Clinical trial NCT03156023
Conditions: Rheumatoid Arthritis
Sponsor: Amgen
Start date: 2017-08-14; Completion date: 2020-06-12
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate safety and tolerability and characterize the pharmacokinetic (PK) profile of rozibafusp alfa following multiple dose administration in adults with rheumatoid arthritis (RA).

Detailed description:

Arms: arm 1: Participants will receive rozibafusp alfa administered subcutaneously once every 2 weeks for up to 10 weeks (6 doses). Rozibafusp alfa doses will range from 70 to 420 mg.

Escalation to a higher dose cohort will be contingent on a review indicating that the previous dose regimen has been found to demonstrate an acceptable safety and tolerability profile at a dose level review meeting (DLRM). arm 2: Participants will receive matching placebo to rozibafusp alfa administered subcutaneously once every 2 weeks for up to 10 weeks (6 doses).
Interventions: intervention 1: Rozibafusp Alfa intervention 2: Placebo
Intervention descriptions: intervention 1: Administered by subcutaneous injection once every 2 weeks. intervention 2: Administered by subcutaneous injection once every 2 weeks.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 1 of 90 
CONFIDENTIAL 
Title:  A Randomized, Double Blind Placebo Controlled Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Subcutaneous 
Doses of AMG 570 in Subjects With Rheumatoid Arthritis 
Amgen Protocol Number (AMG 570) 20150196 
IND number BB-IND 127060 
EudraCT number 2017-000337-31 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Phone: +1 805-447-1000 
Key Sponsor Contact(s): 
, MD, PhD   
Medical Science Medical Director 
Phone:
Email:
Global Early Clinical Development Manager 
Phone:
Email:
 
Original Date: 
Superseding Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
20 February 2017 
09 March 2017 
16 May 2017 
13 November 2017 
08 June 2018 
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; <<for all other countries, insert the local toll-free Medical Information
number>> Amgen’s general number in the US (1-805-447-1000).
Approved
NCT Number: NCT03156023
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 2 of 90 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “ A Randomized, Double Blind Placebo 
Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple 
Ascending Subcutaneous Doses of AMG 570 in Subjects with Rheumatoid Arthritis,” 
dated 08 June 2018 and agree to abide by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
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 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 3 of 90 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Randomized, Double Blind Placebo Controlled Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of Multiple Ascending Subcutaneous Doses of AMG 570 in Subjects with 
Rheumatoid Arthritis 
Study Phase:  1b   
Indication:  Rheumatoid Arthritis 
Primary Objective:   
 
To evaluate the safety and tolerability of AMG 570 following multiple dose subcutaneous 
(SC) administration in subjects with rheumatoid arthritis (RA). 
Secondary Objective(s):   
 
To characterize the pharmacokinetic profile of AMG 570 following multiple dose SC 
administration in subjects with RA. 
Exploratory Objective(s):  
 
To characterize the pharmacodynamic effects of multiple subcutaneous doses of 
AMG 570 in subjects with RA on peripheral blood B cell levels (total B cells as well as 
naive and memory subpopulations), peripheral blood ICOSL Receptor Occupancy on 
B cells, serum BAFF levels, serum Immunoglobulin levels, plasma cells and circulating 
T follicular helper (Tfh) cells. 
 
To characterize pharmacokinetic and pharmacodynamic relationships after multiple 
subcutaneous doses of AMG 570 in subjects with RA.  
 
To characterize effects of multiple subcutaneous doses of AMG 570 on clinical and 
serologic indices of RA disease activity in subjects with RA.  
 
To evaluate the immunogenicity of  multiple subcutaneous doses of AMG 570 in subjects 
RA. 
Hypotheses:   
Multiple SC dose administration of AMG 570 will have acceptable safety and tolerability profiles in 
RA subjects within the proposed dose range (70 to 420 mg AMG 570) 
Primary Endpoint:   
Subject incidence of treatment-emergent adverse events (including clinically significant changes 
in physical examinations), vital signs, laboratory safety tests, and electrocardiograms (ECGs). 
Secondary Endpoint(s):   
 
AMG 570 Serum PK profiles after multiple dose administrations.  PK parameters will 
include, but are not limited to, maximum observed concentration [Cmax] and area under 
the concentration-time curve [AUC] after the first and the last doses, and the 
accumulation ratio. 
Exploratory Endpoint(s):   
 
Peripheral blood ICOSL receptor occupancy. 
 
Baseline levels, post-dose levels and change from baseline in peripheral blood 
percentage and absolute counts of total T cells, B cells and NK cells.   
 
Baseline levels, post-dose levels and change from baseline in peripheral blood 
percentage and absolute counts of naive and memory B cells 
(naïve = CD19+IgD+CD27-, memory = CD19+IgD-CD27+) 
 
Baseline levels, post-dose levels and change from baseline in circulating Plasma cells by 
gene signature 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 4 of 90 
CONFIDENTIAL 
 
 
 
Baseline levels, post-dose levels and change from baseline in circulating Tfh by flow 
cytometry and gene signature 
 
Baseline levels, post-dose levels and change from baseline in serum Immunoglobulin M, 
Immunoglobulin G and Immunoglobulin A 
 
Baseline levels, post-dose levels and change from baseline in serum BAFF 
 
Baseline levels, post-dose levels and change from baseline in serum CRP, ESR, 
IgG+ Rheumatoid Factor, IgM+ Rheumatoid Factor and anti-citrullinated protein antibody 
 
Changes from baseline over time in the disease activity score based on 28 joints 
(DAS 28-CRP) 
 
Changes from baseline over time in Patient Global Assessment of Disease activity 
 
Changes from baseline over time in Physician Global Assessment of Disease activity  
 
Anti-AMG 570 binding antibodies 
Study Design:  This is a randomized, placebo-controlled, double-blind, multiple ascending dose 
(MAD) study in RA subjects.  The study consists of 4 SC cohorts with SC doses ranging from 
70 to 420 mg.  Subjects will be randomized in a 3:1 ratio to receive AMG 570 or placebo 
accordingly. 
Escalation to a higher dose cohort will be contingent on a review indicating that the previous dose 
regimen(s) has (have) been found to demonstrate an acceptable safety and tolerability profile at a 
dose level review meeting (DLRM).  The DLRM will review blinded safety and laboratory data 
once at least 6 subjects in preceding cohorts have reached day 29.  Safety data from the ongoing 
single ascending dose (SAD) study with AMG 570 (20140322) will also be incorporated to ensure 
that any higher dose cohort in the MAD study has already been found to have an acceptable 
safety and tolerability profile in the corresponding dose cohort of the SAD study. 
The 140 mg Q2W, 210 mg Q2W, or 420 mg Q2W doses may be revised based on the data 
received from the earlier cohorts in this study, the higher doses evaluated in the ongoing FIH 
SAD study in healthy subjects, as well as revised PK/PD predictions (if any) based on emerging 
data from the SAD or MAD study. 
Sample Size:  Approximately 32 subjects will be enrolled in 4 cohorts with 6 active and 2 placebo 
in each cohort. 
Summary of Subject Eligibility Criteria:  Subjects in this study will be males and females with 
RA between ages of 18-75 years (inclusive).  Subjects should have a body mass index of ≥18 
and ≤35 kg/m2.  Subjects should be up to date on immunizations with status determined by the 
site investigator.  For a full list of eligibility criteria, please refer to Section 4.1 and Section 4.2. 
Dose Levels 
Cohort # 
Planned Dose 
Route 
N (active:placebo) 
1 
70 mg q 2 wk x 6 doses 
SC 
8 (6:2) 
2 
140 mg q 2 wk x 6 doses 
SC 
8 (6:2) 
3 
210 mg q 2 wk x 6 doses 
SC 
8 (6:2) 
4 
420 mg q 2 wk x 6 doses 
SC 
8 (6:2) 
Investigational Product   
Amgen Investigational Product Dosage and Administration:  AMG 570 will be packaged in 
5-ml clear glass vials containing 1 ml of 70 mg/ml AMG 570 formulated as below.  Placebo will be 
presented in similar containers and stored the same as AMG 570.  Vials will be stored between 
2 oC to 8oC.  
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 5 of 90 
CONFIDENTIAL 
 
 
For Cohorts 1 to 3, doses will be administered in a 1.0 mL per injection format (up to 3 x 1 mL 
injections depending on treatment arm).  For Cohort 4, doses will be administered as a 1.5 mL 
per injection format (4 x 1.5 mL). 
Dosage and IP Administration 
Product Name 
AMG 570 
Placebo 
Formulation 
Description 
10 mM acetate, 9.0% (w/v) sucrose, 
0.01% (w/v) polysorbate 80 
10 mM acetate, 9.0% (w/v) sucrose, 
0.004% (w/v) polysorbate 20 
Dosage Form 
Solution 
Solution 
Unit dose 
Strength 
70 mg/ml 
NA 
Procedures:   
The planned length of participation in the study will be approximately 10 months (22-26 visits) 
which includes up to 6 weeks for screening, 3-8 days for inpatient visit, outpatient visits up to 
10 weeks for drug dosing, 24 weeks for evaluation of drug distribution after last dose, followed by 
end of study (EOS) visit. 
Screening:  After signing the informed consent, subjects will be screened to determine 
eligibility within a period of 42 days before dosing on day 1.  Subjects who require 
additional vaccination will receive vaccines during the screening period and at least 
28 days prior to dosing.  Adverse events will be collected for a subject from the time of 
signed informed consent until the subject concludes participation in the study including 
any extended follow-up for anti-AMG 570 antibodies, B cell counts, or serum IgG levels.  
Concomitant medications will be collected throughout the study. 
Treatment:  Inclusion in the study requires pre-existing background therapy with 
methotrexate (or other non-biologic/non-synthetic DMARD) for ≥12 weeks prior to receipt 
of investigational product (IP), and subjects will remain on this background therapy 
through the length of the study.   
Subjects will be admitted to the research facility on Day -1 to collect baseline clinical and 
laboratory data.  Subjects will receive the first dose of IP on Day 1.  Subjects will check 
out of the research facility no less than on Day 3 and up to Day 11 after all assessments 
have been completed.  Subjects must return to the research facility on an outpatient 
basis at specified time points for collection of blood samples for PK and PD 
measurements, RA disease assessments, and completion of safety assessments. 
Subjects will receive a SC dose of IP on days 1, 15, 29, 43, 57, and 71.  Subjects will be 
followed for 24 weeks after the last dose. 
End of study:  A subject’s participation in the study will conclude with the completion of 
the end of study procedures.  However, if an end of study test result demonstrates a 
significant clinical or laboratory abnormality, the subject will be followed until resolution of 
the abnormality or until it is considered clinically stable by the Principal Investigator.  
o 
If a subject’s CD3-CD19+ B cell count at screening is ≥107 cells/L  at screening 
and is < 107 cells/L at the end of study visit, the subject will return for further 
testing of B cell counts until values are within the healthy range.  If a subject’s 
CD3-CD19+ B cell count at screening is between 70-106 (inclusive) at screening 
and is less than their screening value at the end of study visit, the subject will 
return for further testing of B cell counts until values are greater than or equal to 
baseline values.  If a subject’s serum IgG level is < 639 mg/dl (the lower limit of 
normal for healthy individuals), the subject will return for further testing of serum 
IgG until values are within the healthy range.  Such follow-up visit(s) for B cell 
counts and serum IgG will continue every 3 months, up to 12 months after the 
end of study. 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 6 of 90 
CONFIDENTIAL 
 
 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 4). 
Statistical Considerations:  Descriptive statistics will be provided for selected demographics, 
safety, pharmacokinetics, pharmacodynamics, and biomarker data by dose, dose schedule, and 
time as appropriate.  Descriptive statistics on continuous data will include means, medians, 
standard deviations and ranges, while categorical data will be summarized using frequency 
counts and percentages.  Graphical summaries of the data may also be presented. 
Safety data will be reviewed on an ongoing basis.  Amgen, in consultation with the site 
investigator, will review in Dose Level Review Meetings (DLRMs) all available accumulating data, 
including data from the ongoing AMG 570 SAD study (20140322) prior to making dose escalation 
decisions.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 7 of 90 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 8 of 90 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ACR/EULAR 
American College of Rheumatology/European League Against 
Rheumatism 
ADA 
anti-drug antibodies 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BAFF 
B cell activating factor 
B7RP-1 
B7-related protein-1 (also referred to as ICOSL) 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CRF 
case report form 
DCs 
dendritic cells 
DILI 
drug-induced liver injury 
DLRM 
dose level review meeting 
DLT 
dose limiting toxicity 
DMARD 
disease modifying anti-rheumatic drug 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
EMEA 
European Medicines Agency 
end of study for individual 
subject  
defined as the last date that protocol-specified procedures are 
conducted for an individual subject 
end of treatment 
defined as the date of final assessment for the protocol specified 
treatment phase of the study 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 purposes of final collection of data for the primary 
endpoint(s).   
end of trial 
defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes multiple 
parts (eg, safety follow-up), the end of study  would include these 
additional parts 
FIH 
First in Human 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 9 of 90 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
GSO 
Global Safety Officer 
HBcAb 
hepatitis B core antibody 
HepBsAg 
hepatitis B surface antigen 
HepCAb 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
Ig 
Immunoglobulin 
IC50 
inhibitory concentration at 50% 
IC90 
inhibitory concentration at 90% 
IC99 
inhibitory concentration at 99% 
ICF 
informed consent form 
ICOS 
ICOSL 
inducible co-stimulator 
inducible co-stimulator ligand 
ICH 
IV  
International Conference On Harmonisation 
intravenous 
IP 
Investigational Product 
IPIM 
Investigational Product Instruction Manual 
IPRO 
Immunophenotyping and Receptor Occupancy 
IRB 
Institutional Review Board 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MABEL 
MAD 
Minimum Anticipated Biological Effect Level 
Multiple ascending dose 
MRSD 
maximum recommended starting dose 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PR 
the interval measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart’s electrical cycle as 
measured by electrocardiogram 
QRS 
the interval between the Q wave and the S wave in the heart’s 
electrical cycle as measured by electrocardiogram; represents the 
time it takes for depolarization of the ventricles 
QT 
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 
electrocardiogram 
QTc 
RA 
QT interval corrected for heart rate using accepted methodology 
Rheumatoid arthritis 
RO 
receptor occupancy 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 10 of 90 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
RNA 
ribonucleic acid 
SC 
Subcutaneous 
SLE 
Systemic Lupus Erythematosus 
study day 1 
defined as the first day that protocol specified investigational product 
is administered to the subject 
Tfh 
T follicular helper cell 
tmax 
time to maximum concentration 
ULN 
upper limit of normal 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 11 of 90 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 7 
Study Glossary .................................................................................................................. 8 
1. 
OBJECTIVES ......................................................................................................... 16 
1.1 
Primary ....................................................................................................... 16 
1.2 
Secondary .................................................................................................. 16 
1.3 
Exploratory ................................................................................................. 16 
2. 
BACKGROUND AND RATIONALE ........................................................................ 16 
2.1 
Disease ....................................................................................................... 16 
2.1.1 
Autoantibodies Result From T cell-B cell Interactions ................ 17 
2.1.2 
Modulation of T cell-B cell Function in Rheumatoid 
Arthritis ....................................................................................... 17 
2.2 
Amgen Investigational Product Background ............................................... 18 
2.2.1 
Pharmacology ............................................................................. 18 
2.2.2 
Toxicology .................................................................................. 18 
2.3 
Risk Assessment ........................................................................................ 19 
2.4 
Rationale .................................................................................................... 20 
2.4.1 
AMG 570, AMG 557 and Blisibimod Molecular 
Structure Information .................................................................. 21 
2.4.2 
AMG 557 Clinical Background .................................................... 21 
2.4.3 
Blisibimod Clinical Background .................................................. 21 
2.4.4 
Clinical Studies With AMG 570 ................................................... 22 
2.4.4.1 
FIH Study 20140322 ................................................ 22 
2.4.4.2 
FIH Study 20140322 – Clinical 
Pharmacokinetics ..................................................... 23 
2.4.4.3 
FIH Study 20140322 – Clinical 
Pharmacodynamics ................................................. 23 
2.4.5 
Human Exposure Margins .......................................................... 24 
2.4.6 
Rationale for Dose Selection ...................................................... 25 
2.4.7 
Rationale for Key Aspects of Study Design ................................ 26 
2.5 
Clinical Hypotheses .................................................................................... 26 
3. 
EXPERIMENTAL PLAN ......................................................................................... 27 
3.1 
Study Design .............................................................................................. 27 
3.2 
Number of Sites .......................................................................................... 27 
3.3 
Number of Subjects .................................................................................... 27 
3.4 
Replacement of Subjects ............................................................................ 27 
3.5 
Estimated Study Duration ........................................................................... 27 
3.5.1 
Study Duration for Subjects ........................................................ 27 
3.5.2 
End of Study ............................................................................... 28 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 12 of 90 
CONFIDENTIAL 
 
 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 29 
4.1 
Inclusion Criteria ......................................................................................... 29 
4.2 
Exclusion Criteria ........................................................................................ 30 
5. 
SUBJECT ENROLLMENT ..................................................................................... 32 
5.1 
Randomization/Treatment Assignment ...................................................... 33 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 33 
6. 
TREATMENT PROCEDURES ............................................................................... 34 
6.1 
Classification of Product(s), Medical Device(s), and/or 
Combination Product(s) .............................................................................. 34 
6.2 
Investigational Product ............................................................................... 34 
6.2.1 
Amgen Investigational Product AMG 570 ................................... 34 
6.2.1.1 
Dosage, Administration, and Schedule .................... 35 
6.2.1.2 
Dose-cohort Study Escalation and 
Stopping Rules ......................................................... 35 
6.2.1.3 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 37 
6.3 
Other Protocol-required Therapies ............................................................. 38 
6.4 
Concomitant Therapy ................................................................................. 38 
6.5 
Hepatotoxicity Stopping Rules .................................................................... 40 
6.5.1 
Criteria for Permanent Withholding of AMG 570 due to 
Potential Hepatotoxicity .............................................................. 40 
6.6 
Alcohol, Tobacco, and Exercise Restrictions ............................................. 41 
6.7 
Product Complaints .................................................................................... 41 
7. 
STUDY PROCEDURES ......................................................................................... 41 
7.1 
Schedule of Assessments .......................................................................... 41 
7.2 
General Study Procedures ......................................................................... 46 
7.2.1 
Screening ................................................................................... 46 
7.2.2 
Day -1 and Treatment ................................................................. 48 
7.2.3 
End of Study Visit/ Early Termination ......................................... 49 
7.3 
General Study Assessments ...................................................................... 49 
7.3.1 
Physical Exam ............................................................................ 49 
7.3.2 
Vital Signs ................................................................................... 50 
7.3.3 
Electrocardiogram ...................................................................... 50 
7.3.4 
Adverse Events and Concomitant Medications .......................... 51 
7.4 
Disease Assessments ................................................................................ 51 
7.4.1 
DAS28-CRP  Score .................................................................... 51 
7.4.2 
Physician Global Assessment of Disease Activity ...................... 52 
7.4.3 
Patient Global Assessment of Disease Activity .......................... 52 
7.4.4 
Patient’s Assessment of Physical Function: Disability 
Index of the Health Assessment Question (HAQ-DI) ................. 52 
7.5 
Blood and Urine Assessments ................................................................... 53 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 13 of 90 
CONFIDENTIAL 
 
 
7.5.1 
Blood Volume ............................................................................. 53 
7.5.2 
Drug and Alcohol Screen ............................................................ 53 
7.5.3 
HIV Antibodies, Hepatitis B Surface Antigen, and 
Hepatitis C Antibodies ................................................................ 53 
7.5.4 
Laboratory Safety Tests ............................................................. 54 
7.5.5 
Serum and Urine Pregnancy Test .............................................. 54 
7.5.6 
FSH and Estradiol ...................................................................... 55 
7.5.7 
QuantiFERON-TB Gold .............................................................. 55 
7.6 
Urinalysis .................................................................................................... 55 
7.7 
Immunophenotyping and Receptor Occupancy Assay ............................... 55 
7.8 
Serum Immunoglobulin Levels ................................................................... 55 
7.9 
BAFF Serum Levels ................................................................................... 56 
7.10 
Rheumatoid Arthritis Biomarkers ................................................................ 56 
7.10.1 
C-Reactive Protein ..................................................................... 56 
7.10.2 
Rheumatoid Factor ..................................................................... 56 
7.10.3 
Anti-citrullinated Peptide Antibodies ........................................... 56 
7.11 
Exploratory Autoimmune Antibodies .......................................................... 56 
7.12 
Blood Collection for Pharmacokinetic Analysis .......................................... 56 
7.13 
Antibody Testing Procedures ..................................................................... 56 
7.14 
Biomarker Development ............................................................................. 57 
7.15 
Pharmacogenetic Studies ........................................................................... 57 
7.16 
Sample Storage and Destruction ................................................................ 57 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 58 
8.1 
Subjects’ Decision to Withdraw .................................................................. 58 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 59 
8.3 
Reasons for Removal From Treatment and/or Study ................................. 60 
8.3.1 
Reasons for Removal From Treatment ...................................... 60 
8.3.2 
Reasons for Removal From Study ............................................. 60 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 60 
9.1 
Definition of Safety Events ......................................................................... 60 
9.1.1 
Adverse Events .......................................................................... 60 
9.1.2 
Serious Adverse Events ............................................................. 61 
9.2 
Safety Event Reporting Procedures ........................................................... 61 
9.2.1 
Adverse Events .......................................................................... 61 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 61 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 62 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 64 
9.3 
Pregnancy and Lactation Reporting ........................................................... 64 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 14 of 90 
CONFIDENTIAL 
 
