Clinical trial NCT03451422
Conditions: Systemic Lupus Erythematosus
Keywords: Efavaleukin Alfa Systemic lupus erythematosus Phase 1b
Sponsor: Amgen
Start date: 2018-04-10; Completion date: 2021-10-12
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and tolerability of subcutaneous (SC) dose administrations of Efavaleukin Alfa in participants with systemic lupus erythematosus (SLE).

Detailed description:

Arms: arm 1: Approximately 29 participants will be randomized in a 5:2 ratio (cohorts 1, 2, and 3) or in a 3:1 ratio (cohorts 4 and 5) to Efavaleukin Alfa or placebo in addition to standard of care therapy. Efavaleukin Alfa or placebo will be administered either weekly (QW) or biweekly (Q2W). arm 2: Approximately 29 participants will be randomized in a 5:2 ratio (cohorts 1, 2, and 3) or in a 3:1 ratio (cohorts 4 and 5) to Efavaleukin Alfa or placebo in addition to standard of care therapy. Efavaleukin Alfa or placebo will be administered either weekly (QW) or biweekly (Q2W).
Interventions: intervention 1: Efavaleukin Alfa intervention 2: Placebo
Intervention descriptions: intervention 1: Efavaleukin Alfa will be administered by subcutaneous (SC) injection in the abdomen, thigh or upper arm. intervention 2: The placebo will be administered by subcutaneous (SC) injection in the abdomen, thigh or upper arm.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 1 of 97 
CONFIDENTIAL 
 
Title Page 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled 
Phase 1b Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Immunogenicity of 
Multiple Ascending Subcutaneous Doses of 
AMG 592 in Subjects With Systemic Lupus 
Erythematosus 
Short Protocol Title: 
Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Immunogenicity of 
AMG 592 in Subjects with Systemic Lupus 
Erythematosus 
Protocol Number: 
20170103 
Investigational Product: 
AMG 592 
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen, Inc.  
Address: 
One Amgen Center Drive, 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
+1 (805) 447-1000 
Key 
Sponsor 
Contact 
Name: 
, MD 
Address: 
One Amgen Center Drive, 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
; 
Email Address: 
 
EudraCT Number: 
2017-002564-40 
NCT Number: 
NCT03451422 
Protocol Date: 
Document Version 
Date 
Original 
13 August 2017 
Amendment 1 
26 July 2018 
Amendment 2 
12 June 2019 
Amendment 3 
18 November 2019 
Amendment 4 
06 February 2020 
Superseding 
Amendment 4 
24 February 2020 
Amendment 5 
23 April 2020 
Superseding 
Amendment 5 
25 June 2020 
Approved 
 
 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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CONFIDENTIAL 
 
Version/Date: 
Data Element 
Standards Version 
 
5.0 
 
 
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; all other countries call 1-800-772-6436; Amgen’s general number 
in the US, 1-805-447-1000. 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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Investigator's Agreement: 
I have read the attached protocol entitled A Randomized, Double-blind, 
Placebo-controlled Phase 1b Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Multiple 
Ascending Subcutaneous Doses of AMG 592 in Subjects with Systemic Lupus 
Erythematosus, dated 25 June 2020, and agree to abide by all provisions set forth 
therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator 
Date (DD Month YYYY) 
 
Approved 
 
 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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Table of Contents 
Table of Contents .............................................................................................................. 4 
1. 
Protocol Synopsis..................................................................................................... 9 
2. 
Study Schema and Schedule of Activities .............................................................. 14 
2.1 
Study Schema ............................................................................................ 14 
2.2 
Schedule of Activities ................................................................................. 15 
3. 
Introduction ............................................................................................................ 19 
3.1 
Study Rationale .......................................................................................... 19 
3.2 
Background ................................................................................................ 19 
3.2.1 
Disease ....................................................................................... 19 
3.2.1.1 
Interleukin 2 and T Regulatory Cells in 
Systemic Lupus Erythematous ................................ 19 
3.2.1.2 
Low Dose Interleukin 2 in Inflammatory 
Disease .................................................................... 20 
3.2.1.3 
Clinical Experience With Low Dose IL-2 in 
Systemic Lupus Erythematosus ............................... 21 
3.2.2 
Amgen Investigational Product Background:  
AMG 592 .................................................................................... 21 
3.2.2.1 
Toxicology ................................................................ 22 
3.2.2.2 
Human Exposure ..................................................... 22 
3.3 
Risk Assessment ........................................................................................ 23 
4. 
Objectives, Endpoints and Hypotheses .................................................................. 24 
4.1 
Objectives and Endpoints ........................................................................... 24 
4.2 
Hypotheses ................................................................................................. 24 
5. 
Study Design .......................................................................................................... 25 
5.1 
Overall Design ............................................................................................ 25 
5.2 
Number of Subjects .................................................................................... 27 
5.2.1 
Replacement of Subjects ............................................................ 27 
5.2.2 
Number of Sites .......................................................................... 27 
5.3 
End of Study ............................................................................................... 27 
5.3.1 
End of Study Definition ............................................................... 27 
5.3.2 
Study Duration for Subjects ........................................................ 28 
5.4 
Justification for Investigational Product Dose ............................................. 28 
5.5 
Patient Input on Study Design .................................................................... 29 
6. 
Study Population .................................................................................................... 29 
6.1 
Inclusion Criteria ......................................................................................... 29 
6.2 
Exclusion Criteria ........................................................................................ 30 
6.3 
Lifestyle Restrictions ................................................................................... 34 
6.3.1 
Alcohol and Tobacco .................................................................. 34 
6.3.2 
Activity ........................................................................................ 34 
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Date:  25 June 2020 
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6.4 
Subject Enrollment ..................................................................................... 34 
6.5 
Screen Failures .......................................................................................... 35 
7. 
Treatments ............................................................................................................. 35 
7.1 
Treatment Procedures ................................................................................ 36 
7.1.1 
Investigational Products ............................................................. 36 
7.1.1.1 
Amgen Investigational Product:  AMG 592 .............. 36 
7.1.2 
Non-investigational Products ...................................................... 36 
7.1.3 
Medical Devices ......................................................................... 37 
7.1.4 
Other Protocol-required Therapies ............................................. 37 
7.1.5 
Other Treatment Procedures ...................................................... 37 
7.1.6 
Product Complaints .................................................................... 37 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ................................................ 37 
7.2 
Method of Treatment Assignment .............................................................. 38 
7.3 
Blinding ....................................................................................................... 38 
7.3.1 
Site Personnel Access to Individual Treatment 
Assignments ............................................................................... 38 
7.3.2 
Access to Individual Subject Treatment Assignments 
by Amgen or Designees ............................................................. 39 
7.4 
Dose Modification ....................................................................................... 39 
7.4.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules ........................................................................... 39 
7.4.1.1 
Dose Level Review Meetings ................................... 39 
7.4.1.2 
Dose Cohort Stopping Rules ................................... 39 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 41 
7.4.2.1 
Amgen Investigational Product:  AMG 592 .............. 41 
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules ........................ 41 
7.5 
Preparation/Handling/Storage/Accountability ............................................. 41 
7.6 
Treatment Compliance ............................................................................... 41 
7.7 
Treatment of Overdose ............................................................................... 41 
7.8 
Prior and Concomitant Treatment .............................................................. 41 
7.8.1 
Prior Treatment ........................................................................... 41 
7.8.2 
Concomitant Treatment .............................................................. 41 
7.8.2.1 
SLE Therapies ......................................................... 41 
7.8.2.2 
Corticosteroids ......................................................... 42 
8. 
Discontinuation Criteria .......................................................................................... 42 
8.1 
Discontinuation of Study Treatment ........................................................... 42 
8.2 
Discontinuation From the Study ................................................................. 43 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures ................................................................... 43 
8.2.2 
Reasons for Removal From Study ............................................. 43 
8.3 
Lost to Follow-up ........................................................................................ 44 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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9. 
Study Assessments and Procedures ..................................................................... 44 
9.1 
General Study Periods ............................................................................... 44 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 44 
9.1.2 
Treatment Period ........................................................................ 45 
9.1.3 
Follow-up/Safety Follow-up/End of Study ................................... 45 
9.2 
Description of General Study Assessments and Procedures ..................... 46 
9.2.1 
General Assessments ................................................................ 46 
9.2.1.1 
Informed Consent .................................................... 46 
9.2.1.2 
Demographics .......................................................... 46 
9.2.1.3 
Medical History ........................................................ 46 
9.2.1.4 
Physical Examination ............................................... 46 
9.2.1.5 
Physical Measurements ........................................... 46 
9.2.1.6 
Substance Abuse History ......................................... 46 
9.2.2 
Efficacy Assessments ................................................................. 47 
9.2.2.1 
Systemic Lupus Erythematosus Disease 
Activity Index-2000 ................................................... 47 
9.2.3 
Safety Assessments ................................................................... 47 
9.2.3.1 
Adverse Events ........................................................ 47 
9.2.3.2 
Vital Signs ................................................................ 50 
9.2.3.3 
Electrocardiograms .................................................. 50 
9.2.3.4 
Home Healthcare Services ...................................... 51 
9.2.4 
Clinical Laboratory Assessments ............................................... 52 
9.2.4.1 
Pregnancy Testing ................................................... 53 
9.2.4.2 
Human Immunodeficiency Virus, 
Hepatitis B Surface Antigen, and 
Hepatitis C Antibody ................................................ 53 
9.2.4.3 
Prespecified Biomarker Assessments ..................... 54 
9.2.5 
Pharmacokinetic Assessments ................................................... 54 
9.2.6 
Pharmacodynamic Assessments ............................................... 54 
9.2.7 
Pharmacogenetic Assessments ................................................. 54 
9.2.8 
Antibody Testing Procedures ..................................................... 55 
9.2.9 
Biomarker Development ............................................................. 55 
9.2.10 
Other Assessments .................................................................... 56 
9.2.10.1 
Tuberculosis Testing ................................................ 56 
9.2.10.2 
Peripheral Blood Mononuclear Cell ......................... 56 
10. 
Statistical Considerations ....................................................................................... 56 
10.1 
Sample Size Determination ........................................................................ 56 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 57 
10.2.1 
Analysis Sets .............................................................................. 57 
10.2.1.1 
Safety Analysis Set .................................................. 57 
10.2.1.2 
Pharmacokinetic Concentration Analysis 
Set ............................................................................ 57 
10.2.1.3 
Pharmacokinetic Parameter Analysis Set ................ 57 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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10.2.1.4 
Pharmacodynamic Analysis Set .............................. 57 
10.2.2 
Covariates .................................................................................. 57 
10.2.3 
Subgroups .................................................................................. 57 
10.2.4 
Handling of Missing and Incomplete Data .................................. 58 
10.3 
Statistical Analyses ..................................................................................... 58 
10.3.1 
Planned Analyses ....................................................................... 58 
10.3.2 
Methods of Analyses .................................................................. 58 
10.3.2.1 
General Considerations ........................................... 58 
10.3.2.2 
Efficacy Analyses  .................................................... 58 
10.3.2.3 
Safety Analyses ....................................................... 58 
10.3.2.4 
Other Analyses ........................................................ 59 
11. 
References ............................................................................................................. 61 
12. 
Appendices ............................................................................................................ 63 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 64 
Appendix 2.  Clinical Laboratory Tests ................................................................... 67 
Appendix 3.  Study Governance Considerations .................................................... 69 
Dose Level Review Meetings and Data Review Team ............................... 69 
Regulatory and Ethical Considerations ...................................................... 70 
Informed Consent Process ......................................................................... 71 
Data Protection/Subject Confidentiality ...................................................... 72 
Publication Policy ....................................................................................... 73 
Investigator Signatory Obligations .............................................................. 74 
Data Quality Assurance .............................................................................. 74 
Source Documents ..................................................................................... 75 
Study and Site Closure ............................................................................... 76 
Compensation ............................................................................................ 77 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .......................................................... 78 
Definition of Disease-related Event ............................................................ 78 
Definition of Adverse Event ........................................................................ 78 
Definition of Serious Adverse Event ........................................................... 79 
Recording Adverse Events, Disease-related Events 
(if applicable), and Serious Adverse Events ............................... 80 
Evaluating Adverse Events and Serious Adverse Events .......................... 80 
Reporting of Serious Adverse Event .......................................................... 82 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information .................................................................................. 86 
Definition of Females of Childbearing Potential .......................................... 86 
Collection of Pregnancy Information ........................................................... 87 
Collection of Lactation Information ............................................................. 89 
Appendix 6.  Sample Storage and Destruction ...................................................... 92 
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Protocol Number:  20170103 
Date:  25 June 2020 
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Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ................................................................................................... 94 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies due to Potential 
Hepatotoxicity ............................................................................. 94 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity ............................................................................. 95 
Drug-induced Liver Injury Reporting and Additional 
Assessments .............................................................................. 96 
 
List of Tables 
Table 2-1.  Schedule of Activities:  Screening and Treatment Period ............................. 15 
Table 2-2.  Schedule of Activities Follow-up ................................................................... 18 
... 23 
... 25 
... 28 
Table 7-1.  Dose Cohort Stopping Rules ........................................................................ 40 
Table 12-1.  Analyte Listing ............................................................................................. 67 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ............................................... 95 
 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................. 14 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 83 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 90 
 
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Product:  AMG 592 
Protocol Number:  20170103 
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1. 
Protocol Synopsis 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled Phase 1b Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity of Multiple Ascending Subcutaneous Doses of AMG 592 in 
Subjects with Systemic Lupus Erythematosus 
Short Protocol Title:  Safety, Tolerability, Pharmacokinetics, Pharmacodynamics 
and Immunogenicity of AMG 592 in Subjects with Systemic Lupus Erythematosus 
Study Phase:  1b 
Indication:  Systemic Lupus Erythematosus 
Rationale 
This is a double-blind, placebo-controlled, multicenter, phase 1b study to evaluate the 
safety, tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD), and 
immunogenicity of AMG 592 in subjects with systemic lupus erythematosus (SLE).  
This information will be used to determine the recommended phase 2 dose(s).  
Objective(s)/Endpoint(s) 
 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability 
of subcutaneous (SC) dose 
administrations of AMG 592 in subjects 
with systemic lupus erythematosus 
(SLE) 
• 
Treatment-emergent adverse events 
• 
Clinically significant changes in physical 
examinations, vital signs, and laboratory 
safety tests 
Secondary 
• 
To characterize the pharmacokinetic 
(PK) profile following treatment with 
AMG 592 
• 
AMG 592 serum concentration and PK 
parameters including, but not limited to, 
maximum observed concentration (Cmax), the 
time of maximum observed concentration 
(Tmax), and area under the concentration-time 
curve over a dosing interval (AUCtau) after 
the first and last doses 
• 
To evaluate anti-AMG 592 antibody 
formation 
• 
Incidence of anti-AMG 592 antibodies 
• 
Cross-reactivity of anti-AMG 592 antibodies 
with human interleukin-2 (IL-2) 
• 
Incidence of anti-AMG 592 and anti-IL 2 
neutralizing antibodies 
Exploratory 
 
• 
To explore the effect of 
treatment with AMG 592 on 
measures of inflammation at 
various time points 
• 
Change from baseline in anti-double 
stranded DNA (anti-dsDNA), and C3 
and C4 complements at all time points 
collected 
• 
To explore the effect of 
treatment with AMG 592 on 
measures of disease activity at 
various time points 
• 
SLEDAI-2K score and change from 
baseline at all time points collected 
• 
To evaluate the immunological 
effects of AMG 592 
• 
Fold changes from baseline of Treg, 
Tcon, and NK absolute cell counts 
(cells/µL) after AMG 592 
administration 
• 
Changes in Treg/Tcon ratio after 
AMG 592 administration 
 
Hypotheses 
AMG 592 will be safe and well tolerated in subjects with SLE. 
Overall Design 
This phase 1b study is a double-blind, placebo-controlled, multiple ascending dose 
(MAD) study to evaluate the safety, tolerability, PK, immunogenicity, and PD of 
AMG 592 in subjects with SLE.  Subjects will be treated for a total of 12 weeks after 
which they will be followed for an additional 6 weeks for safety and additional PK/PD 
data collection. 
Approved 
 
 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 11 of 97 
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Five dosing cohorts are planned for the study.  For cohorts 1, 2, and 3, subjects within a 
dosing-cohort will be randomized in a 5:2 ratio to AMG 592 (n = 5) or placebo (n = 2) as 
follows:  cohort 1 (
 µg 
 cohort 2 (
 µg 
 and 
cohort 3 (
 µg 
]), in addition to standard of care therapy.  For 
cohorts 4 and 5, subjects within a dosing-cohort will be randomized in a 3:1 ratio to 
AMG 592 (n = 3) or placebo (n = 1) as follows:  cohort 4 (
 µg 
 and cohort 
5 (
 µg 
 in addition to standard of care therapy.  Dosing cohorts will enroll 
sequentially.  A Dose Level Review Meeting (DLRM) will convene after the last subject in 
each cohort completes the week 4 visit.  The decision to dose the next cohort will be 
based on the aggregated review of safety data.  After incidents of interest (including 
selected adverse events or intolerable PD levels) are observed, a Bayesian logistic 
regression model (BLRM) will be implemented to model these events before each DLRM 
to aid dosing recommendations.  Dose Level Review Meeting members will be 
responsible for dosing recommendations, which may include escalation to the next 
planned dose or a new higher dose, escalation to an intermediate dose (a dose lower 
than the next planned dose), de-escalation to a lower dose; continuation, delay, or 
termination of dosing.  Additional dosing cohorts may be added and/or existing cohorts 
may be expanded based on emerging data.  Dose Level Review Meeting members may 
also consider available aggregated summaries of emerging PK and PD data.  Amgen 
DLRM members may consider safety, PK and PD data from other completed and 
ongoing phase 1b studies to aid dosing recommendations.  Emerging safety, PK, and 
PD data from ongoing AMG 592 studies may be used to support recommendations to 
skip dosing cohorts, reduce dosing cohort size or change doses for a given cohort or 
stop the study entirely. 
Number of Subjects 
Within each cohort subjects will be randomized to AMG 592 or placebo in a 5:2 ratio 
(cohorts 1, 2, and 3) or in a 3:1 ratio (cohorts 4 and 5).  It is planned that approximately 
29 subjects will be randomized, with 21 subjects randomized to AMG 592, and 
8 subjects randomized to placebo.  The total sample size may exceed 29 subjects and 
the number of subjects per cohort may exceed the planned cohort size if, following a 
DLRM recommendation or Amgen decision to evaluate additional doses (or further 
evaluate currently planned doses), dosing cohorts are added and/or existing cohorts are 
expanded, or subjects are replaced as per Section 5.2.1.  Additional subjects may be 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 12 of 97 
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enrolled in each cohort (following originally planned randomization ratio) to enable all 
screened eligible subjects to participate in the study.  
Summary of Subject Eligibility Criteria 
Subjects must be adults with SLE according to the Systemic Lupus International 
Collaborating Clinics (SLICC criteria) or by at least 4 of the 11 criteria of the 1997 
American College of Rheumatology (ACR) classification criteria for SLE, with a history of 
at least one of the following:  antinuclear antibody ≥ 1:80; or elevated anti-dsDNA 
antibodies.  Subjects must be on a SLE treatment for ≥ 12 weeks, may be taking 
≤ 3 SLE treatments, and have a stable dose for ≥ 4 weeks prior to day 1.  Subjects 
must have a prednisone dose ≤ 20 mg daily (or other equivalent OCS) with stable dose 
≥ 2 weeks prior to day 1.  Subjects must be free of infections and significant concurrent 
medical conditions and laboratory abnormalities including a negative test for 
tuberculosis, hepatitis B and C, human immunodeficiency virus, and urine drug and 
alcohol.  Women of childbearing potential must have a negative pregnancy test at 
screening and baseline and must agree to use a highly effective method of birth control.  
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
AMG 592 and placebo will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  Both are liquid 
formulations presented in highly similar glass vials and stored in the same manner.  
AMG 592 or placebo will be administered by SC injection 
. 
Five dose cohorts are planned (cohort 1:  
 µg 
 cohort 2:  
 µg 
 
cohort 3:  
 µg 
 cohort 4:  
 µg 
 and cohort 5:  
 µg 
 
Procedures 
Written informed consent must be obtained from all subjects before any study-specific 
screening procedures are performed.  The following procedures will occur per the 
schedule of activities:  medical and medication history, physical examination, physical 
measures, vital signs, electrocardiograms, prior and concomitant medication 
assessment, tuberculosis testing, urinalysis, and blood draw for serum chemistry, 
hematology, hepatitis B and C testing, human immunodeficiency virus testing, PK/PD, 
anti-AMG 592 antibodies, biomarker development and pharmacogenetics sample.  
Women of childbearing potential will have pregnancy tests performed at screening and 
at regular intervals during the study.  Safety assessments including adverse events, 
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Product:  AMG 592 
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Date:  25 June 2020 
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serious adverse events, and disease-related events, will be performed throughout the 
safety follow-up. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1 and Table 2-2. 
Statistical Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD, 
immunogenicity, and biomarker data.  Descriptive statistics on continuous 
measurements will include means, medians, Q1, Q3, standard deviations, and ranges, 
while categorical data will be summarized using frequency counts and percentages.  
Data will be presented and summarized by treatment and also by time as appropriate. 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Subject incidence 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 incidence of disease-related events, and fatal disease-related 
events, if applicable, will be tabulated by system organ class and preferred term. 
The analyses of safety laboratory endpoints will include summary statistics at selected 
time points by treatment group.  Shifts in grades of safety laboratory values between the 
baseline and the worst on-study value will be tabulated. 
For a full description of statistical analysis methods, please refer to Section 10. 
Click or tap here to enter text.  Enter Sponsor Name 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
 
