Clinical trial NCT03410056
Conditions: Rheumatoid Arthritis RA
Sponsor: Amgen
Start date: 2018-05-22; Completion date: 2020-05-13
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Phase 1b. To evaluate the safety and tolerability of subcutaneous (SC) dose administrations of Efavaleukin alfa in subjects with active rheumatoid arthritis (RA).

Phase 2a. To evaluate the efficacy of Efavaleukin alfa at week 12 as measured by the American College of Rheumatology 20 percent improvement criteria (ACR 20) in adult subjects with moderate to severe RA.

Detailed description:

Arms: arm 1: Matching placebo administered via subcutaneous injection for a total of up to 12 weeks. Participants received placebo in 1 of 2 dosing schedules (i.e. dosing schedule A \[less frequent\] or schedule B \[more frequent\]). arm 2: A low dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks. arm 3: A high dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks. arm 4: A medium dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule B (more frequent than schedule A) for a total of up to 12 weeks. arm 5: A medium/high dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule B (more frequent than schedule A) for a total of up to 12 weeks. arm 6: Matching placebo administered via subcutaneous injection, depending on the recommended phase 2 dose (RP2D) and dosing schedule as determined in phase 1b, for a total of up to 12 weeks. arm 7: Efavaleukin alfa administered via subcutaneous injection depending on the RP2D and dosing schedule determined in phase 1b, for up to a total of up to 12 weeks.
Interventions: intervention 1: Efavaleukin alfa intervention 2: Placebo
Intervention descriptions: intervention 1: Efavaleukin alfa administered as a subcutaneous injection. intervention 2: Placebo administered as a subcutaneous injection.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 592  
Protocol Number:  20170149 
Date:  06 June 2019 
Page 1 of 113 
 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
A Phase 1b/2a Study to Evaluate the Safety and 
Efficacy of AMG 592 in Subjects With Active 
Rheumatoid Arthritis With Inadequate Response 
to Standard of Care Therapy 
Short Protocol Title: 
Safety and Efficacy of AMG 592 in Subjects with 
Active Rheumatoid Arthritis 
Protocol Number: 
20170149 
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 and 
 MD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone 
Number: 
 
Email Address: 
 
EudraCT Number: 
2017‐001944‐36 
NCT Number: 
NCT03410056 
Protocol Date: 
Document Version 
Date 
Original 
26 June 2017 
Amendment 1 
23 May 2018 
Amendment 2 
26 July 2018 
Amendment 3 
06 June 2019 
Version/Date: 
Data Element 
Standards Version 
 
5.0 
 
 
Approved 
 
 


Product:  AMG 592  
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Page 2 of 113 
 
CONFIDENTIAL 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 
Approved 
 
 


Product:  AMG 592  
Protocol Number:  20170149 
Date:  06 June 2019 
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CONFIDENTIAL 
 
 
Investigator's Agreement: 
I have read the attached protocol entitled A Phase 1b/2a Study to Evaluate the Safety 
and Efficacy of AMG 592 in Subjects with Active Rheumatoid Arthritis With Inadequate 
Response to Standard of Care Therapy, dated 06 June 2019, 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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Date:  06 June 2019 
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CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Synopsis ................................................................................................. 10 
2. 
Study Schema and Schedule of Activities ............................................................. 15 
2.1 
Study Schema ........................................................................................... 15 
2.2 
Schedule of Activities ................................................................................ 17 
3. 
Introduction ........................................................................................................... 25 
3.1 
Study Rationale ......................................................................................... 25 
3.2 
Background ............................................................................................... 25 
3.2.1 
Disease ..................................................................................... 25 
3.2.2 
T regulatory Cells in Rheumatoid Arthritis .................................. 25 
3.2.3 
Low Dose Interleukin 2 in Inflammatory Disease ....................... 26 
3.2.5 
Risk Assessment ....................................................................... 28 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 29 
4.1 
Objectives and Endpoints .......................................................................... 29 
4.2 
Hypotheses ............................................................................................... 31 
5. 
Study Design ........................................................................................................ 31 
5.1 
Overall Design .......................................................................................... 31 
5.1.1 
Phase 1b Study Design ............................................................. 31 
 
 
5.2 
Number of Subjects ................................................................................... 34 
5.2.1 
Replacement of Subjects ........................................................... 34 
5.2.2 
Number of Sites ......................................................................... 34 
5.3 
End of Study ............................................................................................. 35 
5.3.1 
End of Study Definition .............................................................. 35 
5.3.2 
Study Duration for Subjects ....................................................... 35 
6. 
Study Population .................................................................................................. 36 
6.1 
Inclusion Criteria ....................................................................................... 37 
6.2 
Exclusion Criteria ...................................................................................... 38 
6.3 
Lifestyle Restrictions ................................................................................. 41 
6.3.1 
Alcohol and Tobacco ................................................................. 41 
6.3.2 
Activity ....................................................................................... 42 
6.4 
Subject Enrollment .................................................................................... 42 
6.5 
Screen Failures ......................................................................................... 42 
Approved 
 
 


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CONFIDENTIAL 
 
 
7. 
Treatments ........................................................................................................... 43 
7.1 
Treatment Procedures............................................................................... 43 
7.1.1 
Investigational Products ............................................................ 43 
7.1.1.1 
Amgen Investigational Product:  AMG 592 .............. 43 
7.1.2 
Non-investigational Products ..................................................... 44 
7.1.3 
Medical Devices ........................................................................ 44 
7.1.4 
Other Protocol-required Therapies ............................................ 45 
7.1.5 
Other Treatment Procedures ..................................................... 45 
7.1.6 
Product Complaints ................................................................... 45 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 45 
7.2 
Method of Treatment Assignment ............................................................. 46 
7.3 
Blinding ..................................................................................................... 46 
7.3.1 
Site Personnel Access to Individual Treatment 
Assignments ............................................................................. 47 
7.3.2 
Access to Individual Subject Treatment Assignments 
by Amgen or Designees ............................................................ 47 
7.4 
Dose Modification ...................................................................................... 47 
7.4.1 
Hepatotoxicity Stopping Rules ................................................... 47 
7.4.2 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules (Phase 1b)........................................................ 48 
7.4.2.1 
Dose Level Review Meetings .................................. 48 
7.4.2.2 
Dose Cohort Stopping Rules ................................... 48 
7.4.3 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 50 
7.4.3.1 
Amgen Investigational Product:  AMG 592 .............. 50 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 50 
7.6 
Treatment Compliance .............................................................................. 50 
7.7 
Treatment of Overdose ............................................................................. 50 
7.8 
Prior and Concomitant Treatment ............................................................. 50 
7.8.1 
Prior Treatment ......................................................................... 50 
7.8.2 
Concomitant Treatment ............................................................. 50 
7.8.2.1 
Methotrexate ........................................................... 50 
7.8.2.2 
Analgesics and NSAIDs .......................................... 51 
7.8.2.3 
Corticosteroids ........................................................ 51 
7.8.2.4 
DMARDS ................................................................ 51 
8. 
Discontinuation Criteria ......................................................................................... 52 
8.1 
Discontinuation of Study Treatment........................................................... 52 
8.2 
Discontinuation From the Study ................................................................ 53 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 53 
8.2.2 
Reasons for Removal From Study ............................................. 53 
8.3 
Lost to Follow-up ....................................................................................... 53 
Approved 
 
 


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9. 
Study Assessments and Procedures .................................................................... 54 
9.1 
General Study Periods .............................................................................. 54 
9.1.1 
Screening, Enrollment and Randomization ................................ 54 
9.1.2 
Treatment Period ....................................................................... 55 
9.1.3 
Follow-up/Safety Follow-up/End of Study for Phase 1b ............. 55 
9.2 
Description of General Study Assessments and Procedures ..................... 56 
9.2.1 
General Assessments ............................................................... 56 
9.2.1.1 
Informed Consent .................................................... 56 
9.2.1.2 
Demographics ......................................................... 56 
9.2.1.3 
Medical History ........................................................ 56 
9.2.1.4 
Physical Examination .............................................. 56 
9.2.1.5 
Physical Measurements .......................................... 56 
9.2.1.6 
Substance Use History ............................................ 57 
9.2.2 
Efficacy Assessments ................................................................ 57 
9.2.2.2 
DAS28-CRP ............................................................ 57 
9.2.3 
Safety Assessments .................................................................. 58 
9.2.3.1 
Adverse Events ....................................................... 58 
9.2.3.2 
Vital Signs ............................................................... 61 
9.2.3.3 
Electrocardiograms ................................................. 62 
9.2.4 
Clinical Laboratory Assessments ............................................... 62 
9.2.4.1 
Tuberculosis Testing ............................................... 64 
9.2.4.2 
Human Immunodeficiency Virus, 
Hepatitis B Surface Antigen, and 
Hepatitis C Antibody ................................................ 64 
9.2.4.3 
Pregnancy Testing .................................................. 64 
9.2.4.4 
Prespecified Biomarker Assessments ..................... 65 
9.2.5 
Pharmacokinetic Assessments .................................................. 65 
9.2.7 
Pharmacogenetic Assessments................................................. 66 
9.2.8 
Antibody Testing Procedures ..................................................... 66 
9.2.9 
Biomarker Development ............................................................ 67 
Approved 
 
 


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CONFIDENTIAL 
 
 
9.2.11 
Other Assessments ................................................................... 68 
10. 
Statistical Considerations ...................................................................................... 69 
10.1 
Sample Size Determination ....................................................................... 69 
10.1.1 
Phase 1b ................................................................................... 69 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 70 
10.2.1 
Analysis Sets ............................................................................. 70 
10.2.1.1 
Phase 1b ................................................................. 70 
10.2.2 
Covariates ................................................................................. 71 
10.2.2.1 
Phase 1b ................................................................. 71 
10.2.3 
Subgroups ................................................................................. 72 
10.2.3.1 
Phase 1b ................................................................. 72 
10.2.4 
Handling of Missing and Incomplete Data .................................. 72 
10.2.4.1 
Phase 1b ................................................................. 72 
10.3 
Statistical Analyses ................................................................................... 72 
10.3.1 
Planned Analyses ...................................................................... 73 
10.3.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 73 
10.3.1.2 
Primary Analysis ..................................................... 73 
10.3.2 
Methods of Analyses ................................................................. 73 
10.3.2.1 
General Considerations ........................................... 73 
10.3.2.2 
Efficacy Analyses .................................................... 74 
10.3.2.3 
Safety Analyses ...................................................... 74 
11. 
References ........................................................................................................... 77 
12. 
Appendices ........................................................................................................... 79 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 80 
Appendix 2.  Clinical Laboratory Tests .................................................................. 83 
Appendix 3.  Study Governance Considerations ................................................... 85 
Dose Level Review Meetings and Data Review Team .............................. 85 
Regulatory and Ethical Considerations ...................................................... 86 
Informed Consent Process ........................................................................ 87 
Data Protection/Subject Confidentiality ..................................................... 88 
Publication Policy ...................................................................................... 89 
Investigator Signatory Obligations ............................................................. 90 
Data Quality Assurance ............................................................................. 90 
Approved 
 
 


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Date:  06 June 2019 
Page 8 of 113 
 
CONFIDENTIAL 
 
 
Source Documents .................................................................................... 92 
Study and Site Closure.............................................................................. 93 
Compensation ........................................................................................... 93 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ......................................................... 94 
Definition of Disease-related Event ........................................................... 94 
Definition of Adverse Event ....................................................................... 94 
Definition of Serious Adverse Event .......................................................... 95 
Recording Adverse Events, Disease-related Events (if 
applicable), and Serious Adverse Events .................................. 96 
Evaluating Adverse Events and Serious Adverse Events .......................... 97 
Reporting of Serious Adverse Event .......................................................... 98 
Adverse Device Effects:  Recording, Evaluating and Reporting ................. 98 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information ............................................................................... 102 
Definition of Females of Childbearing Potential ....................................... 102 
Collection of Pregnancy Information ........................................................ 103 
Collection of Lactation Information .......................................................... 105 
Appendix 6.  Sample Storage and Destruction .................................................... 108 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 110 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity.......................................................................... 110 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 111 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 112 
List of Tables 
Table 2-1.  Phase 1b Schedule of Activities Screening and Treatment Period ............... 17 
Table 2-2.  Phase 1b Schedule of Activities Follow-up .................................................. 20 
Table 7-1.  Dose Cohort Stopping Rules ....................................................................... 49 
Approved 
 