 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 65 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 65 
10.1.1 
Study Endpoints ......................................................................... 65 
10.1.2 
Analysis Sets .............................................................................. 66 
10.1.3 
Covariates and Subgroups ......................................................... 66 
10.1.4 
Handling of Missing and Incomplete Data .................................. 66 
10.2 
Sample Size Considerations ...................................................................... 66 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 67 
10.4 
Planned Analyses ....................................................................................... 67 
10.4.1 
Data Monitoring Committee (DMC), Data Review 
Team (DRT) or Dose Level Review Team (DLRT) .................... 67 
10.4.2 
Primary Analysis ......................................................................... 67 
10.5 
Planned Methods of Analysis ..................................................................... 67 
10.5.1 
General Considerations .............................................................. 67 
10.5.2 
Primary Endpoint(s) .................................................................... 68 
10.5.2.1 
Adverse Event .......................................................... 68 
10.5.2.2 
Clinical Laboratory Tests ......................................... 68 
10.5.2.3 
Vital Signs ................................................................ 68 
10.5.2.4 
Electrocardiograms .................................................. 68 
10.5.3 
Secondary Endpoint(s) ............................................................... 68 
10.5.3.1 
PK Analysis .............................................................. 68 
10.5.4 
Exploratory Endpoints ................................................................ 69 
11. 
REGULATORY OBLIGATIONS ............................................................................. 69 
11.1 
Informed Consent ....................................................................................... 69 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 70 
11.3 
Subject Confidentiality ................................................................................ 70 
11.4 
Investigator Signatory Obligations .............................................................. 71 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 71 
12.1 
Protocol Amendments and Study Termination ........................................... 71 
12.2 
Study Documentation and Archive ............................................................. 72 
12.3 
Study Monitoring and Data Collection ........................................................ 72 
12.4 
Investigator Responsibilities for Data Collection ........................................ 74 
12.5 
Language.................................................................................................... 74 
12.6 
Publication Policy ....................................................................................... 74 
12.7 
Compensation ............................................................................................ 75 
13. 
REFERENCES ....................................................................................................... 76 
14. 
APPENDICES ........................................................................................................ 78 
 
Approved 
 
 


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List of Tables 
Table 1.  Calculated Exposure Margins for Proposed AMG 570 Doses for 
Planned Multiple Ascending Dose ........................................................... 25 
Table 2.  Dose Levels ..................................................................................................... 27 
Table 3.  Dose Cohort Stopping Rules ............................................................................ 37 
Table 4.  Schedule of Assessments – Screening Through Day 43 (Week 6) ................. 42 
Table 5.  Schedule of Assessments – Day 57 (Week 8) Through End of Study 
(Week 34) ................................................................................................ 44 
Table 6.  List of Analytes ................................................................................................. 54 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 79 
Appendix B.  eSerious Event Contingency Form ............................................................ 81 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 86 
Appendix D.  Patient Global Assessment of Disease Activity and Disability 
Index of the Health Assessment Question (HAQ-DI) ............................... 88 
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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the safety and tolerability of AMG 570 following multiple dose subcutaneous 
(SC) administration in subjects with rheumatoid arthritis (RA). 
1.2 
Secondary 
To characterize the pharmacokinetic profile of AMG 570 following multiple dose SC 
administration in subjects with RA. 
1.3 
Exploratory 
 
To characterize the pharmacodynamic effects of multiple subcutaneous 
doses of AMG 570 in subjects with RA on peripheral blood B cell levels (total 
B cells as well as naive and memory subpopulations), peripheral blood 
ICOSL Receptor Occupancy on B cells, serum BAFF levels, serum 
Immunoglobulin levels, plasma cells and circulating T follicular helper (Tfh) 
cells. 
 
To characterize pharmacokinetic and pharmacodynamic relationships after 
multiple subcutaneous doses of AMG 570 in subjects with RA.  
 
To characterize effects of multiple subcutaneous doses of AMG 570 on 
clinical and serologic indices of RA disease activity in subjects with RA.  
 
To evaluate the immunogenicity of  multiple subcutaneous doses of AMG 570 
in subjects RA 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
RA is a chronic inflammatory disease of the joints that can lead to significant disability 
due to cartilage and bone damage.  RA is estimated to have a worldwide prevalence 
between 0.5-1%.  Extra-articular manifestations involving an array of organ systems are 
also observed in some patients (Smolen, 2016). 
RA results from the aberrant infiltration of immune cells into the joint.  This infiltrate is a 
mix of immune cells from both the lymphoid and myeloid lineages.  These cells release 
lipid and protein mediators, including cytokines, proteases, and antibodies, that 
perpetuate the inflammatory response, lead to clinical symptoms, and potentially tissue 
destruction (Catrina, 2016).  The use and proliferation of available disease modifying 
anti-rheumatic drugs (DMARDs), including conventional, biologic, and targeted synthetic 
drugs, have allowed up to 40% of patients with moderate to severe disease achieve a 
low disease activity state as defined by a 70% response in the American College of 
Rheumatology improvement criteria (ACR70)  (Smolen, 2016).  Nonetheless, a number 
of patients remain symptomatic, and innovative therapies hold potential to further 
improve outcomes.   
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2.1.1 
Autoantibodies Result From T cell-B cell Interactions 
A central driver of the inflammatory response in RA is considered to be the production of 
autoantibodies.  Autoantibody production results from maladaptive interactions between 
autoreactive T cells and B cells in lymphoid tissue (Catrina, 2016).  In part reflecting the 
central role of autoantibodies in RA pathogenesis, 50-70% of RA patients have 
detectable autoantibodies such as rheumatoid factor (RF) or anti-citrullinated protein 
antibodies (ACPAs) (Smolen, 2016).  ACPAs are notable as these antibodies may be 
directly responsible for initiating and perpetuating arthritis (Catrina, 2016).  In addition, 
preliminary data indicate that early intervention to forestall the development of 
autoantibodies in individuals susceptible to RA may in turn delay the onset of disease 
(Gerlag, 2016).  Together, these data indicate that the production of autoantibodies is a 
primary precipitant of the inflammatory cascade in RA and that targeting autoantibody 
production through disruption of T cell-B cell interactions provides a means to improve 
clinical outcomes.   
Over the last 15 years, an increasingly clear picture of the molecular cues and temporal 
dynamics of T cell-B cell interactions leading to autoantibody production has emerged.  
In short, antigen-specific T cells survey B cell areas within lymphoid tissue, and upon 
encountering a B cell that displays the requisite antigen, the T cell and B cell engage in a 
bidirectional “crosstalk” that ultimately leads to the differentiation of the T cell into the 
T follicular helper (Tfh) cell lineage and activation of the B cell (Craft, 2012).  Activation 
of autoreactive B cells initiates a differentiation program which leads to the generation of 
autoantibody secreting plasmablasts and plasma cells.  Tfh cells are noteworthy 
because these cells are particularly efficient at further engaging B cells to amplify the 
magnitude and breadth of the antibody response.  Studies in humans as well as 
pre-clinical animal models indicate that the T cell costimulatory molecule, inducible T cell 
costimulator (ICOS), and its ligand, ICOSL, (also known as B7 related protein-1 or 
B7RP-1), expressed on B cells and dendritic cells (DC), is central to the differentiation of 
T cells to the Tfh lineage as the absence of ICOS: ICOSL interactions leads to 
substantial loss in Tfh cells as well as antibody production (Craft, 2012).   
2.1.2 
Modulation of T cell-B cell Function in Rheumatoid Arthritis 
Therapeutics to modulate T cell- B cell interactions and inhibit autoantibody production 
have focused on unilateral targeting of the T cell- B cell dyad.  Abatacept inhibits T cell 
costimulation through blockade of the ligand for the costimulatory molecule, CD28, found 
on T cells.  Abatacept is clinically effective in RA.  B cell targeting has focused on 
Approved 
 
 


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Protocol Number:  20150196 
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modulating B cell numbers to minimize the likelihood of T-B interactions.  Strategies to 
directly deplete B cells with rituximab or neutralize B cell growth factors, such as BAFF, 
have been employed and studied in subjects with RA.  Modulation of T cell costimulation 
as well as depletion of B cells have both shown clinical efficacy in RA subjects with 
abatacept and rituximab approved for this indication.  Though rituximab and abatacept 
are indicated for only partially overlapping subject populations, the proportion of subjects 
who achieve ACR70 responses 6 months after treatment is ~10-20% 
(Cohen 2006, Genovese 2005, Kremer 2003).  Thus, new molecular entities, such as 
AMG 570, that are capable of further modulating T-B interactions may provide enhanced 
efficacy.  
2.2 
Amgen Investigational Product Background  
2.2.1 
Pharmacology 
AMG 570 is a bispecific molecule inhibiting both BAFF and ICOSL.  AMG 570 contains 
two tandem copies of BAFF-binding peptides identical to the BAFF binding peptides of 
blisibimod (also known as AMG 623) fused to the C-terminus of AMG 557, a fully human 
IgG2 against ICOSL currently in clinical development for SLE.  In terms of anti-BAFF 
effect, AMG 570 has similar binding affinity and cellular potency to blisibimod.  AMG 570 
has 29 pM KD BAFF binding affinity and 0.86 nM IC50 in a BAFF cellular assay.  
Blisibimod was reported to have an IC50 of 0.2 nM.  For the anti-ICOSL effect, AMG 570 
has similar binding affinity and inhibitory activity to AMG 557.  AMG 570 has 28 pM KD  
ICOSL binding affinity and 1.36 nM IC50 in a ICOSL cellular assay.  AMG 557 has 
17 pM KD  ICOSL binding affinity and AMG 557 parental antibody 16H has 1.35 nM IC50 
in an ICOSL cellular assay.  AMG 570 binds and inhibits cynomolgus monkey BAFF and 
ICOSL, but not rodent ICOSL.  A mouse surrogate BAFF/ICOSL bispecific molecule 
showed dual-target inhibition in vivo and was more efficacious than the single ICOSL or 
BAFF inhibitors in the mouse NZB/NZW lupus model.  Thus, we hypothesize that 
targeting both BAFF and ICOSL by AMG 570 will achieve a large effect size in the 
treatment of autoantibody associated diseases, including RA and SLE.   
2.2.2 
Toxicology 
AMG 570 has been evaluated in a series of toxicology studies in laboratory animals and 
in vitro test systems.  The Good Laboratory Practice (GLP) 3-month repeat-dose 
toxicology study in the cynomolgus monkey with an 8-month recovery was performed as 
a pivotal toxicology study to support this clinical study.  AMG 570 was administered 
Approved 
 
 


Product:  AMG 570 
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subcutaneously (SC) at 0, 30, 100, or 200 mg/kg once weekly for 13 weeks (4 main 
study animals/sex/group and 2 recovery animals/sex/group at 0 and 200 mg/kg).   
Weekly SC administration of AMG 570 for 13 weeks was well tolerated up to 200 mg/kg 
in cynomolgus monkeys with sustained AMG 570 exposure (TK) and PD response.  The 
no-observed-adverse-effect level (NOAEL) was 200 mg/kg, providing exposure margin 
of ≥29 (Table 1 in Section 2.4.5).  Anti-drug antibodies (ADAs) to AMG 570 were 
detected in all dose groups, affecting AMG 570 exposure and PD response in some 
animals; however, sustained exposure and PD response were observed in 19 of 28 
AMG 570-dosed animals (4 of 8 at 30 mg/kg, 5 of 8 at 100 mg/kg and 10 of 12 at 
200 mg/kg) throughout the 13-week administration period, enabling a robust toxicology 
evaluation.  In these animals, AMG 570 pharmacology-related effects (ie, decreased 
B cells, IgG and lymphoid depletion of the lymphoid tissues) and injection site reactions 
(attributed to a localized response to the SC administered biological protein) were 
observed at all dose levels.  All cellular and lymphoid organ changes were reversible.   
2.3 
Risk Assessment 
AMG 570 is currently being evaluated in an ongoing FIH single ascending dose study in 
healthy subjects (20140322).  As of 01 June 2018, 56 subjects have received blinded 
investigational product at SC doses up to 700 mg.  All subjects receiving dose levels up 
to 420 mg SC in the single ascending dose study have completed and demonstrated 
acceptable safety and tolerability with no severe, life-threatening, or fatal events 
reported.  All adverse events have been of mild to moderate severity.  Subjects receiving 
700 mg SC remain on study with safety data and a dose level review meeting 
anticipated later this year.  Further details may be found in Section 2.4.4. 
For this multiple ascending dose study in RA patients, 17 subjects have received either 
70 mg or 140 mg of blinded investigational product as of 01 June 2018.  As of 
01 June 2018, no deaths or drug-related serious adverse events, dose-limiting toxicities, 
or withdrawals due to adverse events have been reported.  In general, AMG 570 was 
well tolerated at the doses tested.  
An additional assessment of potential side effects of multiple doses of AMG 570 is 
based on the pre-clinical studies conducted to date and by observations of safety and 
tolerability of AMG 557 and blisibimod clinical studies.  Summaries of findings from the 
pre-clinical studies with AMG 570 can be found in the AMG 570 Investigator’s Brochure 
(IB).  No target organs beyond pharmacologic effects of AMG 570 were identified up to 
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the high dose in the 3-month GLP cynomolgus monkey toxicology study (200 mg/kg: 
11 to 64.5- times higher than planned clinical doses [70 to 420 mg]).   
Potential side effects of AMG 570 could also be related to the biological nature of the 
molecule, and mode of administration. 
 
Immunosuppression: risks which may be associated with immunosuppression with 
reduction in humoral and cellular immunity include infection and malignancy.   
 
Hypersensitivity: all therapeutic products (small molecules and biologics) can be 
associated with hypersensitivity reactions.  Most of the hypersensitivity reactions are 
mild in severity, although severe reactions may occur (eg, angioedema, 
anaphylaxis).  
 
Injection site reactions: (eg, erythema, itching, hematoma, swelling or bruising and 
pain) are common side effect of drugs with SC administration.  These reactions can 
range from mild to severe (including injection site necrosis which is an uncommon 
side effect).  
The proposed risk assessment and management plan for the study has been developed 
in accordance with the requirements of regulatory guidelines and strategies to identify 
and mitigate risks for clinical trials with investigational medicinal products.  
Please refer to the AMG 570 IB, Section 7 for a description of these potential side 
effects.  
A newly completed 6-month toxicology study in the cynomolgus monkey has shown an 
increase in RBC and hemoglobin in a small number of animals at exposure levels much 
higher than expected in clinical subjects.  The relevance of this for humans is not 
currently known, and hematology safety laboratory tests will be monitored for any 
changes. 
2.4 
Rationale 
Given the centrality of T-B cell interactions in the production of autoantibodies, 
approaches to disrupt this axis hold promise in providing enhanced efficacy.  AMG 570 
utilizes a bispecific design to simultaneously target both members of the T cell-B cell 
pair.  Through targeting of ICOSL, AMG 570 disrupts the productivity of T cell-B cell 
interactions by interfering with Tfh activity, and through targeting of BAFF, AMG 570 
decreases the pool of B cells available to interact with T cells.  Thus, AMG 570 seeks to 
impact both the qualitative and quantitative outputs of T cell-B cell collaboration to 
decrease autoantibody production and thereby provide enhanced efficacy compared to 
existing therapies.  
Approved 
 
 


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2.4.1 
AMG 570, AMG 557 and Blisibimod Molecular Structure Information 
The bispecific AMG 570 antibody has a peptide-linker-peptide-linker construct fused to 
the C-terminus of each heavy chain of AMG 557.  AMG 557 is a human IgG2.  
Blisibimod has a peptide-linker-peptide-linker construct fused to the N-terminus of each 
chain of a human Fc.  The peptides in AMG 570 are BAFF-binding peptides identical to 
those in blisibimod.  Molecular weights of AMG 570, AMG 557 and blisibimod are 
approximately 161, 148, and 64 kDa, respectively.  Each of the constituent pathways 
targeted by AMG 570 have been investigated in patient populations.  In total, these data 
indicate that in isolation, the two arms have acceptable safety and tolerability profiles 
and show trends indicative of clinical activity (Furie, 2014 and Sullivan, 2016).  A brief 
description of the clinical background of each of the constitutent molecules is found in 
Sections 2.4.2 and 2.4.3. 
2.4.2 
AMG 557 Clinical Background 
Single dose administration of AMG 557 to subjects with mild, stable SLE with 
subcutaneous (SC) doses of 1.8, 6, 18, 60, 140, and IV dosing of 210 mg and 18 mg 
demonstrated an acceptable safety profile with no observed neutralizing antibodies 
(study 20060132).  AMG 557 demonstrated nonlinear pharmacokinetic properties, as 
expected for therapeutic targeting of a cell surface receptor.  The degree of target 
occupancy was dose/concentration-related, reversible, and achieving maximal levels in 
the 140 mg SC group.  Multiple dose administration of AMG 557 to subjects with mild, 
stable SLE with SC doses of 6, 18, 30, 45, 70, 140, and 210 mg demonstrated an 
acceptable safety profile with no observed neutralizing antibodies (study 20060169) 
Consistent, dose-dependent pharmacodynamic effects on  KLH responses were 
observed following multiple doses of AMG 557.  Multiple dose administration of 210 mg 
SC for 6 months was also investigated in patients with active lupus arthritis 
(study 20101103).  Though not statistically significant, trends of improvement in lupus 
arthritis response as well as general metrics of SLE activity (including changes in BILAG 
and SLEDAI) suggested clinical activity of AMG 557. 
The estimated mean AMG 557 target occupancy IC50 was 0.0888 μg/mL (0.60 nM), IC90 
of 0.8 μg/mL (5.4 nM), and IC99 of 8.8 μg/mL (59.5 nM). 
2.4.3 
Blisibimod Clinical Background 
Subjects with mild to moderate SLE were treated with blisibimod single SC doses of 0.1, 
0.3, 1.0, or 3.0 mg/kg or IV doses of 1.0, 3.0, or 6.0 mg/kg in a first-in-human study 
(study 20040147) and multiple dose 0.3, 1.0, 3.0 (SC) or 6.0 (IV) mg/kg in phase1b 
Approved 
 
 


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(study 20040250).  In the multiple dose study, blisibimod treatment led to a significant 
decrease in naïve B cells (IgD+CD27-) and an increase in class-switched memory B cells 
(IgD-CD27+) (Stohl et al, 2015).  This significant reduction in naïve B-cells was observed 
when blisibimod concentration was 3 μg/mL (47 nM) or higher.  No consistent effects on 
T cells, NK cells, plasmablasts, or plasma cells were evident.  The Phase 2 study of 
blisibimod in subjects with moderate-to-severe SLE (Furie, 2014) demonstrated 
significantly higher SLE Responder Index (SRI-5) responses in subjects randomized to 
the highest dose of blisibimod 200 mg once-weekly (QW at Week 20 (p=0.02)).  
2.4.4 
Clinical Studies With AMG 570 
2.4.4.1 
FIH Study 20140322 
In the ongoing FIH study in healthy volunteers, 7 dose cohorts, over a dose range of 
7 mg to 700 mg, are planned with each receiving a single subcutaneous dose of 
AMG 570 or placebo.  Each dose cohort is comprised of 8 subjects with 6 subjects 
receiving AMG 570 and 2 subjects receiving placebo.  As of 1 June 2018, 56 subjects 
have received a single dose of AMG 570 or placebo at the following doses: 7, 21, 
70,140, 210, 420, or 700 mg SC.  44 subjects have completed the study, 1 subject 
withdrew consent, 3 subjects  have been lost to follow up, and 8 subjects are currently 
enrolled.  In general, AMG 570 was well tolerated at the doses tested.  As of 
1 June 2018 no deaths or drug-related serious adverse events, dose limiting toxicities or 
withdrawals due to adverse events (AEs) have been reported.   
The FIH study included two humoral immune status stopping rules that accounted for the 
potential of AMG 570 to decrease total circulating B cells and serum IgG levels.  If a 
single subject in the FIH study satisfied the humoral immune status stopping rules, 
further studies with AMG 570 would shift from healthy volunteers to patients.   
As of the cohort 6 Dose Level Review Meeting on 17 November 2017, no subjects met 
the humoral immune status stopping rules.  Additionally, no clinically significant 
abnormalities in electrocardiograms (ECGs), safety laboratories, or vital signs have been 
reported.  As of  17 November 2017, blinded safety data from the first 6 cohorts (dose 7, 
21, 70, 140, 210 and 420 mg SC) were reviewed by the Dose Level Review team 
(Amgen in collaboration with study investigators) resulting in a 'safe to proceed to the 
next dose level' vote.  As of 1 June 2018, 8 subjects have been dosed in cohort 7 at the 
700 mg SC dose level (allocated 6 subjects AMG 570: 2 subject Placebo).   
Additional accumulating safety data from the ongoing 20140322 study will be 
communicated to investigators during the Dose Level Review meetings for this protocol.   
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2.4.4.2 
FIH Study 20140322 – Clinical Pharmacokinetics 
The pharmacokinetics of AMG 570 are currently being assessed in the ongoing FIH 
study. 
Single dose administration of AMG 570 to healthy subjects with subcutaneous (SC) 
doses of 7, 21, 70, 140, 210, 420 mg demonstrated nonlinear PK and a trend to linear 
PK at dose higher than 210 mg. This is based on preliminary assessment of dose 
normalized AUC and Cmax and PK modeling of the available data. 
2.4.4.3 
FIH Study 20140322 – Clinical Pharmacodynamics 
A validated, semi-quantitative flow cytometry assay was developed to monitor the 
pharmacodynamics properties of the constituent arms of the bispecific in whole blood 
specimens.   
ICOSL arm – peripheral blood receptor occupancy 
ICOSL receptor occupancy was measured using two antibodies:  Free ICOSL levels are 
measured as the MFI of an AMG 570-competing anti-ICOSL antibody conjugated to 
BV421, gated on circulating B cells.  Total ICOSL levels are measured as the MFI of an 
AMG 570-non-competing anti-ICOSL antibody conjugated to BV421, gated on circulating 
B cells. 
The receptor occupancy (RO) equation is: 
RO = [1 - (background subtracted free ICOSL/ background subtracted total 
ICOSL)/(Baseline background subtracted free ICOSL /Baseline background subtracted 
total ICOSL)] * 100 
Where: 
 
