Clinical trial NCT02376790
Conditions: Psoriatic Arthritis
Keywords: Psoriatic Arthritis Arthritis, Psoriasis Etanercept Enbrel Methotrexate Minimal Disease Activity
Sponsor: Amgen
Start date: 2015-03-03; Completion date: 2018-07-06
Enrollment: 851 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to learn more about the role of etanercept alone or in combination with methotrexate on disease activity in adults with psoriatic arthritis.

Detailed description:
The study will consist of a 30-day screening period, a 48-week double-blind treatment period and a 30-day safety follow-up period.

At or after week 24, participants with an inadequate response could receive rescue therapy with etanercept plus methotrexate until the end of the treatment period.

Arms: arm 1: Participants received oral methotrexate 20 mg weekly plus placebo to etanercept subcutaneous injection once a week for 48 weeks. arm 2: Participants received etanercept 50 mg weekly by subcutaneous injection plus oral placebo to methotrexate for 48 weeks. arm 3: Participants received etanercept 50 mg a week by subcutaneous injection plus oral methotrexate 20 mg weekly for 48 weeks.
Interventions: intervention 1: Etanercept intervention 2: Methotrexate intervention 3: Placebo to Etanercept intervention 4: Placebo to Methotrexate
Intervention descriptions: intervention 1: Etanercept was administered by subcutaneous injection once a week intervention 2: Methotrexate capsules taken orally once a week. Dosing was initiated at 10 mg weekly and titrated up to a final dose of 20 mg weekly over a 4-week period. intervention 3: Placebo to etanercept was administered by subcutaneous injection once a week. intervention 4: Placebo to methotrexate capsules taken orally once a week.

Protocol documents:
Prot_000.pdf: 
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Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 2 of 76 
CONFIDENTIAL 
Investigator’s Agreement 
I have read the attached protocol entitled A Multicenter Double-Blind, Randomized 
Controlled Study of Etanercept and Methotrexate in Combination or as Monotherapy in 
Subjects With Psoriatic Arthritis, dated 31 August 2016, and agree to abide by all 
provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
•
me (including, if applicable, my spouse [or legal partner] and dependent children)
•
my subinvestigators (including, if applicable, their spouses [or legal partners] and
dependent children)
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
Signature 
Name of Investigator 
Date (DD Month YYYY) 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 3 of 76 
CONFIDENTIAL
Protocol Synopsis 
Title:  A Multicenter Double-Blind, Randomized Controlled Study of Etanercept and Methotrexate 
in Combination or as Monotherapy in Subjects With Psoriatic Arthritis  
Study Phase:  Phase 3 
Indication:  Psoriatic Arthritis (PsA) 
Primary Objective:  To evaluate the efficacy of etanercept plus methotrexate therapy and 
etanercept monotherapy compared to methotrexate monotherapy, in subjects with PsA as 
measured by the proportion of subjects achieving an American College of Rheumatology (ACR) 
20 response at week 24. 
Key Secondary Objective:  To evaluate the efficacy of etanercept plus methotrexate therapy 
and etanercept monotherapy compared to methotrexate monotherapy as measured by the 
proportion of subjects achieving Minimal Disease Activity (MDA) at week 24. 
Other Secondary Objectives: 
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept monotherapy 
compared to methotrexate monotherapy on the following:  

Other measures of arthritis activity

Measures of non-arthritic PsA disease activity

Key patient reported outcomes (PRO) related to physical function and quality of life
Safety Objectives: 

To evaluate the safety of etanercept and methotrexate
Hypotheses:  Primary:  Etanercept plus methotrexate therapy and etanercept monotherapy are 
more efficacious than methotrexate monotherapy as measured by the proportion of subjects with 
PsA achieving ACR 20 response at week 24. 
Secondary:  Etanercept plus methotrexate therapy and etanercept monotherapy are more 
efficacious than methotrexate as measured by the proportion of subjects with PsA achieving MDA 
response at week 24. 
Primary Endpoint:  ACR 20 response at week 24 
Key Secondary Endpoint:  MDA response at week 24 
Other Secondary Endpoints: 

Modified Nail Psoriasis Severity Index (modified NAPSI) score and change from baseline at
week 24 

Leeds dactylitis score and change from baseline at week 24

Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis score and change
from baseline at week 24

ACR 20 response at all other measured timepoints

MDA response at all other measured timepoints

Psoriatic Arthritis Disease Activity Score (PASDAS) at all measured timepoints

ACR 50, ACR 70, and components of ACR at all measured timepoints

Simplified Disease Activity Index (SDAI) and change from baseline at all measured
timepoints

Clinical Disease Activity Index (CDAI) and change from baseline at all measured timepoints

Disease activity score (28 joint) using the C-reactive protein formula (DAS28-CRP) and
change from baseline at all measured timepoints


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 4 of 76 
CONFIDENTIAL 
 
 
• 
Disability Index of the Health Assessment Questionnaire (HAQ-DI) score and change from 
baseline at week 24 
• 
Medical Outcomes Short Form-36 Questionnaire (SF-36) score and change from baseline at 
week 24 
For subjects with involved body surface area (BSA) ≥ 3% at baseline: 
• 
Static Physician Global Assessment of Psoriasis (sPGA) at week 24 
• 
BSA at week 24  
Safety Endpoints: 
• 
Adverse events 
• 
Serious adverse events 
• 
Laboratory parameters and vital signs 
Study Design:  This is a multicenter, randomized, double-blind controlled study in subjects with 
PsA.  The study will consist of a 30-day screening period, a 48-week double-blind treatment 
period and a 30-day safety follow-up period.  Approximately 840 subjects will be randomly 
assigned in a 1:1:1 ratio to one of three treatment groups (280 per group):  etanercept 50 mg 
weekly by subcutaneous injection plus oral methotrexate 20 mg weekly, etanercept 50 mg weekly 
by subcutaneous injection plus oral placebo for methotrexate, and oral methotrexate 20 mg 
weekly plus placebo for etanercept.  Starting at week 24 visit, subjects who have an inadequate 
response will be provided rescue treatment of etanercept plus methotrexate for the remainder of 
the study. Original treatment assignments will remain blinded until all subjects reach the week 48 
or early termination visit, whichever comes first. 
Sample Size:  Approximately 840 subjects will be enrolled 
Summary of Subject Eligibility Criteria:  Subjects must be adults with active PsA based on the 
Classification Criteria for Psoriatic Arthritis (CASPAR) who are naïve to etanercept and other 
biologics and have no prior use of methotrexate for the treatment of PsA.  Prior treatment with 
methotrexate is allowed if indicated for psoriasis as long as discontinuation was not due to toxicity 
or intolerance and treatment was discontinued ≥ 6 months prior to baseline. For a full list of 
eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2.  
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Etanercept dosing in the 
planned study follows the recommended label dosing for subjects with PsA.  Etanercept will be 
provided as a 50 mg pre-filled syringe or matching placebo for injection once weekly for 
48 weeks.  See Sections 6.2.1. 
Non-Amgen Investigational Product Dosage and Administration:  Methotrexate dosing will 
begin at a dose of 10 mg on day 1 and will be titrated up to 20 mg weekly over a 4-week period. 
Methotrexate will be supplied as 2.5 mg capsules or as matching placebo capsules and will be 
taken once weekly by oral administration for 48 weeks.  For those subjects receiving rescue 
therapy, methotrexate will be dispensed as 2.5 mg tablets.  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 week as 1 mg daily per investigator judgment OR administration according to 
the local standard of care. See Section 6.3.1. 
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, 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 5 of 76 
CONFIDENTIAL 
 
 
C-reactive protein and biomarkers, tender and swollen joint assessment and count, physician 
global assessment, Leeds dactylitis index, SPARCC enthesitis index, modified NAPSI, BSA, 
sPGA, radiographs and PROs. 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 analysis will occur after all data through week 48 is 
finalized.  The primary analysis of the primary and key secondary endpoints will be based on the 
full analysis set.  Treatment effect between etanercept plus methotrexate therapy and 
methotrexate monotherapy and between etanercept monotherapy and methotrexate 
monotherapy will be tested in a Bonferroni-based gatekeeping chain procedure to control the 
family-wise 2-sided type one error rate at 0.05.  Between treatment comparisons will be made 
using the stratified Cochran-Mantel-Haenszel (CMH) test with baseline body mass index and prior 
non-biologic disease modifying antirheumatic drug (DMARD) use as the stratification factors.  All 
other efficacy endpoints will be tested at a significance level of 0.05 without adjusting for 
multiplicity.  Safety endpoints will be summarized descriptively based on the safety analysis set.  
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc 
Data Element Standards 
Version(s)/Date(s):  
Version 4.0  31 October 2013  


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 6 of 76 
CONFIDENTIAL 
Study Design and Treatment Schema 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 7 of 76 
CONFIDENTIAL 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
eSAE contingency form 
electronic serious adverse event contingency form 
ACR 
American College of Rheumatology 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BSA 
Body Suface Area 
CASPAR 
Classification Criteria for Psoriatic Arthritis 
CDAI 
Clinical disease activity index 
CMH 
Cochran-Mantel-Haenszel 
eCRF 
Electronic case report form 
CRP 
C-reactive protein 
DAS28-CRP 
Disease activity score (28 joint) using the C-reactive protein formula 
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   
EOS 
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. 
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 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
GRAPPA 
Group for Research and Assessment of Psoriasis and Psoriatic 
Arthritis 
HAQ-DI 
Disability Index of the Health Assessment Questionnaire 
HBV 
Hepatitis B virus 
HCP 
Health care provider 
ICH 
International Conference on Harmonisation 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 8 of 76 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Interactive Voice 
Response System (IXRS) 
Telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.  
IPIM 
Investigational product instruction manual 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
MIPA study 
Methotrexate in Psoriatic Arthritis Study 
MDA 
Minimal Disease Activity 
Modified NAPSI 
Modified Nail Psoriasis Severity Index 
van der Heijde mTSS 
van der Heijde Modified Total Sharp Score 
NSAID 
Non-steroidal anti-inflammatory drug 
PASDAS 
Psoriatic Arthritis Disease Activity Score  
PCR 
Polymerase chain reaction 
PFS 
Pre-filled syringe 
PI 
principal investigator 
PPD 
Purified protein derivative 
PRO 
Patient reported outcomes 
PsA 
Psoriatic arthritis 
RBC 
Red blood cells 
SAP 
statistical analysis plan 
SDAI 
Simplified Disease Activity Index 
SF-36 
Medical Outcomes Short Form-36 Questionnaire 
SPARCC 
Spondyloarthritis Research Consortium of Canada 
sPGA 
Static Physician Global Assessment of Psoriasis 
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:  20130207 
Date:  31 August 2016 
Page 9 of 76 
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 
Key Secondary Objective ........................................................................... 14 
1.3 
Other Secondary Objectives ....................................................................... 14 
1.4 
Safety Objectives ........................................................................................ 14 
1.5 
Exploratory Objectives ................................................................................ 14 
2.
BACKGROUND AND RATIONALE ........................................................................ 14
2.1 
Disease ....................................................................................................... 14 
2.2 
Etanercept (Enbrel®) Background .............................................................. 15 
2.3 
Non-Amgen Medicinal Product Background:  Methotrexate ....................... 15 
2.4 
Rationale .................................................................................................... 16 
2.5 
Clinical Hypotheses .................................................................................... 18 
3.
EXPERIMENTAL PLAN ......................................................................................... 18
3.1 
Study Design .............................................................................................. 18 
3.1.1 
Rescue Therapy ......................................................................... 18 
3.1.2 
Inadequate Response ................................................................ 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 .......................................................................................... 19
4.1 
Inclusion and Exclusion Criteria ................................................................. 20 
4.1.1 
Inclusion Criteria ......................................................................... 20 
4.1.2 
Exclusion Criteria ........................................................................ 21 
5.
SUBJECT ENROLLMENT ..................................................................................... 23
5.1 
Randomization/Treatment Assignment ...................................................... 24 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 24 
6.
TREATMENT PROCEDURES ............................................................................... 25
6.1 
Classification of Products and/or Medical Device(s) .................................. 25 
6.2 
Investigational Product ............................................................................... 25 
6.2.1 
Amgen Investigational Product:  Etanercept .............................. 25 
6.2.1.1 
Dosage, Administration, and Schedule .................... 25 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 10 of 76 
CONFIDENTIAL 
 
 
6.2.2 
Non-Amgen Investigational Product:  Methotrexate ................... 26 
6.2.2.1 
Dosage, Administration, and Schedule .................... 26 
6.2.2.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 27 
6.3 
Non-investigational Product ........................................................................ 27 
6.3.1 
Non-Amgen Non-investigational Product:  Folic Acid ................. 27 
6.3.2 
Dosage, Administration, and Schedule ...................................... 27 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules, Reporting, and 
Monitoring ................................................................................................... 27 
6.4.1 
Hepatotoxicity Stopping and Rechallenge Rules ........................ 27 
6.4.2 
Hepatotoxicity Reporting and Monitoring .................................... 28 
6.4.3 
Criteria for Reporting Hepatotoxicity as a Serious 
Adverse Event ............................................................................ 28 
6.5 
Concomitant Therapy ................................................................................. 28 
6.5.1 
Analgesics and NSAIDs ............................................................. 28 
6.5.2 
Corticosteroids ............................................................................ 29 
6.6 
Medical Devices ......................................................................................... 29 
6.7 
Product Complaints .................................................................................... 29 
6.8 
Excluded Treatments and/or Procedures During Study Period .................. 29 
6.9 
Contraceptive Requirements ...................................................................... 30 
7. 
STUDY PROCEDURES ......................................................................................... 31 
7.1 
Schedule of Assessments .......................................................................... 31 
7.2 
General Study Procedures ......................................................................... 34 
7.2.1 
Screening ................................................................................... 34 
7.2.2 
Re-screening .............................................................................. 34 
7.2.3 
Baseline Visit (Day 1) ................................................................. 34 
7.2.4 
Treatment ................................................................................... 35 
7.2.5 
Disease Assessment Visit and Disease Assessment 
Follow-up Visit ............................................................................ 35 
7.2.6 
Subject End of Treatment/Early Termination .............................. 35 
7.2.7 
Safety Follow-up/End of Study ................................................... 35 
7.3 
Description of Study Assessments and Procedures ................................... 35 
7.3.1 
Informed Consent ....................................................................... 36 
7.3.2 
Demographic Data ...................................................................... 36 
7.3.3 
Medical History ........................................................................... 36 
7.3.4 
Medication History ...................................................................... 36 
7.3.5 
Physical Examination ................................................................. 36 
7.3.6 
Physical Measurement ............................................................... 36 
7.3.7 
Vital Signs ................................................................................... 37 
7.3.8 
PsA Disease Assessments ......................................................... 37 
7.3.8.1 
Swollen/Tender Joint Counts ................................... 37 
7.3.8.2 
Leeds Dactylitis Index .............................................. 37 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 11 of 76 
CONFIDENTIAL 
 
 
7.3.8.3 
Spondyloarthritis Research Consortium of 
Canada Enthesitis Index .......................................... 38 
7.3.8.4 
Radiographs ............................................................. 38 
7.3.9 
Psoriasis Disease Assessments ................................................. 39 
7.3.9.1 
Static Physician Global Assessment of 
Psoriasis .................................................................. 39 
7.3.9.2 
Body Surface Area Involvement .............................. 39 
7.3.9.3 
Modified Nail Psoriasis Severity Index ..................... 39 
7.3.9.4 
Physician Global Assessment of Disease 
Activity ...................................................................... 40 
7.3.10 
Patient Reported Outcomes ....................................................... 40 
7.3.10.1 
Patient Global Assessment of Joint Pain ................. 40 
7.3.10.2 
Patient Global Assessment of Disease 
Activity ...................................................................... 40 
7.3.10.3 
Disability Index of the Health Assessment 
Questionnaire ........................................................... 40 
7.3.10.4 
Medical Outcomes Short Form-36 
Questionnaire ........................................................... 40 
7.4 
Laboratory Assessments ............................................................................ 41 
7.4.1 
Tuberculosis Testing .................................................................. 42 
7.4.1.1 
PPD .......................................................................... 42 
7.4.1.2 
Quantiferon .............................................................. 42 
7.4.2 
Urine Pregnancy Test ................................................................. 43 
7.5 
Biomarker Development ............................................................................. 43 
7.6 
Pharmacogenetic Studies ........................................................................... 43 
7.7 
Sample Storage and Destruction ................................................................ 43 
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 ...................................... 45 
8.3 
Reasons for Removal From Treatment or Study ........................................ 46 
8.3.1 
Reasons for Removal From Treatment ...................................... 46 
8.3.2 
Reasons for Removal From Study ............................................. 46 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 46 
9.1 
Adverse Events .......................................................................................... 46 
9.1.1 
Definition of Adverse Events ...................................................... 46 
9.1.2 
Definition of Serious Adverse Events ......................................... 47 
9.2 
Reporting of Adverse Events ...................................................................... 47 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria .................................................................. 47 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 48 
9.3 
Pregnancy and Lactation Reporting ........................................................... 50 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 12 of 76 
CONFIDENTIAL 
 
 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 50 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 50 
10.1.1 
Study Endpoints ......................................................................... 50 
10.1.1.1 
Primary Endpoint ..................................................... 50 
10.1.1.2 
Key Secondary Endpoint ......................................... 50 
10.1.1.3 
Other Secondary Endpoints ..................................... 50 
10.1.1.4 
Safety Endpoints ...................................................... 51 
10.1.1.5 
Exploratory Endpoints .............................................. 51 
10.1.2 
Analysis Sets .............................................................................. 51 
10.1.2.1 
Full Analysis Set ...................................................... 51 
10.1.2.2 
Psoriasis Efficacy Analysis Set ................................ 52 
10.1.2.3 
Safety Analysis Set .................................................. 52 
10.1.3 
Covariates and Subgroups ......................................................... 52 
10.2 
Sample Size Considerations ...................................................................... 52 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 54 
10.4 
Planned Analyses ....................................................................................... 54 
10.4.1 
Primary Analysis ......................................................................... 54 
10.5 
Planned Methods of Analysis ..................................................................... 55 
10.5.1 
General Considerations .............................................................. 55 
10.5.2 
Primary and Key Secondary Efficacy Endpoints ........................ 55 
10.5.3 
Other Secondary Efficacy Endpoints .......................................... 58 
10.5.4 
Safety Endpoints ........................................................................ 58 
11. 
REGULATORY OBLIGATIONS ............................................................................. 58 
11.1 
Informed Consent ....................................................................................... 58 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 59 
11.3 
Subject Confidentiality ................................................................................ 60 
11.4 
Investigator Signatory Obligations .............................................................. 60 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 60 
12.1 
Protocol Amendments and Study Termination ........................................... 60 
12.2 
Study Documentation and Archive ............................................................. 61 
12.3 
Study Monitoring and Data Collection ........................................................ 62 
12.4 
Investigator Responsibilities for Data Collection ........................................ 63 
12.5 
Language.................................................................................................... 63 
12.6 
Publication Policy ....................................................................................... 63 
12.7 
Compensation ............................................................................................ 64 
13. 
REFERENCES ....................................................................................................... 65 
14. 
APPENDICES ........................................................................................................ 67 


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List of Tables 
Table 1.  Schedule of Assessments
 
 ................................................................................ 32
Table 2.  Analyte Listing
 
 .................................................................................................. 42
List of Figures 
Figure 1.  Bonferroni-based Gatekeeping Chain Procedure
 
 ........................................... 57
List of Appendices 
Appendix A.  Additional Safety Assessment Information
 
 ................................................ 68
Appendix B.  Electronic Serious Adverse Event Contingency Form
 
 ............................... 72
Appendix C.  Pregnancy and Lactation Notification Worksheets
 
