Conditions: Rheumatoid Arthritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 371
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of etanercept monotherapy compared to methotrexate monotherapy on maintenance of remission in participants with rheumatoid arthritis (RA) who were on etanercept plus methotrexate therapy.

This is a multicenter, randomized withdrawal, double-blind controlled study in participants with rheumatoid arthritis on etanercept plus methotrexate therapy who are in very good disease control for 6 months prior to study entry. The study will consist of a 30-day screening period, a 24-week open label run-in period, a 48-week double-blind treatment period and a 30-day safety follow-up period.

Detailed description:

Arms:
arm 1: Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care. arm 2: Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care.

After randomization, a participant experiencing protocol-defined disease worsening will initiate rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). arm 3: Etanercept 50 mg weekly by subcutaneous injection plus placebo for methotrexate for 48 weeks. Participants also receive folic acid as standard of care.

After randomization, a participant experiencing protocol-defined disease worsening will initiate rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). arm 4: Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care.

After randomization, a participant experiencing protocol-defined disease worsening will continue on the assigned treatments (as rescue treatment).

Interventions: intervention 1: etanercept pre-filled syringe subcutaneous injection intervention 2: Oral methotrexate intervention 3: Placebo for etanercept subcutaneous injection intervention 4: Placebo for methotrexate intervention 5: Folic acid (non-investigational product)
Intervention descriptions: intervention 1: etanercept for injection in pre-filled syringes intervention 2: During the open-label run-in period, methotrexate will be provided as 2.5 mg tablets.

During the double-blind treatment period, methotrexate will be provided as 2.5 mg capsules. intervention 3: etanercept placebo for injection in pre-filled syringes intervention 4: methotrexate placebo capsules intervention 5: Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.

Protocol document:
Prot_000.pdf: 
Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 1 of 74 
CONFIDENTIAL 
 
 
Title:  A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy 
Compared to Methotrexate Monotherapy for Maintenance of Remission in 
Subjects With Rheumatoid Arthritis 
Amgen Protocol Number (Etanercept) 20110186 
EudraCT Number:  2014-004868-38 
NCT Number:  02373813 
 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 
91320-1799 
United States Address 
1-805-447-1000 
Key Sponsor Contact: 
 
1 Uxbridge Business Park, Sanderson Road; 
Uxbridge UB8 1DH, England 
Tel: 
Email: 
 
 
Date: 
29 July 2014 
Amendment 1 
18 May 2015 
Superseding Amendment 1: 
08 July 2015 
Amendment 2 
30 October 2015 
Amendment 3 
03 November 2016 
Amendment 4 
20 December 2016 
Amendment 5 
17 October 2017 
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:  for US sites, 1- 800-77-AMGEN; for Canadian 
sites, 1-866-50-AMGEN; for all other countries 1-805-447-1000.  For all other 
study-related questions, continue to contact the Key Sponsor Contact.  


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 2 of 74 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Randomized Withdrawal Double-blind Study 
of Etanercept Monotherapy Compared to Methotrexate Monotherapy for Maintenance of 
Remission in Subjects With Rheumatoid Arthritis”, dated 17 October 2017 and agree to 
abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) 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) 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 3 of 74 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy Compared to 
Methotrexate Monotherapy for Maintenance of Remission in Subjects With Rheumatoid Arthritis  
Study Phase:  Phase 3 
Indication:  Rheumatoid Arthritis (RA) 
Primary Objective:  To evaluate the efficacy of etanercept monotherapy compared to 
methotrexate monotherapy on maintenance of remission in subjects with RA who were on 
etanercept plus methotrexate therapy.  
Secondary Objective(s):   
• 
To evaluate the efficacy of etanercept plus methotrexate therapy compared to methotrexate 
monotherapy on maintenance of remission 
• 
To evaluate the efficacy of 1) etanercept monotherapy compared to methotrexate 
monotherapy and 2) etanercept plus methotrexate therapy compared to methotrexate 
monotherapy on: 
o 
disease activity  
o 
disease worsening and time to disease worsening 
o 
remission and time to recapture remission after rescue treatment 
Hypothesis:  Etanercept monotherapy is superior to methotrexate monotherapy for maintaining 
remission in subjects with RA who were on etanercept plus methotrexate therapy.  
Primary Endpoint:  Simplified Disease Activity Index (SDAI) remission (≤ 3.3) at week 48 
Secondary Endpoints:  
• 
SDAI score and change from baseline at all measured timepoints 
• 
Disease activity score (28 joint) calculated using the erythrocyte sedimentation rate formula 
(DAS-28-ESR) and change from baseline at all measured timepoints 
• 
Disease activity score (28 joint) using the C-reactive protein formula (DAS-28-CRP) and 
change from baseline at all measured timepoints 
• 
Clinical Disease Activity Index (CDAI) and change from baseline at all measured timepoints 
• 
SDAI remission (≤ 3.3) at all measured timepoints 
• 
Boolean remission at all measured timepoints 
• 
Disease worsening defined as an SDAI > 3.3 and ≤ 11 during two consecutive visits at least 
2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate visits or SDAI > 11 after 
randomization 
• 
Time to disease worsening defined as an SDAI > 3.3 and ≤ 11 during two consecutive visits 
at least 2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate visits or 
SDAI >  11 after randomization 
In subjects that receive rescue treatment: 
• 
Time to recapture SDAI remission after starting rescue treatment 
• 
SDAI remission at week 48 
Study Design:  This is a multicenter, randomized withdrawal, double-blind controlled study in 
subjects with RA on etanercept plus methotrexate therapy who are in very good disease control 
for 6 months prior to study entry.  The study will consist of a 30-day screening period, a 24-week 
open-label run-in period, a 48-week double-blind treatment period and a 30-day safety follow-up 
period. 
Approximately 358 subjects will be enrolled and approximately 250 subjects will be randomly 
assigned in a 2:2:1 ratio to one of three treatment groups:  etanercept 50 mg weekly by 
subcutaneous injection plus oral placebo for methotrexate (n = 100), oral methotrexate 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 4 of 74 
CONFIDENTIAL 
 
 
10 to 25 mg weekly plus placebo for etanercept (n = 100) and etanercept 50 mg weekly by 
subcutaneous injection plus oral methotrexate 10 to 25 mg weekly (n = 50). 
Sample Size:  Approximately 358 subjects enrolled and approximately 250 subjects randomized. 
Summary of Subject Eligibility Criteria:  Subjects must be adults with a history of moderate to 
severe RA.  Subjects must be in very good RA disease control for ≥ 6 months and be in remission 
as defined by an SDAI ≤ 3.3 at screening and at the end of the run-in period.  Subjects must be 
on etanercept 50 mg per week plus methotrexate therapy for ≥ 6 months prior to the start of the 
run-in period.  The methotrexate dose must be 10 to 25 mg per week for ≥ 6 months prior to the 
start of the run-in period and the dose must be stable for ≥ 8 weeks prior to the start of the run-in 
period.  If a subject is taking subcutaneous methotrexate they must switch to an equivalent oral 
methotrexate dose of 10 mg to 25 mg weekly and remain on a stable oral dose ≥ 8 weeks prior to 
run-in visit 1.  For a full list of eligibility criteria, please refer to Section 4.1 through Section 4.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Etanercept dosing in the 
planned study follows the recommended label dosing for subjects with RA.  During the run-in 
period open-label etanercept will be provided as a 50-mg pre-filled syringe for injection once 
weekly for 24 weeks.  During the double-blind treatment period etanercept will be provided as a 
50-mg pre-filled syringe or matching placebo for injection once weekly for 48 weeks.  
See Section 6.2.1. 
Non-Amgen Investigational Product Dosage and Administration:  Methotrexate dosing will 
be 10 to 25 mg weekly.  During the run-in period methotrexate will be provided as 2.5 mg tablets 
and will be taken once weekly by oral administration for 24 weeks.  During the double-blind 
treatment period, methotrexate will be supplied as 2.5 mg methotrexate capsules, or as matching 
placebo capsules and will be taken once weekly by oral administration for 48 weeks.  
See Section 6.2.2. 
Non-investigational Product 
Non-Amgen Non-investigational Product Dosage and Administration:  Folic acid dosing will 
be 5 to 7 mg per investigator judgment or administration according to local standard of care.  
See Section 6.3. 
Procedures:  Written informed consent must be obtained from all subjects before any screening 
procedures are performed.  The following procedures will occur per the schedule of assessments:  
medical and medication history, physical examination, physical measures, vital signs, adverse 
event and concomitant medication assessment, tuberculosis testing, pregnancy testing, 
urinalysis, and blood draw for serum chemistry, hematology, hepatitis B and C testing, CRP and 
biomarkers, tender and swollen joint assessment and count and patient reported outcomes.  For 
a full list of study procedures, including the timing of each procedure, please refer to Section 7 
and the Schedule of Assessments (Table 1). 
Statistical Considerations:  The primary endpoint for this study is SDAI remission (SDAI ≤ 3.3) 
at week 48.  The proportion of subjects achieving this endpoint will be compared across treatment 
arms using the chi-square test.  The etanercept monotherapy treatment arm will be compared to 
the methotrexate monotherapy arm.  Both subjects who drop out and subjects receiving rescue 
therapy due to disease worsening during the double-blind period will be considered 
non-responders.  Furthermore, the randomized subjects who did not receive any dose of any of 
the investigational products will be considered non-responders in the primary analysis.  As a 
sensitivity analysis, subjects who receive rescue therapy or drop out will have their post-rescue 
SDAI responses set to missing and a multiple imputation technique to impute these values will be 
employed. 
Summary statistics will be provided for endpoints listed in this protocol.  For categorical 
endpoints, the summary statistics contain the frequency and percentage.  For continuous 
endpoints, the summary statistics contain number of observations, mean, standard deviation, 
standard error, median, minimum, maximum, and 95% confidence interval.  For a full description 
of statistical analysis methods, please refer to Section 10. 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 5 of 74 
CONFIDENTIAL 
 
 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 4.0  31 October 2013 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 6 of 74 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 0 
(Day 1) 
Etanercept 50 mg QW (n = 100) 
24 wk 
48 wk 
Screening (up to 30 days) 
Etanercept 50 mg QW + Methotrexate 10 to 25 mg QW  (n = 50) 
Randomization 2:2:1 
12 wk 
36 wk 
Enrollment (n = 358) 
 Safety-Follow-up 
Methotrexate  10 to 25 mg QW (n = 100) 
Run-in 
visit 1       
(- 168 d) 
Rescue:  Etanercept 50 mg QW + Methotrexate 
10 to 25 mg QW 
Open-label 
Etanercept 50 mg 
QW + Methotrexate 
10 to 25 mg QW 
Run-in 
visit 2       
(- 84 d) 
Run-in 
visit 3   
(- 7 d) 
Open-label Run-in 
Period 
Double-blind Treatment Period 
EOS 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 7 of 74 
CONFIDENTIAL  
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
eSAE contingency form 
electronic serious adverse event contingency form 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
CDAI 
Clinical disease activity index 
eCRF 
Electronic case report form 
CRP 
C-reactive protein 
DA 
Disease assessment visit 
DAS-28-CRP 
Disease activity score (28 joint) calculated using the C-reactive 
protein formula 
DAS-28-ESR 
Disease activity score (28 joint) calculated using the erythrocyte 
sedimentation rate formula 
Disease Worsening 
Simplified Disease Activity Index (SDAI) > 3.3 and ≤ 11 on two 
consecutive visits at least two weeks apart OR SDAI > 3.3 and 
≤ 11 on three or more separate visits OR SDAI > 11 at any time after 
randomization 
DILI 
Drug-induced liver injury  
DMARD 
Disease modifying antirheumatic drug 
DNA 
Deoxyribonucleic acid 
EDC 
Electronic data capture 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study (for 
individual subject) 
End of study for individual subject defined as the last day that 
protocol-specified procedures are conducted for an individual subject 
End of Study (end of trial) The time when the last subject is assessed or receives an 
intervention for evaluation in the study. 
ESR 
Erythrocyte Sedimentation Rate 
End of Treatment (EOT) 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
ET 
Early termination 
GCP 
Good clinical practice 
HAQ-DI 
Disability Index of the Health Assessment Questionnaire 
HBV 
hepatitis B virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 8 of 74 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
ICMJE 
International Committee of Medical Journal Editors 
IXRS 
Interactive Voice and Web Response System  
IPIM 
Investigational product instruction manual 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
LDA 
Low disease activity 
NSAID 
Non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
PFS 
Prefilled syringe 
PI 
principal investigator 
PPD 
Purified protein derivative 
ePRO 
electronic patient reported outcomes 
PRO 
Patient reported outcomes 
QW 
Once weekly 
RA 
Rheumatoid arthritis 
RBC 
Red blood cells 
SAP 
statistical analysis plan 
SDAI 
Simplified Disease Activity Index 
SF-36 
Medical Outcomes Short Form-36 Questionnaire 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol required therapies is/are administered to the 
subject 
TBL  
Total bilirubin 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cells 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 9 of 74 
CONFIDENTIAL  
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 14 
1.1 
Primary ..................................................................................................... 14 
1.2 
Secondary ................................................................................................. 14 
1.3 
Safety ........................................................................................................ 14 
1.4 
Exploratory ................................................................................................ 14 
2. 
BACKGROUND AND RATIONALE ...................................................................... 14 
2.1 
Disease ..................................................................................................... 14 
2.2 
Etanercept (Enbrel) Background ............................................................. 14 
2.3 
Non-Amgen Medicinal Product Background:  Methotrexate ...................... 15 
2.4 
Rationale ................................................................................................... 15 
2.5 
Clinical Hypothesis .................................................................................... 17 
3. 
EXPERIMENTAL PLAN ........................................................................................ 17 
3.1 
Study Design ............................................................................................. 17 
3.1.1 
Rescue Therapy ........................................................................ 18 
3.1.2 
Disease Worsening ................................................................... 18 
3.2 
Number of Sites ........................................................................................ 19 
3.3 
Number of Subjects ................................................................................... 19 
3.4 
Replacement of Subjects .......................................................................... 19 
3.5 
Estimated Study Duration .......................................................................... 19 
3.5.1 
Study Duration for Subjects ....................................................... 19 
3.5.2 
End of Study .............................................................................. 19 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 20 
4.1 
Inclusion and Exclusion Criteria – Part 1 ................................................... 20 
4.1.1 
Inclusion Criteria – Part 1 .......................................................... 20 
4.1.2 
Exclusion Criteria – Part 1 ......................................................... 21 
4.2 
Inclusion and Exclusion Criteria – Part 2 ................................................... 24 
4.2.1 
Inclusion Criteria – Part 2 .......................................................... 24 
4.2.2 
Exclusion Criteria – Part 2 ......................................................... 24 
5. 
SUBJECT ENROLLMENT .................................................................................... 24 
5.1 
Randomization/Treatment Assignment ...................................................... 25 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 26 
6. 
TREATMENT PROCEDURES .............................................................................. 26 
6.1 
Classification of Products .......................................................................... 26 
6.2 
Investigational Product .............................................................................. 26 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 10 of 74 
CONFIDENTIAL  
 
 
6.2.1 
Amgen Investigational Product Etanercept ................................ 26 
6.2.1.1 
Dosage, Administration, and Schedule .................... 27 
6.2.2 
Non-Amgen Investigational Product:  Methotrexate ................... 27 
6.2.2.1 
Dosage, Administration, and Schedule .................... 28 
6.3 
Non-investigational Product ...................................................................... 28 
6.3.1 
Non-Amgen Non-investigational Product:  Folic Acid ................. 28 
6.3.1.1 
Dosage, Administration, and Schedule .................... 28 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules, Reporting, and 
Monitoring ................................................................................................. 29 
6.4.1 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 29 
6.4.2 
Hepatotoxicity Reporting and Monitoring ................................... 29 
6.4.3 
Criteria for Reporting Hepatotoxicity as a Serious 
Adverse Event ........................................................................... 29 
6.5 
Concomitant Therapy ................................................................................ 29 
6.5.1 
Analgesics and NSAIDs ............................................................ 30 
6.5.2 
Corticosteroids .......................................................................... 30 
6.5.3 
DMARDS ................................................................................... 30 
6.6 
Medical Devices ........................................................................................ 30 
6.7 
Product Complaints ................................................................................... 30 
6.8 
Excluded Treatments and/or Procedures During Study Period .................. 31 
6.9 
Contraceptive Requirements ..................................................................... 31 
7. 
STUDY PROCEDURES ....................................................................................... 33 
7.1 
Schedule of Assessments ......................................................................... 33 
7.2 
General Study Procedures ........................................................................ 36 
7.2.1 
Screening .................................................................................. 36 
7.2.2 
Re-screening ............................................................................. 36 
7.2.3 
Open Label Run-in Period ......................................................... 37 
7.2.4 
Early Termination Run-in ........................................................... 37 
7.2.5 
Baseline Visit (Day 1) ................................................................ 37 
7.2.6 
Treatment .................................................................................. 37 
7.2.7 
Disease Assessment Visit ......................................................... 37 
7.2.8 
Subject End of Treatment/Early Termination ............................. 38 
7.2.9 
Safety Follow-up/End of Study .................................................. 38 
7.3 
Description of Study Assessments and Procedures .................................. 38 
7.3.1 
Informed Consent ...................................................................... 38 
7.3.2 
Demographic Data..................................................................... 38 
7.3.3 
Medical History .......................................................................... 38 
7.3.4 
Medication History ..................................................................... 39 
7.3.5 
Physical Examination ................................................................ 39 
7.3.6 
Physical Measurement .............................................................. 39 
7.3.7 
Vital Signs ................................................................................. 39 
7.3.8 
Rheumatoid Arthritis Disease Assessments .............................. 39 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 11 of 74 
CONFIDENTIAL  
 
 
7.3.8.1 
Swollen/Tender Joint Counts ................................... 39 
7.3.8.2 
Physician Global Assessment of Disease 
Activity..................................................................... 40 
7.3.8.3 
Simplified Disease Activity Index (SDAI) ................. 40 
7.3.9 
Patient Reported Outcomes ...................................................... 40 
7.3.9.1 
Patient Global Assessment of Joint Pain ................. 40 
7.3.9.2 
Patient Global Assessment of Disease 
Activity..................................................................... 41 
7.3.9.3 
Disability Index of the Health Assessment 
Questionnaire .......................................................... 41 
7.3.9.4 
Medical Outcomes Short Form-36 
Questionnaire (SF-36) ............................................. 41 
7.4 
Laboratory Assessments ........................................................................... 41 
7.4.1 
Tuberculosis Testing ................................................................. 43 
7.4.1.1 
PPD ........................................................................ 43 
7.4.1.2 
Quantiferon ............................................................. 43 
7.4.2 
Erythrocyte Sedimentation Rate ................................................ 43 
7.4.3 
Urine Pregnancy Test ................................................................ 43 
7.5 
Biomarker Development ............................................................................ 43 
7.6 
Pharmacogenetic Studies ......................................................................... 44 
7.7 
Sample Storage and Destruction ............................................................... 44 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 45 
8.1 
Subjects’ Decision to Withdraw ................................................................. 45 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 46 
8.3 
Reasons for Removal From Run-in, Treatment, or Study .......................... 46 
8.3.1 
Reasons for Removal From Run-in ........................................... 46 
8.3.2 
Reasons for Removal From Treatment ...................................... 47 
8.3.3 
Reasons for Removal From Study ............................................. 47 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 47 
9.1 
Definition of Safety Events ........................................................................ 47 
9.1.1 
Adverse Events ......................................................................... 47 
9.1.2 
Serious Adverse Events ............................................................ 48 
9.2 
Safety Event Reporting Procedures .......................................................... 48 
9.2.1 
Adverse Events ......................................................................... 48 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 48 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 49 
9.3 
Pregnancy and Lactation Reporting .......................................................... 51 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 52 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 52 
10.1.1 
Study Endpoints ........................................................................ 52 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 12 of 74 
CONFIDENTIAL  
 
 
10.1.1.1 
Primary Endpoint ..................................................... 52 
10.1.1.2 
Secondary Endpoints .............................................. 52 
10.1.1.3 
Safety Endpoints ..................................................... 52 
10.1.1.4 
Exploratory Endpoints ............................................. 52 
10.1.2 
Analysis Sets ............................................................................. 53 
10.1.2.1 
Primary Analysis Set ............................................... 53 
10.1.2.2 
Safety Analysis Set ................................................. 53 
10.1.3 
Covariates and Subgroups ........................................................ 53 
10.2 
Sample Size Considerations ..................................................................... 53 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 54 
10.4 
Planned Analyses ..................................................................................... 55 
10.4.1 
Primary analysis ........................................................................ 55 
10.4.2 
Interim Analyses ........................................................................ 55 
10.5 
Planned Methods of Analysis .................................................................... 55 
10.5.1 
General Considerations ............................................................. 55 
10.5.2 
Primary Efficacy Endpoint .......................................................... 55 
10.5.3 
Secondary Efficacy Endpoints ................................................... 56 
10.5.4 
Exploratory Endpoints ............................................................... 56 
10.5.5 
Safety Endpoints ....................................................................... 56 
11. 
REGULATORY OBLIGATIONS ............................................................................ 57 
11.1 
Informed Consent ...................................................................................... 57 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 57 
11.3 
Subject Confidentiality ............................................................................... 58 
11.4 
Investigator Signatory Obligations ............................................................. 58 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 59 
12.1 
Protocol Amendments and Study Termination .......................................... 59 
12.2 
Study Documentation and Archive ............................................................ 59 
12.3 
Study Monitoring and Data Collection ....................................................... 60 
12.4 
Investigator Responsibilities for Data Collection ........................................ 61 
12.5 
Language .................................................................................................. 61 
12.6 
Publication Policy ...................................................................................... 62 
12.7 
Compensation ........................................................................................... 63 
13. 
REFERENCES ..................................................................................................... 64 
14. 
APPENDICES ...................................................................................................... 65 
List of Tables 
Table 1.  Schedule of Assessments ............................................................................... 34 
Table 2.  Analyte Listing ................................................................................................ 42 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 13 of 74 
CONFIDENTIAL  
 
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 66 
Appendix B.  eSerious Adverse Event Contingency Form ............................................. 70 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 73 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 14 of 74 
CONFIDENTIAL  
 
 
1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the efficacy of etanercept monotherapy compared to methotrexate 
monotherapy on maintenance of remission in subjects with rheumatoid arthritis (RA) who 
were on etanercept plus methotrexate combination therapy. 
1.2 
Secondary 
To evaluate the efficacy of etanercept plus methotrexate therapy compared to 
methotrexate monotherapy on maintenance of remission 
To evaluate the efficacy of 1) etanercept monotherapy compared to methotrexate 
monotherapy and 2) etanercept plus methotrexate therapy compared to methotrexate 
monotherapy on: 
• 
disease activity 
• 
disease worsening and time to disease worsening 
• 
remission and time to recapture remission after rescue treatment 
1.3 
Safety 
To evaluate the safety of etanercept and methotrexate 
1.4 
Exploratory 
• 
To evaluate Patient Reported Outcomes (PRO) 
• 
To investigate potential biomarkers of disease activity and response to etanercept. 
• 
To investigate the effects of genetic variation in disease genes and drug target genes 
on RA and/or subject response to etanercept.  
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
RA is a chronic, systemic, autoimmune, inflammatory disease of unknown etiology that 
primarily affects the joints.  Symptoms include joint stiffness, pain, and swelling that can 
progress to deformities and loss of function of both small and large joints.  RA occurs in 
approximately 1% of adults worldwide in all races.  Disease onset occurs most often 
between the ages of 20 and 60 years, with peak occurrence at 40 to 45 years.  The 
prevalence of RA increases with age in both sexes, and prevalence is higher in women 
than men, with a ratio of approximately 2.5 to 1.0 (Alamanos et al, 2006).  
2.2 
Etanercept (Enbrel) Background 
Tumor Necrosis Factor (TNF) is a naturally occurring cytokine that is involved in normal 
inflammatory and immune responses.  It plays a role in the inflammatory process of 