background subtracted free ICOSL= free ICOSL – Maximally saturated free 
ICOSL 
 
background subtracted total ICOSL= total ICOSL – 191 
RO is 0 at baseline. 
In the ongoing study, preliminary assessment of the pharmacodynamic effects of single 
doses of AMG 570 indicate dose-related and reversible RO.  ICOSL receptor occupancy 
was measured with two antibodies using a similar approach to published literature 
(Sullivan, et al 2016). In the ongoing study, single doses of AMG 570 indicated 
dose-dependent and reversible RO. 
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BAFF arm – circulating B cell populations 
The effects of BAFF blockade on total circulating B cells as well as naïve and memory 
B cell subsets (where naïve = CD19+IgD+CD27- and memory = CD19+IgD-CD27+) in 
the peripheral blood is also being measured.   
As of 01 January 2018, preliminary analysis of results from the 6 cohorts of 
study 20140322, AMG 570 led to a reduction in circulating naïve B cells and an increase 
in circulating memory B cells compared to the accumulated placebo group. There was 
an increase in total B cells at day 8, consistent with pharmacodynamic effects of 
previous BAFF inhibitors (Witcher, 2016 and Furie, 2014). 
2.4.5 
Human Exposure Margins 
The AMG 570 exposures for this AMG 570 MAD clinical study were based on analysis of 
observed AMG 570 human PK data from this study or the ongoing AMG 570 FIH study 
(20140322). 
The exposure margins were calculated from serum AMG 570 exposures at the NOAEL 
of 200 mg/kg in cynomolgus monkeys determined in a 3-month GLP toxicology study, 
and from the projected human PK exposures after the last dose for the proposed dose 
levels (Table 1).  
At the NOAEL in monkey, the mean Cmax following 200 mg/kg dose was 2540 µg/mL and 
estimated AUC of 23000 µg x day/mL for Q2W dosing regimen.  Multiple Q2W x 6 
administration of AMG 570 in the dose range of 70 mg to 420 mg SC is projected to be 
safe and well tolerated, with human exposures less than the exposures at the NOAEL.  
At the highest planned SC dose (420 mg Q2W X 6), the exposures at the NOAEL in 
monkeys are 42- and 29-fold above the Cmax and AUC in humans (Table 1).   
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Table 1.  Calculated Exposure Margins for Proposed AMG 570 Doses for Planned 
Multiple Ascending Dose 
Human Exposurea 
Exposure Marginb 
Dose (mg) 
Route 
Cmax,last dose 
(μg/mL) 
AUC0-tau,last dose 
(μg•day/mL) 
Cmax 
Ratioc 
AUC  
Ratiod 
70 Q2 wk x 6 
(Observed) 
SC 
6.8 
57 
370 
400 
140 Q2 wk x 6 
(Predicted) 
SC 
18 
230 
141 
100 
210 Q2 wk x 6 
(Predicted) 
SC 
30 
400 
85 
58 
420 Q2 wk x 6 
(Predicted) 
 
SC 
60 
800 
42 
29 
Values reported to two significant figures 
AUC0-tau = area under the concentration-time curve from time 0 to 14d after last dose; Cmax = maximum 
observed concentration after the last dose; NOAEL = no observed adverse effect level. 
a Predicted AUC0-tau and Cmax after the last dose, tau = 14 days for Q2W dosing.   
b Based on day 85 toxicokinetic results at the NOAEL dose of 200 mg/kg where AUC0-14=23000 μg•day/mL, 
and Cmax = 2540 µg/mL (Study 117993). 
c  Cmax ratio is the observed Cmax in monkeys after the last SC dose divided by the predicted Cmax in humans 
after multiple dose. 
d AUC ratio is the observed AUC0-tau in monkeys after the last SC dose divided by the predicted AUC0-tau in 
humans after multiple dose.  
2.4.6 
Rationale for Dose Selection 
The proposed doses for AMG 570 MAD clinical study were selected based on observed 
and predicted AMG 570 human exposures at steady-state after multiple administration of 
proposed doses, as well as interim pharmacodynamics results from the ongoing 
AMG 570 FIH study (20140322), as described in section 2.4.4.3. 
Based on interim pharmacodynamics data from the AMG 570 FIH, the predicted typical 
individual steady-state exposure after the last dose at 70 mg Q2W × 6 is anticipated to 
provide sub-optimal pharmacodynamics response with predicted 70% ICOSL RO and at 
least 40% reduction in B cells.  Steady-state exposures at the middle dose of 140 mg 
Q2W ×6  is anticipated to be associated with near maximal effect on ICOSL RO and 
B-cell depletion.  Dose of 210 mg Q2W × 6 is expected to result in higher ICOSL RO, up 
to 90% RO or more at steady-state and to maintain and/or increase B cell depletion 
compared to lower doses.  The 420 mg Q2W × 6 dose will allow further evaluation of 
safety, ICOSL RO response and reduction of B-cells.  This dose range will provide 
additional safety, pharmacokinetics, and pharmacodynamics data that will facilitate the 
understanding of the exposure-response relationship to inform future studies with 
AMG 570. The degree of B cell depletion at the highest dose is not anticipated to be 
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greater than prior BAFF inhibitors, which have demonstrated circulating B cell depletion 
of up to 70% (Furie RA,2014, Wallace, 2009 , and Isenberg, 2015). 
The 210 mg Q2W or 420mg Q2W may be revised based on the data received from the 
earlier cohorts in this study, as well as revised PK/PD predictions (if any) based on 
emerging data from the SAD or MAD study.   
2.4.7 
Rationale for Key Aspects of Study Design 
Given the known clinical benefits of modulation of T cell and/or B cell function in RA, 
subjects with RA are to be enrolled in this multiple ascending dose study.  The 
understanding of both targets of AMG 570, ICOSL and BAFF, and previous experience 
with AMG 557 and blisibimod with their acceptable safety and tolerability profiles justifies 
testing in RA patients 
The multiple ascending dose design requires thorough evaluation of the safety profile for 
dose escalation.  Subjects will be carefully monitored for adverse events and safety 
laboratory results.  Testing in this population will provide further information on the PK of 
AMG 570.  Furthermore, data from the FIH study will be incorporated into dose 
escalation decisions to ensure that any dose to be tested at multiple doses has already 
demonstrated an acceptable safety and tolerability profile in the FIH. 
To investigate potential clinical benefit, serologic and clinical markers of disease activity 
will be investigated.  These will include measurement of changes in: DAS28-CRP 
scores, Patient Global Assessment of Disease Activity, Physician Global Assessment of 
Disease Activity, CRP, ESR, and autoantibodies associated with RA. 
Biomarkers include ICOSL target occupancy on peripheral blood B cells and 
measurement of serum BAFF concentration.  The percentage and absolute counts of 
total lymphocytes, monocytes, granulocytes and lymphocyte populations including 
CD3+ T cells, CD16/56+ NK cells, CD19+ B cells as well as naïve and memory B cell 
subsets (naïve = IgD+CD27-; memory = IgD-CD27+)  will be determined.  The levels of 
serum IgG and IgM immunoglobulins and BAFF levels will also be measured.  Changes 
in circulating plasma cells will be examined by gene signature, and changes in Tfh cells 
will be examined by both flow cytometry and gene signature. 
2.5 
Clinical Hypotheses 
Multiple SC dose administration of AMG 570 will achieve acceptable safety and 
tolerability profiles in RA patients within the proposed dose range (70 to 420 mg SC 
AMG 570).   
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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a randomized, placebo-controlled, double-blind, MAD study in subjects with RA.  
The study consists of 4 SC cohorts.  Subjects will be randomized in a 3:1 ratio to receive 
AMG 570 or placebo according to Table 2.   
Table 2.  Dose Levels 
Cohort # 
Planned 
Dose (mg) 
Route 
Dosing 
interval 
Number of 
planned 
doses 
N(active:placebo) 
1 
70 
SC 
Q 2 weeks 
6 
8 (6:2) 
2 
140 
SC 
Q 2 weeks 
6 
8 (6:2) 
3 
210 
SC 
Q 2 weeks 
6 
8 (6:2) 
4 
420 
SC 
Q 2 weeks 
6 
8 (6:2) 
The overall study design is described by a study schema at the end of the 
protocol synopsis section.  The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 8 sites in the U.S. and Germany will be utilized in this study.  Additional 
sites may be added at the discretion of the medical monitor. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 32 subjects will be enrolled into 4 cohorts (6 active: 2 placebo in each 
cohort).  See Section 10.2 for sample size rationale. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study prior to receiving 
AMG 570 will be replaced at the discretion of the Amgen Medical Monitor and Principal 
Investigator by notifying the unblinded study pharmacist or designee.  The new subject 
will receive the identical treatment as the replaced subject, but will be assigned a 
replacement number associated with this new record.  The unblinded study pharmacist 
or designee will retain the randomization list. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The planned length of participation in the study will be approximately 10 months 
(22-26 visits) which includes up to 6 weeks for screening, 3-8 days for patient visit, 
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outpatient visits up to 10 weeks for drug dosing, 24 weeks for evaluation of drug 
distribution after last dose, followed by end of study (EOS) visit.  Subject’s participation 
in the study will conclude at the completion of the end of study procedures.  Once 
complete, this will conclude the subject’s participation in the study. However, if an end of 
study test result demonstrates a significant clinical or laboratory abnormality, the subject 
will be followed until resolution of the abnormality or until it is considered clinically stable 
by the Principal Investigator.  Specifically, if a subject’s CD3-CD19+ B cell count is 
≥107 cells/µL at screening and is < 107 cells/µL (the lower limit of normal for healthy 
volunteers (Becton, Dickinson, 2015) at the end of study visit, the subject will return for 
further testing of B cell counts until the subject has B cell counts ≥ 107 cells/µL.  If a 
subject’s CD3-CD19+ B cell count at screening is between 70-106 (inclusive) at 
screening and is less than their screening value at the end of study visit, the subject will 
return for further testing of B cell counts until values are greater than or equal to baseline 
values.  Similarly, if a subject’s serum IgG is <639 mg/dl, the subject will also have 
serum IgG monitored until the subject has a serum IgG level ≥ 639 mg/dl 
(Agarwal, 2007).  Follow-up visits for B cell counts and IgG levels will continue every 
3 months, for up to 12 months after the end of study.   
Subject participation may be adjusted based on treatment-emergent data.  All 
adjustments or modifications to the schedule outline above will be agreed upon by the 
Investigator in consultation with the Sponsor.  The Institutional Review Board (IRB) will 
be informed via written correspondence. 
3.5.2 
End of Study 
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.   
The primary completion date is the date when the last subject has completed the 
assessments for EOS visit.   
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). 
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End of Study:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up for significant 
clinical or laboratory abnormality), as applicable. 
The EOS for each cohort may be prolonged pending treatment-emergent data. 
4. 
SUBJECT ELIGIBILITY 
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).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
101. 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102. 
Men or women between 18 to 75 years of age (inclusive) at the time of screening 
103. 
A body mass index (BMI) ≥ 18 kg/m2 and ≤ 35 kg/m2 
104. 
Diagnosed with RA as determined by meeting the 2010 ACR/EULAR 
classification criteria.  The duration of disease must be for at least 6 months 
105. 
Disease Activity Score of 28 joints-CRP (DAS28-CRP) > 2.6 
106. 
On a stable dose of methotrexate (MTX) at 5-25 mg weekly for ≥ 4 weeks at 
day -1.  Subjects on MTX must also take folic acid supplementation, as instructed 
by the investigator. 
107. 
Subjects may continue to take oral corticosteroids, NSAIDs, hydroxychloroquine, 
or sulfasalazine in combination with MTX provided that doses have remained 
stable for ≥4 weeks prior to day 1 and adhere to the following limits: ≤10 mg/ day 
of prednisone or equivalent, ≤400 mg/day hydroxychloroquine, and 
≤3000 mg/day sulfasalazine.   
108. 
Immunizations up to date, as determined by the principal investigator, with a 
minimum of tetanus (either Td or Tdap), diphtheria, pertussis, seasonal influenza 
virus (during flu season), and pneumococcal (polysaccharide) vaccinations.  For 
these vaccines, up to date status should be determined by referencing the 
recommendations for immunizations by the Centers for Disease Control or by 
equivalent governmental agencies for sites outside the US. 
109. 
Subject (male or female) must be willing to use highly effective contraception 
during treatment and up to end-of-study.  Exceptions to the use of effective 
contraception includes females of non-reproductive potential, as defined by:  
 
History of hysterectomy; OR history of bilateral salpingectomy; OR history 
of bilateral oophorectomy; OR  
 
Female subject is considered to be postmenopausal due to absence of 
vaginal bleeding or spotting for at least 12 months and: 
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 
If less than 55 years of age, follicle stimulating hormone (FSH) and 
estradiol must be within the laboratory’s reference range for 
postmenopausal females.  
 
If 55 to 59 years of age and there is uncertainty regarding menopausal 
status, FSH must be within the laboratory’s reference range for 
postmenopausal females 
 
If 60 years of age or older, evaluation of FSH is not needed to confirm 
postmenopausal status 
4.2 
Exclusion Criteria 
201. 
Subject likely to not be available to complete protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
202. 
History or evidence of any other clinically significant disorder, condition or 
disease that, in the opinion of the investigator or Amgen physician, would pose a 
risk to subject safety or interfere with the study evaluation, procedures or 
completion. 
203. 
Subjects who fulfill any of the following criteria are not eligible for the study: 
 
Men and women of reproductive potential who are unwilling to practice an 
acceptable method(s) of effective birth control while on study.  Acceptable 
methods of effective birth control include sexual abstinence (men, 
women); vasectomy; bilateral tubal ligation/occlusion; or a condom with 
spermicide (men) in combination with barrier methods (diaphragm, 
cervical cap or cervical sponge), hormonal birth control or IUD (women).  
 
Women who are lactating/breastfeeding or who plan to breastfeed while 
on study. 
 
Women with a positive pregnancy test. 
 
Women planning to become pregnant while on study. 
 
Men with partners who are pregnant or planning to become pregnant 
while the subject is on study. 
 
Men who are unwilling to abstain from sperm donation while on study. 
204. 
Uncontrolled, clinically significant systemic disease other than RA such as 
diabetes mellitus, liver disease, asthma, cardiovascular disease or hypertension 
205. 
Malignancy within 5 years (except successfully treated in situ cervical cancer or 
squamous or basal cell carcinoma of the skin) 
206. 
Presence of a serious infection (defined as requiring hospitalization or IV 
antibiotics within 8 weeks before Screening), recurrent/chronic infections (defined 
as ≥ 3 infections requiring antibiotics over the past 12 months prior to 
Screening), Prosthetic joint infection within 5 years of screening, or native joint 
infection within 1 year of screening 
207. 
Class IV RA (Hochberg et al, 1992) according to ACR revised response criteria 
208. 
Diagnosed with Felty’s syndrome (RA, splenomegaly, and granulocytopenia) 
209. 
Known or suspected sensitivity to mammalian cell-derived (ie, from Chinese 
hamster ovary) products or any components of the study drug 
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210. 
History of alcohol and/or substance abuse within the last 12 months  
211. 
Chronic pain syndrome requiring daily narcotic analgesics or morphine derived 
medication for analgesic relief at screening 
212. 
All herbal medicines (eg, St. John’s wort), vitamins, and supplements consumed 
by the subject within the 30 days prior to receiving the first dose of investigational 
product, and continuing use if applicable, that has not been reviewed by the 
investigator, in consultation with the Amgen medical monitor, if needed. 
213. 
Subjects who have received ≥ 80 mg of prednisolone equivalents via 
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 
randomization 
214. 
Use of cyclophosphamide, cyclosporine, mycophenolic acid, or gold within the 
previous 6 months prior to day -1 
215. 
The use of any commercial parenteral biologic or oral synthetic DMARD (such as 
tofacitinib or baracitinib) in the 3 months prior to enrollment with the exception of 
rituximab (see below) 
216. 
Receipt of rituximab at any time in the past 
217. 
Subjects who fulfill any of the following criteria are not eligible for the study:  
 
Receiving or has received any investigational drug (or is currently using 
an investigational device) within the 30 days or 5 half-lives (whichever is 
longer), prior to receiving the first dose of AMG 570. 
 