DLRM = Dose Level Review Meeting; 
. 
Each of cohorts 1, 2, and 3 will plan to enroll 5 AMG 592:  2 placebo subjects and cohorts 4 and 5 will plan to enroll 3 AMG 592:  1 placebo subject.  Doses and 
size of treatment cohorts may change as determined by emerging safety data, Bayesian logistic regression model (BLRM), and pharmacokinetic/pharmacodynamic 
modeling.  
DLRM:  4 weeks after the last subject in cohort enrolled 
Treatment Period:  12 weeks  
 
Approved 
 
 
AMG 592 
 µg 
 or Placebo 
~
--!-r-----.--t---------; 
Treatment 
Follow-up 
Week 12 
Week 18 
~
------------"'--iL-_T"A_M_G-59_2
µ--:g:
_o_r-:-P-l_ac_e_b_o __ -:---F-0_1_1o_w_-_u_p_~, 
Treatment 
Week 12 
Week 18 
I 
3 1------------------------------------------------------
AMG 592 
 µg 
 or Placebo 
Follow-up 
Treatment 
Week 12 
Week 18 
AMG 592 
 µg
 or Placebo 
Follow-up 
Treatment 
_J 
Week 12 
Week 18 
EE}------------·--------------------·---
AMG 592 
 µg
 or Placebo 
Follow-up 
Treatment 
_J 
Week 12 
Week 18 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 15 of 97 
CONFIDENTIAL 
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities:  Screening and Treatment Period 
 
Screening (- 28) 
Day -1 
Treatment Period 
Study week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
Study day 
1m 
2m 3m 4m 8 11m 15 22 29 36 43 50 57 64 71 78 
85m 
86m 87m 88m 
Hours post dose 
Pre-
dose 0 
0.25
-2.0 6 12 24 48 72  
 
 
 
 
 
 
 
 
 
 
 
Pre-
dose 
(ET)k 0 
0.25
-2.0 6 12 24 48 
72 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Medical history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use 
X 
X 
X 
 
 
 
 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Strenuous Activity 
Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
ECGa 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-rayb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsc 
 
 
 
 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Serious adverse eventsc 
X 
X 
X 
 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Disease-related eventsc 
 
 
 
 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Prior therapies review 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
 
 
 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Page 1 of 3 
Footnotes are defined on the last page of the table 
 
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Page 16 of 97 
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Table 2-1.  Schedule of Activities:  Screening and Treatment Period 
 
Screening (-28) 
Day -1 
Treatment Period 
Study week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
Study day 
1m 
2m 3m 4m 8 11m 15 22 29 36 43 50 57 64 71 78 
85m 
86m 87m 88m 
Hours post dose 
Pre-
dose 0 
0.25
-2.0 6 12 24 48 72  
 
 
 
 
 
 
 
 
 
 
 
Pre-
dose 
(ETk) 0 
0.25
-2.0 6 12 24 48 
72 
LABORATORY ASSESSMENTS 
Serum and/or urine 
pregnancy testd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Tuberculosis teste 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug/alcohol screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B and Cf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C3 and C4 complementf 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Anti-dsDNA 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Antinuclear antibodyl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyf 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Chemistryf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
FSHg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
PBMCf 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
EFFICACY ASSESSMENTS 
SLEDAI-2K 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
PHARMACODYNAMIC ASSESSMENTS 
Lymphocyte subsetsh 
 
 
X 
 
 
 
 
X 
 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
PHARMACOKINETICS AND ANTIBODIES 
Pharmacokinetic samplesh 
 
 
X 
 
 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Anti-AMG 592 antibodyf 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
BIOMARKER AND PHARMACOGENETICS 
Biomarker development 
samplef 
 
 
X 
 
 
 
 
X 
 
X X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Pharmacogenetics samplei 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 3 
Footnotes are defined on the next page of the table 
 
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Product:  AMG 592 
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Table 2-1.  Schedule of Activities:  Screening and Treatment Period 
 
Screening (-28) 
Day -1 
Treatment Period 
Study week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
Study day 
1m 
2m 3m 4m 8 11m 15 22 29 36 43 50 57 64 71 78 
85m 
86m 87m 88m 
Hours post dose 
Pre-
dose 0 
0.25
-2.0 6 12 24 48 72  
 
 
 
 
 
 
 
 
 
 
 
Pre-
dose 
(ET)k 0 
0.25
-2.0 6 12 24 48 
72 
INVESTIGATIONAL PRODUCT ADMINISTRATION 
Investigational product QWj 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Investigational product 
Q2Wj 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
Page 3 of 3 
ECG = electrocardiogram; ET = early termination; FSH = follicle stimulating hormone; HIV = human immunodeficiency virus; PBMC = peripheral blood mononuclear 
cell; PK = pharmacokinetics; QW = every week; Q2W = every other week; SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000. 
a single ECG will be collected at screening and after day -1.  At day -1 (baseline) a triplicate ECG will be collected.  See Section 9.2.3.3. 
b Only for subjects with a positive tuberculosis test (ie, positive purified protein derivative [PPD] or a positive or indeterminate Quantiferon) 
c For subjects who complete the study at week 18, the visit includes all required safety follow-up data collection (see Table 2-2).  For subjects who terminate the study 
early (ie, prior to completing the week 18 visit), the safety follow-up visit 6 weeks (± 3 days) after the last dose of investigational product will be a visit to collect 
adverse events, serious adverse events, disease related events, ECG, hematology and concomitant medications only. 
d For women of childbearing potential, serum pregnancy test is required at screening.  All other pregnancy tests are urine. 
e Either a PPD or Quantiferon test will be done during screening. 
f Blood samples must be collected prior to administration of investigational product with the exception of the 6 and 12 hour PK samples on days 1 and 85.   
g Can be done as a part of the clinical chemistry 
h Pharmacokinetic and lymphocyte subset blood samples should be collected at the exact nominal time point as noted above (see hour postdose column).  If unable to 
collect a blood sample at the specified nominal time point, collect it as close as possible to the nominal time point and record the actual collection time.  For samples 
without exact nominal time point (ie, days 8 to 78), PK samples must be collected prior to administration of investigational product, where appropriate.  
Pharmacokinetic and lymphocyte subset samples not collected at exact nominal time point will not be considered protocol deviations.  
i DNA will be extracted only in subjects who provide additional consent for pharmacogenetics testing. 
j Investigational product must be administered within ± 12 hours from the scheduled time point up until week 4.  After week 4, investigational product must be 
administered within ± 1 day of the scheduled time point.  If that window is missed, that dose will not be administered, and the next dose will be administered at the 
next scheduled dosing date.  Subjects will remain at the site for at least 1 hour following the first and second doses of investigational product and for at least 
30 minutes following subsequent doses. 
k Subjects who withdraw from investigational product early will complete an early termination visit that includes the week 12 (predose) assessments.   
l To be collected at screening but not required for eligibility unless subject has no documented prior history of antinuclear antibody (ANA) ≥ 1:80 or elevated 
anti-dsDNA. 
m For description of home healthcare services available, see Section 9.2.3.4. 
 
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Table 2-2.  Schedule of Activities Follow-up 
 
Follow-up 
Study week 
13 
14 
16 
18/SFU/EOSa 
Study day 
92 
99 
113 
127 
GENERAL AND SAFETY ASSESSMENTS 
Weight 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
ECG 
 
 
 
X 
Adverse events 
X 
X 
X 
Xa 
Serious adverse events 
X 
X 
X 
Xa 
Disease-related events 
X 
X 
X 
Xa 
Concomitant medications review 
X 
X 
X 
Xa 
LABORATORY ASSESSMENTS 
Urine pregnancy test 
 
 
X 
X 
Anti-dsDNA and C3 and C4 complement 
 
 
 
X 
Hematology  
 
X 
X 
X 
Chemistry 
 
 
 
X 
PBMC 
 
 
 
X 
PHARMACODYNAMIC ASSESSMENTS 
Lymphocyte subsets 
X 
X 
X 
X 
PHARMACOKINETICS AND ANTIBODIES 
Pharmacokinetic samples 
X 
X 
X 
X 
Anti-AMG 592 antibody 
 
 
 
X 
BIOMARKER  
Biomarker development sample 
 
 
 
X 
ECG = electrocardiogram; EOS = end of study for individual subject; PBMC = peripheral blood mononuclear cell; SFU = Safety follow-up  
a For subjects who complete the study at week 18, the visit includes all required safety follow up data collection.  For subjects who terminate the study early (ie, prior to 
completing the week 18 visit), the safety follow-up visit 6 weeks (± 3 days) after the last dose of investigational product will be a visit to collect adverse events, serious 
adverse events, disease related events, ECG, hematology, and concomitant medications only 
 
 
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3. 
Introduction 
3.1 
Study Rationale 
This phase 1b study is a double-blind, placebo controlled, multiple ascending dose 
(MAD) study to evaluate the safety and tolerability of AMG 592 in subjects with systemic 
lupus erythematosus (SLE) and to determine the recommended phase 2 dose(s). 
3.2 
Background 
3.2.1 
Disease 
Systemic lupus erythematosus is a multisystem autoimmune disease of unknown cause 
with diverse clinical manifestations that disproportionately affects minorities (eg, in the 
United States, blacks and Hispanics) and women of childbearing potential 
(Rhaman and Isenberg, 2008; Kotzin, 1996).  In the United States (US), moderate to 
severe SLE is estimated to affect one-third of the more than the 250 000 patients 
diagnosed with lupus.  The progression of Systemic Lupus Erythematosus (SLE) may 
vary from mild episodes to severe, even fatal outcomes with symptoms varying widely in 
individuals over time and characterized by periods of remission and flare.  Systemic 
lupus erythematosus can affect the skin (rash), musculoskeletal system (arthritis, bone 
tissue death), nervous system (seizures, psychosis), lungs (pleuritis, pneumonitis), and 
the blood (venous or arterial clots, anemia).  In addition, approximately 65% of patients 
will develop lupus nephritis, which is an inflammation of the kidney that can range from 
mild glomerulonephritis to severe diffuse proliferative glomerulonephritis 
(Adams et al, 2006).   
Currently, corticosteroids, immunosuppressants, and cytotoxic agents are frequently 
used to control active disease, but significant need exists for more effective therapies 
with fewer short- and long-term toxicities.  Although the clinical heterogeneity of SLE 
presents challenges in the diagnosis, antibodies to nuclear components represent 
almost a prerequisite for the disease.  The presence of class-switched 
immunoglobulin G (IgG) autoantibodies implicate immune dysregulation as a driving 
force for disease pathogenesis, with T cells appearing to play a role in the development 
of autoantibody production by B cells. 
3.2.1.1 
Interleukin 2 and T Regulatory Cells in Systemic Lupus 
Erythematous 
T regulatory cells (Tregs) are a subset of T cells that maintain self- tolerance by 
suppressing the activation and expansion of autoreactive lymphocytes.  Defects in Treg 
numbers or function have been described in SLE patients and are thought to contribute 
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Date:  25 June 2020 
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to SLE pathogenesis (Zhang et al, 2008; Bonelly et al, 2009; Myara et al, 2005; 
Suen et al 2008; von Spee-Mayer et al 2015).  Interleukin-2 (IL-2), a multi-functional 
cytokine produced predominantly by activated cluster of differentiation 4+ (CD4+) 
T cells, is a key growth factor for Tregs and is essential for Treg maintenance, survival 
and metabolism (Malek and Castro, 2010; Boyman and Sprent, 2012).  Impaired IL-2 
production has been reported in patients with SLE (Linker-Israeli et al, 1983; 
Alcocer-Varela and Alarcon Segovia, 1982; von Spee-Mayer et al, 2015).  Moreover, 
reduced levels of circulating IL-2 have been associated with Treg dysfunction in SLE 
patients (Lieberman and Tsokos, 2010; von Spee-Mayer et al, 2015).  These data 
suggest that immune homeostasis in SLE patients may be restored by correction of Treg 
dysfunction and numerical deficiency through treatment with low dose IL-2.  
3.2.1.2 
Low Dose Interleukin 2 in Inflammatory Disease 
Low dose IL-2 (aldesleukin) has been shown to increase Treg numbers in multiple 
inflammatory diseases such as Type 1 Diabetes (Yu et al, 2015), chronic graft versus 
host disease (GVHD) (Koreth et al, 2011), hepatitis c virus induced vasculitis 
(Sadoun et al, 2011) and alopecia areata (Castela et al, 2014); as well as to correct 
defects in Treg function in SLE (von Spee-Mayer et al, 2015), Type 1 Diabetes 
(Long et al, 2010; Long et al, 2012) and GVHD (Matsuoka et al, 2013).  Genetic variants 
of the IL 2 receptor have been associated with the severity of rheumatoid arthritis (RA) 
joint destruction and persistence (van Steenbergen et al, 2015). 
The therapeutic efficacy of low dose IL-2 has also been studied in chronic GVHD 
(cGVHD) (Koreth et al, 2011; Koreth et al, 2016), hepatitis C induced vasculitis 
(Sadoun et al, 2011), and alopecia areata (Castela et al, 2014).  The clinical response to 
low dose IL-2 has been promising in these small early phase studies in multiple diverse 
inflammatory conditions, with efficacy reported in all indications.  In all of these 
conditions the overall safety and tolerability profile of low-dose IL-2 has been acceptable 
with mild to moderate constitutional symptoms associated with higher levels of exposure.  
However, the therapeutic window between adequate Treg enrichment and stimulation of 
effector cells is narrow and may limit achievement of optimal Treg expansion.  
For instance, in a recent phase 1b clinical trial of cGVHD (ClinicalTrials.gov 
NCT00529035), aldesleukin, a human recombinant IL-2, given at the dose of 
3 x 106 IU/m2 daily induced persistent National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) grade 1 constitutional symptoms (fever, malaise, 
and arthralgia) necessitating a 50% dose reduction (Koreth et al, 2011).  In addition, 
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aldesleukin can activate pro-inflammatory/effector lymphocytes such as CD4+ T effector 
cells (Teff) and natural killer (NK) cells, which may compromise efficacy and safety.  
These data suggest the potential for a therapeutic agent with greater Treg selectivity and 
a prolonged PD effect compared with recombinant IL-2. 
3.2.1.3 
Clinical Experience With Low Dose IL-2 in Systemic Lupus 
Erythematosus 
Treatment with low dose IL-2 has been associated with clinical efficacy in 2 small clinical 
trials.  In one recently reported study of 12 patients with moderate to severe 
SLE (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] score ≥ 6 despite 
treatment with 2 different immunosuppressive therapies), 10/12 subjects (83.3%) 
achieved a reduction in SELENA SLEDAI score and 8/12 (66.7%) achieved a clinical 
response after receiving four 5-day cycles of low dose IL-2 therapy separated by 
washout periods of 9 and 16 days.  Clinical responses included complete resolution of 
SLE manifestations including rash, arthralgias, myositis and alopecia.  Complement 
levels increased but no change in anti-double stranded DNA (anti-dsDNA) antibodies 
was observed.  Regulatory T cells numbers increased in all treated subjects 
(Humrich et al, 2016; Humrich et al, 2015).  In a second study of 38 SLE patients who 
completed three 2-week cycles of low dose IL-2 over 12 weeks, 34/38 subjects (89.5%) 
achieved a Systemic Lupus Erythematosus Responder Index 4 (SRI-4) response at the 
end of 12 weeks, with concomitant decreases in anti-dsDNA antibodies and increase in 
complement levels.  Regulatory T cells numbers increased in most treated subjects 
(He et al, 2016).  In both studies low dose IL-2 was generally well- tolerated, though 
constitutional symptoms (eg, fever, myalgias, arthralgias, flu-like symptoms) were 
reported at the higher dose levels.  Overall these studies provide compelling support for 
further investigation of low dose IL-2 for the treatment of SLE.  
3.2.2 
Amgen Investigational Product Background:  AMG 592 
AMG 592 is an Fc IL-2 mutein fusion protein with increased Treg selectivity compared to 
recombinant IL-2, which has been developed to preferentially expand Tregs in subjects 
with inflammatory diseases (refer to the Investigator’s Brochure for more details).  
Interleukin-2 is a key growth factor for Tregs and is essential for Treg development, 
homeostasis and function.  At low doses IL-2 binds preferentially to the α-subunit (CD25) 
of the high-affinity IL-2 receptor which is expressed constitutively by Tregs and is absent 
on naive T-cells and unactivated T memory cells.  This results in selective activation of 
Tregs.  However, at higher doses IL-2 also activates other immune cells such as CD4+ 
and CD8+ Teff, NK cells and natural killer T cells (NKT) cells via the dimeric low affinity 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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IL-2 receptor.  Compared with aldesleukin, AMG 592 exhibits greatly improved selectivity 
for Tregs over Teff and NK cells both in vitro and in vivo, potentially resulting in an 
improved therapeutic margin.  In addition, the Fc domain of AMG 592 provides a 
prolonged half-life compared with aldesleukin, thus reducing dosing frequency to 
maintain Treg enrichment. 
3.2.2.1 
Toxicology 
3.2.2.2 
Human Exposure 
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A detailed description of the chemistry, pharmacology, efficacy, and safety of AMG 592 
is provided in the Investigator’s Brochure. 
3.3 
Risk Assessment 
Repeated SC doses of up to 
 μg administered 
 and 
 have been studied for 
up to 12 weeks in subjects with rheumatoid arthritis and SLE.  In addition, repeated SC 
doses of up to 
 µg 
 for up to 52 weeks have been studied in subjects with 
cGVHD.  The most frequent adverse event was mild (grade 1 or 2) painless erythema 
at or near the injection site, sometimes accompanied by pruritus, that was self-resolving.  
Two serious hypersensitivity reactions to AMG 592 have been reported, though none 
occurred in the current study.  No clinically significant therapeutic related abnormalities 
in electrocardiograms (ECGs), hematological or biochemical laboratory investigations, or 
vital signs have been reported.  No adverse events greater than grade 2 assessed as 
related to AMG 592 nor any deaths have occurred in the phase 1b part of the current 
study in SLE patients.  More detailed information about the known and expected risks 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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and reasonably expected adverse events associated with AMG 592 may be found in the 
Investigator’s Brochure. 
4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability 
of subcutaneous (SC) dose 
administrations of AMG 592 in subjects 
with systemic lupus erythematosus 
(SLE) 
• 
Treatment-emergent adverse events 
• 
Clinically significant changes in physical 
examinations, vital signs, and laboratory 
safety tests 
Secondary 
• 
To characterize the pharmacokinetic 
(PK) profile following treatment with 
AMG 592 
• 
AMG 592 serum concentration and PK 
parameters including, but not limited to, 
maximum observed concentration (Cmax), the 
time of maximum observed concentration 
(Tmax), and area under the concentration-time 
curve over a dosing interval (AUCtau) after 
the first and last doses 
• 
To evaluate anti-AMG 592 antibody 
formation 
• 
Incidence of anti-AMG 592 antibodies 
• 
Cross-reactivity of anti-AMG 592 antibodies 
with human interleukin-2 (IL-2) 
• 
Incidence of anti-AMG 592 and anti-IL 2 
neutralizing antibodies 
Exploratory 
 