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plaque psoriasis.  Elevated levels of TNF are found in involved tissues and fluids of 
patients with RA, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.  
Two distinct receptors for TNF, a 55 kilodalton protein (p55) and a 75 kilodalton protein 
(p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms.  
Biological activity of TNF is dependent upon binding to either cell surface TNF receptor.  
Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind 
TNF molecules.  Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha 
[LT-α]) to cell surface TNFRs, rendering TNF biologically inactive. 
In many countries, etanercept is indicated for the treatment of:  (1) moderately to 
severely active RA; (2) moderately to severely active polyarticular juvenile idiopathic 
arthritis in patients aged 2 and older; (3) psoriatic arthritis; (4) active ankylosing 
spondylitis; and (5) adult patients with chronic moderate to severe plaque psoriasis.  
Refer to the specific section of the investigational brochure or product label for additional 
information related to the physical, chemical, and pharmaceutical properties and 
formulation(s). 
2.3 
Non-Amgen Medicinal Product Background:  Methotrexate 
Methotrexate inhibits dihydrofolic acid reductase and interferes with DNA synthesis, 
repair, and cellular replication.  Its efficacy in RA is well-established and is traditionally 
used as a first line agent for RA treatment.  Although methotrexate is effective, many 
patients continue to have active disease despite maximum dose therapy.  Methotrexate 
can also be used in combination with other Disease Modifying Antirheumatic Drug 
(DMARD) including etanercept.  The combination of methotrexate and etanercept for 
treatment of RA is well-established. 
Refer to the regional manufacturer package insert for additional information. 
2.4 
Rationale 
Etanercept has become a well-established agent in the management of RA.  It can be 
used either as monotherapy or in combination with methotrexate to treat RA.  Etanercept 
is commonly used in combination therapy after monotherapy with a first line agent such 
as methotrexate has failed.  Patients report lower disease activity and improved quality 
of life with the incorporation of etanercept into their traditional DMARD therapies 
(Klareskog et al, 2004). 
Recent studies including PRIZE (Emery et al, 2012), PRESERVE (Smolen et al, 2013), 
and DOSERA (van Vollenhoven et al, 2013a), have characterized the role of etanercept 


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on inducing and maintaining low disease activity in RA subjects.  Importantly, these 
studies demonstrated that a significantly greater proportion of subjects taking 
combination etanercept plus methotrexate therapy are able to maintain low disease 
states compared to subjects taking methotrexate alone.  The DOSERA study importantly 
demonstrated that most patients whose disease activity worsens after drug withdrawal 
are able to return to low disease activity (van Vollenhoven et al, 2013b). 
Other studies provide insights regarding the role of etanercept as monotherapy in the 
maintenance of low disease states.  In the COMET study (Emery et al, 2010) subjects 
who achieved DAS-28 remission on combination etanercept plus methotrexate were 
randomized to continue the combination therapy or to discontinue methotrexate and be 
treated with etanercept alone for one year.  There was a numerically greater decrease in 
the percentage of subjects who maintained remission in the etanercept arm compared to 
the combination arm but the differences were relatively minor.  In the CAMEO study, 
subjects with active RA were treated for 6 months with combination etanercept plus 
methotrexate (Pope et al, 2013).  After 6 months the patients were randomized to 
continue on the combination or to be treated with etanercept monotherapy for the next 
18 months.  In patients who achieved low disease activity (DAS-28-ESR < 3.2) at 
month 6, the disease activity at 24 months was similar whether they discontinued 
methotrexate or remained on combination therapy.  Combination treatment led to lower 
disease activity scores compared to etanercept monotherapy, however, in subjects with 
moderate to high disease activity at randomization (DAS-28-ESR > 3.2).  
Collectively, these studies have shown that etanercept may be required to maintain 
disease control and that etanercept may be sufficient as monotherapy in maintaining 
good disease control.  Sustained disease remission with etanercept alone could 
potentially lead to a reduction in polypharmacy and undesired side effects. 
There are some caveats to these study results that merit consideration.  In the clinical 
practice setting, drug reduction, whether etanercept or methotrexate, would most likely 
be considered in those patients who have been in good disease control for at least one 
year in duration.  The clinical trials described above, with the exception of DOSERA 
which was limited by its small size, were designed to reduce or withdraw etanercept 
and/or methotrexate soon or just after inducing the target low disease state.  Duration of 
good disease control may be a factor that contributes to the proportion of subjects who 
maintain low disease after drug reduction.  Also, there were differences in the trials on 
the key low disease activity target for maintenance including DAS-28 Low Disease 


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Activity (LDA) and DAS-28 remission.  Recently, the FDA released a draft guidance 
document for developing drug products for the treatment of RA (Guidance for Industry 
Rheumatoid Arthritis:  Developing Drug Products for Treatment May 2013) which 
suggested the use of the American College of Rheumatology/European League Against 
Rheumatism criteria for remission.  The criteria include Simplified Disease Activity Index 
(SDAI) remission (SDAI < 3.3) which is a more stringent measurement of remission 
compared to DAS-28 remission.  SDAI is considered a clinically meaningful and an 
achievable target disease activity state for maintenance of disease control.   
The present study will evaluate the effectiveness of three separate treatment regimens 
on maintaining remission of RA in patients who are well controlled and receiving 
etanercept plus methotrexate therapy for at least 12 months prior to randomization.  The 
three treatment arms include, etanercept monotherapy, methotrexate monotherapy and 
combination etanercept plus methotrexate therapy.  Subjects who fail to maintain 
remission and have a meaningful increase in the SDAI score during the randomized 
treatment period of the trial will be rescued in a blinded fashion with combination 
etanercept plus methotrexate therapy. 
2.5 
Clinical Hypothesis 
Etanercept monotherapy is superior to methotrexate monotherapy for maintaining 
remission in subjects with RA who were on etanercept plus methotrexate therapy.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 3, multicenter, randomized withdrawal, double-blind controlled study in 
subjects with RA on etanercept plus methotrexate who are in very good disease control 
for 6 months prior to study entry.  The study will consist of a 30-day screening period, a 
24-week open-label run-in period, a 48-week double-blind treatment period and a 30-day 
safety follow-up period. 
The study will enroll approximately 358 subjects.  During the run-in period subjects will 
receive open-label etanercept and methotrexate at the same dose they were receiving 
during screening.  It is expected that approximately 30% of subjects will early terminate 
the run-in period.  Amgen may choose to alter the sample size of subjects enrolled in 
order to ensure that approximately 250 subjects are randomized to treatment.  


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Approximately 250 subjects will be randomly assigned in a 2:2:1 ratio to one of three 
treatment groups: 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral placebo for 
methotrexate (n = 100) 
• 
Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept (n = 100) 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 
25 mg weekly (n = 50) 
Subjects randomized to the etanercept plus methotrexate group and the methotrexate 
monotherapy group will receive methotrexate at the same dose they were receiving at 
screening and during the run-in period.  
3.1.1 
Rescue Therapy 
After randomization, if a subject experiences disease worsening as defined below 
he/she will initiate rescue treatment with etanercept 50 mg once weekly (QW) plus 
methotrexate (10 to 25 mg).  Those assigned to the etanercept plus methotrexate arm 
will continue on the assigned treatments.  Subjects will receive methotrexate at the same 
dose that they were receiving at screening. 
Original treatment assignments will remain blinded.  Dispensing of etanercept plus 
methotrexate rescue therapy will be managed via the Interactive Voice and Web 
Response System (IXRS). 
3.1.2 
Disease Worsening 
After randomization, disease worsening for the study is defined as: 
• 
SDAI > 3.3 and ≤ 11 on two consecutive visits at least two weeks apart OR  
• 
SDAI > 3.3 and ≤ 11 on three or more separate visits OR 
• 
SDAI > 11 at anytime 
Disease worsening may be assessed at a regularly scheduled visit or at a Disease 
Assessment visit as described in Section 7.2.7.  If subject meets the criteria for disease 
worsening then new investigational product will be re-dispensed in a blinded fashion.  
Subjects will remain on study and complete all study visits as per the Schedule of 
Assessments (Table 1). 
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. 


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3.2 
Number of Sites 
Approximately 105 sites globally will participate in the study.  Additional regions and 
sites may be added if necessary.  Sites that do not enroll subjects within 3 months of site 
initiation may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
The number of subjects expected to be enrolled in the study is approximately 358 of 
which approximately 250 will be randomized to the double-blind treatment period.   
Amgen may choose to alter the sample size of enrolled subjects to ensure that 
approximately 250 subjects are randomized to the double-blind treatment period. 
Sample size considerations are provided in Section 10.2. 
3.4 
Replacement of Subjects 
During the double blind-treatment period, subjects who are removed from treatment or 
from the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The study will consist of up to a 30-day screening, a 24-week open label run-in period, a 
48-week double-blind treatment period, and a 30-day safety follow-up period.  The 
maximal duration of trial participation for an individual subject is approximately 82 weeks 
including the screening, run-in period, treatment period and safety follow-up.  
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. 
If the study concludes prior to the primary completion date originally planned in 
the protocol (ie, early termination of the study), then the primary completion will 
be the date when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study 


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(ie, last subject last visit), following any additional parts in the study 
(eg, long-term follow-up), as applicable. 
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).  Part 1 eligibility criteria will be evaluated during screening.  Part 2 eligibility 
criteria will be evaluated during the run-in period in subjects that successfully meet 
Part 1 eligibility criteria (see Section 5.  Subject Enrollment).  
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion and Exclusion Criteria – Part 1 
4.1.1 
Inclusion Criteria – Part 1 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
≥ 18 years of age at screening 
103 
A history of RA consistent with the 2010 American College of 
Rheumatology/European League Against Rheumatism classification criteria 
104 
History of moderate to severe RA in the opinion of the investigator 
105 
In very good RA disease control for  ≥ 6 months in the opinion of the investigator  
106 
SDAI ≤ 3.3 at screening 
107 
Receiving treatment with etanercept 50 mg per week for RA for ≥ 6 months prior 
to run-in visit 1 
108 
Receiving treatment with methotrexate dose of 10 mg to 25 mg weekly for 
≥ 6 months AND on a stable dose of oral methotrexate for ≥ 8 weeks prior to 
run-in visit 1.  If subject is taking subcutaneous methotrexate they must switch to 
an equivalent oral methotrexate dose of 10 mg to 25 mg weekly and remain on a 
stable oral dose ≥ 8 weeks prior to run-in visit 1. 
109 
May be receiving a stable dose of  ≤ 5 mg oral prednisone or prednisone 
equivalent per day and the dose must be stable for ≥ 4 weeks prior to run-in 
visit 1 
110 
May be receiving a stable dose of sulfasalazine, hydroxychloroquine, minocycline 
and the dose must be stable for ≥ 8 weeks prior to run-in visit 1 
111 
If subject is receiving continuous treatment with acetaminophen, non-steroidal 
anti-inflammatory drug (NSAID) or tramadol, hydrocodone, oxycodone, codeine,  
and/or propoxyphene the dose must be stable for ≥ 4 weeks prior to run-in visit 1 
112 
Negative test for hepatitis B surface antigen, hepatitis B core antibody and 
hepatitis C antibody at screening 


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113 
Subject if female and not at least 2 years postmenopausal or history of 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, has a negative 
serum pregnancy test ≤ 4-weeks prior to run-in visit 1.  
114 
No known history of active tuberculosis 
115 
National guidelines should be followed for appropriate tuberculosis screening in 
the setting of anti-TNF therapy, including a minimum of:  
• 
Subject has a negative test for tuberculosis during screening defined as 
either: 
• 
negative purified protein derivative (PPD) (< 5 mm of induration at 
48 to 72 hours after test is placed) OR 
• 
negative Quantiferon test 
Subjects with a positive PPD and a history of bacillus Calmette-Guérin 
vaccination are allowed with a negative Quantiferon test. 
Subjects with a positive PPD test (without a history of bacillus 
Calmette-Guérin vaccination) or subjects with a positive or indeterminate 
Quantiferon test are allowed if they have all of the following:   
• 
no symptoms, per tuberculosis worksheet provided by Amgen 
• 
documented history of a completed course of adequate treatment or 
prophylaxis (per local standard of care) prior to the start of investigational 
product 
• 
no known exposure to a case of active tuberculosis after most recent 
prophylaxis  
• 
no evidence of active tuberculosis on chest radiograph within 3 months 
prior to the first dose of investigational product 
4.1.2 
Exclusion Criteria – Part 1 
RA Related 
201 
Subject is diagnosed with Felty’s syndrome (RA, splenomegaly and 
granulocytopenia) 
Other Medical Conditions 
202 
Subject has known history of alcoholic hepatitis, nonalcoholic steatohepatitis or 
immunodeficiency syndromes, including Human Immunodeficiency Virus 
infection. 
203 
Subject has any active infection (including chronic or localized infections) for 
which anti-infectives were indicated within 4 weeks prior to run-in visit 1. 
204 
Subject has a serious infection, defined as requiring hospitalization or 
intravenous anti-infectives within 8 weeks prior to run-in visit 1. 


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205 
Subject had prosthetic joint infection within 5 years of screening or native joint 
infection within 1 year of screening. 
206 
Subject has known alcohol addiction or dependency, uses alcohol daily, or has 
current substance use or abuse. 
207 
Subject has one or more significant concurrent medical conditions per 
investigator judgment, including the following: 
• 
poorly controlled diabetes 
• 
chronic kidney disease stage IIIb, IV, or V 
• 
symptomatic heart failure (New York Heart Association class II, III, or IV) 
• 
myocardial infarction or unstable angina pectoris within the past 
12 months prior to randomization 
• 
uncontrolled hypertension 
• 
severe chronic pulmonary disease (eg, requiring oxygen therapy) 
• 
multiple sclerosis or any other demyelinating disease 
• 
major chronic inflammatory disease or connective tissue disease other 
than RA (eg, systemic lupus erythematosus with the exception of 
secondary Sjögren’s syndrome) 
Excluded Medications 
208 
Subject is currently receiving or had treatment ≤ 6 months with 
cyclophosphamide, chlorambucil, nitrogen mustard, or any other alkylating agent. 
209 
Subject has used biologic DMARD (including anakinra and abatacept) other than 
etanercept OR has used an oral janus kinase inhibitor ≤ 6 months prior to run-in 
visit 1 
210 
Subject has used any of the following ≤ 6 months prior to run-in visit 1:  
• 
azathioprine 
• 
cyclosporine 
• 
gold 
• 
mycophenolate mofetil 
• 
Prosorba column 
• 
Systemic tacrolimus 
211 
Subject has used leflunomide ≤ 8 weeks prior to run-in visit 1 
212 
Subject has used any of the following ≤ 4 weeks prior to run-in visit 1:  
• 
intraarticular, intramuscular or intravenous corticosteroids, including 
adrenocorticotropic hormone 
• 
intraarticular hyaluronic acid injections 
• 
live vaccines 


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213 
For subjects not on continuous analgesics, subject has taken the following within 
12 hours prior to screening:  acetaminophen, NSAIDs, hydrocodone, codeine, 
tramadol, propoxyphene and/or oxycodone (unless in the form of oxycontin).  For 
subjects not on continuous analgesics, subject has taken oxycontin within 
24 hours prior to screening. 
Laboratory Abnormalities 
215 
Subject has any other laboratory abnormality, which, in the opinion of the 
investigator poses a safety risk, will prevent the subject from completing the 
study, or will interfere with the interpretation of the study results. 
230 
Subject has laboratory abnormalities during screening, including the following: 
• 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
> 2 x the upper limit of normal (ULN).  If the AST and/or ALT value is 
between 1.5 and 2 x the ULN without a documented etiology of 
aminotransferase elevation or without a history of stable elevated 
aminotransferase for at least 3 months prior to screening. 
• 
Platelet count < 125,000/mm3 
• 
White blood cell count < 3,000 cells/mm3 
• 
Absolute neutrophil count < 1500/mm3 
• 
Estimated creatinine clearance < 30 mL/min (Cockroft-Gault formula, 
calculated value to be provided to sites.  If the estimated creatinine 
clearance is between 30 and 50 mL/min (Cockroft-Gault formula, 
calculated value to be provided to sites) without a documented etiology 
for reduced creatinine clearance or without a 3-month history of stable 
creatinine clearance prior to screening. 
Other 
217 
Other investigational procedures while participating in this study are excluded. 
218 
Female subject is not willing to use highly-effective methods of birth control 
during treatment and for 6 months after the end of treatment (except if at least 
2 years postmenopausal or surgically sterile [hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy] or has had a bilateral tubal ligation). 
219 
Male subject with a partner of child-bearing potential is not willing to use a 
condom during treatment and for 6 months after the end of treatment (except for 
men who are surgically sterile).   
220 
Male subject with a pregnant partner, who is not willing to use a condom to 
prevent exposure of the fetus to semen during treatment and for 6 months after 
the end of treatment.   
221 
Subject is pregnant or breastfeeding, or planning to become pregnant or 
breastfeed while enrolled in the study, up to the subject’s last visit and for 
6 months after the end of treatment. 


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222 
Malignancy, except adequately treated non-melanoma skin cancers, cervical or 
breast ductal carcinoma in situ with no evidence of disease within the last 
5 years. 
223 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
224 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Patient 
Reported Outcomes [PROs]) to the best of the subject’s and investigator’s 
knowledge.  
225 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures, or completion. 
226 
Subject previously has enrolled in this study 
231 
Currently receiving treatment with an investigational device or drug product, or 
< 30 days since ending treatment with an investigational device or drug product 
that is not commercially available. 
4.2 
Inclusion and Exclusion Criteria – Part 2 
4.2.1 
Inclusion Criteria – Part 2 
116 
SDAI ≤ 3.3 at run-in visit 3 
117 
Subject if female and not at least 2 years postmenopausal or history of 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, has a negative 
urine pregnancy test at baseline (day 1).  
4.2.2 
Exclusion Criteria – Part 2 
227 
Any clinically significant change in the Part 1 eligibility criteria during the run-in 
period 
228 
SDAI  > 3.3 and ≤ 11 on two consecutive visits at least two weeks apart OR 
SDAI > 3.3 and ≤ 11 on two or more separate visits OR SDAI > 11 at any time 
during the run-in period 
229 
Subject has a clinically significant laboratory abnormality during run-in period 
which in the opinion of the investigator poses a safety risk, will prevent the 
subject from completing the study, or will interfere with the interpretation of the 
study results during the run-in period. 
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 


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subjects must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures.   
A subject is considered enrolled when the investigator decides that the subject has met 
all Part 1 eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and register enrollment in the IXRS.  Additionally, it is the 
responsibility of the investigator to record the current protocol version each subject 
enrolled under. 
Upon completion of run-in period procedures the subject is evaluated by the investigator, 
and if the subject meets all Part 2 eligibility criteria he/she is subsequently randomized to 
a treatment regimen.  Subjects who do not meet Part 2 eligibility criteria will complete an 
early termination run-in visit. 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number, assigned by IXRS, will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject.  The subject identification number must remain constant throughout the entire 
clinical study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
Subjects not meeting Part 1 eligibility criteria are permitted to re-screen up to 
2 additional times after failing the first screening. 
5.1 
Randomization/Treatment Assignment 
Subjects who meet Part 2 eligibility criteria will be randomized to receive etanercept plus 
placebo for methotrexate, methotrexate plus placebo for etanercept or etanercept plus 
methotrexate in a 2:2:1 ratio via IXRS.   
Assignment to the treatment arms will be based on a computer-generated randomization 
schedule prepared by Amgen before the start of the study.  Each randomized subject will 
receive a single, unique randomization number via IXRS at randomization.  The 
randomization date is to be documented in the subject’s medical record as registered in 
the IXRS.  


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5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  In the 
event that a subject’s treatment assignment must be unblinded by the investigator the 
subject will not be allowed to receive any further investigational product.  Refer to the 
Investigational Product Instruction Manual (IPIM) for a description regarding how 
responsible pharmacists and investigators will access treatment information via IXRS in 
the event that there is a need to break the treatment blind. 
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The investigator is strongly encouraged to contact the Amgen Global Clinical Trial 
Manager before unblinding any subject’s treatment assignment.  If not possible, the 
investigator must inform the Amgen Global Clinical Trial Manager within 1 working day 
after the event. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products 
The Amgen Investigational Product(s) (except if required by local regulation) used in this 
study include(s):  etanercept or placebo for etanercept 
The Non-Amgen Investigational product(s) used in this study include(s):  methotrexate or 
placebo for methotrexate.  
The non-Amgen non-investigational product used in this study includes:  folic acid. 
The IPIM, a document external to this protocol, contains detailed information regarding 
the storage, preparation, and administration of etanercept, methotrexate, and folic acid.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product Etanercept 
Etanercept will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.  Etanercept will be supplied in a 
single-use pre-filled 1mL syringe as a sterile, preservative-free solution for subcutaneous 
injection.  The solution of etanercept is clear and colorless and is formulated at 
pH 6.3 ± 0.2.  Each single-use prefilled syringe (PFS) contains 0.98 mL of 50 mg/mL 
etanercept in a formulation consisting of 100 mM sodium chloride, 25 mM sodium 
phosphate, 25 mM L-arginine-HCl, and 1% sucrose.  Etanercept will be provided with 
4-syringes to a pack.  Placebo will be presented in identical containers and 
stored/packaged the same as etanercept. 


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6.2.1.1 
Dosage, Administration, and Schedule 
Etanercept dosing in the study will follow the recommended label dosing for subjects 
with RA (subcutaneous injection, 50 mg once weekly).  Etanercept will be provided as a 
50-mg PFS (0.98 mL of a 50- mg/mL solution of etanercept).  Each dose of 
investigational product will consist of the complete contents of 1 syringe.  The injection 
site should be rotated with each dose.  During the open-label run-in period subjects will 
receive 1 dose of etanercept per week (scheduled approximately 7 days apart) for 
24 weeks.  During the double-blind treatment period, subjects will receive 1 dose of 
etanercept or matching placebo per week (scheduled approximately 7 days apart) for 
48 weeks.  Throughout the entire trial, administration of etanercept should occur on the 
scheduled dose day; however, if unavoidable, it may be given earlier or later as long as 
the dose is not within 2 days of the next scheduled dose.  If the dosing window is 
missed, that dose should be skipped and the reason for the missed dose must be 
reported on the case report form.  Subsequent doses of investigational product should 
resume on the original schedule, calculated from the run-in visit 1 for the open label 
run-in period of the study and from Day 1 for the double-blind treatment period.  If 
etanercept is to be taken the day of a study visit, it must be taken after the study visit has 
occurred (ie, at the subject’s location on the scheduled dose day).  Injections of 
etanercept will be administered by the subject or a caregiver.  The individual 
administering the dose must demonstrate to the site staff that he or she is competent to 
correctly administer the subcutaneous doses.  The first dose of etanercept in the open 
label run-in period and Day 1 in the double-blind treatment period must be administered 
at the study site.  All subsequent doses will be administered at the subject’s location on 
the scheduled dose day.  Supplies of etanercept will be dispensed to subjects for 
administration at home.  The site will instruct the subject in appropriate handling and 
storage of used and unused syringes and documentation of dosing in the subject diary.  
The dose date, quantity administered and box number of investigational product are to 
be recorded in each subject’s diary/ electronic case report form (eCRF).  Please refer to 
the Investigator’s Brochure for the most recent safety information.  A link to the United 
States Prescribing Information can be found in the Investigator’s Brochure. 
6.2.2 
Non-Amgen Investigational Product:  Methotrexate 
Non-Amgen investigational product methotrexate will also be used in this study.  
Methotrexate will be distributed using Amgen clinical trial drug distribution procedures.  
Methotrexate will be supplied as 2.5 mg methotrexate tablets, capsules, or as matching 
placebo capsules. 


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Additional details regarding the product(s) are provided in the IPIM. 
6.2.2.1 
Dosage, Administration, and Schedule 
Methotrexate dosing in the study will be 10 to 25 mg weekly, consistent with the 
subject’s dosing prior to screening.   
During the open-label run-in period, methotrexate will be provided as 2.5 mg tablets and 
will be taken once weekly by oral administration.  Subjects will receive 1 dose of 
open-label methotrexate per week (scheduled approximately 7 days apart) for 24 weeks.  
Subjects will remain on the same dose of methotrexate that they were receiving at 
screening.   
During the double-blind treatment period, methotrexate will be provided as 
2.5 mg capsules, or as placebo capsules, and will be taken once weekly by oral 
administration.  Subjects will receive 1 dose of methotrexate or placebo per week 
(scheduled approximately 7 days apart) for 48 weeks.  Subjects randomized to 
etanercept plus methotrexate therapy or methotrexate monotherapy arm will remain on 
the same dose that they were receiving at screening/run-in. 
Throughout the entire trial, administration of methotrexate or matching placebo should 
occur on the scheduled dose day; however, if unavoidable, it may be given earlier or 
later as long as the dose is not within 4 days of the next scheduled dose.  If the dosing 
window is missed, that dose should be skipped and the next dose should be resumed at 
the scheduled time.  The reason for the missed dose must be reported on the case 
report form.  Double or extra doses should not be taken.  The dose date, quantity 
administered and bottle number of methotrexate is to be recorded on the subject’s diary 
and entered into the eCRF. 
6.3 
Non-investigational Product 
6.3.1 
Non-Amgen Non-investigational Product:  Folic Acid 
Folic acid will be sourced by the site.  Additional details regarding the product are 
provided in the IPIM. 
6.3.1.1 
Dosage, Administration, and Schedule 
The dose of folic acid will be 5 to 7 mg per week as per investigator judgment or 
according to local standard of care.  The dose of folic acid may be adjusted in response 
to methotrexate-related toxicity. 


