Conditions: Arthritis, Rheumatoid; Arthritis, Psoriatic
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 111
Healthy volunteers: no

Brief summary:
The primary objective was to assess the injection site pain associated with the new formulation of etanercept compared with commercial etanercept in adults with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) as measured by a visual analog scale (VAS).

Detailed description:
This is a phase 3b, multicenter, randomized, double-blind, 2-period, 2-sequence crossover study in adults with RA or PsA who are naive to etanercept. The study will evaluate injection site pain associated with the commercial formulation of etanercept and the new formulation of etanercept immediately after injection of each formulation.The study will consist of a screening period of up to 14 days, a 2 week treatment period with a 30 day post treatment safety follow-up. Each dose will follow the recommended label dosing for adults with RA and PsA: 50 mg weekly (scheduled approximately 7 days apart).

Arms:
arm 1: Participants received a single 50 mg subcutaneous (SC) dose of the commercial formulation etanercept in a prefilled SureClick autoinjector on day 1 (Treatment A) followed by a single 50 mg SC dose of the new formulation of etanercept in a prefilled SureClick autoinjector on day 8 (Treatment B). arm 2: Participants received a single 50 mg SC dose of the new formulation of etanercept in a prefilled SureClick autoinjector on day 1 (Treatment B) followed by a single 50 mg SC dose of the commercial formulation etanercept in a prefilled SureClick autoinjector on day 8 (Treatment A).

Interventions: intervention 1: Commercial Formulation Etanercept intervention 2: New Formulation Etanercept
Intervention descriptions: intervention 1: Etanercept was supplied in a single-use SureClick autoinjector as a sterile, preservative-free solution for SC injection containing 0.98 mL of 50 mg/mL etanercept in the commercial formulation. intervention 2: Etanercept was supplied in a single-use SureClick autoinjector as a sterile, preservative-free solution for SC injection containing 0.98 mL of 50 mg/mL etanercept in the new formulation.