 .................................... 75


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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy, in subjects with psoriatic 
arthritis (PsA) as measured by the proportion of subjects achieving an American College 
of Rheumatology (ACR) 20 response at week 24. 
1.2 
Key Secondary Objective 
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy as measured by the proportion of 
subjects achieving minimal disease activity (MDA) at week 24. 
1.3 
Other Secondary Objectives 
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy on the following: 
• 
Other measures of arthritis activity  
• 
Measures of non-arthritic PsA disease activity 
• 
Key patient reported outcomes (PRO) related to physical function and quality of life 
1.4 
Safety Objectives 
To evaluate the safety of etanercept and methotrexate. 
1.5 
Exploratory Objectives 
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy on the following: 
• 
Other measures of disease activity including the skin 
• 
Other PROs 
• 
Inhibition of radiographic progression as measured by the van der Heijde modified 
Total Sharp score (mTSS) for PsA 
• 
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 PsA and/or subject response to etanercept.  
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
PsA is a chronic inflammatory disorder of the peripheral joints and axial skeleton that 
occurs in 7% to 34% of patients with psoriasis (Scarpa et al, 1984; Biondi et al, 1989; 
Espinoza et al, 1992; Shbeeb et al, 2000), which in turn has a prevalence of 1% to 3% in 
the general population (Biondi et al, 1989; Koo, 1996).  Articular involvement can vary 


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widely from an isolated monoarthritis to a very destructive diffuse arthritis mutilans.  
Other symptoms associated with PsA include dactylitis, enthesitis, and nail changes.  
Typical nail changes include pitting of the nail, onycholysis, ridges, and thickening of the 
nail.  Although most patients have associated psoriasis, PsA can present without skin 
changes.  Radiographic features include joint erosions, joint space loss, osteolysis that 
may cause penciling of the phalanx, and periostitis.  PsA can lead to permanent 
destruction of joints and functional disabilities. 
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 
plaque psoriasis.  Elevated levels of TNF are found in involved tissues and fluids of 
patients with rheumatoid arthritis, PsA, 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 fusion protein consisting of the extracelluar 
ligand-binding portion of the human 75 kilodalton TNF receptor linked to the Fc portion of 
human IgG1.  Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha 
[LT-α]) to cell surface TNF receptors, rendering TNF biologically inactive. 
In many countries, etanercept is indicated for reducing signs and symptoms, inhibiting 
the progression of structural damage of active arthritis, and improving physical function 
in patients with PsA.   
Etanercept is also indicated for the treatment of:  (1) moderately to severely active 
rheumatoid arthritis; (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 Investigator’s Brochure or product label for additional 
information related to physical, chemical, and pharmaceutical properties and 
formulations. 
2.3 
Non-Amgen Medicinal Product Background:  Methotrexate 
Methotrexate is an antimetabolite used in the treatment of certain neoplastic diseases, 
psoriasis, and rheumatoid arthritis.  Methotrexate or its metabolites inhibit dihydrofolic 
acid reductase and antagonize thymidylate synthase.  Methotrexate is thought to inhibit 
5-aminoimidazole 4-carboxamide ribonucleotide transformylase which leads to an 


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increase in both intracellular and extracellular adenosine.  Methotrexate is one of the 
most commonly used non-biologic disease modifying antirheumatic drug (DMARD) in 
PsA.  Although the use of methotrexate is standard therapy in the medical community 
and it is mentioned in guidelines in the treatment of PsA, it is not an approved drug for 
the treatment of PsA in many countries. 
Refer to the regional manufacturer package insert for additional information. 
2.4 
Rationale 
Etanercept has been approved for PsA by the FDA and Health Canada and is indicated 
for reducing the signs and symptoms, inhibiting the progression of structural damage of 
active arthritis, and improving physical function.  Etanercept can be used in combination 
with methotrexate in patients who do not respond adequately to methotrexate alone. 
Methotrexate is one of the most commonly used non-biologic DMARD in PsA as 
monotherapy or in combination therapy with other synthetic DMARDs or with biologic 
DMARDs.  Although methotrexate is commonly used in treating PsA, it is unclear how 
effective it is in PsA.  The most recent randomized placebo-controlled trial of 
methotrexate in PsA is the Methotrexate in Psoriatic Arthritis (MIPA) study 
(Kingsley et al, 2012).  This was a 6-month, double-blind, parallel-group study in  
methotrexate naïve subjects randomized to receive methotrexate (15 mg/wk; n = 109) or 
placebo (n = 112).  In an intent-to-treat analysis, there were no statistically significant 
improvements in measures of disease activity across groups at 24 weeks.  The odds 
ratios (95% CI) for Psoriatic Arthritis Response Criteria, ACR 20, and Disease activity 
score (28 joint) responders for the methotrexate and placebo groups were 1.77 (0.97, 
3.23; p = 0.06), 2.00 (0.65, 6.22; p = 0.23), and 1.70 (0.90, 3.17; p = 0.10), respectively.  
In a completer analysis, percent responders for methotrexate and placebo were 34% and 
21% for ACR 20 respectively for a difference of 13%.  In the PsA pivotal trial, ACR 20 
response at week 24 was 50% and 14% in the etanercept and placebo groups 
respectively for a difference of 36%.  Nevertheless, comparisons with the MIPA trial need 
to be qualified by the fact that the subjects in the etanercept pivotal trial were not 
uniformly methotrexate naïve.  Furthermore, in the MIPA trial the target dose of 
methotrexate was 15 mg QW, a less than maximal clinically used dose level. 
In rheumatoid arthritis, combining TNF inhibitors such as etanercept with methotrexate 
leads to superior efficacy relative to each agent used alone (Klareskog et al, 2004).  The 
role of methotrexate in combination with etanercept in PsA remains unclear. Analysis of 


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data from 440 PsA patients in the Norwegian DMARD longitudinal observational study 
showed no consistent differences in response over a 12-month period between patients 
who started their TNF inhibitor as monotherapy or in combination with methotrexate 
(Fagerli et al, 2014)  Similar findings were found in a United States registry 
(Mease et al, 2013).  No difference was found in reaching clinical disease activity index 
(CDAI) low disease activity or staying in low disease activity on anti-TNF monotherapy 
vs. combination with methotrexate in this study (Mease et al, 2013).  These data suggest 
key differences in the response of PsA patients compared to RA patients to 
methotrexate and highlight the importance of characterizing the role of etanercept as a 
monotherapy agent in PsA. 
A new disease activity state called MDA, has been developed and validated 
(Coates et al, 2010a and Coates et al, 2010b).  MDA represents a low disease activity 
state and would further the ‘treat-to-target’ approach in PsA.  The MDA criteria is specific 
for PsA and incorporates measures of joint and entheseal inflammation, skin disease, 
PROs and functional disability to assess the subject’s disease activity.  The results of the 
validation analysis support the prognostic value of the PsA MDA criteria and show that 
subjects achieving MDA are more likely to have a better radiologic outcome 
(Antoni et al, 2005a, Antoni et al, 2005b). 
This study will also aim to characterize the response rates of etanercept on enthesitis, 
dactylitis, and psoriatic nail changes.  The PRESTA trial, assessed two different 
regimens of etanercept (50 mg twice weekly or 50 mg once weekly) in subjects with 
psoriasis and PsA.  Etanercept 50 mg once weekly resulted in a 70.0% and 
81.3% improvement from baseline in enthesitis at week 12 and 24 respectively.  
Similarly, improvement in dactylitis from baseline at weeks 12 and 24 were 78.4% and 
84.8%, respectively (Sterry et al, 2010).  There is a paucity of data regarding the efficacy 
of methotrexate monotherapy on dactylitis and enthesitis in patients with PsA.  A recent 
study looking at the effect of etanercept on the Nail Psoriasis Severity Index (NAPSI) 
score at week 12 and 24 improved by 50% and 72%, respectively on a weekly dose of 
Enbrel of 50 mgs (Ortonne et al, 2013).  In another recent study comparing improvement 
in nail changes on methotrexate monotherapy compared to cyclosporine monotherapy, 
methotrexate demonstrated a 30% improvement at 12 weeks and a 54% improvement at 
24 weeks in the NAPSI score (Gümüşel et al, 2011). 


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2.5 
Clinical Hypotheses 
Primary:  Etanercept plus methotrexate therapy and etanercept monotherapy are more 
efficacious than methotrexate monotherapy as measured by the proportion of subjects 
with PsA achieving ACR 20 response at week 24. 
Secondary:  Etanercept plus methotrexate therapy and etanercept monotherapy are 
more efficacious than methotrexate as measured by the proportion of subjects PsA 
achieving MDA response at week 24. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3, multicenter, randomized, double-blind controlled study in subjects with 
active PsA naïve to biologics and with no prior use of methotrexate for the treatment of 
PsA.  The study will consist of a 30-day screening period, a 48-week randomized 
double-blind treatment period, and a 30-day safety follow-up period. 
Approximately 840 subjects will be randomly assigned in a 1:1:1 ratio to one of 
three treatment groups (280 per arm): 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 20 mg 
weekly 
• 
Etanercept 50 mg weekly by subcutaneous injection plus oral placebo for 
methotrexate   
• 
Oral methotrexate 20 mg weekly plus placebo for etanercept 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.1.1 
Rescue Therapy 
At or after week 24, subjects who have an inadequate response as defined in 
Section 3.1.2. will receive rescue therapy with etanercept plus methotrexate until the end 
of the treatment period.  Prior to initiation of etanercept plus methotrexate rescue 
therapy subjects must complete the procedures outlined for the disease assessment visit 
as described in Section 7.2.5 and Table 1. 
3.1.2 
Inadequate Response 
Inadequate response is defined by having < 20% improvement in their tender and < 20% 
in their swollen joint counts from baseline at or after week 24.  This will be calculated 
automatically based on the joint count.  Inadequate response may be assessed at a 


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regularly scheduled visit or at a disease assessment visit as described in Section 7.2.5.  
All subjects that initiate rescue treatment must complete a disease assessment follow-up 
visit 4 weeks later to monitor for labs (see Section 7.2.5 and Table 1).  
Subjects randomized to the etanercept plus methotrexate arm that have an inadequate 
response will continue to receive the same treatment. 
3.2 
Number of Sites 
Approximately 105 sites globally will participate in the study.  Additional 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 840.  There will be 
approximately 280 subjects per treatment arm. 
Sample size considerations are provided in Section 10.2. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or 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 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 56 weeks including the screening and safety 
follow-up telephone call. 
3.5.2 
End of Study 
End of study is defined as the time when the last subject is assessed or receives an 
intervention for evaluation in the study. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Before any study specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1). 


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4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101. 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102. 
≥ 18 years of age at screening 
103. 
subject has had a diagnosis of PsA by the Classification Criteria for Psoriatic 
Arthritis (CASPAR) criteria 
104. 
subject has ≥ 3 tender and ≥ 3 swollen joints (as part of a 68/66 joint count) at 
screening and at baseline 
105. 
subject has an active psoriatic skin lesion (at least one psoriatic plaque 
approximately 2 cm or more in diameter) 
106. 
subject is naïve to etanercept and any other biologic for the treatment for PsA or 
psoriasis 
107. 
subject has no prior use of methotrexate for PsA. Prior treatment with 
methotrexate is allowed if indicated for psoriasis as long as discontinuation was 
not due to toxicity or intolerance and treatment discontinued ≥ 6 months prior to 
initiation of investigational product  
108. 
for subjects receiving non-steroidal anti-inflammatory drugs (NSAIDs) (including 
as needed use [PRN]):  the dose must be stable for ≥ 2 weeks prior to initiation of 
investigational product 
109. 
for subjects receiving oral corticosteroids:  the dose must be stable (not to 
exceed the equivalent of 10 mg of prednisone per day) for ≥ 4 weeks prior to 
initiation of investigational product 
110. 
negative test for hepatitis B surface antigen, hepatitis B core antibody and 
hepatitis C antibody 
111. 
no known history of active tuberculosis 
112. 
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: 
o negative purified protein derivative (PPD) (< 5 mm of induration at 
48 to 72 hours after test is placed) OR 
o 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 Inc. 
• 
documented history of a completed course of adequate treatment or 
prophylaxis per local standard of care prior to the start of investigational 
product 


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• 
no known exposure to a case of active tuberculosis after most recent 
prophylaxis 
• 
no evidence of active tuberculosis on chest radiograph within 3 months prior 
to the first dose of investigational product 
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 from starting investigational product and a 
negative urine pregnancy test at baseline (day 1) 
4.1.2 
Exclusion Criteria 
Medical Conditions 
201. 
subject has known history of alcoholic hepatitis, nonalcoholic steatohepatitis or 
immunodeficiency syndromes, including Human Immunodeficiency Virus 
infection. 
202. 
subject has any active infection (including chronic or localized infections) for 
which anti-infectives were indicated within 4 weeks prior to the first dose of 
investigational product. 
203. 
subject has a serious infection, defined as requiring hospitalization or intravenous 
anti-infectives within 8 weeks prior to the first dose of investigational product. 
204. 
subject had prosthetic joint infection within 5 years of screening or native joint 
infection within 1 year of screening. 
205. 
subject has known alcohol addiction or dependency, uses alcohol daily, or has 
current substance use or abuse. 
206. 
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 
PsA (eg, systemic lupus erythematosus with the exception of secondary 
Sjogren’s syndrome) 
Excluded Medications 
207. 
prior or current use of cyclophosphamide, chlorambucil, nitrogen mustard, or any 
other alkylating agent. 


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208. 
subject has used any of the following ≤ 3 months prior to screening:  
• 
abatacept 
• 
anakinra 
• 
azathioprine 
• 
cyclosporine 
• 
gold 
• 
mycophenolate mofetil 
• 
Prosorba column 
• 
Systemic tacrolimus 
• 
Otezla (apremilast) 
209. 
subject has used leflunomide ≤ 12 weeks prior to screening 
210. 
subject has used any of the following ≤ 4 weeks prior to screening: 
• 
sulfasalazine 
• 
intraarticular, intramuscular or intravenous corticosteroids, including 
adrenocorticotropic hormone 
• 
intraarticular hyaluronic acid injections 
• 
live vaccines 
211. 
for subjects not on continuous analgesics, subject has taken the following within 
12 hours prior to screening:  acetaminophen, NSAID, 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 
212. 
Subject has laboratory abnormalities during screening, including the following: 
• 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 x 
the upper limit of normal (ULN) 
• 
Platelet count < 125,000/mm3 
• 
White blood cell count < 3,000 cells/mm3 
• 
Absolute neutrophil count < 1500/mm3 
• 
Estimated creatinine clearance < 50 mL/min (Cockroft-Gault formula, calculated 
value to be provided to sites) 
213. 
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. 


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Other 
214. 
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). 
215. 
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). 
216. 
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. 
217. 
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. 
218. 
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. 
219. 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
220. 
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, PROs) to 
the best of the subject and investigator’s knowledge. 
221. 
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. 
222. 
Currently receiving treatment in another investigational device or drug study, or 
participated in any study involving administration of an investigational drug or 
device within 30 days or 5 terminal elimination half-lives, whichever is longer, 
before enrollment. 
223. 
Other investigational procedures while participating in this study are excluded. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in the enrollment CRF. 


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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 the Interactive Voice Response System 
(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 re-screened.  This number will 
not necessarily be the same as the randomization number assigned for the study. 
Subjects not meeting eligibility criteria are permitted to re-screen twice 
(see Section 7.2.1 and 7.2.2). 
5.1 
Randomization/Treatment Assignment 
Subjects that meet all eligibility criteria will be randomized at baseline to receive 
etanercept plus methotrexate, etanercept plus placebo for methotrexate or methotrexate 
plus placebo for etanercept in a 1:1:1 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 at randomization.  The randomization date is to be documented 
in the subject’s medical record and on the enrollment CRF. 
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. 
Other than rescue therapy situations, in the event of inadvertent unblinding (ie, the blind 
was not intended to be broken as described above), the investigator should immediately 
notify Amgen.  Each scenario will be reviewed individually to determine if the impacted 
subject(s) are able to continue receiving investigational product. 
Unblinding at the study site for any other reason, including the scenarios described 
above, will be considered a protocol deviation.  The investigator is strongly encouraged 


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Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 26 of 76 
CONFIDENTIAL 
 
 
missed, that dose should be skipped and the reason for the missed dose must be 
reported on the electronic case report form (eCRF).  Subsequent doses of 
investigational product should resume on the original schedule.  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 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 start date, quantity administered and box number of investigational 
product are to be recorded in each subject’s 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 capsules or as matching placebo 
capsules.  For those subjects receiving rescue therapy, methotrexate will be dispensed 
as 2.5 mg tablets. 
Additional details regarding the product(s) are provided in the IPIM. 
6.2.2.1 
Dosage, Administration, and Schedule 
Methotrexate dosing will be initiated at 10 mg weekly and will be titrated up to a final 
dose of 20 mg weekly over a 4-week period.  The treatment period for this study is 
48 weeks.  Methotrexate will be provided as 2.5 mg capsules, or as placebo capsules, 
and will be taken once weekly by oral administration.  Capsules should be swallowed 
whole.  Subjects will receive 1 dose of methotrexate or placebo per week (scheduled 
approximately 7 days apart) for 48 weeks.  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 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 27 of 76 
CONFIDENTIAL 
 
 
dose must be reported on the eCRF.  Double or extra doses should not be taken.  The 
start date, quantity administered, and bottle/package number of methotrexate is to be 
recorded on the subject’s diary and entered into the eCRF. 
6.2.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Methotrexate (or placebo for methotrexate) will be initiated at a dosage of 10 mg weekly 
at week 0 (day 1).  The dose will be increased by 2.5 mg weekly up to 20 mg over a 
4 week period.  In cases of typical methotrexate toxicities (eg, increased aspartate 
transaminase or alanine transaminase, or gastrointestinal adverse effects, severe 
stomatitis), the methotrexate dose may be reduced up to 10 mg weekly.  The reason for 
dose change of methotrexate is to be recorded on each subject’s 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. 
6.3.2 
Dosage, Administration, and Schedule 
The dose of folic acid will be 5 to 7 mg per week as 1 mg daily per investigator judgment 
OR administration according to the local standard of care.  The dose of folic acid may be 
adjusted OR folinic acid (leucovorin) can be added not to exceed 5 mg per week in 
response to methotrexate related toxicity. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules, Reporting, and 
Monitoring 
A United States Food and Drug Administration Guidance exists for drug-induced liver 
injury (DILI) (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 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 28 of 76 
CONFIDENTIAL 
 
 
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 Observation 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. 
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 must remain stable up to week 24.  
After week 24 the dose can be reduced or discontinued during the study if necessary for 
safety reasons or standard of care. 
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 must not be used within 24 hours of a scheduled study 
visit. 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 29 of 76 
CONFIDENTIAL 
 
 
6.5.2 
Corticosteroids 
Subjects entering the study while taking oral corticosteroids must remain on a stable 
dose until week 24.  
Corticosteroids may be used by any subject who meets the criteria for inadequate 
response and begins rescue treatment as described in Section 3.1.2. 
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). 
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: 
• 
Abatacept 
• 
Anakinra 
• 
Any other investigational agents or commercially available biologics 
• 
Otezla (apremilast) 
• 
Azathioprine 
• 
Sulfasalazine 
• 
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  
• 
Systemic tacrolimus 
• 
Live vaccines 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 30 of 76 
CONFIDENTIAL 
 
 
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 
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. 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 31 of 76 
CONFIDENTIAL 
 
 
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. 
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 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, and the radiographic 
assessments, all study procedures for a visit should be completed on the same day.  
Radiographs may be done within ± 1 week of the visit date.  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.  
Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling procedures. 
7.1 
Schedule of Assessments


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 32 of 76 
CONFIDENTIAL 
Table 1.  Schedule of Assessments 
30-day 
Screening 
Treatment Period 
Disease Assessment 
(DA) 
30-day 
Follow-Up 
Weeks 
0 (day 1) 
4 
8 
12 
16
 