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6.4 
Hepatotoxicity Stopping and Rechallenge Rules, Reporting, and 
Monitoring 
A United States Food and Drug Administration Guidance exists for drug-induced liver 
injury (Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009).  This guidance is general for all investigational products, and its 
recommendations can be found in Appendix A. 
6.4.1 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, and total bilirubin [TBL]) and/or signs/symptoms of hepatitis (as described below) 
may meet the criteria for withholding of Amgen investigational product or other 
protocol-required therapies as specified in the Guidance for Industry Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation, July 2009.  Criteria for permanent or 
conditional withholding of investigational product in the event that a subject develops 
signs or symptoms of hepatitis during a clinical trial is provided in Appendix A.  Criteria 
for rechallenge of Amgen investigational product and other protocol required therapies 
after potential hepatotoxicity is provided in Appendix A.  
6.4.2 
Hepatotoxicity Reporting and Monitoring 
Subjects with abnormal hepatic laboratory values (eg, ALP, AST, ALT, TBL, or 
signs/symptoms of hepatitis) may require follow-up, depending upon the clinical 
circumstances discussed below (as specified in the Guidance for Industry Drug-Induced 
Liver Injury:  Premarketing Clinical Evaluation, July 2009). 
6.4.3 
Criteria for Reporting Hepatotoxicity as a Serious Adverse Event 
Subjects who have TBL > 2 x ULN and AST or ALT > 3 x ULN must have the event 
submitted to Amgen as a serious adverse event within 24 hours following the 
investigator’s knowledge of the event (ie, before additional etiologic investigations have 
been concluded).  
Additional clinical assessments and observations in subjects who experience AST or 
ALT elevations > 3 x ULN will be performed until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments to be performed during this period are outlined 
in Appendix A. 
6.5 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 


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Concomitant therapies are to be collected in the eCRF from signing of the informed 
consent through the end of study.  Collect therapy name, indication, dose, unit, 
frequency, route, start date, and stop date. 
6.5.1 
Analgesics and NSAIDs 
If the study subject enters the study taking acetaminophen, narcotic analgesics, or 
NSAIDs on a scheduled basis or as needed, the dose can be reduced or discontinued 
during the study if necessary for safety reasons or standard of care.   
If the study subject is not taking acetaminophen, narcotic analgesics, or NSAIDs prior to 
entering the study and they take any of these agents for reasons related to RA, they may 
take these agents but must be seen at a regularly scheduled visit or a Disease 
Assessment visit (Section 7.2.7) no later than 1 week after commencing treatment.  
Analgesics and NSAIDs should not be taken for more than 2 weeks at a time.   
If at any time the subject is taking acetaminophen, narcotic analgesics or NSAIDs these 
must not be used within 12 hours before a scheduled study visit, with the exception of 
oxycontin which may not be used within 24 hours of a scheduled study visit. 
6.5.2 
Corticosteroids 
Subjects entering the study while taking oral corticosteroids cannot exceed the dose of 
5 mg of prednisone or equivalent daily.  The investigator may prescribe corticosteroids at 
a regularly scheduled visit or Disease Assessment visit (Section 7.2.7) if the subject is 
experiencing increased disease activity.  However, any increase in dose or treatment 
with corticosteroids for increased disease activity must not exceed 2-weeks. 
6.5.3 
DMARDS 
Subjects taking sulfasalazine (not to exceed 3 g/day) and/or hydroxychloroquine (not to 
exceed 400 mg/day) must remain on a stable dose throughout the study. 
6.6 
Medical Devices 
Medical devices (eg, alcohol prep pads), that are commercially available are not usually 
provided or reimbursed by Amgen (except, for example, if required by local regulation).  
The investigator will be responsible for obtaining supplies of these devices.   
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 any investigational or non-investigational product(s) or device(s). 


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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. 
6.8 
Excluded Treatments and/or Procedures During Study Period  
Proscribed medications during this study include the following: 
• 
Anakinra 
• 
Abatacept 
• 
Any other investigational agents or commercially available biologics 
• 
Azathioprine 
• 
Leflunomide 
• 
Cyclosporine 
• 
Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or 
other alkylating agents 
• 
Gold 
• 
Intraarticular, intramuscular, or intravenous corticosteroids, including 
adrenocorticotropic hormone 
• 
Intraarticular hyaluronic acid injections 
• 
Mycophenolate mofetil  
• 
Prosorba Column 
• 
Systemic tacrolimus 
• 
Live vaccines 
6.9 
Contraceptive Requirements 
Female Subjects 
Female subjects of child-bearing potential must agree to practice true sexual abstinence 
(refrain from heterosexual intercourse) or use a highly effective method of contraception 
during treatment and for an additional 6 months after the last dose of protocol required 
therapies. 
Contraceptive methods that achieve a failure rate less of less than 1% per year when 
used consistently and correctly are considered highly effective and may include:  
hormonal (combined estrogen and progestogen or progestogen only), contraception 
associated with inhibition of ovulation (oral, injectable, implantable, intravaginal, or 
transdermal route), intrauterine device, intrauterine hormonal-releasing system, bilateral 
tubal occlusion, vasectomized partner (provided that partner is the sole sexual partner of 
the female participant and the vasectomized partner has received medical assessment 
of the surgical success), true sexual abstinence when this is in line with the preferred 


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and usual lifestyle of the subject.  The reliability of sexual abstinence must be evaluated 
by the investigator and be the preferred and usual lifestyle of the subject.   
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed.   
Females not of child-bearing potential are defined as:  any female who has had a 
hysterectomy, OR bilateral salpingectomy, OR bilateral oophorectomy, OR are 
postmenopausal.  Postmenopausal women are those who have had no spontaneous 
menses for at least 2 years. 
Male Subjects 
Male subjects who have had a vasectomy and received medical assessment of surgical 
success or whose female partner has had a bilateral tubal occlusion are not required to 
use additional forms of contraception.   
Otherwise, male subjects with a partner of child-bearing potential must agree to practice 
true sexual abstinence (refrain from heterosexual intercourse) or use a condom with 
spermicide (if spermicide is commercially available) during treatment and for an 
additional 6 months after the last dose of protocol required therapies.  The reliability of 
sexual abstinence must be evaluated by the investigator and be the preferred and usual 
lifestyle of the subject.   
The female partner should also consider using an acceptable method of effective 
contraction such as:  hormonal, intrauterine device, intrauterine hormonal-releasing 
system, female barrier method (diaphragm, cervical cap, contraceptive sponge; a female 
condom is not an option because there is a risk of tearing when both partners use a 
condom). 
Male subjects with a pregnant partner must practice sexual abstinence or wear a 
condom to prevent exposure of the unborn child to methotrexate through semen. 
Unacceptable methods of birth control for male and female subjects include birth control 
methods that are considered unacceptable in clinical trials and include:  periodic 
abstinence (calendar, symptothermal, postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method. 


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7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 can 
only be performed after obtaining informed consent.  This includes any discontinuation of 
the subject’s medication for the purpose of participation in this study. 
All on-study visits during the run-in period should be scheduled from run-in visit 1.  All 
on-study visits during the treatment period should be scheduled from day 1 (date of the 
first dose of investigational product) on the study.  It is very important to attempt to 
perform study procedures and obtain samples at the precise timepoints stipulated below.  
When it is not possible to perform the study visit at the exact timepoint, the visit may be 
performed within the acceptable visit window as defined in the visit-specific section 
below. 
With the exception of the screening and re-screen visits, all study procedures for a visit 
should be completed on the same day.  Any missed visits, tests not done, or 
examinations that are not conducted must be reported as such on the eCRFs.  
Subsequent study visits should resume on the original schedule.  Missed assessments 
at prior visits should not be duplicated at subsequent visits.  
Any blood sample collected according to the Schedule of Assessments (Table 1) may be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
ensure subject safety.  This includes testing to ensure analytical methods produce 
reliable and valid data throughout the course of the study.  This may also include, but is 
not limited to, investigation of unexpected results, incurred sample reanalysis, and 
analysis for method transfer and comparability.  Refer to the applicable supplemental 
laboratory manuals for detailed collection and handling procedures. 
7.1 
Schedule of Assessments  


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Table 1.  Schedule of Assessments 
 
30-day Screening 
Open-Label Run-in Periodh 
Double Blind Treatment Periodg 
 
Follow-Up 
Weeks 
 
Run-in 
Visit 1 
Run-in 
visit 2 
Run-in 
visit 3 
Run-in 
ET 
0g 
12 
24 
36 
48/ET 
Disease 
Assessmente 
Safety 
(EOS)i 
Days 
-198 (from Day 1) 
-168 
(from 
Day 1) 
-84 
(from 
Day 1) 
-7 
(from 
Day 1) 
 
Day 
1 
 
 
 
 
 
30 
GENERAL & SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Part 1 Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Part 2 Eligibility Criteria 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
Medical/Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
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 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum)b 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine)b, c 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Tuberculosis testingd 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistry profile 
X 
 
X 
X 
 
 
 
X 
 
X 
X 
 
Rheumatoid Factor and anti CCP 
antibody 
 
 
 
 
 
X 
 
 
 
 
 
 
Hepatitis B surface antigen/core antibody 
& hepatitis C virus antibodyj 
X 
 
 
 
 
 
 
 
 
 
 
 
Erythrocyte Sedimentation Rate 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
C-reactive Protein 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
X 
 
 
 
 
 
 
 
 
Blood for biomarker analysis 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Page 1 of 2 
Footnotes defined on the next page of the table 


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Table 1.  Schedule of Assessments 
 
30-day Screening 
Open-Label Run-in Periodh 
Double Blind Treatment Periodg 
 
Follow-Up 
Weeks 
 
Run-in 
Visit 1 
Run-in 
visit 2 
Run-in 
visit 3 
Run-in 
ET 
0g 
12 
24 
36 
48/ET 
Disease 
Assessmente 
Safety 
(EOS)i 
Days 
-198 (from Day 1) 
-168 
(from 
Day 1) 
-84 
(from 
Day 1) 
-7 
(from 
Day 1) 
 
Day 
1 
 
 
 
 
 
30 
DOSING 
 
 
 
 
 
 
 
 
 
 
 
 
Etanercept/placebo for etanercept 
dispensation 
 
X 
X 
 
 
X 
X 
X 
X 
 
Xf 
 
Methotrexate/placebo for methotrexate 
dispensation 
 
X 
X 
 
 
X 
X 
X 
X 
 
Xf 
 
Dispense dosing diary 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
Review dosing diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
DISEASE ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
66 Swollen joint count 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
68 Tender joint count 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Physician global assessment of disease 
activity   
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
SUBJECT ASSESSMENTS (PRO) 
 
 
 
 
 
 
 
 
 
 
 
 
Patient global assessment of joint pain  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Patient global assessment of disease 
activity 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Disability Index of the Health 
Assessment Questionnaire (HAQ-DI) 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Medical Outcomes Short Form-36 
Questionnaire (SF-36) 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Page 2 of 2 
ET = early termination; ESR = erythrocyte sedimentation rate; EOS = end of study; HBV = hepatitis B virus; PCR = polymerase chain reaction. 
a Screening physical exam will be a full exam; subsequent exams per standard of care to monitor for any changes 
b For all women, unless at least 2 years postmenopausal or history of hysterectomy, bilateral salpingectomy, or bilateral oophorectomy  
c Additional pregnancy testing may be completed at the discretion of the investigator  
d Subjects will receive either a PPD test or Quantiferon test at screening.  National guidelines should be followed for appropriate tuberculosis screening in the setting of 
anti-TNF therapy. 
e Disease Assessment Visit - disease activity may be assessed at a regularly scheduled visit or at a Disease Assessment visit as described in Section 7.2.7 
f If subjects meet the criteria for disease worsening then etanercept plus methotrexate will be dispensed at the same dose they were receiving at screening 
g Baseline (Day 1) visit must be scheduled ≤7 days from the run-in visit 3 
h Visit window is +/- 7 days for all visits after screening 
I Subjects will be contacted by phone by the site staff to collect any serious adverse events 
j At screening, if the subject is positive for hepatitis B core antibody, the confirmatory reflex testing will be performed using HBV DNA PCR.  


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7.2 
General Study Procedures 
The procedures performed at each study visit are outlined in Table 1.  Details regarding 
each type of procedure are provided in subsequent sub-sections.   
Refer to the applicable supplemental central laboratory, IXRS, IPIM, and study manuals 
for detailed collection and handling procedures. 
7.2.1 
Screening 
Informed consent must be obtained before completing any other screening procedure.  
After written informed consent is signed by the subject, the subject will be screened in 
order to assess eligibility for study participation.  The screening window is 30 days.  If a 
subject has not met all Part 1 eligibility criteria at the end of the 30-day window, the 
subject will be registered as a screen fail.  At screening, if the subject is positive for 
hepatitis B core antibody, the confirmatory reflex testing will be performed using hepatitis 
B virus (HBV) DNA polymerase chain reaction (PCR).  Subjects who screen fail may be 
eligible to rescreen two additional times per Section 7.2.2. 
7.2.2 
Re-screening 
Subjects who are unable to complete or meet Part 1 eligibility criteria on initial screening 
will be permitted to re-screen two additional times after the first screening visit failure.  
Re-screen subjects must first be registered as screen failed in IXRS and subsequently 
registered as a re-screen subject with the same subject identification number.  Once the 
subject is registered as re-screened, a new 30-day screening window will begin. 
If the re-screening period begins more than 30 days after the original signing of the 
informed consent form, all screening procedures, including informed consent must be 
repeated.  If the re-screening occurs within 30 days after the original signing of the 
informed consent, only those criteria that were originally not met would be required to be 
repeated.  Tuberculosis testing will not need to be repeated for re-screen subjects if 
negative at the original screening.  Subjects who fail screening for not meeting inclusion 
criterion 114 are not permitted to re-screen.  Subjects screen failing for not meeting 
inclusion criteria 106 are permitted to re-screen 1 additional time if their initial SDAI 
screening score is < 6.0.  If a subject does not meet inclusion criteria 106 after 
2 screening attempts no additional rescreening is permitted.  Rescreening for failure to 
meet inclusion criteria 106 must occur at least 2 weeks after the initial screening.  


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7.2.3 
Open Label Run-in Period 
Once a subject has met the Part 1 eligibility criteria evaluated during screening, the 
subject will enter the 24-week open-label run-in period.  During the run-in period, 
Part 2 eligibility criteria will be evaluated at the regularly scheduled run-in visits or at a 
Disease Assessment visit (see Section 7.2.7) if required.  If the subject does not meet 
the Part 2 eligibility criteria they must complete a run-in early termination visit. 
Subjects will initiate treatment with open-label etanercept and methotrexate at the same 
dose they were receiving at screening.  Investigational products, subject diaries, and 
related supplies will be dispensed to the subject at every regularly scheduled visit for 
self-administration. 
All procedures during run-in visit 3 (see Table 1) must be completed within 7 days of the 
baseline (day 1) visit in order to confirm the subject’s eligibility. 
7.2.4 
Early Termination Run-in 
Subjects not meeting Part 2 eligibility criteria will complete a run-in early termination visit 
and will complete the procedures described in Table 1.  
7.2.5 
Baseline Visit (Day 1) 
Subjects meeting Part 1 and Part 2 eligibility criteria will be randomized by IXRS as 
described in Section 5.  The date of first dose of blinded investigational product is 
defined as Day 1 Week 0.  All subsequent doses and study visits will be scheduled 
based on the Day 1 date.  Following the first blinded dose, investigational products and 
related supplies will be dispensed to the subject for 12 weeks of self-administration. 
7.2.6 
Treatment 
Visits will occur per the Schedule of Assessments (Table 1) during the treatment period 
from day 1 until week 48.  On-study visits may be completed within ± 7 days of the target 
visit date.  The procedures completed during the 48-week treatment period are those 
listed in the Schedule of Assessments (Table 1).  Administration of investigational 
product is to be administered after all other study procedures, as applicable, during each 
visit that is required. 
7.2.7 
Disease Assessment Visit 
Subjects can be seen at a regularly scheduled visit or at a disease assessment visit any 
time after screening to assess disease activity to either: 
• 
establish Part 2 eligibility criteria during the run-in period OR 
• 
to determine if subject can receive rescue treatment after randomization   


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During the double-blind randomized treatment period, if the subject meets the criteria for 
disease worsening as defined in Section 3.1.2 subjects will initiate treatment with 
etanercept and methotrexate at the same dose they were receiving during the run-in 
period.  Subjects will continue to receive etanercept plus methotrexate for the remaining 
study visits per Table 1.  
7.2.8 
Subject End of Treatment/Early Termination 
Subjects will complete an end of treatment (EOT) visit at week 48 within a window of 
± 7 days of the target visit date (see Table 1).  Subjects ending the study prior to 
week 48 will be asked to complete an Early Termination visit.  
7.2.9 
Safety Follow-up/End of Study 
Approximately 30 days, within a window of + 7 days of the target visit date, after the last 
dose of investigational products, subjects will be contacted by phone by the site staff to 
collect any serious adverse events (refer to Section 9).  
7.3 
Description of Study Assessments and Procedures 
Assessment and procedures are further detailed in this section.  See Table 1 for 
required timepoints. 
7.3.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IEC/IRB approved informed consent before any study-specific procedures are 
performed.  See Section 11.1 for further details. 
7.3.2 
Demographic Data 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally demographic data will be used to study the impact on biomarker variability of 
the protocol required therapies.  
7.3.3 
Medical History 
The subject’s relevant medical and surgical history that started within 5 years or as 
necessary for chronic co-morbid conditions prior to enrollment through the start of the 
adverse event reporting period will be collected.  Medical history will include information 
on the subject’s concurrent medical conditions.  Record all findings on the medical 
history eCRF.  In addition to the medical history above, RA history should date back to 
the original diagnosis. 


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7.3.4 
Medication History 
The subject’s complete history of RA medications will be recorded on the eCRF.  This 
information will include the subject’s DMARDs, NSAIDS, corticosteroid, biologics, and 
investigational medication history.  All other medications taken within 6 months prior to 
screening will be recorded on the eCRF.  For RA medications, the following information 
will be recorded in the eCRF:  medication name, indication, dose, unit, route, frequency, 
and start and stop dates.  For all other medications, only the medication name, 
indication, and start and stop dates will be recorded in the eCRF. 
7.3.5 
Physical Examination 
The screening physical examination is per standard of care.  Physical examination 
findings at screening should be recorded on the appropriate eCRF (eg, medical history).  
The physical examination at subsequent study visits will consist of an interim 
examination to monitor for any changes from the screening physical examination.  Any 
clinically significant changes in physical examination per the Principal Investigator’s 
opinion should be recorded on the adverse events eCRF.   
7.3.6 
Physical Measurement 
Height in inches/centimeters and weight in pounds/kilograms should be measured 
without shoes. 
7.3.7 
Vital Signs 
The following measurements must be performed:  systolic and diastolic blood pressure, 
heart rate, respiratory rate, and temperature.  Subject must be in a supine position in a 
rested and calm state for at least 5 minutes before blood pressure assessments are 
conducted.  If the subject is unable to be in the supine position, the subject should be in 
the 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.  
The body region used to assess temperature for a subject should remain consistent 
throughout the study and documented on the vital signs eCRF.  If abnormalities are 
found and they are considered an adverse event, record on the adverse event summary 
page. 
7.3.8 
Rheumatoid Arthritis Disease Assessments 
7.3.8.1 
Swollen/Tender Joint Counts 
All joint assessments will be performed by an experienced trained joint assessor who 
has been certified as trained by Amgen and must be identified on the delegation of 
authority for this responsibility.  Each subject should have their joint assessments done 


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by the same assessor throughout the study when possible and the user identification of 
the joint assessor is captured in the electronic PRO (ePRO) tablet.  If necessary, study 
visits may be rescheduled within the specified window of ± 7 days to accommodate 
when the specific assessor will be available.  The score for each joint will be recorded 
directly into the ePRO tablet which will serve as the source documentation and will not 
be transposed to the eCRF. 
Joints that have been replaced are considered inevaluable.  For the screening and 
baseline joint assessments, distal interphalangeal joints should be evaluated, but should 
not be included in the total count to determine eligibility. 
Swollen Joint Count Assessments – A total of 66 joints will be scored for presence or 
absence of swelling. 
Tender Joint Count Assessments – A total of 68 joints will be scored for presence or 
absence of tenderness. 
7.3.8.2 
Physician Global Assessment of Disease Activity 
The global assessment of the subject’s arthritis will be assessed by either the joint 
assessor or the principal investigator (PI) for the study by completion of a visual analog 
scale (VAS).  The VAS is 100 mm in length with “0” and “No Activity at All” on the left 
end of the line and “100” and “Worst Activity Imaginable” at the right end of the line.  The 
subject and joint assessor or the PI for the study must complete the global assessments 
independently from each other.  
7.3.8.3 
Simplified Disease Activity Index (SDAI) 
The SDAI is the numerical sum of five outcome parameters:  tender joint count and 
swollen joint count based on a 28‐joint assessment, patient global assessment of 
disease activity, physician global assessment of disease activity and C‐reactive protein 
(CRP in mg/dL).  SDAI is calculated by the sponsor.  
7.3.9 
Patient Reported Outcomes 
PRO assessments should be completed first (before other study procedures and 
administration of study medication) at each visit where they are required. 
7.3.9.1 
Patient Global Assessment of Joint Pain 
The severity of the subject’s joint pain will be assessed by completion of a VAS.  The 
horizontal line is 100 mm in length with “0” and “no pain at all” on the left end of the line 
and “100” and “worst pain imaginable” on the right end of the line.  This questionnaire 
should take approximately 1 minute to complete. 


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7.3.9.2 
Patient Global Assessment of Disease Activity 
The subject’s global assessment of their arthritis disease activity will be assessed by 
completion of a VAS.  The horizontal line is 100 mm in length with “0” and “No RA 
Activity At All” on the left end of the line and “100” and “Worst RA Activity Imaginable” on 
the right end of the line.  The subject and health care provider must complete the global 
assessments independently from each other.  This questionnaire should take 
approximately 1 minute to complete. 
7.3.9.3 
Disability Index of the Health Assessment Questionnaire 
The Disability Index of the Health Assessment Questionnaire (HAQ-DI) will be utilized to 
assess the subject’s physical function or disability according to the subject.  The HAQ-DI 
asks about the degree of difficulty a person has in accomplishing tasks 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 study staff should not clarify any 
of the questions for the subject.  This questionnaire should take approximately 5 minutes 
to complete. 
7.3.9.4 
Medical Outcomes Short Form-36 Questionnaire (SF-36) 
The Medical Outcomes Short Form-36 Questionnaire (SF-36) is a 36-item instrument 
that measures general health status.  It includes 8 multi-item scales, each of which 
assess 1 of the following 8 health concepts:  1) limitations in physical activities because 
of health problems; 2) limitations in social activities because of physical or emotional 
problems; 3) limitations in usual role activities because of physical health problems; 
4) bodily pain; 5) general mental health (psychological distress and well-being); 
6) limitations in usual role activities because of emotional problems; 7) vitality (energy 
and fatigue); and 8) general health perceptions.  The SF-36 assesses the subject’s 
perception of health status over the previous month and takes about 15 minutes to 
complete. 
7.4 
Laboratory Assessments 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory with the exception of erythrocyte sedimentation rate (ESR), urine pregnancy, 
PPD, and Quantiferon (may be done by central or local laboratory).  The central 
laboratory will be responsible for all screening and on-study serum chemistry, 
hematology, serum pregnancy, urinalysis, high sensitivity CRP, and any other laboratory 
tests required.  ESR, urine pregnancy and PPD testing, if applicable, will be performed 


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locally with kits provided by the central laboratory (except PPD).  The results of this 
testing will be maintained in the source documents at the site.  Amgen or designee will 
be responsible for biomarker development and pharmacogenetic assessments, and the 
central laboratory will ship the samples to Amgen or a specialty laboratory for assay 
(depending on the assessment).  The central laboratory will provide a study manual that 
outlines handling, labeling, and shipping procedures for all samples.  All blood samples 
will be obtained by venipuncture before investigational product administration.  The date 
and time of sample collection will be recorded in the source documents at the site.  
Specific analytes for serum chemistry, hematology, urinalysis, and other testing to be 
conducted on blood and urine samples are listed below (Table 2). 
Table 2.  Analyte Listing 
Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted 
calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline 
phosphatase 
LDH 
AST (SGOT) 
ALT (SGPT) 
Urinalysis 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Microscopic (Reflex 
testing if abnormal) 
Hematology 
RBC 
WBC 
Absolute neutrophil count 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
RDW 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
• 
Monocytes 
Other Labs 
Serum beta hCGa 
Hepatitis B surface 
antigen and Hepatitis 
B core antibodyb 
Hepatitis C virus 
antibody 
High sensitivity 
C-reactive protein 
Tuberculosis Testingc 
Rheumatoid Factor 
Anti-CCP 
a For all women, unless at least 2 years postmenopausal or history of hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy 
b At screening, if the subject is positive for hepatitis B core antibody, the confirmatory reflex testing will be 
performed using HBV DNA PCR. 
c Subjects must receive either a PPD test or Quantiferon test at screening.  National guidelines should be 
followed for appropriate tuberculosis screening in the setting of anti-TNF therapy. 