 


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CONFIDENTIAL 
 
 
Table 12-1.  Analyte Listing ........................................................................................... 83 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ............................................. 111 
List of Figures 
Figure 2-1.  Study Schema Phase 1b ............................................................................ 15 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 99 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet .................................... 106 
 
Approved 
 
 


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CONFIDENTIAL 
 
 
1. 
Protocol Synopsis 
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of AMG 592 in 
Subjects with Active Rheumatoid Arthritis With Inadequate Response to Standard of 
Care Therapy 
Short Protocol Title:  Safety and Efficacy of AMG 592 in Subjects with Active 
Rheumatoid Arthritis 
Study Phase:  Phase 1b/2a 
Indication:  Rheumatoid Arthritis (RA) 
Rationale 
This is a double-blind, placebo-controlled, multicenter phase 1b/2a study to evaluate the 
safety and efficacy of AMG 592 in subjects with active RA.  The phase 1b part of the 
study will evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 
AMG 592 and will define the maximum tolerated dose.  This information will be used to 
determine the recommended phase 2a dose (RP2D) for the phase 2a part of the study.  
The phase 2a part of the study will assess the efficacy and safety of AMG 592 in 
subjects with moderate to severe RA treated with the RP2D. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
Phase 1b 
• 
To evaluate the safety and tolerability of 
subcutaneous (SC) dose administrations 
of AMG 592 in subjects with active RA 
Phase 1b 
• 
Treatment-emergent adverse events. 
• 
Clinically significant changes in vital signs, 
laboratory safety tests, and 
electrocardiograms (ECGs) 
Phase 2a 
• 
To evaluate the efficacy of AMG 592 at 
week 12 as measured by the American 
College of Rheumatology 20% 
improvement criteria (ACR 20) in adult 
subjects with moderate to severe RA 
Phase 2a 
• 
ACR 20 at week 12 
Approved 
 
 


Product:  AMG 592  
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Date:  06 June 2019 
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CONFIDENTIAL 
 
 
Objectives 
Endpoints 
Secondary 
Phase 1b 
• 
To characterize the pharmacokinetic (PK) 
profile following treatment with AMG 592 
Phase 1b 
• 
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 (AUCtau) after the 
first and last doses.  Area under the 
concentration-time curve over the dosing 
interval will be calculated & reported for 
each dosing regimen 
• 
To evaluate the incidence of 
anti-AMG 592 antibody formation and 
cross-reactivity to human IL-2. 
• 
Anti-AMG 592 antibodies and 
cross-reactivity to IL-2. 
• 
Anti-AMG 592 and anti-IL 2 neutralizing 
antibodies 
Phase 2a 
• 
To evaluate the effect of treatment with 
AMG 592 on other measures of disease 
activity at week 12  
Phase 2a 
• 
ACR 50/70 at weeks 12  
• 
Disease activity score (28 joint) calculated 
using the erythrocyte sedimentation rate 
formula (DAS28-ESR) score and change 
from baseline at week 12  
• 
Disease activity score (28 joint) calculated 
using the C-reactive protein formula 
(DAS28-CRP) score and change from 
baseline at week 12 
• 
To evaluate the safety of AMG 592 
• 
Treatment-emergent adverse events. 
• 
Clinically significant changes in vital signs, 
laboratory safety tests  
• 
To characterize the PK of AMG 592 in 
subjects with RA 
• 
AMG 592 serum concentration and PK 
parameters  
Hypotheses 
Phase 1b: 
AMG 592 will be safe and well tolerated in subjects with active RA. 
Approved 
 
 


Product:  AMG 592  
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Date:  06 June 2019 
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CONFIDENTIAL 
 
 
Overall Design 
Phase 1b 
The phase 1b part of the study is a double-blind, placebo controlled, multiple ascending 
dose (MAD) study to evaluate the safety, PK, and PD of AMG 592 in subjects with active 
RA with inadequate response to standard of care therapy (ie, methotrexate and other 
standard of care therapies as defined below in the summary of eligibility criteria and 
Section 6.1 and 6.2).  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.  
The phase 1b will include 4 planned dosing-cohorts.  Subjects within a dosing-cohort 
will be randomized in a 3:1 ratio to AMG 592 (n = 6) or placebo (n = 2) as follows:  
cohort 1 
; cohort 2 
 cohort 3 
 
 and cohort 4 
 in addition to standard of care therapy.  
Approximately 8 additional subjects (6 AMG 592; 2 placebo) may be enrolled into 
each of cohorts 2 and 3.  Dosing cohorts will enroll sequentially with the exception of 
cohorts 2 and 3, which will enroll concurrently.  A Dose Level Review Meeting (DLRM) 
will convene after the last subject in each cohort completes the week 4 visit.  The 
exception is for cohorts 2 and 3 where an initial DLRM will convene after the first 16 
enrolled subjects (8 in each cohort) complete the week 4 visit and a second DLRM 
will convene after the remaining 16 enrolled subjects (8 in each cohort) complete 
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) 
(Bailey et al, 2009; Neuenschwander et al, 2008) will be implemented to model these 
events to aid dosing decisions before each DLRM.  DLRM members will be responsible 
for dosing recommendations (followed by an Amgen decision), which may include 
escalation to the next planned 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.  
 
 
 
 
 
  The phase 2a part of the study will 
commence after a RP2D is identified in the phase 1b part of the study.  
 
 
 
 
 
 
Number of Subjects 
In the phase 1b part of the study, sufficient subjects will be randomized to yield 
approximately 48 subjects (approximately 36 randomized to AMG 592 and  
12 randomized to placebo; see Section 5.2.1).  The total sample size may be higher 
than 48 subjects if, following a DLRM recommendation additional dosing cohorts 
Approved 
 
 


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Date:  06 June 2019 
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CONFIDENTIAL 
 
 
are added and/or existing cohorts are expanded, or subjects are replaced as per 
Section 5.2.1.  Additional subjects may be enrolled in each cohort to enable all 
screened eligible subjects to participate in the study.  Within each cohort subjects 
will be randomized to AMG 592 or placebo in a 3:1 ratio. 
Summary of Subject Eligibility Criteria 
Subjects must be adults with active RA and must be receiving treatment with 
methotrexate (oral or subcutaneous) for ≥ 12 weeks and on a stable dose ≥ 15 mg 
weekly for ≥ 8 weeks prior to day 1.  For the phase 1b part of the study, subjects must 
have a DAS28-CRP > 2.6 at screening and the concurrent use of other non-biological 
disease modifying anti-rheumatic drugs (DMARD) is allowed.  For the phase 2a part of 
the study, subjects must have ≥ 6 swollen joints (based on 66-joint count) and ≥ 6 tender 
joints (based on 68-joint count) at screening and baseline and a C-reactive protein 
(CRP) greater than the upper limit of normal at screening.  Subjects must be free of 
infections and significant concurrent medical conditions and laboratory abnormalities.  
Subjects must have negative test for tuberculosis, hepatitis B and C, human 
immunodeficiency virus (phase 1b only), 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 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.  
Placebo will be presented in similar containers and stored in the same manner as 
AMG 592.  AMG 592 or placebo will be administered by subcutaneous injection 
 
  
In the phase 1b part of the study, 4 dose cohorts are planned (cohort 1:  
 
cohort 2:  
 cohort 3:  
 and cohort 4:  
). 
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, concomitant medication assessment, tender 
and swollen joint assessment and count, clinical outcome assessments, tuberculosis 
testing, urinalysis, and blood draw for serum chemistry, hematology, hepatitis B and C 
testing, human immunodeficiency virus testing (phase 1b only), CRP, ESR, PK/PD, 
anti-AMG 592 antibodies, biomarker development and pharmacogenetics sample.  
Women of childbearing potential will have pregnancy tests performed at screening and 
during the study.  Safety assessments including adverse events, serious adverse 
events, and disease related events assessments will be performed throughout the safety 
follow-up. 
Approved 
 
 


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CONFIDENTIAL 
 
 
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, Table 2-2 and Table 2-3. 
Statistical Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD, and 
biomarker data.  Descriptive statistics on continuous measurements will include means, 
medians, 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.  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. 
The analyses of safety laboratory endpoints will include summary statistics at selected 
timepoints 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. 
Sponsor Name:  Amgen Inc 
 
Approved 
 
 


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CONFIDENTIAL 
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema Phase 1b 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
DLRM 2 
(All 32 
subjects) 
DLRM 1 
(Initial 16 
subjects) 
Cohort 1: 
(n = 6) and Placebo (n =2)  
Cohort 2: 
(n = 12) and Placebo (n = 4)  
DLRM 
Cohort 3: 
(n = 12) and Placebo (n = 4)  
DLRM 
Cohort 4: 
(n = 6) and Placebo (n = 2)  
 
Doses and size of subsequent treatment cohorts may change as determined by safety, BLRM by logistic regression modeling, and 
pharmacokinetic/pharmacodynamic modeling: 
• 
DLRM:  4 weeks after last subject in cohort enrolled except for cohorts 2 and 3 where an initial DLRM (DLRM 1) will convene after the first 
16 enrolled subjects (8 in each cohort) completes the week 4 visit and a second DLRM (DLRM 2) will convene after the remaining 16 
enrolled subjects (8 in each cohort) complete the week 4 visit.  
• 
Treatment Period:  12 weeks  
• 
Follow-up:  6 weeks after week 12 for collection of additional safety, pharmacokinetic, pharmacodynamics data.  For subjects who complete 
the study at week 18, the visit includes all required safety follow-up collection.  All subjects who terminate the study early (ie, prior to 
completing the week 18 visit) will complete an Early Termination visit consisting of all assessments included in the week 12, day 85 
pre-dose visit.  In addition, a safety follow-up visit will occur 6 weeks (± 3 days) after the last dose of investigational product to collect all 
required safety data including of adverse events, serious adverse events, disease related events, concomitant therapies, safety 
labs/assessments, anti-AMG 592 antibody, and urine pregnancy test. 
Follow-up (6 weeks) 
Follow-up (6 weeks) 
Follow-up (6 weeks) 
Follow-up (6 weeks) 
 
Approved 
 
 


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2.2 
Schedule of Activities 
Table 2-1.  Phase 1b Schedule of Activities Screening and Treatment Period 
 
Screening BL 
Treatment Period 
Study week 
 
 
 
1 
2 3 4 5 6 7 8 9 10 11 
12 
Study day 
-28 
-1 
1 
2 
3 4 8 11 15 22 29 36 43 50 57 64 71 78 
85 
86 87 88 
Hours post dose 
 
 
Predose 
0 0.25-2.0 
6 12 24 48  
 
 
 
 
 
 
 
 
 
 
 
 Predose 0 0.25-
2.0 
6 12 24 48 72 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
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 
Activity 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
ECG triplicate a  
X 
X 
 
 
 
X X 
X 
 
 X 
 
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-ray b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events c 
 
 
 
 
X 
X X 
X 
X X X X X X X X X X X X X X 
X 
 
X 
X X X X X 
Serious adverse events c 
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 
Disease-related events c 
 
 
 
 
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 
Prior therapies review 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies review c 
 
 
 
 
X 
X X 
X 
X X X X X X X X X X X X X X 
X 
 
 
 
 
X X X 
LABORATORY ASSESSMENTS 
Serum and/or urine pregnancy test c, d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Tuberculosis test e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug/alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B and C f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP & ESR c, f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Chemistry c, f 
X 
X 
 
 
 
 
 
X 
 
 X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Hematology c, f 
X 
X 
 
 
 
 
 
X 
 
 X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
FSH g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC c, f 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
RF & Anti-CCP antibody f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2
 
Footnotes defined on next page 
 
Approved 
 
 


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CONFIDENTIAL 
 
 
Table 2-1.  Phase 1b Schedule of Activities Screening and Treatment Period 
 
Screening 
BL 
Treatment Period 
Study week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 
12 
Study day 
-28 
-1 
1 
2 
3 4 8 11 15 22 29 36 43 50 57 64 71 78 
85 
86 87 88 
Hours post dose 
 
 
Predose 0 0.25-2.0 6 12 24 48  
 
 
 
 
 
 
 
 
 
 
 
 Predose 
0 0.25-2.0 6 12 24 48 72 
PHARMACOKINETICS AND ANTIBODIES 
Pharmacokinetic samples f 
 
 
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 antibody f 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
BIOMARKER AND PHARMACOGENETICS 
Biomarker development sample f 
 
 
X 
 
 
 
 
 
 
 X  
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Pharmacogenetics sample i 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
BL = baseline; ECG = electrocardiogram; HIV = human immunodeficiency virus; FSH = follicle stimulating hormone; 
 SFU = safety follow-up; 
RF = rheumatoid factor; anti-CCP = anti-cyclic citrullinated peptide; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; PBMC = peripheral blood mononuclear cell;  
 PK = pharmacokinetic. 
a Three sets of triplicate ECGs will be collected at the Day -1 visit.  At screening and after Day -1 triplicate ECGs 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 indeterminate Quantiferon) 
c For subjects who complete the study at week 18, the visit includes all required safety follow-up data collection.  All subjects who terminate the study early (ie, prior to completing the week 
18 visit), will complete an Early Termination visit consisting of all assessments included in the week 12, day 85 pre-dose visit.  In addition, a safety follow-up visit will occur 6 weeks  
(± 3 days) after the last dose of investigational product to collect all required safety data including adverse events, serious adverse events, disease related events, concomitant therapies, 
safety labs/assessments, anti-AMG 592 antibody, and urine pregnancy test.      
d For women of childbearing potential, serum pregnancy test is required at screening.  All other pregnancy tests are urine.  Positive urine pregnancy test should be confirmed with serum 
pregnancy test. 
 
