups in TFLs  
Treatment Group 
Order in TFLs 
Chinese 
 AMG 592  
1 
Chinese 
 AMG 592 
2 
Japanese 
 AMG 592 
3 
Caucasian 
 AMG 592 
4 
Overall 
 AMG 592 
5 
 
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.  
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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 592 and 
have at least 1 postdose safety assessment.   
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of AMG 592 and 
have evaluable PK data.  
7.4. Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of AMG 592 and 
have evaluable PD data. 
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database, including 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 1.1 (or higher if a new 
version is issued during the study). Pinnacle 21 Community (version 3.1.2 or higher) 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 
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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 COVID-19 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. 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, with 
the exception of the 12-lead ECG outlier analysis (see Section 8.7.4).   
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.4) and 12-lead ECG outlier analysis (see Section 8.7.4).  
8.1.4. Definitions of Baseline, Change from Baseline, Percent Change from Baseline and 
Fold Change from Baseline  
The baseline will be defined as the value recorded prior to dosing. If the date/time of the 
value is incomplete or missing, it will be excluded from the baseline calculation, unless the 
incomplete date/time indicates the value was recorded prior to dosing.  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint.   
Fold Change from baseline = (Final Value / Baseline Value); 
The summary statistics for change from baseline and fold changes from baseline will be 
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the individual changes from baseline for all subjects, rather than difference between the mean 
value at the postdose timepoint and mean value at baseline).  
See Section 8.1.3 for more detail on handling repeat and unscheduled readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment groups will be provided, based on the safety population.  
8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by treatment groups 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 serum 
concentrations of AMG 592 using noncompartmental methods in validated software program 
Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUClast 
hr*ng/mL 
area under the concentration-time curve from time zero to time 
of last quantifiable concentrationb 
AUCinf 
hr*ng/mL 
area under the concentration-time curve from time zero 
extrapolated to infinityc 
%AUCextrap 
% 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
Cmax 
ng/mL 
maximum observed concentration 
CL/F 
L/hr 
apparent total body clearance, calculated as Dose/AUCinf 
MRTinf 
hr 
mean residence time observed from time zero to infinity 


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Vz/F 
L 
apparent volume of distribution based on the terminal phase, 
calculated as Dose/(AUCinf*z) 
tmax 
hr 
time of maximum observed concentration 
tlast 
hr 
time of the last quantifiable concentration 
t1/2 
hr 
apparent terminal elimination half-life 
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. 
Pharmacokinetic analysis will be carried out where possible using actual dose administered 
(µg) 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, and t1/2) 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 
hr 
end of exponential fit 
λz Lower 
hr 
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 


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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 clinical study report (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) will be 
excluded from the summary statistics.  
8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Serum 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 parameter 
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 serum 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 listing 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 ±10%, 
the serum concentration will be flagged.  
For serum concentration data the following rules will apply: 


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● 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  
No inferential statistical analyses are planned.  
 
 
 
  
 
 
 
 
 
 
   
 
  
 
  
 
  
 
  
 
  
  
 
  
 
 
 
  
 
  
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8.7. Safety and Tolerability Assessments  
8.7.1. 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  
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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  
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.  


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8.7.2. Clinical Laboratory Parameters  
All clinical laboratory parameters, their changes from baseline, 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 and boxplots by treatment and timepoint will be provided by treatment group 
for clinical chemistry and hematology parameters, their changes from baseline, as applicable.  
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.  
8.7.3. Vital Signs Parameters  
All vital signs parameters, their changes from baseline, will be listed, as applicable; any value 
outside the clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided by treatment group 
for all vital signs parameters, their changes from baseline, as applicable.  
8.7.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters such as PR, QT and QTcF will be listed; any value outside the 
clinical reference range will be flagged. 
8.7.5. Antibodies 
The formation of anti-AMG 592 and anti-IL-2 antibodies will be summarized descriptively. 
The incidence and percentage of subjects who develop anti-AMG 592 antibodies and cross 
reactive anti-IL-2 antibodies (binding and if positive, neutralizing) will be summarized by 
treatment group. Furthermore, the incidence and percentage of subjects with treatment 
boosted anti-AMG 592 antibodies will also be summarized. In addition, subjects with 
positive binding and neutralizing anti-AMG 592 results will be listed individually with 
corresponding time points. 
8.7.6. Other Assessments  
Medical history will not be listed.   
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.7.7. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  


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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.  
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. Figg WD, Dukes GE, Lesesne HR et al. Comparison of quantitative methods to assess 
treatment: Pugh’s classification, indocyanine green, antipyrine, and dextromethorphan. 
Pharmacotherapy 1995; 15:693-700. 
5. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
 


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12. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change Summary/Reason for Changes 
Final Version 3.0 
NA 
NA; the first version. 
NA = not applicable