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7.4.1 
Tuberculosis Testing 
National guidelines should be followed for appropriate tuberculosis screening in the 
setting of anti-TNF therapy. 
All subjects must receive either a PPD or Quantiferon test at screening per 
Section 4.1.1.  PPD testing should be performed unless contraindicated. 
7.4.1.1 
PPD 
The PPD test must be read by a trained healthcare professional 48 to 72 hours after the 
test is placed.  PPD reader must be identified on the delegation of authority for this 
responsibility. 
7.4.1.2 
Quantiferon 
If a subject does not receive a PPD test, then a Quantiferon test must be performed per 
Section 4.1.1.  Please refer to the central laboratory manual for instructions on sample 
collection, processing, and shipping of samples (if applicable). 
7.4.2 
Erythrocyte Sedimentation Rate 
ESR will be performed locally at each site and the ESR data will be submitted to the 
central laboratory per the instructions in the study manual provided by the central 
laboratory.  The central laboratory will provide all supplies.  The screening and baseline 
ESR may be performed by any trained staff at the site.  Once the subject has been 
randomized, the ESR may only be performed by a trained individual at the site who does 
not perform any study assessments with subjects on the study.  Staff performing the 
ESR must be identified on the delegation of authority for this responsibility.  The results 
of the ESR performed after the subject has been randomized must be maintained in a 
blinded fashion so that it may not be viewed by staff who perform any study 
assessments with the subjects. 
7.4.3 
Urine Pregnancy Test 
Urine pregnancy tests will be performed locally at each site.  The central laboratory will 
provide the urine pregnancy tests on visits where required.  Urine pregnancy tests must 
be given prior to dispensing investigational product.  If a urine pregnancy test is positive, 
investigational product must be held; if pregnancy is confirmed, then investigational 
product must be discontinued. 
7.5 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 


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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 etanercept and/or methotrexate.  
7.6 
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 Amgen and non-Amgen 
investigational product.  No additional samples are collected for this part of the study.  
For subjects who consent to this/these analysis/analyses, DNA may be extracted.  
7.7 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
inflammatory conditions, the dose response and/or prediction of response to etanercept 
or methotrexate, 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 


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exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
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 can decline to continue receiving investigational product and/or other 
protocol-required therapies or procedures at any time during the study but continue 
participation in the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from investigational product or other 
protocol-required therapies and must discuss with the subject the options for 
continuation of the Schedule of Assessments (Table 1) and collection of data, including 
endpoints and adverse events.  The investigator must document the change to the 
Schedule of Assessments (Table 1) and the level of follow-up that is agreed to by the 
subject (eg, in person, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, from review of the medical 
records). 


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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.  The data generated may 
potentially not be included in the subject’s study data, except in the case of a possibly 
related serious adverse event, where data will be collected.  
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 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. 
8.3 
Reasons for Removal From Run-in, Treatment, or Study  
8.3.1 
Reasons for Removal From Run-in 
Reasons for removal from the run-in 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, pregnancy) 
• 
decision by sponsor (other than subject request or safety concern) 
• 
death 
• 
lost to follow-up 
• 
other protocol-specified criteria 
• 
as per Section 4.2.1 and Section 4.2.2 


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8.3.2 
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, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• 
disease flare requiring treatment not allowed in the protocol (eg, colitis, asthma) 
8.3.3 
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 
• 
other protocol-specified criteria  
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. 


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An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
The 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: 
• 
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 drug-induced liver injury 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 
treatment period 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 (and/or toxicity per protocol), 
• 
Assessment of relatedness to investigational product(s), and 
• 
Action taken. 
The adverse event grading scale used will be the Common Toxicity Criteria Version 4.0.  
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(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 the investigational 
product(s)? 
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.  
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 Adverse Event 
Summary CRF. 
9.2.2 
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 day of the dosing interval of investigational 
product(s) are recorded in the subject’s medical record and are submitted to Amgen.  All 
serious adverse events must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the Event CRF. 


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After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event 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.  
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 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/eSAE 
Contingency Report Form.  For EDC studies where the first notification of a Serious 
Adverse Event is reported to Amgen via the eSerious 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 
any study-mandated activity 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/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 be asked to provide additional follow-up information, 
such as discharge summaries, medical records, or extracts from the medical record.  
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.  Investigators 


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will receive notification of related serious adverse event reports sent to regulatory 
authorities in accordance with local requirements.   
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 (GCP). 
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. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking etanercept, 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 4 weeks after the last dose of etanercept.   
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a 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, 
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 subject breastfeeds while taking protocol-required therapies report the 
lactation case to Amgen as specified below.  
Any lactation case should be reported to Amgen’s 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. 


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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 
10.1.1.1 
Primary Endpoint 
• 
SDAI remission (≤ 3.3) at week 48 
10.1.1.2 
Secondary Endpoints 
• 
SDAI score and change from baseline at all measured timepoints 
• 
DAS-28-ESR and change from baseline at all measured timepoints 
• 
DAS-28-CRP and change from baseline at all measured timepoints 
• 
CDAI and change from baseline at all measured timepoints 
• 
SDAI remission (≤ 3.3) at all measured timepoints 
• 
Boolean remission at all measured timepoints 
• 
Disease worsening defined as an SDAI > 3.3 and ≤ 11 during two consecutive visits 
at least 2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate visits or 
SDAI > 11 after randomization 
• 
Time to disease worsening defined as an SDAI > 3.3 and ≤ 11 during two 
consecutive visits at least 2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more 
separate visits or SDAI > 11 after randomization 
In subjects that receive rescue treatment during the double-blind treatment period 
• 
Time to recapture SDAI remission after starting rescue treatment 
• 
SDAI remission at week 48 
10.1.1.3 
Safety Endpoints 
• 
Adverse events 
• 
Serious adverse events 
• 
Laboratory parameters 
10.1.1.4 
Exploratory Endpoints 
• 
Components of SDAI at all measured timepoints  
• 
HAQ-DI at all measured timepoints 
• 
SF-36 domains, physical component summary, and mental component summary at 
all measured timepoints 
• 
Biomarkers 
• 
Pharmacogenetic parameters 


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10.1.2 
Analysis Sets 
10.1.2.1 
Primary Analysis Set 
The primary analysis set will include all randomized subjects.  The analysis will be 
conducted according to the original randomization regardless of the actual treatment 
received during the study (as per intent-to-treat principle).  All the primary, secondary, 
and exploratory efficacy endpoints will be evaluated on the primary analysis set. 
10.1.2.2 
Safety Analysis Set 
This subset will include all randomized subjects who received at least one dose of any 
investigational product during the study.  For all safety endpoints, subjects will be 
analyzed based on the actual treatment received. 
10.1.3 
Covariates and Subgroups 
The following baseline covariates will be considered to assess their influence on the 
primary and secondary endpoints:  
• 
age (years) (continuous) 
• 
sex (male/female) 
• 
race  
• 
ethnicity (Hispanic or Latino vs Non-Hispanic or Latino) 
• 
disease duration (years) 
• 
baseline methotrexate dose 
• 
other covariates may be evaluated as necessary 
Subgroup analyses, which would be considered exploratory, may be performed if an 
examination of the above covariates suggests that any treatment difference for the 
primary and secondary endpoints depends on any baseline covariates. 
10.2 
Sample Size Considerations 
The sample size was determined from a hypothesis of superiority of etanercept 
monotherapy over methotrexate monotherapy.  The proportion of subjects achieving 
SDAI remission after 52 weeks of double-blind treatment in the PRESERVE and 
COMET studies was used to estimate the treatment effects.  PRESERVE was a 
two-period study conducted in subjects with RA who had moderate disease activity 
despite a stable dose of oral methotrexate for a minimum of 8 weeks at the time of 
screening.  Among all subjects who were in SDAI remission at both week 28 and 
week 36 (the last two visits of the open-label run-in period), the proportion of subjects 
who were still in remission after the 52-week double-blind period was 86.1% and 38.1% 


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for the etanercept plus methotrexate therapy and methotrexate monotherapy treatment 
groups, respectively.  COMET was a two-period study conducted in subjects with active 
early RA.  Among all subjects who received etanercept plus methotrexate therapy in 
Period 1 and were in SDAI remission at week 52, the last visit of Period 1, the proportion 
of subjects who were in still in remission after the 52-week double-blind Period 2 was 
78.3% and 72.4%, respectively, for the etanercept plus methotrexate therapy and 
etanercept monotherapy treatment groups.  Given key differences noted in this study, 
including the sustained period of remission prior to withdrawal, the response rate in the 
methotrexate monotherapy arm is approximated to be higher at 50%, with the response 
rate in the etanercept monotherapy arm at approximately 72%.  It is expected that 
compared to PRESERVE, subjects in the current study will have more stable disease at 
the time of randomization.  Namely, subjects must be in very good disease control for 
6 months prior to study entry and must be in SDAI remission at the end of a 24-week 
open-label run-in period.  
The sample size is based on the adequacy to evaluate the efficacy of etanercept 
monotherapy compared to methotrexate monotherapy as measured by the primary 
endpoint of SDAI remission at week 48 at a significance level of 0.05.  Based on a 
two-sided chi-square test with 90% power, 100 subjects per arm are required at 
randomization. 
Using an assumed attrition rate of 30% in the open-label run-in period, due to exclusion 
of subjects with disease worsening during the run-in period, or other reasons, 
approximately 358 subjects will be enrolled in order to have approximately 250 subjects 
randomized in a 2:2:1 ratio to one of three treatment groups:  etanercept monotherapy 
(n = 100), methotrexate monotherapy (n = 100), and etanercept plus methotrexate 
combination therapy (n = 50).  Amgen may choose to alter the sample size of subjects 
enrolled in order to ensure that approximately 250 subjects are randomized to treatment.  
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators, or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 5.2 and Section 9.2.2, and 
Statistical Analysis Plan [SAP]). 


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10.4 
Planned Analyses 
10.4.1 
Primary analysis 
Primary analysis activities are commenced based on achieving the End of Study 
milestone described in Section 3.5.2. 
10.4.2 
Interim Analyses 
No interim analysis is planned for this study. 
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Baseline demographics and disease characteristics will be summarized descriptively. 
Summary descriptive statistics by each treatment group will be provided.  For categorical 
endpoints, the descriptive statistics will contain the frequency and percentage.  For 
continuous endpoints, the descriptive statistics will include the number of observations, 
mean, standard deviation, median, minimum, maximum and 95% confidence interval. 
Non-responder imputation will be employed for the missing values of the primary 
endpoint.  Secondary efficacy endpoints will be summarized using observed cases only.  
As supportive analysis, the primary endpoint will also be summarized using observed 
cases. 
The statistical test for the primary efficacy endpoint will be two-sided with a significance 
level of 0.05. 
10.5.2 
Primary Efficacy Endpoint 
The primary analysis for the primary endpoint for this study, SDAI remission at week 48, 
will be performed using the primary analysis set.  The primary endpoint will be measured 
by the proportion of subjects who maintain SDAI remission (SDAI ≤ 3.3) at week 48. 
SDAI remission at week 48 for the etanercept monotherapy treatment arm will be 
compared to the methotrexate monotherapy arm using the chi-square test.   
Both subjects who drop out and subjects receiving rescue therapy due to disease 
worsening during the double-blind period will be considered non-responders.  
Furthermore, the randomized subjects who did not receive any dose of any of the 
investigational products will be considered non-responders in the primary analysis. 
As a sensitivity analysis, subjects who receive rescue therapy or that drop out will have 
their post-rescue SDAI responses set to missing and a multiple imputation technique to 
impute these values will be employed.  The multiple imputation method is less 


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conservative than the non-responder imputation method and will be prospectively 
described in more detail in the SAP.  
A subject’s SDAI score is calculated as follows: 
SDAI = 28-joint tender joint count + 28-joint swollen joint count + Patient Global 
Assessment of Disease Activity + Physician Global Assessment of Disease Activity 
+ C-reactive protein (mg/dL). 
10.5.3 
Secondary Efficacy Endpoints 
• 
Simplified Disease Activity Index remission (≤ 3.3) at week 48 for the etanercept 
plus methotrexate treatment arm will be compared to the methotrexate 
monotherapy arm using the chi-square test and will be presented with nominal 
p-values only (eg, no adjustment for multiplicity will be done). 
• 
The proportion of subjects achieving SDAI remission, SDAI continuous score and 
SDAI change from baseline at all study timepoints will be summarized by 
treatment group.  DAS28-ESR, DAS28-CRP and CDAI and their changes from 
baseline will be also summarized at all study timepoints by treatment group.  
Proportion of subjects achieving Boolean remission will be tabulated at all study 
timepoints by treatment group.  Proportion of subjects with disease worsening 
(defined as an SDAI > 3.3 and ≤ 11 during two consecutive visits at least 
2-weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate visits or 
SDAI > 11 after randomization) as well as time to disease worsening will be 
evaluated.  
• 
In subjects that receive rescue treatment during the double-blind treatment 
period time to recapture of SDAI remission after starting rescue treatment will be 
analyzed.  Additionally, the proportion of subjects who recapture SDAI remission 
at week 48 will be summarized. 
10.5.4 
Exploratory Endpoints 
Exploratory endpoints will also be summarized by treatment group at all timepoints.  
Exploratory endpoints include 28-swollen joint count, 28-tender joint count, Physician 
Global Assessment of Disease Activity (0-10 VAS), Patient Global Assessment of 
Disease Activity (0-10 VAS), HAQ-DI and SF-36.  
10.5.5 
Safety Endpoints 
Safety analyses will be based on the safety analysis set.  Subject incidence of all 
treatment-emergent adverse events will be tabulated by system organ class and 
preferred term.  Tables of fatal adverse events, serious adverse events, adverse events 
leading to withdrawal from investigational product or other protocol-required therapies, 
and significant treatment-emergent adverse events will also be provided. 
Laboratory parameters with grade 3 or above will be summarized by study visit and 
treatment group.  Vital signs will be reported in baseline summaries.  Shift tables of the 


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worst on-study laboratory toxicity for analytes of interest based on Common Toxicity 
Criteria relative to baseline will be tabulated by treatment group (as described in the 
SAP). 
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 Global Clinical Trial Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient 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 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.  
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 


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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 for 
documents submitted to Amgen. 
• 
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 CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.  
• 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and 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 confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information. 
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. 


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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 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  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 to Amgen. 
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 study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
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, and 
correspondence. 
In this study, the IXRS system captures the following data points and these are 
considered source data:  subject identification number, randomization number among 
others. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data).  In this study, ePROs 
may be considered as source documents. 


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The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
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, 
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 R&D Compliance and Audit function 
(or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 
storage areas, laboratories) and review of study-related records will occur to evaluate 


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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 CRFs must be maintained and 
readily available. 
• 
Updates to 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 and/or site notifications 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 EDC study.  
This signature indicates that investigator inspected or reviewed the data on the CRF, 
the data queries, and the site notifications, and agrees with the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self-Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.   
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 1), 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.  CRFs must be 


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completed in English.  TRADENAMES (if used) for concomitant medications may be 
entered in the local language. 
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 Publications 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; (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, 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. 
• 
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 review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 


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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 
Alamanos Y, Voulgari PV, Drosos AA.  Incidence and prevalence of rheumatoid arthritis, 
based on the 1987 American College of Rheumatology criteria:  a systematic review.  
Semin Arthritis Rheum.  2006;36:182-188. 
Emery P, Breedveld F, van der Heijde D, et al.  Two-Year clinical and radiographic 
results with combination etanercept-methotrexate therapy versus monotherapy in early 
rheumatoid arthritis.  A two-year, double blind, randomized study.  Arthritis Rheum.  
2010;62:674-682. 
Emery P, Hamoudeh M, FitzGerald OM, Combe B, Gaylord S, et al.  Induction of 
remission in patients with up to 12 months of moderate-to-severe rheumatoid arthritis 
symptoms treated with etanercept plus methotrexate for 52 weeks.  Arthritis Rheum 
2012;64(Supp 10) S1077. 
Klareskog L, van der Heijde D, Jager JP, Gough A, Kalden J et al.  Therapeutic effect of 
combination of etanercept and methotrexate compared to each treatment alone in 
patients with rheumatoid arthritis:  double-blind randomized controlled trial.  
Lancet. 2004; 363(9410):675-681 
Pope J, Haraoui B, Thorne JC et al.  The Canadian Methotrexate and Etanercept 
Outcome Study:  a randomized trial of discontinuing versus continuing methotrexate 
after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis.  Ann 
Rheum Dis.  2013;0:1-8 
Smolen JS, Nash P, Durez, P, et al.  Maintenance, reduction, or withdrawal of 
etanercept after treatment with etanercept and methotrexate in patients with moderate 
rheumatoid arthritis (PRESERVE):  a randomized controlled trial.  Lancet. 
2013;381:918-929 . 
Van Vollenhoven R, Franck-Larsson M, Leirisalo-Repo M, et al.  In rheumatoid arthritis 
patients with stable low disease activity on methotrexate plus etanercept, continuation of 
etanercept 50 mg or 25 mg weekly are both clinically superior to discontinuation:  results 
from a randomized, 3-arm, double–blind study.  Ann Rheum Dis. 2013a;72:A434-A435. 
Van Vollenhoven R, Franck-Larsson M, Leirisalo-Repo M, et al.  In rheumatoid arthritis 
patients with stable low disease activity on methotrexate plus etanercept, continuation of 
etanercept 50 mg or 25 mg weekly are both clinically superior to discontinuation:  results 
from a randomized, 3-arm, double–blind study.  Poster presented at:  EULAR; 
June 12-15, 2013b; Madrid, Spain.  Poster FRI0185. 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Toxicity Criteria Version 4.0 is available at the following link:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications\ctc.htm 
General United States Food and Drug Administration Guidance on Hepatotoxicity 
Stopping and Rechallenge Rules 
As noted in Section 6.4, a Food and Drug Administration Guidance exists for 
drug-induced liver injury (DILI).  This guidance is general for all investigational and 
marketed products, and is synopsized here as a reference.  It provides criteria for 
reporting, monitoring, and withholding investigational product in the event that a subject 
develops signs or symptoms of hepatotoxicity during a clinical trial. 
Criteria for Permanent Withholding of Investigational Product due to Potential 
Hepatotoxicity 
Investigational product should be discontinued permanently and the subject should be 
followed for possible drug-induced liver injury, if ALL of the criteria below are met:  
• 
TBL > 2 x ULN or international normalized ratio > 1.5 
• 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
≤ 1.5 ULN 
> 3 x ULN 
• 
AND no other cause for the combination of laboratory abnormalities is immediately 
apparent; important potential causes for abnormal AST/ALT or total bilirubin values 
include, but are not limited to the following: 
• 
obstructive gall bladder or bile duct disease 
• 
viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella) 
• 
progression of malignancy involving the liver (note that metastatic disease to the 
liver, by itself, should not be used as an explanation for significant AST/ALT 
elevations) 
• 
hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right-sided heart failure 
• 
concomitant administration of other hepatotoxins, including drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
• 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome); 
alpha-one antitrypsin deficiency 
• 
autoimmune hepatitis 
• 
nonalcoholic steatohepatitis or other “fatty liver disease” 


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It should be noted that some of the circumstances above may nevertheless warrant 
discontinuation of investigational product without requiring assessment for drug-induced 
liver injury. 
Criteria for Conditional Withholding of Investigational Product due to Potential 
Hepatotoxicity 
For subjects that do not meet the criteria for permanent withholding of investigational 
product outlined above, investigational product should be withheld if ANY of the following 
criteria are met, and the subject should be evaluated for drug-induced liver injury:   
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation 
Any 
> 8 x ULN at any time 
Any 
> 5 x ULN but < 8 x ULN for ≥ 2 weeks 
Any 
> 5 x ULN but < 8 x ULN and unable to adhere to enhanced 
monitoring schedule 
• 
OR:  clinical signs or symptoms that are, in the opinion of the investigator, consistent 
with hepatitis (such as right upper quadrant pain/tenderness, fever, nausea, 
vomiting, jaundice, rash or eosinophilia > 5%).  If such signs or symptoms are 
coupled with ALT or AST elevations > 3 x ULN, investigational product should be 
withheld.  
• 
OR:  total bilirubin > 3 x ULN at any time 
• 
OR:  alkaline phosphatase > 8 x ULN at any time 
Investigational product should be withheld pending investigation into alternative causes 
of drug-induced liver injury.  If investigational product is withheld, the subject should be 
followed according to recommendations above for possible drug-induced liver injury.  
Rechallenge may be considered if an alternative cause is discovered and the laboratory 
abnormalities resolve to normal or baseline.   
Criteria for Rechallenge of investigational product after Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, principal investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then investigational product should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation should never be rechallenged. 


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Drug-induced Liver Injury Reporting & Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL according to the criteria specified in Section 6.4 (3 x ULN for AST/ALT and 
2 x ULN for TBL) 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 9.2.2. 
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 above or 
who experience AST or ALT elevations >3 x ULN 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: 
− 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
− 
Obtain serum acetaminophen (paracetamol) levels 
− 
Obtain a more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  


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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 
− 
Obtain viral serologies 
− 
Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain 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.  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. 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 70 of 74 
CONFIDENTIAL 
 
 
Appendix B.  eSerious Adverse Event Contingency Form 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 71 of 74 
CONFIDENTIAL 
 
 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 72 of 74 
CONFIDENTIAL 
 
 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 73 of 74 
CONFIDENTIAL 
 
 
Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 74 of 74 
CONFIDENTIAL 
 
 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 1 of 8 
CONFIDENTIAL 
 
 
Amendment 5 
Protocol Title:  A Randomized Withdrawal Double-blind Study of Etanercept 
Monotherapy Compared to Methotrexate Monotherapy for Maintenance of 
Remission in Subjects With Rheumatoid Arthritis 
 
Amgen Protocol Number (Etanercept) 20110186 
EudraCT Number:  2014-004868-38 
NCT Number:  02373813 
Amendment Date: 
17 October 2017 
 
Rationale: 
This protocol is being amended to: 
• 
Reduce study sample size due to adjustments in estimated effect sizes for 
treatment groups. 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 2 of 8 
CONFIDENTIAL 
 
 
Description of Changes 
Section:  Global 
Change:  Version date updated throughout document from 20 December 2016 to 
17 October 2017. 
Section:  Global 
Replace:   
International Conference on Harmonisation 
With: 
International Council for Harmonisation 
Section:  Global 
Change:  Editorial changes (including typographical, grammatical, and formatting) have 
been made throughout the document. 
Section:  Title Page 
Add:   
NCT Number:  02373813 
Section:  Title Page 
Add:   
Date: 
29 July 2014 
Amendment 1 
18 May 2015 
Superseding Amendment 1: 
08 July 2015 
Amendment 2 
30 October 2015 
Amendment 3 
03 November 2016 
Amendment 4 
20 December 2016 
Amendment 5 
17 October 2017 
Section:  Protocol Synopsis, Study Design, Paragraph 2 
Replace:   
Approximately 465 subjects will be enrolled and approximately 325 subjects will be 
randomly assigned in a 2:2:1 ratio to one of three treatment groups:  etanercept 
50 mg weekly by subcutaneous injection plus oral placebo for methotrexate (n = 130), 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 3 of 8 
CONFIDENTIAL 
 
 
oral methotrexate 10 to 25 mg weekly plus placebo for etanercept (n = 130) and 
etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg 
weekly (n = 65). 
With:   
Approximately 358 subjects will be enrolled and approximately 250 subjects will be 
randomly assigned in a 2:2:1 ratio to one of three treatment groups:  etanercept 
50 mg weekly by subcutaneous injection plus oral placebo for methotrexate (n = 100), 
oral methotrexate 10 to 25 mg weekly plus placebo for etanercept (n = 100) and 
etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg 
weekly (n = 50). 
Section:  Protocol Synopsis, Sample Size 
Replace:   
Approximately 465 subjects enrolled and approximately 325 subjects randomized. 
With:   
Approximately 358 subjects enrolled and approximately 250 subjects randomized. 
Section:  Protocol Synopsis, Non-Amgen Investigational Product Dosage and 
Administration 
Delete: 
During the double-blind treatment period, methotrexate will be supplied as 
2.5 mg methotrexate tablets, capsules, or as matching placebo capsules and will be 
taken once weekly by oral administration for 48 weeks. 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 4 of 8 
CONFIDENTIAL 
 
 
Section:  Study Design and Treatment Schema 
Replace:   
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 5 of 8 
CONFIDENTIAL 
 