24 
36 
48/ET
 
DA Visit
e 
DA Follow-up
e 
Safety (EOS)
g
GENERAL & SAFETY ASSESSMENTS 
Informed consent 
X 
Randomization via IXRS 
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 examination
a 
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 
X 
X 
Height 
X 
LABORATORY ASSESSMENTS 
Pregnancy test (serum)
b
X 
Pregnancy test (urine)
b,c
X 
X 
X 
X 
X 
Tuberculosis testing
d 
X 
Hematology and chemistry profile
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B surface antigen & core antibody; Hepatitis C virus 
antibody
i
X 
High Sensitivity C-reactive Protein 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
Biomarker blood sample 
X 
X 
X 
X 
INVESTIGATIONAL PRODUCT DISPENSING 
Etanercept/placebo for etanercept dispensation 
X 
X 
X 
X 
X 
X 
X
f 
X 
Methotrexate/placebo for methotrexate dispensation 
X 
X 
X 
X 
X 
X 
X
f 
X 
Folic Acid
h 
X 
X 
X 
X 
SUBJECT DIARY DISPENSING 
Dispense subject diary 
X 
X 
X 
X 
X 
X 
X 
Review subject diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DISEASE ASSESSMENTS 
Swollen and Tender joint count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician Global Assessment of Disease Activity (VAS 0 to 100) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Leeds Dactylitis Index 
X 
X 
X 
X 
X 
X 
X 
X 
Spondyloarthritis Research Consortium of Canada (SPARCC) 
Enthesitis Index 
X 
X 
X 
X 
X 
X 
X 
X 
Modified Nail Psoriasis Severity Index (NAPSI) 
X 
X 
X 
X 
X 
X 
Static Physician Global Assessment of Psoriasis 
X 
X 
X 
X 
X 
X 
X 
X 
Body Surface Area 
X 
X 
X 
X 
X 
X 
X 
X 
Radiographs (hands, feet) 
X 
X
X 
Page 1 of 2 
Footnotes defined on next page 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 33 of 76 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
 
30-day 
Screening 
Treatment Period 
Disease Assessment 
(DA) 
30-day 
Follow-Up 
Weeks 
 
0 (day 1) 
4 
8 
12 
16
 
24 
36 
48/ET
 
DA Visit
e 
DA Follow-up
e 
Safety (EOS)
g 
PATIENT REPORTED OUTCOMES 
 
 
 
 
 
 
 
 
 
 
 
 
Patient global assessment of pain (VAS 0 to 100) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient global assessment of disease activity (VAS 0 to 100) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Disability Index of the Health Assessment Questionnaire 
(HAQ-DI) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical Outcomes Short Form-36 Questionnaire (SF-36) 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
Page 2 of 2 
ET: early termination; DA:  Disease Assessment; EOS:  end of study; HBV:  hepatitis B virus; IXRS:  Interactive voice response system; PCR:  polymerase chain 
reaction; VAS:  visual analog scale 
aScreening physical exam will be a full exam; subsequent exams per standard of care to monitor for any changes 
bFor 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  
dSubjects 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. 
eDisease Assessment Visit - disease activity may be assessed at a regularly scheduled visit or at a Disease Assessment visit as described in Section 7.2.5.  If subject 
initiates rescue treatment then they must return for a Disease Assessment Follow-up visit 4 to 5 weeks later. 
fIf subjects meet the criteria for inadequate response as described in Section 3.1.2 they will be allowed to receive rescue treatment with etanercept plus methotrexate 
gSubjects will be contacted by phone by the site staff to collect any serious adverse events 
hFrequency of dispensation will vary with quantity dispensed and individual subject dose 
i At screening if the subject is positive for hepatitis B core antibody, the confirmatory reflex testing will be performed using HBV DNA PCR.   


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 34 of 76 
CONFIDENTIAL 
 
 
7.2 
General Study Procedures 
The procedures performed at each study visit are outlined above 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 eligibility criteria at the end of the 30-day window, the subject will 
be registered as a screen fail.  Abnormal laboratory assessments used to determine 
subject eligibility may be repeated once during the primary screening period before the 
subject is considered a screen failure.  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 re-screen two additional times per Section 7.2.2. 
7.2.2 
Re-screening 
Subjects who are unable to complete or meet all 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.  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.  Subjects who screen fail for not meeting inclusion criterion 106 or 111 are not 
permitted to re-screen. 
7.2.3 
Baseline Visit (Day 1) 
Subjects meeting all 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 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 35 of 76 
CONFIDENTIAL 
 
 
day 1 date.  Following the first blinded dose, investigational products and related 
supplies will be dispensed to the subject for self-administration per Table 1. 
7.2.4 
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. 
7.2.5 
Disease Assessment Visit and Disease Assessment Follow-up Visit 
Subjects can be seen at any time at or after week 24 to assess disease activity to 
evaluate if a subject can receive rescue treatment due to inadequate response to 
treatment.  If a subject meets the criteria for inadequate response as defined in 
Section 3.1.2, he/she will initiate rescue treatment with etanercept (50 mg QW) plus  
methotrexate (titrated up to 20 mg QW).  Sites will register the requirement for rescue in 
the IXRS for assignment of rescue therapy.  Refer to the IPIM for additional details.  
Subjects will continue to receive etanercept plus methotrexate for the remaining study 
visits per Table 1.  The procedures completed during the Disease Assessment visit are 
listed in the Schedule of Assessments (Table 1).  Subjects who initiate rescue treatment 
must complete a Disease Assessment Follow-up visit 4 to 5 weeks later to complete all 
the procedures listed in the Schedule of Assessments (Table 1). 
7.2.6 
Subject End of Treatment/Early Termination 
Subjects will complete an end of treatment 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. 
7.2.7 
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. 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 36 of 76 
CONFIDENTIAL 
 
 
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 full PsA history and other significant medical history should be recorded 
starting at the time of the original diagnosis.  Other relevant medical and surgical history 
that started within 5 years and information on the subject’s concurrent medical 
conditions will be recorded. Record all findings on the medical history eCRF. 
7.3.4 
Medication History 
The subject’s full history of psoriasis and PsA medications starting at the time of 
diagnosis and up to screening will be recorded on the eCRF.  This information will 
include the subject’s non-biologic DMARDs, NSAIDs, corticosteroids, biologics, and 
investigational medication history.  For PsA 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. 


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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 
PsA Disease Assessments 
All joint assessments will be performed by an experienced assessor who has been 
certified and trained by Amgen.  Each subject should have their assessments done by 
the same assessor throughout the study, if possible.  If necessary, study visits may be 
rescheduled within the allowed window period per visit in order to accommodate when 
the same assessor will be available. 
7.3.8.1 
Swollen/Tender Joint Counts 
All joint assessments will be performed by an experienced assessor who has been 
trained by viewing Amgen’s Group for Research and Assessment of Psoriasis and 
Psoriatic Arthritis (GRAPPA) training module and must be identified on the delegation of 
authority for this responsibility.  The user ID of the joint assessor will be recorded at each 
assessment.  The score for each joint will be recorded directly into the electronic 
PRO tablet which will serve as the source documentation and will not be transposed to 
the eCRF.  Joints that have been replaced are considered inevaluable. 
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 
Leeds Dactylitis Index 
Assessment will be performed by the same assessor as the joint counts.  The assessor 
will be trained by viewing the GRAPPA training module to perform the Leeds Dactylitis 
measurement. 


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The assessor will assess all fingers and toes for tenderness in the area between the 
joints and will score each on a scale of 0 to 3 where 0 = not tender; 1 = tender; 
2 = tender and wince; 3 = tender and withdraw.  Using a Leeds dactylometer, the 
circumference of only the tender digits and their contralateral counterpart will be 
measured and reported on the eCRF. 
7.3.8.3 
Spondyloarthritis Research Consortium of Canada Enthesitis Index 
Assessment will be performed by the same assessor as the joint counts.  The assessor 
will be trained by viewing the GRAPPA training module to perform the Spondyloarthritis 
Research Consortium of Canada (SPARCC) enthesitis assessment.  The SPARCC 
enthesitis index assesses enthesitis at 18 sites with a resultant score of 0 to 16.  
Tenderness at each site is assessed as 0 = non-tender or 1 = tender. Entheses 
assessed are left and right medial and lateral epicondyles, supraspinatus insertion into 
greater tuberosity of humerus, greater trochanter, quadriceps insertion into superior 
border of patella, patellar ligament insertion into inferior pole of patella, tibial tubercle, 
Achilles tendon insertion into calcaneum and bilateral plantar fascia insertion into the 
calcaneum.  Higher count represents greater enthesitis burden.  Tenderness at the 
inferior pole of patella and/or tibial tubercle will be scored as a maximum score of 1. 
7.3.8.4 
Radiographs 
Radiographs of bilateral hands and feet will be taken in the required views:  
posterior/anterior for the hands and anterior/posterior for the feet.  Radiographs will be 
done locally and read centrally. 
The central imaging vendor will measure using the van der Heijde mTSS method for 
PsA.  This method is based on the Sharp-van der Heijde method for assessing erosions 
and joint space narrowing of the hands and feet in RA and is adapted for evaluation of 
PsA by including the distal interphalangeal joints of the hand and scoring not only for 
erosions and joint space narrowing but also for subluxation, ankylosis, gross osteolysis, 
and pencil in cup phenomena.  Erosions are scored from 0 to 3 in each joint and joint 
space narrowing is scored from 0 to 4 at each joint and includes assessment for 
ankylosis.  Gross osteolysis and pencil in cup are scored separately.  The maximum 
possible total score is 528.  The radiographs will be read at a central location by two 
independent readers. 


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7.3.9 
Psoriasis Disease Assessments 
7.3.9.1 
Static Physician Global Assessment of Psoriasis 
The assessor who conducts the tender and swollen joint counts will be trained and 
certified by GRAPPA training module to perform the Static Physician Global Assessment 
of Psoriasis (sPGA).  The sPGA is designed to evaluate the physician’s global 
assessment of the subject’s psoriasis based on severity of induration, scaling, and 
erythema.  The sPGA is assessed on a scale of 0 (clear) to 5 (severe). 
7.3.9.2 
Body Surface Area Involvement 
The assessor who conducts the tender and swollen joint counts will be trained and 
certified by GRAPPA training module to perform the assessment for involved body 
surface area (BSA).  BSA is a numerical score (0 to 100) used to measure the proportion 
of the subject’s total BSA involvement with psoriasis. 
7.3.9.3 
Modified Nail Psoriasis Severity Index 
The assessor who conducts the tender and swollen joint counts will be trained and 
certified by GRAPPA to perform the modified NAPSI assessment.  The modified NAPSI 
scale is an objective, numeric, and reproducible grading system for nail psoriasis that 
incorporates the many different features of nail psoriasis.  For assessments in this study 
(including selection of the target nail), a nail is graded on the following 8 clinical features 
and the modified NAPSI score results. 
• 
pitting (scores 0-3, depending on the number of pits) 
• 
nail plate crumbling (scores 0-3, depending on % of nail involvement) 
• 
onycholysis and oil drop discoloration considered together (scores 0-3, depending on 
% of nail involvement) 
• 
leukonychia (0 or 1 – absent or present) 
• 
red spots in lunula (0 or 1 – absent or present) 
• 
nail bed hyperkeratosis (0 or 1 – absent or present) 
• 
splinter hemorrhages (0 or 1 – absent or present) 
In randomized subjects with nails involved with psoriasis, each finger nail will be scored 
at baseline to determine the worst nail (ie, the nail with the highest modified NAPSI 
score); this nail will be followed for the remainder of the study.  If multiple nails have the 
same worst score, only 1 target nail will be followed.  Identify the selected nail in the 
source document and eCRF, if applicable. 


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7.3.9.4 
Physician Global Assessment of Disease Activity 
This assessment will be completed 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 
PI for the study must complete the global assessments independently from each other. 
7.3.10 
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. 
7.3.10.1 
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. 
7.3.10.2 
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 arthritis 
activity at all” on the left end of the line and “100” and “Worst arthritis activity imaginable” 
on the right end of the line.  The subject and physician must complete the global 
assessments independently from each other.  This questionnaire should take 
approximately 1 minute to complete. 
7.3.10.3 
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. 
7.3.10.4 
Medical Outcomes Short Form-36 Questionnaire 
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 


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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 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 
C-reactive protein, and any other laboratory tests required.  Urine pregnancy and PPD 
testing, if applicable, will be performed locally with kits provided by the central laboratory 
(except PPD).  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, C-reactive protein, urinalysis, and other testing to be conducted on blood 
and urine samples are listed below (Table 2). 


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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 > trace) 
•
Bands/stabs
Hematology 
WBC 
Absolute neutrophil 
count 
RBC 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC Differential 
•
Eosinophils
•
Basophils
•
Lymphocytes
•
Neutrophils
•
Monocytes
a For all women, unless at least 2 years postmenopausal or history of hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy 
b 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. 
c At screening if the subject is positive for hepatitis B core antibody, the confirmatory reflex testing 
will be performed using HBV DNA PCR. 
Other Labs 
Serum beta hCGa 
Hepatitis B surface 
antigen and 
Hepatitis B core 
antibodyc 
Hepatitis C virus 
antibody 
High sensitivity 
C-reactive protein 
Tuberculosis Testingb 
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. 
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. 
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). 


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7.4.2 
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 
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.  Biomarker 
development may be pursued by use of advanced biochemical analyses, such as 
proteomic methods or ribonucleic acid transcript profiling.  A cell pellet from the blood 
plasma tube may be utilized to assess the impact of etanercept and/or methotrexate on 
circulating immune cells via deoxyribonucleic acid (DNA) methylation analysis, a 
pharmacodynamic assessment of methylation patterns of relevant genes.  The DNA 
extracted will not be used for optional pharmacogenetic analyses unless the subject 
signs the additional consent. 
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 PsA 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 


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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 
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, 


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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). 
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. 


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8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
subject request 
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, death or lost to 
follow-up) 
• 
disease flare requiring treatment not allowed in the protocol (eg, colitis, asthma) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of 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 (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened 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. 
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 


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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 
Definition of 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, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
9.2 
Reporting of Adverse Events 
9.2.1 
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 first dose of investigational 
product(s) through the end of treatment period are reported using the applicable CRF 
(eg, Adverse Event Summary). 
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. 


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The adverse event grading scale used will be the Common Toxicity Criteria Version 4.  
The grading scale used in this study is described in Appendix A.  The investigator must 
assess whether the adverse event is possibly related to the investigational product(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 applicable eCRF. 
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. 


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If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an 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 eSAE 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.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable eCRF 
(eg, Adverse Event Summary 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 
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 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 procedures and statutes. 


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9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur through 4 weeks after the last dose of etanercept. 
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix C).  The Pregnancy 
Surveillance Program will seek to follow the pregnant woman throughout her pregnancy 
and her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur through 4 weeks after the last dose of etanercept. 
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
within 24 hours of the investigator’s knowledge of event.  Report a lactation case on the 
Lactation Notification Worksheet (Appendix C). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
ACR 20 response at week 24 
10.1.1.2 
Key Secondary Endpoint 
• 
MDA response at week 24 
10.1.1.3 
Other Secondary Endpoints 
• 
Modified NAPSI score and change from baseline at week 24  
• 
Leeds dactylitis score and change from baseline at week 24  
• 
SPARCC enthesitis score and change from baseline at week 24  
• 
ACR 20 response at all other measured timepoints 
• 
MDA response at all other measured timepoints 
• 
Psoriatic Arthritis Disease Activity Score (PASDAS) at all measured timepoints 
• 
ACR 50, ACR 70, and components of ACR at all measured timepoints 


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• 
Simplified Disease Activity Index (SDAI) and change from baseline at all measured 
timepoints 
• 
Clinical Disease Activity Index (CDAI) and change from baseline at all measured 
timepoints 
• 
Disease activity score (28 joint) using the C-reactive protein formula (DAS28-CRP) 
and change from baseline at all measured timepoints 
• 
HAQ-DI score and change from baseline at week 24 
• 
SF-36 score and change from baseline at week 24 
For subjects with involved BSA ≥ 3% at baseline: 
• 
sPGA at week 24  
• 
BSA at week 24 
10.1.1.4 
Safety Endpoints 
• 
Adverse events 
• 
Serious adverse events 
• 
Laboratory parameters and vital signs 
10.1.1.5 
Exploratory Endpoints 
• 
Change from baseline in van der Heijde mTSS at week 24 and week 48 
• 
Non-progression in van der Heijde mTSS defined as change ≤ 0 from baseline at 
week 24 and week 48 
• 
Modified NAPSI score and change from baseline at all other measured timepoints 
• 
Leeds dactylitis score and change from baseline at all other measured timepoints 
• 
SPARCC enthesitis score and change from baseline at all other measured 
timepoints 
• 
HAQ-DI and change from baseline at all other measured timepoints 
• 
SF-36v2 and change from baseline at all other measured timepoints 
For subjects with involved body surface area ≥ 3% at baseline: 
• 
sPGA at all other measured timepoints  
• 
BSA at all other measured timepoints 
10.1.2 
Analysis Sets 
10.1.2.1 
Full Analysis Set 
The full analysis set will include all randomized subjects.  Subjects will be analyzed 
according to their randomized treatment group.  Demographics, baseline disease 
characteristics, and non-psoriasis efficacy analyses will be based on the full analysis set. 