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CONFIDENTIAL 
 
 
e Either a PPD or Quantiferon test will be done during screening. 
f All clinical laboratory (ie, chemistry, hematology) and pre-dose blood samples must be collected prior to administration of investigational product.  Pharmacokinetic (PK), pharmacodynamic 
and antibody blood samples may not be drawn through a central or peripheral line.  PK samples should be collected at the exact nominal time point as noted.  If unable to collect a PK 
sample at the specified nominal time point collect it as close as possible to the nominal time point and record the actual collection time.  PK samples not collected at exact nominal time 
point will not be considered protocol deviations. 
g Can be done as a part of the clinical chemistry. 
 
 
i DNA will be extracted only in subjects who provide additional consent for pharmacogenetics testing. 
 
 
 
 
 
 
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Table 2-2.  Phase 1b Schedule of Activities Follow-up 
Follow-up 
Study week 
13 
14 
16 
18/SFUa/EOS 
Study day 
92 
99 
113 
127 
GENERAL AND SAFETY ASSESSMENTS 
Weight 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
Xa 
Serious adverse events 
X 
X 
X 
Xa 
Disease-related events 
X 
X 
X 
Xa 
Concomitant therapies review 
X 
X 
X 
Xa 
LABORATORY ASSESSMENTS 
Urine pregnancy test  
 
 
 
Xa 
CRP and ESR 
 
 
 
Xa 
Hematology 
 
X 
X 
Xa 
Chemistry 
 
 
 
Xa 
PBMC 
 
 
 
Xa 
PHARMACOKINETICS AND ANTIBODIES 
Pharmacokinetic samples 
X 
X 
X 
X 
Anti-AMG 592 antibody 
 
 
 
X 
BIOMARKER  
Biomarker development sample 
 
 
 
X 
SFU = Safety follow-up; EOS = end of study for individual subject; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; PBMC = peripheral blood 
mononuclear cell. 
a For subjects who complete the study at week 18, the visit includes all required safety follow-up data collection.  All subjects who terminate the study early (ie, prior to 
completing the week 18 visit), will complete an Early Termination visit consisting of all assessments included in the week 12 day 85 pre-dose visit.  In addition, a 
safety follow-up visit will occur 6 weeks (± 3 days) after the last dose of investigational product to collect all required safety data including adverse events, serious 
adverse events, disease related events, concomitant therapies, safety labs/assessments, anti-AMG 592 antibody, and urine pregnancy test. 
 
Approved 
 
 


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3. 
Introduction 
3.1 
Study Rationale 
The phase 1b part of this study is a double-blind, placebo controlled, multiple ascending 
dose (MAD) study to evaluate the safety and tolerability of AMG 592 in subjects with 
active rheumatoid arthritis (RA) and to determine the recommended phase 2a dose 
(RP2D) for the phase 2a part of the study.  The phase 2a part of this study is a proof of 
concept study to evaluate efficacy and safety of AMG 592 in subjects with moderate to 
severe RA.  There are no data available yet demonstrating the use of AMG 592 in active 
rheumatoid arthritis patients who are inadequately responding to methotrexate.  This 
study will help determine if AMG 592 could be a useful therapeutic agent in the current 
treatment landscape where subjects use methotrexate as a part of standard of care and 
have ongoing disease activity that requires additional treatment. 
3.2 
Background 
3.2.1 
Disease 
Rheumatoid arthritis is an incurable, chronic, disabling autoimmune disease that affects 
0.5% to 1% of the population and is 3 times more prevalent in women than in men.  It is 
characterized by inflammation of the membrane lining in the joints, leading to joint 
damage and bone destruction and causing severe disability and increased morbidity and 
mortality.  The current therapeutic approach is to start with disease modifying 
anti- rheumatic drugs (DMARDs) early in the illness to prevent joint damage, and 
conventional DMARDs such as methotrexate have been the mainstay of treatment for 
decades.  A significant advance in the management of RA is the use of biological 
agents, including multiple tumor necrosis factor (TNF)-blockers, B-cell depletion 
(rituximab), anti-interleukin-6 receptor monoclonal antibody (tocilizumab), and agents 
which interfere with T-cell activation (abatacept).  However, up to a third of patients do 
not adequately respond to treatment, and about 50% stop responding to any particular 
DMARD within 5 years, either owing to lack of efficacy or following the development of 
adverse events.  Up to 50% of patients with RA are disabled within 10 years of the onset 
of disease and overall life expectancy is reduced (Emery, 2010; Weinblatt, 1996). 
3.2.2 
T regulatory Cells in Rheumatoid Arthritis 
T regulatory cells (Tregs) are a subset of CD4 T cells that suppresses inflammation and 
whose numbers and function are maintained by interleukin 2 (IL-2).  Many inflammatory 
conditions, including RA, are characterized by a loss in the homeostatic balance 
between Tregs and effector T cells or by defects in Treg function.  
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Several studies have demonstrated reduced Treg numbers in RA patients compared to 
healthy subjects or a lower ratio of Treg to pro-inflammatory T cells such as TH17 or Th1 
T cells in RA blood or synovial tissue (Morita et al, 2016; Guggino et al, 2014; 
Samson et al, 2012; Behrens et al, 2007).  RA is also associated with defects in Treg 
function such as impaired suppression of inflammatory cytokine production 
(Ehrenstein et al, 2004).  Clinical improvement in response to RA therapies correlates 
with increased Treg numbers, suggesting that correction of this imbalance by increasing 
Tregs, may play a role in disease amelioration (Kikuchi et al, 2015; Samson et al, 2012; 
Nadkarni et al, 2007). 
3.2.3 
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 systemic lupus erythematosus ([SLE] 
Humrich et al, 2015), 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 RA joint destruction and 
persistence (van Steenbergen et al, 2015). 
The therapeutic efficacy of low dose IL-2 has been studied in chronic GVHD 
(Koreth et al, 2011; Koreth et al, 2016), hepatitis C induced vasculitis 
(Sadoun et al, 2011), SLE (Humrich et al, 2015), 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.  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 chronic GVHD 
(ClinicalTrials.gov NCT00529035), an IL-2 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 adesleukin can activate 
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CONFIDENTIAL 
 
 
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 IL-2. 
Approved 
 
 


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3.2.5 
Risk Assessment 
As of 12 March 2019, approximately 100 subjects have received at least 1 dose of 
AMG 592.  Repeated subcutaneous doses of up to 
 
have been studied for up to 3 months in subjects with RA and systemic lupus 
erythematosus.  The most common adverse event experienced by subjects was mild 
(grade 1) painless erythema at or near the injection site, sometimes accompanied by 
pruritus, that was self-resolving.  Two serious hypersensitivity reactions to AMG 592 
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CONFIDENTIAL 
 
 
have been reported.  In addition, worsening arthritis deemed related to AMG 592 
has been reported in the ongoing 20170149 study.  The majority of these events 
were reported by a single site.  No clinically significant therapeutic related 
abnormalities in electrocardiograms, hematological or biochemical laboratory 
investigations, or vital signs have been reported.  More detailed information about 
the known and expected risks and reasonably expected adverse events of  
AMG 592 may be found in the Investigator’s Brochure. 
4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
Phase 1b 
• 
To evaluate the safety and tolerability of 
subcutaneous (SC) dose administrations 
of AMG 592 in subjects with active RA 
Phase 1b 
• 
Treatment-emergent adverse events. 
• 
Clinically significant changes in vital signs, 
laboratory safety tests, and 
electrocardiograms (ECGs) 
Phase 2a 
• 
To evaluate the efficacy of AMG 592 at 
week 12 as measured by the American 
College of Rheumatology 20% 
improvement criteria (ACR 20) in adult 
subjects with moderate to severe RA 
Phase 2a 
• 
ACR 20 at week 12 
Secondary 
Phase 1b 
• 
To characterize the pharmacokinetic (PK) 
profile following treatment with AMG 592 
Phase 1b 
• 
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 (AUCtau) after the 
first and last doses.  Area under the 
concentration-time curve over the dosing 
interval will be calculated & reported for 
each dosing regimen 
• 
To evaluate the incidence of 
anti-AMG 592 antibody formation and 
cross-reactivity to human IL-2. 
• 
Anti-AMG 592 antibodies and 
cross-reactivity to IL-2. 
• 
Anti-AMG 592 and anti-IL 2 neutralizing 
antibodies 
Phase 2a 
• 
To evaluate the effect of treatment with 
AMG 592 on other measures of disease 
activity at week 12  
Phase 2a 
• 
ACR 50/70 at weeks 12  
• 
Disease activity score (28 joint) calculated 
using the erythrocyte sedimentation rate 
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Objectives 
Endpoints 
formula (DAS28-ESR) score and change 
from baseline at week 12  
 
Disease activity score (28 joint) calculated 
using the C-reactive protein formula 
(DAS28-CRP) score and change from 
baseline at week 12 
 
To evaluate the safety of AMG 592 
 
Treatment-emergent adverse events. 
 
Clinically significant changes in vital signs, 
laboratory safety tests  
 
To characterize the PK of AMG 592 in 
subjects with RA 
 
AMG 592 serum concentration and PK 
parameters  
   
Exploratory 
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4.2 
Hypotheses 
Phase 1b: 
AMG 592 will be safe and well tolerated in subjects with active RA. 
5. 
Study Design 
5.1 
Overall Design 
5.1.1 
Phase 1b Study Design 
The phase 1b part of the study is a double-blind, placebo controlled, MAD study to 
evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of 
AMG 592 in subjects with active RA with inadequate response to standard of care 
therapy.  Subjects within a dosing cohort will be randomized in a 3:1 ratio to AMG 592 or 
placebo in addition to standard of care therapy as shown in Table 5-1.  AMG 592 or 
placebo will be administered 
 by subcutaneous 
(SC) injection.  Dosing cohorts will enroll sequentially with the exception of cohorts 2 and 
3, which will enroll concurrently and share dose level review meetings (DLRMs). 
Approved 
 
 


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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 exception is for cohorts 
2 and 3 where an initial DLRM will convene after the first 16 enrolled subjects (8 in 
each cohort) complete the week 4 visit and a second DLRM will convene after the 
remaining 16 enrolled subjects (8 in each cohort) complete 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) (Bailey et al, 2009; 
Neuenschwander et al, 2008) will be implemented to model these events before each 
DRLM to aid dosing decisions.  DLRM members may also consider available aggregated 
summaries of emerging safety, PK and PD data.  
Amgen DLRM members may consider safety, PK, PD data from other completed and 
ongoing phase 1b AMG 592 studies to aid in dosing decisions.  Emerging safety, PK and 
PD data from ongoing AMG 592 studies may be used to support decisions to skip dosing 
cohorts, reduce dosing cohort size or change doses for a given cohort.  If emerging 
safety data from other ongoing studies is used in support of dosing decisions, 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.  DLRM members will be responsible for 
dosing recommendations (followed by an Amgen decision), which may include 
escalation to the next planned 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.  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 
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CONFIDENTIAL 
 
 
tolerable.  Additional dose levels will not exceed 
 
 
 
  For additional 
details on the DLRM see Appendix 3. 
Subjects will be treated for a total of 12 weeks after which they will complete a 6-week 
follow-up until week 18 for collection of additional safety, PK and PD data as described 
in the Schedule of Activities (Table 2-2).  For subjects who complete the study at 
week 18, the visit includes all required safety follow-up data collection.  All subjects who 
terminate the study early (ie, prior to completing the week 18 visit), will complete an 
Early Termination visit consisting of all assessments included in the week 12 day 85 
pre-dose visit.  In addition, a safety follow-up visit will occur 6 weeks (± 3 days) after the 
last dose of investigational product to collect all required safety data including adverse 
events, serious adverse events, disease related events, concomitant therapies, safety 
labs/assessments, anti-AMG 592 antibody, and urine pregnancy test. 
 