 
With: 
 
 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 6 of 8 
CONFIDENTIAL 
 
 
Section:  3.1 Study Design, Paragraph 2-3 and Bullet 1-3 
Replace:   
The study will enroll approximately 465 subjects.  During the run-in period subjects will 
receive open-label etanercept and methotrexate at the same dose they were receiving 
during screening.  It is expected that approximately 30% of subjects will early terminate 
the run-in period.  Amgen may choose to alter the sample size of subjects enrolled in 
order to ensure that approximately 325 subjects are randomized to treatment.  
Approximately 325 subjects will be randomly assigned in a 2:2:1 ratio to one of three 
treatment groups: 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral placebo for 
methotrexate (n = 130) 
• 
Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept (n = 130) 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 
10 to 25 mg weekly (n = 65) 
With:   
The study will enroll approximately 358 subjects.  During the run-in period subjects will 
receive open-label etanercept and methotrexate at the same dose they were receiving 
during screening.  It is expected that approximately 30% of subjects will early terminate 
the run-in period.  Amgen may choose to alter the sample size of subjects enrolled in 
order to ensure that approximately 250 subjects are randomized to treatment.  
Approximately 250 subjects will be randomly assigned in a 2:2:1 ratio to one of three 
treatment groups: 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral placebo for 
methotrexate (n = 100) 
• 
Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept (n = 100) 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 
10 to 25 mg weekly (n = 50) 
Section:  3.3 Number of Subjects, Paragraph 2-3 
Replace:   
The number of subjects expected to be enrolled in the study is approximately 465 of 
which approximately 325 will be randomized to the double-blind treatment period.   
Amgen may choose to alter the sample size of enrolled subjects to ensure that 
approximately 325 subjects are randomized to the double-blind treatment period. 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 7 of 8 
CONFIDENTIAL 
 
 
With:   
The number of subjects expected to be enrolled in the study is approximately 358 of 
which approximately 250 will be randomized to the double-blind treatment period.   
Amgen may choose to alter the sample size of enrolled subjects to ensure that 
approximately 250 subjects are randomized to the double-blind treatment period. 
Section:  3.5.2 End of Study 
Replace:   
End of Study will be the time when the last subject is assessed or receives an 
intervention for evaluation in the study. 
With: 
Primary Completion:  The primary completion date is defined as the date when the 
last subject is assessed or receives an intervention for the final collection of data 
for the primary endpoint(s), for the purposes of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was terminated early. 
If the study concludes prior to the primary completion date originally planned in 
the protocol (ie, early termination of the study), then the primary completion will 
be the date when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the study 
(eg, long-term follow-up), as applicable. 
Section:  10.2 Sample Size Considerations, Paragraph 1 
Delete:   
The sample size was determined from a hypothesis of superiority of both etanercept plus 
methotrexate therapy and etanercept monotherapy over methotrexate monotherapy.  
Section:  10.2 Sample Size Considerations, Paragraph 1 
Replace: 
Given key differences noted in this study, including the sustained period of remission 
prior to withdrawal, the response rate in the methotrexate monotherapy arm is 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  17 October 2017 
Page 8 of 8 
CONFIDENTIAL 
 
 
approximated to be higher at 50%, while the response rate in the etanercept 
monotherapy arm is a more conservative 70%.   
With:   
Given key differences noted in this study, including the sustained period of remission 
prior to withdrawal, the response rate in the methotrexate monotherapy arm is 
approximated to be higher at 50%, with the response rate in the etanercept 
monotherapy arm at approximately 72%.   
Section:  10.2 Sample Size Considerations, Paragraph 2 
Replace:   
Based on a two-sided chi-square test with 90% power, 130 subjects per arm are 
required at randomization. 
With: 
Based on a two-sided chi-square test with 90% power, 100 subjects per arm are 
required at randomization. 
Section:  10.2 Sample Size Considerations, Paragraph 3 
Replace:   
Using an assumed attrition rate of 30% in the open-label run-in period, due to exclusion 
of subjects with disease worsening during the run-in period, or other reasons, 
approximately 465 subjects will be enrolled in order to have approximately 325 subjects 
randomized in a 2:2:1 ratio to one of three treatment groups:  etanercept monotherapy 
(n = 130), methotrexate monotherapy (n = 130) and etanercept plus methotrexate 
combination therapy (n = 65).  Amgen may choose to alter the sample size of subjects 
enrolled in order to ensure that approximately 325 subjects are randomized to treatment.  
With: 
Using an assumed attrition rate of 30% in the open-label run-in period, due to exclusion 
of subjects with disease worsening during the run-in period, or other reasons, 
approximately 358 subjects will be enrolled in order to have approximately 250 subjects 
randomized in a 2:2:1 ratio to one of three treatment groups:  etanercept monotherapy 
(n = 100), methotrexate monotherapy (n = 100), and etanercept plus methotrexate 
combination therapy (n = 50).  Amgen may choose to alter the sample size of subjects 
enrolled in order to ensure that approximately 250 subjects are randomized to treatment.  


Product:  Etanercept 
Protocol Number:  20110186 
Date:  20 December 2016 
Page 1 of 33 
CONFIDENTIAL 
 
Amendment 4 
Protocol Title:  A Randomized Withdrawal Double-blind Study of Etanercept 
Monotherapy Compared to Methotrexate Monotherapy for Maintenance of 
Remission in Subjects With Rheumatoid Arthritis 
 
Amgen Protocol Number (Etanercept) 20110186 
EudraCT Number:  2014-004868-38 
Amendment Date: 
20 December 2016 
Rationale: 
This protocol amendment change document captures changes made from Version 2 to 
Version 3, as well as changes made from Version 3 to Version 4.  Version 3 was 
approved 03 November 2016; however, submission of the protocol to sites was halted 
once it was learned there would be updates specific to VHP countries in Europe. 
This protocol is being amended to: 
• 
Update clinical hypothesis to align with the primary objective of the study. 
• 
Update CTCAE grading version to 4.0 to reflect the most recent version. 
• 
Update inclusion and exclusion criteria in order to decrease the stringency of 
subject eligibility. 
• 
Reduce strictness of subject re-screening criteria. 
• 
Reduce study sample size due to adjustments in estimated effect sizes for 
treatment groups. 
• 
Remove prior use of a biologic agent as a covariate influencing primary and 
secondary endpoints. 
• 
Remove sequential testing in order to align with the updated clinical hypothesis. 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  03 November 2016 
Page 1 of 32 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Randomized Withdrawal Double-blind Study of Etanercept 
Monotherapy Compared to Methotrexate Monotherapy for Maintenance of 
Remission in Subjects With Rheumatoid Arthritis 
 
Amgen Protocol Number (Etanercept) 20110186 
EudraCT Number:  2014-004868-38 
Amendment Date: 
03 November 2016 
 
Rationale: 
This protocol is being amended to: 
• 
Update clinical hypothesis to align with the primary objective of the study. 
• 
Update CTCAE grading version to 4.0 to reflect the most recent version. 
• 
Update inclusion and exclusion criteria in order to decrease the stringency of 
subject eligibility. 
• 
Reduce study sample size due to adjustments in estimated effect sizes for 
treatment groups. 
• 
Remove prior use of a biologic agent as a covariate influencing primary and 
secondary endpoints. 
• 
Remove sequential testing in order to align with the updated clinical hypothesis. 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  30 October 2015 
Page 1 of 4 
CONFIDENTIAL 
 
Amendment 2 
Protocol Title:  A Randomized Withdrawal Double-blind Study of Etanercept 
Monotherapy Compared to Methotrexate Monotherapy for Maintenance of 
Remission in Subjects With Rheumatoid Arthritis 
 
Amgen Protocol Number (Etanercept) 20110186 
EudraCT Number:  2014-004868-38 
 
Original Protocol: 
29 July 2014 
Amendment 1 Date: 
18 May 2015 
Superseding Amendment 1 Date:   08 July 2015 
Amendment 2 Date: 
30 October 2015 
Rationale: 
The protocol is being amended to be consistent with international regulations and 
requirements. 


Product:  Etanercept 
Protocol Number:  20110186 
Date:  18 May 2015 
Page 1 of 10 
CONFIDENTIAL 
 
Amendment 1 
Protocol Title:  A Randomized Withdrawal Double-blind Study of Etanercept 
Monotherapy Compared to Methotrexate Monotherapy for Maintenance of 
Remission in Subjects With Rheumatoid Arthritis 
 
Amgen Protocol Number (Etanercept) 20110186 
 
 
Original Protocol: 
29 July 2014 
Amendment Date: 
18 May 2015 
Rationale: 
The protocol is being amended to: 
• 
Provide clarification for reporting hepatotoxicity as a serious adverse event 
• 
Clarify indications regarding use of etanercept in the US and Canada, and add 
medical information phone number as a reference for countries other than US and 
Canada 
• 
Provide clarification for inclusion criteria for etanercept use, specifying the dose 
• 
Provide clarification for inclusion criteria for methotrexate use, accommodating 
conversion from subcutaneous to oral route 
• 
Provide clarification regarding formulation of methotrexate, as it is available in 
tablets, but will be encapsulated when given as placebo 
• 
Provide clarifications regarding joint assessments, to strengthen wording related to 
continuity of assessors in the study, and allowing for assessments by principal 
investigators 
• 
Provide updates throughout to reflect the number of global participating sites 
• 
Add the EudraCT number 
• 
Add medical information phone number as a reference for countries other than US 
and Canada 
• 
Make minor corrections and clarifications throughout 

SAP_001.pdf: 
16.1.9
Documentation of Statistical Methods
Product: 
Date: 
Etanercept
Clinical Study Report:  20110186
23 April 2020
Page 1


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 1 
 
 
STATISTICAL ANALYSIS PLAN 
A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy 
Compared to Methotrexate Monotherapy for Maintenance of Remission in 
Subjects With Rheumatoid Arthritis 
 
 
Protocol Number: 
20110186 
Version: 
Version 2.0 
Date: 
7 January 2020 
Author: 
 
 
Product: 
Date: 
Etanercept
Clinical Study Report:  20110186
23 April 2020
Page 2


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 2 
 
Table of Contents 
Table of Abbreviations ...................................................................................................... 5 
1. 
Introduction .............................................................................................................. 7 
2. 
Objectives ................................................................................................................ 7 
2.1 
Primary Objective ......................................................................................... 7 
2.2 
Secondary Objectives ................................................................................... 7 
2.3 
Safety Objective ........................................................................................... 7 
2.4 
Exploratory Objectives .................................................................................. 7 
3. 
Study Overview ........................................................................................................ 7 
3.1 
Study Design ................................................................................................ 7 
3.2 
Sample Size ................................................................................................. 8 
4. 
Study Endpoints and Covariates .............................................................................. 9 
4.1 
Study Endpoints ........................................................................................... 9 
4.1.1 
Primary Endpoint .......................................................................... 9 
4.1.2 
Secondary Endpoints ................................................................. 10 
4.1.3 
Safety Endpoints ........................................................................ 10 
4.1.4 
Exploratory Endpoints ................................................................ 10 
4.2 
Planned Covariates .................................................................................... 11 
5. 
Hypotheses and/or Estimations .............................................................................. 12 
6. 
Definitions .............................................................................................................. 13 
6.1 
Study Time Points ...................................................................................... 13 
6.2 
Primary Endpoint ........................................................................................ 15 
6.3 
Basic Definitions ......................................................................................... 16 
6.4 
Derived Variables ....................................................................................... 18 
6.5 
Study Endpoints ......................................................................................... 19 
7. 
Analysis Subsets .................................................................................................... 25 
7.1 
Primary Analysis Set .................................................................................. 25 
7.2 
Full Analysis Set ......................................................................................... 25 
7.3 
Disease-Worsening Analysis Set ............................................................... 25 
7.4 
Rescue Analysis Set ................................................................................... 25 
7.5 
Run-In Failure Analysis Set ........................................................................ 25 
7.6 
Run-In Safety Analysis Set ......................................................................... 25 
7.7 
Post-Run-In Safety Analysis Set ................................................................ 25 
8. 
Subgroup Analyses ................................................................................................ 26 
9. 
Interim Analysis and Early Stopping Guidelines ..................................................... 26 
10. 
Data Screening and Acceptance ............................................................................ 26 
10.1 
General Principles ...................................................................................... 26 
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Date: 
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Clinical Study Report:  20110186
23 April 2020
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Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 3 
 
10.2 
Data Handling and Electronic Transfer of Data .......................................... 26 
10.3 
Handling of Missing and Incomplete Data .................................................. 26 
10.3.1 
Missing Baseline Evaluation ....................................................... 26 
10.3.2 
Missing Post-Baseline Evaluation .............................................. 26 
10.3.3 
Missing Components of Composite Endpoints ........................... 26 
10.3.4 
Missing and Incomplete Dates ................................................... 26 
10.4 
Detection of Bias ........................................................................................ 27 
10.5 
Outliers ....................................................................................................... 28 
10.6 
Distributional Characteristics ...................................................................... 28 
10.7 
Validation of Statistical Analyses ................................................................ 28 
11. 
Statistical Methods of Analysis ............................................................................... 29 
11.1 
General Considerations .............................................................................. 29 
11.2 
Subject Accountability ................................................................................ 29 
11.3 
Important Protocol Deviations .................................................................... 30 
11.4 
Demographic and Baseline Characteristics ................................................ 30 
11.5 
Efficacy Analyses ....................................................................................... 30 
11.5.1 
Primary Efficacy Endpoint .......................................................... 31 
11.5.1.1 
Primary Analysis of Primary Estimand ..................... 31 
11.5.1.2 
Sensitivity/Exploratory Analyses of 
Primary Estimand ..................................................... 31 
11.5.2 
Secondary Efficacy Endpoint(s) ................................................. 31 
11.5.3 
Exploratory Endpoints ................................................................ 36 
11.6 
Safety Analyses .......................................................................................... 42 
11.6.1 
Adverse Events .......................................................................... 42 
11.6.2 
Laboratory Test Results ............................................................. 42 
11.6.3 
Vital Signs ................................................................................... 42 
11.6.4 
Exposure to Investigational Product ........................................... 42 
11.6.5 
Exposure to Concomitant Medication ......................................... 43 
12. 
Changes From Protocol-specified Analyses .......................................................... 43 
13. 
Literature Citations / References ............................................................................ 45 
14. 
Appendices ............................................................................................................ 46 
List of Tables 
Table 1.  Primary and Secondary Endpoints Summary Table ........................................ 33 
Table 2.  Exploratory Endpoints Summary Table ............................................................ 38 
 
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Date: 
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Clinical Study Report:  20110186
23 April 2020
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Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 4 
 
List of Appendices 
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ....................................................... 47 
Appendix B.  Code Fragments ........................................................................................ 53 
Appendix C.  Reference Values/Toxicity Grades ............................................................ 57 
Appendix D.  Patient-reported Outcome Forms/Instruments .......................................... 58 
Appendix E.  Concomitant Medications .......................................................................... 59 
 
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Date: 
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Clinical Study Report:  20110186
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Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 5 
 
Table of Abbreviations 
Abbreviation 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CDAI 
Clinical disease activity index 
eCRF 
Electronic case report form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DAS28-CRP 
Disease activity score (28 joint) calculated using the C-reactive 
protein formula 
DAS28-ESR 
Disease activity score (28 joint) calculated using the erythrocyte 
sedimentation rate formula 
DW 
Disease-Worsening 
EOS 
End of Study 
EOT 
End of Treatment 
ESR 
Erythrocyte Sedimentation Rate 
ET 
Early termination 
ETN 
Etanercept 
HAQ-DI 
Disability Index of the Health Assessment Questionnaire 
ICH 
International Conference on Harmonisation 
IP 
Investigational product 
IPD 
Important protocol deviation 
IXRS 
Interactive Voice and Web Response System  
LDA 
Low Disease Activity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTX 
Methotrexate 
NRI 
Non-responder Imputation 
PhGA 
physician global assessment of arthritis disease activity 
PtGA 
patient global assessment of arthritis disease activity 
PRO 
Patient reported outcomes 
QW 
Once weekly 
RA 
Rheumatoid arthritis 
SAP 
Statistical analysis plan 
Page 1 of 2 
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Date: 
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Clinical Study Report:  20110186
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Page 6


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 6 
 
Abbreviation 
Definition/Explanation 
SDAI 
Simplified Disease Activity Index 
SF-36 
Medical Outcomes Short Form-36 Questionnaire 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cells 
WHODRUG 
World Health Organization Drug 
Page 2 of 2 
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Date: 
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Clinical Study Report:  20110186
23 April 2020
Page 7


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
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 etanercept Study 20110186 
dated 17 October 2017. The scope of this plan includes the final analysis that is planned 
and will be executed by the Biostatistics department unless otherwise specified. 
2. 
Objectives 
2.1 
Primary Objective 
To evaluate the efficacy of etanercept monotherapy compared to methotrexate 
monotherapy on maintenance of remission in subjects with rheumatoid arthritis (RA) who 
were on etanercept plus methotrexate combination therapy. 
2.2 
Secondary Objectives 
To evaluate the efficacy of etanercept plus methotrexate therapy compared to 
methotrexate monotherapy on maintenance of remission. 
To evaluate the efficacy of 1) etanercept monotherapy compared to methotrexate 
monotherapy and 2) etanercept plus methotrexate therapy compared to methotrexate 
monotherapy on: 
• 
disease activity 
• 
disease-worsening and time to disease-worsening 
• 
remission and time to recapture remission after rescue treatment 
2.3 
Safety Objective 
To evaluate the safety of etanercept and methotrexate 
2.4 
Exploratory Objectives 
• 
To evaluate Patient Reported Outcomes (PRO) 
• 
To investigate potential biomarkers of disease activity and response to 
etanercept. 
• 
To investigate the effects of genetic variation in disease genes and drug target 
genes on RA and/or subject response to etanercept.  
3. 
Study Overview 
3.1 
Study Design 
This is a Phase 3, multicenter, randomized withdrawal, double-blind controlled study in 
subjects with RA on etanercept plus methotrexate who are in very good disease control 
for 6 months prior to study entry.  The study will consist of a 30-day screening period, a 
Product: 
Date: 
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Clinical Study Report:  20110186
23 April 2020
Page 8


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 8 
 
24-week open-label run-in period, a 48-week double-blind treatment period and a 30-day 
safety follow-up period. 
The study will enroll approximately 358 subjects. During the run-in period subjects will 
receive open-label etanercept and methotrexate at the same dose they were receiving 
during screening. It is expected that approximately 30% of subjects will early terminate 
the run-in period. Amgen may choose to alter the sample size of subjects enrolled in 
order to ensure that approximately 250 subjects are randomized to treatment.  
Approximately 250 subjects will be randomly assigned in a 2:2:1 ratio to one of three 
treatment groups: 
 
Etanercept 50 mg weekly by subcutaneous injection plus oral placebo for 
methotrexate (n = 100) 
 
Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept (n = 100) 
 
Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 
25 mg weekly (n = 50) 
Subjects randomized to the etanercept plus methotrexate group and the methotrexate 
monotherapy group will receive methotrexate at the same dose they were receiving at 
screening and during the run-in period.  
3.2 
Sample Size 
The sample size was determined from a hypothesis of superiority of etanercept 
monotherapy over methotrexate monotherapy. The proportion of subjects achieving 
SDAI remission after 52 weeks of double-blind treatment in the PRESERVE and 
COMET studies was used to estimate the treatment effects. PRESERVE was a 
two-period study conducted in subjects with RA who had moderate disease activity 
despite a stable dose of oral methotrexate for a minimum of 8 weeks at the time of 
screening.  Among all subjects who were in SDAI remission at both week 28 and 
week 36 (the last two visits of the open-label run-in period), the proportion of subjects 
who were still in remission after the 52-week double-blind period was 86.1% and 38.1% 
for the etanercept plus methotrexate therapy and methotrexate monotherapy treatment 
groups, respectively. COMET was a two-period study conducted in subjects with active 
early RA.  Among all subjects who received etanercept plus methotrexate therapy in 
Period 1 and were in SDAI remission at week 52, the last visit of Period 1, the proportion 
of subjects who were in still in remission after the 52-week double-blind Period 2 was 
78.3% and 72.4%, respectively, for the etanercept plus methotrexate therapy and 
etanercept monotherapy treatment groups. Given key differences noted in this study, 
including the sustained period of remission prior to withdrawal, the response rate in the 
methotrexate monotherapy arm is approximated to be higher at 50%, with the response 
Product: 
Date: 
Etanercept
Clinical Study Report:  20110186
23 April 2020
Page 9