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10.1.2.2 
Psoriasis Efficacy Analysis Set 
The psoriasis efficacy analysis set will consist of all randomized subjects with baseline 
BSA ≥ 3%.  Analyses of psoriasis efficacy endpoints (eg, sPGA, BSA) will be based on 
the psoriasis efficacy analysis set. 
10.1.2.3 
Safety Analysis Set 
The safety analysis set will consist of all randomized subjects who receive at least one 
dose of investigational product.  Subjects will be analyzed according to the actual 
treatment received.  Analyses of safety endpoints will be based on the safety analysis 
set. 
10.1.3 
Covariates and Subgroups 
The following covariates will be considered to assess their influence on the primary and 
key secondary endpoints: 
• 
Age (≤ 65, > 65) 
• 
Sex (male, female) 
• 
Race (Caucasian, Non-Caucasian) 
• 
Ethnicity (Hispanic or Latino vs Non-Hispanic or Latino) 
• 
Baseline body mass index (BMI) (≤ 30, > 30) 
• 
Baseline weight (≤ 100 kg, > 100 kg) 
• 
Baseline BSA (≤ 3%, > 3%) 
• 
Prior use of non-biologic DMARD (yes, no) 
• 
Disease duration (≤ median, > median) 
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 
A total of 840 subjects will be enrolled in the study and randomized in a 1:1:1 ratio to 
etanercept plus methotrexate therapy, etanercept monotherapy and methotrexate 
monotherapy. 
To preserve the family-wise 2-sided type one error rate at 0.05 for the multiple 
comparisons of the etanercept plus methotrexate therapy and etanercept monotherapy 
groups with methotrexate monotherapy, a Bonferroni-based gatekeeping chain 
procedure (Burman et al, 2009 and Millen et al, 2011) will be used to determine 
statistical significance for the primary and key secondary endpoints as described in 


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Section 10.5.2.  This procedure will split alpha of 0.05 equally to test in parallel the 
primary and key secondary endpoints (ACR 20, MDA) for etanercept plus methotrexate 
therapy vs. methotrexate monotherapy and etanercept monotherapy vs. methotrexate 
monotherapy sequentially within each parallel path.  If one of the parallel paths rejects 
both hypotheses sequentially, and the other parallel path has at least one hypothesis not 
rejected, then unspent alpha of 0.025 from the successful path will be propagated to the 
hypotheses in the other path to re-test them sequentially at a level of 0.05. 
The sample size is based on the adequacy to evaluate the efficacy of etanercept 
monotherapy compared with methotrexate monotherapy as measured by the primary 
endpoint of ACR 20 response at week 24 at a significance level of 0.025 based on the 
Bonferroni-based gatekeeping chain procedure. 
There are no published studies of etanercept monotherapy versus methotrexate 
monotherapy for the treatment of PsA.  Therefore for the purpose of this study the  
assumed response rates for ACR 20 for the etanercept monotherapy and methotrexate 
monotherapy arms are derived from separate studies.  In the etanercept PsA pivotal 
phase 3 study (20021630 Study) the ACR 20 response rate at week 24 was 50% for the 
etanercept arm.  However, subjects were allowed to be on a stable dose of methotrexate 
at study entry.  Assuming a methotrexate naïve population would respond better, the 
response rate for the etanercept monotherapy arm in this planned phase 3 study is 
assumed to be 60%. 
In a recent randomized placebo-controlled trial of methotrexate monotherapy in PsA 
(Kingsley et al, 2012) the ACR 20 response rate for the methotrexate monotherapy arm 
was 34%.  However, the dose of methotrexate was 15 mg QW.  Assuming a higher dose 
of methotrexate (ie, 20 mg QW) would yield better responses, the response rate for the 
methotrexate monotherapy arm in this planned phase 3  study is assumed to be 44%. 
Therefore, in order to detect a difference of 16% between the etanercept monotherapy 
and methotrexate monotherapy arms, using a two-sided Chi-square test at a significance 
level of 0.025 and 90% marginal power, each treatment arm will have approximately 
280 subjects adjusting for an anticipated 10% dropout. 
This sample size will provide marginal power > 90% to detect a treatment difference in 
ACR 20 response at week 24 between the etanercept plus methotrexate therapy arm 
and the methotrexate monotherapy arm at a two-sided 0.025 significance level.  As 
previously mentioned, the ACR response rate at week 24 is assumed to be 44% for the 


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methotrexate monotherapy arm.  The ACR response rate at week 24 for the etanercept 
plus methotrexate therapy arm is assumed to be 5% higher than the etanercept 
monotherapy arm (ie, 65%).  This is based on a longitudinal observational study 
assessing the role of TNF-inhibitor plus methotrexate combination therapy versus 
TNF-inhibitor monotherapy (Fagerli et al, 2014). 
In addition, this sample size will provide marginal power > 90% to detect treatment 
differences in MDA response at week 24 between both etanercept arms and the 
methotrexate arm at a two-sided 0.025 significance level, assuming response rates of 
15%, 30%, and 35% for the methotrexate monotherapy, etanercept monotherapy, and 
etanercept plus methotrexate therapy arms, respectively.  In recent PsA trials, the MDA 
24-week response rates for the placebo arm range from 3 to 7% (Coates et al, 2010a; 
Kavanaugh et al, 2013).  Therefore, for the methotrexate monotherapy arm, the 
response rate is assumed to be higher at 15%.  In the pivotal phase 3 randomized 
placebo-controlled trial of etanercept in PsA, the MDA response rate for the etanercept 
monotherapy arm is estimated to be approximately 20% at week 24 (data on file).  For a 
methotrexate naïve population, the response rate is assumed to be higher at 30%.  In 
addition, the etanercept plus methotrexate therapy arm is assumed to have a 
5% improvement over the etanercept monotherapy arm. 
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, Section 9.2.2 and Statistical 
Analysis Plan [SAP]). 
10.4 
Planned Analyses 
10.4.1 
Primary Analysis 
The objective for the primary analysis is to evaluate the efficacy of etanercept plus 
methotrexate therapy and etanercept monotherapy compared to methotrexate 
monotherapy in subjects with PsA at week 24 as measured by the proportion of subjects 
achieving an ACR 20 response.  The primary analysis will be performed when the last 
subject completes the week 48 visit or terminates early from the study, at which time the 
study will be unblinded. 


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For the primary and key secondary efficacy endpoints, treatment effect will be tested 
using a Bonferroni-based gatekeeping chain procedure (Burman et al, 2009 and 
Millen et al, 2011) as described in Section 10.5.2 to control the family-wise 2-sided type 
one error rate at 0.05.  Between-treatment comparisons will be made using the stratified 
Cochran-Mantel-Haenszel (CMH) test with baseline BMI and prior non-biologic DMARD 
use as the stratification factors.  Missing data will be imputed using non-responder 
imputation for the primary analysis. 
For other efficacy endpoints, the significance level will be 0.05 without adjusting for 
multiplicity and data will be analyzed as observed. 
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Subject disposition, demographics, and baseline disease characteristics will be 
summarized descriptively by randomized treatment group. 
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 error, standard deviation, median, minimum, and 
maximum. 
Treatment effect will be tested for the primary and key secondary endpoints using a 
Bonferroni-based gatekeeping chain procedure to control the family-wise 2-sided type 
one error rate at 0.05.  The significance level for the analyses of other secondary 
endpoints and exploratory endpoints will be 0.05 without adjusting for multiplicity and the 
p-values for these endpoints will therefore be treated as a descriptive statistic only. 
Safety endpoints will be tabulated by actual treatment received during the study.  No 
formal statistical testing will be performed for safety analyses. 
Details of all statistical methods will be provided in the SAP. 
10.5.2 
Primary and Key Secondary Efficacy Endpoints 
The primary analysis for the primary endpoint and key secondary endpoints, ACR 20 
response and MDA response at week 24, will be performed using the full analysis set.  
Treatment effect will be tested using the stratified CMH test with baseline BMI and prior 
non-biologic DMARD use as the stratification factors. 
To control the family-wise 2-sided type one error rate at 0.05 for the multiple 
comparisons of the etanercept plus methotrexate therapy and etanercept monotherapy 


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groups with methotrexate monotherapy across the primary and key secondary 
endpoints, the hypotheses will be tested using a Bonferroni-based gatekeeping chain 
procedure (Burman et al, 2009 and Millen et al, 2011) as shown in Figure 1.  This 
procedure will split alpha of 0.05 equally to test in parallel the primary and key secondary 
endpoints (ACR 20, MDA) for etanercept plus methotrexate therapy vs. methotrexate 
monotherapy and etanercept monotherapy vs. methotrexate monotherapy sequentially 
within each parallel path.  If one of the parallel paths rejects both hypotheses 
sequentially, and the other parallel path has at least one hypothesis not rejected, then 
unspent alpha of 0.025 from the successful path will be propagated to the hypotheses in 
the other path to re-test them sequentially at a level of 0.05.  For example, suppose the 
nominal p-values for hypotheses A1, B1, A2, and B2 (Figure 1) are 0.01, 0.02, 0.03, and 
0.055, respectively.  In the first round of testing, hypotheses A1 and B1 are rejected, 
whereas hypotheses A2 and B2 are not rejected.  However, since both hypotheses A1 
and B1 are rejected, the procedure gives a second chance to re-test hypotheses A2 and 
B2 (according to the left arm of the figure) at a lower threshold of 0.05 rather than the 
original threshold of 0.025.  Note that in this example A2 is rejected and hypothesis B2 is 
not rejected. 


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Figure 1.  Bonferroni-based Gatekeeping Chain Procedure 
          Bonferroni 
         parallel testing 
      ETN: Etanercept; MTX: Methotrexate 
For the primary analysis of the primary and key secondary endpoints, missing data will 
be imputed as nonresponder.  Sensitivity analyses using observed data and using last 
observation carried forward imputation will also be performed. 
Hypothesis A1: No treatment 
difference in proportions of     
ACR 20 responders between    
ETN plus MTX and MTX groups    
(2-sided, α=0.025)       
Hypothesis A2: No treatment 
difference in proportions of     
MDA responders between      
ETN plus MTX and MTX groups    
(2-sided, α=0.025)       
Hypothesis B1: No treatment 
difference in proportions of     
ACR 20 responders between    
ETN and MTX groups      
(2-sided, α=0.025)       
Hypothesis B2: No treatment 
difference in proportions of     
MDA responders between      
ETN and MTX groups      
(2-sided, α=0.025)       
Hypothesis A2 Retested:     
No treatment difference in 
proportions of MDA responders 
between ETN plus MTX and 
MTX groups        
(2-sided, α=0.05)        
Hypothesis B2 Retested:     
No treatment difference in 
proportions of MDA responders 
between ETN and MTX groups     
(2-sided, α=0.05)        
Hypothesis A1 Retested:     
No treatment difference in 
proportions of ACR 20 
responders between ETN plus 
MTX and MTX groups      
(2-sided, α=0.05)        
Hypothesis B1 Retested:     
No treatment difference in 
proportions of ACR 20 
responders between ETN and 
MTX groups        
(2-sided, α=0.05)        
  Null hypothesis is rejected       
  Null hypothesis is not rejected     


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10.5.3 
Other Secondary Efficacy Endpoints 
The primary analysis of other secondary endpoints will be performed using the full 
analysis set for non-psoriasis endpoints or the psoriasis efficacy analysis set for 
psoriasis endpoints.  For binary endpoints, treatment effect will be tested using the 
stratified CMH test with BMI and prior non-biologic DMARD use as the stratification 
factors.  For continuous endpoints that exhibit normal distribution, ANCOVA model will 
be used.  The model will include treatment groups and baseline BMI and prior 
non-biologic DMARD as covariates.  For continuous endpoints that are not normally 
distributed, endpoint data will be first transformed to their joint ranks and then further 
transformed by the Van der Waerden transformation to normalize them before applying 
ANCOVA model.  The significance level for other secondary endpoints will be 
0.05 without adjusting for multiplicity and p-values will therefore be treated as a 
descriptive statistic only. 
Data will be analyzed as observed with no imputation for missing data. 
10.5.4 
Safety Endpoints 
Safety endpoints will be summarized descriptively for all subjects by treatment group 
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 
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. 


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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 
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. 


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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. 
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. 


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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, radiographs, 
and correspondence. 
In this study, the IXRS system captures the following data points and these are 
considered source data:  subject identification number and 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, 
electronic PROs may be considered source documents. 
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. 


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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 
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 the investigator inspected or reviewed the data on the 
CRF, the data queries, and the site notifications, and agrees with the content. 


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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 
completed in English.  TRADENAMES® (if used) for concomitant medications may be 
entered in the local language. 
12.6 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), 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. 


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• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 65 of 76 
CONFIDENTIAL 
 
 
13. 
REFERENCES 
Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for 
dermatologic and articular manifestations of psoriatic arthritis: results from the Infliximab 
Multinational Psoriatic Arthritis Controlled Trial (IMPACT). Arthritis Rheum. 
2005a;52:1227–1236. 
Antoni C, Krueger GG, de Vlam K, et al. Infliximab improves signs and symptoms of 
psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005b;64:1150–1157. 
Biondi Oriente C, Scarpa R, Pucino A, Oriente P. Psoriasis and psoriatic arthritis. 
Dermatological and rheumatological co-operative clinical report. Acta Derm Venereol. 
1989;146(Suppl):69-71. 
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat.Med. 2009; 28:739–761. 
Coates LC, Fransen J, Helliwell PS. Defining minimal disease activity in psoriatic 
arthritis: a proposed objective target for treatment. Ann Rheum Dis. 2010a;69:48-53.  
Coates L.C. Helliwell P.S. Validation of minimal disease activity criteria for psoriatic 
arthritis using interventional trial data. Arthritis Care Res. 2010b; 62:965-969. 
Espinoza L, Zakraoui L, Espinoza CG, et al. Psoriatic arthritis: clinical response and side 
effects to methotrexate therapy. J. Rheum. 1992;19:872-877. 
Fagerli KM, Lie E, van der Heidje D,  et al. The role of methotrexate co-medication in 
TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients 
included in the NOR-DMARD study. Ann Rheum Dis. 2014;73:132–137. 
Gümüşel M, Özdemir M, Mevlitoğlu I, Bodur S. Evaluation of the efficacy of methotrexate 
and cyclosporine therapies on psoriatic nails: a one-blind, randomized study.  J Eur 
Acad Dermatol Venereol. 2011;25:1080-1084. 
Kavanaugh A, McInnes IB, Mease PJ, et al. Impact of persistent minimal disease activity 
on long-term outcomes in psoriatic arthritis: results from 5 years of the long term 
extension of a randomized, placebo-controlled, Study. Abstract #341. Presented at the 
ACR/ARHP Annual Meeting, 27 Oct 2013. 
Kingsley GH, Kowalcyzk A, Taylor H, et al. A randomized placebo-controlled trial of 
methotrexate in psoriatic arthritis. Rheumatology. 2012;51:1368-1377 
Klareskog L, van der Heijde D, de Jager JP et al. Therapeutic effect of the combination 
of etanercept and methotrexate compared with each treatment alone in patients with 
rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 
2004;363(9410):675-681. 
Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life 
assessment. Dermatol Clin. 1996;14:485-496. 
Mease P, Collier D, Saunders KC, et al. Biologic therapy, time to low disease activity, 
and effect of mono vs. background oral DMARD therapy among psoriatic arthritis 
patients in a US registry. Ann Rheum Dis. 2013;72(suppl 3):671. 
Millen B, Dmitrienko A. Chain procedures: a class of flexible closed testing procedures 
with clinical trial applications. Statistics in Biopharmaceutical Research 2011;3:14–30. 
Ortonne JP, Paul C, Berardesca E, et al.  A 24-week randomized clinical trial 
investigating the efficacy and safety of two doses of etanercept in nail psoriasis.  Br J 
Dermatol. 2013;168:1080-1087.  


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 66 of 76 
CONFIDENTIAL 
 
 
Scarpa R, Oriente P, Pucino A, et al. Psoriatic arthritis in psoriatic patients. Br J 
Rheumatol. 1984;23:246-250. 
Shbeeb M., Uramoto KM, Gibson LE, et al. The epidemiology of psoriatic arthritis in 
Olmsted County, Minnesota, USA, 1982-1991. J. Rheum. 2000;27:1247-1250. 
Sterry W, Ortonne JP, Kirkham B, et al. Comparison of two etanercept regimens for 
treatment of psoriasis and psoriatic arthritis: PRESTA randomised double blind 
multicentre trial. BMJ. 2010;340:c147. 
US Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER). Guidance for industry. Drug induced liver injury: premarketing clinical 
evaluation. July 2009. 
www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc
m174090.pdf 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 67 of 76 
CONFIDENTIAL 
 
 
14. 
APPENDICES 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 68 of 76 
CONFIDENTIAL 
 
 
Appendix A.  Additional Safety Assessment Information 
As noted in Section 
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 
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 TBL 
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” 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 69 of 76 
CONFIDENTIAL 
 
 
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:  TBL > 3 x ULN at any time 
• 
OR:  ALP > 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. 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 70 of 76 
CONFIDENTIAL 
 
 
Drug-induced Liver Injury Reporting & Additional Assessments  
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL according to the criteria specified in Section 
Reporting 
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. 
• 
Repeat AST, ALT, ALP and bilirubin (total and direct) within 24 hours  
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: 
• 
In cases of TBL > 2x ULN retesting of liver tests, bilirubin (total and direct) 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 with differential to assess for eosinophilia 
○ Obtain serum total immunoglobulin IgG, Anti-nuclear antibody, 
Anti Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 to 
assess for autoimmune hepatitis 
○ Obtain serum acetaminophen (paracetamol) levels 
○ Obtain a more detailed history of: 
− 
Prior and/or concurrent diseases or illness 
− 
Exposure to environmental and/or industrial chemical agents  


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 71 of 76 
CONFIDENTIAL 
 
 
− 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and 
fever 
− 
Prior and/or concurrent use of alcohol, recreational drugs and 
special diets 
− 
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) 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:  20130207 
Date:  31 August 2016 
Page 72 of 76 
CONFIDENTIAL 
 
 
Appendix B.  Electronic Serious Adverse Event Contingency Form 
 
 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 73 of 76 
CONFIDENTIAL 
 
 
 
 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 74 of 76 
CONFIDENTIAL 
 
 
 
 
 
 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 75 of 76 
CONFIDENTIAL 
 
 
Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 76 of 76 
CONFIDENTIAL 
 
 
 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 1 of 7 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Multicenter Double-blind, Randomized Controlled Study of 
Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With 
Psoriatic Arthritis 
 
Amgen Protocol Number (Etanercept) 20130207 
 
Amendment 1: 
Superseding Amendment 1: 
Amendment 2: 
Amendment 3: 
20 May 2015 
09 July 2015 
30 October 2015 
31 August 2016 
 
Rationale: 
Updated CTCAE grading version to 4.0 to reflect most recent version and added 
“confirmatory reflex testing by HBV DNA PCR for subjects with Hepatitis-B positive core 
antibody.” and removed the “in order to confirm viral load is not detected” language. 


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Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 3 of 7 
CONFIDENTIAL 
 
 
Section:  5.2 Site Personnel Access to Individual Treatment Assignments 
Paragraph 3, sentence 2 
Replace: 
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager 
before unblinding any subject’s treatment assignment. 
With: 
The investigator is strongly encouraged to contact the Amgen Global Clinical Trial 
Manager before unblinding any subject’s treatment assignment. 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 4 of 7 
CONFIDENTIAL 
 
 
Section:  7.1 Schedule of Assessments 
Table 1 
Replace: 
 
30-day 
Screening 
Treatment Period 
Disease Assessment (DA) 
30-day 
Follow-Up 
Weeks 
 
0 (day 1) 
4 
8 
12 
16
 
24 
36 
48/ET
 
DA Visit
e 
DA Follow-up
e 
Safety (EOS)
g 
GENERAL & SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen & core antibody; Hepatitis C virus 
antibody
 
X 
 
 
 
 
 
 
 
 
 
 
 
With: 
 
30-day 
Screening 
Treatment Period 
Disease Assessment (DA) 
30-day 
Follow-Up 
Weeks 
 
0 (day 1) 
4 
8 
12 
16
 
24 
36 
48/ET
 
DA Visit
e 
DA Follow-up
e 
Safety (EOS)
g 
GENERAL & SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen & core antibody; Hepatitis C virus 
antibody
i 
X 
 
 
 
 
 
 
 
 
 
 
 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 5 of 7 
CONFIDENTIAL 
 
 
Section:  7.1 Schedule of Assessments 
Table Abbreviations 
Added: 
HBV: hepatitis B virus; PCR: polymerase chain reaction; 
Section:  7.1 Schedule of Assessments 
Footnote i 
Added: 
i At screening if the subject is positive for hepatitis B core antibody, the 
confirmatory reflex testing will be performed using HBV DNA PCR. 
Section:  7.2.1 Screening 
Sentence 6 
Added: 
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). 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 6 of 7 
CONFIDENTIAL 
 
 
Section:  7.4 Laboratory Assessments 
Table 2 
Replace: 
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 > trace) 
Hematology 
WBC 
Absolute neutrophil 
count 
RBC 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC Differential 
 
Bands/stabs 
 
Eosinophils 
 
Basophils 
 
Lymphocytes 
 
Neutrophils 
 
Monocytes 
Other Labs 
Serum beta hCGa 
Hepatitis B surface 
antigen and Hepatitis 
B core antibody 
Hepatitis C virus 
antibody 
High sensitivity 
C-reactive protein 
Tuberculosis Testingb 
With: 
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 > trace) 
Hematology 
WBC 
Absolute neutrophil 
count 
RBC 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC Differential 
 
Bands/stabs 
 
Eosinophils 
 
Basophils 
 
Lymphocytes 
 
Neutrophils 
 
Monocytes 
Other Labs 
Serum beta hCGa 
Hepatitis B surface 
antigen and Hepatitis 
B core antibodyc 
Hepatitis C virus 
antibody 
High sensitivity 
C-reactive protein 
Tuberculosis Testingb 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  31 August 2016 
Page 7 of 7 
CONFIDENTIAL 
 