• 
To explore the effect of 
treatment with AMG 592 on 
measures of inflammation at 
various time points 
• 
Change from baseline in anti-double 
stranded DNA (anti-dsDNA), and C3 
and C4 complements at all time points 
collected 
• 
To explore the effect of 
treatment with AMG 592 on 
measures of disease activity at 
various time points 
• 
SLEDAI-2K score and change from 
baseline at all time points collected 
• 
To evaluate the immunological 
effects of AMG 592 
• 
Fold changes from baseline of Treg, 
Tcon, and NK absolute cell counts 
(cells/µL) after AMG 592 
administration 
• 
Changes in Treg/Tcon ratio after 
AMG 592 administration 
  
4.2 
Hypotheses 
AMG 592 will be safe and well tolerated in subjects with SLE. 
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5. 
Study Design 
5.1 
Overall Design 
This phase 1b study is a double-blind, placebo-controlled, multiple ascending 
dose (MAD) study to evaluate the safety, tolerability, PK, immunogenicity, and PD of 
AMG 592 in subjects with SLE.  Subjects within a dosing cohort will be randomized to 
AMG 592 or placebo in a 5:2 ratio (cohorts 1, 2, and, 3) or in a 3:1 ratio (cohorts 4 and 5) 
in addition to standard of care therapy as shown in
 AMG 592 or placebo will 
be administered either 
 by SC injection.  Dosing cohorts will enroll 
sequentially. 
The decision to dose-escalate will be based on the blinded review of safety data during 
the dose level review meeting(s) (DLRM).  The DLRM team will include representatives 
from Amgen’s AMG 592 Early Development Team (Amgen Medical Monitor, Amgen 
Global Safety Officer, Clinical Study Manager, and other team members, as appropriate) 
and the site investigator(s).  The DLRM members will be responsible for dosing 
recommendations, which may include escalation to the next planned dose or a new 
higher dose, escalation to an intermediate dose (a dose lower than the next planned 
dose), de-escalation to a lower dose; continuation, delay, or termination of dosing.  For 
further details on the DLRM see Appendix 3.  
After the last subject enrolled in each cohort completes the week 4 visit, a DLRM will 
convene to determine the acceptability of dose escalation.  The recommendation to dose 
the next cohort will be based on the aggregated review of safety data as well as other 
information as described below.  After incidents of interest (including selected adverse 
events or intolerable PD levels) are observed, a Bayesian logistic regression 
model (BLRM) (Bailey et al, 2009; Neuenschwander et al, 2008) will be implemented to 
model these events before each DLRM to aid dosing decisions.  Dose level review 
meeting members may also consider available aggregated summaries of emerging PK 
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and PD data.  Amgen DLRM members may consider safety, PK and PD data from other 
completed and ongoing phase 1b studies to aid dosing recommendations including 
skipping dosing cohorts, reducing dosing cohort size or changing doses for a given 
cohort or stopping the phase 1b portion of the study entirely.  If emerging data from other 
studies is used in support of dosing recommendations, a dose will only be declared 
tolerable if it is supported by safety from at least 5 subjects at or above this dose level 
across all phase 1b studies.   
Additional dosing cohorts may be added and/or existing cohorts may be expanded.  
These cohorts may be used to explore alternate dosing levels and/or dosing schedules 
or add additional subjects at previously given dose levels.  A DLRM is required for 
escalation to higher doses but not for allocation of additional subjects to doses 
equivalent to or lower than previously given that have been deemed tolerable.   
Subjects will be treated for a total of 12 weeks after which they will complete a 6-week 
follow-up period until week 18 for collection of additional safety, PK and PD data as 
described in the Schedule of Activities (Table 2-2).  In the event that a subject terminates 
the study early (ie, prior to week 18), a safety follow-up visit will be completed 
(6 weeks [± 3 days]) after the last dose of investigational product for collection of 
adverse events, serious adverse events, disease related events, ECG, hematology and 
concomitant medications only. 
Home Healthcare Services 
The investigator may utilize a qualified home healthcare service provider approved by 
the sponsor to conduct the procedures (described in Section 9.2.3.4) required during 
study visits, subject to the investigator’s direction.  Home healthcare services will not be 
used for investigational product administration.  Home healthcare staff must be included 
on the study delegation log (authorized by the investigator) before any study-related 
tasks to be conducted by each home healthcare provider are started. 
In addition, study-specific training including requirements for recording source 
documentation for the home healthcare provider, must be completed before they 
conduct any study-related tasks. 
If ordered by the principal investigator (PI) or authorized physician, the subject will be 
visited by a qualified home healthcare service provider at designated study visits as 
specified in Section 9.2.3.4. 
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Following home healthcare visit, this information will be documented on the home health 
care services visit worksheet and forwarded to the investigator. 
A comprehensive list of all home healthcare services, as well as mandatory procedural 
and data collection requirements, will be separately provided in a home health care 
manual.  
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Subjects will be randomized to receive AMG 592 or placebo in a 5:2 ratio (cohorts 1, 2, 
and 3) or in a 3:1 ratio (cohorts 4 and 5).  Sufficient subjects will be randomized to yield 
approximately 29 subjects (approximately 21 randomized to AMG 592 and 8 randomized 
to placebo; see Section 5.2.1).  The total sample size may exceed 29 subjects and the 
number of subjects per cohort may exceed the planned cohort size if, following a DLRM 
recommendation or Amgen decision to evaluate additional doses or further evaluate 
currently planned doses, dosing cohorts are added and/or existing cohorts are 
expanded, or if subjects are replaced as per Section 5.2.1.  Additional subjects may be 
enrolled in each cohort (following originally planned randomization ratio) to enable all 
screened eligible subjects to participate in the study. 
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who have been randomized but discontinue investigational medicinal product 
before completing the week 4 visit may be replaced. 
5.2.2 
Number of Sites 
Approximately 20 sites in North America and Europe will participate in the study.  Sites 
that do not enroll subjects within 3 months of site initiation may be closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the 
last subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), whether the study concluded as planned in the protocol or was 
terminated early. 
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If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, safety follow-up), as 
applicable. 
5.3.2 
Study Duration for Subjects 
The study will consist of up to a 28-day screening period, a 12-week treatment period 
and a 6-week follow up.  The maximum duration of trial participation for an individual 
subject will be 22 weeks.   
5.4 
Justification for Investigational Product Dose 
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5.5 
Patient Input on Study Design 
Patient input was not obtained for design of this study. 
6. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log will be completed and updated via an Interactive Response 
Technology (IRT). 
Eligibility criteria will be evaluated during screening and day -1.  
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
6.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Age ≥ 18 years to ≤ 70 years at screening. 
103 
Fulfills diagnostic criteria for SLE according to the Systemic Lupus International 
Collaborating Clinics (SLICC) criteria or by at least 4 of the 11 criteria of the 1997 
American College of Rheumatology (ACR) classification criteria for SLE, with a 
history of at least one of the following: 
• 
Antinuclear antibody ≥ 1:80; or 
• 
Elevated anti-dsDNA antibodies 
104 
Removed 
105 
Removed 
106 
Removed 
107 
May be taking ≤ 3 systemic SLE treatments and the dose must be stable for 
≥ 4 weeks prior to day 1. 
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108 
Prednisone dose ≤ 20 mg daily (or other equivalent oral corticosteroid) with 
stable dose ≥ 2 weeks prior to day 1 
109 
Normal or clinically acceptable ECG values (12-lead reporting ventricular rate 
and PR, QRS, QT and QTc interval) at screening and baseline based on opinion of 
the investigator. 
110 
Immunizations (tetanus, diphtheria, pertussis [Td/Tdap]), seasonal influenza 
(during flu season), and pneumococcal (polysaccharide) vaccinations] up to date per 
local standards as determined by the investigator. 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
Disease Related 
201 
History of lupus nephritis requiring induction therapy and/or lupus cerebritis ≤ 1 
year prior to screening. 
202 
Removed 
Other Medical Conditions 
203 
Diagnosis of inflammatory joint or skin disease other than SLE which would 
interfere with SLE disease assessment based on investigator judgement. 
204 
Diagnosis of fibromyalgia which would interfere with SLE assessment according 
to the investigator. 
205 
Prosthetic joint infection within 3 years of screening or native joint infection within 
1 year prior to screening. 
206 
Active infection (including chronic or localized infections) for which anti-infectives 
were indicated within 4 weeks prior to day 1 OR presence of serious infection, 
defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior 
to day 1. 
207 
Known history of active tuberculosis 
208 
Positive test for tuberculosis during screening defined as either: 
• 
positive purified protein derivative (PPD) (≥ 5 mm of induration at 
48 to 72 hours after test is placed) OR positive Quantiferon test 
o a positive PPD and a history of Bacillus Calmette-Guérin vaccination 
are allowed with a negative Quantiferon test and negative chest X-ray. 
o a positive PPD test (without a history of Bacillus Calmette-Guérin 
vaccination) or a positive or indeterminate Quantiferon test are 
allowed if they have ALL of the following at screening: 
− 
no symptoms per tuberculosis worksheet provided by Amgen 
− 
documented history of a completed course of adequate 
prophylaxis (completed treatment for latent tuberculosis per local 
standard of care prior to the start of investigational product) 
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− 
no known exposure to a case of active tuberculosis after most 
recent prophylaxis 
− 
negative chest X-ray. 
209 
Positive for hepatitis B surface antigen, hepatitis B core antibody (confirmed by 
hepatitis B DNA polymerase chain reaction [PCR] test) or detectable hepatitis C virus 
RNA by PCR (screening is generally done by hepatitis C antibody [HepCAb], 
followed by hepatitis C virus RNA by PCR if HepCAb is positive).  A history of 
hepatitis B vaccination without history of hepatitis B is allowed. 
210 
Positive for Human Immunodeficiency Virus (HIV) at screening, or known to be 
HIV positive. 
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211 
Presence of one or more significant concurrent medical conditions per 
investigator judgment, including but not limited to the following: 
• 
poorly controlled diabetes or hypertension 
• 
chronic kidney disease stage IIIb, IV, or V 
• 
symptomatic heart failure (New York Heart Association class II, III, or IV) 
• 
myocardial infarction or unstable angina pectoris within the past 12 months 
prior to randomization 
• 
severe chronic pulmonary disease (eg, requiring oxygen therapy) 
• 
multiple sclerosis or any other demyelinating disease 
• 
major chronic inflammatory disease or connective tissue disease other than 
SLE (eg, RA). 
212 
Malignancy except non-melanoma skin cancers, cervical, or breast ductal 
carcinoma in situ within 5 years of screening. 
213 
Subjects with a urine test positive for illicit drugs or alcohol at the screening visit.  
Prescription medications detected by the drug test are allowed if they are being 
taken under the direction of a physician. 
214 
History of alcohol or substance abuse within 6 months of screening. 
215 
Current smoker, and/or use of any nicotine or tobacco containing products within 
the last 6 months prior to day 1.  These types of products include but are not limited 
to:  snuff, chewing tobacco, cigars, cigarettes, electronic cigarettes, pipes, or nicotine 
patches. 
216 
Subject unwilling to limit alcohol consumption to ≤ 1 drink of alcohol per day and 
≤ 3 drinks per week for the duration of the study, where a drink is equivalent to 
12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine, or 
1.5 ounces of 80 proof distilled spirits. 
Prior/Concomitant Therapy 
217 
Currently receiving or had treatment with:  cyclophosphamide, chlorambucil, 
nitrogen mustard, or any other alkylating agent ≤ 6 months prior to day 1 OR oral 
calcineurin inhibitors (eg, cyclosporine, tacrolimus, and sirolimus) ≤ 4 weeks prior to 
day 1. 
218 
Current or previous treatment for SLE with a biologic agent as follows:  
rituximab < 6 months prior to day 1, belimumab < 3 months prior to day 1, 
abatacept < 8 weeks prior to day 1. 
219 
Currently receiving or had treatment with T cell depleting agents 
(eg, antithymocyte globulin, Campath) or recombinant IL-2 (eg, Proleukin). 
220 
Subjects who have received intra-articular or systemic corticosteroid injections 
within 4 weeks prior to day 1 or topical steroids within 2 weeks prior to day 1. 
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221 
Administration of herbal supplements, vitamins, or nutritional supplements within 
30 days prior to the first dose of investigational product, and continuing use, if 
applicable, will be reviewed by the Investigator and the Amgen Medical Monitor to 
determine acceptability.  Written documentation of this review and Amgen 
acknowledgment is required for subject participation. 
Prior/Concurrent Clinical Study Experience 
222 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days at day 1 since ending treatment on another investigational device 
or drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
223 
Subject previously enrolled in this study may not be re-enrolled unless they fulfill 
the following criteria: 
• 
Have completed the study previously without any adverse events deemed 
related to study drug. 
• 
Have received the last dose of AMG 592/placebo > 6 months prior to the 
screening visit. 
• 
Must not have tested positive for neutralizing antibodies against AMG 592 at 
any time. 
Diagnostic Assessments 
224 
Presence of laboratory abnormalities at screening including the following: 
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x 
upper limit of normal (ULN). 
• 
Serum total bilirubin (TBL) ≥ 1.5 mg/dL (≥ 26 µmol/L) 
• 
Hemoglobin < 9.0 g/dL (< 90 g/L) 
• 
Platelet count < 100,000/mm3 (100 x 109/L) 
• 
White blood cell count < 2,000 cells/mm3 (2.0 x 109/L) 
• 
Absolute neutrophil count (ANC) < 1,000/mm3 (1.0 x 109/L) 
• 
Calculated glomerular filtration rate of ≤ 50 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease (MDRD) formula. 
225 
Any other laboratory abnormality, which, in the opinion of the investigator, poses 
a safety risk, will prevent the subject from completing the study, will interfere with the 
interpretation of the study results, or might cause the study to be detrimental to the 
subject. 
Other Exclusions 
226 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 6 weeks after the last dose of 
investigational product.  
227 
Females of child-bearing potential with a positive pregnancy test (assessed by a 
serum pregnancy test at screening and a urine pregnancy test at baseline). 
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Date:  25 June 2020 
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228 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 6 weeks after the last 
dose of investigational product.  Refer to Appendix 5 for additional contraceptive 
information. 
229 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
230 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge. 
231 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety or 
interfere with the study evaluation, procedures or completion. 
6.3 
Lifestyle Restrictions 
6.3.1 
Alcohol and Tobacco 
At screening and throughout the duration of the study, subjects should not consume 
> 1 drink of alcohol per day and no more than 3 drinks per week, where a drink is 
equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine, 
or 1.5 ounces of 80 proof distilled spirits. 
Subjects must abstain from alcohol consumption within 48 hours prior to each visit 
(including screening). 
Subjects must not use any nicotine or tobacco containing products throughout the study.  
These types of products include but are not limited to:  snuff, chewing tobacco, cigars, 
cigarettes, pipes, electronic cigarettes, or nicotine patches. 
6.3.2 
Activity 
Subjects will abstain from strenuous exercise (eg, running, weight lifting for greater than 
1 hour) for 72 hours before each blood collection for clinical laboratory tests.   
6.4 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information, if applicable (see Appendix 3). 
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
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Protocol Number:  20170103 
Date:  25 June 2020 
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A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned by IRT.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.  
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study.  In the case of a subject re-enrolling to a new cohort, a new 
subject identification number will be assigned. 
6.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened (Section 9.1.1). 
7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Section 7.1 below. 
Approved 
 
 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 36 of 97 
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7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
7.1.1.1 
Amgen Investigational Product:  AMG 592 
AMG 592 and placebo will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures. 
Both are liquid formulations presented in highly similar glass vials and stored in the 
same manner.  An IPIM containing detailed information regarding the storage, 
preparation, and administration of investigational product will be provided separately. 
7.1.1.1.1 
Dosage Administration and Schedule 
AMG 592 or placebo will be administered by SC injection 
 starting on Day 1.  
The following dose cohorts are planned: 
• 
Cohort 1:  
 µg 
 or placebo 
• 
Cohort 2:  
 µg 
 or placebo 
• 
Cohort 3:  
 µg 
 or placebo 
• 
Cohort 4:  
 µg 
 or placebo 
• 
Cohort 5:  
 µg 
 or placebo 
Investigational product will be administered by SC injection in the abdomen, thigh or 
upper arm by authorized site personnel.  A physician must be available at the time of 
investigational product administration.  
The dose of investigational product must be given within ± 12 hours of the specified time 
point up until week 4 (see Schedule of Activities, Table 2-1).  After week 4, doses of 
investigational product must be given within ± 1 day of the scheduled time point 
(see Schedule of Activities, Table 2-1).  If that window is missed, that dose will not be 
administered, and the next dose will be administered at the next scheduled dosing date. 
Subjects will remain at the site for at least 1 hour following the first and second doses of 
investigational product and for at least 30 minutes following subsequent doses. 
The amount of investigational product used in preparation, total volume of preparation, 
quantity administered, start date, start time, and box number of AMG 592/placebo are to 
be recorded on each subject’s CRF. 
7.1.2 
Non-investigational Products 
There are no therapies designated as non-investigational products in the study. 
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Date:  25 June 2020 
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7.1.3 
Medical Devices 
There are no investigational medical device(s) 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 Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
7.1.4 
Other Protocol-required Therapies 
There are no other protocol-required therapies. 
7.1.5 
Other Treatment Procedures 
There are no other treatment procedures. 
7.1.6 
Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Amgen will collect product complaints in this study for AMG 592. 
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following medications are not allowed at any time during the study: 
• 
investigational therapies or commercially available biologic agents 
• 
cytotoxic agents including:  chlorambucil, cyclophosphamide, nitrogen mustard, or 
other alkylating agents 
• 
live vaccines 
• 
systemic or topical calcineurin inhibitors (eg, tacrolimus, cyclosporine, etc.) 
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• 
T cell depleting agents (eg, antithymocyte globulin, Campath) 
• 
recombinant IL-2 (eg, Proleukin) 
• 
Topical, intra-articular, intramuscular, or intravenous corticosteroids, including 
adrenocorticotropic hormone 
• 
Intra-articular hyaluronic acid injections 
Herbal supplements, vitamins, or nutritional supplements approved by the Amgen 
Medical Monitor will be allowed. 
7.2 
Method of Treatment Assignment 
Subjects will be randomized to receive AMG 592 or placebo in a 5:2 ratio (cohorts 1, 2, 
and 3) or in a 3:1 ratio (cohorts 4 and 5) via IRT. 
Assignment to the treatment arms will be based on a computer-generated randomization 
schedule prepared by Amgen before the start of the study.  Each randomized subject will 
receive a single, unique randomization number via IRT at randomization.  The 
randomization date is to be documented in the subject’s medical record as registered in 
the IRT. 
7.3 
Blinding 
The study is double-blind.  Treatment assignment will be blinded to all subjects and site 
personnel as described below.   
7.3.1 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment is to only be unblinded when knowledge of the 
treatment is essential for further clinical management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The Amgen Trial Manager must be notified before the blind is broken unless 
identification of the study treatment is required for a medical emergency in which the 
knowledge of the specific blinded study treatment will affect the immediate management 
of the subject’s condition.  In this case, the Amgen Trial Manager must be notified within 
24 hours after breaking the blind.  The date and reason that the blind was broken must 
be recorded in the source documentation and CRF, as applicable. 
Approved 
 