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 9 
 
rate in the etanercept monotherapy arm at approximately 72%. It is expected that 
compared to PRESERVE, subjects in the current study will have more stable disease at 
the time of randomization. Namely, subjects must be in very good disease control for 
6 months prior to study entry and must be in SDAI remission at the end of a 24-week 
open-label run-in period.  
The sample size is based on the adequacy to evaluate the efficacy of etanercept 
monotherapy compared to methotrexate monotherapy as measured by the primary 
endpoint of SDAI remission at week 48 at a significance level of 0.05. The sample size 
was also ensured to be sufficient to evaluate the efficacy of the etanercept plus 
methotrexate treatment arm compared to methotrexate monotherapy.  Based on a 
two-sided chi-square test with 90% power, 100 subjects per arm are required at 
randomization. 
Using an assumed attrition rate of 30% in the open-label run-in period, due to exclusion 
of subjects with Disease-Worsening during the run-in period, or other reasons, 
approximately 358 subjects will be enrolled in order to have approximately 250 subjects 
randomized in a 2:2:1 ratio to one of three treatment groups: etanercept monotherapy  
(n = 100), methotrexate monotherapy (n = 100) and etanercept plus methotrexate 
combination therapy (n = 50). Amgen may choose to alter the sample size of subjects 
enrolled in order to ensure that approximately 250 subjects are randomized to treatment.  
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoint  
• 
SDAI remission (≤ 3.3) at week 48  
The primary estimand consists of: 
• 
Target population – patients with a history of moderate to severe rheumatoid 
arthritis (RA) who are on etanercept and methotrexate combination therapy and 
who are in very good disease control. 
• 
Endpoint – SDAI remission (SDAI<=3.3) at week 48 
• 
Intercurrent events – there are 2 intercurrent events: first, discontinuation of IP 
before week 48; second, disease-worsening after randomization which triggers 
initiation of rescue therapy. Treatment effects will be estimated for subjects 
regardless of whether subjects complete 48 weeks of IP.  
• 
Summary measure – difference in the proportion of subjects achieving 
SDAI<=3.3 (yes/no) at Week 48 on etanercept monotherapy and that of subjects 
achieving SDAI<=3.3 (yes/no) at Week 48 on methotrexate monotherapy. 
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In summary, the primary estimand is the difference in proportions of subjects in 
etanercept monotherapy and methotrexate monotherapy maintaining SDAI remission at 
Week 48 without experiencing disease-worsening on study in adults with a history of 
moderate to severe RA who have been on etanercept and methotrexate combination 
therapy and in very good RA disease control, regardless of adherence to treatment and 
completion of 48 weeks of IP.  
4.1.2 
Secondary Endpoints 
• 
SDAI score and change from baseline at all measured timepoints 
• 
DAS-28-ESR and change from baseline at all measured timepoints 
• 
DAS-28-CRP and change from baseline at all measured timepoints 
• 
CDAI and change from baseline at all measured timepoints 
• 
SDAI remission (≤ 3.3) at all measured timepoints 
• 
Boolean remission at all measured timepoints 
• 
Disease-Worsening defined as an SDAI > 3.3 and ≤ 11 during two consecutive 
visits at least 2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate 
visits or SDAI > 11 after randomization 
• 
Time to Disease-Worsening as an SDAI > 3.3 and ≤ 11 during two consecutive 
visits at least 2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate 
visits or SDAI > 11 after randomization 
In subjects that receive rescue treatment during the double-blind treatment period 
• 
Time to recapture SDAI remission after starting rescue treatment 
• 
SDAI remission at week 48 
4.1.3 
Safety Endpoints 
• 
Adverse events 
• 
Serious adverse events 
• 
Laboratory parameters 
4.1.4 
Exploratory Endpoints 
• 
Components of SDAI at all measured timepoints  
• 
HAQ-DI at all measured timepoints 
• 
SF-36 domains, physical component summary, and mental component summary 
at all measured timepoints 
Additional exploratory endpoints pertaining to the Run-In Period are: 
• 
SDAI score at run-in visits 
• 
Time to run-in failure 
• 
Time to randomization failure  
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Additional exploratory endpoints pertaining to the Double-Blind Period are: 
• 
Observed SDAI Remission (<= 3.3) at all timepoints 
• 
Patient Global Assessment of Joint Pain at all timepoints 
• 
SDAI LDA at all timepoints 
• 
DAS28-ESR remission at all timepoints 
• 
DAS28-ESR LDA at all timepoints 
• 
DAS28-CRP remission at all timepoints 
• 
Reason for Disease-Worsening 
• 
SDAI score at Disease-Worsening 
• 
Disease Activity at Disease-Worsening 
In subjects that receive rescue treatment and in subjects that fulfill disease-worsening 
criteria during the double-blind treatment period: 
• 
Observed SDAI remission (yes/no) at visits following rescue  
• 
SDAI LDA (yes/no) at visits following rescue 
• 
Time to SDAI LDA 
• 
SDAI score on Disease-Worsening Date and at subsequent visits 
• 
Change in SDAI from Disease-Worsening Date and at subsequent visits 
• 
DAS28-ESR remission (yes/no) at visits following rescue 
• 
Time to DAS28-ESR remission 
• 
DAS28-ESR LDA (yes/no) at visits following rescue 
• 
DAS28-CRP remission (yes/no) at visits following rescue 
• 
Time to DAS28-CRP remission. 
4.2 
Planned Covariates 
The following baseline covariates will be considered to assess their influence on the 
primary and secondary endpoints:  
• 
age (years) (continuous) 
• 
sex (male, female) 
• 
race (Caucasian, non-Caucasian) 
• 
ethnicity (Hispanic or Latino vs Non-Hispanic or Latino) 
• 
disease duration (in years)  
• 
baseline methotrexate dose (continuous) 
• 
additional covariates will be evaluated (baseline methotrexate dose  
[<15 mg / ≥15 mg], smoking [never, former, current])   
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The rationale for inclusion of baseline methotrexate dose [<15 mg / ≥15 mg] and 
smoking status is provided in Section 12. 
Subgroup analyses, which would be considered exploratory, may be performed if an 
examination of the above covariates suggests that any treatment difference for the 
primary and secondary endpoints depends on any baseline covariates. 
5. 
Hypotheses and/or Estimations 
There are two clinical hypotheses. First, 
Etanercept monotherapy is superior to methotrexate monotherapy for maintaining 
remission in subjects with RA who were on etanercept plus methotrexate therapy as 
measured by the proportion of subjects who maintain SDAI remission (SDAI ≤ 3.3) at 
week 48. 
Specifically, the null (H0) and alternative (H1) hypotheses are defined as follows: 
H0: The difference in proportion of subjects who maintain SDAI remission at week 48 in 
the etanercept monotherapy arm and in that of the methotrexate monotherapy 
arm = 0   
H1: The difference in proportion of subjects who maintain SDAI remission at week 48 in 
the etanercept monotherapy arm and in that of the methotrexate monotherapy 
arm ≠ 0.   
Second, 
Etanercept and Methotrexate combination therapy is superior to methotrexate 
monotherapy for maintaining remission in subjects with RA who were on etanercept 
plus methotrexate therapy as measured by the proportion of subjects who maintain 
SDAI remission (SDAI ≤ 3.3) at week 48. 
Specifically, the null (H0) and alternative (H1) hypotheses are defined as follows: 
H0: The difference in proportion of subjects who maintain SDAI remission at week 48 in 
the etanercept and methotrexate combination arm and in that of the methotrexate 
monotherapy arm = 0   
H1: The difference in proportion of subjects who maintain SDAI remission at week 48 in 
the etanercept and methotrexate combination arm and in that of the methotrexate 
monotherapy 
arm ≠ 0.   
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6. 
Definitions 
6.1 
Study Time Points 
Enrollment Date 
A subject’s Enrollment Date is defined as the date he or she has met all Part 1 eligibility 
criteria and the enrollment call in the IXRS system has been completed. 
Part 1/Run-in Period 
The 24-week period after enrollment and prior to randomization. Specifically, the period 
begins when a subject initiates treatment with open-label run-in etanercept and/or 
open-label run-in methotrexate per the eCRF at the same dose he or she was receiving 
at screening. There are three visits associated with the Run-in Period: Run-in Visit 1, 
Run-in Visit 2, and Run-in Visit 3. 
Run-In Day 1 
A subject’s Run-In Day 1 is defined as the date of the first dose of IP administration 
during Part 1. 
Run-In Day 
A subject’s Run-In Day = (Visit Date – Run-In Day 1 date) + 1. 
Run-In Failure Date 
A subject’s Run-In Failure Date is the date the subject ended run-in due to protocol 
specified criteria per the eCRF. 
Randomization Failure Date 
A subject’s Randomization Failure Date is the date the subject ended run-in due to any 
reason and was not randomized. 
End-of Run-In Date 
A subject’s End-of Run-In Date is the date subject ends the run-in period per the CRF. 
Randomization Date 
A subject’s Randomization Date is the date when a randomization number is assigned to 
him or her through the Interactive Voice/Web Response System (IXRS). 
Study Day 1 
A subject’s Study Day 1 is defined as the date of the first dose of IP administration after 
randomization, or the randomization date if the subject is not dosed. 
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Baseline 
The last measurement for the endpoint of interest taken on or prior to Study Day 1 and 
after Run-In Visit 3. Hematology and chemistry profiles were not assessed on Day 1; 
their Run-in Visit 3 values will be used when reporting baseline. 
Baseline for Concomitant Medications 
Run-In Period Baseline for Concomitant Medications is enrollment date, and Post-Run-In 
Period Baseline for Concomitant Medications is randomization date. 
Study Day  
For a given study visit, the study day for a subject is defined as: 
Study Day = (Visit Date – Study Day 1 date) + 1. 
Part 2/Treatment Period 
The up-to 48-week double-blind period beginning with Study Day 1 and ending with the 
End of Study date.  
SDAI Assessment Datea 
The SDAI Assessment Date is the latest date of the assessments for Tender Joint 
Count, Swollen Joint Count, Physician Global Assessment, Patient Global Assessment, 
and CRP for a given SDAI score. 
Disease-Worsening Date (DW Date) 
A subject’s Disease-Worsening Date is the first Visit Date in which the subject meets the 
definition for Disease-Worsening. With the exception of analysis using multiple 
imputation method, Disease-Worsening classification is based on observed SDAI values 
only. Each subject will have at most one DW Date. A subject’s disease-worsening date 
is used to define his/her Disease-Worsening Baseline. 
Rescue Date 
A subject’s rescue date is the Visit Date in which he or she first receives rescue therapy 
as identified by the Investigational Product Administration (Rescue Therapy Etanercept) 
or Investigational Product Administration (Rescue Therapy Methotrexate) form. 
Rescue Therapy Period  
For the Rescue Analysis Set as defined in Section 7.4, the Rescue Therapy Period 
begins with the Rescue Date through the EOS Date.  
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Disease-Worsening Analysis Visit (DW_visit) 
The DW_visit defines the analysis visit after a subject fulfills disease-worsening criteria. 
Details of DW_visit derivation are in Appendix A. 
Rescue Analysis Visit (Rescue_visit) 
Rescue_visits define the analysis visits after a subject initiates rescue therapy. Details of 
Rescue_Visit derivation are in Appendix A. 
End of Treatment (EOT) 
The End of Treatment for a subject is the subject’s last assessment for the 
protocol-specified treatment phase of the study. 
End of Study Date 
The End of Study Date for a subject is the date the subject completes the safety 
follow-up phone call, or the date of the Early Termination (ET) visit if no safety follow-up 
phone call is completed. The date the subject has ended the study is recorded on the 
End of Study Electronic Case Report Form (eCRF). 
End of Study 
The End of Study is the date when the last subject across all sites is assessed or 
receives an intervention for evaluation in the study (ie, last subject last visit). 
6.2 
Primary Endpoint 
Primary Endpoint - SDAI remission at week 48 
The primary endpoint of SDAI remission is defined as achievement of SDAI ≤ 3.3 at 
Week 48 without fulfilling the definition of disease-worsening during the study. 
Primary endpoint of SDAI remission will be defined as follows: 
• 
SDAI_remission_maintenance (<= 3.3) at Week 48 = 1, 
if SDAI ≤ 3.3 at Week 48 AND subject did not fulfill the definition of 
disease-worsening during the study; 
• 
SDAI_remission_maintenance (<= 3.3) at Week 48 = missing, 
if subject has no Week 48 SDAI value AND subject did not fulfill the definition 
of disease-worsening during the study; 
• 
SDAI_remission_maintenance (<= 3.3) at Week 48 = 0, 
otherwise. 
Different statistical methods for addressing missing SDAI remission status are 
addressed in Section 11.5. 
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6.3 
Basic Definitions 
Age 
Number of years at time of enrollment as recorded on the electronic case report form. 
Investigational Product (IP) 
Etanercept (or placebo for etanercept) and methotrexate (or placebo for methotrexate).   
Adverse Event 
In addition to the International Conference on Harmonisation (ICH) Guidance definition, 
an adverse event also includes any occurrence or worsening of a pre-existing medical 
condition. 
Treatment-Emergent Adverse Event (TEAE) 
TEAE during the run-in period is an adverse event that occurs on or after Run-In Day 1 
(as determined by adverse event start date and pre-treatment flag NE ‘Y’ on the Events 
CRF) and up to Study Day 1. TEAE during the double-blind period is an adverse event 
that occurs on or after Study Day 1 (as determined by adverse event start date and 
pre-treatment flag NE ‘Y’ on the Events CRF) and up to 30 days after the last dose of IP. 
Subject Incidence Rate 
The subject incidence rate for a given event in a given time period is defined as the 
number of subjects with a first reported occurrence of the event divided by the number of 
subjects who entered the time period. For subjects with multiple occurrences of the 
same event, the event will only be counted once per subject.   
Actual treatment received 
Safety analyses will be performed on the Safety Analysis Sets, which analyzes subjects 
by actual treatment received. Actual treatment is defined below: 
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Actual Treatment In the Open-Label Run-In Period 
• 
Actual Treatment = Etanercept + Methotrexate 
Actual Treatment In the Double-Blind Treatment Period 
If a subject receives 
- any active methotrexate and no active etanercept, then his/her actual 
treatment assignment is methotrexate 
- any active etanercept and no active methotrexate, then his/her actual 
treatment assignment is etanercept 
- any active etanercept and any active methotrexate, then his/her actual 
treatment assignment is etanercept + methotrexate 
- no active etanercept and no active methotrexate, then he/she received 
no actual treatment and will not be included in the safety analysis set 
Actual Treatment In the Rescue Therapy Period 
• 
Actual Treatment = Etanercept + Methotrexate 
Run-in Failure 
The subjects who participate in the run-in period but fulfill any of the below criteria are 
deemed not eligible for randomization and are considered run-in failures.  
• 
SDAI > 3.3 at run-in visit 3 
• 
if female and not at least 2 years postmenopausal or having a history of 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, does not have 
a negative urine pregnancy test at baseline 
• 
has any clinically significant change in the Part 1 eligibility criteria during the 
run-in period 
• 
SDAI > 3.3 and ≤ 11 on two consecutive visits at least two weeks apart 
OR  
SDAI > 3.3 and ≤ 11 on two or more separate visits 
OR 
SDAI > 11 at any time during the run-in period  
• 
Clinically significant laboratory abnormality in run-in which per investigator poses 
a safety risk, will prevent the subject from completing the study, or will interfere 
with the interpretation of the study results during the run-in period. 
Rescue Therapy 
After randomization, if a subject experiences Disease-Worsening as defined in 
Section 6.3, he/she will initiate rescue treatment with etanercept 50 mg once weekly 
(QW) plus methotrexate (10 to 25 mg). Those assigned to the etanercept plus 
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methotrexate arm will continue on the assigned treatments, but are still considered to be 
on rescue therapy once the open-label rescue etanercept or open-label methotrexate 
eCRF forms are used. Subjects will receive methotrexate at the same dose that they 
were receiving at screening. 
Original treatment assignments will remain blinded. Dispensing of etanercept plus 
methotrexate rescue therapy will be managed via the Interactive Voice and Web 
Response System (IXRS). 
6.4 
Derived Variables 
Duration of Rheumatoid Arthritis 
The number of years between the date of diagnosis (DXDT) and Run-in Day 1, rounded 
to one decimal place, is given by formula below to calculate the duration: 
Observed portion  Missing portion  
Formula to Calculate Duration  
Year, Month, Day 
 
(Run-in Day 1 – DXDT + 1)/365.25 
Year, Month  
Day  
[Year(Run-in Day 1)-Year(DXDT)]+ [Month(Run-in 
Day 1)-Month(DXDT)]/12 
*if duration equals 0, add 1 month or 1/12 years (to 
avoid a disease duration of 0) 
Year 
Month, Day 
[Year(Run-in Day 1)-Year(DXDT)]   
*if duration equals 0, add 1 month or 1/12 years (to 
avoid a disease duration of 0) 
Time to Disease-Worsening  
Time to Disease-Worsening = DW Date – Study Day 1 + 1 
The subjects without Disease-Worsening will be censored at their last SDAI assessment 
date. 
Only time to subject’s first instance of disease-worsening will be evaluated. 
Time-to-Event (for Rescue Analysis Set) 
Time-to-Event = Earliest Date of Achievement of Event of Interest During the Rescue 
Therapy Period – Rescue Date + 1 
For example, for subjects who recapture SDAI remission: 
Time-to-Recapture SDAI remission = Earliest Date of Achievement of Observed SDAI 
remission During the Rescue Therapy Period – Rescue Date + 1 
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The subjects who do not experience the event of interest will be censored at their last 
SDAI assessment date. 
Only time to subject’s first instance of each event of interest will be evaluated. 
Time-to-Event (for Disease-Worsening Analysis Set) 
Time-to-Event = Earliest Date of Achievement of Event of Interest After 
Disease-Worsening – DW Date + 1 
For example, for subjects who recapture SDAI remission: 
Time-to-Recapture SDAI remission = Earliest Date of Achievement of Observed SDAI 
remission After Disease-Worsening – DW Date + 1 
The subjects who do not experience the event of interest will be censored at their last 
SDAI assessment date. 
Only time to subject’s first instance of each event of interest will be evaluated. 
6.5 
Study Endpoints 
Patient Global Assessment of Joint Pain (PtGAJP) 
An assessment of the severity of the subject’s joint pain (0=no pain at all, 100=worst 
pain imaginable) completed by the patient using a visual analog scale (VAS) in mm.  
Patient Global Assessment of Disease Activity (PtGA) 
A global assessment of the subject’s arthritis (0=no arthritis activity at all, 100=worst 
arthritis activity imaginable) completed by the patient using a visual analog scale (VAS). 
Physician Global Assessment of Disease Activity (PhGA) 
A global assessment of the subject’s arthritis (0=no activity at all, 100=worst activity 
imaginable) completed by the physician using a visual analog scale (VAS).  
Swollen Joint Count 
A score that assesses the presence or absence of swelling in 66 joints. There are also a 
28-joint Swollen Joint Count and a 28-joint Plus Feet and Ankles Swollen Joint Count.  
Details of the scoring algorithm are described in Appendix A. 
Tender Joint Count 
A score that assesses the presence or absence of tenderness in 68 joints. There are 
also a 28-joint Tender Joint Count and a 28-joint Plus Feet and Ankles Tender Joint 
Count.  Details of the scoring algorithm are described in Appendix A. 
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Simplified Disease Activity Index (SDAI) 
A composite score that is based on the number of tender and swollen joints using a 
28-joint count, PhGA (0-10 visual analog scale), PtGA (0-10 visual analog scale), and 
CRP in mg/dL.  A higher score represents worse disease.  
Details of the scoring algorithm are described in Appendix A. 
SDAI Remission at Analysis Visit k 
For Analysis Visits other than Week 48, SDAI Remission at a given Visit will be derived 
using the same approach as in Section 6.2, replacing Week 48 with the Analysis Visit 
Week k, and replacing “subject did not fulfill the definition of disease-worsening during 
the study” with “subject did not previously fulfill the definition of disease-worsening”. 
Specifically,  
• 
SDAI_remission_maintenance (<= 3.3) at Week k = 1, 
if SDAI ≤ 3.3 at Week k AND subject did not previously fulfill the definition of 
disease-worsening; 
• 
SDAI_remission_maintenance (<= 3.3) at Week k = missing, 
if subject has no Week k SDAI value AND subject did not previously fulfill the 
definition of disease-worsening; 
• 
SDAI_remission_maintenance (<= 3.3) at Week k = 0, 
otherwise. 
Observed SDAI Remission at Analysis Visit k 
• 
Observed_SDAI_Remission at Analysis Visit k =1, 
if SDAI ≤ 3.3 at Analysis Visit k; 
• 
Observed_SDAI_remission (<= 3.3) at Analysis Visit k = missing, 
if subject has no SDAI value at Analysis Visit k; 
• 
Observed_SDAI_remission (<= 3.3) at Analysis Visit k = 0, 
if SDAI > 3.3 at Analysis Visit k. 
Observed SDAI Remission at DW Visit (or Rescue Visit) k 
• 
Observed_SDAI_Remission at DW Visit (or Rescue Visit) k = 1, 
if SDAI ≤ 3.3 at DW Visit k; 
• 
Observed_SDAI_remission (<= 3.3) at DW Visit (or Rescue Visit) k = missing, 
if subject has no SDAI value at DW Visit k; 
• 
Observed_SDAI_remission (<= 3.3) at DW Visit (or Rescue Visit) k = 0, 
if SDAI > 3.3 at DW Visit k. 
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Disease Activity 
For a specific timepoint, subjects are classified as having 
• 
SDAI Low Disease Activity (LDA): 3.3 < SDAI ≤ 11 
• 
SDAI Moderate Disease Activity (MDA): 11 < SDAI ≤ 26 
• 
SDAI High Disease Activity (HDA): SDAI > 26 
Disease-Worsening 
During the double-blind treatment period, disease-worsening for the study is defined as: 
• 
SDAI > 3.3 and ≤ 11 on two consecutive visits at least two weeks apart OR  
• 
SDAI > 3.3 and ≤ 11 on three or more separate visits OR 
• 
SDAI > 11 at anytime   
Disease-Worsening may be assessed at a regularly scheduled visit or at an 
unscheduled Disease Assessment visit. Subjects will remain on study and complete all 
study visits. 
Disease Activity Score using the erythrocyte sedimentation rate formula (DAS28-ESR) 
A modified composite index that was designed to measure disease activity in subjects 
using the number of tender and swollen joints based upon a 28-joint count, ESR in 
mm/hr, and a 100 mm visual analog scale measuring the subject’s general health.   
A higher score represents worse disease. 
Details of the scoring algorithm are described in Appendix A. 
Disease Activity Score using the C-reactive protein formula (DAS28-CRP) 
A composite index that was designed to measure disease activity in subjects using the 
number of tender and swollen joints based upon a 28-joint count, CRP in mg/L, and a 
100 mm visual analog scale measuring the subject’s general health. A higher score 
represents worse disease. 
Details of the scoring algorithm are described in Appendix A. 
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DAS28-ESR remission 
Subjects are classified as achieving DAS28-ESR remission at a specific timepoint if their 
DAS28-ESR < 2.6 at that timepoint. Specifically, let DAS28ESR_remission be defined as 
follows: 
• 
DAS28ESR_remission (< 2.6) = 1, 
if DAS28-ESR < 2.6; 
• 
DAS28ESR_remission (< 2.6) = missing, 
if subject has no DAS28-ESR value; 
• 
DAS28ESR_remission (<2.6) = 0, 
otherwise. 
DAS28-ESR LDA 
Subjects are classified as achieving DAS28-ESR LDA at a specific timepoint if their 
DAS28-ESR >= 2.6 and < 3.2 at that timepoint. Specifically, let DAS28ESR_LDA be 
defined as follows: 
• 
DAS28ESR_LDA = 1, 
if DAS28-ESR >= 2.6 and < 3.2; 
• 
DAS28ESR_LDA = missing, 
if subject has no DAS28-ESR value; 
• 
DAS28ESR_LDA = 0, 
otherwise. 
DAS28-CRP remission 
Subjects are classified as achieving DAS28-CRP remission at a specific timepoint if their 
DAS28-CRP < 2.6 at that timepoint. Specifically, let DAS28CRP_remission be defined 
as follows: 
• 
DAS28CRP_remission (< 2.6) = 1, 
if DAS28-CRP < 2.6; 
• 
DAS28CRP_remission (< 2.6) = missing, 
if subject has no DAS28-CRP value; 
• 
DAS28CRP_remission (<2.6) = 0, 
otherwise. 
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DAS28-CRP LDA 
Subjects are classified as achieving DAS28-CRP LDA at a specific timepoint if their 
DAS28-CRP >= 2.6 and < 3.2 at that timepoint. Specifically, let DAS28CRP_LDA be 
defined as follows: 
• 
DAS28CRP_LDA = 1, 
if DAS28-CRP >= 2.6 and < 3.2; 
• 
DAS28CRP_LDA = missing, 
if subject has no DAS28-CRP value; 
• 
DAS28CRP_LDA = 0, 
otherwise. 
Clinical Disease Activity Index (CDAI) 
A composite score that is based on the number of tender and swollen joints using a 
28-joint count, PhGA (0-10 visual analog scale), and PtGA (0-10 visual analog scale). A 
higher score represents worse disease. 
Details of the scoring algorithm are described in Appendix A. 
Boolean remission status (28-joint count) 
A subject achieves Boolean remission (28-joint count) if all of the following criteria are 
met: 
• 
28-joint tender joint count ≤ 1, 
• 
28-joint swollen joint count ≤ 1, 
• 
CRP (mg/dL) ≤ 1, and 
• 
patient global assessment  ≤ 1 (on a 0-10 scale). 
Specifically, let Boolean_28 be defined as follows: 
• 
Boolean_28 = 1, 
if a subject fulfills the definition of Boolean remission (28-joint count); 
• 
Boolean_28 = missing, 
if any components of the Boolean remission definition are missing; 
• 
Boolean_28 = 0, 
otherwise. 
Boolean remission (28 joints plus feet/ankles) 
A subject achieves Boolean remission (28-joint count plus feet/ankles) if all of the 
following criteria are met: 
• 
28-joint plus feet and ankles tender joint count ≤ 1, 
• 
28-joint plus feet and ankles swollen joint count ≤ 1, 
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• 
CRP (mg/dL) ≤ 1, and 
• 
patient global assessment  ≤ 1 (on a 0-10 scale). 
Boolean remission (66/68 joint count) 
A subject achieves Boolean remission (66/68-joint count) if all of the following criteria are 
met: 
• 
68-joint tender joint count ≤ 1, 
• 
66-joint swollen joint count ≤ 1, 
• 
CRP (mg/dL) ≤ 1, and 
• 
patient global assessment  ≤ 1 (on a 0-10 scale). 
Let Boolean_68 be defined in a manner similar to that of Boolean_28. 
C-Reactive Protein (CRP) 
A specific measure of inflammatory activity measured in mg/dL.  
Disability Index of the Health Assessment Questionnaire (HAQ-DI) 
The HAQ-DI assesses the subject’s physical function or disability. The questionnaire 
asks about the degree of difficulty a person has in accomplishing tasks in 8 functional 
areas (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and 
activities). Responses in each functional area are scored from 0 indicating no difficulty to 
3 indicating inability to perform a task in that area. 
Details of the scoring algorithm are described in Appendix D. 
Medical Outcomes Health Survey Short Form 36 Items Version 2 (SF-36 v2) 
The SF-36 v2 is a 36-item instrument that measures general health status and will be 
scored using the QualityMetric Health Outcomes Scoring Software. It includes 
8 multi-item scales, each of which assesses one of the following 8 health concepts over 
the previous month: 1) limitations in physical activities because of health problems;  
2) limitations in social activities because of physical or emotional problems; 3) limitations 
in usual role activities because of physical health problems; 4) bodily pain; 5) general 
mental health (psychological distress and well-being); 6) limitations in usual role 
activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general 
health perceptions. SF-36 v2 includes the Physical Component Summary and Mental 
Component Summary measures.  A higher score represents less disability. 
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7. 
Analysis Subsets 
7.1 
Primary Analysis Set 
The Primary Analysis Set (PAS) will include all randomized subjects. The analysis will be 
conducted according to the original randomization assignment regardless of the actual 
treatment received during the study (as per intent-to-treat principle).  All the primary, 
secondary, and exploratory efficacy endpoints will be evaluated on the Primary Analysis 
Set, unless otherwise specified. 
7.2 
Full Analysis Set 
The Full Analysis Set (FAS) includes all the subjects who have enrolled in the run-in 
period.  
7.3 
Disease-Worsening Analysis Set  
The Disease-Worsening Analysis Set includes randomized subjects who meet the 
definition of Disease-Worsening at any point after randomization.  
7.4 
Rescue Analysis Set  
This includes randomized subjects who meet the definition of Disease-Worsening and 
have received both at least one dose of active rescue therapy etanercept and at least 
one dose active rescue therapy methoxrexate as recorded in the eCRF.  
7.5 
Run-In Failure Analysis Set 
The Run-In Failure Analysis Set includes all enrolled subjects who do not complete 
run-in due to failing to meet Part 2 Inclusion Criteria or due to fulfilling Part 2 Exclusion 
Criteria per Sections 4.2.1 and 4.2.2, respectively, in the protocol. 
7.6 
Run-In Safety Analysis Set 
The Run-In Safety Analysis Set includes all enrolled subjects who received at least 
one dose of open label run-in etanercept and/or at least one dose of open label run-in 
methotrexate (as specified in the eCRF).  
7.7 
Post-Run-In Safety Analysis Set 
The Post-Run-In Safety Analysis Set includes all subjects who received at least 
one dose of any investigational product after randomization.   
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8. 
Subgroup Analyses 
Subgroup analyses, which would be considered exploratory, may be performed if an 
examination of the covariates in Section 4.2 suggests that any treatment difference for 
the primary and secondary endpoints depends on any baseline covariates. 
9. 
Interim Analysis and Early Stopping Guidelines 
No interim analysis is planned for this study.   
10. 
Data Screening and Acceptance 
10.1 
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. 
10.2 
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. 
10.3 
Handling of Missing and Incomplete Data 
Subjects may be missing specific data points for a variety of reasons. In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or inability 
to evaluate an endpoint at a particular point in time. The general procedures outlined 
below describe what will be done when a data point is missing. 
10.3.1 
Missing Baseline Evaluation 
Missing baseline evaluations will not be imputed. 
10.3.2 
Missing Post-Baseline Evaluation 
See Section 11.5. 
10.3.3 
Missing Components of Composite Endpoints 
Missing components of composite endpoints will not be imputed. 
10.3.4 
Missing and Incomplete Dates 
For any listings, missing or incomplete dates will be listed as is. No imputation will be 
done on incomplete stop date of an adverse event unless specified otherwise.  
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In the case where the start or stop date of an event or medication is missing or 
incomplete, the following rule will be applied:  
 