 
 
 
  The phase 2a part of the study will commence 
after a RP2D is identified in the phase 1b part of the study.  
 
 
 
 
 
  
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The overall study designs for the phase 1b 
 parts of the study are 
described by the study schemas in Section 2.1.  The endpoints are defined in 
Section 4.1. 
5.2 
Number of Subjects 
In the phase 1b part of the study sufficient subjects will be randomized to yield 
approximately 48 evaluable subjects (approximately 36 randomized to AMG 592 
and 12 randomized to placebo; see Section 5.2.1).  The total sample size may be 
higher than 48 subjects 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.  Additional subjects may be enrolled in each cohort 
to enable all screened eligible subjects to participate in the study.  Within each 
cohort subjects will be randomized to AMG 592 or placebo in a 3:1 ratio. 
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 
In the phase 1b part of the study subjects who are randomized but discontinue 
investigational medicinal product before completing the week 4 visit may be 
replaced.   
5.2.2 
Number of Sites 
Approximately 18 sites in North America and Europe will participate in the phase 1b part 
of the study 
 
  Sites that do not enroll subjects within 3 months of site 
initiation may be closed. 
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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), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
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 phase 1b part of 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.  
 
 
 
  
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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 may be completed and updated via an Interactive Voice Response 
System (IVRS). 
Eligibility criteria will be evaluated during screening.   
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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 to ≤ 70 years of age at screening 
103 
A diagnosis of RA consistent with the 1987 or 2010 American College of 
Rheumatology (ACR)/European League Against Rheumatism classification 
criteria 
104 
Active RA defined as: 
• 
Phase 1b:  DAS28-CRP > 2.6 at screening.  The 28-joint count consists of 
the finger joints excluding the distal interphalangeal joints, the wrists, elbows, 
shoulders, and knees.  
• 
Phase 2a:  ≥ 6 swollen joints (based on 66-joint count) and ≥ 6 tender joints 
(based on 68-joint count) at screening and baseline.  The distal 
interphalangeal joint should be evaluated but not included in the total count to 
determine eligibility.  Additionally, C-reactive protein (CRP) must be greater 
than the upper limit of normal (ULN) per the central laboratory at screening.   
105 
Receiving treatment with methotrexate for ≥ 12 weeks and on a stable dose 
≥ 15 mg weekly for ≥ 8 weeks prior to day 1.  A lower methotrexate dose is 
acceptable (but no lower than 10 mg weekly) if it is the highest tolerated dose 
and gastrointestinal or hematologic toxicity at doses ≥ 15 mg weekly is 
documented by the investigator. 
106 
Receiving treatment with folic or folinic acid per investigator judgment or 
according to local standard of care.  
107 
Phase 1b only:  Subject may be receiving a stable dose of leflunomide, 
sulfasalazine, hydroxychloroquine, minocycline in combination with methotrexate 
and the dose must be stable for ≥ 8 weeks prior to day 1. 
108 
Subject may be receiving a stable dose of prednisone ≤ 10mg daily or other 
equivalent corticosteroid dose and the dose must be stable for ≥ 2 weeks prior to 
day 1. 
109 
Phase 1b only.  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, seasonal influenza [during flu 
season], and pneumococcal [polysaccharide] vaccinations) up to date per local 
standards as determined by the investigator.   
Approved 
 
 


Product:  AMG 592  
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6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
Disease Related 
201 
Class IV RA according to ACR revised response criteria 
202 
Diagnosis of Felty’s Syndrome (RA, splenomegaly and granulocytopenia) 
Other Medical Conditions 
203 
Prosthetic joint infection within 3 years of screening or native joint infection within 
1 year prior to screening. 
204 
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. 
205 
Known history of active tuberculosis. 
206 
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 
• 
a positive PPD and a history of Bacillus Calmette-Guérin vaccination are 
allowed with a negative Quantiferon test and negative chest x ray 
• 
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 
− 
document 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) 
− 
no known exposure to a case of active tuberculosis after most recent 
prophylaxis 
− 
negative chest X-ray 
207 
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. 
208 
Phase 1b only:  Positive for Human Immunodeficiency Virus (HIV) at screening 
or known to be HIV positive.  Phase 2a only:  Known history of HIV 
209 
Phase 1b only:  Positive drug or alcohol urine test for illicit drugs at screening.  
Prescription medications detected by the drug test are allowed if they are 
being taken under the direction of a physician. 
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210 
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 RA (eg, systemic lupus erythematosus with the exception of 
secondary Sjögren’s syndrome) 
211 
Malignancy except non-melanoma skin cancers, cervical or breast ductal 
carcinoma in situ within the last 5 years. 
212 
History of alcohol or substance abuse within 6 months of screening 
213 
Phase 1b only:  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, electronic cigarettes, 
cigarettes, pipes, or nicotine patches. 
214 
Phase 1b only:  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.  Phase 1b only:  
Unwilling or unable to abstain from alcohol consumption within 48 hours prior to 
each visit (including screening).   
Prior/Concomitant Therapy 
215 
Subjects who have received intra-articular or systemic corticosteroid injections 
for treatment of acute RA flare (not being part of a regular therapeutic regimen) 
within 4 weeks prior to screening. 
216 
Currently receiving or had treatment with cyclophosphamide, chlorambucil, 
nitrogen mustard, or any other alkylating agent ≤ 6 months prior to day 1. 
217 
Prior treatment with more than a total of 3 therapies that include biologic 
DMARDs or oral synthetic DMARDs (such as tofacinitib, baricitinib).  Prior 
treatment consists of at least 4 doses of a given therapy where the doses were 
given solely for treatment of RA disease.  Prior therapies must not have been 
used within the following time periods: 
• 
≤ 4 weeks prior to day 1 for etanercept and anakinra 
• 
≤ 6 months for rituximab  
• 
≤ 2 weeks for oral janus kinase inhibitors 
• 
≤ 9 weeks prior to day 1 for all therapies not listed above 
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218 
Currently receiving or had treatment with any of the following ≤ 12 weeks prior to 
day 1:  
• 
azathioprine 
• 
cyclosporine 
• 
gold 
• 
mycophenolate mofetil 
• 
Prosorba column 
• 
Tacrolimus 
219 
Phase 2a only:  Currently receiving or had treatment with leflunomide ≤ 12 weeks 
prior to day 1 unless an active washout with cholestyramine has been performed.  
220 
Phase 2a only:  Currently receiving or had treatment with any of the following 
≤ 4 weeks prior to day 1:  
• 
hydroxychloroquine 
• 
sulfasalazine 
• 
minocycline 
• 
intra-articular, intramuscular or intravenous corticosteroids, including 
adrenocorticotropic hormone 
• 
intra-articular hyaluronic acid injections 
• 
live vaccines 
221 
For Phase 2 only:  Unstable dose of non-steroidal anti-inflammatory drugs 
(NSAID), acetaminophen, and/or analgesics which is taken on an unscheduled 
basis (ie, not daily or scheduled every certain number of hours) and/or initiated 
< 4 weeks prior to day 1. 
222 
Received the following within 12 hours prior to screening or day 1:  
acetaminophen, NSAIDs, tramadol, and/or any narcotic analgesics such as but 
not limited to hydrocodone, codeine, tramadol, propoxyphene and/or oxycodone 
(unless in the form of oxycontin).  Subject has taken oxycontin within 24 hours 
prior to screening or day 1. 
223 
Phase 1b only:  Received any herbal medicines (eg, St John’s wort), or 
non-vitamin dietary supplements (eg, magnesium) with the exception of calcium 
within 4 weeks prior to day 1. 
Prior/Concurrent Clinical Study Experience 
224 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
Diagnostic Assessments 
225 
Presence of laboratory abnormalities at screening including the following: 
• 
Aspartate aminotransferase (AST) or alanine amino transferase (ALT) at 
screening > 1.5X upper limit of normal (ULN) 
Approved 
 
 


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• 
Serum total bilirubin (TBL) ≥ 1.5 mg/dL (≥ 26 µmol/L) 
• 
Hemoglobin ≤ 10.5 g/dL(≤ 105 g/L) 
• 
Platelet count < 100,000/mm3 (< 100 x 109/L) 
• 
White blood cell count < 2,500 cells/mm3 (< 2.5 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  
226 
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 
227 
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. 
228 
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). 
229 
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. 
230 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
231 
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 [COAs]) to the best of the subject and investigator’s 
knowledge. 
232 
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 
The following alcohol and tobacco restrictions apply to the phase 1b part of the study 
only.  
At screening and throughout the duration of the study, subjects must 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.  
Approved 
 
 


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Subjects must abstain from alcohol consumption within 48 hours prior to each visit 
(including screening).   
Subjects must not use of 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 
In the phase 1b part of the study subjects will abstain from strenuous exercise for 
72 hours (eg, running, weight lifting for greater than 1 hour) 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 and/or recruitment material, 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. 
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 IVRS.  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. 
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 
Approved 
 
 


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information will be collected that includes demography, screen failure details, eligibility 
criteria, 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 investigational product. 
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 investigational product instruction manual (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 
In the phase 1b part of the study, AMG 592 or placebo will be administered by SC 
injection 
 starting on day 1.  The following dose cohorts are planned in the 
phase 1b portion of the study: 
Approved 
 
 


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For both the phase 1b and phase 2a part of the study 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.  
In the phase 1b part of the study doses of investigational product through week 4 and 
during week 12, must be given within 1 hour after the specified time point for the day 1 
pre-dose blood samples, and within 12 hours after the rest of scheduled pre-dose blood 
sampling time points.  After week 4 (excluding week 12) doses of investigational product 
must be given within ± 1 day of the scheduled visit 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. 
In the phase 1b part of the study, study subjects must remain at the site at least 6 hours 
following the first dose and at least 1 hour following the second dose of investigational 
product.  The site must contact the subject by phone 6, 12, and 24 hours after the 
second dose of study drug to ascertain safety.  Thereafter study subjects must remain 
on site for at least 30 minutes following the third and all subsequent doses of 
investigational product.  
 