 
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Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
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7.3.2 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
The Amgen early development lead will be unblinded and will monitor the study on an 
ongoing basis.  Other Amgen staff and their designees involved in the study will not be 
blinded, but will be given access to the unblinding or potentially unblinding information 
only when there is a need to use the information for analysis, discussion and internal 
decision-making, in particular, when concerning safety issues.  Access to treatment 
assignments and other restricted data are described in Amgen standard documents.  
Unblinded individuals will ensure the keeping of the blind.  Unblinding and potentially 
unblinding information should not be distributed to the investigators or subjects prior to a 
study cohort being formally unblinded. 
7.4 
Dose Modification 
7.4.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules  
7.4.1.1 
Dose Level Review Meetings 
After all subjects within a cohort have had the opportunity to complete the week 4 visit, a 
DLRM will be held to review data and make dose escalation/de-escalation decisions 
(see Appendix 3). 
7.4.1.2 
Dose Cohort Stopping Rules 
The following dose cohort stopping rules will be used the study.  Dosing will be stopped 
or modified as shown in Table 7-1. 
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Table 7-1.  Dose Cohort Stopping Rules 
Scenario 
Action 
Any occurrence of a CTCAE version 
4.03 Grade 3 suspected adverse event 
deemed related to investigational 
product drug reaction of the same 
system organ class (eg, hepatobiliary, 
cardiovascular) observed in ≥ 2 or 
more subjects in a single dosing the 
same cohort. 
Stop dosing and convene DLRM (if event occurs 
outside the regularly scheduled DLRM) 
Review adverse event and all relevant safety data for 
evidence of relationship to treatment and clinical or 
medical significance. 
Consider unblinding, as appropriatea. 
Based on the DLRM members’ majority vote, one of 
the following recommendations may be made: 
• 
stop enrollment of the cohort (if applicable) 
• 
resume enrollment of the cohort as planned 
• 
expand the cohort at the same dose 
• 
enrollment of the study may continue at a lower 
dose 
Based on the DLRM members’ unanimous vote one 
of the following recommendations may be made: 
• 
escalate to an intermediate dose (a dose lower 
than the next planned dose) 
• 
escalate to the next planned dose 
Any occurrence of a CTCAE 
version 4.03 ≥ Grade 4 or greater 
suspected adverse drug reaction 
Stop dosing additional subjects in the cohort and 
convene DLRM (if the event occurs outside the 
regularly scheduled DLRM). 
Review adverse event and all relevant safety data for 
evidence of relationship to treatment and clinical or 
medical significance. 
Consider unblinding to determine relatedness to 
investigational producta. 
If the adverse event is determined by a majority vote 
of the DLRM members to be related to the study drug 
and clinically or medically significant, recommend 
that no further doses should be administered at this 
dose and no dose escalation should proceed.  
Recommend that enrollment of the study continue at 
a lower dose or a lower dose cohort may be added to 
the study. 
Otherwise, based on the majority vote of the DLRM 
members, one of the following recommendations 
may be made: 
• 
resume enrollment of the cohort as planned 
• 
expand the cohort at the same dose 
• 
continue enrollment of the study at a lower dose 
or add a lower dose cohort to the study 
DLRM = Dose Level Review Meeting; CTCAE = common terminology criteria for adverse events. 
a Subject’s treatment assignment should only be unblinded when knowledge of the treatment is essential for 
the further management of the subject or may impact the safety of subjects currently enrolled or of 
subjects in subsequent cohorts.  A decision to stop dosing will not occur without unblinding of the subject’s 
treatment assignment. 
Approved 
 
 
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7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.2.1 
Amgen Investigational Product:  AMG 592 
No dosage adjustments are allowed in the study.  
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Appendix 7 for details regarding drug-induced liver injury (DILI) guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Subjects will receive the SC doses of study drug (AMG 592 or placebo) at the research 
facility administered by qualified study personnel for the duration of the study. 
7.7 
Treatment of Overdose 
The effects of overdose of AMG 592 are not known. 
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies that were being taken/used from 6 months prior to enrollment through the 
first dose of investigational product will be collected.  For SLE related therapies collect 
full history of prior treatment.  For prior therapies collect therapy name, indication, dose, 
unit, frequency, route, start date and stop date.  
7.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
Concomitant medications are to be collected from first dose of investigational product 
through the end of safety follow-up period.  Collect therapy name, indication, dose, unit, 
frequency, route, start date and stop date. 
7.8.2.1 
SLE Therapies 
Subjects who were receiving treatment with systemic SLE therapies must maintain a 
stable dose and the same route of administration through the end of study.  No new 
systemic SLE therapies may be initiated during the study. 
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Date:  25 June 2020 
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7.8.2.2 
Corticosteroids 
For subjects entering the study while taking oral steroids, no dose adjustments are 
allowed for 12 weeks.  After week 12 new corticosteroids administered by any route may 
be added or dose adjusted per investigator judgement.  
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 2-1, 
Table 2-2) including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
disease-related events, and must document this decision in the subject’s medical 
records.  Subjects who have discontinued investigational product and/or other 
protocol-required therapies or procedures should not be automatically removed from the 
study.  Whenever safe and feasible, it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with Appendix 3. 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
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Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
Decision by Sponsor 
• 
Lost to follow-up 
• 
Death 
• 
Ineligibility determined 
• 
Protocol deviation 
• 
Non-compliance 
• 
Adverse event 
• 
Subject request 
• 
Disease flare requiring treatment not allowed in the protocol (eg, colitis, asthma) 
8.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study and must document the 
subject’s decision to withdraw in the subject’s medical records. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see Appendix 
6 for further details).  Refer to the Schedule of Activities (Table 2-1 and Table 2-2) for 
data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable to this study. 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
Decision by sponsor 
• 
Withdrawal of consent from study 
• 
Death 
• 
Lost to follow-up 
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8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
• 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
• 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
• 
For subjects who are lost to follow-up, the investigator can search publicly available 
records (where permitted) to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1 and Table 2-2).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IRT and screen 
the subject in order to assess eligibility for participation.  The screening window is up to 
28 days. 
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All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 2 times. 
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  Subjects rescreening within the original 28-day 
screening period only need to repeat the assessment(s) that did not originally meet the 
eligibility criteria; all other initial screening assessments do not need to be repeated.  
Subjects rescreening after the original 28-day screening period has ended must repeat 
all screening procedures including being re-consented.  However, a tuberculosis test 
that was negative at the original screening does not need to be repeated as long as the 
subject has not had exposure to active tuberculosis after the original screening 
tuberculosis test was completed. 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1).  On-study visits may be 
completed within a visit window of ± 1 day from the scheduled dose date.  The date of 
the first dose of investigational product is defined as day 1.  All subsequent doses and 
study visits will be scheduled based on the day 1 date.  Investigational product should be 
administered after all other study procedures have been completed, except at day 1 and 
week 12 of the study per the Schedule of Activities (Table 2-1). 
If a subject discontinues investigational product early then he/she should complete an 
early termination visit as outlined in the Schedule of Activities (Table 2-1 and Table 2-2).  
9.1.3 
Follow-up/Safety Follow-up/End of Study  
After the 12 week treatment period, subjects will be followed for an additional 6 weeks 
up until week 18 for collection of additional safety, PK and PD data as described in the 
Schedule of Activities (Table 2-2).  In the event that a subject terminates the study early 
(ie, prior to week 18), a safety follow-up visit (6 weeks ± 3 days after the last dose of 
investigational product) will be performed for collection of adverse events, serious 
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adverse events, disease-related events, ECG, hematology, and concomitant 
medications only. 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC and Amgen approved informed 
consent before any study-specific procedures are performed. 
9.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarkers variability 
and PK of the protocol-required therapies. 
9.2.1.3 
Medical History 
The Investigator or designee will collect a relevant medical and surgical history that 
started within 5 years or as necessary for chronic or co-morbid conditions prior to 
enrollment through the start of the adverse event reporting period.  Medical history will 
include information on the subject's concurrent medical conditions.  Record all findings 
on the medical history CRF.  In addition to the medical history above, SLE history must 
date back to the original diagnosis.  The current toxicity grade will be collected for each 
condition that has not resolved. 
9.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
9.2.1.5 
Physical Measurements 
Weight in kilograms and height in centimeters should be measured without shoes. 
9.2.1.6 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of alcohol and of nicotine or 
tobacco containing products. 
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9.2.2 
Efficacy Assessments 
9.2.2.1 
Systemic Lupus Erythematosus Disease Activity Index-2000  
The systemic lupus erythematosus disease activity index-2000 (SLEDAI-2K) is a global 
index that evaluates disease activity and includes 24 items collecting specific 
manifestations in 9 organ systems:  neurological, musculoskeletal, renal, 
mucocutaneous, general, heart, respiratory, vascular, and hematological.  The maximum 
score is 105.   
A SLEDAI score will be used for eligibility purposes but the anti-dsDNA antibodies and 
serum complement will not count towards the total score.  After screening, anti-dsDNA 
antibodies and serum complement will be counted toward the total SLEDAI-2K score. 
Systemic lupus erythematosus disease activity index-2000 descriptors will be scored 
based on a review of medical history, physical examination, and clinical laboratory 
findings.  Findings should reflect activity during the 10 days prior to the current visit.   
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Table 2-1 and Table 2-2). 
9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Disease-related Events 
Disease-related events are defined in Appendix 4. 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product(s)/study treatment/protocol-required therapies through the safety follow-up visit 
are recorded using the Event CRF.   
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours.  The investigator will submit any updated serious 
disease-related event data to the sponsor within 24 hours of it being available. 
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational product(s)/study treatment/protocol-required 
therapies, and determined to be serious, must be reported on the Event CRF as serious 
adverse events and recorded and reported per Sections 9.2.3.1.1.3 and Appendix 4. 
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Disease-related events pre-defined for this study include:  lupus-related joint pain, joint 
stiffness, joint swelling, rash, alopecia, and mucosal ulcers. 
9.2.3.1.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Appendix 4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the safety follow-up visit are reported using the Event CRF. 
9.2.3.1.1.3 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through safety follow-up visit are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events. 
9.2.3.1.1.4 
Serious Adverse Events After the Protocol-required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after end of study.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
The method of recording, evaluating, and assessing causality of adverse events, 
disease-related events, and serious adverse events and the procedures for completing 
and transmitting serious adverse event reports are provided in Appendix 4. 
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9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
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To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team (SAT) as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, female partners of 
male subjects will be collected after the start of study treatment and until 6 weeks after 
the last dose of investigational product. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 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, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
9.2.3.2 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
9.2.3.3 
Electrocardiograms 
At day -1 (baseline) ECGs should be performed, prior to blood draws or other invasive 
procedures.  Each ECG must include the following measurements:  QRS, QT, QTc, RR, 
and PR intervals.   
Single ECGs will be collected at screening and after day -1 (baseline) as outlined in the 
Schedule of Activities (Table 2-1).  Subject must be in supine position in a rested and 
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calm state for at least 5 minutes before ECG assessment is conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position as 
possible.  The ECG should be performed prior to blood draws or other invasive 
procedures and must include the following measurements:  heart rate, QRS, QT, QTc, 
and PR intervals. 
The PI or designated site physician will review all ECGs.  Once signed, the original ECG 
tracing will be retained with the subject's source documents.  At the request of the 
sponsor, a copy of the original ECG will be made available to Amgen.  Standard ECG 
machines should be used for all study-related ECG requirements.  Amgen will provide 
standard ECG machines for use by the site. 
9.2.3.4 
Home Healthcare Services 
The investigator may utilize a qualified home healthcare service provider to conduct the 
procedures required during study visits, subject to the investigator’s direction and 
sponsor’s approval. 
The study may include up to 11 home visits, including Week 1, Days 1 
(6 hours postdose and 12 hours postdose), 2, 3, 4, and 11, and Week 12, Days 85 
(6 hours postdose and 12 hours postdose), 86, 87 and 88.  In addition to the 
assessments listed below, adverse events, serious adverse events, and disease-related 
events will be collected as per the Schedule of Activities (Table 2-1). 
Home visits on Day 1 will include:  
• 
biologic sample collection (PK sampling) 
• 
collection of vital signs 
• 
assessment of changes in signs, symptoms, and concomitant medications 
Home visits on Days 2, 3, 4, and 11 will include: 
• 
biologic sample collection (PK and biomarker sampling) 
• 
assessment of substance use 
• 
collection of vital signs 
• 
assessment of changes in signs, symptoms, and concomitant medications 
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In addition, on Days 2, 4, and 11, PD samples will also be drawn; on Day 2 hematology 
sample will also be drawn. 
Home visits on Day 85 will include: 
• 
biologic sample collection (PK sampling) 
• 
collection of vital signs 
• 
assessment of changes in signs and symptoms 
Home visits on Days 86, 87, and 88 will include:  
• 
biologic sample collection (PK sampling) 
• 
assessment of substance use 
• 
collection of vital signs 
• 
assessment of changes in signs, symptoms, and concomitant medications 
In addition, on Day 86 a single ECG will be collected. 
9.2.4 
Clinical Laboratory Assessments 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory with the exception of urine pregnancy, PPD, and Quantiferon (may be done 
by central or local laboratory).  The central laboratory will be responsible for all screening 
and on-study serum chemistry, hematology, serum pregnancy, urinalysis, hepatitis C 
antibody, hepatitis B surface antigen and core antibody, and any other laboratory tests 
required.  Urine pregnancy and PPD testing, if applicable, will be performed locally with 
kits provided by the central laboratory (except PPD).  If Quantiferon testing is performed 
locally, the central laboratory will also provide kits.  The results of this testing will be 
maintained in the source documents at the site. 
Subjects will abstain from strenuous exercise for 72 hours before each blood collection 
for clinical laboratory tests. 
Amgen or designee will be responsible for biomarker and pharmacogenetic 
assessments, and the central laboratory will ship the samples to Amgen or a specialty 
laboratory for assay (depending on the assessment).  The central laboratory will provide 
a study manual that outlines handling, labeling, and shipping procedures for all samples.  
All blood samples will be obtained by venipuncture before investigational product 
administration.  The date and time of sample collection will be recorded in the source 
documents at the site. 
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Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities.  
After baseline, PK/PD parameters that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.   
9.2.4.1 
Pregnancy Testing 
A highly sensitive serum pregnancy test will be completed at screening and a urine 
pregnancy test will be completed at baseline prior to initiation of investigational product 
for females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
Additional pregnancy testing should be performed at monthly intervals during treatment 
with investigational product and 6 weeks (± 3 days) after the last dose of investigational 
product. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.4.2 
Human Immunodeficiency Virus, Hepatitis B Surface Antigen, and 
Hepatitis C Antibody 
HIV testing at screening will be performed if HIV status is unknown.  Subjects will be 
assessed for hepatitis B surface antigen and hepatitis C virus antibody titers at 
screening (see Section 6.2).  The results of these tests must be negative for inclusion in 
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the study and will be documented in the source document but will not be recorded on the 
electronic CRF (eCRF). 
9.2.4.3 
Prespecified Biomarker Assessments 
9.2.4.3.1 
C3 and C4 Complement and Anti-dsDNA  
Serological tests may be useful in assessing disease activity in SLE.  Recent studies 
have shown an increase in C3, C4 complement (Humrich et al, 2015, He et al, 2016) 
and a reduction in anti- dsDNA antibodies (He et al, 2016) in SLE patients treated with 
low dose IL-2.  Thus, in the current study, blood samples for the measurement of C3 and 
C4 complement and anti-dsDNA will be collected as outlined in the Schedule of Activities 
(Table 2-1 and Table 2-2). 
9.2.5 
Pharmacokinetic Assessments 
All subjects randomized to AMG 592 will have pharmacokinetic samples assessed. 
Blood samples will be collected for measurement of serum concentrations of AMG 592 
as specified in the Schedule of Activities (Table 2-1, and Table 2-2).  Instructions for the 
collection and handling of biological samples will be provided by the sponsor.  The actual 
date and time (24-hour clock time) of each sample will be recorded. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
9.2.6 
Pharmacodynamic Assessments 
Lymphocyte subsets:  Blood samples will be collected for all subjects at the time points 
indicated in the Schedule of Activities (Table 2-1 and Table 2-2).  These samples will be 
used to evaluate Treg, Tcon, and NK cells.   
Detailed instructions on sample collection, processing, and shipping will be provided in a 
separate manual. 
9.2.7 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of inflammatory conditions 
and/or to identify subjects who may have positive or negative response to AMG 592.  
Additional samples are not collected for this part of the study.  For subjects who consent 
to these analyses, DNA may be extracted. 
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The final disposition of samples will be described in Appendix 6.  
9.2.8 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Table 2-1 and Table 2-2) for the measurement of 
anti-AMG 592 binding antibodies.  Samples testing positive for binding antibodies will 
also be tested for neutralizing antibodies and may be further characterized.  Additional 
blood samples may be obtained to rule out anti-AMG 592 antibodies during the study. 
Subjects who test positive for anti-AMG 592 antibodies that cross-react with and 
neutralize native human IL-2 at the final scheduled study visit will be asked to return for 
additional follow up testing.  This testing is to occur approximately every 3 months 
starting from when the site has been notified of the positive result until: (1) Interleukin-2 
neutralizing antibodies are no longer detectable; or (2) the subject has been followed for 
a period of at least 1 year (± 4 weeks) post administration of AMG 592.  All follow-up 
results, both positive and negative will be communicated to the sites.  This notification is 
independent of and may be in advance of the time point when the entire study is planned 
to be unblinded.  Refer to Section 7.3 for additional information regarding unblinding.  
More frequent testing (eg, every month) or testing for a longer period of time may be 
requested in the event of safety-related concerns.  Follow-up testing is not required 
where it is established that the subject did not receive AMG 592. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-AMG 592 antibody response 
may also be asked to return for additional follow-up testing.  Refer to the Schedule of 
Activities (Table 2-1 and Table 2-2), as applicable, for specific time points, and the 
laboratory manual for detailed collection and handling instructions. 
9.2.9 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to AMG 592. 
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Blood samples are to be collected for biomarker development at the time points 
specified in the Schedule of Activities (Table 2-1 and Table 2-2).  
9.2.10 
Other Assessments  
9.2.10.1 
Tuberculosis Testing 
All subjects must receive either a PPD or Quantiferon test at screening per Section 6.2. 
9.2.10.1.1 
PPD 
If a subject does not receive a Quantiferon test, then a PPD test must be performed per 
Section 6.2.  The PPD test must be read by a trained healthcare professional 48 to 
72 hours after the test is placed.  Purified protein derivative reader must be identified on 
the delegation of authority for this responsibility. 
9.2.10.1.2 
Quantiferon 
If a subject does not receive a PPD test, then a Quantiferon test must be performed per 
Section 6.2.  Please refer to the central laboratory manual for instructions on sample 
collection, processing, and shipping of samples (if applicable). 
9.2.10.1.3 
Chest X-Ray 
Subjects with a positive PPD test with a history of Bacillus Calmette-Guerin vaccination 
or subjects with a positive PPD test (without a history of Bacillus Calmette-Guerin 
vaccination) or a positive or indeterminate Quantiferon test will require a chest 
radiograph including posterior-anterior and lateral views.  The radiograph report should 
be read by a radiologist or per local requirement and the report must be reviewed by the 
investigator before enrollment of the subject. 
9.2.10.2 
Peripheral Blood Mononuclear Cell 
Blood samples will be collected for subjects in the study at the time points indicated in 
the Schedule of Activities (Table 2-1 and Table 2-2) for peripheral blood mononuclear 
cell (PBMC) collection.  Detailed instructions on sample collection, processing, and 
shipping will be provided in a separate manual. 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
Within each cohort subjects will be randomized to AMG 592 or placebo in a 5:2 ratio for 
cohorts 1, 2 and 3 and in a 3:1 ratio for cohorts 4 and 5.  It is planned that approximately 
29 subjects will be enrolled with 7 subjects assigned to each cohort (5 to AMG 592 and 
2 to placebo) for cohorts 1, 2 and 3 and 4 subjects assigned to cohorts 4 and 5 (3 to 
AMG 592 and 1 to placebo).  The total sample size may exceed 29 subjects and the 
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number of subjects within a cohort may exceed the planned cohort size if, following a 
DLRM recommendation, additional dosing cohorts are added and/or existing cohorts are 
expanded, or if subjects are replaced as per Section 5.2.1.  If additional subjects are 
added to a cohort the randomization ratio may not be preserved. 
The sample size is based on practical considerations.  With 5 subjects receiving 
AMG 592 per cohorts 1, 2, and 3, there is a 76% chance of at least 1 subject 
experiencing an adverse event, if the true event rate is 25%.  The chance of at least 
1 subject experiencing an adverse event will be 67% if the event rate becomes 20%.  
With a total of 21 subjects planned to receive AMG 592 in the study, there is a 19% 
chance of at least 1 subject experiencing an adverse event with a true event rate of 1%.  
The chance of at least 1 subject experiencing an adverse event will be 66% if the true 
event rate becomes 5%. 
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
10.2.1.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects who received at least 1 dose of 
investigational product.  Safety analysis set will be used for analyses unless otherwise 
specified.  Subjects will be analyzed according to the actual treatment received. 
10.2.1.2 
Pharmacokinetic Concentration Analysis Set 
The PK concentration analysis set will contain all subjects who have received AMG 592 
and have at least one reported PK concentration. 
10.2.1.3 
Pharmacokinetic Parameter Analysis Set 
The PK parameter analysis set will consist of all subjects who have received AMG 592 
and for whom at least one PK parameter can be adequately estimated. 
10.2.1.4 
Pharmacodynamic Analysis Set 
The PD analysis set will consist of all subjects who have received AMG 592 or placebo, 
and for whom at least 1 PD parameters has a quantifiable baseline sample and at least 
one quantifiable post-baseline PD sample has been collected. 
10.2.2 
Covariates 
There are no pre-specified covariates. 
10.2.3 
Subgroups 
There are no pre-specified subgroup analyses. 
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10.2.4 
Handling of Missing and Incomplete Data 
All endpoints in the study will be analyzed as-is and no imputation is planned.  
10.3 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 5.3.1. 
10.3.1 
Planned Analyses 
There are no interim analyses planned for this study.  The final analysis will be done 
after all subjects have completed the study (ie, safety follow-up).   
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD, 
immunogenicity, efficacy, and biomarker data.  Descriptive statistics on continuous 
measurements will include means, medians, Q1, Q3, standard deviations, and ranges, 
while categorical data will be summarized using frequency counts and percentages.  
Data will be presented and summarized by treatment and also by time as appropriate. 
10.3.2.2 
Efficacy Analyses  
As an exploratory endpoint, SLEDAI-2K score and change from baseline will be 
provided at all time points collected. 
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Analyses of Primary Endpoint(s) 
The primary endpoint for this study is safety.  Safety analysis set will be used for 
analyses included in this section.  Please refer to Section 10.3.2.3.2 to 10.3.2.3.8 for 
analyses of safety endpoints. 
10.3.2.3.2 
Adverse Events and Disease-related Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies, and significant treatment emergent adverse events will also 
be provided.  Subject incidence of disease-related events, fatal disease-related events, 
and device-related events, if applicable, will be tabulated by system organ class and 
preferred term. 
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10.3.2.3.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at selected 
time points by treatment group.  Shifts in grades of safety laboratory values between the 
baseline and the worst on-study value will be tabulated. 
10.3.2.3.4 
Vital Signs 
The analyses of vital signs will include summary statistics at selected time points by 
population and treatment group.  Shifts in vital sign values between the baseline and the 
worst on-study value will be tabulated. 
10.3.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at selected time 
points by treatment group. 
10.3.2.3.6 
Electrocardiogram 
The ECG measurements will be performed as per standard of care for routine safety 
monitoring, rather than for purposes of assessment of potential QTc effect.  Since these 
evaluations may not necessarily be performed under the rigorous conditions expected to 
lead to meaningful evaluation of QTc data, summaries and statistical analyses of ECG 
measurements are not planned, and these data would not be expected to be useful for 
meta-analysis with data from other trials. 
10.3.2.3.7 
Exposure to Investigational Product 
The number of days on investigational product and the total dose of investigational 
product will be summarized using descriptive statistics.  Subject-level data may be 
provided instead of the summary if the subject incidence is low or single dose is given. 
10.3.2.3.8 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category for each treatment group as coded by the World Health 
Organization Drug dictionary. 
10.3.2.4 
Other Analyses 
Secondary endpoints in study include PK endpoints and immunogenicity 
endpoints.  Exploratory endpoints in this study include biomarker endpoints, 
efficacy endpoint, and PD endpoints. 
10.3.2.4.1 
Pharmacokinetic Analysis 
Pharmacokinetic concentration data will be analyzed using PK concentration 
analysis set.  Individual serum concentration-time plots for AMG 592 will be 
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presented for each subject as well as mean concentration-time plots for each 
treatment. 
Pharmacokinetic parameters will be analyzed using PK parameter analysis set. 
10.3.2.4.2 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 592 or anti-IL-2 
antibodies (binding and if positive, neutralizing) at any time will be tabulated by 
treatment group. 
10.3.2.4.3 
Exploratory Endpoints 
All exploratory endpoints will be summarized using descriptive statistics.  The 
change from baseline and/or fold change from baseline may also be summarized. 
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11. 
References 
Adams A, MacDermott EJ, Lehman TJ. Pharmacotherapy of lupus nephritis in children: 
a recommended treatment approach.  Drugs.  2006;66:1191-1207. 
AMG 592 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Alcocer-Varela J, Alarcon Segovia D. Decreased production of and response to 
interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus.  
J Clin Invest.  1982;69:1388-1392. 
Bailey S, Neuenschwander B, Laird G et al.  A Bayesian case study in oncology Phase 1 
combination dose-finding using logistic regression with covariates.  J Biopharm Stat.  
2009;19:469-484. 
Bonelly M, Savitskaya A, Steiner CW, Rath E, Smolen JS, Scheinecker C. Phenotypic 
and functional analysis of CD4+ CD2-Foxp3+.  J Immunol.  2009;82:1689-1695. 
Boyman O, Sprent J. The role of interleukin.2 during homeostasis and activation of the 
immune system.  Nat Rev Immunol.  2012;12:180-190. 
Castela E, Le Duff F, Butori C, et al.  Effects of Low-Dose Recombinant Interleukin 2 to 
Promote T-Regulatory Cells in Alopecia Areata.  JAMA Dermatol.  2014;150(7):748-751. 
He J, Zhang X, Wei Y et al. Low-dose interleukin-2 treatment selectively modulates 
CD4(+) T cell subsets in patients with systemic lupus erythematosus.  Nat Med.  2016;  
22: 991-993. 
Humrich J, von Spee-Mayer C, Siegert E, et al. Rapid induction of clinical remission by 
low-dose interleukin-2 in a patient with refractory SLE.  Ann Rheum Dis.  2015;74: 
791-792. 
Humrich J, von Spee-Mayer, Siegert E et al. Low-dose IL-2 therapy in refractory SLE: 
results from single center phase I/IIa clinical trial (abstract).  Arthritis Rheumatol.  
2016;68 (suppl 10). http://acrabstracts.org/abstract/low-dose-il-2-therapy-in-refractory-
sle-results-from-single-center-phase-iiia-clinical-trial/.  
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Koreth J, Matsuoka K, Kim HT, et al.  Interleukin-2 and Regulatory T cells in 
Graft-versus-Host Disease.  N Engl J Med.  2011;365:2055-2066. 
Koreth J, Kim HT, Jones KT, et al.  Efficacy, durability, and response predictors of 
low-dose interleukin-2 therapy for chronic graft-versus-host disease.  Blood.  2016; 
128:130-137. 
Kotzin BL. Systemic lupus erythematosus.  Cell.  1996;85:303-306. 
Lieberman LA and Tsokos GC. The IL-2 defect in systemic lupus erythematosus disease 
has an expansive effect on host immunity.  Journal of Biomedicine and Biotechnology.  
2010. Article ID 740619. http://dx.doi.org/10.1155/2010/740619 
Linker-Israeli M, Bakke AC, Kitridou RC et al. Defective production of interleukin 1 and 
interleukin 2 in patients with systemic lupus erythematosus (SLE).  0J Immunol.  
1983;130:2651-2655. 
Long A, Cerosaletti K, Bollyky P, et al.  Defects in IL-2R signaling contribute to 
diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-Cells of type 
1 diabetic subjects.  Diabetes.  2010;59:407-415. 
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Long S, Rieck M, Sanda S, et al.  Rapamycin/IL-2 combination therapy in patients with 
type 1 diabetes augments Tregs yet transiently impairs B-cell function.  Diabetes.  2012; 
61:2340-2348.   
Malek TR and Castro I. Interleukin-2 receptor signaling: at the interface between 
tolerance and immunity.  Immunity.  2010;33:153-165 
Matsuoka K, Koreth J, Kim HT, et al. Low-dose interleukin-2 therapy restores regulatory 
T cell homeostasis in patients with chronic graft-versus-host disease.  Sci Transl Med.  
2013;5(179). 
Myara M, Amoura Z, Parizot C et al. Global natural regulatory T cell depletion in active 
systemic lupus erythematosus.  J Immunol.  2005;175:8392-8400. 
Neuenschwander B; Branson M; Gsponer T. Critical aspects of the Bayesian approach 
to phase 1 cancer trials.  Stat Med.  2008;27:2420-2439. 
Rhaman A and Isenberg DA. Systemic lupus erythematosus.  N Engl J Med.  2008;358: 
929-939. 
Sadoun D, Rosenzwajg M, Jolly F, et al.  Regulatory T-Cell Responses to Low-Dose 
Interleukin-2 in HCV-Induced Vasculitis.  N Engl J Med.  2011;365:2067-2077. 
Suen JL, Li HT, Jong YJ, Chiang BL and Yen JH. Altered homeostasis of CD4+ FoxP3+ 
regulatory T-cell subpopulations in systemic lupus erythematosus.  Immunology.  2008; 
127:196-205.  
van Steenbergen H, van Nies J, Ruyssen-Witrand A, et al. IL2RA is associated with 
persistence of rheumatoid arthritis.  Arthritis Research & Therapy.  2015; 17:244, 
von Spee-Mayer C, Siegert E, Abdirama D et al.  Low-dose interleukin-2 selectively 
corrects regulatory T cell defects in patients with systemic lupus erythematosus.  
Ann Rheum Dis.  2015;0:1-9. 
Yu A, Snowhite I, Vendrame F, et al. Selective IL-2 responsiveness of regulatory T cells 
through multiple intrinsic mechanisms supports the use of low-dose IL-2 therapy in type 
1 diabetes.  Diabetes.  2015;64: 2172–2183. 
Zhang B, Zhang X, Tang FL et al. Clinical significance of increased CD4+ CD25- Foxp3+ 
T cells in patients with new-onset systemic lupus erythematosus.  Ann Rheum Dis.  
2008;67:1037–1040. doi:10.1136/ard.2007.083543  
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12. 
Appendices 
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Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ACR 
American College of Rheumatology 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
Anti-dsDNA 
Anti-double stranded DNA 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCtau 
area under the concentration-time curve over a dosing interval 
BIL 
bilirubin 
BLRM 
Bayesian logistic regression model 
CBC 
complete blood count 
cGvHD 
chronic graft versus host disease 
CIOMS 
Council for International Organizations of Medical Sciences 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
DILI 
drug-induced liver injury  
DLRM 
dose level review meeting 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), whether the study concluded as planned in 
the protocol or was terminated early  
End of Study (end of trial) 
defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study 
(eg, safety follow-up), as applicable 
eCRF 
electronic CRF 
FIH 
first in human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GVHD 
graft versus host disease 
HepCAb 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
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Abbreviation or Term 
Definition/Explanation 
HIV 
Human Immunodeficiency Virus 
HRT 
hormonal replacement therapy 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IgG 
immunoglobin G 
IL-2 
Interleukin-2 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IQR 
interquartile range 
IRB 
Institutional Review Boards 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
MAD 
multiple ascending dose 
MDRD 
Modification of Diet in Renal Disease 
NK cells 
natural killer cells 
NKT cells 
natural killer T cells 
NOAEL 
no observed adverse effect level 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PK 
Pharmacokinetic 
PPD 
purified protein derivative 
PR Interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
QRS interval 
QRS interval is the interval between the Q wave and the S wave 
in the heart's electrical cycle as measured by ECG; represents 
the time it takes for the depolarization of the ventricles 
QT interval 
QT interval is a measure of the time between the start of the 
Q wave and the end of the T wave in the heart's electrical cycle 
as measured by ECG. 
QTc interval 
QT interval corrected for heart rate using accepted methodology  
QW 
every week 
Q2W 
every other week 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
SAT 
safety assessment team 
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Abbreviation or Term 
Definition/Explanation 
SC 
subcutaneous 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
SRI-4 
Systemic Lupus Erythematosus Responder Index-4 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
Tcon 
conventional T cell 
Teff 
T effector cells 
Tmax 
time of maximum observed concentration 
Treg 
regulatory T cells 
ULN 
upper limit of normal 
US 
United States 
 