Subjects who were previously exposed to AMG 570 
218. 
The use of any other experimental/investigational biologic DMARD that impacts 
the immune system requires a) > 6 months off the investigational agent prior to 
enrollment, b) approval by the sponsor, and c) reasonable confidence by the 
investigator that the pharmacodynamic effect of the agent has returned to 
baseline at the time of enrollment.  
219. 
Subject received a live attenuated vaccine within 3 months before screening or a 
non-live, inactivated vaccine within 28 days of randomization or plan to receive 
live attenuated vaccine within 30 days and 5 half-lives of the last dose of study 
medication 
220. 
Subjects with a history of residential exposure (within 6 months) to tuberculosis 
(TB) without a documented history of prophylactic treatment or subject has a 
positive interferon-gamma release assay (QuantiFERON® Gold or equivalent) 
within 6 weeks before randomization 
221. 
Subject is positive for HIV antibodies, hepatitis B surface antigen, hepatitis B 
core antibody (confirmed by hepatitis B deoxyribonucleic acid [DNA] polymerase 
chain reaction [PCR] test) or detectable hepatitis C virus ribonucleic acid [RNA] 
by PCR (screening is generally done by hepatitis C antibody [HepCAb], followed 
by hepatitis C virus RNA by PCR if HepCAb is positive).  Subjects with a history 
of hepatitis B vaccination without history of hepatitis B are allowed. 
222. 
Clinically significant abnormalities on ECG (as defined by the Investigator) and/or 
QTc > 480 msec. 
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223. 
CD3-CD19+ B cell count < 70 cells/μL.  For B cell counts of 70-106, a discussion 
with the Amgen medical monitor to include evaluation of humoral immune 
functional status (assessed by IgM and IgG levels as well as history of recurrent 
infections) is required for pre-approval prior to enrollment 
224. 
Serum IgM or IgG level < LLN (measured at a central lab) 
225. 
White blood cell count < 3.0 x 103/μL, or absolute neutrophil count (ANC) 
< 2.0 x 103/μL or platelet count < 140 x 109/L 
226. 
Elevated AST or ALT > 1.5 x upper limit of normal at Screening if subjects are 
receiving MTX.  
227. 
Elevated serum creatinine > 1.5 x upper limit of normal at screening 
228. 
Positive urine screen for alcohol and/or potential drugs of abuse at screening or 
Day -1 
229. 
Blood donation of > 500 mL within 60 days of study drug administration 
230. 
Evidence of renal disease, defined as:  Calculated glomerular filtration rate 
< 60 mL/min using the Modification of Diet in Renal Diseases (MDRD) equation:  
186 x (Creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black) 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures.  Adverse Events are to be 
collected for a subject once they are enrolled in the study.  A subject is considered 
enrolled when the investigator decides that the subject has met all eligibility criteria.  
The Investigator is to document the enrollment decision and date, in the subject’s 
medical record and in/on the enrollment CRF. 
Each subject who enters into the screening period for the study, which is the first time 
that a subject undergoes detailed assessments to determine their potential for eligibility, 
receives a unique subject identification number before any study procedures are 
performed.  The subject identification number will be assigned manually.  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.  A screen failed subject may be rescreened 
up to two times at the discretion of the PI with the agreement of the Amgen Medical 
Monitor. 
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The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study.  
5.1 
Randomization/Treatment Assignment 
Randomization to AMG 570 or placebo will be based on a randomization schedule 
prepared by Amgen before the start of the study and retained by the unblinded study 
pharmacist or designee.  After eligibility for study participation has been confirmed 
(based on data collected during screening visits and on Day -1), eligible subjects will be 
randomized to receive either AMG 570 or placebo.  The randomization date is to be 
documented in the subject’s medical record and on the enrollment eCRF. 
Unique randomization numbers will be assigned in sequential order according to when 
each subject met the eligibility criteria.  At no time will the same randomization number 
be assigned to more than one subject. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment case report form (CRF).  
In the event a subject is randomized, but withdraws before receiving study medication, 
or during the study for reasons other than adverse events (Section 8.3), a replacement  
subject may be enrolled at the discretion of the Amgen Medical Monitor and Principal 
Investigator.  The unblinded study pharmacist or designee will be notified.  The new 
subject will receive the identical treatment as the replaced subject but will be assigned a 
replacement number per the randomization list. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded at study site when 
knowledge of the treatment is essential for the further management of the subject on this 
study or may potentially impact the safety of subjects currently enrolled or subjects in 
subsequent cohorts.  Unblinding at the study site for any other reason will be considered 
a protocol deviation.  The investigator is strongly encouraged to contact the Amgen 
Study Manager before unblinding any subject’s treatment assignment, but must do so 
within 1 working day after the event.   
Treatment assignments will be unblinded at study site after database lock.  After initial 
database lock and receipt of written authorization from Amgen to unblind, the unblinded 
pharmacist will release the specified unblinded pharmacy records to site staff designated 
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to enter the subject treatment into each subject’s Unblinded Investigational Product 
Administration Case Report Form (CRF). 
6. 
TREATMENT PROCEDURES 
The planned doses of AMG 570 are 70 mg SC, 140 mg SC, 210 mg SC and 420 mg SC 
administered once every 2 weeks for 10 weeks (last study drug administration on 
Day 71/Week 10).  Each randomized subject will receive a total of 6 SC doses of 
AMG 570 or matching placebo.  Dose escalation review meetings will be held prior to 
escalation to a higher dose.  Dose escalation will only occur provided adequate safety 
from the prior multiple dose cohort, and no dose will be given unless adequate safety 
from the equivalent dose tested in the single ascending dose study (20140322) with 
AMG 570 has also been determined to have adequate safety. 
6.1 
Classification of Product(s), Medical Device(s), and/or Combination 
Product(s) 
The Amgen Investigational Product and/or placebo used in this study include: AMG 570 
and placebo.  The Investigational Product Instruction Manual (IPIM), a document 
external to this protocol, contains detailed information regarding the storage, 
preparation, destruction, and administration of AMG 570 and placebo. 
6.2 
Investigational Product 
All investigational products will be administered at the research facility by a qualified staff 
member.  A physician must be present at the time of investigational product 
administration.  
6.2.1 
Amgen Investigational Product AMG 570 
AMG 570 will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.  AMG 570, which is a clear colorless 
sterile solution which will be packaged in open label 5mL glass vials containing 70 mg/ml 
of AMG 570 formulated with 10mM acetate, 9.0%(w/v) sucrose, 0.01%(w/v)  polysorbate 
80 at pH 5.2.  Placebo will be presented in identical containers and stored/packaged the 
same as AMG 570, but will not contain AMG 570 protein.  All AMG 570 and placebo will 
be shipped to the study site and should be stored the same as AMG 570 at 2°C to 8°C 
with limited exposure to light. 
For more information regarding investigational product handling and preparation please 
see the study specific IPIM which is provided as a separate document.  
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6.2.1.1 
Dosage, Administration, and Schedule 
All study drug will be administered (Table 2) at the research facility by a qualified staff 
member.  A physician must be available during each administration of investigational 
product.  The date, time, lot number and volume of investigational product administered 
will be recorded on the individual subject’s electronic case report form (eCRF).  Subject 
will be randomized only once to one of 4 Cohorts starting with Cohort 1 and continuing in 
a sequential manner to Cohort 4.  Within each cohort, subjects will be randomized to 
receive 6 SC doses of AMG 570 or placebo in a ratio of 6:2.  Once a dose is selected for 
a cohort, no dose adjustments will be made for an individual subject within the cohort.   
Subcutaneous Administration of AMG 570/Placebo 
The appropriate volume of the IP administered will be based on the set dosage amounts. 
Doses for Cohorts 1-3 will be administered as a 1 mL per injection format (up to 3 x 1mL 
injections depending on treatment cohort).  For Cohort 4, doses will be administered as 
a 1.5 mL per injection format (4 x 1.5 mL).  For individual SC dose volumes that exceed 
1.0 mL, the dose will be split into separate syringes and administered into different sites 
on the subject’s anterior abdominal wall.  Using the umbilicus as a center point, the 
abdomen will be divided into four quadrants – the right upper quadrant (RUQ), left upper 
quadrant (LUQ), right lower quadrant (RLQ) and left lower quadrant (LLQ).  Each 
quadrant may be injected once, starting with the subjects’ upper right, and progressing in 
a clockwise manner to the upper left, lower left and lower right quadrants.   
6.2.1.2 
Dose-cohort Study Escalation and Stopping Rules 
Dose level review meetings (DLRM) will be held to review data, monitor safety, and 
make dosing decisions.  The DLRM members will be composed of the investigator(s), 
Amgen Medical Monitor, Amgen Global Safety Officer (GSO) or designee, Early 
Development Leader or designee, Clinical Study Manager or designee, and Biostatistics 
representative or designee.  Additional members may be added as needed (eg, PK 
Scientist).  The DLRM voting members will include the investigator(s), Amgen Medical 
Monitor and Amgen GSO or designee. 
The DLRM voting members will be responsible for dosing decisions, which may include:  
1) escalation to the next planned dose 
2) escalation to an intermediate dose (a dose lower than the next planned dose) 
3) de-escalation to a lower dose 
4) continuation, delay, or termination of dosing  
5) repetition or expansion of a cohort. 
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Dose escalation for all cohorts will be based upon unanimous decision of the DLRM 
members. 
The dosing decisions will be based on the review of safety data during the DLRM.  
Within each cohort, the safety data will be assessed after all 8 subjects have been 
enrolled and at least 6 subjects have completed the day 29 visit, which corresponds to 
receipt of the third dose of IP.  In addition to the review of safety data, emerging PK and 
PD data will also be reviewed in a blinded fashion at the DLRM as these data become 
available.  Emerging safety, PK, and PD data from equivalent dose level cohorts of the 
AMG 570 Single Ascending Dose (SAD) study in healthy volunteers will also be 
reviewed prior to dose escalation in the multiple ascending dose study.  As of 
1 June 2018, blinded safety review for the 700 mg SC dose hasnot yet occurred for the 
SAD.  Thus, dose escalation for cohort 4 will only proceed if safety, PK, and PD data 
from the 700 mg SC cohort of the SAD have been reviewed by the DLRM and no 
significant safety concerns are observed . 
Dose adjustments (if any) will be made on a treatment cohort basis and not on an 
individual basis, and will be agreed upon by Amgen after reviewing emerging safety, PK, 
and/or PD data.  
The , 210 mg Q2W or 420 mg Q2W doses may be revised based on the data received 
from the earlier cohorts in this study, the higher doses evaluated in the ongoing FIH SAD 
study in healthy subjects, as well as revised PK/PD predictions (if any) based on 
emerging data from the SAD or MAD study. 
Dose Stopping and Review 
Further dosing of AMG 570 will be either stopped or modified to a lower dose if 
suspected adverse drug reactions and/or changes in safety data (including but not 
limited to vital signs, ECGs, clinical laboratory results, or laboratory parameters reflecting 
humoral immune status) are observed and these changes pose a health risk.  A DLRM 
is held when a dose limiting toxicity (DLT) has occurred.  A DLT is defined as any 
treatment-related fatal, life threatening or disabling serious adverse event (SAE).  In 
addition, any adverse event or change in vital signs, clinical laboratory test value, or 
ECG which is considered drug related, and poses a significant health risk, as determined 
by the Investigators and Sponsor, would also constitute a DLT and form the basis for 
stopping dose escalation in the study.  In addition, dosing will be stopped or modified if 
any of the scenarios shown in Table 3 are met.   
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Dose Cohort Stopping Rules 
This section addresses how subject safety will be monitored through adherence to rules 
for stopping dosing within a dose cohort (which precludes any further dose escalation). 
Table 3 describes the dose stopping rules to be used for stopping dosing within a cohort. 
Table 3.  Dose Cohort Stopping Rules 
Scenario 
Action 
Occurrence of a CTCAE Grade 3 or greater 
adverse event in at least 2 subjects in a dose 
cohort 
OR 
Any adverse event or change in above safety 
parameters, which is considered drug related, 
and poses a significant health risk to the 
subject. 
OR 
A change in vital signs, clinical laboratory 
value, or ECG that would be classified as 
Grade 3 or higher by the CTCAE v. 4.0 and 
considered drug related 
OR 
A fatal, life threatening or disabling serious 
adverse event (SAE) 
Stop dosing additional subjects in the cohort 
and convene DLRM.  
Review AE and all relevant safety data for 
evidence of relationship to treatment and 
clinical significance.  Consider unblinding to 
determine relatedness to investigational 
product.*  
If Grade 3 or higher adverse event is 
determined to be related to study drug, and 
clinically significant by the DLRM, no further 
dose escalation to proceed.  
Otherwise, upon unanimous decision of the 
review team, one of the following decisions 
may be made:  
 
Enrollment of the cohort may resume, 
 
The cohort may be expanded at the same 
dose,   
 
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 
subjects in subsequent cohorts 
Dosing will be stopped or modified by the DLRM members if treatment-related AEs, 
changes in vital signs, ECGs, or clinical laboratory results are observed and these 
changes pose a significant health risk. 
The dosing schedule is described by a schema in the protocol synopsis. 
6.2.1.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
This protocol allows for some alterations from the currently outlined dosing schedule, but 
the maximum dose will not exceed 420 mg. 
The actual dose to be administered may be adjusted by the DLRM voting members 
based on safety, tolerability, and preliminary PK data of previous dose levels.  Dose 
adjustments may involve either an increase or a decrease in the planned dose, but will 
not exceed pharmacokinetic criteria defined in the Rationale for Dose Selection 
(Section 2.4.6). 
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If consistent adverse events of moderate or severe intensity occur in the group, or if 
unacceptable pharmacological effects, reasonably attributable in the opinion of the 
investigator to dosing with AMG 570, are observed in more than 2 subjects in a group, 
the dose escalation will be temporarily halted and no additional subjects will be dosed 
until a full safety review by DLRM of the study has taken place.  Relevant data will be 
reviewed and discussed with the investigator, appropriate Amgen personnel, and IRB 
prior to resumption of dosing. 
Clinically or medically significant suspected adverse drug reactions, and serious adverse 
events considered to be related to study procedures will be followed until resolved or 
considered stable.  The study may be terminated at any point in time at the discretion of 
the sponsor.  
6.3 
Other Protocol-required Therapies 
All subjects must maintain a stable dose and the same route of administration of MTX.  
The doses of MTX should be taken on the same day of the week.  Subjects must also 
take folic acid supplementation, as instructed by the investigator, during the trial if 
receiving MTX.  Dose adjustment of MTX will be limited as follows: 
 
Subjects who have documented toxicity of MTX (defined as ALT/AST > 2x ULN 
for 2 consecutive measures within 14 days) may have 2 dose reductions of up to 
5 mg/week each. However, for those subjects with < 15 mg/week dose at study 
entry, dose reduction of 2.5 mg/week will be allowed for 2 weeks and then will be 
returned to full dose. If the toxicity episode persists, the MTX dose can be 
reduced to the next level at the discretion of the investigator. 
 
Subjects experiencing a flare in the underlying RA during the study treatment 
period may receive a single 7 day course of oral corticosteroids as described 
below. 
6.4 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care.  All use of 
concomitant medications and supplements (nutritional and prophylactic) will be recorded 
on the applicable eCRF. 
After the completion of Week 13 visit procedures, subjects may receive additional 
therapeutic interventions to treat signs and symptoms of RA and to enable the subject to 
remain on study for follow-up assessments through Week End of Study (EOS) as 
indicated in the Schedules of Assessments (Section 7.1). 
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DMARDS 
New medications to treat RA including biologic and non-biologic DMARDS must not be 
introduced during the study unless it is deemed necessary to provide adequate 
supportive care for any intercurrent illness.  Any subject who receives a new 
concomitant DMARD for either RA or another concurrent illness during the course of the 
study should be discontinued from investigational product, and the appropriate 
evaluations and case report form (CRF) must be completed.  Unless the subject 
withdraws full consent and early terminates from the study, the subject will be requested 
to return for follow up visits. 
NSAIDs 
Subjects taking NSAIDs must be on stable dose ≥ 4 weeks prior to screening and 
remain on stable dose during the treatment period of the study.  If necessary for safety 
reasons, the dose of NSAIDS can be reduced or stopped during the duration of the 
study.  In cases of flare, the dose of NSAIDS can be temporarily increased as needed.  
However, the subject must return to the maintenance dose (the dose at baseline) as 
soon as the flare resolves.  This includes the addition of an NSAID to treat flare in 
subjects who were not taking an NSAID at baseline. 
Hydroxychloroquine 
Subjects may remain on a stable dose of hydroxychloroquine up to 400 mg/day in 
combination with DMARDs. 
Sulfasalazine 
Subjects may remain on a stable dose of sulfasalazine up to 3000 mg/day in 
combination with DMARDs. 
Analgesics 
Rescue analgesics (eg, hydrocodone, oxycodone, codeine, propoxyphene, and/or 
dextropropoxyphene) may be used for up to 5 consecutive days except within 12 hours 
before a scheduled study efficacy evaluation. 
Corticosteroids 
Subjects taking oral corticosteroids (not to exceed the equivalent of 10 mg of Prednisone 
per day) must be on stable dose ≥4 weeks prior to screening and remain on stable dose 
during the treatment period of the study.  In the event of worsening RA, subjects may 
receive a single 7 day course of oral corticosteroids following approval by Amgen.  This 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 40 of 90 
CONFIDENTIAL 
 
 
rescue regimen of corticosteroids (up to 10 mg/day of Prednisone above their stable 
baseline dose) must return to baseline levels within 2 weeks. 
Joint count assessments for 2 weeks following the receipt of the increased 
corticosteroids will be excluded from efficacy analyses.  Intra-articular corticosteroid 
injections are not permitted during the treatment period of the study (through week 12).  
An increase in the dose of corticosteroids due to elective surgery is permitted.  Should a 
subject require an increase in his/her corticosteroid dose during the peri-operative stage, 
every attempt should be made to reduce the corticosteroid dose to their baseline dose 
within 14 days post surgery.  Joint count assessments for 2 weeks following the receipt 
of the increased corticosteroids will be excluded from efficacy analyses.   
6.5 
Hepatotoxicity Stopping Rules 
6.5.1 
Criteria for Permanent Withholding of AMG 570 due to Potential 
Hepatotoxicity 
AMG 570 should be permanently withheld, and the subjects should be followed 
according to the recommendations in Appendix A (Additional Safety Assessment 
Information) for possible drug-induced liver injury (DILI), if ALL of the criteria below are 
met:  
 
Total Bilirubin  > 2x upper limit of normal (ULN) or INR >  1.5 
AND 
 
ALT or AST >3x ULN  
AND 
 
No other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
elevated TBL values include, but are not limited to: 
o Hepatobiliary tract disease  
o Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, 
and parvovirus) 
o Right sided heart failure, hypotension, or any cause of hypoxia to 
the liver causing ischemia  
o Exposure to hepatotoxic agents/drugs or hepatotoxins including 
herbal and dietary supplements, plants, and mushrooms,  
o Heritable disorders causing impaired glucuronidation (eg, 
Gilbert’s syndrome, Crigler-Najjar syndrome) and drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir) 
o Alpha-one antitrypsin deficiency 
o Alcoholic hepatitis 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 41 of 90 
CONFIDENTIAL 
 
 
o Autoimmune hepatitis 
o Wilson’s disease and hemochromatosis 
o Nonalcoholic fatty liver disease including steatohepatitis 
o Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
6.6 
Alcohol, Tobacco, and Exercise Restrictions 
 
Prior to admission to the clinic for each clinic visit, subject will abstain from 
alcohol consumption for 24 hours. 
 
Smoking will be limited to no more than 10 cigarettes per day 
 
Subjects are required to refrain from strenuous exercise 48 hours prior to each 
blood collection for clinical laboratory testing.  Subjects may participate in light 
recreational activities during the study. 
6.7 
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.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
See the following pages for Schedule of Assessments. 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 42 of 90 
CONFIDENTIAL 
 
 
Table 4.  Schedule of Assessments – Screening Through Day 43 (Week 6) 
  
Screening 
Baseline 
Treatment 
Week 
- 6 to 0 
0 
1 
2 
4 
6 
Study Day[1] 
- 42 to -1 
-1 
1[1] 
2 
3 
4 
7 
8 
15 
29 
43 
Relative to FIRST DOSE 
Pre 
0 
0.5 h 
1 h 
4 h 
6 h 
12 h 
24 
h 
48 
h 
72 
h 
144 
h 
168 
h 
336 
h 
28 
d 
42 
d 
Treatment Assignment 
x 
Dosing[2]   
x 
x 
x 
x 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Med/Drug/Alcohol History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI (Ht. & Wt.) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments of Disease Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tender/Swollen Joint Count (28 joints) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Patient Global Assessment of Disease 
Activity 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Physician Global Assessment of Disease 
Activity 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
HAQ-DI 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
Vitals 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
 
ECG[3] 
x 
x 
x[4] 
x 
 
x 
x 
 
x 
x 
x 
x 
 
 
 
 
 
AEs and Con Meds 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serious Adverse Events  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lab Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/Alcohol Screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
HIV, HepC, HepB 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Hematology, including reticulocyte count 
and CBC w/Differential 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Page 1 of 2 
[1] Inpatient visit (3-8 days) may be scheduled for 1st dose and 6th dose (Day 1 and Day 71) 
[2]  For visits when dosing is required, administration of investigational product should occur after other required assessments have been completed. 
[3]  ECGs must be done in tripilicate and obtained before blood samples are drawn. 
[4] ECG Day 1 pre-dose – Triplicate ECGs will be performed on 3 occasions separated by at least 30 minutes (total 9 ECGs) 
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 43 of 90 
CONFIDENTIAL 
 
 
Table 4.  Schedule of Assessments – Screening Through Day 43 (Week 6) 
  
Screening 
Baseline 
Treatment 
Week 
- 6 to 0 
0 
1 
2 
4 
6 
Study Day[1] 
- 42 to -1 
-1 
1[1] 
2 
3 
4 
7 
8 
15 
29 
43 
Relative to FIRST DOSE 
Pre 
0 
0.5 
h 
1 h 
4 h 
6 h 
12 
h 
24 
h 
48 
h 
72 
h 
144 
h 
168 
h 
336 
h 
28 
d 
42 
d 
Treatment Assignment 
x 
Dosing[2]   
x 
x 
x 
x 
Lab Assessments (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
b-HCG 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH/Estradiol 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-Reactive Protein (CRP) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
QuantiFERON-TB Gold 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythrocyte Sedimentation Rate (ESR) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
PK Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Draw[3] 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Biomarker & Immunological 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunophenotyping and Receptor 
Occupancy (IPRO) Assay by flow 
cytometry 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Tfh by flow cytometry 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Whole blood microarray  
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
IgG, IgA and IgM Serum 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
BAFF Serum Levels 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Rheumatoid Factor (RF total and 
isotypes ) 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
ACPAs (αCCP) 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Exploratory Biomarkers (serum and 
plasma) 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Exploratory Autoimmune Antibodies 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Exploratory Pharmacogenomics cell 
pellet 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
[1] Inpatient visit (3-8 days) may be scheduled for 1st dose and 6th dose (Day 1 and Day 71) 
[2]  For visits when dosing is required, administration of investigational product should occur after other required assessments have been completed. 
[3] When PK draw and IP dosing are scheduled on the same day, PK draw should be collected pre-dose.   
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 44 of 90 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments – Day 57 (Week 8) Through End of Study (Week 34) 
  
Treatment 
Follow-up 
EOS 
Week 
8 
10 
11 
12 
13 
14 
15 
16 
18 
20 
22 
26 
30 
34 
Study Day[1] 
57 
71[1] 
72 
73 
74 
77 
78 
85 
92 
99 
106 
113 
127 
141 
155 
183 
211 
239 
Relative to LAST DOSE 
0 
6h 
12 
h 
24 
h 
48 
h 
72 
h 
144 
h 
168 h 
336 h 
3 w 
4 w 
5 w 
6 w 
8 w 
10 
w 
12 
w 
16 
w 
20 
w 
24 w 
Treatment Assignment 
Dosing[2]   
x 
x 
Clinical Assessments of Disease 
Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tender/Swollen Joint Count (28 
joints) 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
Patient Global Assessment of 
Disease Activity 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
Physician Global Assessment of 
Disease Activity 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
HAQ-DI 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
Vitals 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
ECG[3] 
 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
AEs and Con Meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serious Adverse Events  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lab Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/Alcohol Screen 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
HIV, HepC, HepB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
Hematology, including 
reticulocyte count and CBC w/ 
Differential 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
Urinalysis 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
b-HCG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
FSH/Estradiol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
[1] Inpatient visit (3-8 days) may be scheduled for 1st dose and 6th dose (Day 1 and Day 71) 
[2]  For visits when dosing is required, administration of investigational product should occur after other required assessments have been completed. 
[3]  ECGs must be done in tripilicate and obtained before blood samples are drawn. 
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 45 of 90 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments – Day 57 (Week 8) Through End of Study (Week 34) 
  
Treatment 
Follow-up 
EOS 
Week 
8 
10 
11 
12 
13 
14 
15 
16 
18 
20 
22 
26 
30 
34 
Study Day[1] 
57 
71[1] 
72 
73 
74 
77 
78 
85 
92 
99 
106 
113 
127 
141 
155 
183 
211 
239 
Relative to LAST DOSE 
0 
6h 
12 
h 
24 
h 
48 
h 
72 
h 
144 
h 
168 h 
336 h 
3 w 
4 w 
5 w 
6 w 
8 w 
10 
w 
12 
w 
16 
w 
20 
w 
24 w 
Treatment Assignment 
Dosing[2]   
x 
x 
Lab Assessments (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-Reactive Protein (CRP) 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
QuantiFERON-TB Gold 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythrocyte Sedimentation Rate 
(ESR) 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
PK Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Draw[3] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Biomarker & Immunological 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Immunophenotyping and 
Receptor Occupancy (IPRO) 
Assay by flow cytometry 
x 
x 
 
 
 
 
 
 
x 
x 
 
x 
 
 
x 
 
x 
 
 
x[4] 
Tfh by flow cytometry 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
Whole blood microarray  
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
IgG, IgA and IgM Serum 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x[5] 
BAFF Serum Levels 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
Rheumatoid Factor (RFtotal 
and isotypes) 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
ACPAs (αCCP) 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
Exploratory Biomarkers (serum 
and plasma) 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
Exploratory Autoimmune 
Antibodies 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
Page 2 of 2 
[1] Inpatient visit (3-8 days) may be scheduled for 1st dose and 6th dose (Day 1 and Day 71) 
[2] For visits when dosing is required, administration of investigational product should occur after other required assessments have been completed. 
[3] When PK draw and IP dosing are scheduled on the same day, PK draw should be collected pre-dose.   
[4] B cell repletion:  If a subject’s CD3-CD19+ B cell counts are < 107 cells/uL (the lower limit of normal for healthy volunteers), the subject will return for further testing of B cell counts until 
the subject has B cell counts ≥ 107 cells/uL or greater than or equal to their screening B cell value if the screening B cell count was 70-106 cells/uL. Follow-up visits for B cell counts will 
continue every 3 months, for up to 12 months after the end of study. 
[5] IgG repletion:  If a subject’s IgG levels are < 639 mg/dL (the lower limit of normal for healthy volunteers), the subject will return for further testing of IgG levels until the subject has IgG 
levels ≥ 639 mg/dL. Follow-up visits for IgG levels will continue every 3 months, for up to 12 months after the end of study.
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 46 of 90 
CONFIDENTIAL 
 
 
Refer to the applicable supplemental laboratory and electrocardiogram [ECG] manuals 
for detailed collection and handling procedures.  Ensure these manual(s) are provided 
separately from the protocol to the sites.  
7.2 
General Study Procedures 
Adherence to the study design requirements, including those specified in the Schedule 
of Assessments (Section 7.1) are essential and required for study conduct. 
This section lists the procedure and parameters of each planned study assessment.  
The exact timing of each assessment is listed in the Schedule of Assessments 
(Section 7.1).  
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same 
nominal time, the assessment should occur in the following order: ECGs, vital signs, 
blood draws.  The timing of the assessment should allow the blood draw to occur at the 
exact nominal time. 
The timing and number of planned study assessments, including: Safety, PK, PD and 
Immunogenicity assessment may be altered during the course of the study based on 
newly available data (eg, to obtain data closer to the time of peak plasma concentration) 
to ensure appropriate monitoring. 
The IRB will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form. 
No more than 300 mL of blood, including from any extra assessments that may be 
required, will be collected over any 8-week period for duration of the study. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
7.2.1 
Screening 
Before any study-related screening or baseline procedure can be completed, a subject 
must sign and date the IRB approved ICF.  
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 47 of 90 
CONFIDENTIAL 
 
 
The following procedures are to be completed during the screening period and may also 
be completed at time points designated in the Schedule of Assessments (Section 7.1). 
 