Missing 
Imputation 
Exception 
Start date 
(AE, concomitant 
medication) 
Day 
01 
Default to Study Day 1 if an 
event starts the same year 
and month as Study Day 1 
and Stop date is after Study 
Day 1 
Day/Month 
01JAN 
Default to Study Day 1 if an 
event started the same year 
as Day1 and Stop date is 
after Study Day 1 
Day/Month/Year 
No imputation 
 
Stop date 
(concomitant 
medication) 
Day 
Last day of the 
month 
Default to the End of Study 
Date or the primary analysis 
cut-off date for ongoing 
subjects if the concomitant 
medication stopped the 
same year and month as the 
End of Study Date or 
primary analysis cut-off date 
Day/Month 
31DEC 
Default to the End of Study 
Date or the primary analysis 
cut-off date for ongoing 
subjects if the concomitant 
medication stopped the 
same year as the End of 
Study Date or primary 
analysis cut-off date 
Day/Month/Year 
No imputation 
 
In case a subject dies during the study, impute the missing AE and CM end dates using 
the subject’s date of death. 
10.4 
Detection of Bias  
Subject selection and treatment group allocation were performed in a manner minimizing 
potential bias. Assessing endpoints and handling withdrawals were done without 
knowledge of treatment group.  Other factors that may introduce bias include: 
• 
Important protocol deviations likely to impact the analysis or interpretation of 
results; 
• 
Breaking blind before database lock and formal unblinding; 
• 
IP dosing non-compliance; 
• 
Reasons for early withdrawal from treatment or from study. 
The incidence of these factors will be assessed. Important protocol deviations likely to 
impact the analysis and interpretation of results will be listed and/or tabulated in the 
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Clinical Study Report (CSR). If a significant number of major protocol deviations are 
observed, an additional sensitivity analysis may be performed on the efficacy data 
excluding subjects with major protocol deviations. 
Any breaking of the blind for individual subjects prior to formal unblinding of the study will 
be documented in the CSR, including the timing and reason for unblinding. The impact 
of such unblinding on the results will be assessed. 
Tabulations of important protocol deviations (IPDs) related to IP dosing non-compliance 
by treatment group will be provided. 
Reasons for early withdrawals from treatment and from study will be summarized. If a 
significant pattern is observed, additional sensitivity analyses may be performed on 
efficacy data adjusting for reasons for early withdrawal. 
10.5 
Outliers 
Descriptive summaries will be examined to identify unexpected values. Outliers due to 
data entry errors will be corrected by the study team before data lock. Outliers that are 
not due to data entry will be included in the analysis. If it is deemed necessary after the 
team reviews the output from the planned analyses after data lock, a post-hoc sensitivity 
analysis excluding subjects with outliers may be performed. 
10.6 
Distributional Characteristics 
The Chi-squared test with contuinity correction allows for analysis of categorical 
endpoints even when some or all contingency cells have less than 5 subjects. The t-test 
used for continuous endpoints assumes that the means of two independent populations 
follow normal distributions. With all three treatment arms having more than 30 subjects, 
this assumption is fair per the central limit theorem. When standard deviations are 
statistically significantly different as identified by an F-test with p-value less than or equal 
to 0.05, the Satterthwaite approximation is used. 
10.7 
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 to  
produce the specified outputs. 
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example SAS System version 9.4 or later. 
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11. 
Statistical Methods of Analysis 
11.1 
General Considerations 
The primary analysis will be performed after all subjects have completed the 
Week 48/ET assessment and the 30-day safety follow-up period and all data have been 
finalized. 
Subject disposition, demographics, and baseline disease characteristics will be 
summarized descriptively by randomized treatment group. 
For categorical endpoints, descriptive statistics will report frequency and percentage. For 
continuous endpoints, descriptive statistics will include the number of observations, 
mean, standard error or standard deviation, median, minimum, and maximum. 
The statistical test for the primary efficacy endpoint will have a significance level of 0.05. 
Non-responder imputation will be employed for the missing values of the primary 
endpoint.  
For continuous secondary endpoints, t-tests will compare 1) etanercept monotherapy vs 
methotrexate monotherapy, and 2) etanercept and methotrexate combination therapy vs 
methotrexate monotherapy. No multiplicity adjustments will be made. 
For binary secondary endpoints, Chi-squared tests with continuity correction will 
compare 1) etanercept monotherapy vs methotrexate monotherapy, and 2) etanercept 
and methotrexate combination therapy vs methotrexate monotherapy. No multiplicity 
adjustments will be made. 
For time-to-event secondary endpoints, the number of subjects achieving the event and 
the number of subjects censored as defined in Section 6.4 will be provided. 
Kaplan-Meier (KM) curves, estimates, and 95% CIs will be provided by treatment group. 
A two-sided log-rank test incorporating treatment group will evaluate 1) etanercept 
monotherapy vs methotrexate monotherapy, and 2) etanercept and methotrexate 
combination therapy vs methotrexate monotherapy. Median time-to-event will be 
provided for each of the treatment arms.  
11.2 
Subject Accountability 
Analysis Set Disposition 
The number (percent) of subjects in each of the Analysis Subsets detailed in Section 7 
will be summarized. 
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During the Run-In Period 
The subject disposition for the run-in period will be summarized descriptively for all 
subjects enrolled in the run-in period, and will include the number (percent) of subjects 
who  
• 
are enrolled 
• 
are dosed with open-label etanercept and methotrexate  
• 
complete the 24-week open-label run-in period 
• 
discontinued prematurely and their reasons for discontinuation.  
After Randomization 
The subject disposition will be summarized descriptively for all randomized subjects by 
randomized treatment group, and will include the number (percent) of subjects who 
• 
are randomized 
• 
are dosed with investigational product 
• 
complete investigational product 
• 
complete the study 
• 
discontinued prematurely and their reasons for discontinuation.  
11.3 
Important Protocol Deviations 
Important Protocol Deviation (IPD) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD reviews throughout the study prior 
to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.   
11.4 
 Demographic and Baseline Characteristics 
Subject demographic and disease characteristics at enrollment will be summarized 
descriptively for all subjects in the run-in period. 
Subject demographic and baseline disease characteristics at randomization will be 
summarized descriptively for all subjects in the double-blind treatment period by 
randomized treatment group. 
11.5 
Efficacy Analyses  
All efficacy analyses will be conducted using the PAS, unless otherwise specified.  
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11.5.1 
Primary Efficacy Endpoint 
11.5.1.1 
Primary Analysis of Primary Estimand 
The primary analysis of the primary estimand as defined in Section 4.1.1 will be 
performed using the PAS. The primary endpoint is defined in Section 6.2. When an 
endpoint cannot be derived due to missing SDAI assessment, a subject will be assumed 
to have not achieved the outcome, that is, Non-Responder Imputation (NRI).  
The treatment effect for SDAI remission at Week 48 will be tested using a chi-squared 
test at significance level of 0.05. Difference in proportions and a 95% CI will be provided 
comparing etanercept monotherapy with methotrexate monotherapy. 
11.5.1.2 
Sensitivity/Exploratory Analyses of Primary Estimand 
SDAI remission at Week 48 will be tested using a chi-squared test at significance level of 
0.05 using observed cases only. 
In addition, multiple-imputation will be implemented to impute SDAI values when missing 
for randomized subjects. SDAI values after rescue are also set to missing and imputed 
in this analysis. The composite SDAI values will be imputed rather than its components. 
A chi-squared test will compare the resulting values under the etanercept monotherapy 
arm and the methotrexate monotherapy arm. 
11.5.2 
Secondary Efficacy Endpoint(s) 
For secondary endpoints, unless otherwise noted, the Chi-squared test will be used for 
categorical endpoints, the t-test for continuous endpoints, and Log-rank test for  
time-to-event endpoints. In comparison of means, the Satterthwaite t-test may be used 
when variances between the two groups are different. These tests will evaluate 
etanercept monotherapy vs methotrexate monotherapy and etanercept and 
methotrexate combination therapy vs methotrexate monotherapy.  
Proportion of subjects achieving SDAI remission at week 48 for the etanercept plus 
methotrexate treatment arm will be compared to that of the methotrexate monotherapy 
arm using the chi-squared test and will be presented with nominal p-values only (eg, no 
adjustment for multiplicity will be done). To parallel the the primary analysis of the 
primary estimand, the proportion of subjects in the etanercept plus methotrexate 
treatment arm and the methotrexate monotherapy arm achieving SDAI remission at 
week 48 will be evaluated using non-responder imputation, as observed data, and 
multiple imputation. 
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The proportion of subjects achieving SDAI remission (≤ 3.3), SDAI continuous score, 
and SDAI change from baseline at all visits will be summarized by treatment group using 
the PAS. Subjects with missing SDAI value at week 48 and subjects who 
disease-worsened are considered non-responders. 
DAS28-ESR, DAS28-CRP, and CDAI, and their changes from baseline will also be 
summarized by visit for each treatment group using the PAS. Missing data will not be 
imputed for these continuous endpoints. T-tests will compare means between etanercept 
vs methotrexate and etanercept + methotrexate vs methotrexate.  
Proportion of subjects achieving Boolean remission will be tabulated by visit for each 
treatment group using the PAS. Boolean remission using 28-joint-count, 28-joint-count  
+ feet and ankles, and 66/68 joint count will be assessed. 
Proportion of subjects with Disease-Worsening and time-to-disease-worsening will be 
evaluated by treatment group for the PAS. Time-to-disease-worsening wil be evaluated 
using Kaplan-Meier (KM) curves, estimates, and 95% CIs by treatment group. For 
subjects with more than one DW Date, the first DW date will be used. Subjects who do 
not experience disease-worsening will be censored at last SDAI assessment date. In 
addition, a two-sided log-rank test will evaluate the etanercept monotherapy vs 
methotrexate monotherapy arms, and the etanercept plus methotrerxate combination vs 
methotrexate monotherapy arms. 
Time-to-recapture observed SDAI remission from Rescue Date will be evaluated for the 
Rescue Analysis Set using Kaplan-Meier (KM) curves, estimates, and 95% confidence 
intervals by treatment group; subjects who do not recapture SDAI remission will be 
censored at their last SDAI assessment date. This analysis will be repeated for  
Time-to-recapture SDAI remission from Disease-Worsening Date for the 
Disease-Worsening Analysis Set. For subjects with more than one recapture of 
observed SDAI remission, the first recapture date will be used. Additionally, the 
proportion of subjects who recapture observed SDAI remission at week 48 will be 
summarized for both the Rescue Analysis Set and the Disease-Worsening Analysis Set.  
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Table 1.  Primary and Secondary Endpoints Summary Table 
Endpoint 
Primary Analysis Method 
Sensitivity/Exploratory 
Analysis 
Primary Endpoint 
SDAI remission (<= 3.3) at 
week 48 as defined by 
SDAI_remission_maintenance 
detailed in Section 6.2 
Count (percentage) of subjects 
achieving SDAI remission as 
defined by 
SDAI_remission_maintenance 
detailed in Section 6.2 at 
Week 48 for the PAS. 
 
A chi-squared test comparing 
etanercept monotherapy and 
methotrexate monotherapy 
using the PAS. 
 
Subjects who have a missing 
SDAI_remission value will be 
considered as non-responders. 
Observed_SDAI_remission 
using as observed 
approach as detailed in 
Section 6.5 (missing data 
will be excluded). 
 
Multiple imputation 
method: 
impute SDAI values when 
missing and after rescue 
for randomized subjects. 
The composite SDAI 
values will be imputed 
rather than its 
components. 
Secondary Endpoints 
SDAI remission (<= 3.3) at 
week 48  
Count (percentage) of subjects 
achieving SDAI remission as 
defined by 
SDAI_remission_maintenance 
detailed in Section 6.2 at 
Week 48 for the PAS. 
A chi-squared test comparing 
etanercept plus methotrexate 
combination arm and 
methotrexate monotherapy 
using the PAS. 
Subjects who have a missing 
SDAI_remission value will be 
considered as non-responders. 
Nominal p-values will be 
provided. 
Observed_SDAI_remission 
using as observed 
approach as detailed in 
Section 6.5 (missing data 
will be excluded). 
 
Multiple imputation 
method: 
impute SDAI values when 
missing and after rescue 
for randomized subjects. 
The composite SDAI 
values will be imputed 
rather than its 
components. 
SDAI score and change from 
baseline at all measured 
timepoints 
Summary statistics for SDAI 
score and change from 
baseline at each Analysis Visit 
for the PAS. 
T-test comparing etanercept 
monotherapy vs methotrexate 
monotherapy 
T-test comparing etanercept 
and methotrexate combination 
therapy vs methotrexate 
monotherapy  
 
DAS28-ESR and change from 
baseline at all measured 
timepoints 
Similar analysis as for SDAI 
score and change from 
baseline at all measured 
timepoints 
 
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Table 1.  Primary and Secondary Endpoints Summary Table 
Endpoint 
Primary Analysis Method 
Sensitivity/Exploratory 
Analysis 
Secondary Endpoints (Continued) 
DAS28-CRP and change from 
baseline at all measured 
timepoints 
Similar analysis as for SDAI 
score and change from baseline 
at all measured timepoints 
 
CDAI and change from 
baseline at all measured 
timepoints 
Similar analysis as for SDAI 
score and change from baseline 
at all measured timepoints 
 
SDAI remission (≤ 3.3) at all 
measured timepoints 
Count (percentage) of subjects 
achieving SDAI remission as 
defined by 
SDAI_remission_maintenance 
detailed in Section 6.5 for the 
PAS. 
Chi-squared test comparing 
etanercept monotherapy vs 
methotrexate monotherapy 
Chi-squared test comparing 
etanercept and methotrexate 
combination therapy vs 
methotrexate monotherapy 
 
Boolean remission at all 
measured timepoints 
Observed count (percentage) of 
subjects achieving Boolean 
remission at each Analysis Visit 
for the PAS. Boolean remission 
using 28-joint-count,  
28-joint-count + feet and ankles, 
and 66/68 joint count will be 
assessed. 
Chi-squared test comparing 
etanercept monotherapy vs 
methotrexate monotherapy 
Chi-squared test comparing 
etanercept and methotrexate 
combination therapy vs 
methotrexate monotherapy 
 
Disease-Worsening defined as 
an SDAI > 3.3 and ≤ 11 during 
two consecutive visits at least 
2 weeks apart or SDAI > 3.3 
and ≤ 11 on three or more 
separate visits or SDAI > 11 
after randomization 
Observed count (percentage) of 
subjects fulfilling 
Disease-Worsening criteria at 
each Analysis Visit for the PAS. 
 
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Table 1.  Primary and Secondary Endpoints Summary Table 
Endpoint 
Primary Analysis Method 
Sensitivity/Exploratory 
Analysis 
Secondary Endpoints (Continued) 
Time to Disease-Worsening as 
an SDAI > 3.3 and ≤ 11 during 
two consecutive visits at least 
2 weeks apart or SDAI > 3.3 
and ≤ 11 on three or more 
separate visits or SDAI > 11 
after randomization 
Kaplan-Meier curves, estimates, 
and 95% CIs assessing Time to 
Disease-Worsening by 
treatment group for the PAS. 
Subjects with more than one 
DW Date will be analyzed using 
the first DW Date. 
Subjects who do not experience 
disease-worsening will be 
censored at last SDAI 
assessment date. 
Log-rank test comparing 
etanercept monotherapy versus 
methotrexate monotherapy. 
Log-rank test comparing 
etanercept and methotrexate 
combination therapy versus 
methotrexate monotherapy. 
 
Time to recapture observed 
SDAI remission after starting 
rescue treatment 
Kaplan-Meier curves assessing 
Time to recapture observed 
SDAI remission from Rescue 
Date for the Rescue Analysis 
Set. 
Subjects with more than one 
recapture of SDAI remission will 
be analyzed using their first 
recapture date.  
Subjects who do not recapture 
SDAI remission are censored at 
their last SDAI assessment 
date. 
Log-rank test comparing 
etanercept monotherapy versus 
methotrexate monotherapy. 
Log-rank test comparing 
etanercept and methotrexate 
combination therapy versus 
methotrexate monotherapy. 
Similar analysis as the 
Primary Analysis Method 
but using the 
Disease-Worsening 
Analysis Set, looking at 
time to recapture SDAI 
remission from DW 
Date. 
Observed SDAI remission at 
Week 48 
Observed count (percentage) of 
subjects achieving SDAI 
remission as defined by 
Observed_SDAI_remission as 
detailed in Section 6.5 at 
Week 48 for the Rescue 
Analysis Set. 
Similar analysis as the 
Primary Analysis Method 
but using the 
Disease-Worsening 
Analysis Set. 
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11.5.3 
Exploratory Endpoints 
For the exploratory endpoints listed below, unless otherwise noted, the Chi-squared test 
will be used for categorical endpoints, the t-test for continuous endpoints, and Log-rank 
test for time-to-event endpoints. In comparison of means, the Satterthwaite t-test may be 
used when variances between the two groups are different. These tests will evaluate 
etanercept monotherapy vs methotrexate monotherapy and etanercept and 
methotrexate combination therapy vs methotrexate monotherapy.  
Components of SDAI at all measured timepoints 
The five components of SDAI will be summarized as observed with descriptive statistics 
by treatment arm for the PAS.  
HAQ-DI at all measured timepoints 
HAQ-DI will be summarized with descriptive statistics as observed by treatment arm for 
the PAS.  
SF-36 domains, physical component summary, and mental component summary at all 
measured timepoints 
SF-36 domains will be summarized with descriptive statistics as observed by treatment 
arm for the PAS.  
SDAI score at run-in visits 
SDAI score at Run-In Visit 1, Run-In Visit 2, and Run-In Visit 3 will be summarized with 
descriptive statistics as observed for the FAS. No statistical tests will be performed. 
Time to run-in failure 
Kaplan-Meier curves will assess time to run-in failure for the FAS. Subjects who do not 
experience run-in failure are censored at their end of run-in date, where reason is not 
stated as protocol specified criteria or ineligibility determined due to failing to meet Part 2 
Inclusion Criteria (116) or due to fulfilling Part 2 Exclusion Criteria (228) per 
Section 4.2.1 and 4.2.2, respectively, in the protocol. 
Time to Randomization Failure 
Kaplan-Meier curves will assess time to randomization failure for the FAS. Subjects who 
are randomized are censored at their end of run-in date. 
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Patient Global Assessment of Joint Pain at all measured timepoints 
Patient Global Assessment of Joint Pain will be summarized with descriptive statistics as 
observed by treatment arm for the PAS.  
Observed SDAI remission at all measured timepoints 
Observed SDAI remission at each analysis visit will be summarized for the Primary 
Analysis Set, where observed SDAI remission is defined in Section 6.5. 
Observed SDAI remission at visits following rescue 
Observed SDAI remission by Rescue_Visit and by DW_Visit will be summarized for the 
Rescue Analysis Set and the Disease-Worsening Analysis Set, respectively, where 
Rescue_Visit and DW_Visit are defined in Appendix A.  
SDAI LDA, DAS28-ESR LDA at all measured timepoints, SDAI LDA, DAS28-ESR LDA 
at visits following rescue 
The observed proportion of subjects achieving SDAI LDA and DAS28-ESR LDA will be 
tabulated at each Analysis Visit for the PAS. A similar analysis will be done for the 
Rescue Analysis Set and the Disease-Worsening Analysis Set by Rescue_Visit and 
DW_visit, respectively.  
DAS28-ESR remission and DAS28-CRP remission at all measured timepoints, 
DAS28-ESR remission and DAS28-CRP remission at visits following rescue 
The observed proportion of subjects achieving DAS28-ESR remission and DAS28-CRP 
remission will be tabulated at each Analysis Visit for the PAS. A similar analysis will be 
done for the Recue Analysis Set and the Disease-Worsening Analysis Set by 
Rescue_Visit and DW_visit, respectively.  
Reason for Disease-Worsening (DW) 
Reason for Disease-Worsening (DW) will be summarized by Analysis Visit for the 
Disease-Worsening Analysis Set. If a subject’s visit results in fulfillment of more than one 
of these criteria, only a single reason for disease-worsening will be counted, with priority 
given in the following order: 
Priority 1: SDAI > 11 
Priority 2: SDAI > 3.3 and ≤ 11 on two consecutive visits at least two weeks apart 
Priority 3: SDAI > 3.3 and ≤ 11 on three or more separate visits  
No statistical tests will be performed. 
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SDAI score at Disease-Worsening and at visits following rescue; Change in SDAI from 
Disease-Worsening Date at visits following rescue 
SDAI score at Disease-Worsening Date and by DW_Visit will be summarized with 
descriptive statistics by treatment arm for the Disease-Worsening Analysis Set. A similar 
analysis will be done for Change in SDAI from Disease-Worsening Date by DW_Visit. 
Similar analyses will be performed for the Rescue Analysis Set by Rescue Visit. The 
latest SDAI score on or prior to a subject’s rescue date is used as their Rescue Baseline 
SDAI value.   
Disease Activity at Disease-Worsening 
The magnitude of disease activity as measured by the SDAI score at 
Disease-Worsening Date will be summarized per the definition in Section 6.5 for the 
Disease-Worsening Analysis Set. Chi-squared tests will evaluate etanercept 
monotherapy vs methotrexate monotherapy and etanercept and methotrexate 
combination therapy vs methotrexate monotherapy. 
Time to SDAI LDA, Time to DAS28-ESR Remission, Time to DAS28-CRP Remission  
Time to SDAI LDA, time to DAS28-ESR remission, time to DAS28-CRP remission will be 
evaluated with Kaplan Meier curves and Log-rank tests for the Rescue Analysis Set and 
the Disease-Worsening Analysis Set. 
Table 2.  Exploratory Endpoints Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Exploratory Analysis 
Exploratory Endpoints 
Components of SDAI at all 
measured timepoints  
Summary statistics for the 
components of SDAI at each 
Analysis Visit for the PAS. 
T-test comparing etanercept 
monotherapy vs methotrexate 
monotherapy 
T-test comparing etanercept and 
methotrexate combination therapy 
vs methotrexate monotherapy 
 
HAQ-DI at all measured 
timepoints 
Summary statistics for the 
components of HAQ-DI at each 
Analysis Visit for the PAS. 
T-test comparing etanercept 
monotherapy vs methotrexate 
monotherapy 
T-test comparing etanercept and 
methotrexate combination therapy 
vs methotrexate monotherapy 
 
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Table 2.  Exploratory Endpoints Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Exploratory 
Analysis 
Exploratory Endpoints(Continued) 
SF-36 domains, physical 
component summary, and 
mental component summary at 
all measured timepoints 
Summary statistics for SF-36 
domains at each Analysis Visit for the 
PAS. 
T-test comparing etanercept 
monotherapy vs methotrexate 
monotherapy 
T-test comparing etanercept and 
methotrexate combination therapy vs 
methotrexate monotherapy 
 
SDAI score at run-in visits 
Summary statistics for SDAI for the 
FAS. 
A scatter plot for each subject’s SDAI 
score at Run-in Visits 1, 2, and 3. 
 