 
Section:  7.4 Laboratory Assessments 
Table 2, footnote C 
Add: 
c At screening if the subject is positive for hepatitis B core antibody, the 
confirmatory reflex testing will be performed using HBV DNA PCR.. 
Section:  9.2.1 Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
Paragraph 3, sentence 1 
Replace: 
The adverse event grading scale used will be the Common Toxicity Criteria Version 2. 
With: 
The adverse event grading scale used will be the Common Toxicity Criteria Version 4. 
Section:  11.1 Informed Consent 
Paragraph 1, sentence 2 
Replace: 
Updates to the template are to be communicated formally in writing from the Amgen 
Clinical Study Manager to the investigator. 
With: 
Updates to the template are to be communicated formally in writing from the Amgen 
Global Clinical Trial Manager to the investigator. 
Section:  Appendix A 
Adverse Event Grading Scale 
Replace: 
The Common Toxicity Criteria Version 2.0 is available at the following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-
992.pdf 
With: 
The Common Toxicity Criteria Version 4.0 is available at the following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


Product:  Etanercept 
Protocol Number:  20130207 
Date:  30 October 2015 
Page 1 of 4 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Multicenter Double-Blind, Randomized Controlled Study of 
Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With 
Psoriatic Arthritis 
 
Amgen Protocol Number (Etanercept) 20130207 
EudraCT Number 2014-004869-24 
 
Original Protocol: 
29 July 2014 
Amendment 1 Date: 
20 May 2015 
Superseding Amendment 1 Date:   
09 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:  20130207 
Date:  09 July 2015 
Page 1 of 18 
CONFIDENTIAL 
 
 
Superseding Amendment 1 
Protocol Title:  A Multicenter Double-Blind, Randomized Controlled Study of 
Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With 
Psoriatic Arthritis 
 
Amgen Protocol Number (Etanercept) 20130207 
Original Protocol: 
29 July 2014 
Amendment 1 Date: 
20 May 2015 
Superseding Amendment 1 Date:   09 July 2015 
Rationale: 
The protocol is being amended to: 
• 
Provide updated pregnancy and contraception language.  Updated language for 
pregnancy and contraception became available immediately following approval of 
Amendment 1, thus, a superseding amendment to Amendment 1 was created to 
include the updated language.  Changes related to both Amendment 1 and 
Superseding Amendment 1 are detailed below.  Likewise, changes in bold include all 
changes from Amendment 1 and Superseding Amendment 1.   
• 
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 
• 
Update and clarify inclusion/exclusion criteria regarding tender and swollen joint 
counts, minimum number of weeks required for stable dosing of NSAIDs, excluded 
medications, and minimum number of months since use of excluded medications. 
• 
Provide clarification regarding exclusion criteria to expand wording related to 
substances of abuse 
• 
Provide clarifications regarding joint assessments, to strengthen wording related to 
continuity of assessors in the study, and allowing for assessments by principal 
investigators 
• 
Add folic acid and folinic acid dosing information 
• 
Add additional information regarding laboratory assessments used to determine 
subject eligibility 
• 
Clarify process for when inadvertent unblinding occurs 
• 
Provide updates throughout to reflect the number of global participating sites 
• 
Clarify formulation of methotrexate used for rescue therapy 
• 
Add the EudraCT number 
• 
Update the Key Sponsor Contact 
• 
Provide an updated eSAE example form, pregnancy worksheet, and lactation 
worksheet 
• 
Make minor corrections and clarifications throughout 

SAP_001.pdf: 
Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
Page 1
STATISTICAL ANALYSIS PLAN
A Multicenter Double-blind, Randomized Controlled Study of Etanercept and 
Methotrexate in Combination or as Monotherapy in Subjects With Psoriatic 
Arthritis
Protocol Number:
20130207
Version:
Version 2.0  
Date:
06 June 2018
Authors:
PPD
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Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
Page 2
Table of Contents
Table of Abbreviations.....................................................................................................5
1.
Introduction.............................................................................................................7
2.
Objectives...............................................................................................................7
2.1
Primary Objective........................................................................................7
2.2
Key Secondary Objective............................................................................7
2.3
Other Secondary Objectives .......................................................................7
2.4
Safety Objectives ........................................................................................7
2.5
Exploratory Objectives ................................................................................7
3.
Study Overview ......................................................................................................8
3.1
Study Design...............................................................................................8
3.2
Sample Size................................................................................................8
4.
Study Endpoints and Covariates...........................................................................10
4.1
Study Endpoints........................................................................................10
4.1.1
Primary Endpoint.......................................................................10
4.1.2
Key Secondary Endpoint ...........................................................10
4.1.3
Other Secondary Endpoints.......................................................10
4.1.4
Safety Endpoints .......................................................................11
4.1.5
Exploratory ................................................................................11
4.2
Planned Covariates...................................................................................12
5.
Hypotheses and/or Estimations ............................................................................13
6.
Definitions.............................................................................................................13
6.1
Basic Definitions........................................................................................13
6.2
Study Points of Reference.........................................................................15
6.3
Study Dates ..............................................................................................15
6.4
Study Time Intervals .................................................................................15
6.5
Calculations ..............................................................................................16
6.6
Study Endpoints........................................................................................17
7.
Analysis Subsets ..................................................................................................22
7.1
Full Analysis Set........................................................................................22
7.2
Psoriasis Efficacy Analysis Set..................................................................22
7.3
Safety Analysis Set ...................................................................................22
7.4
Adequate Methotrexate Analysis Set.........................................................22
7.5
Leeds Dactylitis Index (LDI) Analysis Set ..................................................23
7.6
Modified Nail Psoriasis Severity Index (mNAPSI) Analysis Set .................23
7.7
SPARCC Enthesitis Analysis Set ..............................................................23
7.8
Subgroup Analysis ....................................................................................23


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
Page 3
8.
Interim Analysis and Early Stopping Guidelines....................................................23
9.
Data Screening and Acceptance...........................................................................23
9.1
General Principles.....................................................................................23
9.2
Data Handling and Electronic Transfer of Data .........................................24
9.3
Handling of Missing and Incomplete Data .................................................24
9.3.1
Missing Baseline Evaluation......................................................24
9.3.2
Missing Post-baseline Evaluation ..............................................24
9.3.3
Missing Components of Composite Endpoints...........................25
9.3.4
Missing and Incomplete Dates...................................................25
9.4
Detection of Bias.......................................................................................25
9.5
Outliers .....................................................................................................26
9.6
Distributional Characteristics.....................................................................26
9.7
Validation of Statistical Analyses...............................................................26
10.
Statistical Methods of Analysis..............................................................................26
10.1
General Principles.....................................................................................26
10.2
Subject Accountability ...............................................................................27
10.3
Important Protocol Deviations ...................................................................27
10.4
Demographic and Baseline Characteristics...............................................27
10.5
Efficacy Analyses......................................................................................28
10.5.1
Analyses of Primary and Key Secondary Efficacy 
Endpoints..................................................................................28
10.5.2
Analyses of Other Secondary Efficacy and Selected 
Exploratory Endpoints ...............................................................31
10.5.3
Analyses of Exploratory Endpoints ............................................32
10.5.4
Biomarker Endpoints .................................................................32
10.6
Safety Analyses ........................................................................................32
10.6.1
Adverse Events .........................................................................32
10.6.2
Laboratory Test Results ............................................................33
10.6.3
Vital Signs .................................................................................33
10.6.4
Exposure to Investigational Product ..........................................33
10.6.5
Exposure to Concomitant Medication ........................................33
11.
Changes From Protocol-specified Analyses..........................................................33
12.
Literature Citations / References...........................................................................37
13.
Appendices...........................................................................................................38
List of Figures
Figure 1.  Bonferroni-based Gatekeeping Chain Procedure...........................................30


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List of Appendices
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs......................................................39
Appendix B.  Code Fragments.......................................................................................53
Appendix C.  Reference Values/Toxicity Grades ...........................................................56


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Table of Abbreviations
Abbreviation or Term
Definition/Explanation
ACR
American College of Rheumatology
ANCOVA
Analysis of covariance
BMI
body mass index
BSA
body surface area
CDAI
Clinical Disease Activity Index
CMH
Cochran Mantel Haenszel
CRP
C-reactive protein
DAS28-CRP
Disease Activity Score (28 Joints) using CRP
DAPSA
Disease Activity index for Psoriatic Arthritis
DMARD
Disease Modifying Anti-rheumatic Drug
EOS
End of Study
ES
Erosion Score
ET
Early Termination
HAQ-DI
Health Assessment Questionnaire Disability Index
ICH
International Conference on Harmonisation
IP
Investigational product
IPD
Important protocol deviation
ITT
Intent-to-treat
JSN
Joint Space Narrowing
LOCF
Last observation carried forward
LDI
Leeds Dactylitis Index
MDA
minimal disease activity
mNAPSI
Modified Nail Psoriasis Severity Index
mTSS
van der Heijde modified Total Sharp Score
MI
Multiple imputation
NRI
Non-responder imputation
PASDAS
Psoriatic Arthritis Disease Activity Score
PRO
patient reported outcome
PsA
psoriatic arthritis
QW
Weekly
SAP
statistical analysis plan
SDAI
Simplified Disease Activity Index
SF-36 v2
Medical Outcomes Health Survey Short Form 36 items version 2


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Abbreviation or Term
Definition/Explanation
SPARCC
Spondyloarthritis Research Consortium of Canada
sPGA
Static Physician Global Assessment
TNF
tumor necrosis factor
VAS 
visual analog scale
VLDA
Very Low Disease Activity


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1.
Introduction
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 3 for etanercept 
Study 20130207 dated 31 August 2016.  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 plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy, in subjects with psoriatic arthritis 
(PsA) as measured by the proportion of subjects achieving an American College of 
Rheumatology (ACR) 20 response at week 24.
2.2
Key Secondary Objective
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy as measured by the proportion of 
subjects achieving minimal disease activity (MDA) at week 24.
2.3
Other Secondary Objectives
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy on the following:

Other measures of arthritis activity

Measures of non-arthritic PsA disease activity

Key patient reported outcomes (PRO) related to physical function and quality of life
2.4
Safety Objectives
To evaluate the safety of etanercept and methotrexate.
2.5
Exploratory Objectives
To evaluate the efficacy of etanercept plus methotrexate therapy and etanercept 
monotherapy compared to methotrexate monotherapy on the following:

Other measures of disease activity including the skin

Other PROs

Inhibition of radiographic progression as measured by the van der Heijde modified 
Total Sharp score (mTSS) for PsA

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 PsA and/or subject response to etanercept


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3.
Study Overview
3.1
Study Design
This is a phase 3, multicenter, randomized, double-blind controlled study in subjects with 
active PsA naïve to biologics and with no prior use of methotrexate for the treatment of 
PsA.  The study will consist of a 30-day screening period, a 48-week randomized 
double-blind treatment period, and a 30-day safety follow-up period.
Approximately 840 subjects will be randomly assigned in a 1:1:1 ratio to one of three 
treatment groups (280 per arm):

Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 
20 mg weekly

Etanercept 50 mg weekly by subcutaneous injection plus oral placebo for 
methotrexate

Oral methotrexate 20 mg weekly plus placebo for etanercept.
At or after week 24, subjects who have an inadequate response will receive rescue 
therapy with etanercept plus methotrexate until the end of the treatment period.  
Inadequate response is defined by having < 20% improvement in their tender joint 
counts and < 20% improvement in their swollen joint counts from baseline at or after 
week 24.  Inadequate response may be assessed at a regularly scheduled visit or at a 
disease assessment visit.  All subjects that initiate rescue treatment must complete a 
disease assessment follow-up visit 4 weeks later to monitor for labs.
3.2
Sample Size
A total of 840 subjects will be enrolled in the study and randomized in a 1:1:1 ratio to 
etanercept plus methotrexate therapy, etanercept monotherapy, and methotrexate 
monotherapy.
To preserve the family-wise 2-sided type one error rate at 0.05 for the multiple 
comparisons of the etanercept plus methotrexate therapy and etanercept monotherapy 
groups with methotrexate monotherapy, a Bonferroni-based gatekeeping chain 
procedure (Burman et al 2009 and Millen et al 2011) will be used to determine statistical 
significance for the primary and key secondary endpoints as described in Section 10.5.1.  
This procedure will split alpha of 0.05 equally to test in parallel the primary and key 
secondary endpoints (ACR 20, MDA) for etanercept plus methotrexate therapy vs. 
methotrexate monotherapy and etanercept monotherapy vs. methotrexate monotherapy 
sequentially within each parallel path.  If one of the parallel paths rejects both 
hypotheses sequentially, and the other parallel path has at least one hypothesis not 


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rejected, then the unspent alpha of 0.025 from the successful path will be propagated to 
the hypotheses in the other path to re-test them sequentially at a level of 0.05.
The sample size is based on the adequacy to evaluate the efficacy of etanercept 
monotherapy compared with methotrexate monotherapy as measured by the primary 
endpoint of ACR 20 response at week 24 at a significance level of 0.025 based on the 
Bonferroni-based gatekeeping chain procedure.
There are no published studies of etanercept monotherapy versus methotrexate 
monotherapy for the treatment of PsA.  Therefore for the purpose of this study the 
assumed response rates for ACR 20 for the etanercept monotherapy and methotrexate 
monotherapy arms are derived from separate studies. In the etanercept PsA pivotal 
phase 3 study (20021630 Study) the ACR 20 response rate at week 24 was 50% for the 
etanercept arm.  However, subjects were allowed to be on a stable dose of methotrexate 
at study entry.  Assuming a methotrexate naïve population would respond better, the 
response rate for the etanercept monotherapy arm in this planned phase 3 study is 
assumed to be 60%. 
In a recent randomized placebo-controlled trial of methotrexate monotherapy in PsA 
(Kingsley et al, 2012) the ACR 20 response rate for the methotrexate monotherapy arm 
was 34%. However, the dose of methotrexate was 15 mg QW.  Assuming a higher dose 
of methotrexate (ie, 20 mg QW) would yield better responses, the response rate for the 
methotrexate monotherapy arm in this planned phase 3 study is assumed to be 44%.  
Therefore, in order to detect a difference of 16% between the etanercept monotherapy 
and methotrexate monotherapy arms, using a two-sided Chi-square test at a significance 
level of 0.025 and 90% marginal power, each treatment arm will have approximately 
280 subjects adjusting for an anticipated 10% dropout.
This sample size will provide marginal power > 90% to detect a treatment difference in 
ACR 20 response at week 24 between the etanercept plus methotrexate therapy arm 
and the methotrexate monotherapy arm at a two-sided 0.025 significance level.  As 
previously mentioned, the ACR response rate at week 24 is assumed to be 44% for the 
methotrexate monotherapy arm.  The ACR response rate at week 24 for the etanercept 
plus methotrexate therapy arm is assumed to be 5% higher than the etanercept 
monotherapy arm (ie, 65%). This is based on a longitudinal observational study 
assessing the role of TNF-inhibitor plus methotrexate combination therapy versus 
TNF-inhibitor monotherapy (Fagerli et al, 2014).


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In addition, this sample size will provide marginal power > 90% to detect treatment 
differences in MDA response at week 24 between both etanercept arms and the 
methotrexate arm at a two-sided 0.025 significance level, assuming response rates of 
15%, 30%, and 35% for the methotrexate monotherapy, etanercept monotherapy, and 
etanercept plus methotrexate therapy arms, respectively.  In recent PsA trials, the MDA 
24-week response rates for the placebo arm range from 3 to 7% (Coates et al, 2010a; 
Kavanaugh et al, 2013).  Therefore, for the methotrexate monotherapy arm, the 
response rate is assumed to be higher at 15%.  In the pivotal phase 3 randomized 
placebo-controlled trial of etanercept in PsA, the MDA response rate for the etanercept 
monotherapy arm is estimated to be approximately 20% at week 24 (data on file).  For a 
methotrexate naïve population, the response rate is assumed to be higher at 30%.  In 
addition, the etanercept plus methotrexate therapy arm is assumed to have a 
5% improvement over the etanercept monotherapy arm.  
4.
Study Endpoints and Covariates
4.1
Study Endpoints
4.1.1
Primary Endpoint

ACR 20 response at week 24
4.1.2
Key Secondary Endpoint

MDA response at week 24
4.1.3
Other Secondary Endpoints

ACR 20 response at all measured time points other than week 24

MDA response at all measured time points other than week 24

Psoriatic Arthritis Disease Activity Score (PASDAS) at all measured time points and 
change from baseline at all measured time points

ACR 50, ACR 70, and components of ACR at all measured time points

Simplified Disease Activity Index (SDAI) and change from baseline at all measured 
time points

Clinical Disease Activity Index (CDAI) and change from baseline at all measured 
time points

Disease activity score (28 joint) using the C-reactive protein formula (DAS28-CRP)
and change from baseline at all measured time points

Health Assessment Questionnaire Disability Index (HAQ-DI) score and change from 
baseline at week 24

Short Form (36) Health Survey Version 2 (SF-36v2) (MCS and PCS) score and
change from baseline at week 24


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For subjects with non-zero mNAPSI at baseline,

mNAPSI and change from baseline at week 24 

achievement of mNAPSI = 0 at week 24 
For subjects with non-zero Leeds Dactylitis Index (LDI) at baseline,

LDI and change from baseline at week 24 

achievement of LDI = 0 at week 24 
For subjects with non-zero Spondyloarthritis Research Consortium of Canada 
(SPARCC) enthesitis at baseline, 

SPARCC enthesitis score and change from baseline at week 24 

achievement of SPARCC score = 0 at week 24 
For subjects with involved body surface area (BSA) ≥3% at baseline, < 3% at baseline, 
and ≥3% but < 10% at baseline, ≥10% at baseline:

Static Physician Global Assessment (sPGA) categorical summary by 0,1,2,3,4,5 at 
week 24

sPGA continuous summary at week 24

sPGA of 0 or 1 (yes/no) at week 24

sPGA one grade improvement from baseline at week 24 

sPGA two grade improvement from baseline at week 24

BSA, change and percent improvement from baseline at week 24
4.1.4
Safety Endpoints

Adverse events

Serious adverse events

Laboratory parameters and vital signs
4.1.5
Exploratory

mTSS, Erosion Score (ES), and Joint Space Narrowing (JSN) at baseline, week 24, 
and week 48

Change from baseline in mTSS, ES and JSN at week 24 and week 48 

Percent change from baseline in mTSS, ES and JSN at week 24 and week 48

Non-progression in mTSS defined as change in 3 levels: change ≤ 0 , change ≤0.5, 
change ≤3, from baseline at week 24 and week 48

Very Low Disease Activity (VLDA) response at week 24 and all other measured time 
points

Disease Activity index for Psoriatic Arthritis (DAPSA) and change from baseline at 
week 24 and all other measured time points


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
Health Assessment Questionnaire Disability Index (HAQ-DI) score and change from 
baseline at all measured time points other than week 24

Short Form (36) Health Survey Version 2 (SF-36v2) (MCS and PCS) score and 
change from baseline at all measured time points other than week 24
For subjects with non-zero mNAPSI at baseline,

mNAPSI and change from baseline at all measured time points other than week 24

achievement of mNAPSI = 0 at all measured time points other than week 24
For subjects with non-zero Leeds Dactylitis Index (LDI) at baseline,

LDI and change from baseline at all measured time points other than week 24

achievement of LDI = 0 at all measured time points other than week 24
For subjects with non-zero Spondyloarthritis Research Consortium of Canada 
(SPARCC) enthesitis at baseline, 

SPARCC enthesitis score and change from baseline at all other measured time 
points other than week 24

achievement of SPARCC score = 0 at all measured time points other than week 24
For subjects with involved body surface area (BSA) ≥3% at baseline, < 3% at baseline, 
and ≥3% but < 10% at baseline, ≥10% at baseline:

Static Physician Global Assessment (sPGA) categorical summary by 0,1,2,3,4,5 at 
all measured time points other than week 24

sPGA continuous summary at all measured time points other than week 24

sPGA of 0 or 1 (yes/no) at all measured time points other than week 24

sPGA one grade improvement from baseline at all measured time points other than 
week 24

sPGA two grade improvement from baseline at all measured time points other than 
week 24

BSA, change and percent improvement from baseline at all measured time points
other than week 24
4.2
Planned Covariates
The following covariates will be considered to assess their influence on the primary and 
key secondary endpoints:

Age (≤65, > 65)

Sex (male, female)

Race (Caucasian, non-Caucasian)

Ethnicity (Hispanic or Latino, non-Hispanic or Latino)


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
Baseline body mass index (BMI) (≤30, > 30)

Baseline weight (≤100 kg, > 100 kg)

Baseline BSA (≤3%, > 3%, 3-10%, ≥10%)

Prior use of non-biologic DMARD (yes, no)

Disease duration (≤median, > median, < = mean, > mean)
Subgroup analyses based on these covariates will be performed for the primary and key 
secondary endpoints to examine any differences in drug responses.
5.
Hypotheses and/or Estimations
The primary hypothesis of this study is that etanercept plus methotrexate therapy and 
etanercept monotherapy are more efficacious than methotrexate monotherapy as 
measured by the proportion of subjects with PsA achieving ACR 20 response at 
week 24.
The secondary hypothesis of this study is that etanercept plus methotrexate therapy and 
etanercept monotherapy are more efficacious than methotrexate monotherapy as 
measured by the proportion of subjects with PsA achieving MDA response at week 24.
6.
Definitions
6.1
Basic Definitions
Actual treatment received
Actual treatment for a subject is defined as the treatment the subject is randomized. An 
exception would be when a subject receives a different treatment other than the 
randomized treatment throughout the whole course of the study period, and then the 
actual treatment will be defined as the actual treatment received. In this context, 
treatment may refer to one Investigational product (IP), or a combination of IPs. 