Protocol document:
Prot_000.pdf: 
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Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 2 of 65 
Investigator’s Agreement 
I have read the attached protocol entitled A Multicenter, Randomized, Double-blind, 
Crossover Study to Assess the Injection Site Pain Associated With a Modified 
Etanercept Formulation in Adult Subjects With Either Rheumatoid Arthritis or Psoriatic 
Arthritis, dated 30 March 2017, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my sub investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 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) 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 3 of 65 
Protocol Synopsis 
Title:  A Multicenter, Randomized, Double-blind, Crossover Study to Assess the Injection Site 
Pain Associated With a Modified Etanercept Formulation in Adult Subjects With Either 
Rheumatoid Arthritis or Psoriatic Arthritis 
Study Phase:  3b 
Indication:  Rheumatoid Arthritis (RA) or Psoriatic Arthritis (PsA) 
Primary Objective:   
• 
To assess the injection site pain associated with a modified formulation of etanercept 
compared to the currently marketed etanercept in adult subjects with either rheumatoid 
arthritis (RA) or psoriatic arthritis (PsA) as measured by a visual analog scale (VAS)  
Secondary Objective:   
• 
To describe the injection site pain by disease indication 
Safety Objective:   
• 
To evaluate the safety of etanercept 
Hypotheses:  The primary hypothesis of this study is that the modified etanercept formulation will 
be associated with less injection site pain compared to the currently marketed etanercept 
formulation. 
Primary Endpoint:   
• 
Change in injection site pain score between the current formulation and the modified 
formulation as measured by the VAS 
Safety Endpoints:   
• 
Adverse events 
Study Design:  This is a phase 3b, multicenter, randomized, double-blind, 2-period, 2-sequence 
crossover study in subjects with RA or PsA who are naive to etanercept.  The study will evaluate 
injection site pain associated with the current formulation of etanercept and the modified 
formulation of etanercept immediately after injection of each formulation. 
Subjects will be randomized in a 1:1 ratio to receive each etanercept formulation in 1 of 
2 crossover treatment sequences.  Subjects randomized to the first treatment sequence 
(ie, sequence AB) will receive 1 dose of the current formulation during the first study period 
(ie, treatment A), followed by a second visit 1 week later during the second study period at which 
time subjects will receive 1 dose of the modified formulation (ie, treatment B).  Subjects 
randomized to the second treatment sequence will undergo the same procedures but will receive 
investigational product in the opposite order (ie, sequence BA).  Subjects who dropout after the 
first injection will not be replaced by new subjects.  At each study visit, subjects will inject the 
blinded treatment and immediately (ie, within 30 seconds of injection) record the associated 
injection site pain using the VAS.  A total of 112 subjects will be enrolled with 56 subjects in each 
treatment sequence, stratified by disease indication (RA or PsA).  A minimum of 20 PsA subjects 
will be enrolled. 
After study completion subjects may continue with commercially available etanercept.  The study 
will consist of a screening period of up to 14 days, a treatment period of 2 weeks, and a 30-day 
safety follow-up period. 
Sample Size:  The proposed sample size of 112 (ie, 56 per sequence treatment arm with at least 
10 subjects with PsA) would provide approximately 53 subjects for each sequence treatment arm 
at the completion of the study, assuming an early termination or dropout rate of 5% for each 
sequence treatment arm over the course of the study. 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 4 of 65 
Summary of Subject Eligibility Criteria:   
• 
Male or female subject is ≥ 18 years of age at time of signing the informed consent form.  
• 
Subject has a diagnosis of RA or PsA and indicated for treatment with etanercept per the 
current label, based on investigator judgment. 
• 
Subject is naïve to etanercept. 
For a full list of eligibility criteria, please refer to Section 4.1.  
Investigational Product 
Amgen Investigational Product Dosage and Administration:  All injections of etanercept will 
be administered by the subject as a subcutaneous injection at the study site on the scheduled 
dose day.  The subject must demonstrate to the site staff that he or she is competent to correctly 
administer the subcutaneous doses.  Supplies of etanercept will be dispensed to subjects during 
the study visit.   
Each dose of etanercept will consist of the complete contents of 1 SureClick autoinjector.  If the 
first injection site occurs on the thigh, the second injection site should be performed on the 
contralateral limb.  If the injection occurs in the abdomen, the first injection should be on either 
the right or left half of the abdomen with the second injection occurring on the opposite side of the 
abdomen.  Each dose will follow the recommended label dosing for subjects with RA and PsA: 
50 mg weekly (scheduled approximately 7 days apart).  Throughout the entire study, 
administration of etanercept should occur on the scheduled day; however, if unavoidable, it may 
be given earlier or later as long as the dose is not within 3 days of the previous or next scheduled 
dose.  If the dosing window is missed, that dose should be skipped.  Etanercept is to be taken the 
day of a study visit in the presence of the investigator or designee. 
Procedures:  At specified time points outlined in the Schedule of Assessments subjects will 
undergo the following procedures: collection of informed consent form, medical/medication 
history, demographics, physical examination, height, weight, vital signs, and chest x-ray (if 
needed).  Subjects will provide samples for hematology, blood chemistry, hepatitis B and 
C serologies, and tuberculosis testing.  Females of childbearing potential will provide serum and 
urine pregnancy tests.  Research staff will document the use of concomitant medications and all 
adverse events reported by the subject.  Thirty days (+ 7 days) after the last dose of etanercept, 
subjects will undergo a safety follow-up visit.  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 set will include all subjects who received the 
dose of investigational product during each study period and who completed the injection site 
pain score during each study period.  The primary endpoint will be evaluated based on this 
primary analysis set. 
The safety analysis set will include all subjects who received at least 1 dose of investigational 
product during the study.  All safety endpoints will be evaluated using the safety analysis set. 
Analysis of covariance will be used to compare the difference in injection site pain score within 
subjects receiving etanercept in the currently marketed formulation and in the modified 
formulation, with the disease indication (RA or PsA) and the treatment as factors, adjusting for 
period effect and sequence effect. 
Descriptive statistics for continuous variables, consists of number of observations, mean, 
standard error and/or standard deviation, median, 25th percentile (Q1), 75th percentile (Q3), 
minimum, maximum, and for categorical variables, the number of observations, frequency, and 
percentage will be presented.  Subject disposition, demographics, baseline characteristics, and 
safety information will be summarized.  There will be no adjustment for multiplicity and no 
imputation techniques for missing values.  All analyses will be based on observed data. 
For a full description of statistical analysis methods, please refer to Section 10. 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 5 of 65 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 5.0, 20 March 2015 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 6 of 65 
Study Design and Treatment Schema 
 
Abbreviations: QW = every week. 
 