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Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the central laboratory and/or by the 
local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 12-1.  Analyte Listing 
Central Laboratory 
Chemistry 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatininea 
Total bilirubin 
Direct bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
Specific gravity 
pH 
Blood 
Protein (reflex urine 
protein to creatinine 
ratio if +1) 
Glucose 
Ketones 
Urobilinogen 
Bilirubin 
Microscopic (reflex 
testing if abnormal) 
 
 
Red blood cells 
Antinuclear antibody 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
White blood cells 
WBC Differential 
• Total neutrophils or 
segmented 
neutrophils 
• Bands 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
 
Central Laboratory:  
Quantiferonb 
Hepatitis B surface 
Antigen 
Hepatitis B core 
antibody 
Hepatitis C virus 
antibody 
HIV  
FSHc 
Serum pregnancyd 
Anti-dsDNA  
C3 and C4 complement 
Lymphocyte subsets 
PBMC 
AMG 592 PK 
Anti-AMG 592 
antibodies 
Biomarker development 
Pharmacogenetics 
sample 
SLE drug levels 
Urine drug/alcohol 
screen  
Local Laboratory: 
Urine Pregnancy 
PPD 
ALT = alanine aminotransferase; Anti-dsDNA = anti-double stranded deoxyribonucleic acid; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; HIV = human immunodeficiency virus; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; RDW = red cell distribution width; PBMC = peripheral blood mononuclear cell; SGOT = serum 
glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell 
count; MDRD = Modification of Diet in Renal Disease; PK = pharmacokinetics; FSH = Follicle stimulating 
hormone; PPD = purified protein derivative 
a Glomerular filtration rate will be calculated by MDRD formula 
b Quantiferon testing can be done locally or by the central laboratory 
c Can be done as a part of the clinical chemistry 
d Only at screening  
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After baseline, pharmacokinetics (PK)/pharmacodynamics (PD) parameters that could 
unblind the study will not be reported to investigative sites or other blinded personnel 
until the study has been unblinded.   
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Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings and Data Review Team 
Dose Level Review Meetings 
The study will employ Dose Level Review Meetings (DLRM).  The DLRM team will be 
composed of the investigator(s), Amgen Medical Monitor, and Amgen Global Safety 
Officer or designee.  Other optional Amgen representatives (eg, Amgen biostatistics 
representative, Clinical Trial Manager) may be included as appropriate.  A quorum, 
defined as > 50% of the participating investigators who have enrolled at least 1 subject 
in the study or their qualified designee (ie, sub-investigator or research nurse or study 
coordinator possessing hard copy documentation [eg, email] of the investigator’s vote 
regarding the dose level review), must be in attendance for the DLRM.  The DLRM will 
be rescheduled if a quorum is not reached. 
Voting members of the DLRM will include the Amgen medical monitor, the Amgen global 
safety officer or designated safety scientist, and all participating investigators or their 
qualified medical doctor designee(s).  The majority opinion of the investigators will count 
as 1 vote; the medical monitor will cast 1 vote and the global safety officer will cast 
1 vote.  A majority positive vote indicating an acceptable safety profile for the 
investigational product is required to allow dose level escalation or modification and/or 
cohort continuation/expansion to proceed.  All available study data including 
demographics, medical history, concomitant medications, adverse events, 
electrocardiograms, vital signs, laboratory results, and emerging pharmacokinetic and 
pharmacodynamics data will be reviewed.  Data to be reviewed may be unqueried.  
Study investigators will be informed of DLRM dosing decisions via email notification.  
Only in the following limited circumstances, dose decisions can be made by the Amgen 
Medical Monitor and Amgen Global Safety Officer without convening a DLRM: 
• 
The Amgen Medical Monitor and Amgen Global Safety Officer may decide to begin 
the next cohort using a de-escalated dose (de-escalated from the dose level of the 
most recent cohort), if this de-escalated dose had been previously evaluated during 
a DLRM. 
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Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board/International Ethics Committee (IRB/IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
• 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
• 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
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Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, the aims, 
methods, anticipated benefits, and potential hazards of the study before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered, and answer all questions regarding the study.   
Subjects must be informed that their participation is voluntary.  Subjects will then be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the [IRB/IEC] or study 
site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 
withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 8. 
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Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study. 
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject.  
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 28 days from the previous informed consent form signature 
date. 
The informed consent form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each subject the objectives of the exploratory 
research.  Subjects will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  
A separate signature will be required to document a subject’s agreement to allow any 
remaining specimens to be used for exploratory research.  Subjects who decline to 
participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
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medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors (ICMJE) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
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All persons designated as authors must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
A recognized expert in the therapeutic area 
• 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
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any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case report forms must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the IRT (if 
used, such as subject identification and randomization number) and CRF entries if the 
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CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
• 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable] 
• 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
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Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
Definition of Disease-related Event 
Disease-related Event Definition 
Disease-related events are events (serious or non-serious) anticipated to occur in the study 
population due to the underlying disease.  See Section 9.2.3.1.1.1 for the list of 
disease-related events.  All serious disease-related events will be recorded and reported to 
the sponsor or designee within 24 hours.  
Disease-related events that would qualify as an adverse event or serious adverse event: 
o 
An event based on the underlying disease that is worse than expected as assessed by 
the investigator for the subject’s condition or if the investigator believes there is a 
causal relationship between the investigational product(s)/study 
treatment/protocol-required therapies and disease worsening, this must be reported as 
an adverse event or serious adverse event. 
Disease-related events that do not qualify as adverse events or serious adverse events:  
o 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be reported 
as a disease-related event.   
Definition of Adverse Event 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
Note:  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device or procedure. 
Events Meeting the Adverse Event Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram [ECG], radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related to 
progression of underlying disease). 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported regardless of 
sequelae. 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an adverse event or serious adverse event.  Such instances will be captured in the 
efficacy assessments.  However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as adverse event or serious adverse event if they fulfill 
the definition of an adverse event or serious adverse event. 
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Events NOT Meeting the Adverse Event Definition 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to 
the procedure is the adverse event. 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that meets 
at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are an adverse event.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition.  These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
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Recording Adverse Events, Disease-related Events (if applicable), and Serious 
Adverse Events 
Adverse Event, Disease-related Event, and Serious Adverse Event Recording 
When an adverse event, disease-related 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/disease-related event/serious 
adverse event information in the Event case report form (CRF). 
o 
Additionally, the investigator is required to report a fatal disease-related event on the 
Event CRF. 
The investigator must assign the following adverse event attributes: 
o 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o 
Dates of onset and resolution (if resolved); 
o 
Severity (or toxicity defined below); 
o 
Assessment of relatedness to investigational product, other protocol-required 
therapies; 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 Event CRF. 
It is not acceptable for the investigator to send photocopies of the subject’s medical records 
to sponsor in lieu of completion of the Event CRF page. 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to Amgen. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse 
event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and serious 
adverse event reported during the study.  The assessment of severity will be based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
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Assessment of Causality 
The investigator is obligated to assess the relationship between investigational product, 
protocol-required therapies, and/or study-mandated procedure and each occurrence of 
each adverse event/serious adverse event. 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
The investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
For each adverse event/serious adverse event, the investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and has 
provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the serious adverse event data. 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Amgen to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully 
as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a subject is permanently withdrawn from protocol-required therapies because of a serious 
adverse event, this information must be submitted to Amgen. 
If a subject dies during participation in the study or during a recognized follow-up period, the 
investigator will provide Amgen with a copy of any post-mortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed Event CRF. 
The investigator will submit any updated serious adverse event data to Amgen within 
24 hours of receipt of the information. 
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Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
The primary mechanism for reporting serious adverse event will be the electronic data 
capture (EDC) system via the Safety Report Form.  
If the EDC system is unavailable for more than 24 hours, then the site will report the 
information to Amgen using an Electronic Serious Adverse Event Contingency Form (paper 
form; see Figure 12-1) within 24 hours of the investigator’s knowledge of the event. 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
After the study is completed at a given site, the EDC system will be taken off-line to prevent 
the entry of new data or changes to existing data. 
If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been taken 
off-line, then the site can report this information on an Electronic Serious Adverse Event 
Contingency Form (paper form; see Figure 12-1). 
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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
Approved 
 