Confirmation that the Informed Consent Form has been signed  
 
Demographic data 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 pharmacodynamics 
and pharmacokinetics of the protocol- required therapies.  
 
Medical History 
 
Complete Physical Examination  
 
BMI (Height and Weight) 
 
Vital signs (blood pressure, heart rate, respiration rate, temperature) 
 
Electrocardiogram (ECG) 
 
Clinical Assessments of Disease Activity 
o Tender/Swollen 28-Joint Count  
o Patient Global Assessment of Disease Activity 
o Physician Global Assessment of Disease Activity   
o HAQ-DI 
 
Drug and Alcohol Screen 
 
HIV (human immunodeficiency virus), HBcAb (hepatitis B core antibody), HepBsAg 
(hepatitis B surface antigen),HepCAb (Hepatitis C antibody)  
 
Laboratory Assessments (including creatinine clearance, chemistry, hematology, and 
urinalysis) 
 
b-HCG 
 
Follicle-Stimulating Hormone and estradiol (postmenopausal females only) and 
Pregnancy Test (females only) 
 
C-Reactive Protein (CRP) 
 
QuantiFERON-TB Gold 
 
Erythrocyte Sedimentation Rate (ESR) 
 
Immunophenotyping and Receptor Occupancy, IPRO assay, IgG and IgM  
 
Serious Adverse Event reporting 
Subjects may be rescreened only with permission of the Amgen medical monitor.  A new 
informed consent form must be signed unless it has been < 30 days since the previous 
ICF signature was obtained (Section 5). 
Approved 
 
 


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Protocol Number:  20150196 
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7.2.2 
Day -1 and Treatment 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Section 7.1).  Administration of 
protocol-required therapies is to be administered last during each visit that it is required. 
Subjects will be admitted to the clinical unit on Day -1 at which time the following 
assessments will be obtained: 
 
Physical Examination 
 
Vital Signs  
 
ECG  
 
Clinical Assessments of Disease Activity 
o Tender/Swollen 28-Joint Count  
o Patient Global Assessment of Disease Activity 
o Physician Global Assessment of Disease Activity   
o HAQ-DI 
 
Drug and Alcohol Screen 
 
Laboratory Assessments (chemistry, hematology, and urinalysis)  
 
Laboratory Assessments of Disease Activity (CRP and ESR) 
 
Pregnancy Testing (females only) 
 
Treatment Assignment (can occur any time prior to dosing) 
 
Whole blood microarray  
 
Serious Adverse Event reporting 
Subject will stay overnight and then undergo Day 1 assessments as follows: 
 
Pre-dose Vitals 
 
Pre-dose ECGs 
 
Pre-dose Biomarker and Immunological Assessments  
 
Pre-dose PK 
 
Dosing 
 
Post-dose Vitals 
 
Post-dose ECG(s) 
 
Post-dose PK draws 
 
Adverse Events and Serious Adverse Events reporting 
 
Documentation of concomitant and rescue medications 
Additional dosing days and assessments will be conducted per cohort assignment and 
dosing schedule.   
Approved 
 
 


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Protocol Number:  20150196 
Date:  08 June 2018 
Page 49 of 90 
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Subject will return to clinical unit on an outpatient basis for scheduled study procedures 
including blood draws for PK assessment, safety, immunogenicity, and other 
assessment as per Schedule of Assessments (Section 7.1). 
If the subject stops treatment (eg, due to an Adverse Event), ensure there is a plan for 
continued follow-up until the subject completes all protocol-required visits or withdraws 
from the study.  During this interval, there may be a reduction in the frequency and type 
of assessments required, preserving the end points of the study where possible.  
7.2.3 
End of Study Visit/ Early Termination 
The following procedures will be completed at the EOS visits as per Schedule of 
Assessments (Section 7.1): 
 
Complete Physical Examination 
 
ECG 
 
Vitals  
 
Clinical Assessments of Disease Activity 
o Tender/Swollen 28-Joint Count  
o Patient Global Assessment of Disease Activity 
o Physician Global Assessment of Disease Activity   
o HAQ-DI 
 
Drug and Alcohol Screen 
 
Laboratory Assessments (chemistry, hematology, and urinalysis) 
 
Pregnancy Testing (females only) 
 
C-Reactive Protein (CRP) 
 
Erythrocyte Sedimentation Rate (ESR) 
 
Biomarker and Immunological Assessments 
The EOS for each cohort may be prolonged pending treatment emergent data. 
If a subject terminates enrollment in the study early, women of child-bearing potential 
and men should be counseled to continue contraception for a period of time equivalent 
to 5 half-lives after receiving the terminal dose of IP. 
7.3 
General Study Assessments 
7.3.1 
Physical Exam 
The investigator or designated site physician will perform a complete physical 
examination (excluding breast, rectal examination, and genital examination) including 
height (screening only) and weight measurements at screening and at timepoints 
specified in the Schedule of Assessments (Section 7.1). 
Approved 
 
 


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Date:  08 June 2018 
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The individual performing the physical examination at screening and on admission to the 
research facility will characterize their findings as either normal or abnormal.  Abnormal 
findings found during screening or baseline will be reported on the medical history page 
of the eCRF.  Once enrolled, any change from the baseline physical examination, which 
represents deterioration, will be documented on the adverse event page of the eCRF. 
Height measurement (in cm and without shoes) and weight measurement (in kg and 
without shoes) will be obtained. 
7.3.2 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure (BP), 
heart rate (HR), respiration rate, and temperature.  Subject must be in a supine position 
in a rested and calm state for at least 5 minutes before BP 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 eCRF. 
Record all measurements on the vital signs eCRF.  The temperature location selected 
for a subject should be the same that is used throughout the study and documented on 
the vital signs/temperature log eCRF. 
Vital signs will be recorded by the investigator or designated site physician at screening 
and time points specified in the Schedule of Assessments (Section 7.1). 
Abnormal measurements may be repeated at the discretion of the investigator and must 
be reported on the corresponding eCRF page.  When vital signs and blood sample 
collection occur at the same time, vital signs should be performed before blood samples 
are drawn. 
7.3.3 
Electrocardiogram 
Electrocardiograms will be performed by the PI or designee at the time points listed in 
the Schedule of Assessments (Section 7.1).  Subjects must be supine for at least 
5 minutes before each ECG is obtained.  All ECGs must be done in triplicate 
(approximately 1 minute apart).  ECGs should be obtained before blood samples are 
drawn.  On Day 1 pre-dose, triplicate ECGs will be performed on 3 occasions separated 
by at least 30 minutes for a total of 9 ECGs on Day 1 (ie, completed at 90, 60, and 
30 minutes prior to dosing) and will serve as baseline.  The original ECG tracings 
[reporting parameters including ventricular rate, PR, QRS, QT, QTc (corrected QT) and 
QTcF (QT interval corrected for heart rate using Fridericia’s formula) intervals] will be 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 51 of 90 
CONFIDENTIAL 
 
 
retained in the source documents.  The principal investigator or designated physician will 
review all ECGs.  Digital copies of ECGs for all subjects will be made available to 
Amgen. 
7.3.4 
Adverse Events and Concomitant Medications 
Subjects will be assessed for adverse events (Section 9) and concomitant medication(s) 
throughout the study at each study visit.  Any adverse event or concomitant medication 
use reported throughout the study will be recorded in the source documentation and on 
the subject’s corresponding eCRF. 
7.4 
Disease Assessments 
7.4.1 
DAS28-CRP  Score 
The Disease Activity Score using 28 joints (DAS28) will be completed as listed in the 
Schedule of Assessments (Section 7.1) and will be calculated by Amgen.  The DAS 28 
is a composite score that is based on 28-joint count (using tender and swollen joints), 
CRP, and Patient Global Assessment of Disease Activity. 
Calculation of the DAS28-CRP score is as follows: 
DAS 28-CRP = 0.56 √TJC28 + 0.28 √SJC28 + 0.36 x ln (CRP + 1) + 0.014 x Patient 
Global Assessment of Disease Activity + 0.96 
where TJC28 and SJC28 represent the tender and swollen 28 joint counts, respectively. 
The 28 joint counts includes 10 proximal interphalangeal, 10 metacarpophalangeal, 
2 wrist, 2 elbow, 2 shoulder, and 2 knee joints.  CRP will be analyzed at a central 
laboratory as noted in Section 7.10.1.  Only screening CRP values will be released to 
sites for determination of eligibility.  These values will be entered into a CRF associated 
with screening where the DAS28-CRP score will be derived.   
Joint Assessments 
All joint assessments will be performed by an experienced independent and blinded joint 
evaluator.  The evaluator cannot be the treating physician and cannot interact with the 
subject throughout the study beyond the assessment of joints nor for any other subject 
assessments or laboratory measures of efficacy.  The evaluator should not discuss the 
subject’s clinical status nor should the evaluator have access to subject medical records 
or eCRFs including prior joint assessments.  The investigator physician may perform the 
screening assessment, however, if so, the independent evaluator will be required to 
confirm eligibility with the baseline visit joint assessment. 
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Unevaluable Joints 
Joints that are or have been replaced are considered unevaluable. 
Tender Joint Count (TJC) Assessments 
A total of 28 joints will be scored for presence or absence of tenderness. 
Swollen Joint Count (SJC) Assessments 
A total of 28 joints will be scored for presence or absence of swelling. 
7.4.2 
Physician Global Assessment of Disease Activity 
The treating physician will rate the patient’s arthritis by marking an “X” between 0 and 
100 on the 100 mm horizontal line (visual analog scale).  The physician evaluator and 
subject must complete the global assessments independently from each other.  The 
physician assessing the subject’s global disease activity will have access to the joint 
assessments. 
7.4.3 
Patient Global Assessment of Disease Activity 
The patient will rate the patient’s arthritis status by marking an “X” between 0 and 100 on 
the 100 mm horizontal line (visual analog scale).  The physician evaluator and subject 
must complete the global assessments independently from each other.  This 
questionnaire (along with the HAQ-DI) will be given to subjects to complete before any 
other study procedures are performed on the subjects on the day of assessments.  
See Appendix D for sample of the Patient Global Assssment of Disease Activity 
questionnaire.  
7.4.4 
Patient’s Assessment of Physical Function: Disability Index of the 
Health Assessment Question (HAQ-DI) 
The subject’s self assessment of physical function or disability will be assessed by the 
HAQ-DI.  The HAQ-DI was developed as a comprehensive measure of outcome in 
subjects with a wide variety of rheumatic diseases, including RA.  Its focus is on 
self-reported subject-oriented outcome measures.  HAQ-DI (along with the Patient’s 
Assessment of Disease Activity) will be given to subjects to complete before any other 
procedures are performed on the subjects on the day of the assessment.  This 
questionnaire asks about the degree of difficulty a person has in accomplishing task in 
8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping and 
errands and chores).  Responses in each functional area are scored from 0 indicating no 
difficulty, to 3, indicating inability to perform a task in that area.  The subject should be 
instructed to read each question carefully and mark an “X” for the option that best 
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represents their answer.  The study staff should not clarify any of the questions for the 
subject, if asked.  See Appendix D for sample of the Disability Index of the Health 
Assessment Question (HAQ-DI). 
7.5 
Blood and Urine Assessments 
7.5.1 
Blood Volume 
Subjects enrolled in this study will provide whole blood for safety, PK, PD and biomarker 
assessments during their participation in this study.  Estimated volume of blood 
collection is indicated in Table 6.  The total blood volume per subject is approximately 
900 mL. 
7.5.2 
Drug and Alcohol Screen 
A urine screen for drugs of abuse (cannabis, cocaine, amphetamines, benzodiazepines, 
opiates, barbiturates) and urine (or breath) ethanol screens will be performed at time 
points specified in the Schedule of Assessments (Section 7.1).  Subjects with a positive 
test result will be excluded from the study, unless medication is prescribed by a 
physician and approved by the investigator and Amgen medical monitor. 
7.5.3 
HIV Antibodies, Hepatitis B Surface Antigen, and Hepatitis C 
Antibodies 
Hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HBcAb), hepatitis C 
HepCAb, and HIV status will be assessed.  If the results show a negative HepBsAg and 
positive for HBcAb, a positive hepatitis B virus DNA by polymerase chain reaction (PCR) 
is necessary.   
If the results show a positive HepCAb:  hepatitis C virus ribonucleic acid (RNA) by PCR 
is necessary.  The test must be confirmed negative at screening for the subject to be 
eligible for this study. 
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7.5.4 
Laboratory Safety Tests 
Table 6.  List of Analytes 
Local Laboratory 
Chemistry 
(approx. 8 mL) 
Local Laboratory 
Hematology 
(approx. 5 mL) 
Local Laboratory 
Urinalysis 
Other 
(approx. 3-8 mL) 
Alanine 
aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate 
aminotransferase 
(AST) 
Bicarbonate (HCO3) or 
Carbon Dioxide 
Bilirubin 
• 
Total 
• 
Direct 
Blood urea nitrogen or 
Urea 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatine 
phosphokinase (CPK) 
Gamma-glutamyl 
transferase (GGT) 
Glucose 
High-density lipoprotein 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Hemoglobin A1C** 
Erythrocyte 
Sedimentation Rate 
(ESR) 
Hemoglobin 
Hematocrit 
Mean corpuscular 
volume (MCV) 
Platelets 
Reticulocyte count 
White blood cell count 
White blood cell 
Differential (in absolute 
cell numbers) 
• 
Total neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
RBC count 
• 
MCV 
• 
MCH 
• 
MCHC 
 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Urobilinogen 
Microscopic exam 
(performed at the 
discretion of the 
Investigator or 
designee): 
• 
White blood cells 
• 
Red blood cells 
• 
Epithelial cells 
• 
Bacteria 
• 
Casts 
• 
Crystals 
Central 
Laboratory: 
CRP 
Antibodies 
Hepatitis B 
surface antigen 
Hepatitis C 
antibody 
HIV 
 
Local Laboratory: 
QuantiFERON-TB 
Gold** 
FSH/Estradiol** 
Serum beta-HCG 
and/or Urine 
Pregnancy*** 
*All subjects must fast from all food and drink (except water) for at least 8 hours prior to any clinical lab 
evaluation 
**Screening only 
***Per schedule of assessments (Section 7.1) 
7.5.5 
Serum and Urine Pregnancy Test 
A serum pregnancy test will be conducted for all women at Screening.  A urine 
pregnancy test will be performed on Screening and days -1, 85, 239 (EOS).  The results 
of these tests will be retained in the source document. In the event a female subject 
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becomes pregnant while on study, a pregnancy notification worksheet (Appendix C) 
must be completed and forwarded to the Sponsor. 
7.5.6 
FSH and Estradiol 
Additional serum will be collected for an FSH and estradiol for females who are at least 
1 year postmenopausal at screening unless 60 years or older.  Results must be 
consistent with postmenopausal status per local laboratory ranges to be eligible for this 
study.  Postmenopausal status will be recorded on the medical history eCRF. 
7.5.7 
QuantiFERON-TB Gold 
A QuantiFERON®-TB Gold test will be completed during screening for all subjects, and 
results must be negative to be eligible for this study. 
7.6 
Urinalysis 
All laboratory tests must be reviewed and signed by the principal investigator or qualified 
designee.  Additional safety laboratory assessments may be performed for subject 
safety.  Urine samples will be collected at time points specified in the Schedule of 
Assessments (Section 7.1). 
The tests listed below will be conducted and analyzed by standard laboratory 
procedures. 
7.7 
Immunophenotyping and Receptor Occupancy Assay 
Whole blood samples for Immunophenotyping and Receptor Occupancy (IPRO) will be 
collected at timepoints indicated in the Schedule of Assessments (Section 7.1).  The 
Immunophenotyping assay will measure T, B, and NK cells and B cell subsets.  The 
Receptor Occupancy assay will measure ICOSL receptor occupancy.  Instructions for 
collecting, processing, and shipping the IPRO samples will be provided in a separate 
document from Amgen.  Immunophenotyping blood collection instructions for collecting, 
processing, and shipping samples are provided in a separate document from Amgen. 
7.8 
Serum Immunoglobulin Levels 
Blood samples will be collected for measurement of serum Immunoglobulins (IgM, IgG 
and IgA) at time points indicated in the Schedule of Assessments (Section 7.1).  
Instructions for collecting, processing, and shipping samples will be provided in a 
separate document from Amgen. 
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7.9 
BAFF Serum Levels 
Blood samples will be collected for determination of serum BAFF levels at time points 
indicated in the Schedule of Assessments (Section 7.1).  Instructions for collecting, 
processing, and shipping samples will be provided in a separate document from Amgen. 
7.10 
Rheumatoid Arthritis Biomarkers 
7.10.1 
C-Reactive Protein 
Blood samples for CRP will be collected at timepoints according to the Schedule of 
Assessments (Section 7.1).  The central laboratory will provide CRP results to sites at 
screening for eligibility assessment.   
7.10.2 
Rheumatoid Factor 
A blood sample for determination of RF will be collected and analyzed at a central 
laboratory.  Total RF and isotypes will be assessed. 
7.10.3 
Anti-citrullinated Peptide Antibodies 
A blood sample will be collected to measure antibodies against citrullinated peptides at 
timepoints specified in the Schedule of Assessments (Section 7.1)  and analyzed at a 
central laboratory. 
7.11 
Exploratory Autoimmune Antibodies 
A blood sample will be collected for exploratory autoimmune antibody analysis at 
timepoints specified in the Schedule of Assessments (Section 7.1). 
7.12 
Blood Collection for Pharmacokinetic Analysis 
A blood sample will be collected for pharmacokinetic analysis at timepoints specified in 
the Schedule of Assessments (Section 7.1). 
7.13 
Antibody Testing Procedures 
Blood samples will be collected as outlined in the Schedule of Assessments 
(Section 7.1) for the measurement of anti-AMG 570 binding antibodies.  Samples testing 
positive for binding antibodies may be further characterized for quantity/titer, isotype, 
affinity, or in vitro neutralizing activity.  Additional blood samples may be obtained to 
evaluate any anti-AMG 570 antibody mediated impact on safety, PK and/or PD, and 
efficacy during the study.  Subjects who test positive for binding antibodies and have 
clinical sequelae that are considered potentially related to an  anti-AMG 570 antibody 
response may also be asked to return for additional follow-up testing. 
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7.14 
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 investigational product(s) (eg, Amgen or non-Amgen 
investigational product or protocol required therapies to investigate and further 
understand RA.   
Blood Samples 
Blood samples are to be collected for biomarker development as specified in Schedule 
of Assessments (Section 7.1). 
7.15 
Pharmacogenetic Studies 
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 RA and/or to identify 
subjects who may have positive or negative response to investigational product or 
protocol required therapies.  No additional samples are collected for this part of the 
study.  For subjects who consent to this/these analysis/analyses, DNA may be extracted.  
7.16 
Sample Storage and Destruction 
Any blood (eg, biomarker, PK) sample collected according to the Schedule of 
Assessments (Section 7.1) 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.   
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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 RA, 
the dose response and/or prediction of response to AMG 570, as required, 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 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
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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, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Assessments 
(Section 7.1) 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.  Subjects who have discontinued investigational product 
and/or 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.  The 
investigator must document the level of follow-up that is agreed to by the subject.   
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, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, medical device(s), and/or other protocol required therapies, protocol 
procedures, or the study as a whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.  
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8.3 
Reasons for Removal From Treatment and/or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
subject request   
 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, protocol-specified 
criteria (list criteria), pregnancy) 
 
death 
 
lost to follow-up 
 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.2 
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 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study, or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
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.  The 
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investigator’s clinical judgment is used to determine whether a subject is to be removed 
from treatment due to an adverse event.  In the event a subject, or subject’s legally 
acceptable representative requests to withdraw from protocol-required therapies or the 
study due to an adverse event, refer to Section 8.1 for additional instructions on the 
procedures recommended for safe withdrawal from protocol-required therapies or the 
study.   
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease-Related Event as 
defined in Section 9.1.1): 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after enrollment through the end of 
study are reported using the Event CRF. 
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The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Severity (using CTCAE scale) 
 