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The following scenarios are examples of how actual treatment is defined in double 
blinded period:
Planned Treatment
Actual Treatment 
Etanercept + Methotrexate
If subject receives all placebo doses of Etanercept and all 
placebo doses of Methotrexate then 
Actual arm = Etanercept+ Methotrexate
Else  if subject receives at least one dose Etanercept and all 
placebo doses for Methotrexate then 
Actual arm = Etanercept + Placebo Methotrexate
Else If subject receives at least one dose Methotrexate and all 
placebo doses for Etanercept then 
Actual arm = Methotrexate + Placebo Etanercept 
Else Actual arm = Etanercept + Methotrexate
Etanercept + Placebo 
Methotrexate
If subject receives all doses of placebo Etanercept and at 
least one dose of placebo Methotrexate then 
Actual arm = Etanercept +Placebo Methotrexate ,
Else if subject receives at least one dose Etanercept and all 
doses of Methotrexate then 
Actual arm = Etanercept + Methotrexate
Else Actual arm = Etanercept + Placebo Methotrexate
Methotrexate + Placebo 
Etanercept 
If subject receives at least one dose placebo Etanercept and 
all placebo doses for Methotrexate then 
Actual arm =Placebo Etanercept + Methotrexate
Else if subject receives at least one dose Methotrexate and all 
doses of Etanercept then 
Actual arm = Etanercept + Methotrexate
Else Actual arm = Methotrexate + Placebo Etanercept 
Actual treatment received in rescue period is defined as etanercept + methotrexate.
Age
Number of years at time of enrollment as recorded on the electronic case report form.
Imputed Value
A value substituted for a missing value.
Investigational Product (IP)
Etanercept (or placebo for etanercept) and methotrexate (or placebo for methotrexate).  
Last Observation Carried Forward (LOCF) Imputation
A method of imputation where missing post-baseline efficacy data will be carried forward 
from the last non-missing post-baseline value for that endpoint.
Rescue Therapy
It is defined as subjects whose IP admin CRF forms indicate whether a subject receives
rescue IPs or not. 


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6.2
Study Points of Reference
Study Baseline
The last non-missing measurement for the endpoint of interest taken on or before the 
first dose of investigational product. 
For swollen joint count and tender joint count, the baseline values are the values taken 
on or before the day of the first dose of investigational product, and on or after 
randomization date.
Study Day
The number of days from Study Day 1, inclusive, given by the following formula:
Study Day = (Date of Interest – Date of Study Day 1) + 1, for Date of Interest is 
on/after Study Day 1
Study Day = Date of Interest - Date of Study Day 1, for Date of Interest is before 
Study Day 1 
Study Day 1
The first day of IP administration after randomization, if a subject is never dosed but 
randomized, then set study day 1 to randomization date.
6.3
Study Dates
End of Study Date
Date of the End of Study (EOS) safety follow-up phone call (for subjects who complete 
the study) or Early Termination (ET) visit (for subjects who withdraw from the study 
prematurely).
First Dose Date
The date of the first dose of IP.
Last Dose Date
The date of the last dose of IP. 
Randomization Date
The date when a randomization number is assigned through the Interactive Voice/Web 
Response System (IVRS/IWRS).
6.4
Study Time Intervals
Double-blind Treatment Period
The period of time beginning when a subject receives their first dose of IP through the 
first dose of rescue treatment, or end of study if they are never rescued. In case where a 


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subject is randomized but never dosed, the double blind period will start on the 
randomization date. 
Rescue Therapy Period
The period of time between the first dose of open-label rescue therapy at or after 
week 24 through end of study.
6.5
Calculations
Body Mass Index (BMI)
A measure utilizing both height and weight, as given by the following formula: weight 
(kg) / squared height (m2).
Duration of Psoriatic Arthritis
The number of years between the date of diagnosis (DXDT) and study 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
(DAY 1 – DXDT + 1)/365.25
Year, Month 
Day 
[Year(DAY 1)-Year(DXDT)]+
[Month(DAY 1)-Month(DXDT)]/12
*if duration equals 0, add 1 month or 1/12 years (this is 
to avoid a disease duration of 0)
Year
Month, Day
[Year(DAY 1)-Year(DXDT)] 
*if duration equals 0, add 1 month or 1/12 years (this is 
to avoid a disease duration of 0)
Improvement from Baseline
The arithmetic difference between the baseline value and a post-baseline value, as 
given by the following formulas:
For endpoints with higher scores as better clinical results,              
Improvement from baseline = (Post-baseline Value – Baseline Value)
For endpoints with lower scores as better clinical results,                   
Improvement from baseline = (Baseline Value – Post-baseline Value)
Percent Improvement from Baseline
The improvement from baseline divided by baseline and multiplied by 100, as given by 
the following formula:
(Improvement from Baseline / Baseline) * 100
Note:  If improvement from baseline is 0, the percent improvement from baseline will be 
set to 0 regardless of the baseline value.  If the baseline value is 0, substitute 1 in the 
denominator for the percent improvement from baseline calculation.


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6.6
Study Endpoints
ACR 20
A positive ACR 20 response is defined as at least 20% improvement from baseline in 
both tender/painful (68 joints) and swollen joint counts (66 joints), and at least 
20% improvement in at least 3 of the following criteria:  physician global assessment of 
arthritis disease activity (PhGA, 0-100 visual analog scale), patient global assessment of 
arthritis disease activity (PtGA, 0-100 visual analog scale), patient global assessment of 
joint pain (0-100 visual analog scale), functional disability (HAQ-DI), and acute phase 
reactant [C-reactive protein (CRP)].
Details of the scoring algorithm are described in Appendix A.
ACR 50
A positive ACR 50 response is defined by using the definition of ACR 20 response 
described above but requiring at least 50% improvement.
ACR 70
A positive ACR 70 response is defined by using the definition of ACR 20 response 
described above but requiring at least 70% improvement.
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.
Body Surface Area (BSA)
A numerical score (0% to 100%) that measures psoriasis involvement by the proportion 
of the subject’s total body surface area involved with psoriasis.
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.
C-Reactive Protein (CRP)
A specific measure of inflammatory activity measured in mg/dL.


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Disease Activity Score (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.
Disease Activity index for Psoriatic Arthritis (DAPSA)
This index is a composite measure, which comprises swollen and tender joint counts,
patient global and pain assessment and an acute phase reactant. Details of the scoring 
algorithm are described in Appendix A.
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, arising, eating, walking, hygiene, reaching, gripping, and usual 
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 A.
Leeds Dactylitis Index (LDI)
The Leeds Dactylitis Index (LDI) quantitatively measures dactylitis using the
circumference of involved digits and circumference of control digits (either contralateral 
digit, ie, digits on opposite hand or foot, or digit in standard reference table), and 
tenderness of involved digits.  The ratio of affected digit circumference to control digit 
circumference is multiplied by a tenderness score if ratio difference is greater than 10%.  
The results from each involved digit are then summed to provide the final LDI.  A higher 
LDI is associated with worse dactylitis.  
Details of the scoring algorithm are described in Appendix A.
Leeds Enthesitis Index
The Leeds enthesitis index assesses enthesitis at 6 sites for palpitation with a resultant 
score of 0 to 6.  Tenderness at each site is quantified on a dichotomous basis (0 = non-
tender, 1 = tender).  Entheses assessed are lateral epicondyles (left and right), medial 
femoral condyles (left and right), and achilles tendon insertions (left and right).  A higher 
count represents greater enthesitis burden.
Details of the scoring algorithm are described in Appendix A.


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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 Quality Metric 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.
Minimal Disease Activity (MDA)
A measure of low disease activity specific for PsA that incorporates measures of joint
and entheseal inflammation, skin disease, PROs and functional disability to assess the 
subject’s disease activity.  Subjects are classified as achieving MDA if they fulfill 5 of the 
following 7 outcome measures:

Tender joint count (0-68) ≤ 1

Swollen joint count (0-66) ≤1

Body Surface Area (BSA) ≤3

Patient global assessment of joint pain (0-100) ≤ 15

Patient global assessment of disease activity VAS (0-100) ≤20

HAQ-DI (0-3) ≤ 0.5

SPARCC enthesitis index ≤ 1
Details of the scoring algorithm are described in Appendix A.
Modified Nail Psoriasis Severity Index (mNAPSI)
The modified NAPSI scale is an objective, numeric, and reproducible grading system for 
nail psoriasis that incorporates the following 7 clinical features:

pitting (scores 0-3, depending on the number of pits)

nail plate crumbling (scores 0-3, depending on the % of nail involvement)

onycholysis and oil drop dyschromia (scores 0-3, depending on the % of nail 
involvement)

leukonychia (0 = absent, 1 = present)

red spots in lunula (0 = absent, 1 = present)


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
nail bed hyperkeratosis (0 = absent, 1 = present)

splinter hemorrhages (0 = absent, 1 = present)
In randomized subjects with fingernails involved with psoriasis, each fingernail will be 
scored at baseline to determine the worst fingernail (ie, the fingernail with the highest 
mNAPSI score).  This fingernail will be followed for the remainder of the study.  If 
multiple fingernails have the same worst score, only one target fingernail will be 
followed.  Scores will range from 0-13 where higher scores represent worse nail disease.
Details of the scoring algorithm re described in Appendix A
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). 
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). 
Psoriatic Arthritis Disease Activity Score (PASDAS)
A score of disease activity consisting of the following domains:  physician and patient 
global assessment of disease activity (0-100 visual analog scale), peripheral joint counts
based upon 68/66 joints, tender dactylitis count, Leeds enthesitis index, CRP in mg/L 
and SF-36 v2 physical component summary.  
Details of the scoring algorithm are described in Appendix A.
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.
Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index
The SPARCC enthesitis index assesses enthesitis at 18 sites for palpitation with a 
resultant score of 0 to 16.  Tenderness at each site is quantified on a dichotomous basis 
(0 = non-tender, 1 = tender).  Entheses assessed are medial epicondyle (left and right), 


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lateral epicondyle (left and right), supraspinatus insertion into greater tuberosity of 
humerus (left and right), greater trochanter (left and right), quadriceps insertion into
superior border of patella (left and right), patellar ligament insertion into inferior pole of 
patella or tibial tubercle (left and right), Achilles tendon insertion into calcaneum (left and 
right), plantar fascia insertion into calcaneum (left and right).  A higher count represents 
greater enthesitis burden.
Details of the scoring algorithm are described in Appendix A.
Static Physician Global Assessment of Psoriasis (sPGA)
The static Physician Global Assessment of psoriasis (sPGA) evaluates the physician’s 
global assessment of the subject’s psoriasis based on severity of induration, scaling, and 
erythema.  The sPGA is assessed on a scale of 0 (clear) to 5 (severe).
Swollen Joint Count
A score that assesses the presence or absence of swelling in 66 joints. 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. Details of the 
scoring algorithm are described in Appendix A.
Treatment Emergent AE 
A treatment emergent AE is defined as an event that occurs on or after the initiation of 
the IP and prior to the EOS date (ie, 30 days after last dose of IP). It is determined by
the pre-treatment flag (ie, AE.AEPRETRT NE 'Y') on the Events CRF with a start date up 
to 30 days after the end of investigational product or the End of Study date, whichever is 
earlier.
Van der Heijde Modified Total Sharp Score (mTSS)
A method for assessing erosions and joint space narrowing of the hands and feet based
on the Sharp-van der Heijde method in rheumatoid arthritis.  The method is adapted for 
evaluation of PsA by including the distal interhpalengeal joints of the hand and scoring 
not only for erosions and joint space narrowing but also for subluxation, ankylosis, gross 
osteolysis, and pencil in cup phenomena. The maximum possible total score is 528. 
A higher score represents worse destruction.  Details of the scoring algorithm are 
described in Appendix A.


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Very Low Disease Activity (VLDA)
A measure of very low disease activity specific for PsA that incorporates measures of 
joint and entheseal inflammation, skin disease, PROs and functional disability to assess 
the subject’s disease activity.  Subjects are classified as achieving VLDA if they fulfill all 
the following 7 outcome measures:

Tender joint count (0-68) ≤ 1

Swollen joint count (0-66) ≤1

Body Surface Area (BSA) ≤3

Patient pain VAS (0-100) ≤ 15

Patient global disease activity VAS (0-100) ≤20

HAQ (0-3) ≤ 0.5

Tender entheseal points ≤ 1 
Details of the scoring algorithm are described in Appendix A.
7.
Analysis Subsets
7.1
Full Analysis Set
The full analysis set will include all randomized subjects.  Subjects will be analyzed 
according to their randomized treatment group.  Demographics, baseline disease 
characteristics, and non-psoriasis efficacy analyses will be based on the full analysis set.
7.2
Psoriasis Efficacy Analysis Set
The psoriasis efficacy analysis set will include all randomized subjects with baseline 
BSA ≥ 3%.  Subjects will be analyzed according to their randomized treatment group.  
Analyses of psoriasis efficacy endpoints (eg, sPGA, BSA) will be based on the psoriasis 
efficacy analysis set.
7.3
Safety Analysis Set
The safety analysis set will consist of all randomized subjects who receive at least one 
dose of investigational product.  Subjects will be analyzed according to the actual 
treatment received as defined in Section 6.1.  Analyses of safety endpoints will be based 
on the safety analysis set.
7.4
Adequate Methotrexate Analysis Set
The adequate methotrexate analysis set will consist of all randomized subjects who 
receive weekly dose of at least 15 mg of methotrexate for at least 15 weeks during the 
course of week 4 (inclusive) to week 24 (inclusive) on etanercept plus methotrexate arm 
or methotrexate mono arm, and all subjects randomized to etanercept mono arm.


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7.5
Leeds Dactylitis Index (LDI) Analysis Set
The leeds dactylitis index analysis set will consist of all the randomized subjects with
non-zero LDI at baseline. Subjects will be analyzed according to their randomized 
treatment group. Analyses of LDI efficacy endpoints will be based on the leeds dactylitis 
index analysis set.
7.6
Modified Nail Psoriasis Severity Index (mNAPSI) Analysis Set
The mNAPSI analysis set will consist of all the randomized subjects with non-zero 
mNAPSI at baseline. Subjects will be analyzed according to their randomized treatment 
group. Analyses of mNAPSI efficacy endpoints will be based on this analysis set.
7.7
SPARCC Enthesitis Analysis Set
The SPARCC Enthesitis Analysis Set will consist of the randomized subjects with 
non-zero SPARCC enthesitis at baseline. Subjects will be analyzed according to their 
randomized treatment group. Analyses of SPARCC efficacy endpoints will be based on 
the SPARCC Enthesitis analysis set.
7.8
Subgroup Analysis
Subgroup analyses based on age (≤65, > 65), sex (male, female), race (Caucasian, 
non-Caucasian), ethnicity (Hispanic or Latino, non-Hispanic or Latino), baseline BMI
(≤30, > 30), baseline weight (≤100 kg, > 100 kg), baseline BSA (< 3%, > = 3%, > = 3% 
and < 10%, > = 10%), prior use of non-biologic DMARD (yes, no), and disease duration 
(≤median, > median, median is based on all randomized subjects.) will be performed for 
the primary and key secondary endpoints to examine any differences in drug responses.
Also subgroup analyses based on baseline BSA (< 3%, ≥3% but < 10%, and > = 10%) 
will be performed for sPGA and BSA in exploratory analysis.
Subgroup analysis containing a subgroup of less than 5% of the whole study population 
will not be conducted.
8.
Interim Analysis and Early Stopping Guidelines
No interim analysis is planned for this study.  
9.
Data Screening and Acceptance
9.1
General Principles
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses.


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9.2
Data Handling and Electronic Transfer of Data 
Amgen’s Clinical Data Management department will provide all data to be used in the 
planned analyses.  This study will use the RAVE database for all data except patient 
reported outcomes (PROs) and tender and swollen joint counts, which will be collected 
electronically on a tablet, and radiographic and laboratory data.  All PROs, tender and 
swollen joint counts, radiographic data, and laboratory data will be transferred to 
Amgen’s Clinical Data Management and stored outside the RAVE database as 
described in the Data Management Plan and Data Transfer Plan.  
9.3
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.
9.3.1
Missing Baseline Evaluation
Missing baseline evaluations will not be imputed.
9.3.2
Missing Post-baseline Evaluation
Subjects with missing post-baseline efficacy data will be imputed as non-responder, ie,
non-responder imputation (NRI) for the primary analysis of primary and key secondary
efficacy endpoints (ACR 20 and MDA).  Data will also be analyzed using multiple 
imputation (MI) as sensitivity analyses for primary and key secondary endpoints (ACR20 
and MDA). 
For analyses of other efficacy endpoints after week 24, data from subjects who remain in 
the double-blind period will be analyzed as observed with no imputation for missing data. 
Data from subjects who enter open-label rescue therapy will be imputed using last 
observation carried forward (LOCF).
For non-radiograph exploratory endpoints, data will be analyzed as observed without 
imputation for missing data.
For radiographic exploratory endpoints, data will be analyzed as observed with no 
imputation for missing data or for subjects who enter rescue treatment.  In addition, data 
will be analyzed using LOCF imputation for missing radiographs and for subjects who 
enter rescue treatment as sensitivity analysis.
Baseline data will not be carried forward to any missing post-baseline value unless 
otherwise specified.
Missing post-baseline safety data will not be imputed.


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9.3.3
Missing Components of Composite Endpoints
The rules for handling missing individual joints and missing components of composite 
endpoints are described in Appendix A.
9.3.4
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.
For tables, in the case where the start or stop date of an adverse event or concomitant 
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, or 
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
If the imputed start date is after the end date of concomitant medication or AE, then imputed start date will 
be default to end date of concomitant medication or AE. 
9.4
Detection of Bias
The study has been designed to minimize potential bias by selecting subjects, allocating 
treatment groups, assessing endpoints, and handling withdrawals without knowledge of 
the treatment.  Other factors that may introduce bias include:

Important protocol deviations likely to impact the analysis or interpretation of results

Blind breaking 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 
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.  


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Tabulations of important protocol deviations (IPDs) related to IP dosing non-compliance 
by treatment group will be provided.  A sensitivity analysis including subjects who 
tolerated at least 15 mg weekly of methotrexate (or placebo for methotrexate) after the 
initial 4-week titration through week 24 will be performed to assess the potential bias of 
methotrexate intolerance, as previously described in Section 7.4.
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.
9.5
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.
9.6
Distributional Characteristics
All continuous endpoints that will be analyzed with an ANCOVA model will be evaluated 
with regards to their distributional characteristics.  If they deviate from normality, data will 
be first transformed to their joint ranks and then further transformed by the van der 
Waerden method to normalize them before applying the ANCOVA model.
9.7
Validation of Statistical Analyses
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System version 9.2 or 
later.  
10.
Statistical Methods of Analysis
10.1
General Principles
The primary analysis will be performed after all subjects have completed the week 48 
assessments and the 30-day safety follow-up period and all data have been finalized.  