 
-
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Product:  AMG 592 
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Date:  25 June 2020 
Page 84 of 97 
CONFIDENTIAL 
 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
Approved 
 
 
AdJEN 
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Product:  AMG 592 
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Date:  25 June 2020 
Page 85 of 97 
CONFIDENTIAL 
 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
Approved 
 
 
AMt3EN 
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Page 86 of 97 
CONFIDENTIAL 
 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
Study-specific contraception requirements for female of childbearing potential are 
outlined in Section 6.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
6 weeks (± 3 days) after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  In addition, male subjects 
may also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
• 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
• 
Premenarchal female 
• 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement 
therapy (HRT).  However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 87 of 97 
CONFIDENTIAL 
 
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of < 1% per year when used consistently and correctly. 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
• 
Intrauterine device  
• 
Intrauterine hormonal-releasing system  
• 
Bilateral tubal ligation/occlusion 
• 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
• 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus) 
• 
Spermicides only 
• 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
• 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 6 weeks (± 3 days) after 
the last dose of investigational product. 
• 
Information will be recorded on the Pregnancy Notification Worksheet (see Figure 
12-2).  The worksheet must be submitted to Amgen Global Patient Safety within 24 
hours of learning of a subject’s pregnancy.  (Note:  Sites are not required to provide 
any information on the Pregnancy Notification Worksheet that violates the country 
or regions local privacy laws.) 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 88 of 97 
CONFIDENTIAL 
 
• 
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 6 weeks 
(± 3 days) after the last dose of the study drug.  This information will be forwarded 
to Amgen Global Patient Safety.  Generally, infant follow-up will be conducted up to 
12 months after the birth of the child (if applicable). 
• 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
• 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
• 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
• 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Appendix 4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
• 
Any female subject who becomes pregnant while participating will discontinue 
investigational product (see Section 8.1 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 
6 weeks (± 3 days) after discontinuing protocol-required therapies, the information 
will be recorded on the Pregnancy Notification Worksheet.  The worksheet 
(see Figure 12-2) must be submitted to Amgen Global Patient Safety within 
24 hours of the site’s awareness of the pregnancy.  (Note:  Sites are not required to 
provide any information on the Pregnancy Notification Worksheet that violates the 
country or regions local privacy laws.) 
• 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner to 
obtain additional pregnancy information. 
• 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 89 of 97 
CONFIDENTIAL 
 
• 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
• 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
• 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 6 weeks after the last dose of 
investigational product. 
• 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
• 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 226. 
• 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 6 weeks after discontinuing 
protocol-required therapies. 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 90 of 97 
CONFIDENTIAL 
 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 
Approved 
 
 
Amgen Proprietary - Confidonlial 
AtttGEH
0 
Pregnancy Notification Form 
Study Design: 
lnterventional D Observational (If Observational: D Prospective D Retrospective) 
2. Contact Information 
Investigator Name _____________________ 
Site # ____________ _ 
Phone {_~---------
Fax (_) ________ _ 
Email ____________ 
_ 
Institution ________________________________________ _ 
Address 
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
Frequency 
Route 
conception 
Was the Amgen product (or study drug) discontinued? D Yes O No 
II yes. provide product (or study drug) stop date: mm __ 
ldd __ 
lyyyy __ 
Did the subject withdraw from the study? D Yes D No 
S. Pregnancy Information 
Pregnant female's last menstrual period (LMP) 
mm ___ 
/ dd _
_ 
/ 'fYYY ___ _ 
Estimated date of delivery mm ___ / dd ___ 
/ 'fYYY __ 
If NIA, date of termination (actual or planned) mm ___ 
/ dd_/ yyyy ____ 
_ 
Has the pregnant female already delivered? D Yes D No D Unknown D NIA 
If yes. provide date of delivery: mm ___ 
/ dd ___ 
l 'fYYY __ _ 
Was the infant healthy? D Yes 
D No 
D Unknown D NIA 
Start Date 
mm __ 
/dd __ lyyyy __ 
If any Adverse Event was experienced by the infant. provide brief deta.ils: _______________ 
_ 
Form Comnleted hv: 
Print Name: _______________ _ 
Title: ________________ _ 
Signature: ________________ _ 
Date: ________________ _ 
FORM-115199 
Version 1.0 
Erfeclive Date: 24-Seol-2018 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 91 of 97 
CONFIDENTIAL 
 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 
Approved 
 
 
Amgon Proprietary - Conlidenti31 
AIVGEN• Lactation Notification Form 
Study Design: C2l lnterventional 
O Observational (If Observational: 0 Prospective O Relrospective) 
2. Contact Information 
Investigator Name _____________________ 
Site# ____________ _ 
Phone (__) ________ 
_ 
Fax .._ _ _,_ ________ 
_ 
Email _ ___________ 
_ 
Institution ________________________________________ _ 
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
Frequency 
Route 
breast feedinq 
Was the Amgen product (or study drug) discontinued? O Yes O No 
If yes, provide product (or study drug) stop date: mm __ 
ldd __ 
/yyyy __ 
Did the subject withdraw from the study? O Yes O No 
5. Breast Feeding Information 
Start Date 
mm__Jdd_/yyyy __ 
Did the motl1er breasttee<J or provide the infant with pumped breast milK While actively taKing an Amgen product? 0 Yes 
O No 
If No, provide stop date: mm ___ 
/dd ___ /yyyy ___ 
_ 
Infant date of birth: mm ___ 
ldd ___ 
lyyyy __ 
_ 
Infant gender: 0 Female O Male 
Is the infant healthy? 0 Yes 
O No O UnKnown O NIA 
If any Adverse Event was experienced by the mother or the infant, provide brief details: _______________ 
_ 
form Completed by 
Print Name: _______________ _ 
Title: ________________ _ 
Signature: ________________ _ 
Date: ________________ _ 
FORM-1 15201 
Version 1.0 
Ettective Date, 24-Sept-2018 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 92 of 97 
CONFIDENTIAL 
 
Appendix 6.  Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Activities (Table 2-1 and Table 
2-2) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
inflammatory conditions, the dose response and/or prediction of response to AMG 592, 
and characterize aspects of the molecule (eg, mechanism of action/target, metabolites).  
Results from this analysis are to be documented and maintained but are not necessarily 
reported as part of this study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any 
remaining blood samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 93 of 97 
CONFIDENTIAL 
 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See Appendix 
3 for subject confidentiality. 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 94 of 97 
CONFIDENTIAL 
 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
• 
Hepatobiliary tract disease 
• 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
• 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
• 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms 
• 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin (BIL) glucuronidation 
(eg, indinavir, atazanavir) 
• 
Alpha-one antitrypsin deficiency 
• 
Alcoholic hepatitis 
• 
Autoimmune hepatitis 
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic fatty liver disease including steatohepatitis  
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible 
drug-induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 95 of 97 
CONFIDENTIAL 
 
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3 x ULN at any time 
> 2 x ULN 
 
 
OR 
INR 
-- 
> 1.5 x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8 x ULN at any time 
> 5 x ULN but < 8 x ULN for ≥ 2 weeks 
> 5 x ULN but < 8 x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3 x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3 x ULN (when baseline was < ULN) 
 
OR 
ALP 
> 8 x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then investigational product is to be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Table 12-2) are never to be rechallenged. 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 96 of 97 
CONFIDENTIAL 
 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate case report form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Appendix 4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in Table 
12-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) or 
2-fold increases above baseline values for subjects with elevated values before drug are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.   
Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, BIL (total and direct), and INR within 24 hours 
• 
In cases of TBL > 2 x ULN or INR > 1.5, retesting of liver tests, BIL (total and 
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
• 
Complete blood count with differential to assess for eosinophilia 
• 
Serum total immunoglobulin G, antinuclear antibody, anti smooth muscle antibody, 
and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
• 
Serum acetaminophen (paracetamol) levels 
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 97 of 97 
CONFIDENTIAL 
 
• 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
• 
Viral serologies 
• 
Creatine phosphokinase (CPK), 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, and INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  
Approved 
 
 
AMGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  25 June 2020 
Page 1 of 1 
CONFIDENTIAL 
 
 
Superseding Amendment 5 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled Phase 1b Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity of Multiple Ascending Subcutaneous Doses of AMG 592 in 
Subjects With Systemic Lupus Erythematosus 
 
Amgen Protocol Number 20170103 
 
 
Amendment Date: 
23 April 2020 
Superseding Amendment 
Date: 
25 June 2020 
Rationale: 
The current protocol (amendment 4) is designed as a seamless phase 1b/2a study to 
evaluate the safety and efficacy of AMG 592 in subjects with active systemic lupus 
erythematosus.   
The phase 2a will now be converted into a phase 2b.  Due to the complexity of the new 
phase 2b design, it was decided that splitting the study into 2 protocols would avoid 
logistical problems for clinical development and clinical operations (vendors, etc).  
Having separate protocols also alleviates any possibility of unblinding in a shared 
database.  
The following changes were made to the superseding protocol dated 25 June 2020: 
It was noted that in the amendment process for protocol amendment 1, the exploratory 
endpoints for the phase 1b portion of the study were accidentally deleted.  These have 
been added back to support the analyses of these endpoints. 
Approved 
 
 
ANIGEN® 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  23 April 2020 
Page 1 of 1 
CONFIDENTIAL 
 
 
Amendment 5 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled Phase 1b Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity of Multiple Ascending Subcutaneous Doses of AMG 592 in 
Subjects With Systemic Lupus Erythematosus 
 
Amgen Protocol Number 20170103 
 
 
Amendment Date: 
23 April 2020 
Rationale: 
The current protocol (amendment 4) is designed as a seamless phase 1b/2a study to 
evaluate the safety and efficacy of AMG 592 in subjects with active systemic lupus 
erythematosus (SLE) with inadequate response to standard of care therapy.   
The study has become part of the Food and Drug Administration (FDA) Complex 
Innovative Design (CID) pilot program.  With the opportunity to implement a CID to the 
SLE development program, the phase 2a is now a phase 2b.  Due to the complexity of 
the new phase 2b design, it was decided that split the study into 2 protocols would avoid 
logistical problems for clinical development and clinical operations (vendors, etc).  
Having separate protocols also alleviates any possibility of unblinding in a shared 
database.  
In addition, it was noted that in the amendment process for protocol amendment 1, the 
exploratory endpoints for the phase 1b portion of the study were accidentally deleted.  
These have been added back to the protocol, with some additional text to support the 
analyses of these endpoints. 
Approved 
 
 
ANIGEN® 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  24 February 2020 
Page 1 of 4 
CONFIDENTIAL 
 
 
Superseding Amendment 4 
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy 
 
Amgen Protocol Number (AMG 592) 20170103 
NCT Number:  NCT03451422 
EudraCT Number 2017-002564-40 
 
Amendment Date: 
24 February 2020 
Rationale: 
This superseding amendment is to address administrative details that were erroneously 
included in protocol amendment 4 dated 06 February 2020. 
Approved 
 
 
ANIGEN® 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  06 February 2020 
Page 1 of 20 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy 
 
Amgen Protocol Number (AMG 592) 20170103 
NCT Number:  NCT03451422 
EudraCT Number 2017-002564-40 
 
Amendment Date: 
06 February 2020 
Rationale: 
This protocol is being amended to add 2 additional dosing cohorts to the phase 1b part 
of the protocol in order to investigate whether treatment with higher doses of AMG 592 is 
safe and may result in greater Treg expansion with continued maintenance of selectivity. 
This amendment also allows re-enrollment of previously enrolled study subjects provided 
they meet additional entry criteria. 
Approved 
 
 
AMGEN® 


Not Approved 
 
 
Product:  AMG 592 
Protocol Number:  20170103 
Date:  18 November 2019 
Page 1 of 6 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy 
 
Amgen Protocol Number (AMG 592) 20170103 
NCT Number:  NCT03451422 
EudraCT Number:  2017-002564-40 
 
Amendment Date: 
18 November 2019 
Rationale: 
This protocol is being amended to add language for home healthcare provided services 
and to remove Amgen retired template language in regards to self-evident corrections. 
ANIGEN® 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  12 June 2019 
Page 1 of 21 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy 
 
Amgen Protocol Number: AMG 592 20170103 
 
Amendment Date: 
12 June 2019 
Rationale: 
The rationale for this protocol amendment is: 
1. To update the phase 1b sample size language throughout the protocol to allow 
flexibility for expansion and/or addition of cohorts per DLRM recommendation, for 
replacement of subjects who discontinue investigational drug product prior to 
completing week 4 of the study and to allow enrollment of additional eligible 
screened subjects in each cohort.  
2. To allow subjects to meet entry criteria with a history of positive ANA and anti-dsDNA 
antibody rather than positive results at screening because these tests may wax and 
wane in SLE patients. 
3. To update the Risk Assessments section of the protocol to align with recent change 
to the Investigator’s Brochure.  
4. To update the dose for cohort 3, from 
 µg  
 to 
 µg 
 in order to allow 
exploration of a wider dose range in the phase 1b part of the study. Administration of 
the 
 µg 
 dose to all subjects in cohort 2 has been completed through the 
DLRM evaluation period.  Blinded review has revealed no concerning safety signals 
and investigational product (AMG 592 or placebo) has been generally well-tolerated.  
These data provide justification for consideration of dose escalation to the 
 µg 
 dose. 
Approved 
 
 
ANIGEN~ 


Product:  AMG 592 
Protocol Number:  20170103 
Date:  26 July 2018
Page 1 of 3
CONFIDENTIAL
Amendment 1
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy
Amgen Protocol Number (AMG 592) 20170103
NCT Number: NCT03451422
EudraCT Number 2017-002564-40
Amendment Date:
26 July 2018
Rationale:
This protocol is being amended to change subject urine drug/alcohol testing, during 
screening, from the local laboratory to the central laboratory.
Approved 
 
 
AMGEN® 

SAP_001.pdf: 
Product:  AMG 592  
Protocol Number:  20170103 
Date:  09 November 2021 
Page 1 of 34 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled 
Phase 1b Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Immunogenicity of 
Multiple Ascending Subcutaneous Doses of 
AMG 592 in Subjects with Systemic Lupus 
Erythematosus 
Short Protocol Title: 
Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Immunogenicity of AMG 592 
in Subjects with Systemic Lupus Erythematosus 
Protocol Number: 
20170103 
NCT Number: 
NCT03451422 
Authors: 
 
 
Sponsor: 
Amgen, Inc.  
One Amgen Center Drive, 
Thousand Oaks, CA 91320, USA 
SAP Date: 
Document Version 
Original  
Date 
12 December 2017 
Amendment 1 
01 December 2020 
Amendment 2 
26 October 2021 
Amendment 3 
09 November 2021 
ANIGEN~ 


Product:  AMG 592  
Protocol Number:  20170103 
Date:  09 November 2021 
Page 2 of 34 
CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original  
12 December 2017 
NA 
Amendment 1  
01 December 2020 
Changes related to protocol superseding 
amendment 5 (dated 25 June 2020)  
Amendment 2  
26 October 2021 
Changes updated in definitions, statistical 
method of analyses and Appendix B 
Amendment 3 
09 November 2021 
Changes updated in laboratory test 
results and Appendix B 
ANIGEN~ 


Product:  AMG 592  
Protocol Number:  20170103 
Date:  09 November 2021 
Page 3 of 34 
CONFIDENTIAL  
 