Assessment of relatedness to investigational product, and 
 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.  The grading scale used in this study is described 
in Appendix A.  The investigator must assess whether the adverse event is possibly 
related to the investigational product.  This relationship is indicated by a “yes” or “no” 
response to the question:  Is there a reasonable possibility that the event may have been 
caused by the investigational product?   
The investigator must assess whether the adverse event is possibly related to any study 
mandated activity and/or procedure.  This relationship is indicated by a “yes” or “no” 
response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity and/or procedure”?  
The investigator is responsible for reviewing laboratory test results and determining 
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. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
Reporting Procedures for 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 30 days after the last administered dose of the study drug.  All serious 
adverse events must be submitted to Amgen within 24 hours following the investigator’s 
knowledge of the event via the Event CRF.  All Grade 4 (life-threatening) events should 
be reported as Serious Adverse Events. 
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If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form.  
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the Electronic Serious Adverse Event Contingency Report Form, the data 
must be entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product.  This relationship is indicated by a “yes” or “no” response to 
the question: Is there a reasonable possibility that the event may have been caused by 
the investigational product?  Relatedness means that there are facts or reasons to 
support a relationship between investigational product and the event.   
The investigator must assess whether the serious adverse event is possibly related to 
any study mandated activity and/or procedure (including any screening procedure(s)).  
This relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity and/or 
procedure”? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for 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. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.   
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.  
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Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.1.3 
Reporting 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.  In some countries (eg, European Union [EU] 
member states), 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 for the purposes of expedited 
reporting.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking investigational product (AMG 570 or placebo), report the pregnancy to 
Amgen Global Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur through 20 weeks after the last dose of AMG 570.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
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stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur through 20 weeks after the last dose of protocol-required 
therapies.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoint:   
Subject incidence of treatment-emergent adverse events (including clinically significant 
changes in physical examinations), vital signs, laboratory safety tests, and 
electrocardiograms (ECGs). 
Secondary Endpoint(s):   
 
AMG 570 Serum PK profiles after multiple dose administrations. PK parameters 
will include, but are not limited to, maximum observed concentration [Cmax] and 
area under the concentration-time curve [AUC] after the first and the last doses, 
and the accumulation ratio. 
Exploratory Endpoint(s):   
 
Peripheral blood ICOSL receptor occupancy 
 
Baseline levels, post-dose levels and change from baseline in peripheral blood 
percentage and absolute counts of total T cells, B cells and NK cells  
 
Baseline levels, post-dose levels and change from baseline in peripheral blood 
percentage and absolute counts of naive and memory B cells 
(naïve = CD19+IgD+CD27-, memory = CD19+IgD-CD27+) 
 
Baseline levels, post-dose levels and change from baseline in circulating Plasma 
cells by gene signature 
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 
Baseline levels, post-dose levels and change from baseline in circulating Tfh by 
flow cytometry and gene signature 
 
Baseline levels, post-dose levels and change from baseline in serum 
Immunoglobulin M, Immunoglobulin G and Immunoglobulin A 
 
Baseline levels, post-dose levels and change from baseline in serum BAFF 
 
Baseline levels, post-dose levels and change from baseline in serum CRP, ESR, 
IgG+ Rheumatoid Factor, IgM+ Rheumatoid Factor and anti-citrullinated protein 
antibody 
 
Changes from baseline over time in the disease activity score based on 28 joints 
(DAS 28-CRP) 
 
Changes from baseline over time in Patient Global Assessment of Disease 
activity 
 
Changes from baseline over time in Physician Global Assessment of Disease 
activity  
 
Anti-AMG 570 binding antibodies 
10.1.2 
Analysis Sets 
The safety analysis set will include all randomized subjects who received at least one 
dose of AMG 570/placebo. 
The PK concentration analysis set will contain all randomized subjects who received 
AMG 570 and have at least one quantifiable PK sample collected.  The PK parameter 
analysis set will contain all randomized subjects who received AMG 570 and for whom 
PK parameters can be adequately estimated. 
The PD analysis set will contain all randomized subjects who received at least 1 dose of 
investigational product (AMG 570 or Placebo) and for whom at least 1 PD parameter has 
baseline and at least 1 post baseline measurement available. 
10.1.3 
Covariates and Subgroups 
No subgroup analysis is planned.   
10.1.4 
Handling of Missing and Incomplete Data  
Statistical analysis plan will detail the handling of missing and incomplete data. 
10.2 
Sample Size Considerations 
Approximately 32 RA patients will be enrolled into 4 cohorts with 6 active and 2 placebo 
in each cohort. 
This sample size is based on practical considerations and is typical for this type of study. 
For safety considerations, for a cohort, with 6 subjects receiving AMG 570, there is an 
82% chance of at least one subject experiencing an adverse event with a true incidence 
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rate of 25% and a 74% chance of at least one subject experiencing an adverse event 
with 20% true incidence rate.  With a total of 18 subjects expected toreceive AMG 570 
across all 3 cohorts, there is a 17% chance of at least 1 subject experiencing an adverse  
event with a true incidence rate of 1% and the chance of at least 1 subject experiencing 
an adverse event increases to 60% and 85% with a true incidence rate of 5% and 10%, 
respectively. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
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. 
10.4 
Planned Analyses 
10.4.1 
Data Monitoring Committee (DMC), Data Review Team (DRT) or Dose 
Level Review Team (DLRT) 
A Dose Level Review Team (DLRT) will be used to oversee progress of the study and 
make recommendations relating to early closure/extension or alteration of the study 
based on ongoing monitoring of the study data.  The DLRT members will consist of the 
principal investigator or designee, Amgen Medical Monitor, Amgen Global Safety Officer 
or designee, Amgen Clinical Research Study Manager or designee, and biostatistics 
representative or designee.  Additional members may be added as needed (eg, PK 
scientist).  The key objectives of the DLRT are to review data, monitor safety, and make 
dose change decisions. 
10.4.2 
Primary Analysis 
The primary analysis will occur after all subjects have completed the study. 
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, immunogenicity, 
PK, PD, and biomarker data.  Descriptive statistics on continuous measurements will 
include means, medians, standard deviations, and ranges, while categorical data will be 
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summarized using frequency counts and percentages.  Data will summarized by 
treatment and by scheduled timepoint unless specified otherwise. 
10.5.2 
Primary Endpoint(s) 
Safety analysis set will be used for analyses included in this section. 
10.5.2.1 
Adverse Event 
Subject incidence of all treatment-emergent adverse events (including clinically 
significant changes in physical examinations) will be tabulated by system organ class 
and preferred term.  Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities.  Tables of treatment related adverse events, fatal adverse events, 
serious adverse events, and adverse events leading to withdrawal from investigational 
product or other protocol-required therapies or from study will also be provided.  Subject 
incidence of treatment emergent events and treatment related treatment emergent 
events will further be summarized by worst severity grade. 
10.5.2.2 
Clinical Laboratory Tests 
The analyses of safety laboratory endpoints may include summary statistics over time 
and/or changes from baseline.  Shifts in grades of selected analytes between the 
baseline and the worst on-study value may be tabulated.   
10.5.2.3 
Vital Signs 
Summary statistics over time and/or changes from baseline over time in vital signs will 
be provided.   
10.5.2.4 
Electrocardiograms 
Descriptive summary statistics of ECG values over time and/or changes from baseline 
over time may be provided for each ECG parameters.  Subjects’ maximum change from 
baseline in QTcF will be categorized and the number and percentage of subjects in each 
category will be summarized.  Subjects’ maximum post baseline values will also be 
categorized and the number and percentage of subjects in each category will be 
summarized. 
10.5.3 
Secondary Endpoint(s) 
10.5.3.1 
PK Analysis 
Serum AMG 570 concentrations will be determined using a validated assay.  Individual 
serum concentration-time plots for AMG 570 will be presented for each subject as well 
as mean concentration-time plots for each treatment.   
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Pharmacokinetic parameters (eg, maximum observed concentration [Cmax], time at 
Cmax [tmax,], and area under the concentration-time curve [AUC]) will be calculated using 
non-compartmental methods.  Actual dosing and sampling times will be used for 
calculation of individual PK parameters.  Summary statistics will be generated for each 
PK parameter.   
Additional analyses using compartmental methods or population PK analysis may be 
performed. 
10.5.4 
Exploratory Endpoints 
All exploratory end points will be summarized using descriptive statistics.  The change 
from baseline and/or fold change from baseline also may be summarized.   
The incidence and percentage of subjects who develop anti-AMG 570 antibodies 
(binding and if positive, neutralizing) at any time will be tabulated. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
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 template are to 
be communicated formally in writing from the Amgen Study Manager to the investigator.  
The written informed consent form is to be prepared in the language(s) of the potential 
subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol specific screening procedures or any investigational product(s) is/ are 
administered.   
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.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  The acquisition of informed consent and 
the subject’s agreement or refusal of his/her notification of the primary care physician is 
to be documented in the subject’s medical records, and the informed consent form is to 
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be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  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. 
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 is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for 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. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
 
On the demographics page, in addition to the unique subject identification number, 
include the age at the 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 date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in strict confidence by the investigator, except as described below. 
In compliance with governmental/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 named such individuals to have access to his/her study related 
records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center 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 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  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. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen. 
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Subjects may be eligible for continued treatment with Amgen investigational product 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 it is available commercially. 
12.2 
Study Documentation and Archive 
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 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. 
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 CRF, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (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. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
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upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
Clinical Monitor is to have access to subject medical records and other study related 
records needed to verify the entries on the CRFs. 
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. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing 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. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the electronic CRFs must be 
maintained and readily available. 
 
Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail”. 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the investigator inspected or reviewed 
the data on the CRF, the data queries, and agrees with the content. 
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 
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response if the confirming datum is provided in the “other, specify” field (eg, for race, 
reason for ending study). 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 4), the investigator can search publically 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.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
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 International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals, which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 
1, 2, and 3 and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
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 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should 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 corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
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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13. 
REFERENCES 
AMG 570 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
Agarwal S, Cunningham-Rundles, C.  Assessment and clinical interpretation of reduced 
IgG values.  Ann Allergy Asthma Immunol.  2007; 99(3):281-283.  
Becton, Dickinson and Company.  BD Multitest TM 6-color TBNK. 50 Tests-Catalog No. 
644611, 50 Tests with BD Trucount Tubes- Catalog No. 337166 
http://www.bdbiosciences.com/ds//is/tds/23-10834.pdf. Published February 10, 2014.  
Accessed February July 14, 2015. 
Catrina AI, Joshua V, Klareskog, L, Malmström V, Mechanisms involved in triggering 
rheumatoid arthritis. Immunological Reviews. 2016; 269:162-174. 
Cohen SB, Emery P, Greenwald M, et al, Rituximab for Rheumatoid Arthritis Refractory 
to Anti-Tumor Necrosis Factor Therapy. Arthritis & Rheumatism. 2006; 54(9): 
2793-2806. 
Craft J, Follicular Helper T cells in Immunity and Systemic Autoimmunity. Nat. Rev. 
Rheumatol. 2012; 8:337-347. 
Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, Martin RS, Scheinberg MA; 
for the PEARL-SC Study.  A phase 2, randomised, placebo-controlled clinical trial 
of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe 
systemic lupus erythematosus, the PEARL-SC study.  Ann Rheum Dis. 2014 Apr 19. 
doi: 10.1136/annrheumdis-2013-205144. [Epub ahead of print]. 
Genovese M, Becker J-C, Schiff M, et al, Abatacept for Rheumatoid Arthritis Refractory 
to Tumor Necrosis Factor α Inhibition. N Engl J Med. 2005; 353: 1114-1123. 
Gerlag D, Safy M, Maijer K, et al, Prevention of Rheumatoid Arthritis By B CELL 
Directed Therapy In The Earliest Phase of the Disease: The PRAIRI Study. Ann Rheum 
Dis. 2016; 75(Suppl2):125. 
Hochberg MC, Chang RW, Dwosh I, et al. The American College of Rheumatology 1991 
Revised Criteria for the Classification of Global Functional Status in Rheumatoid 
Arthritis, Arthritis & Rheumatism.1992; 35(5):498-502. 
Isenberg DA, Petri M, Kalunian K, et al.  Efficacy and safety of subcutaneous tabalumab 
in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, 
phase III, multicenter, randomized, double-blind, placebo-controlled study.  Ann Rheum 
Dis  Published Online First: 3 September 2015; doi:10.1136/annrheumdis-2015-207653 
Kremer J, Westhovens R, Leon M, et al, Treatment of Rheumatoid Arthritis by Selective 
Inhibition of T-Cell Activation with Fusion Protein CTLA4Ig. N Engl J Med. 2003; 349: 
1907-1915. 
Smolen J, Aletaha D, McInnes IB, Rheumatoid Arthritis. The Lancet. 2016; Online. 
Stohl W, Merrill JT, Looney RJ, et al. Treatment of systemic lupus erythematosus 
patients with the BAFF antagonist “peptibody” blisibimod (AMG 623): Results from 
randomized, double-blind phase 1a and phase 1b trials. Arthritis Research & Therapy. 
2015; 17: 215-228. 
Sullivan BA, Tsuji W, Kivitz A, et al. Inducible T-cell co-stimulator ligand (ICOSL) 
blockade leads to selective inhibition of anti-KLH IgG responses in subjects with 
systemic lupus erythematosus. Lupus Science & Medicine 2016;3: e000146. 
Wallace D, Stohl W, Furie R, et al. Arthritis & Rheumatism (Arthritis Care & Research). 
American College of Rheumatology. 2009; 61(9):1168-1178. 
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Witcher J, Fleischmann R, Chindalore V, et al. Pharmacokinetics and safety of single 
doses of tabalumab in subjects with rheumatoid arthritis or systemic lupus 
erythematosus. British Journal of Clinical Pharmacology. 2016: 81(5):908-917. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used 
and is available at the following location:  https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
Drug-induced Liver Injury Reporting & 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 Section 6.5 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, Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1.2. 
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 
Section 6.5 or who experience AST or ALT elevations > 3 x ULN or 2-fold increase 
above baseline values for subjects with evaluated 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 (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
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 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
CPK, haptoglobin, 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 an 
hepatologist) 
 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
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CONFIDENTIAL 
 
 
Appendix B.  eSerious Event Contingency Form 
 
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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CONFIDENTIAL 
 
 
Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
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CONFIDENTIAL 
 
 
 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
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CONFIDENTIAL 
 
 
Appendix D.  Patient Global Assessment of Disease Activity and Disability Index 
of the Health Assessment Question (HAQ-DI) 
 
Approved 
 
 


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Protocol Number:  20150196 
Date:  08 June 2018 
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Approved 
 
 


Product:  AMG 570 
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Date:  08 June 2018 
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Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  08 June 2018 
Page 1 of 8 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Randomized, Double Blind Placebo Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Multiple Ascending 
Subcutaneous Doses of AMG 570 in Subjects With Rheumatoid Arthritis 
 
Amgen Protocol Number (AMG 570) 20150196 
IND number BB-IND 127060 
EudraCT number 2017-000337-31 
 
Amendment Date: 
08 June 2018 
Rationale: 
The protocol has been amended to include an additional cohort – Cohort 4.  Enrollees in 
Cohort 4 will receive multiple subcutaneous (SC) doses of 420 mg AMG 570 IP.  
Subjects will receive a SC dose of IP on days 1, 15, 29, 43, 57, and 71 (every 2 weeks 
for 6 doses).  The addition of this cohort will extend enrollment to an additional 
8 subjects for a total of 32 subjects and will provide additional safety, pharmacokinetics, 
and pharmacodynamics data that will facilitate the understanding of the 
exposure-response relationship to inform future studies with AMG 570.  Available data 
from the single ascending dose (SAD) study with AMG 570 (20140322) have been used 
to support updates to dose selection, study design, safety and biostatistical information 
throughout the protocol.  Where available, observed data have replaced predicted 
values for increased accuracy.   
Additional changes have been made for increased clarity throughout the protocol where 
applicable. 
Administrative, typographical and formatting changes were made throughout the 
protocol where applicable. 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  13 November 2017 
Page 1 of 6 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Randomized, Double Blind Placebo Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Multiple Ascending 
Subcutaneous Doses of AMG 570 in Subjects With Rheumatoid Arthritis 
 
Amgen Protocol Number (AMG 570) 20150196 
IND number BB-IND 127060 
EudraCT number 2017-000337-31 
 
Amendment Date: 
13 November 2017 
Rationale: 
The protocol has been amended to make revisions to laboratory assessments, eligibility 
criteria, and biomarker tests. 
Laboratory assessments: 
Changes have been made to hematology labs in light of findings outlined in the safety 
report submitted on 15-Nov-2017. 
1. Reticulocyte counts will now be assessed along with CBC with differential. 
2. Hematology labs (CBC with differential and reticulocyte count) will be examined 
at all outpatient visits beginning on Day 8.  After day 8, hematology monitoring 
will occur at least every 2 weeks during treatment period and hematology 
parameters will continue to be monitored until the end of study at day 239. 
3. RBCs are named parameters of interest in the CBC with differential. 
Eligibility criteria: 
Exclusion Criterion 223 has been revised to better account for population of interest and 
ensure medical monitor input prior to enrollment.  The lower limit of normal for the assay 
being employed in study 20150196 for absolute B cell counts in the peripheral blood is 
107 B cells per µL.  Though absolute B cell counts in patients with rheumatoid arthritis 
(RA) are on average in the normal, healthy range, the counts tend to be lower than 
healthy controls.  In a study of 208 RA patients prior to receiving rituximab, 
Sellam, et. al. (Arthritis & Rheumatism 63: 3692), report that RA patients averaged 188.6 
B cells per µL compared to 257.3 B cells per µL in healthy controls.  Thus, B cell 
numbers in patients with RA are ~70% of healthy controls.  Despite tending to have 
lower B cell numbers, patients with RA mount protective antibody responses to 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  13 November 2017 
Page 2 of 6 
CONFIDENTIAL 
 
 
vaccination against pneumococcus or influenza virus at rates of 70-98% (BMC 
Musculoskelet Disord 17: 231 and J Rheumatology 34: 272).  In addition, RA patients 
treated with rituximab who have evidence of normal B cell function assessed by IgG 
levels benefit from complete peripheral B cell depletion with an acceptable safety profile 
(Arthritis & Rheumatism 54: 2793).  Thus, changes to the eligibility criteria related to 
B cell numbers would be considered safe in the context of up-to-date vaccine status 
(inclusion criterion 108), normal antibody levels (exclusion criterion 224), and a lack of 
history of recurrent/chronic infections (exclusion criteria 206). 
Biomarker tests: 
Biomarker testing has been changed from plasma cell by flow cytometry to Tfh by flow 
cytometry.  There has been no change to the sampling schedule or to the amount of 
blood and type of tube to be drawn. 
Additional changes have been made for increased clarity throughout the protocol where 
applicable. 
Administrative, typographical and formatting changes were made throughout the 
protocol where applicable. 
Approved 
 
 


Product:  AMG 570 
Protocol Number:  20150196 
Date:  16 May 2017 
Page 1 of 3 
Amendment 1 
Protocol Title:  A Randomized, Double Blind Placebo Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Multiple Ascending 
Subcutaneous Doses of AMG 570 in Subjects With Rheumatoid Arthritis 
Amgen Protocol Number AMG 570 20150196 
 
Amendment Date: 
16 May 2017 
 
Rationale: 
The protocol has been amended to make corrections to required laboratory 
assessments prior to first dose. 
• 
Laboratory assessments have been added to applicable protocol sections: 
o Pre-dose C-Reactive Protein (CRP) is a required assessment which was 
omitted in error.   
o Pre-dose Erythrocyte Sedimentation Rate (ESR) is a required assessment 
which was omitted in error. 
• 
Laboratory assessments deemed not technically feasible have been removed 
from applicable protocol sections: 
o Pre-dose Plasma Cell by flow cytometry 
Additional changes have been made for increased clarity throughout the protocol where 
applicable. 
Administrative, typographical and formatting changes were made throughout the 
protocol where applicable. 
CONFIDENTIAL 
 
 
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 1
STATISTICAL ANALYSIS PLAN
Title:  A Randomized, Double Blind Placebo Controlled Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of Multiple Ascending Subcutaneous 
Doses of AMG 570 in Subjects With Rheumatoid Arthritis
Protocol Number:
20150196
Version:
2.0
Date:
13 Aug 2019
Authors:
NCT Number: NCT03156023
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  AMG 570 
Statistical Analysis Plan:  20150196 
Date:  13 Aug 2019 
Page 2 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
12JUN2017 
 
[Amendment 1 (v2.0)] 
13AUG2019 
Changes in the protocol amendment related 
to addition of Cohort 4 
Removal of unnecessary listings as per recent 
process 
Note: Please see the Appendix C for detailed summary of changes and rationale for 
changes to Amendment 1 (change-Memo). 