 
  
7.1.1.1.2 
Accountability 
The amount of investigational product used in preparation, total volume of preparation, 
quantity administered, start date, start time, and box number of AMG 592 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. 
7.1.3 
Medical Devices 
There are no investigational medical device(s) used in this study.  
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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 investigational product. 
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:  
• 
azathioprine 
• 
gold 
• 
mycophenolate mofetil 
• 
Prosorba column 
• 
Any other investigational agents or commercially available biologic DMARDs 
• 
Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or 
other alkylating agents 
• 
oral janus kinase inhibitor (eg, tofacitinib, baricitinib) 
Approved 
 
 


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• 
Live vaccines 
• 
Tacrolimus 
• 
Cyclosporine 
• 
T cell depleting agents ( eg, antithymocyte globulin, Campath) 
• 
Recombinant IL-2 (eg, Proleukin) 
During the phase 1b part of the study all herbal medicines (eg St John’s wort), vitamins, 
and supplements are not allowed, with the exception of Vitamin D and calcium. 
7.2 
Method of Treatment Assignment 
In the phase 1b part of the study subjects will be randomized to receive AMG 592 or 
placebo in a 3:1 ratio via IVRS.   
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 IVRS at randomization.  The 
randomization date is to be documented in the subject’s medical record as registered in 
the IVRS. 
7.3 
Blinding 
The phase 1b part of the study is double-blind.  Treatment assignment will be blinded to 
all subjects and site personnel described below.  
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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. 
7.3.2 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Phase 1b 
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 
Hepatotoxicity Stopping 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.  
Approved 
 
 


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7.4.2 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
(Phase 1b) 
7.4.2.1 
Dose Level Review Meetings 
After all evaluable subjects within a cohort have completed the week 4 visit, a DLRM will 
be held to review data and make dose escalation/de-escalation decisions 
(see Appendix 3).  The exception is for cohorts 2 and 3 where an initial DLRM will 
convene after the first 16 enrolled subjects (8 in each cohort) complete the week 4 
visit and a second DLRM will convene after the remaining 16 enrolled subjects  
(8 in each cohort) complete the week 4 visit.   
7.4.2.2 
Dose Cohort Stopping Rules 
The following dose cohort stopping rules will be used in the phase 1b part of 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  
Occurrence of a CTCAE version 
4.03 Grade 3 adverse event deemed 
related to investigational product in 2 
or more subjects within in a single 
dosing 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 
Upon majority vote by the DLRM members, one of the 
following recommendations may be made 
• 
stop enrollment of the cohort (if applicable) 
• 
enrollment of the cohort may resume as 
planned 
• 
the cohort may be expanded at the same dose  
• 
enrollment of the study may continue at a lower 
dose 
OR 
Upon unanimous vote by the DLRM members, 1 of the 
following recommendations may be made: 
• 
escalation to an intermediate dose (a dose 
lower than the next planned dose) may take 
place 
• 
escalation to the next planned dose may occur 
Any occurrence of a CTCAE  
version 4.03 ≥ Grade 4 adverse 
event 
Stop dosing additional subjects in the cohort and 
convene DLRM (if the event occurs outside the 
regularly scheduled DLRM) 
Review adverse event and all relevant safety data for 
evidence of relationship to treatment and clinical or 
medical significance. 
Consider unblinding to determine relatedness to 
investigational producta 
If the adverse event is determined by majority vote of 
the DLRM members to be related to the investigational 
product and clinically or medically significant, no further 
doses should be administered at this dose and no dose 
escalation should proceed.  Enrollment of the study 
may continue at a lower dose or a lower dose cohort 
may be added to the study. 
Otherwise, upon majority vote of the DLRM members, 
one of the following recommendations may be made: 
• 
enrollment of the cohort may resume as planned 
• 
the cohort may be expanded at the same dose 
• 
enrollment of the study may continue at a lower 
dose or a lower dose cohort may be added to the 
study 
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. 
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7.4.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.3.1 
Amgen Investigational Product:  AMG 592 
No dosage adjustments are allowed in either the phase 1b or phase 2 parts of the study. 
The reason for dose change of investigational product is to be recorded on each 
subject’s CRF. 
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 AMG 592 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 the first dose of 
investigational product will be collected.  Collect complete prior therapy history for RA.  
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 therapies or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7 and those mentioned below.  
Concomitant therapies are to be collected from first dose of investigational product 
through the safety follow-up.  Collect therapy name, indication, dose, unit, frequency, 
route, start date and stop date 
7.8.2.1 
Methotrexate 
All subjects must maintain a stable dose and the same route of administration (ie, oral or 
subcutaneous) of methotrexate through the treatment period in both the phase 1b and 
phase 2a parts of the study.  The doses of methotrexate should be taken on the same 
day of the week (± 2 days).  After the treatment period the dose of methotrexate may be 
adjusted. 
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Subjects must also take folic acid or folinic acid supplementation during the study.  The 
dose of folic acid or folinic acid will be as per investigator judgment or according to local 
standard of care.  The dose of folic acid may be adjusted in response to 
methotrexate-related toxicity. 
7.8.2.2 
Analgesics and NSAIDs 
If the study subject enters the study taking a stable dose of acetaminophen, analgesics, 
or NSAIDs on a scheduled basis (see exclusion criterion 221), the dose can be reduced 
or discontinued during the study if necessary for safety reasons or standard of care.  No 
new analgesics or NSAIDs may be added during the treatment period.  
During treatment period analgesics or NSAIDs must not be used within 12 hours before 
a scheduled study visit where efficacy is assessed, with the exception of oxycontin which 
may not be used within 24 hours of a scheduled study visit where efficacy is assessed.  
In both the phase 1b and phase 2a parts of the study, efficacy is assessed at baseline 
and at weeks 4, 8, and 12.  
After the treatment period, analgesics and NSAIDs may be added as required or the 
dose adjusted per investigator judgment in both the phase 1b and phase 2a parts of the 
study.   
7.8.2.3 
Corticosteroids 
Subjects entering the study while taking oral corticosteroids cannot change their dose 
during the treatment period.  Addition of new corticosteroids regardless of route of 
administration is not allowed.  After the treatment period new corticosteroids, 
administered by any route may be added or dose adjusted per investigator judgment.  
Investigators should make every effort to reduce the steroid dose for subjects 
responding to investigational product and to taper steroids after the resolution of disease 
flare. 
7.8.2.4 
DMARDS 
In the phase 1b part of the study only, subjects entering the study taking sulfasalazine, 
hydroxychloroquine, minocycline or leflunomide cannot change their dose during the 
initial treatment period.  After the treatment period, new non-biologic DMARDs may be 
added or dose adjusted per investigator judgment.  
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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 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 and Table 2-3) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
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. 
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 
Approved 
 
 


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• 
Protocol deviation 
• 
Non-compliance  
• 
Adverse event 
• 
Subject request 
• 
Requirement for alternative therapy 
• 
Protocol-specified criteria; see Section 7.4.2 
• 
Pregnancy 
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 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 
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.  
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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, Table 2-2, and Table 2-3). 
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and 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 IVRS and 
screen the subject in order to assess eligibility for participation.  The screening window is 
up to 28 days. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
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If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
rescreening 2 times.  
Rescreen subjects must first be registered as screen failures in IVRS 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 and Table 2-3).  On-study visits 
may be completed within a visit window of ± 1 day for phase 1b and ± 2 days for phase 
2a 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 in the phase 1b part of 
the study per the Schedule of Activities (Table 2-1). 
9.1.3 
Follow-up/Safety Follow-up/End of Study for Phase 1b 
After the 12-week treatment period, subjects in the phase 1b part of the study 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).  For subjects who 
complete the study at week 18, the visit includes all required safety follow-up data 
collection.  All subjects who terminate the study early (ie, prior to completing the week 18 
visit), will complete an Early Termination visit consisting of all assessments included in 
the week 12 day 85 pre-dose visit.  In addition, a safety follow-up visit will occur 6 weeks 
(± 3 days) after the last dose of investigational product to collect all required safety data 
including adverse events, serious adverse events, disease related events, concomitant 
therapies, safety labs/assessments, anti-AMG 592 antibody, and urine pregnancy test.   
Approved 
 
 


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9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
timepoints. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC 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 pharmacokinetics 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, RA 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. 
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9.2.1.6 
Substance Use History  
For the phase 1b part of the study, obtain a detailed history of prior and/or concurrent 
use of alcohol and of nicotine or tobacco containing products. 
9.2.2 
Efficacy Assessments 
9.2.2.2 
DAS28-CRP 
The DAS28-CRP will be calculated in the phase 1b part of the study to determine 
subject eligibility during screening.  
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9.2.3 
Safety Assessments 
Planned timepoints for all safety assessments are listed in the Schedule of Activities. 
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) through the safety follow-up are reported using the Event CRF.   
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. 
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Disease-related events pre-defined for this study include joint pain, joint stiffness, joint 
swelling, worsening of rheumatoid arthritis.  
9.2.3.1.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (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 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 the safety follow-up 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. 
Approved 
 
 


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9.2.3.1.1.5 
Serious Adverse Events That Are Not to be Reported by the Sponsor 
to Regulatory Agencies in an Expedited Manner 
Not applicable 
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 according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
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An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team (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, if indicated, 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, 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. 
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9.2.3.3 
Electrocardiograms 
Phase 1b 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  ECGs should be 
performed in a standardized method, in triplicate, and run consecutively 
(ie, < 30 seconds apart), prior to blood draws or other invasive procedures.  Each ECG 
must include the following measurements:  QRS, QT, QTc, RR, and PR intervals. 
• 
≥ 3 baseline ECGs collected ≥ 30 minutes apart, with each baseline ECG in 
triplicate run consecutively (ie, < 30 seconds apart [ie, total ≥ 9 ECGs])  
• 
Triplicate ECGs at screening and timepoints after baseline per the Schedule of 
Activities 
Baseline is defined as day -1. 
The PI or designated site physician, will review all ECGs.  ECGs will be transferred 
electronically to an ECG central reader for analysis per Amgen instructions.  Once 
signed, the original ECG tracing will be retained with the subject's source documents.  At 
the request of the sponsor, a copy of the original ECG will be made available to Amgen.  
Standard ECG machines should be used for all study-related ECG requirements.  
Amgen will provide standard ECG machines for use by the site.   
9.2.4 
Clinical Laboratory Assessments 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory with the exception of erythrocyte sedimentation rate (ESR), 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, 
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hematology, serum pregnancy, urinalysis, hepatitis C antibody, hepatitis B surface 
antigen and core antibody, high sensitivity CRP, and any other laboratory tests required.  
ESR, urine pregnancy and PPD testing, if applicable, will be performed locally with kits 
provided by the central laboratory (except PPD).  The results of this testing will be 
maintained in the source documents at the site.   
Subjects in the phase 1b part of the study 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.   
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, CRP results as well as 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.  ESR will be performed locally.  The results of the ESR performed after 
the subject has been randomized must be maintained in a blinded fashion so that it may 
not be viewed by other staff who perform any study assessments with the subjects. 
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9.2.4.1 
Tuberculosis Testing 
All subjects must receive either a PPD or Quantiferon test at screening per Section 6.2.   
9.2.4.1.1 
PPD 
The PPD test must be read by a trained healthcare professional 48 to 72 hours after the 
test is placed.  PPD reader must be identified on the delegation of authority for this 
responsibility. 
9.2.4.1.2 
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). 
9.2.4.1.3 
Chest X-Ray 
Subjects with a positive PPD test without a history of Bacillus Calmette-Guerin 
vaccination or subjects with 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. 
9.2.4.2 
Human Immunodeficiency Virus, Hepatitis B Surface Antigen, and 
Hepatitis C Antibody  
HIV testing at screening will be performed only in subjects in the phase 1b part of the 
study if HIV status is unknown.  In both phase 1b and phase 2a, subjects will be 
assessed for HBsAg, and HepCAb titers at screening.  The results of these tests must 
be negative and will be documented in the source document but will not be recorded on 
the eCRF. 
9.2.4.3 
Pregnancy Testing 
A high sensitive (urine or serum) pregnancy test should be completed at screening and 
within 7 days of initiation of investigational product for females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements (If a female subject, or the partner of a male 
subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
Additional pregnancy testing (urine) should be performed at monthly intervals during 
treatment with investigational product and 6 weeks (± 3 days) after the last dose of 
Approved 
 
 