N = 56 
N = 56 
CONFIDENTIAL 
 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 7 of 65 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CRF 
Case Report Form 
DILI 
drug-induced liver injury  
EDC 
electronic data capture 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End-of-Study (end of 
study) 
defined as  when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject completes 
safety follow-up) 
End of Study (primary 
completion) 
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
analysis (ie, last subject completes Study Visit 2) 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.   
Interactive Web 
Response (IWR) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information.   
IRB 
institutional review board 
PGA 
Physician Global Assessment 
PPD 
purified protein derivative 
PsA 
psoriatic arthritis 
PsO 
psoriasis 
RA 
rheumatoid arthritis 
SD 
standard deviation 
Page 1 of 2 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 8 of 65 
Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study.  Source data are 
contained in source documents (original records or certified copies).  
(ICH Guideline (E6)).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
TNF 
tumor necrosis factor 
TNFβ 
tumor necrosis factor beta 
ULN 
Upper limit of normal 
US 
United States 
VAS 
visual analog scale 
Page 2 of 2 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 9 of 65 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 13 
1.1 
Primary ..................................................................................................... 13 
1.2 
Secondary ................................................................................................. 13 
1.3 
Safety ........................................................................................................ 13 
2. 
BACKGROUND AND RATIONALE ...................................................................... 13 
2.1 
Disease ..................................................................................................... 13 
2.2 
Amgen Investigational Product Background .............................................. 13 
2.3 
Rationale ................................................................................................... 14 
2.4 
Clinical Hypotheses ................................................................................... 15 
3. 
EXPERIMENTAL PLAN ........................................................................................ 15 
3.1 
Study Design ............................................................................................. 15 
3.2 
Number of Sites ........................................................................................ 16 
3.3 
Number of Subjects ................................................................................... 16 
3.4 
Replacement of Subjects .......................................................................... 16 
3.5 
Estimated Study Duration .......................................................................... 17 
3.5.1 
Study Duration for Subjects ....................................................... 17 
3.5.2 
End-of-Study ............................................................................. 17 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 17 
4.1 
Inclusion and Exclusion Criteria ................................................................ 17 
4.1.1 
Inclusion Criteria ........................................................................ 17 
4.1.2 
Exclusion Criteria ...................................................................... 17 
5. 
SUBJECT ENROLLMENT .................................................................................... 21 
5.1 
Randomization/Treatment Assignment ...................................................... 22 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 22 
6. 
TREATMENT PROCEDURES .............................................................................. 22 
6.1 
Classification of Products and/or Medical Devices .................................... 22 
6.2 
Investigational Product .............................................................................. 23 
6.2.1 
Amgen Investigational Product Etanercept ................................ 23 
6.2.1.1 
Dosage, Administration, and Schedule .................... 23 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 23 
6.3.1 
Criteria for Permanent Discontinuation of Etanercept 
Due to Potential Hepatotoxicity ................................................. 24 
6.3.2 
Criteria for Conditional Withholding of Etanercept due 
to Potential Hepatotoxicity ......................................................... 25 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 10 of 65 
6.3.3 
Criteria for Rechallenge of Etanercept After Potential 
Hepatotoxicity............................................................................ 25 
6.4 
Concomitant Therapy ................................................................................ 26 
6.5 
Medical Devices ........................................................................................ 26 
6.6 
Product Complaints ................................................................................... 26 
6.7 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 27 
6.8 
Contraceptive Requirements ..................................................................... 27 
6.8.1 
Female Subjects ........................................................................ 27 
6.8.2 
Unacceptable Methods of Birth Control for Male and 
Female Subjects ....................................................................... 28 
7. 
STUDY PROCEDURES ....................................................................................... 28 
7.1 
Schedule of Assessments ......................................................................... 28 
7.2 
General Study Procedures ........................................................................ 31 
7.2.1 
Screening Period ....................................................................... 31 
7.2.2 
Re-screening ............................................................................. 31 
7.2.3 
Treatment Period ....................................................................... 31 
7.2.4 
Safety Follow-up/End-of-Study .................................................. 32 
7.3 
Description of Study Procedures ............................................................... 32 
7.3.1 
Informed Consent ...................................................................... 32 
7.3.2 
Demographic Data..................................................................... 32 
7.3.3 
Medical History .......................................................................... 32 
7.3.4 
Medication History ..................................................................... 32 
7.3.5 