 
Table of Contents 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints/Estimands .......................................................... 7 
2.2 
Hypotheses and/or Estimations ................................................................... 9 
3. 
Study Overview ...................................................................................................... 9 
3.1 
Study Design ............................................................................................... 9 
3.2 
Sample Size .............................................................................................. 10 
4. 
Covariates and Subgroups ................................................................................... 10 
4.1 
Planned Covariates ................................................................................... 10 
4.2 
Subgroups ................................................................................................. 10 
5. 
Definitions ............................................................................................................. 10 
5.1 
Basic Definitions........................................................................................ 10 
5.2 
Study Points of Reference ......................................................................... 11 
5.3 
Arithmetic Calculations .............................................................................. 12 
5.4 
Definitions of Study Endpoints ................................................................... 12 
5.5 
Demographic and Characteristics ............................................................. 14 
6. 
Analysis Sets ........................................................................................................ 14 
6.1 
Safety Analysis Set ................................................................................... 14 
6.2 
Pharmacokinetic Concentration Analysis Set ............................................ 14 
6.3 
Pharmacokinetic Parameter Analysis Set .................................................. 14 
6.4 
Pharmacodynamic Analysis Sets .............................................................. 14 
7. 
Planned Analyses ................................................................................................. 14 
7.1 
DLRMs ...................................................................................................... 14 
7.2 
Final Analysis ............................................................................................ 15 
8. 
Data Screening and Acceptance ........................................................................... 15 
8.1 
General Principles ..................................................................................... 15 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 15 
8.3 
Handling of Missing and Incomplete Data ................................................. 15 
8.4 
Detection of Bias ....................................................................................... 15 
8.5 
Outliers ..................................................................................................... 15 
8.6 
Distributional Characteristics ..................................................................... 15 
8.7 
Validation of Statistical Analyses ............................................................... 16 
9. 
Statistical Methods of Analysis.............................................................................. 16 
9.1 
General Considerations ............................................................................. 16 
9.2 
Subject Accountability ............................................................................... 16 
9.3 
Important Protocol Deviations ................................................................... 16 
9.4 
Demographic and Baseline Characteristics ............................................... 18 
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9.4.1 
Demographic ............................................................................. 18 
9.4.2 
Baseline Characteristics ............................................................ 18 
9.5 
Efficacy Analyses ...................................................................................... 18 
9.5.1 
Analyses of Exploratory Efficacy Endpoint (s) ............................ 18 
9.6 
Safety Analyses ........................................................................................ 18 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 18 
9.6.2 
Adverse Events ......................................................................... 18 
9.6.3 
Laboratory Test Results ............................................................ 19 
9.6.4 
Vital Signs ................................................................................. 20 
9.6.5 
Physical Measurements ............................................................ 20 
9.6.6 
Electrocardiogram ..................................................................... 20 
9.6.7 
Antibody Formation ................................................................... 21 
9.6.8 
Exposure to Investigational Product .......................................... 21 
9.6.9 
Exposure to Concomitant Medication ........................................ 21 
9.7 
Other Analyses ......................................................................................... 21 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 22 
9.7.1.1 
Analysis of Pharmacokinetic Endpoint ..................... 22 
9.7.1.2 
Analysis of Pharmacodynamic Endpoints ................ 22 
9.7.2 
Analyses of Biomarker Endpoints .............................................. 23 
10. 
Changes From Protocol-specified Analyses.......................................................... 23 
11. 
Literature Citations / References ........................................................................... 24 
12. 
Appendices ........................................................................................................... 25 
 
List of Appendices 
Appendix A. Concomitant Medications/Adverse Event Missing Value 
Imputation ............................................................................................... 25 
Appendix B.  Analytical Windows ................................................................................... 26 
Appendix C.  Summary of Changes and Rationale for Change to the SAP 
Amendment 3 ......................................................................................... 31 
 
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List of Abbreviations 
 
Abbreviation or Term 
Definition/Explanation 
Anti-dsDNA 
Anti-double stranded DNA 
AUC 
area under the concentration-time curve 
AUCtau 
area under the concentration-time curve over a dosing interval 
BLRM 
Bayesian logistic regression model 
Cmax 
maximum observed concentration 
CPMS 
Clinical Pharmacology Modeling and Simulation 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
DLRM 
dose level review meeting 
ECG 
Electrocardiogram 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early  
End of Study (end of trial) 
defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study  
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable 
GSO-DM 
The Amgen Global Study Operations-Data Management 
IL-2 
Interleukin 2 
IP 
Investigational Product 
IPD 
Important Protocol Deviations 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
ISR 
Injection Site Reaction 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NK cells 
natural killer cells 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
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PR Interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
QRS interval 
QRS interval is the interval between the Q wave and the S wave 
in the heart's electrical cycle as measured by ECG; represents 
the time it takes for the depolarization of the ventricles 
QT interval 
QT interval is a measure of the time between the start of the 
Q wave and the end of the T wave in the heart's electrical cycle 
as measured by ECG. 
QTc interval 
QT interval corrected for heart rate using accepted methodology  
QW 
every week 
Q2W 
every other week 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
Source Data 
Information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Tcon 
conventional T cell 
Tmax 
time of maximum observed concentration 
TEAE 
Treatment Emergent Adverse Events 
Treg 
regulatory T cells 
 
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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the superseding protocol amendment 5 for study 
20170103, AMG 592 dated 25 June 2020. The scope of this plan includes the analysis 
for dose level review meetings (DLRM) and the final analysis that is planned and will be 
executed by the Amgen Global Biostatistical Science department unless otherwise 
specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
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Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of subcutaneous 
(SC) dose administrations of 
AMG 592 in subjects with 
systemic lupus erythematosus 
(SLE) 
 
Treatment-emergent adverse events 
 
Clinically significant changes in 
physical examinations, vital signs, 
and laboratory safety tests 
Secondary 
 
To characterize the 
pharmacokinetic (PK) profile 
following treatment with 
AMG 592 
 
AMG 592 serum concentration and 
PK parameters including, but not 
limited to, maximum observed 
concentration (Cmax), the time of 
maximum observed concentration 
(Tmax), and area under the 
concentration-time curve over a 
dosing interval (AUCtau) after the 
first and last doses 
 
To evaluate anti-AMG 592 
antibody formation 
 
Incidence of anti-AMG 592 
antibodies 
 
Cross-reactivity of anti-AMG 592 
antibodies with human 
interleukin-2 (IL-2) 
 
Incidence of anti-AMG 592 and 
anti-IL 2 neutralizing antibodies 
Exploratory 
 
 
To explore the effect of 
treatment with AMG 592 on 
measures of inflammation at 
various time points 
 
Change from baseline in anti-double 
stranded DNA (anti-dsDNA), and C3 
and C4 complements at all time 
points collected 
 
To explore the effect of 
treatment with AMG 592 on 
measures of disease activity at 
various time points 
 
SLEDAI-2K score and change from 
baseline at all time points collected 
 
To evaluate the immunological 
effects of AMG 592 
 
Fold changes from baseline of Treg, 
Tcon, and NK absolute cell counts 
(cells/µL) after AMG 592 
administration 
 
Changes in Treg/Tcon ratio after 
AMG 592 administration 
 
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2.2 
Hypotheses and/or Estimations 
AMG 592 will be safe and well tolerated in subjects with SLE. There is no formal 
hypothesis planned for the study. 
3. 
Study Overview 
3.1 
Study Design 
This phase 1b study is a double-blind, placebo-controlled, multiple ascending dose 
(MAD) study to evaluate the safety, tolerability, PK, immunogenicity, and PD of 
AMG 592 in subjects with SLE.  Subjects will be treated for a total of 12 weeks after 
which they will be followed for an additional 6 weeks for safety and additional PK/PD 
data collection. 
Five dosing cohorts are planned for the study.  For cohorts 1, 2, and 3, subjects within a 
dosing-cohort will be randomized in a 5:2 ratio to AMG 592 (n = 5) or placebo (n = 2) as 
follows:  cohort 1 (
 g 
]); cohort 2 (
 g 
); and 
cohort 3 (
 g 
]), in addition to standard of care therapy. For cohorts 
4 and 5, subjects within a dosing-cohort will be randomized in a 3:1 ratio to 
AMG 592 (n = 3) or placebo (n = 1) as follows:  cohort 4 (
 g 
) and cohort 
5 (
 g 
), in addition to standard of care therapy.  Dosing cohorts will enroll 
sequentially.  A Dose Level Review Meeting (DLRM) will convene after the last subject in 
each cohort completes the week 4 visit.  The decision to dose the next cohort will be 
based on the aggregated review of safety data.  After incidents of interest (including 
selected adverse events or intolerable PD levels) are observed, a Bayesian logistic 
regression model (BLRM) if required will be implemented to model these events before 
each DLRM to aid dosing recommendations.  Dose Level Review Meeting members will 
be responsible for dosing recommendations, which may include escalation to the next 
planned dose or a new higher dose, escalation to an intermediate dose (a dose lower 
than the next planned dose), de-escalation to a lower dose; continuation, delay, or 
termination of dosing.  Additional dosing cohorts may be added and/or existing cohorts 
may be expanded based on emerging data.  Dose Level Review Meeting members may 
also consider available aggregated summaries of emerging PK and PD data.  Amgen 
DLRM members may consider safety, PK and PD data from other completed and 
ongoing phase 1b studies to aid dosing recommendations.  Emerging safety, PK, and 
PD data from ongoing AMG 592 studies may be used to support recommendations to 
skip dosing cohorts, reduce dosing cohort size or change doses for a given cohort or 
stop the study entirely. 
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3.2 
Sample Size 
Within each cohort subjects will be randomized to AMG 592 or placebo in a 5:2 ratio for 
cohorts 1, 2 and 3 and in a 3:1 ratio for cohorts 4 and 5.  It is planned that approximately 
29 subjects will be enrolled with 7 subjects assigned to each cohort (5 to AMG 592 and 
2 to placebo) for cohorts 1, 2 and 3 and 4 subjects assigned to cohorts 4 and 5 (3 to 
AMG 592 and 1 to placebo).  The total sample size may exceed 29 subjects and the 
number of subjects within a cohort may exceed the planned cohort size if, following a 
DLRM recommendation, additional dosing cohorts are added and/or existing cohorts are 
expanded, or if subjects are replaced as per protocol Section 5.2.1.  If additional 
subjects are added to a cohort the randomization ratio may not be preserved. 
The sample size is based on practical considerations.  With 5 subjects receiving 
AMG 592 per cohorts 1, 2, and 3, there is a 76% chance of at least 1 subject 
experiencing an adverse event, if the true event rate is 25%.  The chance of at least 
1 subject experiencing an adverse event will be 67% if the event rate becomes 20%.  
With a total of 21 subjects planned to receive AMG 592 in the study, there is a 19% 
chance of at least 1 subject experiencing an adverse event with a true event rate of 1%.  
The chance of at least 1 subject experiencing an adverse event will be 66% if the true 
event rate becomes 5%. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
There are no pre-specified covariates. 
4.2 
Subgroups 
There are no pre-specified subgroup analyses. 
5. 
Definitions 
5.1 
Basic Definitions 
Investigational Product (IP) 
The term ‘investigational product’ is used in reference to AMG 592 all dose levels and 
placebo. 
Prior Medication and Concomitant Medications 
Prior medication is defined as any medication with start date prior to the first dose date 
of investigational product and ended before the 1st IP dose. Concomitant medication is 
defined as any medication with start date prior to the first dose date of investigational 
product but which continued to be taken after the first dose of investigational product or 
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 any medication with start date on or after first dose date of investigational product and 
up to and including 42 days after the last dose date of investigational product. 
5.2 
Study Points of Reference 
Baseline  
For any variable, baseline is the last assessment taken prior to or on the first 
investigational product administration unless stated otherwise; for subjects who did not 
receive any investigational product, baseline is the last assessment on or before 
enrollment date. 
Baseline for Pharmacodynamics (PD) 
For lymphocyte subsets, if 2 or more time points are collected at day -1 and day 1 pre-
dose, then the average of those time points will be reported. 
Baseline medication 
Baseline medication is defined as any medication with start date on or before Study Day 
1 and ongoing while on study. If the medication is taken on the same day as the first 
dose and the exact time relative to the first dose is unknown, it will be assumed to have 
been taken prior to the first dose of IP. 
Study Day 
Study day is defined as the number of days from Study Day 1. 
Post study day 1:  study day = (date of interest – date of Study Day 1) + 1 
Pre study day 1:   study day = (date of interest – date of Study Day 1) 
Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product or 
the day of enrollment if the subject does not receive any investigational product. The day 
prior to Study Day 1 is considered as Day -1. 
End of Study Date 
The end of study date is recorded on the End of Study CRF. 
Enrollment (Randomization) Date 
The date on which a subject is assigned to receive AMG592 or placebo through the IRT. 
End of Investigational Product Date 
The date on which a subject is administered the last dose of investigational product. 
Duration of Treatment-emergent Injection Site Reaction (ISR) 
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Duration = (min (ISR end date, EOS date) – ISR start date) + 1. 
Duration of IP exposure 
The duration of IP exposure will be derived as earliest date of the last IP administration 
plus <dosing frequency> -1, end of study, whichever occurs first, minus the date of first 
IP administration plus 1 day, where dosing frequency is 7 for QW dosing and 14 for 
Q2W dosing. 
Study Visit 
Since the actual visit for a subject may not exactly coincide with their scheduled visit 
date, the actual visit date is mapped to the analysis visit as per the analysis visit 
windows described in Appendix B. 
5.3 
Arithmetic Calculations 
Change From Baseline 
Change from baseline is the arithmetic difference between post-baseline and baseline. 
Fold Change From Baseline 
Fold change from baseline equals the post-baseline value divided by the baseline value. 
If the change from baseline is not equal to 0 and the baseline value is 0, then fold 
change is not defined. If the change from baseline is equal to 0 and the baseline value is 
also 0, then fold change is 1. 
Number of Days on Investigation Product 
Number of days on IP is defined as last dose date – first dose date +1. 
Treg to Tcon Ratio 
The ratio is defined as number of Tregs divided by number of Tcons. When the value of 
Tcon is 0, then the ratio of Treg to Tcon is reported as 1. 
5.4 
Definitions of Study Endpoints 
Systemic Lupus Erythematosus Disease Activity Index 2000  
The SLEDAI-2K is a global index that evaluates disease activity and includes 24 items 
collecting specific manifestations in 9 organ systems: neurological, musculoskeletal, 
renal, mucocutaneous, general, heart, respiratory, vascular, and hematological. The 
maximum score is 105. 
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Incidence of Events of Interest 
Incidents of events of interest such as selected adverse events or intolerable PD levels 
will be identified after safety data is collected and before each DLRM convenes. 
Treatment-emergent Adverse Event (TEAE) 
A treatment-emergent adverse event is any adverse event starting or worsening on or 
after the first dose of investigational product (as determined by the flag indicating if the 
adverse event started prior to the first dose or not on the Adverse Events eCRF) and up 
to and including 42 days after the last dose date or the End of Study date on eCRF form, 
whichever is earlier. 
Treatment-related Adverse Event (TRAE) 
A treatment-related AE is any treatment-emergent AE with the relationship flag on the 
Events eCRF indicating there is a reasonable possibility that the event may have been 
caused by investigational medicinal product. In the unlikely event that the relationship is 
missing, the treatment-emergent event will be considered treatment-related and 
documented in a footnote of the treatment-related summary. 
Disease-related Event 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease. All serious disease-related events will be 
recorded and reported to the sponsor or designee within 24 hours. The investigator will 
submit any updated serious disease-related event data to the sponsor within 24 hours of 
it being available. 
Disease-related events that would qualify as an adverse event or serious adverse event: 
  An event based on the underlying disease that is worse than expected as assessed by 
the investigator for the subject’s condition or if the investigator believes there is a causal 
relationship between the investigational product(s)/study treatment/protocol-required 
therapies and disease worsening, this must be reported as an adverse event or serious 
adverse event. 
Disease-related events that do not qualify as adverse events or serious adverse events: 
  An event which is part of the normal course of disease under study (e.g., disease 
progression in oncology or hospitalization due to disease progression) is to be reported 
as a disease-related event. 
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Disease-related events pre-defined for this study include: lupus-related joint pain, joint 
stiffness, joint swelling, rash, alopecia, and mucosal ulcers. 
5.5 
Demographic and Characteristics 
Age 
Age in years at randomization, which is collected in eCRF. 
6. 
Analysis Sets 
6.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects who received at least 1 dose of 
investigational product.  Safety analysis set will be used for analyses unless otherwise 
specified. 
6.2 
Pharmacokinetic Concentration Analysis Set 
The PK concentration analysis set will contain all subjects who have received AMG 592 
and have at least one reported PK concentration. 
6.3 
Pharmacokinetic Parameter Analysis Set 
The PK parameter analysis set will consist of all subjects who have received AMG 592 
and for whom at least one PK parameter can be adequately estimated. 
6.4 
Pharmacodynamic Analysis Sets 
The PD analysis set will consist of all subjects who have received AMG 592 or placebo, 
and for whom at least 1 PD parameters has a quantifiable baseline sample and at least 
one quantifiable post-baseline PD sample has been collected. 
7. 
Planned Analyses 
7.1 
DLRMs 
The study will have DLRMs for each cohort after the last subject in the cohort completes 
week 4 visit. Section 3.1 details the timings and scope of each DLRM planned for the 
study. 
All available data the subjects up to and including the data snapshot date will be 
included in the analysis based on an “as-is” snapshot of the database without data 
locking. Data will be subject to ongoing checks for integrity, completeness and accuracy 
in accordance with the Data Management Plan; however, there is no requirement to 
resolve outstanding data issues ahead of the DLRM snapshot. DLRM analysis will 
include subject-level listings and plots of available safety data (labs, and vitals) for each 
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cohort and the BLRM analysis if required. The recommendations for dose 
escalation/dose modifications will be based on the DLRMs. 
7.2 
Final Analysis 
The final analysis will be done after all subjects have completed the study (i.e., the 
safety follow-up visit). Final lock for the study will be performed at this point and the 
study will be unblinded. All outstanding data issues will be resolved ahead of the final 
lock. All study data will be included in the clean snapshot of the database after the final 
data lock. All analyses described in this analysis plan will be performed as part of final 
analysis. Results from these analyses will be included in the Clinical Study Report. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
All endpoints in the study will be analyzed as-is and no imputation is planned. 
8.4 
Detection of Bias 
Important protocol deviations and early withdrawal from treatment and from study may 
bias the results of the study.  The incidence of these factors will be assessed and reason 
for early withdrawals will be tabulated. 
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified. 
Pharmacokinetic (PK) serum concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Not applicable for this study. 
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8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures. 
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs. 
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD, 
immunogenicity, efficacy, and biomarker data.  Descriptive statistics on continuous 
measurements will include means, medians, Q1, Q3, standard deviations, standard 
errors and ranges, while categorical data will be summarized using frequency counts 
and percentages.  Data will be presented and summarized by treatment and also by time 
as appropriate. 
For the DLRM analyses safety data will be listed and figures may be provided.  The 
scope of review includes all available study data including demographics, medical 
history, concomitant therapies, adverse events, electrocardiograms, vital signs, 
laboratory results, and emerging pharmacokinetic and pharmacodynamics data. 
9.2 
Subject Accountability 
The number and percent of subjects who were enrolled, received at least one dose of 
investigational product, completed investigational product, discontinued from 
investigational product (including reasons for discontinuing), completed study, 
discontinued the study (including reasons for discontinuing) will be summarized overall 
and by dose cohort. 
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented. 
A summary of number of subjects in each analysis subset will be provided. 
9.3 
Important Protocol Deviations 
Important protocol deviations (IPDs) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD reviews throughout the study prior 
to database lock.  These definitions of IPD categories, subcategory codes, and 
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descriptions will be used during the course of the study.  The final IPD list is used to 
produce the Summary of IPDs table and the List of Subjects with IPDs. 
Eligibility deviations are defined in the protocol.  A list of deviations from eligibility criteria 
will also be generated. 
The number of subjects with important protocol deviations and protocol deviations due to 
COVID-19 will be summarized in a table. A list of important protocol deviations and 
protocol deviations for subjects impacted by COVID-19 will also be provided. 
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9.4 
Demographic and Baseline Characteristics 
9.4.1 
Demographic  
 
Age (years) at enrollment (continuous summary statistics) 
 
Age in categories (number and percentage of 18 – 64, 65 – 74, 75 – 84, ≥ 85 
years) 
 
Sex (number and percentage of males and females) 
 
Ethnicity (number and percentage of Hispanic or Latino and Not Hispanic or 
Latino) 
 
Race (number and percentage of subjects in each race, or mixed-race 
combination) 
9.4.2 
Baseline Characteristics 
 
Height, weight and Body Mass Index (BMI) (continuous summary statistics) 
 
Baseline SLEDAI-2K score (number and percentage of 0 to 5, 6 to 9, ≥ 10) 
 