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investigational product.  Positive urine pregnancy test should be confirmed with serum 
pregnancy test.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.4.4 
Prespecified Biomarker Assessments 
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, Table 2-2 and Table 2-3).  
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. 
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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. 
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 timepoints 
specified in the Schedule of Activities (Table 2-1, Table 2-2 and Table 2-3) 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) IL-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 
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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 timepoints, 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. 
Blood samples are to be collected for biomarker development at the timepoints specified 
in the Schedule of Activities (Table 2-1, Table 2-2, and Table 2-3).   
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9.2.11 
Other Assessments  
Peripheral Blood Mononuclear Cell 
Blood samples will be collected for subjects in the phase 1b part of the study at the 
timepoints indicated in the Schedule of Activities (Table 2-1, Table 2-2) for PBMC 
collection.  Detailed instructions on sample collection, processing, and shipping will be 
provided in a separate manual. 
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10. 
Statistical Considerations 
10.1 
Sample Size Determination 
10.1.1 
Phase 1b 
It is anticipated that approximately 48 subjects will be randomized in the phase 1b part 
of the study, with 8 subjects randomized to each of cohorts 1 and 4 and 
approximately 16 subjects randomized to each of cohorts 2 and 3.  The total 
sample size may be higher than 48 subjects 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.  Within each cohort subjects will be 
randomized to AMG 592 or placebo in a 3:1 ratio.   
The sample size of the phase 1b part of the study is based on practical 
considerations.  For cohorts 1 and 4, with 6 subjects receiving AMG 592 in each 
cohort, there is an 82% chance of at least 1 subject within a cohort experiencing an 
adverse event, if the true event rate is 25%.  The chance of at least 1 subject 
experiencing an adverse event within a cohort will be 74% if the event rate becomes 
20%. 
For cohorts 2 and 3, with 12 subjects receiving AMG 592 in each cohort, the 
chance of at least 1 subject experiencing an adverse event within a cohort 
increases to 97% and 93% for true event rates of 25% and 20%, respectively.  In 
addition, with a total of 36 subjects planned to receive AMG 592 in the phase 1b part 
of the study, the chance of at least 1 subject experiencing an adverse event across 
the cohorts increases to 30% and 84% if the true event rates are 1% and 5%, 
respectively.   
Additional subjects may be enrolled at a randomization ratio of 3:1 to AMG 592 or 
placebo to enable all screened eligible subjects to participate in the study, for 
addition and/or expansion of cohorts based on DLRM recommendations, or for 
replacement of subjects as per Section 5.2.1.   
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10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
10.2.1.1 
Phase 1b 
10.2.1.1.1 
Safety Analysis Set 
The safety analysis set for phase 1b will consist of all subjects who received at least 
1 dose of investigational product.  The safety analysis set will be used for the phase 1b 
analyses unless otherwise specified.  Subjects will be analyzed according to the actual 
treatment received.  
10.2.1.1.2 
Pharmacokinetic Concentration Analysis Set  
The PK concentration analysis set for phase 1b will contain all subjects who have 
received AMG 592 and have at least one quantifiable PK sample collected.  
10.2.1.1.3 
Pharmacokinetic Parameter Analysis Set  
The PK parameter analysis set for phase 1b will consist of all subjects who have 
received AMG 592 and for whom at least one PK parameter can be adequately 
estimated.  
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10.2.2 
Covariates 
10.2.2.1 
Phase 1b 
There are no pre-specified covariates. 
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10.2.3 
Subgroups 
10.2.3.1 
Phase 1b 
There are no pre-specified subgroup analyses. 
10.2.4 
Handling of Missing and Incomplete Data 
10.2.4.1 
Phase 1b 
All endpoints in the phase 1b part of 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 
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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 
10.3.1.1 
Interim Analysis and Early Stopping Guidelines 
Phase 1b 
There is no formal interim analysis for phase 1b. 
10.3.1.2 
Primary Analysis 
10.3.1.2.1 
Phase 1b 
The primary analysis will be done after all subjects have had the opportunity to complete 
the study and performed the 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, and 
biomarker data.  Descriptive statistics on continuous measurements will include means, 
medians, 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.  
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10.3.2.2 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Phase 1b 
The primary endpoint of phase 1b is not an efficacy endpoint.  
Secondary 
Exploratory 
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Phase 1b: 
The primary endpoint for phase 1b is safety.  Please refer to section 10.3.2.3.2 
to 10.3.2.3.6 below 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 
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protocol-required therapies, and significant treatment emergent adverse events will also 
be provided.   
10.3.2.3.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at selected 
timepoints 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 timepoints.  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 
timepoints by treatment group. 
10.3.2.3.6 
Electrocardiogram 
Phase 1b 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.  Subjects' maximum change from baseline in QTcF, QTcB will be 
categorized and the number and percentage of subjects in each group will be 
summarized.  Subjects' maximum post baseline values will also be categorized and the 
number and percentage of subjects in each group will be summarized.  All on-study 
electrocardiogram (ECG) data will be listed. 
10.3.2.3.7 
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. 
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10.3.2.3.8 
Exposure to Investigational Product 
The number of days on investigational product, 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. 
10.3.2.3.9 
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. 
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11. 
References 
AMG 592 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
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(3): 469-484. 
Behrens F, Himsel A, Rehart S, et al.  Imbalance in distribution of functional autologous 
regulatory T cells in rheumatoid arthritis.  Ann Rheum Dis.  2007; 66: 1151–1156. 
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. 
Ehrenstein M, Evans J, Singh A, et al.  Compromised function of regulatory T cells in 
rheumatoid arthritis and reversal by anti-TNFα therapy.  J Exp Med.  2004; 200: 
277-285. 
Emery P. New biologic for treating rheumatoid arthritis: clinical trial experience with 
tocilizumab. Int J Clin Rheum. 2010; 5(1): 17-24. 
Guggino G, Giardina A, Raimondo S, et al.  Targeting IL-6 signaling in early rheumatoid 
arthritis is followed by Th1 and Th17 suppression and Th2 expansion.  Clin Exp 
Rheumatol. 2014; 32(1): 77-81. 
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/ 
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. 
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(1):130-137. 
Kikuchi J, Hashizume M, Kaneko Y, et al.  Peripheral blood CD4+CD25+CD127 low 
regulatory T cells are significantly increased by tocilizumab treatment in patients with 
rheumatoid arthritis: increase in regulatory T cells correlates with clinical response.  
Arthritis Res Ther. 2015; 17(10). doi:10.1186/s13075-015-0526-4. 
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. 
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.   
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). 
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Morita T, Shima Y, Wing JB, et al.  The Proportion of Regulatory T Cells in Patients with 
Rheumatoid Arthritis: A Meta-Analysis. PLOS ONE 2016;11: e0162306. 
Nadkarni S, Mauri C, Ehrenstein M.  Anti–TNF-α therapy induces a distinct regulatory T 
cell population in patients with rheumatoid arthritis via TGF-β.  J Exp Med. 2007; 204(1): 
33-39. 
Neuenschwander B; Branson M; Gsponer T.  Critical aspects of the Bayesian approach 
to phase 1 cancer trials.  Stat Med.  2008; 27(13): 2420-2439. 
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. 
Samson M, Audia S, Janikashvili N, et al.  Inhibition of interleukin-6 function corrects 
Th17/Treg cell imbalance in patients with rheumatoid arthritis.  Arthritis & Rheumatism.  
2012; 64(8): 2499-2503. 
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. 
Ware JE. SF-36 Health Survey Update. SPINE. 2000; 25:3130-3139. 
Weinblatt ME. Rheumatoid arthritis: treat now, not later! Ann Intern Med. 1996; 124: 
773-774. 
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. 
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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 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
Anti-CCP  
anti-cyclic citrullinated peptide 
AUCtau 
area under the concentration-time curve 
BLRM  
Bayesian logistic regression model 
Cmax 
maximum observed concentration 
CRF 
case report form 
CRP 
C-reactive protein 
CTCAE 
common terminology criteria for adverse events 
DAS28-CRP 
disease activity score (28 joint) calculated using the C-reactive 
protein formula 
DAS28-ESR 
disease activity score (28 joint) calculated using the erythrocyte 
sedimentation rate formula 
DILI 
drug-induced liver injury  
DLRM 
dose level review meeting 
DMARD 
disease modifying anti-rheumatic drug 
DNA 
deoxyribonucleic acid 
DRT 
data review team 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
EDC 
electronic data source 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
ESR 
erythrocyte sedimentation rate 
Exposure-Response  
Analysis 
mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic [PK] exposure 
(eg, population pharmacokinetic modeling) and response, which 
may include biomarkers, pharmacodynamic (PD) effects, 
efficacy and safety endpoints. 
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 (EOS) 
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  
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Abbreviation or Term 
Definition/Explanation 
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 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
FIH 
first in human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
GVHD 
graft versus host disease 
HCP 
health care provider 
HepCAb 
hepatitis c antibody 
 
 
HIV 
human immunodeficiency virus 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IL-2 
interleukin 2 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IUD 
intrauterine device 
IRB 
Institutional Review Board 
Interactive Voice Response 
System (IVRS) 
telecommunication 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 
NSAID 
non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamics 
PK 
pharmacokinetic 
POS 
probability of success 
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 
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Abbreviation or Term 
Definition/Explanation 
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  
RA 
rheumatoid arthritis 
RF 
rheumatoid factor 
RNA 
ribonucleic acid 
RP2D 
recommended phase 2 dose 
SFU 
Safety follow-up 
SAT 
safety assessment team 
SC 
subcutaneous 
SLE 
systemic lupus erythematosus 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
 
 
Teff 
T effector cells 
Tmax 
time of maximum observed concentration 
TNF 
tumor necrosis factor 
Treg 
T regulatory cells 
ULN 
upper limit of normal 
 
 
 
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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 
Chemistry 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinineb 
Total bilirubin 
Direct bilirubin 
Alkaline 
phosphatase 
AST (SGOT) 
ALT (SGPT) 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Ketones 
Urobilinogen 
Bilirubin 
Microscopic (reflex 
testing if abnormal) 
Red blood cells 
White blood cells 
ANC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
White blood cells 
differential 
• 
Total neutrophils 
or segmented 
neutrophils  
• 
Bands 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Central Laboratory:  
Quantiferond 
Hepatitis B surface 
Antigen 
Hepatitis B core 
antibody 
Hepatitis C virus 
antibody 
HIV 
FSHc 
Serum pregnancya 
High sensitivity CRP 
Rheumatoid  
Factor 
Anti-CCP antibody 
PBMC 
AMG 592 PK 
Anti-AMG 592 
antibodies 
Biomarker 
development 
Optional 
pharmacogenetics 
sample 
Urine drug/alcohol 
screen 
Local Laboratory: 
Urine Pregnancy 
PPD 
ESR 
Footnotes is defined on next page 
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ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
Hep = hepatitis; HIV = human immunodeficiency virus;; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood 
cell count; 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; Modification of Diet in Renal Disease = MDRD; PK = pharmacokinetics; PBMC = peripheral blood 
mononuclear cell; FSH = Follicle stimulating hormone; Anti-CCP = anti-cyclic citrullinated peptide antibody; 
CRP = C28-reactive protein; ESR = erythrocyte sedimentation rate; PPD = positive purified derivative 
a Only at screening 
b Glomerular filtration rate will be calculated by Modification of MDRD formula 
c Can be done as a part of the clinical chemistry 
d Quantiferon testing can be done locally or by the central laboratory 
After baseline, CRP results as well as 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.  ESR will be performed locally.  The results of the ESR performed after 
the subject has been randomized must be maintained in a blinded fashion so that it may 
not be viewed by other staff who perform any study assessments with the subjects.  
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Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings and Data Review Team 
Dose Level Review Meetings 
The phase 1b part of the study will employ Dose Level Review Meetings (DLRMs).  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.   
DLRM members will vote on dosing recommendations (followed by an Amgen decision).  
Voting members of the DLRM will include the Amgen Medical Monitor, the Amgen 
Global Safety Officer or designated Safety Scientist, and all participating investigators 
who have enrolled at least 1 subject in the study 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 unanimous 
positive vote indicating an acceptable safety profile for the investigational product is 
required to recommend dose level escalation to the next planned dose or to an 
intermediate dose.  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 DRLM. 
All other recommendations regarding dose modification and/or cohort 
continuation/expansion will require a majority DLRM vote (ie, ≥ 2 of 3 votes).  
All available study data including demographics, medical history, concomitant therapies, 
adverse events, electrocardiograms, vital signs, laboratory results, and emerging 
pharmacokinetic and pharmacodynamics data will be reviewed.  Data to be reviewed 
may be unqueried.  The DLRM vote and final dosing decision will be summarized in a 
DLRM memo which the study investigators will receive via email notification.   
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Data Review Team 
A Data Review Team (DRT) will review unblinded safety data periodically in the phase 
2a part of the study only.  A DRT is a group, internal to Amgen but external to the 
relevant AMG 592 product team, that reviews accumulating data from the ongoing 
clinical trial to ensure no avoidable increased risk for harm to subjects.  In order to 
maintain trial integrity, the unblinded data reviewed by the DRT will be restricted and not 
accessible by the AMG 592 product team.  The DRT is composed of members that are 
external to the study team and include a clinician, a safety physician, and a 
biostatistician.  Membership, procedures, and meeting timing will be described in detail 
in the study DRT charter. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• 
Applicable 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 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 
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• 
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, ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject the aims, 
methods, anticipated benefits, and potential hazards of the study before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered, and answer all questions regarding the study.   
Subjects must be informed that their participation is voluntary.  Subjects will then be 
required to sign a statement of informed consent that meets the requirements of 
21 Code of Federal Regulations 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act requirements, where applicable, and the IRB/IEC or 
study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
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. 
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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. 
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 CRF demographics page, in addition to the unique subject identification number, 
include the age at time of enrollment. 
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For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with [governmental regulations/ICH GCP Guidelines], it is required that 
the investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the [IRB/IEC] direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
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 
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ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
All persons designated as authors must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
A recognized expert in the therapeutic area 
• 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
An Investigator contributing a high number of eligible subjects 
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.   
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The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Quality, 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. 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the CRF Standard Instructions 
and the CRF Specific Instructions, both of these will be available through the EDC 
system.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (ie, the same results sent twice with the same 
date with different visit, [eg, week 4 and early termination]) and updating a specific 
response if the confirming datum is provided in the “other, specify” field (eg, for race, 
reason for ending study). 
CRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
therapies may be entered in the local language.  Consult the country-specific language 
requirements. 
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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 
Interactive Voice Response System (IVRS) system (if used, such as subject ID and 
randomization number) and CRF entries if the CRF is the site of the original recording 
(ie, there is no other written or electronic record of data, such as paper questionnaires 
for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
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 
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• 
Investigational product-related correspondence including [Proof of Receipts 
(POR), Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable 
• 
Non-investigational product(s), and/or medical device(s) or combination 
product(s) documentation, as applicable] 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
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.   
• 
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. 
 