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 3
Table of Contents
Table of Contents............................................................................................................3
1.
Introduction.............................................................................................................7
2.
Objectives...............................................................................................................7
2.1
Primary .......................................................................................................7
2.2
Secondary...................................................................................................7
2.3
Exploratory..................................................................................................7
3.
Study Overview ......................................................................................................7
3.1
Study Design...............................................................................................7
3.2
Sample Size................................................................................................8
4.
Study Endpoints .....................................................................................................8
4.1
Primary Endpoint.........................................................................................8
4.2
Secondary Endpoint(s)................................................................................8
4.3
Exploratory Endpoint(s)...............................................................................8
5.
Hypotheses and/or Estimations ..............................................................................9
6.
Definitions...............................................................................................................9
6.1
General Definitions......................................................................................9
7.
Analysis Subsets ..................................................................................................12
7.1
Safety Analysis Set ...................................................................................12
7.2
Pharmacokinetic Concentration Analysis Set ............................................12
7.3
Pharmacokinetic Parameter Analysis Set..................................................13
7.4
Pharmacodynamic Analysis Set................................................................13
8.
Planned Analyses.................................................................................................13
8.1
Interim Analysis and Early Stopping Guidelines ........................................13
8.2
Primary Analysis .......................................................................................13
8.3
Final Analysis............................................................................................13
9.
Data Screening and Acceptance...........................................................................13
9.1
General Principles.....................................................................................13
9.2
Data Handling and Electronic Transfer of Data..........................................13
9.3
Handling of Missing and Incomplete Data .................................................14
9.4
Detection of Bias.......................................................................................14
9.5
Outliers .....................................................................................................14
9.6
Distributional Characteristics.....................................................................14
9.7
Validation of Statistical Analyses...............................................................14
10.
Statistical Methods of Analysis..............................................................................15
10.1
General Considerations.............................................................................15
10.2
Subject Accountability ...............................................................................15


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 4
10.3
Important Protocol Deviations ...................................................................15
10.4
Demographic and Baseline Characteristics...............................................16
10.5
Safety Analyses ........................................................................................16
10.5.1
Adverse Events and Disease Related Events............................16
10.5.2
Laboratory Test Results.............................................................16
10.5.2.1
Chemistry and Hematology .....................................16
10.5.2.2
Urinalysis ................................................................17
10.5.3
Vital Signs .................................................................................18
10.5.4
Electrocardiogram (ECG) ..........................................................18
10.5.5
Antibody Formation ...................................................................18
10.5.6
Exposure to Investigational Product ..........................................19
10.5.7
Exposure to Concomitant Medication ........................................19
10.5.8
Subjects With potential DILI events ...........................................19
10.6
Analysis of Exploratory Efficacy Endpoints................................................19
10.6.1
Disease Activity Score Based on 28 Joints (DAS 
28-CRP)....................................................................................19
10.6.2
Patient Global Assessment of Disease Activity..........................20
10.6.3
Physician Global Assessment of Disease Activity......................20
10.6.4
Disability Index of the Health Assessment 
Question(HAQ-DI).....................................................................20
10.7
Pharmacokinetic Analysis .........................................................................21
10.8
Pharmacodynamic Analysis ......................................................................21
11.
Changes From Protocol-specified Analyses..........................................................22
12.
Prioritization of Analyses.......................................................................................22
13.
Data Not Covered by This Plan.............................................................................22
14.
Appendices...........................................................................................................23
List of Tables
Table 1.  Dose Levels......................................................................................................7
Table 2. List of Laboratory Parameters.........................................................................17
Table 3.  Companion Devices/Help Items for HAQ-DI Categories .................................21
List of Appendices
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs......................................................24
Appendix B.  Reference Values/Toxicity Grades ...........................................................25
Appendix C.  Summary of Changes and Rationale for Changes to the SAP 
Amendement 1 .......................................................................................26


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 5
Table of Abbreviations
Abbreviation/Acronym
Definition
AE
Adverse event
ALP
Alkaline Phosphate
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under the concentration-time curve
AUC0-inf
Area under the concentration-time curve from 
time zero to infinity
AUC0-last
Area under the concentration-time curve from 
time zero to the time of the last quantifiable 
concentration
BAFF
B cell activating factor
B7RP-1
B 7 related protein 1, aka ICOSL
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
Cmax
Maximum observed serum concentration
CPMS
Clinical Pharmacology, Modeling and 
Simulation
CTCAE 
Common terminology criteria for adverse 
events 
DBP
Diastolic Blood Pressure
DILI
Drug-induced liver injury
DLRM 
Dose Level Review Meeting
DMP
Data management plan
CRP
C-Reactive Protein
DAS
Disease Activity Score
ESR
Erythrocyte Sedimentation Rate
eCRF 
Electronic case report form 
ECG
Electrocardiogram
EOS
End of study
GBS
Global Biostatistical Science
GGT
Gamma Glutamyl Transferase
HR
Heart Rate
ICOSL
Inducible co-stimulator ligand
IP
Investigational Product, 
in this double-blind study, investigational 
product may be AMG 570 or placebo 
IPD 
Important Protocol Deviation


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 6
Abbreviation/Acronym
Definition
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MAD
Multiple Ascending Dose
NK Cells
Natural Killer Cells
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKDM
Pharmacokinetics and drug metabolism
PR
The interval measured from the beginning of 
the P wave to the beginning of the QRS 
complex in the heart’s electrical cycle as 
measured by electrocardiogram 
Q1
First quartile
Q3
Third quartile
QRS 
The interval between the Q wave and the S 
wave in the heart’s electrical cycle as 
measured by electrocardiogram; represents 
the time it takes for depolarization of the 
ventricles 
QT 
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 
electrocardiogram 
QTc 
QT interval corrected for heart rate using 
accepted methodology 
QTcB 
Bazett-corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
RA
Rheumatoid arthritis
RBC
Red Blood Cells
RO
Receptor Occupancy
SAE 
Serious Adverse event 
SAP
Statistical Analysis plan
SBP
Systolic Blood Pressure
SC
Subcutaneous 
SOP
Standard Operating Procedure
Tmax
Time to Cmax
TEAE
Treatment Emergent Adverse Events
Tfh
T follicular helper
VAS
Visual Analogue Scale
WBC
White Blood Cells


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 7
1.
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for AMG 570 study 20150196 dated 
08 June 2018. The scope of this plan includes the primary analysis that are planned at 
the primary completion of the study and will be executed by the Amgen Global 
Biostatistical Sciences (GBS) unless otherwise specified.
2.
Objectives
2.1
Primary
To evaluate the safety and tolerability of AMG 570 following multiple dose subcutaneous 
(SC) administration in subjects with rheumatoid arthritis (RA).
2.2
Secondary
To characterize the pharmacokinetic profile of AMG 570 following multiple dose SC 
administration in subjects with RA.
2.3
Exploratory

To characterize the pharmacodynamic effects of multiple subcutaneous 
doses of AMG 570 in subjects with RA on peripheral blood B cell levels (total 
B cells as well as naive, memory subpopulations), peripheral blood ICOSL 
Receptor Occupancy on B cells, serum BAFF levels , serum Immunoglobulin 
levels, plasma cells and circulating T follicular helper (Tfh) cells.

To characterize pharmacokinetic and pharmacodynamic relationships after 
multiple subcutaneous doses of AMG 570 in subjects with RA. 

To characterize effects of multiple subcutaneous doses of AMG 570 on 
clinical and serologic indices of RA disease activity in subjects with RA. 

To evaluate the immunogenicity of  multiple subcutaneous doses of AMG 570 
in subjects RA
3.
Study Overview
3.1
Study Design
This is a randomized, placebo-controlled, double-blind, MAD study in subjects with RA.  
The study consists of 4 SC cohorts.  Subjects will be randomized in a 3:1 ratio to receive 
AMG 570 or placebo according to Table 1.
Table 1.  Dose Levels
Cohort #
Planned 
Dose (mg)
Route
Dosing 
interval
Number of 
planned doses
N(active:placebo)
1
70
SC
Q 2 weeks
6
8 (6:2)
2
140
SC
Q 2 weeks
6
8 (6:2)
3
210
SC
Q 2 weeks
6
8 (6:2)
4
420
SC
Q 2 weeks
6
8 (6:2)


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 8
The overall study design is described in the section 3.1 of the protocol.  The study 
endpoints are defined in Section 4.
3.2
Sample Size
Approximately 32 RA patients will be enrolled into 4 cohorts with 6 subjects randomized 
to AMG570 and 2 subjects randomized to placebo in each cohort.
This sample size is based on practical considerations and is typical for this type of study. 
For safety considerations, for a cohort, with 6 subjects receiving AMG 570, there is an 
82% chance of at least one subject experiencing an adverse event assuming a true 
incidence rate of 25% and a 74% chance of at least one subject experiencing an 
adverse event assuming 20% true incidence rate. With a total of 24 subjects expected to
receive AMG 570 across all 4 cohorts, there is a 21% chance of at least 1 subject
experiencing an adverse event assuming a true incidence rate of 1% and the chance of 
at least 1 subject experiencing an adverse event increases to 71% and 92% assuming a 
true incidence rate of 5% and 10%, respectively.
4.
Study Endpoints
4.1
Primary Endpoint
Subject incidence of treatment-emergent adverse events (including clinically significant
changes in physical examinations), vital signs, laboratory safety tests, and
electrocardiograms (ECGs).
4.2
Secondary Endpoint(s)

AMG 570 serum PK profiles after multiple dose administrations. PK
parameters will include, but are not limited to, maximum observed
concentration [Cmax], area under the concentration-time curve [AUC] after
the first and the last doses, and the accumulation ratio.
4.3
Exploratory Endpoint(s)

Peripheral blood ICOSL receptor occupancy

Baseline levels, post-dose levels and change from baseline in peripheral
blood percentage and absolute counts of total T cells, B cells and NK cells

Baseline levels, post-dose levels and change from baseline in peripheral
blood percentage and absolute counts of naive and memory B cells
(naive = CD19+IgD+CD27-, memory = CD19+IgD-CD27+)

Baseline levels, post-dose levels and change from baseline in circulating
Plasma cells  by gene signature

Baseline levels, post-dose levels and change from baseline in circulating Tfh
by flow cytometry and gene signature

Baseline levels, post-dose levels and change from baseline in serum
Immunoglobulin M, Immunoglobulin G and Immunoglobulin A


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 9

Baseline levels, post-dose levels and change from baseline in serum BAFF

Baseline levels, post-dose levels and change from baseline in serum CRP, 
ESR, IgG+ Rheumatoid Factor, IgM+ Rheumatoid Factor and
anti-citrullinated protein antibody

Changes from baseline over time in the disease activity score based on
28 joints (DAS 28-CRP)

Changes from baseline over time in Patient Global Assessment of Disease 
Activity

Changes from baseline over time in Physician Global Assessment of Disease 
Activity 

Incidence of anti-AMG 570 binding and neutralizing antibodies
5.
Hypotheses and/or Estimations
Multiple SC dose administration of AMG 570 will have acceptable safety and tolerability
profiles in RA subjects within the proposed dose range (70 to 420 mg AMG 570)
6.
Definitions
6.1
General Definitions
Accumulation Ratio
Accumulation Ratio is the ratio of AUC after the last dosing interval divided by AUC after 
the first dosing interval
Age at Enrollment
Subject age at enrollment will be collected  in years in the clinical database
AUC0_last
Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration.
Baseline 
For any variable, unless otherwise defined, baseline is the last assessment taken prior to 
the first investigational product administration.
Baseline ECG 
The baseline ECG is defined as the average of the mean of the triplicates at
Day 1 pre-dose; the mean of values in a triplicate should be calculated before taking the 
mean of the triplicate averages.


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 10
Bazett-corrected QT Interval (QTcB) 
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows: 
QTcB=QT/(RR/1000)1/2
BMI
Subject’s BMI will be derived in kg/m2 in the clinical database
Change From Baseline
Change from Baseline is the arithmetic difference between post-Baseline and Baseline.
Cmax
Maximum observed serum concentration.
ECG analysis value 
ECGs will be performed in triplicate, approximately 1 minute apart, at time points 
specified in the Schedule of Assessments. On Day 1 pre-dose, three sets of triplicate 
ECGs will be collected, with each set being ≥ 30 minutes apart (ie, total of 9 ECGs). At 
other time points single triplicate ECGs will be collected. The mean value of each 
triplicate will be calculated and used in the analysis. If an ECG is missing within a 
triplicate, all available data will be averaged for that time point. Further, unscheduled 
ECG measurements taken up to 5 minute after the last assessment of a triplicate at a 
time point will be included in the mean for that time point. 
End of IP Admin Date
End of IP Admin for each subject is defined as the date the decision was made to end IP 
as recorded on the End of IP eCRF.
End-of-Study 
Primary Completion: the date when the last subject has completed the EOS visit as 
outlined in Section 7.1 of the Schedule of Assessments in the protocol.
End of Study: the time when the last subject has completed either the EOS visit or the 
last safety follow-up visit (if applicable). The EOS for each cohort may be prolonged 
pending treatment- emergent data. 
Enrollment Date 
Enrollment Date is defined as the randomization date and will be collected on the 
enrollment eCRF.


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 11
Dose administered
For AMG 570 subjects, dose administered (mg) is the quantity administered (mg) 
as recorded on IP administration eCRF. For placebo subjects, the dose 
administered will be 0 mg. The actual treatment assignment (AMG 570 versus 
placebo) will be determined based on package lot numbers entered on IP 
administration eCRF and concentration of active drug in those lots as per the 
information in manufacturing lot file. 
Fold change from Baseline 
Fold change from Baseline equals the post-Baseline value divide by the Baseline value.
Fridericia-corrected QT Interval (QTcF)
The Fridericia correction will be calculated from the investigator reported QT and RR 
interval (QTcF=QT/(RR/1000)0.33).
Investigational Product 
The term ‘investigational product’ is used in reference to AMG 570 or placebo.
Last IP Dose Date
Last  IP Dose Date for each subject is defined as the latest date IP is administered
Percent Change From Baseline 
Percent change from Baseline is the arithmetic difference between post-Baseline and 
Baseline divided by Baseline values times 100. Percent Change From Baseline Percent 
change from baseline = [(Post-baseline Value – Baseline Value) / Baseline Value] x 100
Peripheral blood ICOSL receptor occupancy (RO) (MFI-based)
RO on total B cells, memory B cells, and monocytes will be calculated as follows:
RO= [1 - (background subtracted free ICOSL/ background subtracted total 
ICOSL)/(Baseline background subtracted free ICOSL /Baseline background subtracted 
total ICOSL)] * 100 
Where 
background subtracted free ICOSL = free ICOSL – Maximally saturated free ICOSL 
background subtracted total ICOSL = total ICOSL – background subtraction factor
Background subtraction factor is 171, 208 and 96 for total B cells, memory B cells 
and monocytes respectively. 


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 12
RO is 0 at baseline.
Randomization Date
Randomization Date is defined as the date subject was allocated to a randomization 
number and assigned to either AMG 570 or placebo group.
Study Day 
Post study day 1: study day= (date - date of Study Day 1) + 1 
Pre study day 1: study day= (date – date of Study Day 1) 
Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment. The day prior to Study Day 1 is considered as Day -1.
Subject-level End of Study (EOS) Date
End of study for each subject is defined as the date the subject completed the EOS visit. 
The date will be recorded on the End of Study eCRF.
Treatment-emergent adverse event
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product (as determined by the flag indicating if the adverse event started 
prior to the first dose or not on the Events eCRF) and up to the end of study (ie, EOS 
visit).
Treatment-Related AE 
A treatment-related AE is any treatment-emergent adverse event that per investigator 
review has a reasonable possibility of being caused by the investigational product and 
marked accordingly on the Events eCRF.
7.
Analysis Subsets
For all analyses, subjects will be analyzed according to the treatment they received.
7.1
Safety Analysis Set
The safety analysis set will include all randomized subjects who received at least
one dose of AMG 570/placebo.
7.2
Pharmacokinetic Concentration Analysis Set
The pharmacokinetic (PK) concentration analysis set will contain all randomized subjects 
who received AMG 570 and have at least one quantifiable PK sample collected.   


Product:  AMG 570
Statistical Analysis Plan:  20150196
Date:  13 Aug 2019
Page 13
7.3
Pharmacokinetic Parameter Analysis Set 
The pharmacokinetic (PK) parameter analysis set will contain all randomized subjects 
who received AMG 570 and for whom PK parameters can be adequately estimated
7.4
Pharmacodynamic Analysis Set 
The pharmacodynamic (PD) analysis set will contain all randomized subjects who 
received at least 1 dose of investigational product (AMG 570 or Placebo) and for whom 
at least 1 PD parameter has baseline and at least 1 post baseline measurement 
available.
8.
Planned Analyses
8.1
Interim Analysis and Early Stopping Guidelines
No interim analysis is planned for this study. However the study will have Dose Level 
Review Meetings (DLRMs) after all 8 subjects have been enrolled in each cohort and at 
least 6 of them have completed the day 29 visit. Details of DLRMs are given in section 
6.2.1.2 of the protocol.
8.2
Primary Analysis
The primary analysis will be performed when all subjects have completed the 
study ie, the end of study (EOS) visit.
8.3
Final Analysis
Primary analysis is the final analysis for the study ie, no analysis will be done 
after the primary analysis. 
9.
Data Screening and Acceptance
9.1
General Principles
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses.
9.2
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database.  The database will be subject to edit checks outlined in the Clinical Data 
Management Plan (DMP).


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9.3
Handling of Missing and Incomplete Data
The following imputation of missing values will be done:

Incomplete adverse event dates and concomitant medication dates will be 
imputed as per Appendix A. If imputed dates are used, then they will be 
identified as such in the final study report.

Laboratory measurements that are below the quantification limits will be 
considered equal to the lower limit of quantification for all analyses unless 
explicitly noted otherwise.

Biomarker data that are below the quantification limits will be considered equal to 
half of the lower limit of quantification for all analyses unless specified otherwise. 

PK concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PK parameters.
9.4
Detection of Bias
Any source that may introduce the bias in the analysis eg, important protocol deviations, 
imbalance in baseline characteristics among treatment groups, subject dropout for study 
or treatment related reasons, nonrandom or informative censoring will be noted in the 
clinical study report.
9.5
Outliers
Details of detecting outliers can be found in the DMP or other data management 
documents. In addition, outliers may be identified via the use of descriptive statistics. All 
confirmed outlier data will be included in the analyses presented in this statistical 
analysis plan unless there is sufficient scientific justification to exclude them.
9.6
Distributional Characteristics
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. Data distribution will be explored, if required, data transformations or 
alternative non-parametric methods of analyses will be utilized.
9.7
Validation of Statistical Analyses
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later.


Product:  AMG 570
Statistical Analysis Plan:  20150196
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10.
Statistical Methods of Analysis
10.1
General Considerations
Descriptive statistics will be provided for selected subject disposition, demographics, 
safety, immunogenicity, PK, PD, and biomarker data. Descriptive statistics on 
continuous measurements will include means, medians, Q1, Q3, standard deviations, 
and ranges, while categorical data will be summarized using frequency counts and 
percentages. Data will summarized by treatment and by scheduled timepoint unless 
specified otherwise. Graphical summaries of the data may also be presented. When 
data are summarized by time, the scheduled time points listed in the protocol will be 
used. For statistical analyses comparing change from baseline, only subjects with both 
baseline and at least one post-baseline assessment will be included. When assessing 
minimum/maximum increases or decreases over the study, all assessments, including 
unscheduled assessments will be used.
Only critical subject-level data listings will be provided. Additional listings of  
subject-level data will be reviewed during DLRM meetings for assessment of 
subjects’ safety and as part of ongoing data review to check the quality of data, 
but will not be included in the clinical study report to protect subjects’ privacy. 
10.2
Subject Accountability
The number and percent of subjects who were enrolled, randomized, received 
investigational product, completed investigational product, discontinued from 
investigational product (including reasons for discontinuing), completed study, 
discontinued the study (including reasons for discontinuing) will be summarized by 
treatment group. 
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented.
The number and percent of subjects enrolled will be tabulated by study site.
A summary noting inclusion in each analysis subset will be provided for all subjects 
enrolled. A subject listing will be provided for randomization information, randomized 
treatment and actual treatments. 
10.3
Important Protocol Deviations
The final list of important protocol deviations (IPDs) will be used to produce the listing 
of subjects with IPDs. In addition, a separate listing of all inclusion and exclusion 
deviations will be provided.


Product:  AMG 570
Statistical Analysis Plan:  20150196
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10.4
Demographic and Baseline Characteristics
Demographic (age, age groups [18-64 years, 65-74 years and >=75 years], sex, race, 
and ethnicity) and baseline characteristics (height, weight, and BMI) will be summarized 
by treatment group and overall. If multiple races have been reported for a subject, the 
subject will be categorized as multiple races as well as by the combination of races. 
10.5
Safety Analyses
10.5.1
Adverse Events and Disease Related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 22.0 or later will be 
used to code all events categorized as adverse events (AEs) to a system organ class 
and a preferred term.  
The subject incidence of AEs by treatment group will be summarized for all
treatment-emergent AEs, serious treatment-emergent AEs, treatment related AEs,
serious treatment related AEs, AEs leading to withdrawal of investigational product, and 
fatal AEs.
The severity of each adverse event will be graded using CTCAE version 4.0 or later 
version (Refer - Appendix B). Subject incidence of treatment emergent events and 
treatment related treatment emergent events will further be summarized by worst 
severity grade. 
Subject incidence of all treatment-emergent AEs, serious treatment-emergent 
AEs,Treatment-related AEs, Serious treatment-related AEs, those leading to withdrawal 
of investigational product, and fatal AEs will be tabulated by system organ class and 
preferred term in descending order of frequency. 
10.5.2
Laboratory Test Results
10.5.2.1
Chemistry and Hematology 
Parameters that will be collected are listed in Table 2.
Unscheduled assessments will be incorporated in the laboratory analyses where 
possible. 
For the parameters that are bolded in Table 2, summary of baseline lab value, change 
from baseline to post dose maximum, time to post-baseline maximum, change from 
baseline to post- baseline minimum, and the time to post-baseline minimum will be 
provided. Further, shifts in grades based on CTCAE version 4.0 or later between the 
baseline and the worst on-study value will be provided for the parameters where 
CTCAE grading is available .