Time to run-in failure 
Kaplan-Meier curves assessing 
Time to run-in failure for the FAS.  
Subjects who do not experience 
run-in failure are censored at their 
End of Run-In date. 
 
Time to Randomization Failure 
Kaplan-Meier curves assessing 
Time to end of run-in for the FAS.  
Subjects who are randomized are 
censored at End of Run-In Date. 
 
Observed SDAI Remission  
(<= 3.3) at all timepoints 
Similar analysis as SDAI remission at 
all measured timepoints for the PAS. 
See definitinition of Observed SDAI 
Remission in Section 6.5. 
 
Patient Global Assessment of 
Joint Pain at all timepoints 
Summary statistics for PtGAJP at 
each Analysis Visit for the PAS. 
T-test comparing etanercept 
monotherapy vs methotrexate 
monotherapy 
T-test comparing etanercept and 
methotrexate combination therapy vs 
methotrexate monotherapy 
 
SDAI LDA at all timepoints 
Similar analysis as SDAI remission at 
all measured timepoints for the PAS. 
 
DAS28-ESR remission at all 
timepoints 
Similar analysis as SDAI remission at 
all measured timepoints for the PAS. 
 
DAS28-ESR LDA at all 
timepoints 
Similar analysis as SDAI remission at 
all measured timepoints for the PAS. 
 
DAS28-CRP remission at all 
timepoints 
Similar analysis as SDAI remission at 
all measured timepoints for the PAS. 
 
Reason for Disease-Worsening 
Observed count (percentage) of 
reason for disease-worsening at 
each Analysis Visit for the 
Disease-Worsening Analysis Set. 
 
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Table 2.  Exploratory Endpoints Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Exploratory Analysis 
Exploratory Endpoints(Continued) 
SDAI score at 
Disease-Worsening 
Summary statistics for the SDAI 
score at DW Date for the 
Disease-Worsening Analysis Set. 
T-test comparing etanercept 
monotherapy vs methotrexate 
monotherapy 
T-test comparing etanercept and 
methotrexate combination therapy 
vs methotrexate monotherapy 
 
Disease Activity at 
Disease-Worsening 
Observed count (percentage) of 
subjects in each Disease Activity 
category (Low, Moderate, High) at 
DW Date for the 
Disease-Worsening Analysis Set. 
Chi-squared test comparing 
etanercept monotherapy vs 
methotrexate monotherapy 
Chi-squared test comparing 
etanercept and methotrexate 
combination therapy vs 
methotrexate monotherapy 
 
Observed SDAI remission at 
visits following rescue 
Observed count (percentage) of 
subjects achieving observed SDAI 
remission by Rescue_Visit for the 
Rescue Analysis Set. 
Chi-squared test comparing 
etanercept monotherapy vs 
methotrexate monotherapy 
Chi-squared test comparing 
etanercept and methotrexate 
combination therapy vs 
methotrexate monotherapy 
Similar to the Primary 
Analysis Method but 
using the 
Disease-Worsening 
Analysis Set and 
DW_Visit. 
SDAI LDA at visits following 
rescue 
Similar analysis as for SDAI 
remission at visits following rescue 
Similar to the Primary 
Analysis Method but 
using the 
Disease-Worsening 
Analysis Set. 
Time to SDAI LDA 
Similar analysis as Time to 
recapture SDAI remission after 
starting rescue treatment. 
 
Similar analysis as the 
Primary Analysis Method 
but using the 
Disease-Worsening 
Analysis Set, looking at 
time to SDAI LDA from 
DW Date. 
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Table 2.  Exploratory Endpoints Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Exploratory Analysis 
Exploratory Endpoints(Continued) 
SDAI score on 
Disease-Worsening Date 
and at visits following 
rescue 
Summary statistics for SDAI by 
Rescue_Visit for the Rescue 
Analysis Set. 
T-test comparing etanercept 
monotherapy vs methotrexate 
monotherapy 
T-test comparing etanercept and 
methotrexate combination therapy 
vs methotrexate monotherapy 
Similar to the Primary 
Analysis Method but using 
the Disease-Worsening 
Analysis Set and DW_Visit. 
Change in SDAI from 
Disease-Worsening Date 
and at visits following 
rescue 
Similar anlaysis as for SDAI score 
on Disease-Worsening Date and 
at visits following rescue 
Similar to the Primary 
Analysis Method but using 
the Disease-Worsening 
Analysis Set and DW_Visit. 
DAS28-ESR remission at 
visits following rescue 
Similar analysis as for SDAI 
remission at visits following rescue 
Similar to the Primary 
Analysis Method but using 
the Disease-Worsening 
Analysis Set and DW_visit. 
Time to DAS28-ESR 
remission 
Kaplan-Meier curves assessing 
Time to DAS28-ESR remission 
from Rescue Date for the Rescue 
Analysis Set. 
Subjects with more than 
one event of DAS28-ESR 
remission will be analyzed using 
their first event date.  
Subjects who do not have 
DAS28-ESR remission are 
censored at their last SDAI 
assessment date. 
Log-rank test comparing 
etanercept monotherapy versus 
methotrexate monotherapy. 
Similar to the Primary 
Analysis Method but using 
the Disease-Worsening 
Analysis Set, from DW 
Date. 
DAS28-ESR LDA(yes/no) 
at visits following rescue 
Similar analysis as for SDAI 
remission at visits following rescue 
Similar to the Primary 
Analysis Method but using 
the Disease-Worsening 
Analysis Set and DW_Visit. 
DAS28-CRP remission 
(yes/no) at visits following 
rescue 
Similar analysis as for SDAI 
remission at visits following rescue 
Similar to the Primary 
Analysis Method but using 
the Disease-Worsening 
Analysis Set and DW_Visit. 
Time to DAS28-CRP 
remission 
Similar analysis as Time to  
DAS28-ESR remission 
Similar to the Primary 
Analysis Method but using 
the Disease-Worsening 
Analysis Set, from DW 
Date. 
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11.6 
Safety Analyses 
All safety analyses will be conducted using the Run-in Period Safety Analysis Set and 
the Post-Run-In Safety Analysis Set. Subjects will be analyzed according to the actual 
treatment received as defined in Section 6.3. 
11.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 or later will be 
used to code all adverse events (AE) to a system organ class and a preferred term. All 
adverse events occurring in the Run-In Period will be summarized for the Run-In Period 
Safety Analysis Set). All adverse events occurring during the double-blind treatment 
period and 30-day safety follow-up will be summarized for the Post-Run-In Safety 
Analysis Set. The subject incidence of AEs will be summarized for all 
treatment-emergent AEs, serious AEs, AEs leading to withdrawal of investigational 
product, and fatal AEs.  
11.6.2 
Laboratory Test Results 
Laboratory parameters with grade 3 toxicity or above may be descriptively summarized 
by study visit and actual treatment received during the study.  Shift tables of the worst 
on-study laboratory toxicity based on the Common Toxicity Criteria (CTC) grade relative 
to baseline may be tabulated for analytes of interest (ie, creatinine, total bilirubin, AST 
(SGOT), ALT (SGPT), hemoglobin, platelets, WBC, absolute neutrophil count, 
lymphocytes) by treatment group. Modifications to CTC version 4.0 used for this analysis 
are described in Appendix C. Subject listings of grades 3 and 4 laboratory values will be 
provided.   
11.6.3 
Vital Signs 
Vital signs may be descriptively summarized in baseline disease summaries, if there are 
unexpected safety findings. 
11.6.4 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to etanercept 
monotherapy, methotrexate monotherapy, and etanercept + methotrexate combination 
therapy, including number of doses, number of missed doses, and duration of dosing 
during the Run-in period. Descriptive statistics will be produced to describe the exposure 
to IP for each treatment group, including number of doses, number of missed doses, and 
duration of dosing. 
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11.6.5 
Exposure to Concomitant Medication  
A summary of all concomitant medications reported may be provided by preferred term 
as coded by the World Health Organization Drug (WHODRUG) dictionary. Only 
concomitant medications with a partial or complete end date are tabulated. 
12. 
Changes From Protocol-specified Analyses 
Protocol Section 10.5.2 states “Furthermore, the randomized subjects who did not 
receive any dose of any of the investigational products will also be considered 
non-responders in the primary analysis.” 
However, although subjects may not receive any dose of IP, they may still have an 
observed SDAI value at week 48. Any randomized subjects with non-missing SDAI at 
week 48 will be assessed according to their original randomized treatment arm with their 
observed values. 
Changes to Planned Covariates 
We modify the listed continuous covariates by dichotomizing them at clinically 
meaningful cutoffs to demonstrate their influence on the primary endpoint. The following 
dichotomizations are used: 
Age (years): < 65 years, ≥ 65 years 
Disease duration: <= median, > median; <= mean, > mean 
Baseline methotrexate dose: <15 mg, ≥15 mg 
This dichotomous variable has been added to the pre-specified analysis because 
when a subject is taken off a biologic, we suspect that subjects on a higher dose 
of methotrexate at baseline would have a higher probability of SDAI remission 
than subjects on a lower dose of methotrexate at baseline. The threshold of  
<15 mg / ≥15 mg was selected based on the minimum and maximum 
methotrexate doses in this study, 10mg and 25mg, respectively. 
Smoking: Never, former, current 
This categorical variable has been added to the pre-specified analysis due to 
recognition of association of poorer arthritis disease activity with smoking. 
Maintenance of SDAI remission is the primary endpoint of interest; subgroup analyses 
shall not be performed on secondary endpoints. 
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Changes to Analysis Sets 
The protocol states that time to recapture SDAI remission and SDAI remission at 
week 48 will be evaluated for subjects that receive rescue treatment during the 
double-blind period. This led to the creation of the Rescue Analysis Set detailed in 
Section 7.4. 
However, due to the possibility of subjects fulfilling the definition of Disease-Worsening 
but not receiving rescue therapy, we also added a Disease-Worsening Analysis Set, 
as detailed in Section 7.3. 
A Full Analysis Set was also added to evaluate all subjects who enrolled. 
The Safety Analysis Set defined in the protocol was re-named to Post-Run-In Safety 
Analysis Set for clarity, detailed in Section 7.7. For the separate evaluation of safety 
events during Run-In, the Run-In Safety Analysis Set detailed in Section 7.6 was also 
created. 
Changes to Exploratory Endpoints 
Biomarkers and Pharmacogenetic Parameters were listed in the protocol as exploratory 
endpoints. Samples were collected from this study for potential future analyses. 
Exploratory endpoints not originally included in the protocol are detailed in Section 4.1.4. 
Their addition to the exploratory analysis is due to our interest in seeing a) the Disease 
Activity at disease-worsening; b) the degree of improvement after rescue, even if a 
subject does not recapture SDAI remission; c) the proportion of disease-worsening 
subjects who achieve SDAI remission at Week 48. Further analyses on additional 
endpoints may be performed later on an ad-hoc basis. 
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13. 
Literature Citations / References 
Mantel, N. (1963). Chi-square tests with one degree of freedom: Extensions of the 
Mantel-Haenszel procedure, Journal of the American Statistical Association, 58, 
690-700.  
Ratitch, B., Lipkovich, I., O’Kelly, M. (2013). Combining Analysis Results from Multiply 
Imputed Categorical Data, PharmaSUG 2013. 
https://www.pharmasug.org/proceedings/2013/SP/PharmaSUG-2013-SP03.pdf 
Rubin, DB.  Inference and Missing Data. Biometrika 1976; 63: 581-592. 
Stokes M.  E., Davis C. S., Koch G. G. (2000). Categorical Data Analysis Using the SAS 
System, Cary, NC: SAS Institute Inc. pp 75,128.  
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14. 
Appendices  
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Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
Visit Windows for Selected Efficacy and Safety Evaluations 
Per protocol, visits are to be performed within 7 days of the protocol-specified study day.  
To allow for variations in scheduling, the following visit windows will be applied to 
selected efficacy and safety evaluations (ie, vital signs, laboratory evaluations) to assign 
a most appropriate nominal visit for the analysis (ie, analysis visit). If more than one visit 
falls within the same defined window, the closest visit to the target day (ie, scheduled 
visit week x 7 + 1) will be considered for analysis. If two assessment dates are the same 
distance from the target day, then the latest visit will be considered for analysis. If more 
than one evaluation exists on the same date and time, the record with the lower 
accession number will be used. 
Run-In Period Visits 
Visit 
Week 
Target Day 
Window 
Definition 
Interval 
(days) 
Run-in 1 
Run-in Day 1  
Last evaluation prior to or on Run-In Study 
Day 1 and after Enrollment Date 
43+ 
Run-in 2 
Run-in Day 86  
Run-in Day 44 to 125 
82 
Run-in 3 
Run-in Day 162 
Run-in Day > = 126 
43 
Double-Blind Treatment Period Analysis Visits 
Visit 
Week 
Target Day 
Window 
Definition 
Interval 
(days) 
Baseline  
Study Day 1 
Last evaluation prior to or on Study Day 1 
and after Run-in Visit 3* 
N/A 
Week 12 
Study Day 85 
Study Day 2 to 126 
125 
Week 24 
Study Day 169 
Study Day 127 to 210 
84 
Week 36 
Study Day 253 
Study Day 211 to 294 
84 
Week 48 
Study Day 337 
> =Study Day 295  
N/A 
* Hematology and chemistry profiles were not assessed on Day 1; their Run-in Visit 3 values will be used 
when reporting baseline. 
Visit window for SF-36  and HAQ-DI  
Visit 
Week 
Target 
Day 
Window 
Definition 
Interval 
(days) 
Baseline 
(Day1) 
1 
Last evaluation prior to or on study day 1 in DB 
N/A 
Week 24 
169 
Study Day 2 to 253 
252 
Week 48 
337 
> =Study Day 254  
n/a 
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Time After Disease-Worsening 
Let Visit0 = the Analysis Visit at which a subject fulfills disease-worsening criteria, where 
Analysis Visit is for SDAI score and is defined in the Double-Blind Treatment Period 
Analysis Visits Table above. Visit0 will be summarized in tables as “Disease-Worsening 
Baseline”. 
Let Visit1 represent the Analysis Visit on or after Visit0. 
Then DW_visit will be defined as follows: 
• 
DW_visit = 12, 
If Visit1 – Visit0 = 0 or 12 
• 
DW_visit = Visit1 – Visit0, 
Otherwise. 
If a subject has multiple observations for the same DW_Visit, the latest observation will 
be used in the analysis.  
Time After Rescue 
“Rescue Baseline” is defined as the latest assessment on or before a subject’s rescue 
date. 
Let Visit0 = the Analysis Visit at which a subject initiates rescue, where Analysis Visit is 
for SDAI score and is defined in the Double-Blind Treatment Period Analysis Visits Table 
above. 
Let Visit1 represent the Analysis Visit on or after Visit0. 
Then Rescue_visit will be defined as follows: 
If subject has received rescue (Study Day Subject Received Rescue <= Study Day): 
• 
Rescue_visit = 12, 
If Visit1 – Visit0 = 0 or 12 
• 
Rescue_visit = Visit1 – Visit0, 
Otherwise. 
If a subject has not yet received rescue at a specific visit, Rescue_visit missing. 
If a subject has multiple observations for the same Rescue_Visit, the latest observation 
will be used in the analysis.  
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Efficacy Endpoint Scoring Algorithms 
Abbreviations: 
TEN28 
28-joint Tender Joint Count 
SW28 
28-Joint Tender Joint Count 
PtGA 
Patient Global Assessment 
PhGA 
Physician Global Assessment 
ESR 
Erythrocyte Sedimentation Rate 
Simplified Disease Activity Index (SDAI) 
The SDAI is a composite measure that sums the total number of tender and swollen 
28-joint counts, the PtGA on a 0-10 scale, the PhGA on a 0-10 scale, and the CRP in 
mg/dL.  PtGA and PhGA are collected in a 0-100 scale, so they will need to be divided 
by 10. 
The SDAI is scored as follows: 
TEN28 + SW28 + PtGA/10 + PhGA/10 + CRP (mg/dL) 
Clinical Disease Activity Index (CDAI) 
The CDAI is a further simplification of the SDAI that excludes the acute phase reactant.  
It sums the total number of tender and swollen 28-joint counts, the PtGA on a 0-10 scale 
and the PhGA on a 0-10 scale.  PtGA and PhGA are collected in a 0-100 scale, so they 
will need to be divided by 10. 
The CDAI is calculated using the following formula: 
TEN28 + SW28 + PtGA/10 + PhGA/10 
DAS28-CRP 
A subject’s DAS28-CRP score is calculated as follows: 
DAS28-CRP = 0.56*√TEN28 + 0.28*√SJC28 + 0.36*ln(CRP+1) + 0.014*PtGA + 0.96, 
where CRP is measured in mg/L.  
DAS28-ESR 
A subject’s DAS28-ESR score is calculated as follows: 
DAS28-ESR = 0.56*√ TEN28 + 0.28*√SJC28 + 0.70*ln(ESR) + 0.014*PtGA, 
where ESR is measured in mm/hr. 
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Swollen Joint Count 
The swollen joint count is an assessment of the swelling of joints using 0-1 point scale 
(0=none, 1=present). Joints that are marked as permanently inevaluable due to being 
replaced or fused are not counted as swollen for that specific visit. Joints that are 
marked with an intra-articular corticosteroid injection are considered swollen for that 
specific visit. The total swollen joint count is calculated by summing the number of joints 
with present swelling.   
Swollen Joint Count (66) 
Temporomandibular joints (n=2) 
Metacarpophalangeal joints (MCP) (n=10) 
Sternoclavicular joints (n=2) 
Fingers distal interphalangeal joints (DIP) (n=8) 
Acromioclavicular joints (n=2) 
Knees (n=2) 
Shoulders (n=2) 
Ankles (n=2) 
Elbows (n=2) 
Tarsi (n=2) 
Wrists (n=2) 
Metatarsal phalangeal joints (MTP) (n=10) 
Fingers proximal interphalangeal joints (PIP) 
(n=10) 
Toes proximal interphalangeal joints (PIP) 
(n=10) 
 
Swollen Joint Count (28) Plus Feet and Ankles 
Shoulders (n=2) 
Metacarpophalangeal joints (MCP) (n=10) 
Elbows (n=2) 
Proximal interphalangeal joints (Fingers PIP) 
(n=10) 
Wrists (n=2) 
Knees (n=2) 
Ankles (n=2) 
Tarsi (n=2) 
Metatarsal phalangeal joints (MTP) (n=10) 
Toes proximal interphalangeal joints (PIP) 
(n=10) 
 
Swollen Joint Count (28) 
Shoulders (n=2) 
Metacarpophalangeal joints (MCP) (n=10) 
Elbows (n=2) 
Proximal interphalangeal joints (Fingers PIP) 
(n=10) 
Wrists (n=2) 
Knees (n=2) 
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Tender Joint Count 
The tender joint count is an assessment of the pain and/or tenderness of joints using 0-1 
point scale (0=none, 1=present).  Joints that are marked as permanently inevaluable due 
to being replaced or fused are not counted as tender for that specific visit. Joints that are 
marked with an intra-articular corticosteroid injection are considered tender for that 
specific visit. The total tender joint count is calculated by summing the number of joints 
with present tenderness.   
Tender Joint Count (68) 
Temporomandibular joints (n=2) 
Metacarpophalangeal joints (MCP) (n=10) 
Sternoclavicular joints (n=2) 
Metatarsal phalangeal joints (MTP) (n=10) 
Acromioclavicular joints (n=2) 
Toes proximal interphalangeal joints (PIP) 
(n=10) 
Shoulders (n=2) 
Knees (n=2) 
Elbows (n=2) 
Ankles (n=2) 
Wrists (n=2) 
Tarsi (n=2) 
Fingers proximal interphalangeal joints 
(PIP) (n=10) 
Hip (n=2) 
Fingers distal interphalangeal joints (DIP) 
(n=8) 
 
 
Tender Joint Count (28) Plus Feet and Ankles 
Shoulders (n=2) 
Metacarpophalangeal joints (MCP) (n=10) 
Elbows (n=2) 
Proximal interphalangeal joints (Fingers PIP) 
(n=10) 
Wrists (n=2) 
Knees (n=2) 
Ankles (n=2) 
Tarsi (n=2) 
Metatarsal phalangeal joints (MTP) (n=10) 
Toes proximal interphalangeal joints (PIP) 
(n=10) 
 
Tender Joint Count (28) 
Shoulders (n=2) 
Metacarpophalangeal joints (MCP) (n=10) 
Elbows (n=2) 
Proximal interphalangeal joints (Fingers PIP) 
(n=10) 
Wrists (n=2) 
Knees (n=2) 
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Boolean remission status (28-joint counts) 
A remission measure defined as having 28-joint tender joint count ≤ 1, 28-joint swollen 
joint count ≤ 1, CRP (in mg/dL) ≤ 1, and patient global assessment  ≤ 1. 
Boolean remission status (28-joint count + feet and ankles) 
A remission measure defined as having 28-joint + feet and ankles tender joint count  ≤ 1, 
28-joint + feet and ankles swollen joint count   ≤ 1, CRP (in mg/dL) ≤ 1, and patient 
global assessment  ≤ 1. 
The joints used in 28-joint count + feet and ankles for both swollen and tender 
assessments are: 
ankles (2), tarsi (2), metatarsal phalangeal joints (10), toes proximal interphalangeal 
joints (10) and tender: metatarsal phalangeal joints (MTP) (10), toes proximal 
interphalangeal joints (10), ankles (2), tarsi (2). 
Boolean remission (66/68 joint counts) 
A remission measure defined as having 68-joint tender joint count ≤ 1, 66-joint swollen 
joint count ≤ 1, CRP (in mg/dL) ≤ 1, and patient global assessment  ≤ 1. 
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Appendix B.  Code Fragments  
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23 April 2020
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Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 56 
 
Product: 
Date: 
Etanercept
Clinical Study Report:  20110186
23 April 2020
Page 57


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 57 
 
Appendix C.  Reference Values/Toxicity Grades 
Adverse event severity is graded based on the National Cancer Institute Common 
Toxicity Criteria for Adverse Events (CTCAE) version 4.0.   
Laboratory toxicity is graded based on the National Cancer Institute Common Toxicity 
Criteria (CTC) version 2.0 with the following additions: 
 
Grade 
0 
1 
2 
3 
4 
BUN 
WNL 
>1.5 – 2.0 
x ULN 
>2.0 – 3.0 x ULN 
>3.0 – 4.0 x ULN 
>4.0 x ULN 
HGB 
WNL 
>ULN 
>(ULN+1) – 
(ULN+2) 
>(ULN+2) 
- 
Urine 
Protein 
NEG, 
NEGATIVE, 
TRACE, 
NORMAL, 
NOT 
DETECTED 
+, +1, 1+ 
++, +2, 2+,  
+++, +3, 3+ 
++++, +4, 4+ 
- 
Platelet 
Count 
WNL 
> ULN – 
1.0x1012/L 
> 1.0x1012/L 
- 
- 
Leukocyte 
Count 
WNL 
> ULN – 
2.0x1010/L 
> 2.0x1010/L – 
4.0x1010/L 
> 4.0x1010/L 
- 
Product: 
Date: 
Etanercept
Clinical Study Report:  20110186
23 April 2020
Page 58


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 58 
 
Appendix D.  Patient-reported Outcome Forms/Instruments  
Scoring Algorithm of Health Assessment Questionnaire Disability Index (HAQ-DI) 
All language versions will use the following scoring system.  
• HAQ-DI scores range from 0 (no difficulty) to 3 (much difficulty) for each of the 
20 questions in the 8 categories.  
• Calculate the maximum score for each of the 8 categories. At least one question in 
each category needs to be answered to compute the maximum score.  
• If an aid or device is used or help from another person is needed, adjust the score for 
the associated category by increasing a zero or a 1 to a 2. If a patient’s highest score 
for that category is a 2, it remains a 2, and if a three, it remains a three.  
 
Sub-domain  
Aids or devices  
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)  
Activities 
N/A 
If no more than 2 categories have missing scores, then the disability score is the mean 
of the non-missing category scores (the summed category scores divide by the number 
of categories answered). Otherwise, the disability score is set to missing.  
Product: 
Date: 
Etanercept
Clinical Study Report:  20110186
23 April 2020
Page 59


Product:  Etanercept 
Statistical Analysis Plan:  20110186 
Dated:  7 January 2020 
Page 59 
 
Appendix E.  Concomitant Medications 
The following concomitant medications will be tabulated: 
• 
hydroxychloroquine, 
• 
sulfasalazine, 
• 
minocycline, 
• 
prednisone (5mg daily or less), 
• 
and NSAIDs 
The Prednisone dosage of 5 mg daily or less is of interest because entry criteria allows 
for this dosage. 
Only concomitant medications with a partial or complete end date are tabulated. 
Product: 
Date: 
Etanercept
Clinical Study Report:  20110186
23 April 2020
Page 60