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Events Meeting the Adverse Event Definition 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event. 
 
Events NOT Meeting the Adverse Event Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
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. 
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A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
• 
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. 
Recording Adverse Events, Disease-related Events (if applicable), and Serious 
Adverse Events 
Adverse Event, Disease-related Event (if applicable) 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 the sponsor in lieu of completion of the Event CRF page. 
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Adverse Event, Disease-related Event (if applicable) and Serious Adverse Event 
Recording 
• 
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 4.0 
which is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
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. 
 
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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. 
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 (eSAE) 
Contingency Report 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 a 
paper Serious Adverse Event Report Form (see Figure 12-1). 
Adverse Device Effects:  Recording, Evaluating and Reporting 
• 
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event CRF page. 
• 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident. 
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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
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Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
Study-specific contraception requirements for females 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 
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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 (IUD) 
• 
Intrauterine hormonal-releasing system (IUS) 
• 
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 amenorrhoea 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.) 
• 
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 investigational product.  This information will be 
forwarded to Amgen Global Patient Safety.  Generally, infant follow-up will be 
conducted up to 12 months after the birth of the child (if applicable). 
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• 
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. 
• 
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. 
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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 227.
•
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 
 
 


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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 
Approved 
 
 


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Approved 
 
 


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Appendix 6.  Sample Storage and Destruction 
Any blood samples collected according to the Schedule of Activities (Table 2-1) 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  
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 
[sample types (eg, blood, tumor)] samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
Approved 
 
 


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CONFIDENTIAL 
 
 
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 
 
 


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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 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 DILI 
according to recommendations in the last section of this appendix.  
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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 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 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
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 
 
 


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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 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, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and 
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
• 
Complete blood count (CBC) with differential to assess for eosinophilia 
• 
Serum total immunoglobulin IgG, anti-nuclear antibody, anti-smooth muscle 
antibody, and liver kidney microsomal antibody -1 to assess for autoimmune 
hepatitis 
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• 
Serum acetaminophen (paracetamol) levels 
• 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
• 
Viral serologies 
• 
Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
• 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already 
been collected 
• 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
therapies and laboratory results must be captured in the corresponding CRFs.  
 
Approved 
 
 


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Page 1 of 16 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Rheumatoid Arthritis With Inadequate Response 
to Standard of Care Therapy 
 
Amgen Protocol Number AMG 592 20170149 
 
Amendment Date: 
06 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 overenrollment of additional eligible 
screened subjects in each cohort.  
2. To expand phase 1b dosing cohorts 2 and 3 by 8 subjects per cohort in order to 
gain additional pharmacokinetic, pharmacodynamic and safety data at these 
doses. Due to a large number of early drop outs the pharmacokinetic and 
pharmacodynamic data from these cohorts was insufficient to understand  
dose - response relationships. 
3. To update the Risks section of the protocol to align with updates to the 
Investigator Brochure.  
4. To update the dose for cohort 3 from 
 to reflect the 
DLRM recommendation that this dose be increased. 
5. To reduce the thresholds for white blood cell count and absolute neutrophil count 
in the exclusion criteria because leukopenia is common in this patient population. 
Approved 
 
 


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CONFIDENTIAL 
 
 
Description of Changes 
Section:  Global 
Change:  Version date updated throughout document from 26 July 2018 to  
06 June 2019. 
Section:  Global 
Change:  Editorial changes (including typographical, grammatical, and formatting) have 
been made throughout the document. 
Section:  Title Page 
Replace: 
Name: 
 MD 
With:  
Name: 
 MD and 
MD 
Section:  Title Page 
Replace: 
Email Address: 
 
With:  
Email Address: 
 
 
Section:  Title Page 
Add:  Amendment 3 06 Jun 2019 
Section:  1  Protocol Synopsis, Overall Design 
Replace:  The phase 1b will include 4 dosing-cohorts.  Subjects within a dosing-cohort 
will be randomized in a 3:1 ratio to AMG 592 (n = 6) or placebo (n = 2) as follows:  
cohort 1 
 cohort 2 
 cohort 3 
 
 and cohort 4 
 in addition to standard of care therapy.  Dosing 
cohorts will enroll sequentially with the exception of cohorts 2 and 3, which will enroll 
concurrently.  A Dose Level Review Meeting (DLRM) will convene after the last subject 
in each cohort completes the week 4 visit.  The exception is for cohorts 2 and 3 where 
the DLRM will convene after the last subject enrolled in both cohorts completes the 
week 4 visit.   
With:  The phase 1b will include 4 planned dosing-cohorts.  Subjects within a  
dosing-cohort will be randomized in a 3:1 ratio to AMG 592 (n = 6) or placebo (n = 2) as 
follows:  cohort 1 
 cohort 2 
 cohort 3 
 and cohort 4 
 in addition to standard of care 
therapy.  Approximately 8 additional subjects (6 AMG 592; 2 placebo) may be 
Approved 
 
 


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CONFIDENTIAL 
 
 
enrolled into each of cohorts 2 and 3.  Dosing cohorts will enroll sequentially with the 
exception of cohorts 2 and 3, which will enroll concurrently.  A Dose Level Review 
Meeting (DLRM) will convene after the last subject in each cohort completes the week 4 
visit.  The exception is for cohorts 2 and 3 where thean initial DLRM will convene after 
the last subjectfirst 16 enrolled subjects (8 in both cohorts completeseach cohort) 
complete the week 4 visit and a second DLRM will convene after the remaining 
16 enrolled subjects (8 in each cohort) complete the week 4 visit.   
Section:  1  Protocol Synopsis, Overall Design 
Section:  1  Protocol Synopsis, Number of Subjects 
Replace:  Approximately 32 subjects will be randomized in the phase 1b part of the 
study (24 to AMG 592 and 8 to placebo).   
With:  In the phase 1b part of the study, sufficient subjects will be randomized to 
yield approximately 48 subjects (24approximately 36 randomized to AMG 592 and 
812 randomized to placebo; see Section 5.2.1).  The total sample size may be 
higher than 48 subjects 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.  Additional subjects may be enrolled in each cohort 
to enable all screened eligible subjects to participate in the study.  Within each 
cohort subjects will be randomized to AMG 592 or placebo in a 3:1 ratio. 
Section:  1  Protocol Synopsis, Treatments 
Replace:  In the phase 1b part of the study, 4 dose cohorts are planned (cohort 1:   
 cohort 2:  
 cohort 3:  
 and cohort 4:  
 
With:  In the phase 1b part of the study, 4 dose cohorts are planned (cohort 1:  
 
; cohort 2:  
; cohort 3:  
 and cohort 4:  
 
Approved 
 
 


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Section:  2.1 Study Schema 
Replace:   
Figure 2-1.  Study Shema Phase 1b 
 
 
 
Approved 
 
 


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With:   
Figure 2-1.  Study Shema Phase 1b 
 
Approved 
 
 


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Approved 
 
 


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Section:  3.2.5  Risk Assessment 
Replace:  Single doses of AMG 592 ranging from 
 have been 
administered to 8 cohorts of healthy subjects in a phase 1a FIH single ascending and 
multiple dose study of AMG 592 (Study 20140324).  Treatment with AMG 592 resulted in 
a dose-dependent increase in Treg cells with minimal expansion of CD4+ and CD8+ 
 or NK cells.  No deaths, serious adverse events, or 
concerning safety signals have been observed.  The most common adverse events 
include mild (grade 1) painless erythema at or near the injection site, sometimes 
accompanied by pruritus, that is self-resolving.  Please refer to the 
Investigator’s Brochure for further details. 
With:  Single doses of AMG 592 ranging from 
 have been administered 
to 8 cohorts of healthy subjects in a phase 1a FIH single ascending and multiple dose 
study of AMG 592 (Study 20140324).  Treatment with AMG 592 resulted in a 
dose-dependent increase in Treg cells with minimal expansion of CD4+ and CD8+ 
 or NK cells.  No deaths, serious adverse events, or 
concerning safety signals have been observed.  As of 12 March 2019, approximately 
100 subjects have received at least 1 dose of AMG 592.  Repeated subcutaneous 
doses of up to 
 have been studied for up to 3 months in 
subjects with RA and systemic lupus erythematosus.  The most common adverse 
events include experienced by subjects was mild (grade 1) painless erythema at or 
near the injection site, sometimes accompanied by pruritus, that iwas self-resolving.  
Please refer toTwo serious hypersensitivity reactions to AMG 592 have been 
reported.  In addition, worsening arthritis deemed related to AMG 592 has been 
reported in the ongoing 20170149 study.  The majority of these events were 
reported by a single site.  No clinically significant therapeutic related 
abnormalities in electrocardiograms, hematological or biochemical laboratory 
investigations, or vital signs have been reported.  More detailed information about 
the known and expected risks and reasonably expected adverse events of  
AMG 592 may be found in the Investigator’s Brochure. 
Section:  5.1.1  Phase 1b Study Design 
Replace:  Dosing cohorts will enroll sequentially with the exception of cohorts 2 and 3, 
which will enroll concurrently and share a single dose level review meeting (DLRM). 
Approved 
 
 


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CONFIDENTIAL 
 
 
After the last subject enrolled in each cohort completes the week 4 visit, a dose level 
review meeting (DLRM) will convene to determine the acceptability of dose escalation.  
The exception is for cohorts 2 and 3 where the DLRM will convene after the last subject 
enrolled in both cohorts completes the week 4 visit.   
With:  Dosing cohorts will enroll sequentially with the exception of cohorts 2 and 3, 
which will enroll concurrently and share a single dose level review meeting 
(DLRMmeetings (DLRMs). 
After the last subject enrolled in each cohort completes the week 4 visit, a dose level 
review meeting (DLRM) will convene to determine the acceptability of dose escalation.  
The exception is for cohorts 2 and 3 where thean initial DLRM will convene after the last 
subjectfirst 16 enrolled subjects (8 in both cohorts completeseach cohort) complete 
the week 4 visit and a second DLRM will convene after the remaining 16 enrolled 
subjects (8 in each cohort) complete the week 4 visit.   
Section:  5.1.1  Phase 1b Study Design 
Replace:  Additional dosing cohorts may be added or substituted based on emerging 
data. 
With:  Additional dosing cohorts may be added and/or substitutedexisting cohorts may 
be expanded based on emerging data.   
Approved 
 
 


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Page 9 of 16 
CONFIDENTIAL 
 
 
Section:  5.2  Number of Subjects 
Replace:  Approximately 32 subjects will be randomized in the phase 1b part of the 
study (24 to AMG 592 and 8 to placebo).  
 