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Subject disposition, demographics, and baseline disease characteristics will be 
summarized descriptively by randomized treatment group.
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 error, standard deviation, median, minimum, and
maximum.
Treatment effect will be tested for the primary and key secondary endpoints using a
Bonferroni-based gatekeeping chain procedure to control the family-wise 2-sided type
one error rate at 0.05. The significance level for the analyses of other secondary
endpoints and exploratory endpoints will be 0.05 without adjusting for multiplicity and the
p-values for these endpoints will therefore be treated as a descriptive statistic only.
Safety endpoints will be tabulated by actual treatment received during the study. No
formal statistical testing will be performed for safety analyses.
10.2
Subject Accountability
Subject disposition will be summarized descriptively for all randomized subjects by 
randomized treatment group.  
The disposition for the double-blind treatment period will include the number of subjects 
who are randomized, who are dosed with investigational product, who complete 
24 weeks, who complete 48 weeks, who complete the study, and who withdraw 
prematurely including their reasons for withdrawal. 
The disposition for the rescue therapy subjects will include the number of subjects who 
enter rescue therapy, who complete 48 weeks, who complete the study, and who 
withdraw prematurely including their reasons for withdrawal.
10.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, sub-category codes and 
descriptions will be used during the course of the study. 
10.4
Demographic and Baseline Characteristics
Subject demographic and baseline disease characteristics will be summarized 
descriptively for all randomized subjects by randomized treatment group.  Demographic 
and baseline disease characteristics may be re-evaluated for the safety evaluable 
subset if the subset is materially different from the full analysis set.


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In addition, subject demographic and baseline disease characteristics will be 
summarized descriptively for all subjects who receive rescue therapy by randomized 
treatment group.
10.5
Efficacy Analyses
All efficacy analyses of non-psoriasis efficacy endpoints will be conducted using the full 
analysis set (ie, intent-to-treat set).  Analyses of psoriasis efficacy endpoints (eg, sPGA, 
BSA) will be based on the psoriasis efficacy analysis set and other subgroups using 
different cutoffs of baseline BSA.  Some PsA efficacy endpoints will be analyzed using 
analysis sets corresponding to those PsA indications. Subjects will be analyzed 
according to their original randomized treatment regardless of the actual treatment 
received during the study.
For the primary and key secondary endpoints, missing post-baseline data will be 
imputed using non-responder imputation (NRI) for the primary analysis. In addition, the 
primary and key secondary endpoints will be analyzed using multiple imputation (MI) as 
a sensitivity analysis. Another sensitivity analysis for primary and key secondary 
endpoints will also be performed using Adequate Methotrexate Analysis Set. For 
analyses of other efficacy endpoints after week 24, data from subjects who remain in the 
double-blind period will be analyzed as observed with no imputation for missing data. 
Data from subjects who enter rescue period will be imputed using LOCF.
10.5.1
Analyses of Primary and Key Secondary Efficacy Endpoints
The primary analysis of the primary and key secondary endpoints, ACR 20 response 
and MDA response at week 24, will be performed using the full analysis set. Missing 
post-baseline data will be imputed using non-responder imputation (NRI) for the primary 
analysis. Treatment effect will be tested using the stratified Cochran-Mantel-Haenszel 
(CMH) test with baseline BMI and prior non-biologic DMARD use as the stratification 
factors.
To control the family-wise 2-sided type one error rate at 0.05 for the multiple 
comparisons of the etanercept plus methotrexate therapy and etanercept monotherapy 
groups with methotrexate monotherapy across the primary and key secondary 
endpoints, the hypotheses will be tested using a Bonferroni-based gatekeeping chain 
procedure (Burman et al 2009 and Millen et al 2011) as shown in Figure 1.  This 
procedure will split alpha of 0.05 equally to test in parallel the primary and key secondary 
endpoints (ACR 20, MDA) for etanercept plus methotrexate therapy vs. methotrexate 
monotherapy and etanercept monotherapy vs. methotrexate monotherapy sequentially 


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within each parallel path.  If one of the parallel paths rejects both hypotheses 
sequentially, and the other parallel path has at least one hypothesis not rejected, then 
the unspent alpha of 0.025 from the successful path will be propagated to the 
hypotheses in the other path to re-test them sequentially at a level of 0.05.  For example, 
suppose the nominal p-values for hypotheses A1, B1, A2, and B2 (Figure 1) are 0.01, 
0.02, 0.03, and 0.055, respectively.  In the first round of testing, hypotheses A1 and B1 
are rejected, whereas hypotheses A2 and B2 are not rejected.  However, since both 
hypotheses A1 and B1 are rejected, the procedure gives a second chance to re-test 
hypotheses A2 and B2 (according to the left arm of the figure) at a lower threshold of 
0.05 rather than the original threshold of 0.025.  Note that in this example A2 is rejected 
and hypothesis B2 is not rejected.


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Figure 1.  Bonferroni-based Gatekeeping Chain Procedure
          Bonferroni
         parallel testing
     
    ETN: Etanercept; MTX: Methotrexate
In addition, the primary and key secondary endpoints will be analyzed using multiple 
imputation (MI) as a sensitivity analysis. Another sensitivity analysis for primary and key 
secondary endpoints will also be performed using Adequate Methotrexate Analysis Set. 
Sensitivity analyses of primary and key secondary endpoints are descriptively without 
adjusting for multiplicity.
Hypothesis A1: No treatment 
difference in proportions of       
ACR 20 responders between      
ETN plus MTX and MTX groups    
(2-sided, α = 0.025)              
Hypothesis A2: No treatment 
difference in proportions of       
MDA responders between        
ETN plus MTX and MTX groups    
(2-sided, α = 0.025)              
Hypothesis B1: No treatment 
difference in proportions of     
ACR 20 responders between       
ETN and MTX groups            
(2-sided, α = 0.025)              
Hypothesis B2: No treatment 
difference in proportions of      
MDA responders between         
ETN and MTX groups            
(2-sided, α = 0.025)              
Hypothesis A2 Retested:       
No treatment difference in 
proportions of MDA responders 
between  ETN plus MTX and 
MTX groups                    
(2-sided, α = 0.05)              
Hypothesis B2 Retested:       
No treatment difference in 
proportions of MDA responders 
between ETN and MTX groups     
(2-sided, α = 0.05)               
Hypothesis A1 Retested:       
No treatment difference in 
proportions of ACR 20 
responders between ETN plus 
MTX and MTX groups            
(2-sided, α = 0.05)               
Hypothesis B1 Retested:       
No treatment difference in 
proportions of ACR 20 
responders between ETN and 
MTX groups                    
(2-sided, α =0.05)               
                       Null hypothesi is rejected                                     Null hypothesis is not rejected       


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10.5.2
Analyses of Other Secondary Efficacy and Selected Exploratory 
Endpoints
The analysis of the following secondary and exploratory endpoints at week 24 will be 
performed using the LDI analysis set for LDI endpoints, SPARCC Enthesitis analysis set 
for SPARCC endpoints, mNAPSI analysis set for mNAPSI endpoints, and the full 
analysis set for the other efficacy endpoints unless otherwise specified:

LDI change from baseline at week 24 (LDI analysis set) 

Achievement of LDI=0 at week 24 (LDI analysis set).

SPARCC change from baseline at week 24 (SPARCC analysis set)

Achievement of SPARCC=0 at week 24 (SPARCC analysis set)

mNAPSI change from baseline at week 24 (mNAPSI analysis set)

Achievement of mNAPSI=0 at week 24 (mNAPSI analysis set)

PASDAS change from baseline at week 24

DAS28-CRP change from baseline at week 24

SDAI change from baseline at week 24

CDAI change from baseline at week 24

VLDA at week 24

DAPSA change from baseline at week 24
For binary endpoints, treatment effect will be tested using the stratified CMH test with 
BMI and prior non-biologic DMARD use as the stratification factors.  For continuous 
endpoints that exhibit normal distribution, ANCOVA model will be used. The model will 
include treatment groups and baseline BMI and prior non-biologic DMARD as 
covariates. For continuous endpoints that are not normally distributed, endpoint data will 
be first transformed to their joint ranks and then further transformed by the Van der 
Waerden transformation to normalize them before applying the ANCOVA model. The 
significance level for other secondary endpoints will be 0.05 without adjusting for 
multiplicity and p-values will therefore be treated as a descriptive statistic only.  All the 
testing will be performed for endpoints at week 24 and methotrexate monotherapy group 
will be the reference group.     
Analyses to other secondary endpoints will be summarized descriptively only. sPGA and 
BSA summary analyses will be performed using psoriasis efficacy analysis set and 
subgroups of subjects with the baseline BSA < 3%, > = 3% but < 10%, and > = 10%.


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10.5.3
Analyses of Exploratory Endpoints 
The analysis of the exploratory endpoints will be performed using the LDI analysis set for 
LDI endpoints, SPARCC Enthesitis analysis set for SPARCC endpoints, mNAPSI 
analysis set for mNAPSI endpoints, psoriasis efficacy analysis set and subgroups of 
subjects with the baseline BSA < 3%, > = 3% but < 10%, and > = 10% for sPGA and 
BSA summary analyses, and the full analysis set for the other efficacy endpoints unless 
otherwise specified.
For radiographic exploratory endpoints, data will be analyzed as observed with no 
imputation for missing data or for subjects who enter rescue treatment.  In addition, data 
will be analyzed using LOCF imputation for missing radiographs and for subjects who 
enter rescue treatment as sensitivity analysis. Probability plots and mean change plots 
will also be produced based on observed data.
Analyses to other exploratory endpoints will be summarized descriptively only. For VLDA 
and DAPSA, additional analyses at week 24 will also be performed as described in 
Section 10.5.2.
10.5.4
Biomarker Endpoints 
Data collected on biomarkers may be analyzed to help characterize subjects who are 
most likely to respond positively or negatively to etanercept or methotrexate. If the study 
team decides to perform such an analysis, it will be considered exploratory and will be 
described in a separate analysis plan.
10.6
Safety Analyses
All safety analyses will be conducted using the safety analysis set.  Subjects will be 
analyzed according to the actual treatment received.  Subjects who meet the inadequate 
response criteria at or after week 24 have the opportunity to enter rescue therapy and 
begin receiving etanercept plus methotrexate.  In order to accurately reflect the safety 
experiences in these subjects with respect to the treatment received during rescue 
therapy, all events experienced during rescue therapy will be summarized separately.    
10.6.1
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 18.0 or later will be 
used to code all adverse events (AE) to a system organ class and a preferred term.  All 
adverse event tables will be summarized by treatment group for the double-blind 
treatment period and the rescue therapy period.  The subject incidence of AEs will be 


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summarized for all treatment-emergent AEs, serious AEs, AEs leading to withdrawal of 
investigational product, and fatal AEs.
Subject incidence of all treatment-emergent AEs, serious AEs, AEs leading to 
withdrawal of investigational product, and fatal AEs will be tabulated by system organ 
class and preferred term in descending order of frequency.  
Summaries of treatment-emergent and serious AEs occurring in at least 1% of the 
subjects by preferred term in any treatment arm will be provided in descending order of 
frequency.  
10.6.2
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.  
10.6.3
Vital Signs
Vital signs may be descriptively summarized in baseline disease summaries, if there is 
unexpected safety finding.
10.6.4
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group, including number of doses, number of missed doses, and duration 
of dosing.
10.6.5
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. 
11.
Changes From Protocol-specified Analyses
Changes are made only for secondary or exploratory endpoints. The changes are 
instituted to adopt the standardized ways to report the efficacy endpoints in PsA trials. 
The changes to LDI, SPARCC, and mNAPSI are made to focus on relevant 
sub-populations for analysis. Modeling analyses described in Section 10.5.2 will be 


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limited to selected secondary endpoints at week 24 only, for the inclusion in CSR.  
Further analyses may be performed later on an ad hoc basis. 
Specifically, the changes are as follows: 
1.
These analysis sets are added to the SAP because they are more relevant to the 
purpose of the analyses focusing on the subpopulations with disease progression.
Leeds Dactylitis Index (LDI) Analysis Set
The leeds dactylitis index analysis set will consist of all the randomized subjects with 
non-zero LDI at baseline. Subjects will be analyzed according to their randomized 
treatment group. Analyses of LDI efficacy endpoints will be based on the leeds dactylitis 
index analysis set.
Modified Nail Psoriasis Severity Index (mNAPSI) Analysis Set
The mNAPSI analysis set will consist of all the randomized subjects with non-zero 
mNAPSI at baseline. Subjects will be analyzed according to their randomized treatment 
group. Analyses of mNAPSI efficacy endpoints will be based on this analysis set.
SPARCC Enthesitis Analysis Set
The SPARCC Enthesitis Analysis Set will consist of the randomized subjects with 
non-zero SPARCC enthesitis at baseline. Subjects will be analyzed according to their 
randomized treatment group. Analyses of SPARCC efficacy endpoints will be based on 
the SPARCC Enthesitis analysis set.
2. Modification of the other secondary endpoints limited to specific subpopulation in in 
Section 4.1.3 as follows:
For subjects with non-zero mNAPSI at baseline,

mNAPSI and change from baseline at week 24 

achievement of mNAPSI = 0 at week 24 
For subjects with non-zero Leeds Dactylitis Index (LDI) at baseline,

LDI and change from baseline at week 24 

achievement of LDI = 0 at week 24 
For subjects with non-zero Spondyloarthritis Research Consortium of Canada 
(SPARCC) enthesitis at baseline, 

SPARCC enthesitis score and change from baseline at week 24 

achievement of SPARCC score = 0 at week 24 


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For subjects with involved body surface area (BSA) ≥3% at baseline, < 3% at baseline, 
and ≥3% but < 10% at baseline, ≥10% at baseline:

Static Physician Global Assessment (sPGA) categorical summary by 0,1,2,3,4,5 at 
week 24 

sPGA continuous summary at week 24 

sPGA of 0 or 1 (yes/no) at week 24 

sPGA one grade improvement from baseline at week 24 

sPGA two grade improvement from baseline at week 24 

BSA, change and percent improvement from baseline at week 24
The changes are in Section 4.1.5 Exploratory Endpoints:

mTSS, Erosion Score (ES), and Joint Space Narrowing (JSN) at baseline, week 24, 
and week 48 

Change from baseline in mTSS, ES and JSN at week 24 and week 48 

Percent change from baseline in mTSS, ES and JSN at week 24 and week 48

Non-progression in mTSS defined as change in 3 levels: change ≤ 0 , change ≤0.5, 
change ≤3, from baseline at week 24 and week 48

Very Low Disease Activity (VLDA) response at week 24 and all other measured time 
points

Disease Activity index for Psoriatic Arthritis (DAPSA) and change from baseline at 
week 24 and all other measured time points
For subjects with non-zero mNAPSI at baseline,

mNAPSI and change from baseline at all other measured time points other than 
week 24

achievement of mNAPSI = 0 at all other measured time points other than week 24
For subjects with non-zero Leeds Dactylitis Index (LDI) at baseline,

LDI and change from baseline at all other measured time points other than week 24

achievement of LDI = 0 at all other measured time points other than week 24
For subjects with non-zero Spondyloarthritis Research Consortium of Canada 
(SPARCC) enthesitis at baseline, 

SPARCC enthesitis score and change from baseline at all other measured time 
points other than week 24

achievement of SPARCC score = 0 at all other measured time points other than 
week 24


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For subjects with involved body surface area (BSA) ≥3% at baseline, < 3% at baseline, 
≥3% but < 10% at baseline, and ≥10% at baseline:

Static Physician Global Assessment (sPGA) categorical summary by 0,1,2,3,4,5 at 
all other measured time points other than week 24

sPGA continuous summary at all other measured time points other than week 24

sPGA of 0 or 1 (yes/no) at all other measured time points other than week 24

sPGA one grade improvement from baseline at all other measured time points other 
than week 24

sPGA two grade improvement from baseline at all other measured time points other 
than week 24

BSA, change and percent improvement from baseline at all other measured time 
points other than week 24
3. Changes to Section 10.5.2 are made to focus on selected other secondary and 
exploratory efficacy endpoints at week 24 only, which is the primary time point of 
interest, as follows:
The analysis of the following secondary endpoints at week 24 will be performed using 
the LDI analysis set for LDI endpoints, SPARCC Enthesitis analysis set for SPARCC 
endpoints, mNAPSI analysis set for mNAPSI endpoints, and the full analysis set for the 
other efficacy endpoints unless otherwise specified:

LDI change from baseline at week 24 (LDI analysis set) 

Achievement of LDI = 0 at week 24 (LDI analysis set).

SPARCC change from baseline at week 24 (SPARCC analysis set)

Achievement of SPARCC = 0 at week 24 (SPARCC analysis set)

mNAPSI change from baseline at week 24 (mNAPSI analysis set)

Achievement of mNAPSI = 0 at week 24 (mNAPSI analysis set)

PASDAS change from baseline at week 24

DAS28-CRP change from baseline at week 24

SDAI change from baseline at week 24

CDAI change from baseline at week 24

VLDA at week 24

DAPSA change from baseline at week 24


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12.
Literature Citations / References
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat. Med. 2009; 28:739–761
Coates LC, Fransen J, Helliwell PS. Defining minimal disease activity in psoriatic 
arthritis: a proposed objective target for treatment. Ann Rheum Dis. 2010a;69:48-53. 
Fagerli KM, Lie E, van der Heidje D,  et al. The role of methotrexate co-medication in 
TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients 
included in the NOR-DMARD study. Ann Rheum Dis. 2014 73:132–137.
Kavanaugh A, McInnes IB, Mease PJ, et al. Impact of persistent minimal disease activity 
on long-term outcomes in psoriatic arthritis: results from 5 years of the long term 
extension of a randomized, placebo-controlled, Study. Abstract #341. Presented at the 
ACR/ARHP Annual Meeting, 27 Oct 2013.
Kingsley GH, Kowalcyzk A, Taylor H, et al. A randomized placebo-controlled trial of 
methotrexate in psoriatic arthritis. Rheumatology. 2012;51:1368-1377
Millen B, Dmitrienko A. Chain procedures: a class of flexible closed testing procedures 
with clinical trial applications. Statistics in Biopharmaceutical Research 2011; 3:14–30.