Product:  AMG 570
Statistical Analysis Plan:  20150196
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10.5.2.2
Urinalysis
Parameters that will be collected are listed in Table 2.
Blood, protein, glucose and bilirubin will be graded in the following manner: 0=’0 or 
Trace’, 1=’1+’, 2=’2+’, 3=’3+’, 4=’4+’. The number and percent of subjects by worst
post-dose levels will be presented for these analytes. 
Microscopic parameters (WBC, RBC, epithelial cells, bacteria, casts, and crystals) will 
be graded in the following manner: 0=’0-4 none, rare, occasional’, 1=’5-50 moderate, 
few’, 2=’>50 many, heavy, too numerous to count’. The number and percent of subjects 
in these categories at each scheduled time point will be presented. Summary statistics
and change from baseline over time will be provided for Specific gravity, and pH values. 
Descriptive statistics will be provided for Urobilinogen. 
Table 2. List of Laboratory Parameters
Chemistry
Hematology
Urinalysis
Alanine aminotransferase (ALT)
Albumin
Alkaline phosphatase
Aspartate aminotransferase 
(AST)
Bicarbonate (HCO3) or Carbon 
Dioxide
Bilirubin
•
Total
•
Direct
Blood urea nitrogen or Urea
Calcium
Chloride
Cholesterol
Creatinine
Creatine phosphokinase (CPK)
Gamma-glutamyl transferase 
(GGT)
Glucose
High-density lipoprotein
Magnesium
Phosphorus
Potassium
Sodium
Total protein
Triglycerides
Uric acid
Hemoglobin A1C**
CRP
Erythrocyte Sedimentation 
Rate (ESR)
Hemoglobin
Hematocrit
Mean corpuscular volume 
(MCV)
Mean Corpuscular Hemoglobin 
(MCH)
Mean Corpuscular Hemoglobin 
Conc (MCHC)
Red Blood Cell count
Platelets
Reticulocyte count
White blood cell count
White blood cell Differential (in 
absolute cell numbers)
•
Total neutrophils
•
Eosinophils
•
Basophils
•
Lymphocytes
•
Monocytes
Specific gravity
pH
Blood
Protein
Glucose
Bilirubin
Urobilinogen
Microscopic exam
White blood cells
•
Red blood cells
•
Epithelial cells
•
Bacteria
•
Casts
•
Crystals


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Statistical Analysis Plan:  20150196
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10.5.3
Vital Signs
The summary statistics over time and/or changes from baseline over time by treatment 
will be produced for SBP, DBP, pulse rate, HR and temperature.
10.5.4
Electrocardiogram (ECG)
Each ECG will include the following measurements: QRS, QT, QTc, RR, and PR 
intervals. The Bazett’s (QTcB) and Fridericia’s (QTcF) QT correction will be computed as 
specified in section 6 of this document. 
Summaries of baseline value, maximum post-baseline and change from baseline to 
post – baseline maximum by treatment group will be provided for all 12-lead ECG 
parameters. 
Further, subjects’ maximum change from baseline in QTcF and QTcB will be categorized 
in following categories and the number and percentage of subjects in each group will be 
summarized. Unscheduled assessments will be included in the determination of the 
maximum change. 

<= 30 msec 

> 30 – 60 msec 

> 60 msec 
Subjects’ maximum post baseline values in QTcF and QTcB will also be categorized in 
the following categories and the number and percentage of subjects in each group will 
be summarized. Unscheduled assessments will be included in the determination of the 
maximum post baseline value 

<= 450 msec 

> 450 – 480 msec 

> 480 – 500 msec 

> 500 msec 
In addition, the relationship between serum concentration of AMG 570 and change from 
baseline in QTcF and QTcB will be explored graphically.
10.5.5
Antibody Formation
The number and percentage of subjects who have developed anti- AMG 570 antibodies 
(binding and if positive, neutralizing) at any time, at baseline and during post-baseline 
visits will be summarized by treatment group.  


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Statistical Analysis Plan:  20150196
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10.5.6
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to AMG 570 by 
treatment group.  
A listing of the unique manufacturing lot numbers, and a listing of the subjects
administered each manufacturing lot number will be provided
10.5.7
Exposure to Concomitant Medication
All medications will be coded using the WHO drug dictionary. Summary of concomitant 
medication use by preferred name will be provided. 
10.5.8
Subjects With potential DILI events
For subjects identified with potential DILI events (including those satisfying Hy’s law 
criteria) during the study, listings of hepatic history, results of additional laboratory tests, 
vital signs, liver imaging results (if performed), liver biopsy results (if performed), and 
substance use will be separately provided.
10.6
Analysis of Exploratory Efficacy Endpoints
Safety analyses set will be used for the analyses described in this section
10.6.1
Disease Activity Score Based on 28 Joints (DAS 28-CRP)
The DAS28-CRP is a composite score that is based on 28-joint count (using tender and 
swollen joints), CRP (mg/L) , and Patient Global Assessment of Disease Activity. 
Calculation of the DAS28-CRP score is as follows: 
DAS28-CRP = 0.56 √TJC28 + 0.28 √SJC28 + 0.36 x ln (CRP + 1) + 0.014 x Patient 
Global Assessment of Disease Activity score + 0.96
Where TJC28 and SJC28 represent the tender and swollen 28 joint counts, respectively. 
The 28 joint counts includes 10 proximal interphalangeal, 10 metacarpophalangeal,
2 wrist, 2 elbow, 2 shoulder, and 2 knee joints. 
To calculate the swollen joint counts at least half of those joints listed above
(ie, 14 joints) need to be evaluated ie, have an entry of (0 or 1) where 0 is none (no 
swelling or effusion) and 1 is positive (detectable effusion or synovial thickening) ; 
otherwise the SJC28 will be missing. If all joints are evaluated, then SJC28 is the
number of joints with 1. If some joints are missing, but still have at least 14 joints 
evaluated, then SJC28 is (number of joints with (1) / number of evaluated joints) *
28. Similarly, TJC28 will be calculated.  If any of TJC28, SJC28, Patient Global 
Assessment of Disease Activity score or CRP value is missing, then DAS28-CRP will be 


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Statistical Analysis Plan:  20150196
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Page 20
missing. Summary statistics of DAS28-CRP and change from baseline in DAS28-CRP 
will be provided at all applicable time-points. 
10.6.2
Patient Global Assessment of Disease Activity
The patient will rate the patient’s arthritis status by marking an “X” on the 100 mm 
horizontal line where 0 is no activity at all and 100 is worst activity imaginable. The score 
will be documented on the eCRF. Summary statistics of the score and change from 
baseline in the score will be provided at all evaluable time-points.
10.6.3
Physician Global Assessment of Disease Activity
The treating physician will rate the patient’s disease activity by marking an “X” on the 
100 mm horizontal line where 0 is no activity at all and 100 is worst activity imaginable.  
The score will be documented on the eCRF. Summary statistics of the score and change 
from baseline in the score will be provided at all evaluable time-points.
10.6.4
Disability Index of the Health Assessment Question(HAQ-DI)
HAQ is used to assess a subject’s physical function or disability according to the subject. 
It includes a Disability Index (DI) and a VAS for pain. Disability Index include
8 categories (dressing and grooming, arising, eating, walking, hygiene, reaching, 
gripping, and activities ie,errands or chores). Responses for each category range from 0 
(without any difficulty) to 3 (unable to do). The scoring algorithm is as follows: 

Obtain the maximum score reported for any component question of the above
8 categories (the highest score reported for any component question of the eight 
categories determines the score for that category); 

If either devices or help from another person are checked for a category, then the 
category score is set to “2”, but if the subject’s highest score for that category is a 
“2”, it remains a “2”, and if a “3”, it remains a “3”. Please see Table 3 for the 
companion devices for calculating the HAQ-DI category scores (the eighth 
category ―Activities is not listed in Table 3 due to lack of questions regarding 
use of devices).

A global DI score is the mean of the nonmissing category scores. If there are 
more than 2 categories with missing responses, a DI score will be set to missing. 


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Statistical Analysis Plan:  20150196
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Table 3. Companion Devices/Help Items for HAQ-DI Categories
HAQ-DI Category
Companion Device Item
Dressing & Grooming
Devices used for dressing (Button hook, zipper pull, long-handled 
shoe horn, etc.)
Arising
Special or built up chair
Eating
Built up or special utensils
Walking
Cane, Walker, Crutches, Wheelchair
Hygiene
Raised toilet seat, Bathtub seat, Bathtub bar, Long-handled 
appliances in bathroom
Reach
Long-handled appliances for reach
Grip
Jar opener (for jars previously opened)
Descriptive statistics for HAQ-DI global score and change from baseline in the score will 
be provided at each evaluable timepoint. 
The pain VAS scale measures the distance (D in cm) from the left side of the line to the 
mark on a 100 mm scale where 0 is no pain and 100 is severe pain. Descriptive 
statistics for pain score and change from baseline in the score will be provided at each 
evaluable timepoint. 
10.7
Pharmacokinetic Analysis
Pharmacokinetics analyses will be performed by Clinial Pharmacology, Modeling 
and Simulation (CPMS) group. Serum AMG 570 concentrations will be determined 
using a validated assay. Individual serum concentration-time plots for AMG 570 will be 
presented for each subject as well as mean concentration-time plots for each treatment. 
Descriptive statistics for PK concentrations will be provided by treatment group and time. 
Mean concentration-time profiles for each dose will be provided. Pharmacokinetic 
parameters may include, but are not limited to, maximum observed concentration 
[Cmax] time at Cmax [tmax], area under the concentration-time curve [AUC], after the 
first and the last dose, in addition to the accumulation ratio.Parameters will be calculated
using non-compartmental methods. Actual dosing and sampling times will be used for 
calculation of individual PK parameters. Summary statistics will be generated for each 
PK parameter. Additional analyses using compartmental methods or population PK 
analysis may be performed.
10.8
Pharmacodynamic Analysis
The endpoints such as a peripheral blood ICOSL receptor occupancy, percentage and 
absolute counts of total T cells, B cells and NK cells, percentage and absolute counts of 


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Statistical Analysis Plan:  20150196
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naive and memory B cells (naive = CD19+IgD+CD27-, memory = CD19+IgD-CD27+), 
serum Immunoglobulin M, Immunoglobulin G and Immunoglobulin A, serum BAFF, 
serum CRP, ESR, IgG+ Rheumatoid Factor, IgM+ Rheumatoid Factor, IgA+ Rheumatoid 
Factor and anti-citrullinated protein antibody will be summarized by treatment group 
using descriptive statistics at each visit. For each end point,the change from baseline,
percent change from baseline, and/or fold change from baseline will be summarized 
by treatment using descriptive statistics at post-baseline visit. For selected analytes, 
plots of selected summary statistics (eg, mean, mean change, mean fold change 
or mean percent change) over time may be plotted by treatment group as deemed 
necessary. 
11.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses.
12.
Prioritization of Analyses
Tables to precede listings.
13.
Data Not Covered by This Plan
Exploratory data not included in this plan may be analyzed at a later date or may be 
analyzed by a different Amgen Department.


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Statistical Analysis Plan:  20150196
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14.
Appendices


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Statistical Analysis Plan:  20150196
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Appendix A. Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs
Imputation Rules for Partial or Missing Stop Dates
If the month and year are present, impute the last day of the month.  If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing.  If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial. Imputation Rules for Partial or 
Missing Start Dates
Stop Date
Complete: 
yyyymmdd
Partial: yyyymm
Partial: yyyy
Missing
Start Date
< 1st
Dose
1st
Dose
< 1st
Dose 
yyyymm
1st Dose 
yyyymm
< 1st Dose 
yyyy
1st Dose 
yyyy
Partial: 
yyyymm
= 1st Dose 
yyyymm
2
1
2
1
N/A
1
1
1st Dose 
yyyymm
2
2
2
2
2
Partial: 
yyyy
= 1st Dose 
yyyy
3
1
3
1
N/A
1
1
1st Dose 
yyyy
3
3
3
3
3
Missing
4
1
4
1
4
1
1
1 = Impute the date of first dose
2 = Impute the first of the month
3 = Impute January 1 of the year
4 = Impute January 1 of the stop year
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month.
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date.


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Statistical Analysis Plan:  20150196
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Appendix B. Reference Values/Toxicity Grades
The Common Terminology Criteria for Adverse Events (CTCAE) v4.0 is available at the 
following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm


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Statistical Analysis Plan:  20150196
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Appendix C.  Summary of Changes and Rationale for Changes to the SAP 
Amendement 1
The statistical analysis plan for this study was amended to reflect the changes in recent 
protocol amendment 3.
Editorial changes and minor clarifications were also implemented throughout the 
document. 
Description of Changes
Global

Header date was replaced with 11 July 2019.

Header version number was replaced with Version 2.0.

Changes related to addition of Cohort 4

Removal of unnecessary listings as per recent process
Table of Abbreviations
Added below Abbreviations
BAFF
B cell activating factor
DILI
Drug-induced liver injury
CRP
C-Reactive Protein
DAS
Disease Activity Score
ESR
Erythrocyte Sedimentation Rate
ICOSL
Inducible co-stimulator ligand
Q1
First quartile
Q3
Third quartile
RA
Rheumatoid arthritis
RO
Receptor Occupancy
Tfh
T follicular helper
1.
INTRODUCTION 
Replaced: dated 13 November 2017 with amendment 3 dated 08 June 2018.
3.
Study Overview 
3.1
Study Design 
Added: Cohort 4 SC 420 mg.


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Table 1  Dose Levels
Cohort #
Planned 
Dose (mg)
Route
Dosing 
interval
Number of 
planned 
doses
N(active:placebo)
4
420
SC
Q 2 weeks
6
8 (6:2)
Reason for change: Updates as per change in the protocol amendment 3.
3.2
Sample Size 
Added: 
Approximately 32 RA patients will be enrolled into 4 cohorts with 6 subjects randomized 
to AMG 570 and 2 randomized to placebo in each cohort.
This sample size is based on practical considerations and is typical for this type of study. 
For safety considerations, for a cohort, with 6 subjects receiving AMG 570, there is an 
82% chance of at least one subject experiencing an adverse event assuming a true 
incidence rate of 25% and a 74% chance of at least one subject experiencing an 
adverse event assuming 20% true incidence rate. With a total of 24 subjects expected to 
receive AMG 570 across all 4 cohorts, there is a 21% chance of at least 1 subject 
experiencing an adverse event assuming a true incidence rate of 1% and the chance of 
at least 1 subject experiencing an adverse event increases to 71% and 92% assuming a 
true incidence rate of 5% and 10%, respectively.
Deleted:
Approximately 24 RA patients will be enrolled into 3 cohorts with 6 active and 2 placebo 
in each cohort.
This sample size is based on practical considerations and is typical for this type of study. 
For safety considerations, for a cohort, with 6 subjects receiving AMG 570, there is an 
82% chance of at least one subject experiencing an adverse event assuming a true 
incidence rate of 25% and a 74% chance of at least one subject experiencing an 
adverse event assuming 20% true incidence rate. With a total of 18 subjects expected to 
receive AMG 570 across all 3 cohorts, there is a 17% chance of at least 1 subject 
experiencing an adverse event assuming a true incidence rate of 1% and the chance of 
at least 1 subject experiencing an adverse event increases to 60% and 85% assuming a 
true incidence rate of 5% and 10%, respectively.


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Statistical Analysis Plan:  20150196
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Reason for change: As per protocol amendment 3, 4th cohort added and number of 
subjects increased from 24 to 32.
4.
Study Endpoints
Minor changes to exploratory endpoints to reflect changes in the protocol amendment
5.
Hypotheses And/Or Estimates
Added: 420 mg.
Reason for change: To reflect changes in protocol amendment 3.
6.
Definitions
Added: 
Dose administered
For AMG 570 subjects, dose administered (mg) is the quantity administered (mg) as 
recorded on IP administration eCRF. For placebo subjects, the dose administered will be 
0 mg. The actual treatment assignment (AMG 570 versus placebo) will be determined 
based on package lot numbers entered on IP administration eCRF and concentration of 
active drug in those lots as per the information in manufacturing lot file.
For Peripheral blood ICOSL receptor occupancy, added MFI-based in the definition to 
indicate that calculations are based on MFI method. Further, added MFI-based 
background subtraction factors for Peripheral blood ICOSL receptor occupancy on total 
B cells, memory B cells, and monocytes.
Replaced:
For ECG analysis value, the baseline is changed to Day 1 pre-dose instead of Day -1 as 
per the protocol.
Added sections:
Added section 8.2: Primary Analyses: The primary analysis will be performed when all 
subjects have completed the study ie, the end of study (EOS) visit.
Added section 8.3: Final Analysis: Primary analysis is the final analysis for the study ie, 
no analysis will be done after the primary analysis.
10.1
Replaced General Principles with General Considerations 
Added: Subject disposition, Q1 and Q3 in the following paragraph.


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Descriptive statistics will be provided for selected subject disposition, demographics, 
safety, immunogenicity, PK, PD, and biomarker data. Descriptive statistics on 
continuous measurements will include means, medians, Q1, Q3, standard deviations, 
and ranges, while categorical data will be summarized using frequency counts and 
percentages.
Added: 
Only critical subject-level data listings will be provided. Additional listings of  subject-level 
data will be reviewed during DLRM meetings for assessment of subjects’ safety and as 
part of ongoing data review to check the quality of data, but will not be included in the 
clinical study report to protect subjects’ privacy. 
10.4
Demographic and Baseline Characteristics 
Modified the age group categories to 18-64 years, 65-74 years and >=75 years as per 
new EU regulatory requirements.
10.5.1
Adverse Events and Disease Related Events
Replaced: MedDRA version 19.1 with MedDRA version 22.0
Deleted: adverse event tables will not be created if two or fewer subjects in the study 
experience the event. 
Details of each adverse event will be listed. Listings and/or narratives of any on study 
deaths, serious adverse events, including early withdrawals due to adverse events, also 
will be provided should they occur.
10.5.2.1
Chemistry and Hematology
Deleted: 
Individual Chemistry and Hematology laboratory data will be listed. Values outside the 
normal laboratory reference ranges will be flagged as high or low.
Replaced:
“Shifts in grades based on CTCAE version 4.0 or later of safety laboratory values 
between the baseline and the worst on-study value will be tabulated by treatment group” 
replaced as follows
“Shifts in grades based on CTCAE version 4.0 or later between the baseline and the 
worst on-study value will be provided for the parameters where CTCAE grading is 
available.” 


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Deleted following analysis as it is not value-added as confirmed by EDL and it is not 
mentioned in the protocol
Plots of the mean values of analytes with 95% confidence intervals over time for each 
treatment group may also be produced for selected analytes.
10.5.2.2
Urinalysis
Deleted: 
Individual urinalysis data will be listed.
Added:
Descriptive statistics will be provided for Urobilinogen.
Table 2 List of Laboratory Parameters:
Deleted heading “Local Laboratory”
Added below parameters to reflect changes in protocol amendment 3:
CRP under Chemistry, and Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular 
Hemoglobin Conc (MCHC) Red Blood Cell count and Reticulocyte count under 
hematology 
Deleted text “(performed at discretion of investigator or designee)” at Microscopic exam 
under Urinalysis
10.5.3
Vital signs
Deleted: vital signs data listing will be provided. 
Physical Measurement section deleted
10.5.4
Electrocardiogram (ECG)
Deleted following statistics to match with standard summary table shell for ECG data: 
Change from baseline to post dose maximum, time to post baseline maximum, change 
from baseline to post baseline minimum, and the time to post baseline minimum.
10.5.5
Antibody Formation
Deleted: A listing will be provided for subjects who have developed anti AMG570 
antibodies.
10.5.6
Exposure to Investigational Product 
Replaced: investigational product with AMG 570.


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Deleted: Details for each AMG 570 administration will be listed for each subject. In 
addition 
10.5.7
Exposure to Concomitant Medication
Deleted: A subject listing of all concomitant medications will be provided.
10.6
Analysis of exploratory Efficacy Endpoints
Deleted: Listings by subject will be produced if deemed necessary for all endpoints listed 
below.
10.6.1
Disease Activity Score Based on 28 Joints (DAS 28-CRP)
Added: mg/L unit was added for CRP
10.7
Pharmacokinetic Analysis
Added: Pharmacokinetics analyses will be performed by Clinical Pharmacology, 
Modeling and Simulation (CPMS) group.
Deleted: by Clinical Pharmacology, Modeling and Simulation (CPMS) group. 
10.7
Pharmacodynamic Analysis
Deleted: Following analytes were deleted from analysis since these analytes are of 
exploratory nature and may be collected and analyzed by separate department (eg,
Computational Biology) in future.

circulating Plasma cells by flow cytometry and gene signature

circulating Tfh by gene signature
Added: 
Added Percentage change from baseline for summary of PD data. 
Added:
For selected analytes, plots of selected summary statistics (eg, mean, mean change, 
mean fold change or mean percent change) over time may be plotted by treatment 
group as deemed necessary.
Deleted: 
Listings by subject will be produced if deemed necessary.