  
With:  Approximately 32 subjects will be randomized in the phase 1b part of the study 
(24 to AMG 592 and 8 to placebo).In the phase 1b part of the study, sufficient 
subjects will be randomized to yield approximately 48 evaluable subjects 
(approximately 36 randomized to AMG 592 and 12 randomized to placebo; see 
Section 5.2.1).  The total sample size may be higher than 48 subjects 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.  Additional 
subjects may be enrolled in each cohort to enable all screened eligible subjects to 
participate in the study.  Within each cohort subjects will be randomized to  
AMG 592 or placebo in a 3:1 ratio. 
Section:  5.2.1  Replacement of Subjects 
Replace:  In the phase 1b part of the study subjects who have been randomized but 
withdraw prior to administration of investigational product will be replaced. 
With:  In the phase 1b part of the study subjects who have beenare randomized but 
withdraw prior to administration ofdiscontinue investigational medicinal product 
willbefore completing the week 4 visit may be replaced. 
Section:  5.2.2  Number of Sites 
Replace:  Approximately 14 sites in North America and Europe will participate in the 
phase 1b part of the study 
 
   
With:  Approximately 1418 sites in North America and Europe will participate in the 
phase 1b part of the study 
 
   
Approved 
 
 


Product:  AMG 592 
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Date:  06 June 2019 
Page 10 of 16 
CONFIDENTIAL 
 
 
Approved 
 
 


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Protocol Number:  20170149 
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CONFIDENTIAL 
 
 
Section:  6.2  Exclusion Criteria 
Replace:   
209 
Positive drug or alcohol urine test at screening.   
With: 
209 
Phase 1b only:  Positive drug or alcohol urine test for illicit drugs at 
screening.  Prescription medications detected by the drug test are 
allowed if they are being taken under the direction of a physician. 
Section:  6.2  Exclusion Criteria 
Replace:   
225 
Presence of laboratory abnormalities at screening including the following: 
• 
Aspartate aminotransferase (AST) or alanine amino transferase (ALT) at 
screening > 1.5X upper limit of normal (ULN) 
• 
Serum total bilirubin (TBL) ≥ 1.5 mg/dL (≥ 26 µmol/L) 
• 
Hemoglobin ≤ 10.5 g/dL(≤ 105 g/L) 
• 
Platelet count < 100,000/mm3 (< 100 x 109/L) 
• 
White blood cell count < 3,000 cells/mm3 (< 3.0 x 109/L) 
• 
Absolute neutrophil count (ANC) < 1,500/mm3 (< 1.5 x 109/L) 
• 
Calculated glomerular filtration rate of ≤ 50 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease (MDRD) formula  
With: 
225 
Presence of laboratory abnormalities at screening including the following: 
• 
Aspartate aminotransferase (AST) or alanine amino transferase (ALT) at 
screening > 1.5X upper limit of normal (ULN) 
• 
Serum total bilirubin (TBL) ≥ 1.5 mg/dL (≥ 26 µmol/L) 
• 
Hemoglobin ≤ 10.5 g/dL(≤ 105 g/L) 
• 
Platelet count < 100,000/mm3 (< 100 x 109/L) 
• 
White blood cell count < 3,0002,500 cells/mm3 (< 3.02.5 x 109/L) 
• 
Absolute neutrophil count (ANC) < 1,500000/mm3 (< 1.50 x 109/L) 
• 
Calculated glomerular filtration rate of ≤ 50 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease (MDRD) formula 
Approved 
 
 


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Page 12 of 16 
CONFIDENTIAL 
 
 
Section:  7.1.1.1.1 Dosage Adminsitration and Schedule 
Replace:  In the phase 1b part of the study, AMG 592 or placebo will be administered by 
SC injection 
 starting on day 1.  The following dose cohorts are planned in 
the phase 1b portion of the study: 
With: In the phase 1b part of the study, AMG 592 or placebo will be administered by SC 
injection 
 starting on day 1.  The following dose cohorts are planned in the 
phase 1b portion of the study: 
Section:  7.4.2.1  Dose Level Review Meetings 
Replace:  After all evaluable subjects within a cohort have completed the week 4 visit, a 
DLRM will be held to review data and make dose escalation/de-escalation decisions 
(see Appendix 3).   
With:  After all evaluable subjects within a cohort have completed the week 4 visit, a 
DLRM will be held to review data and make dose escalation/de-escalation decisions 
(see Appendix 3).  The exception is for cohorts 2 and 3 where an initial DLRM will 
convene after the first 16 enrolled subjects (8 in each cohort) complete the week 4 
visit and a second DLRM will convene after the remaining 16 enrolled subjects  
(8 in each cohort) complete the week 4 visit. 
Approved 
 
 


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Page 13 of 16 
CONFIDENTIAL 
 
 
Section:  7.4.2.2  Dose Cohort Stopping Rules 
Replace: 
Table 7-1.  Dose Cohort Stopping Rules 
Scenario 
Action  
Occurrence of a CTCAE version 4.0 
Grade 3 adverse event deemed 
related to investigational product in 2 
or more subjects within in a single 
dosing 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 
Upon majority vote by the DLRM members, one of the 
following decisions may be made 
• 
stop enrollment of the cohort (if applicable) 
• 
enrollment of the cohort may resume as 
planned 
• 
the cohort may be expanded at the same dose  
• 
enrollment of the study may continue at a lower 
dose 
OR 
Upon unanimous vote by the DLRM members, 1 of the 
following decisions may be made: 
• 
escalation to an intermediate dose (a dose 
lower than the next planned dose) may take 
place 
• 
escalation to the next planned dose may occur 
Any occurrence of a CTCAE  
version 4.0 ≥ Grade 4 adverse event 
Stop dosing additional subjects in the cohort and 
convene DLRM (if the event occurs outside the 
regularly scheduled DLRM) 
Review adverse event and all relevant safety data for 
evidence of relationship to treatment and clinical or 
medical significance. 
Consider unblinding to determine relatedness to 
investigational producta 
If the adverse event is determined by majority vote of 
the DLRM members to be related to the investigational 
product and clinically or medically significant, no further 
doses should be administered at this dose and no dose 
escalation should proceed.  Enrollment of the study 
may continue at a lower dose or a lower dose cohort 
may be added to the study. 
Otherwise, upon majority vote of the DLRM members, 
one of the following decisions may be made: 
• 
enrollment of the cohort may resume as planned 
• 
the cohort may be expanded at the same dose 
• 
enrollment of the study may continue at a lower 
dose or a lower dose cohort may be added to the 
study 
 
Approved 
 
 


Product:  AMG 592 
Protocol Number:  20170149 
Date:  06 June 2019 
Page 14 of 16 
CONFIDENTIAL 
 
 
With: 
Table 7-1.  Dose Cohort Stopping Rules 
Scenario 
Action  
Occurrence of a CTCAE version 
4.03 Grade 3 adverse event deemed 
related to investigational product in 2 
or more subjects within in a single 
dosing 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 
Upon majority vote by the DLRM members, one of the 
following decisionsrecommendations may be made 
• 
stop enrollment of the cohort (if applicable) 
• 
enrollment of the cohort may resume as 
planned 
• 
the cohort may be expanded at the same dose  
• 
enrollment of the study may continue at a lower 
dose 
OR 
Upon unanimous vote by the DLRM members, 1 of the 
following decisionsrecommendations may be made: 
• 
escalation to an intermediate dose (a dose 
lower than the next planned dose) may take 
place 
• 
escalation to the next planned dose may occur 
Any occurrence of a CTCAE  
version 4.03 ≥ Grade 4 adverse 
event 
Stop dosing additional subjects in the cohort and 
convene DLRM (if the event occurs outside the 
regularly scheduled DLRM) 
Review adverse event and all relevant safety data for 
evidence of relationship to treatment and clinical or 
medical significance. 
Consider unblinding to determine relatedness to 
investigational producta 
If the adverse event is determined by majority vote of 
the DLRM members to be related to the investigational 
product and clinically or medically significant, no further 
doses should be administered at this dose and no dose 
escalation should proceed.  Enrollment of the study 
may continue at a lower dose or a lower dose cohort 
may be added to the study. 
Otherwise, upon majority vote of the DLRM members, 
one of the following decisionsrecommendations may 
be made: 
• 
enrollment of the cohort may resume as planned 
• 
the cohort may be expanded at the same dose 
• 
enrollment of the study may continue at a lower 
dose or a lower dose cohort may be added to the 
study 
 
Approved 
 
 


Product:  AMG 592 
Protocol Number:  20170149 
Date:  06 June 2019 
Page 15 of 16 
CONFIDENTIAL 
 
 
Section:  10.1.1  Phase 1b 
Replace:  It is anticipated that approximately 32 subjects will be enrolled in the phase 1b 
part of the study with 8 subjects assigned to each cohort (3:1 ratio AMG 592 vs 
placebo).   
The sample size of the phase 1b part of the study is based on practical considerations.  
With 6 subjects receiving AMG 592 per cohort, there is an 82% 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 74% if the event rate becomes 
20%.  With a total of 24 subjects planned to receive AMG 592 in phase 1b, there is a 
21% 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 71% if the 
true event rate becomes 5%.  
With:  It is anticipated that approximately 3248 subjects will be enrolledrandomized in 
the phase 1b part of the study, with 8 subjects assignedrandomized to each of cohorts 
1 and 4 and approximately 16 subjects randomized to each of cohorts 2 and 3(3:1 
ratio AMG 592 vs placebo).  The total sample size may be higher than 48 subjects 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.  
Within each cohort subjects will be randomized to AMG 592 or placebo in a  
3:1 ratio.   
The sample size of the phase 1b part of the study is based on practical considerations.  
With   For cohorts 1 and 4, with 6 subjects receiving AMG 592 perin each cohort, 
there is an 82% chance of at least 1 subject within a cohort experiencing an adverse 
event, if the true event rate is 25%.   The chance of at least 1 subject experiencing an 
adverse event within a cohort will be 74% if the event rate becomes 20%.  With a total 
of 24 subjects  
For cohorts 2 and 3, with 12 subjects receiving AMG 592 in each cohort, the 
chance of at least 1 subject experiencing an adverse event within a cohort 
increases to 97% and 93% for true event rates of 25% and 20%, respectively.  In 
addition, with a total of 36 subjects planned to receive AMG 592 in the  
phase 1b, there is a 21% chance of at least 1 subject experiencing an adverse event 
with a true event rate of 1%.  The part of the study, the chance of at least 1 subject 
Approved 
 
 


Product:  AMG 592 
Protocol Number:  20170149 
Date:  06 June 2019 
Page 16 of 16 
CONFIDENTIAL 
 
 
experiencing an adverse event will be 71across the cohorts increases to 30% and 
84% if the true event rate becomes 5%.rates are 1% and 5%, respectively.   
Additional subjects may be enrolled at a randomization ratio of 3:1 to AMG 592 or 
placebo to enable all screened eligible subjects to participate in the study, for 
addition and/or expansion of cohorts based on DLRM recommendations, or for 
replacement of subjects as per Section 5.2.1.   
Approved 
 
 


Product:  AMG 592
Protocol Number:  20170149
Date:  26 July 2018
Page 1 of 3
CONFIDENTIAL
Amendment 2
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Rheumatoid Arthritis With Inadequate Response 
to Standard of Care Therapy
Amgen Protocol Number (AMG 592) 20170149
NCT Number:  NCT03410056
EudraCT Number 2017-001944-36
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 
 
 


Product:  AMG 592
Protocol Number:  20170149
Date:  23 May 2018
Page 1 of 23
CONFIDENTIAL
Amendment 1
Protocol Title:  A Phase 1b/2a Study to Evaluate the Safety and Efficacy of 
AMG 592 in Subjects With Active Rheumatoid Arthritis With Inadequate Response 
to Standard of Care Therapy
Amgen Protocol Number (AMG 592) 20170149
Amendment Date:
23 May 2018
Rationale:
The purpose of this protocol amendment is to:

Update language to clarify aspects of Early Termination and Safety Follow-up visits, 
as previously outlined in clarification memos for authorities.

Change exclusion criterion 217 to allow up to 3 prior biologic or oral synthetic 
DMARD therapies; update wash out periods for these prior therapies.

Clarify exclusion criterion 221, prohibition of as needed nonsteroidal 
anti-inflammatory drugs (NSAIDs), acetaminophen and/or analgesics, applies to 
phase 2a only.

Clarify exclusion criterion 223 and prohibited medications to allow Vitamin D and 
calcium to be taken.

Replace sentinel dosing in Phase 1b with longer direct observation after the first 
dose and close telephone follow-up after the second dose of investigational product
for all subjects.

Incorporate a cohort stopping rule of ≥2 Grade 3 adverse events to replace the 
existing ≥3 Grade 3 adverse event cohort stopping rule.

Clarify that Pharmacokinetic, pharmacodynamic, and antibody blood samples may 
not be drawn through a central or peripheral line.

Include pharmacokinetic sampling at day 92, 99, and 113 to align with other studies 
in AMG 592 program.

Include earlier clinical lab assessments prior to day 15 for additional safety review.

Updated language within protocol to align with latest version of the DLRM SOP.
Approved 
 
 

SAP_001.pdf: 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
































































 


















































 
 
 




post-baseline maximum/minimum and change from baseline to post-baseline 
maximum/minimum