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13.
Appendices


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Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs
Analysis Windows for 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 analysis.  If more than one assigned 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 on the same date and time, the average of the 
results will be used. Only laboratory results collected from the central laboratory will be 
averaged in the case of duplicate results. 
Any visit that falls in an unscheduled visit for that assessment (eg, an enthesitis 
assessment done at week 16) will be excluded from the analysis. 
Visit Windows for Radiographic Endpoints
Visit
Week
Target
Day
Window
Definition
Interval
(days)
Baseline
1
Last Evaluation prior to or on Study Day 1
n/a
Week 24
169
Study Day 15 to 252
118
Week 48
337
>=Study Day 253
n/a
a If results from baseline radiograph are not available, the results from scan taken on or before Study Day 14 
will be considered as baseline values. 
Visit window for SPARCC, Dactylitis, mNAPSI, sPGA, BSA
Visit
Week
Target
Day
Window
Definition
Interval
(days)
Baseline
1
Last Evaluation prior to or on Study Day 1
n/a
Week 4
29
Study Day 2 to 56
54
Week 12
85
Study Day 57 to126 
70
Week 24
169
Study Day 127 to 210
84
Week 36
253
Study Day 211 to 294
84
Week 48
337
>=Study Day 295
n/a


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Visit window for  SF-36 and PASDAS
Visit
Week
Target
Day
Window
Definition
Interval
(days)
Baseline
1
Last Evaluation prior to or on Study Day 1
n/a
Week 12
85
Study Day 2 to 126
124
Week 24
169
Study Day 127 to 210
84
Week 36
253
Study Day 211 to 294
84
Week 48
337
>=Study Day 295
n/a
For the rest of the endpoints of interest, use the following window:
Visit
Week
Target
Day
Window
Definition
Interval
(days)
Baselinea
1
Last Evaluation prior to or on Study Day 1 
n/a
Week 4
29
Study Day 2 to 42
41
Week 8
57
Study Day 43 to 70
28
Week 12
85
Study Day 71 to 98
28
Week 16
113
Study Day 99 to 140
42
Week 24
169
Study Day 141 to 210
70
Week 36
253
Study Day 211 to 294
84
Week 48
337
>=Study Day 295
n/a
a For swollen joint count and tender joint count, the baseline values are the values taken on the day of 
randomization before the first dose of investigational product.
Scoring Algorithms for Efficacy Endpoints
ACR Responder
The ACR response is a composite endpoint that classifies a patient as a responder or 
non-responder based upon improvement from baseline as defined by 7 endpoints.  To 
be considered an ACR 20/50/70 responder, a subject must experience the following:

At least 20/50/70% improvement in tender joint count (68 joints), AND

At least 20/50/70% improvement in swollen joint count (66 joints), AND

At least 20/50/70% improvement in 3 of the 5 following endpoints:
o
Physician global assessment (PhGA)
o
Patient global assessment (PtGA)
o
Patient global assessment of joint pain
o
Functional disability (HAQ-DI)
o
Acute phase reactant (CRP)


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If joint data are partially missing, the joint counts will be prorated prior to deriving ACR 
responses. There is no imputation for missing secondary individual components (ie, 
HAQ-DI, CRP or ESR, pain VAS, PtGA, and PhGA).  
In the case that some ACR components are missing, the ACR scores will be based on 
the non-missing components.  If a subject’s non-missing components are not sufficient 
to determine ACR response, then that subject will be considered as missing ACR 
response.  The corresponding algorithm is listed below (using ACR 20 as an example):
1. If either swollen or tender joint counts is not improved at least 20%, the subject is an 
ACR non-responder
2. If both tender and swollen joint counts are improved at least 20%, and  
a. If 3 or more of the other 5 ACR components are improved at least 20%, the 
subject is an ACR 20 responder;
b. If 3 or more of the other 5 ACR components are not improved at least 20%, the 
subject is an ACR 20 non-responder;
c. If none of the above, the ACR response for the subject cannot be determined due 
to missing data and is therefore set to missing.
3. If the percent improvement of either swollen or tender joint counts is missing, and
a. If 3 or more of the other 5 ACR components are not improved at least 20%, the 
subject is an ACR 20 non-responder;
b. Otherwise, the ACR response for the subject cannot be determined due to 
missing data and is therefore set to missing.
Clinical Disease Activity (CDAI)
CDAI will be calculated based on the number of tender (TEN28) and swollen (SW28) 
joint using a 28-joint count, physician global assessment on a 0-10 scale (PhGA), and 
patient global assessment on a 0-10 scale (PtGA).  Since PhGA and PtGA are collected 
on a 0-100 scale, the formula has been modified to convert these scores to a 0-10 scale 
as such:
CDAI = SW28 +TEN28 +PhGA/10 + PtGA/10
If one or more components are missing in the formula, then CDAI is set to be missing.


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Leeds Dactylitis Index (LDI)
The Leeds Dactylitis Index (LDI) will be calculated based on the tenderness and 
circumference of dactylitic digits.  First, identify involved digit (A) as a digit with 
tenderness score greater than 0. Second, identify control digit (B) as in the following 
scenarios:
1. contralateral digit (the digit on opposite hand and foot ) if tenderness score 
associated with contralateral digit is 0. 
2. If the tenderness score for contralateral digit is also greater than 0, then control digit 
is the digit listed in standard reference table below.
Note in scenario 2), the contralateral digit is also an involved digit (A), look up its control 
digit from standard reference table below. 
For any digit with a missing tenderness score, it will be removed from LDI calculation.
For any involved digit with contralateral digit circumference missing, only calculate LDI 
when both involved digit and its contralateral are tender (tenderness score > 0). In latter 
case, refer to standard reference table in the same fashion as in scenario 2 above.
To calculate LDI for (A), take the ratio of circumference in mm of the involved digit (A) 
and control digit (B) . If the ratio difference [(A/B)-1] is greater than 10%, multiply 
100 and the ratio difference [(A/B)-1] by the tenderness score corresponding to involved
digit (A): : 
LDI = (A/B-1) x100 x tenderness score of A, if [(A/B)-1] > 10%  
The scores from each involved digit are summed by subject by visit to give a grand total
Standard reference table for LDI:
Digit
Men
Women
thumb
70
58
index
63
54
middle finger
63
54
ring
59
50
little finger
52
44
Great Toe
82
72
2nd toe
52
46
middle toe
50
44
4th toe
50
44
toe
52
45


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Example:
Raw data for subject 1:
Folder
BODYCD
SEX
circum_right
circum_left
tender_right
tender_left
D1
Toe #2
Male
70
61
1
0
D1
Toe #3
Male
71
61
1
2
D1
Finger #4
Male
85
90
0
1
There are 4 involved digits: Toe# 2 right, Toe#3 left, Toe#3 right, Finger#4 left.
To calculate LDI for Toe#2 right, A = 70, B = 61, ratio difference = A/B-1 = 14.75%, 
therefore LDI = (A/B-1) x 100 x tenderness score= 14.75*1 = 14.75
Digit
Circumference 
of Involved Digit
(A)
Contralateral 
Digit 
(B)
Ratio
[(A/B)-1] (C)
Tenderness 
0, 1, 2, 3 
(D)
Final Score
if C≥10%
C*D*100 
Finger #4
90
85
5.88%
1
n/a
Toe #2
70
61
14.75%
1
14.75
Toe #3 
71
50
42%
1
42
Total LDI at 
D1
14.75+42+44=100.75
Tender Dactylitis Count
Tender dactylitis count will be calculated based on the tenderness of each dactylitis 
digits. If the tenderness for a digit (finger or toe) is greater than 0, then the count will be 
coded as 1 for that digit. The total score for tender dactylitis count will be the sum of the 
tender dactylitis count for each digit, ranging from 0 to 20.
Disease Activity Score (DAS28-CRP)
DAS28-CRP will be calculated based on the number of tender (TEN28) and swollen 
(SW28) joints using a 28-joint count, CRP in mg/L, and a 100 mm visual analog scale 
measuring the subject’s general health (PtGA).  Since CRP is collected in mg/dL, the 
formula has been modified to convert this measure to mg/L as such:
DAS28-CRP = 0.56*√TEN28 + 0.28*√SW28 + 0.36*ln[(CRP*10)+1] + 0.014*PtGA +0.96
If one or more components are missing in the formula, then DAS28_CRP is set to be 
missing.


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Disease Activity index for Psoriatic Arthritis (DAPSA) (range 0-164)
DAPSA will be calculated based on the number of tender (TEN68) and swollen (SW66) 
joints, patient global assessment on a 0-10 scale (PtGA), patient global assessment of 
pain on a 0-10 scale (PtGAJP) and CRP in mg/dL.  Since PtGA and PtGAJP are 
collected on a 0-100 scale, the formula has been modified to convert these scores to a 
0-10 scale as such:
DAPSA = SW66 +TEN68 +PtGA/10 + PtGAJP/10 + CRP
If one or more components are missing in the formula, then DAPSA is set to be missing.
Leeds Enthesitis Index
The Leeds enthesitis index will be used for the PASDAS derivation only and will be 
calculated based on the following entheses:
Entheses
Tenderness (0=Not Tender,
1= Tender)
Medial femoral condyle (left)
0 or 1
Medial femoral condyle (right)
0 or 1
Lateral epicondyle (left)
0 or 1
Lateral epicondyle (right)
0 or 1
Achilles tendon into calcaneum (left)
0 or 1
Achilles tendon into calcaneum (right)
0 or 1
Total Leeds Enthesitis Index
sum (range 0-6)
If one or more components are missing, then enthesitis index is set to be missing.


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SPARCC enthesitis index
SPARCC enthesitis index will be calculated based on the following entheses:
Entheses
Tenderness (0=Not Tender,
1= Tender)
Medial epicondyle (left)
0 or 1
Medial epicondyle (right)
0 or 1
Lateral epicondyle (left)
0 or 1
Lateral epicondyle (right)
0 or 1
Supraspinatus (left)
0 or 1
Supraspinatus (right)
0 or 1
Greater trochanter (left)
0 or 1
Greater trochanter (right)
0 or 1
Quads into superior patella (left)
0 or 1
Quads into superior patella (right)
0 or 1
Max {Patella ligament into inferior patella (left), 
Patella ligament into tibial tubercle (left)}
0 or 1
Max{Patella ligament into inferior patella (right), 
Patella ligament into tibial tubercle (right)}
0 or 1
Achilles tendon into calcaneum (left)
0 or 1
Achilles tendon into calcaneum (right)
0 or 1
Plantar fascia into calcaneum (left)
0 or 1
Plantar fascia into calcaneum (right)
0 or 1
Total SPARCC Enthesitis Index
sum (range 0-16)
If one or more components are missing, then SPARCC is set to be missing.
HAQ-DI
The HAQ-DI is the disability assessment component of the HAQ that assesses a 
patient’s level of functional ability.  It is calculated based on the mean score from the 
following eight categories: dressing & grooming, rising, eating, walking, hygiene, reach, 
grip, and usual activities.  Each category is comprised of two or three questions that are 
scored as 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), or 
3 (unable to do). The highest score for questions in each category (range 0 to 3) 


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determines the score for the category, unless aids or devices are required. Dependence 
on equipment or physical assistance increases a lower score (ie, scores of 0 or 1) to the 
level of 2 to more accurately represent underlying disability. If the subject’s highest score 
is a 3 then it stays a 3.  Devices and aids are assigned to the categories as follows:
HAQ-DI Category
Companion AIDS OR DEVICES item
DRESSING & 
GROOMING
Devices used for dressing (button hook, zipper pull, long-handled 
shoe horn, etc.)
ARISING
Built up or special 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)
The eight category scores are averaged into an overall HAQ-DI score on a scale from 0 (no disability) to 
3 (completely disabled) when 6 or more categories are non-missing.  If more than 2 categories are missing, 
the HAQ-DI score is set to missing.  
Minimal Disease Activity (MDA)
MDA response will be derived based on the following criteria:
Outcome
Criteria
Tender joint count (0-68)
≤ 1
Swollen joint count (0-66)
≤ 1
Body surface area (0-100)
≤ 3
Patient global assessment of joint pain – PTGAJP (0-100)
(used for patient pain VAS)
≤ 15
Patient global assessment of disease activity – PTGA (0-100)
(used for patient global disease activity VAS)
≤ 20
HAQ-DI (0-3)
(used for HAQ)
≤ 0.5
SPARCC enthesitis index (0-16)
(used for tender entheseal points)
≤ 1
Use prorated scores for Tender and Swollen joint count. If 5 of 7 criteria are met then the subject has 
achieved MDA response.
If all components are missing, then MDA is set to be missing. If one or more but not all components are 
missing in the formula, then MDA is set to be zero.


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Very Low Disease Activity (VLDA)
VLDA response will be derived based on the following criteria:
Outcome
Criteria
Tender joint count (0-68)
≤ 1
Swollen joint count (0-66)
≤ 1
Body surface area (0-100)
≤ 3
Patient global assessment of joint pain (0-100)
(used for patient pain VAS)
≤ 15
Patient global assessment of disease activity (0-100)
(used for patient global disease activity VAS)
≤ 20
HAQ-DI (0-3)
(used for HAQ)
≤ 0.5
SPARCC enthesitis index (0-16)
(used for tender entheseal points)
≤ 1
Use prorated scores for Tender and Swollen joint count. If all 7 criteria are met then the subject has 
achieved VLDA response. If all components are missing, then VLDA is set to be missing. If one or more but 
not all components are missing in the formula, then VLDA is set to be zero.
mNAPSI
The modified NAPSI will be calculated for all fingernails at baseline.  For remaining 
visits, the modified NAPSI will only be calculated for the worst fingernail (ie, the fingernail 
with the highest score) based on the baseline assessment.  The total score will range 
from 0-13 as follows:
Clinical feature
Score
Pitting (0-3 based on severity)*
0, 1, 2 or 3
Nail plate crumbling (0-3 based on severity)*
0, 1, 2 or 3
Onycholysis and oil drop dyschromia (0-3 based on severity)*
0, 1, 2 or 3
Leukonychia (0=absent, 1=present)
0 or 1
Red spots in lunula (0=absent, 1=present)
0 or 1
Nail bed hyperkeratosis (0=absent, 1=present)
0 or 1
Splinter hemorrhages (0=absent, 1=present)
0 or 1
Total mNAPSI Score
sum (range 0-13)


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Severity Codes
Clinical feature
Score=0
Score=1
Score=2
Score=3
Pitting 
no pits
1-10 
11-49 
≥50 
Nail plate crumbling 
no crumbling
1-25% 
26-50%
>50%
Onycholysis and oil drop 
dyschromia 
no onycholysis
1-10%
11-30%
>30%
If one or more components are missing, then mNAPSI is set to be missing.
PASDAS
PASDAS will be calculated based on the physician global assessment (PhGA), patient 
global assessment (PtGA), SF-36 physical component scale (SF-36PCS), number of 
swollen joints based on a 66 joint count (SW66), number of tender joints based on a 
68 joint count (TEN68), Leeds enthesitis index (0-6), tender dactylitis count (0-20), and 
CRP in mg/L.  Since CRP is collected in mg/dL, the formula has been modified to 
convert this measure to mg/L as such:
PASDAS = (0.18√PhGA) + (0.159√PtGA) – (0.253√SF-36PCS) + (0.101*ln(SW66+1)) + 
(0.048*ln(TEN68+1)) + (0.23*ln(Leeds enthesitis index +1)) + (0.37*ln(tender dactylitis count +1)) + 
(0.102*ln((CRP*10)+1) +2) * 1.5
If one or more components are missing, then PASDAS is set to be missing.
Simplified Disease Activity Index (SDAI)
SDAI will be calculated based on the number of tender (TEN28) and swollen (SW28) 
joint using a 28-joint count, physician global assessment on a 0-10 scale (PhGA), patient 
global assessment on a 0-10 scale (PtGA) and CRP in mg/dL.  Since PhGA and PtGA 
are collected on a 0-100 scale, the formula has been modified to convert these scores to 
a 0-10 scale as such:
SDAI = SW28 +TEN28 +PhGA/10 + PtGA/10 + CRP
If one or more components are missing, then SDAI is set to be missing.
Sharp-van der Heijde Modified Scoring (mTSS) of Radiographs
Erosions are scored on a 0 to 5 scale for the hands and on a 0 to 10 scale for the feet.  
The following 20 locations in each hand will be scored for hand erosions .

4 Distal inter-phalangeal joints (2-5) 

4 Proximal Inter-Phalangeal Joints (2-5) 

5 Metacarpo-Phalangeal Joints (1-5) 


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
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
Inter-Phalangeal Joint of the thumb 

Proximal first Metacarpal Bone 

Radius Bone 

Ulnar Bone 

Trapezium and Trapezoid (as one unit; multangular) 

Navicular Bone 

Lunate Bone 
The following 6 locations in each foot will be scored for foot erosions : 

5 Metatarso-phalangeal joints (1-5) 

Inter-phalangeal joint of the great toe 
The maximum score per joint is 10, with a maximum of 5 at each side of the joint. There 
is a maximum of two large, middle line passing erosions per joint in the foot (in the hand, 
technically only one is allowed as a score of six (6) is not permitted). Likewise, a 
maximum of 4 large erosions not passing the middle line is permitted (five ‘2s’ to achieve 
a score of 10 is not feasible). Thus, the maximum erosion score (ES) in the hands/wrist 
is 200 and in the feet 120.  
Joint space narrowing (JSN) is scored on a scale of 0 to 4 for hands and feet resulting in 
a maximum JSN score of 160 and 48, respectively. The following 20 joints in each hand 
and 6 joints in each foot will be scored for JSN:
Hand Joints:

4 Distal inter-phalangeal joints (2-5)

5 Metacarpo-phalangeal joints (1-5) 

4 Proximal inter-phalangeal joints (2-5) 

3 Carpo-metacarpal joints (3-5) 

Interphalangeal Joint of thumb (IP) 

Radio-carpal joint 

Multangular-navicular joint 

Capitate-navicular-lunate joint 
Foot Joints: 

5 Metatarso-phalangeal joints 

Inter-phalangeal joint of great toe 


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
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To obtain the total mTSS to identify cases requiring adjudication, scores for erosions and 
Joint Space Narrowing (JSN) in both the hands and feet will be added together. Any “P” 
or “G” will be considered the maximal score for the feature (erosions and JSN) per 
location in the calculation of the total mTSS. Any “N” or “S” will be considered null in the 
calculation of the total mTSS. The range of scores is summarized below.
Parameter
hands/wrists
feet
Total      
(hands + feet)
ES range
40 joints * 5 score = 0-200
12 joints * 10 score = 0- 120
0-320
JSN range
40 joints * 4 score =0- 160
12 joints * 4 score = 0-48
0-208
mTSS range
0-360
0-168
0-528
In addition, since the radiographs will be read at a central location by two independent 
readers and possibly an adjudicator, calculate the score using the following rules:

Use the scores from adjudicator where available. If adjudicator results are present for 
one subject at any time point, then use adjudicator results for the same subject at all 
time points and ignore the results from either reader 1 or reader 2. 

Use the mean of the scores from 2 readers if both are non-missing when adjudicator 
scores are unavailable. 

Use the non-missing score from the reader if the score from the other reader is 
missing, and adjudicator scores are unavailable

Set to missing if both scores from 2 readers are missing and no adjudicator scores 
are available
Swollen Joint Count
The swollen joint count is an assessment of the swelling of joints using 0-1 point scale 
(0 = none, 1 = present).  The total swollen joint count is calculated by summing the 
number of joints with present swelling.  If a joint has been replaced, fused, fractured or 
receives an intra-articular steroid injection, it will be counted as swollen at all visits
subsequent to the replacement or injection.  


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
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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)
Shoulders (n=2)
Metacarpophalangeal joints (MCP) (n=10)
Elbows (n=2)
Proximal interphalangeal joints (Fingers PIP)
(n=10)
Wrists (n=2)
Knees (n=2)
If at least half but not all joints are evaluable (33 for the 66 joint count or 14 for the 28 joint count), then the 
prorated swollen joint count will be calculated.  The prorated score will be adjusted based upon the number 
of evaluable joints: the counted score will be multiplied by 66 or 28 as applicable and divided by the number 
of joints evaluated.  Otherwise, the number of swollen joints is missing.
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).  The total tender joint count is calculated by 
summing the number of joints with present tenderness.  If a joint has been replaced, 
fused, fractured or receives an intra-articular steroid injection, it will be counted as tender 
at all visits subsequent to the replacement or injection.  


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
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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)
Shoulders (n=2)
Metacarpophalangeal joints (MCP) (n=10)
Elbows (n=2)
Proximal interphalangeal joints (Fingers 
PIP) (n=10)
Wrists (n=2)
Knees (n=2)
If at least half but not all joints are evaluable (34 for the 68 joint count or 14 for the 28 joint count), then the 
prorated tender joint count will be calculated.  The prorated score will be adjusted based upon the number of 
evaluable joints: the counted score will be multiplied by 68 or 28 as applicable and divided by the number of 
joints evaluated.  Otherwise, the number of tender joints is missing.


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
Page 53
Appendix B.  Code Fragments
CCI


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
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CCI


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
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CCI


Product:  Etanercept
Statistical Analysis Plan:  20130207
Dated: 06 June 2018
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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 4.0 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
-