Subject incidence (number and percentage) of baseline corticosteroids and 
baseline SLE-related medication 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Exploratory Efficacy Endpoint (s) 
The SLEDAI-2K total score and change from baseline will be provided at all time points 
collected. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
The primary endpoint of this study is safety.  The analysis will include the descriptive 
summary statistics for adverse events, disease-related events, laboratory measures, 
vital signs, physical measurements.  Details are described in respective section below. 
Safety analysis set will be used for analyses included in this section. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 or later will be 
used to code all events categorized as adverse events, all disease-related events to a 
system organ class and a preferred term.  The severity of each adverse event will be 
graded using CTCAE criteria version 4.03. 
Subject incidence of all treatment-emergent, serious treatment-emergent, treatment-
related, serious treatment-related, disease-related treatment-emergent, those leading to 
withdrawal from investigational product, and fatal adverse events will be tabulated by 
system organ class in alphabetical order, preferred term and grade in descending order 
of frequency.  Subject incidence of treatment-emergent adverse events identified by 
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COVID-19 standardized MedDRA queries and serious adverse events occurring on or 
after the COVID-19 infection will also be summarized. 
Subject incidence of treatment-emergent events of interest (standardized MedDRA 
queries and/or Amgen Medical Queries) will also be summarized according to their 
categories, preferred term, and worst severity grade. Events of interest could include but 
are not limited to Hypersensitivity, Tachyarrhythmias, Tachypnea, Hematopoietic 
Cytopenia, Drug Reaction with Eosinophilia, Leucocyte Changes, Infection and Infestation, 
Cytokine Release Syndrome, and Injection Site Reaction. Number of episodes and 
duration of treatment-emergent injection site reactions will be further summarized by 
treatment group. 
9.6.3 
Laboratory Test Results 
The laboratory analytes listed below in the Table 9-1 will be analyzed. Unscheduled 
assessments (Appendix B) will be incorporated in the laboratory analyses where 
possible. 
For chemistry and hematology lab analytes, the analyses of safety laboratory 
endpoints will include summary statistics of baseline, post-baseline values at all time 
points, change from baseline to post-baseline values at all time points, post-baseline 
maximum/minimum and change from baseline to post-baseline maximum/minimum by 
treatment group. Shifts in grades of safety laboratory values between the baseline and 
the worst on-study value will be tabulated based on CTCAE version 4.03. Subject 
incidence of worst post-baseline level of eosinophils counts by the laboratory 
normal range will be tabulated by treatment group. 
The urine protein analyte in the urinalysis will be graded in the following manner: 
Negative, Trace, 1+, 2+, 3+, 4+. The number and percent of subjects in these 
categories at all time points will be presented. 
Table 9-1.  Analyte Listing 
Chemistry 
Hematology  
Urinalysis 
Sodium 
Red blood cells 
Urine protein 
Potassium 
Antinuclear antibody 
Chloride 
Hemoglobin 
Bicarbonate 
Hematocrit 
Total protein 
Mean corpuscular volume 
(MCV) 
Albumin 
Mean corpuscular 
hemoglobin (MCH) 
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Calcium 
Mean corpuscular 
hemoglobin concentration 
(MCHC) 
Magnesium 
Red cell distribution width 
(RDW) 
Phosphorus 
Reticulocytes 
Glucose 
Platelets 
BUN or Urea 
White blood cells 
Creatinine 
WBC Differential 
 Total neutrophils or 
segmented neutrophils  
 Bands/stab  
 Eosinophils  
 Basophils  
 Lymphocytes  
 Monocytes  
Total bilirubin 
Direct bilirubin 
Alkaline Phosphatase 
(ALP) 
Aspartate 
Aminotransferase 
(AST) (Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)) 
Alanine 
Aminotransferase 
(ALT) (Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)) 
 
9.6.4 
Vital Signs 
The analyses of vital signs will include summary statistics for baseline, post-baseline 
values at all time points, change from baseline to post-baseline values at all time points, 
post-baseline maximum/minimum and change from baseline to post-baseline 
maximum/minimum by treatment group for systolic blood pressure, diastolic blood 
pressure, heart rate and temperature. 
9.6.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at all time points 
by treatment group. 
9.6.6 
Electrocardiogram 
The ECG measurements will be performed as per standard of care for routine safety 
monitoring, rather than for purposes of assessment of potential QTc effect.  Since these 
evaluations may not necessarily be performed under the rigorous conditions expected to 
lead to meaningful evaluation of QTc data, summaries and statistical analyses of ECG 
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measurements are not planned, and these data would not be expected to be useful for 
meta-analysis with data from other trials. 
9.6.7 
Antibody Formation 
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. 
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. The number of days on investigational product and the total dose of 
investigational product will be summarized using descriptive statistics.  Subject-level 
data may be provided instead of the summary if the subject incidence is low or single 
dose is given. 
Descriptive statistics of the total dose, number of doses received, duration of usage, 
and number and percentage of subjects with number of doses received, dose 
change/withheld and reasons for dose change/withheld will be summarized. Number 
and percentage of subjects with missed IP doses due to COVID-19 will be also 
summarized. 
A listing of the unique manufacturing lot numbers and a listing of the subjects 
administered by each manufacturing lot number will be provided. 
9.6.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category for each treatment group as coded by the World Health 
Organization Drug dictionary.   
9.7 
Other Analyses 
Secondary endpoints in study include PK endpoints and immunogenicity endpoints. 
Exploratory endpoints in this study include biomarker endpoints, efficacy endpoint and 
PD endpoints. 
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9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
9.7.1.1 
Analysis of Pharmacokinetic Endpoint 
The Pharmacokinetic Concentration Analysis Set defined in Section 6 will be used in 
analyzing PK concentration data and the Pharmacokinetic Parameter Analysis Set will 
be used in analyzing PK parameters.  Serum concentrations of AMG592 will be 
expressed in ng/mL.  All concentrations below the limit of quantification or missing data 
will be labeled as such in the concentration data listings.  Concentrations below the 
lower limit of quantification will be treated as zero in summary statistics. 
Nominal sampling times will be used for individual concentration-time plots and tables.  
Actual dose administered, and actual sampling times will be used for the calculation of 
PK parameters for each subject.  The reasons for excluding any sample from the 
analyses will be provided. 
From the serum concentration-time data, the following PK parameters will be 
determined, as data permit: maximum observed concentration (Cmax), the time of 
maximum observed concentration (Tmax), and area under the concentration-time curve 
over a dosing interval (AUCtau) after the first and last doses. 
Individual concentration-time data will be tabulated and presented graphically.  Summary 
of PK concentration over time and PK parameters will be provided.  Mean concentration 
time profiles for each dose will be provided.  PK parameters will be summarized for each 
dose using descriptive statistics, including, but not limited to mean, standard deviation, 
CV, median and range by treatment group.  Analyses will be conducted by Amgen 
Clinical Pharmacology Modeling and Simulation (CPMS). 
9.7.1.2 
Analysis of Pharmacodynamic Endpoints 
The pharmacodynamic analysis set defined in Section 6 will be used. PD assessments 
include but are not limited to: 
 
Regulatory T cells (Treg), Conventional T cells (Tcon), CD8 T cells and Natural 
Killer (NK) absolute cell counts and percentages 
 
Treg/Tcon ratio 
Fold changes from baseline in the above PD assessments at all time points will be 
summarized by treatment group. Furthermore, the mean (+/- standard error) of fold 
changes from baseline will be plotted for each treatment group at all time points. Due to 
the skewed distribution of PD data, the mean, standard deviation and standard error will 
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be estimated based on log-transformed data, and the estimates will be back-transformed 
and presented, which are equivalent to the geometric mean, geometric standard 
deviation and geometric standard error respectively. 
To maintain the integrity of PD results, data collected at an early termination visit which 
is completed outside the protocol defined window (> 9 days after the last dose date for 
QW cohorts and > 16 days for Q2W cohorts) will not be included in the analysis. In 
addition, data collected at a visit after skipping one or more consecutive doses prior to 
the visit will be also excluded. 
9.7.2 
Analyses of Biomarker Endpoints 
Absolute and change from baseline in anti-double stranded DNA (anti-dsDNA), and C3 
and C4 complements at all time points will be summarized by treatment group. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
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11. 
Literature Citations / References 
Babb J, Rogatko A, Zacks S.  Cancer Phase I Clinical Trias:  Efficient Dose Escalation 
with Overdose Control.  Statistics in Medicine 1998;17:1103-1120 
Bailey S, Neuenschwander B, Laird G et al.  A Bayesian case study in oncology Phase 1 
combination dose-finding using logistic regression with covariates.  J Biopharm Stat.  
2009;19:469-484. 
Jolly M, Pickard AS, Wilke C et al. Lupus-specific health outcome measure for US 
patients: the LupusQoL-US version. Ann Rheum Dis. 2010;69:29-33. 
McElhone K, Abbott J, Shelmerdine J et al. Development and validation of a disease 
specific health-related quality of life measure, the LupusQol, for adults with systemic 
lupus erythematosus. Arthritis Rheum. 2007;57:972-979. 
Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared 
with fatigue in the general United States population. Cancer. 2002;94:528-538. 
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12. 
Appendices 
Appendix A. Concomitant Medications/Adverse Event Missing Value Imputation 
Imputation Rules for Partial or Missing Stop Dates 
If the month and year are present, impute the last day of the month.  If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing.  If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial. 
Imputation Rules for Partial or Missing Start Dates 
 
Stop Date 
 
 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start Date 
 
<1st 
Dose 
1st 
Dose 
<1st Dose 
yyyymm 
1st Dose 
yyyymm 
<1st 
Dose 
yyyy 
1st 
Dose 
yyyy 
Partial: 
yyyymm 
=1st Dose 
yyyymm 
2 
1 
2 
1 
N/A 
1 
1 
 1st Dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
=1st Dose 
yyyy 
3 
1 
3 
1 
N/A 
1 
1 
 1st Dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month. 
Note: If the start date imputation leads to a start date that is after the stop date, then do not impute the start 
date. 
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Appendix B.  Analytical Windows 
The last measurement for the endpoint of interest taken prior to or on the first dose of 
investigational product in this study, unless stated otherwise will be defined as a 
baseline visit and the analysis visit name will be “Baseline”.  For any visit up to Day 1 
pre-dose which is not a baseline visit, the analysis visit will be ‘Pre-Analysis’. 
For post-dose assessments on Day 1, post-dose assessments on Day 85 (the day 
corresponding to week 12 dosing) and assessments at Safety follow-up/EOS visit, the 
analysis visit will be same as the scheduled visit. 
Remaining visits (scheduled or unscheduled) after Day 1 for any assessment will be 
mapped to the analysis visit based on visit windows defined in the tables below for that 
assessment.  Only visits applicable for that assessment will be considered for analysis. 
Data collected through central lab and local lab will both be mapped into analysis visit 
windows.  The local lab data can only be used in analysis when there are no central lab 
data available in the analysis visit window. 
If more than one visit with non-missing data falls within an analysis visit window, the visit 
closest to the target day will be considered for analysis. If two visits are equidistant from 
the target day, the latest visit (or time if on the same day) will be considered. If more 
than one evaluation has same date and time (for chemistry, hematology or 
pharmacodynamics results), the value with the smallest accession number will be 
considered. 
Analysis visit windows for selected assessments are included in tables below. For 
remaining assessments, no visit window will be applied. ‘Day 85’ used in study day 
window calculation in the tables below is the actual study day when Week 12 dose was 
received. If that dose is missing, then target Day 85 is used for the calculation. 
Vital Sign 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 1, Day 2 
2 
2 
2 
Week 1, Day 3 
3 
3 
3 
Week 1, Day 4 
4 
4 
6 
Week 1, Day 8 
8 
7 
9 
Week 1, Day 11 
11 
10 
12 
Week 2, Day 15 
15 
13 
19 
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Week 3, Day 22 
22 
20 
26 
Week 4, Day 29 
29 
27 
33 
Week 5, Day 36 
36 
34 
40 
Week 6, Day 43 
43 
41 
47 
Week 7, Day 50 
50 
48 
54 
Week 8, Day 57 
57 
55 
61 
Week 9, Day 64 
64 
62 
68 
Week 10, Day 71 
71 
69 
75 
Week 11, Day 78 
78 
76 
 ‘Day 85’ - 1 
Week 12, Day 85 
85 
‘Day 85’ 
Week 12, Day 86 
86 
‘Day 85’ + 1 
‘Day 85’ + 1 
Week 12, Day 87 
87 
‘Day 85’ + 2 
‘Day 85’ + 2 
Week 12, Day 88 
88 
‘Day 85’ + 3 
‘Day 85’ + 3 
Week 13, Day 92 
92 
‘Day 85’ + 4 
96 
Week 14, Day 99 
99 
97 
106 
Week 16, Day 113 
113 
107 
120 
Week 18 (SFU), Day 
127 
127 
>120 
 
Chemistry 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 4, Day 29 
29 
2 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
Week 18 (SFU), Day 
127 
127 
>‘Day 85’ 
 
Hematology 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 1, Day 2 
2 
2 
3 
Week 2, Day 15 
15 
4 
22 
Week 4, Day 29 
29 
23 
36 
Week 6, Day 43 
43 
37 
50 
Week 8, Day 57 
57 
51 
64 
Week 10, Day 71 
71 
65 
78 
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Week 12, Day 85 Pre-
Dose 
85 
79 
‘Day 85’ 
Week 14, Day 99 
99 
‘Day 85’ + 1 
106 
Week 16, Day 113 
113 
107 
120 
Week 18 (SFU), Day 
127 
127 
>120 
 
Urinalysis 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 4, Day 29 
29 
2 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
Weight 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 12, Day 85 Pre-
Dose 
85 
2 
‘Day 85’ 
Week 18 (SFU), Day 
127 
127 
>’Day 85’ 
 
Pharmacodynamic Assessments 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 1, Day 2 
2 
2 
2 
Week 1, Day 4 
4 
3 
6 
Week 1, Day 8 
8 
7 
9 
Week 1, Day 11 
11 
10 
12 
Week 2, Day 15 
15 
13 
19 
Week 3, Day 22 
22 
20 
26 
Week 4, Day 29 
29 
27 
33 
Week 5, Day 36 
36 
34 
40 
Week 6, Day 43 
43 
41 
47 
Week 7, Day 50 
50 
48 
54 
Week 8, Day 57 
57 
55 
61 
Week 9, Day 64 
64 
62 
68 
Week 10, Day71 
71 
69 
75 
Week 11, Day 78 
78 
76 
82 
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Week 12, Day 85 Pre-
dose 
85 
83 
‘Day 85’ 
Week 13, Day 92 
92 
‘Day 85’ +1 
96 
Week 14, Day 99 
99 
97 
106 
Week 16, Day 113 
113 
107 
120 
Week 18 (SFU), Day 
127 
127 
>120 
 
Antibody Assessments 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 2, Day 15 
15 
2 
22 
Week 4, Day 29 
29 
23 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
Week 18 (SFU), Day 
127 
127 
>’Day 85’ 
 
Efficacy assessments (SLEDAI-2K) 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 4, Day 29 
29 
2 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
Anti-double stranded DNA 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 1, Day 8 
8 
2 
15 
Week 4, Day 29 
29 
16 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
Week 18 (SFU), Day 
127 
127 
>’Day 85’ 
 
 
 
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C3 and C4 Complement 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 1, Day 8 
8 
2 
15 
Week 4, Day 29 
29 
16 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
Week 18 (SFU), Day 127 
127 
>’Day 85’ 
 
 
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Appendix C.  Summary of Changes and Rationale for Change to the SAP 
Amendment 3 
The statistical analysis plan for this study was amended to reflect the changes in  
laboratory test results and Appendix B. Editorial changes and minor clarifications were 
also implemented throughout the document. 
Description of Changes 
Global 
Header date was replaced with 09 November 2021. 
9. Statistical Methods of analysis 
9.6.3 Laboratory Test Results 
Removed:  
Individual chemistry and hematology laboratory data will be listed.  Values outside the 
normal laboratory reference ranges will be flagged as high or low on the listings.  
CTCAE grades will also be highlighted where appropriate 
Added: 
The urine protein analyte in the urinalysis will be graded in the following manner: 
Negative, Trace, 1, 2, 3, 4. The number and percent of subjects in these categories 
at all time points will be presented. 
Revised: 
For chemistry and hematology lab analytes, the analyses of safety laboratory 
endpoints will include summary statistics of baseline, post-baseline values at all time 
points, change from baseline to post-baseline values at all time points, post-baseline 
maximum/minimum and change from baseline to post-baseline maximum/minimum by 
treatment group. Shifts in grades of safety laboratory values between the baseline and 
the worst on-study value will be tabulated based on CTCAE version 4.03. Subject 
incidence of worst post-baseline level of eosinophils counts by the laboratory 
normal range will be tabulated by treatment group. 
 
 
 
 
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Table 9-1.  Analyte Listing 
Chemistry 
Hematology  
Urinalysis 
Sodium 
Red blood cells 
Urine protein 
Potassium 
Antinuclear antibody 
Chloride 
Hemoglobin 
Bicarbonate 
Hematocrit 
Total protein 
Mean corpuscular volume 
(MCV) 
Albumin 
Mean corpuscular 
hemoglobin (MCH) 
Calcium 
Mean corpuscular 
hemoglobin concentration 
(MCHC) 
Magnesium 
Red cell distribution width 
(RDW) 
Phosphorus 
Reticulocytes 
Glucose 
Platelets 
BUN or Urea 
White blood cells 
Creatinine 
WBC Differential 
 Total neutrophils or 
segmented neutrophils  
 Bands/stab  
 Eosinophils  
 Basophils  
 Lymphocytes  
 Monocytes  
Total bilirubin 
Direct bilirubin 
Alkaline Phosphatase 
(ALP) 
Aspartate 
Aminotransferase 
(AST) (Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)) 
Alanine 
Aminotransferase 
(ALT) (Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)) 
9.6.8 Exposure to Investigational Product 
Revised:  
Descriptive statistics of the total dose, number of doses received, duration of usage, 
and number and percentage of subjects with number of doses received, dose 
change/withheld and reasons for dose change/withheld will be summarized. Number 
and percentage of subjects with missed IP doses due to COVID-19 will be also 
summarized. 
 
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12. Appendices 
Appendix B. Analytical Windows 
Removed:  
ECG 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 1, Day 2 
2 
2 
3 
Week 1, Day 8 
8 
4 
12 
Week 2, Day 15 
15 
13 
22 
Week 4, Day 29 
29 
23 
36 
Week 6, Day 43 
43 
37 
50 
Week 12, Day 86 
86 
51 
91 
Week 14, Day 99 
99 
92 
106 
Week 16, Day 113 
113 
107 
120 
Week 18 (SFU), Day 
127 
127 
120 
 
 
Added: 
Chemistry 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 4, Day 29 
29 
2 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
Week 18 (SFU), Day 
127 
127 
‘Day 85’ 
 
Urinalysis 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 4, Day 29 
29 
2 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
 
 
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Revised: 
Hematology 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 1, Day 2 
2 
2 
3 
Week 2, Day 15 
15 
4 
22 
Week 4, Day 29 
29 
23 
36 
Week 6, Day 43 
43 
37 
50 
Weight 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 12, Day 85 Pre-
Dose 
85 
2 
‘Day 85’ 
Week 18 (SFU), Day 
127 
127 
’Day 85’ 
 
Efficacy assessments (SLEDAI-2K) 
Analysis Visit 
Target Day 
Start Day 
End Day 
Week 4, Day 29 
29 
2 
43 
Week 8, Day 57 
57 
44 
71 
Week 12, Day 85 Pre-
Dose 
85 
72 
‘Day 85’ 
 
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