Physical Examination ................................................................ 32 
7.3.6 
Physical Measurements ............................................................ 33 
7.3.7 
Vital Signs ................................................................................. 33 
7.3.8 
Chest Radiograph ..................................................................... 33 
7.3.9 
Adverse Events and Serious Adverse Events ............................ 33 
7.3.10 
Concomitant Medications .......................................................... 33 
7.3.11 
Injection Site Pain Score ........................................................... 33 
7.3.12 
Physician Global Assessment of Disease Activity 
(PGA) ........................................................................................ 34 
7.3.13 
Laboratory Assessments ........................................................... 34 
7.3.14 
Tuberculosis Testing ................................................................. 35 
7.3.14.1 
Purified Protein Derivative (PPD) ............................ 35 
7.3.14.2 
Quantiferon ............................................................. 35 
7.3.15 
Urine Pregnancy Test ................................................................ 36 
7.3.16 
Hepatitis B and C Status ........................................................... 36 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 36 
8.1 
Subjects’ Decision to Withdraw ................................................................. 36 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 37 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 11 of 65 
8.3 
Reasons for Removal From Treatment or Study ....................................... 37 
8.3.1 
Reasons for Removal From Treatment ...................................... 37 
8.3.2 
Reasons for Removal From Study ............................................. 37 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 37 
9.1 
Definition of Safety Events ........................................................................ 37 
9.1.1 
Adverse Events ......................................................................... 37 
9.1.2 
Serious Adverse Events ............................................................ 38 
9.2 
Safety Event Reporting Procedures .......................................................... 39 
9.2.1 
Adverse Events ......................................................................... 39 
9.2.1.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 39 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 40 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 41 
9.2.1.4 
Serious Adverse Events That Are Not To 
Be Reported By The Sponsors To 
Regulatory Agencies In An Expedited 
Manner .................................................................... 42 
9.3 
Pregnancy and Lactation Reporting .......................................................... 42 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 43 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 43 
10.1.1 
Study Endpoints ........................................................................ 43 
10.1.1.1 
Primary Endpoint ..................................................... 43 
10.1.1.2 
Safety Endpoints ..................................................... 43 
10.1.2 
Analysis Sets ............................................................................. 43 
10.1.3 
Covariates and Subgroups ........................................................ 43 
10.1.4 
Handling of Missing and Incomplete Data .................................. 43 
10.2 
Sample Size Considerations ..................................................................... 43 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 44 
10.4 
Planned Analyses ..................................................................................... 45 
10.4.1 
Primary Analyses ...................................................................... 45 
10.5 
Planned Methods of Analysis .................................................................... 45 
10.5.1 
General Considerations ............................................................. 45 
10.5.2 
Primary Efficacy Endpoint .......................................................... 45 
10.5.3 
Safety Endpoints ....................................................................... 46 
11. 
REGULATORY OBLIGATIONS ............................................................................ 46 
11.1 
Informed Consent ...................................................................................... 46 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 47 
11.3 
Subject Confidentiality ............................................................................... 47 
11.4 
Investigator Signatory Obligations ............................................................. 48 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 12 of 65 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 48 
12.1 
Protocol Amendments and Study Termination .......................................... 48 
12.2 
Study Documentation and Archive ............................................................ 48 
12.3 
Study Monitoring and Data Collection ....................................................... 49 
12.4 
Investigator Responsibilities for Data Collection ........................................ 50 
12.5 
Language .................................................................................................. 51 
12.6 
Publication Policy ...................................................................................... 51 
12.7 
Compensation ........................................................................................... 52 
13. 
REFERENCES ..................................................................................................... 53 
14. 
APPENDICES ...................................................................................................... 54 
List of Tables 
Table 1.  Schedule of Assessments ............................................................................... 29 
Table 2.  Laboratory Analyte Listing .............................................................................. 35 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 55 
Appendix B.  Electronic Serious Event Contingency Form ............................................. 57 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 62 
Appendix D.  Subject Injection Site Pain Perception Assessment (English 
Version) .................................................................................................. 64 
Appendix E.  Subject Injection Site Pain Perception Assessment (Spanish 
Version) .................................................................................................. 65 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 13 of 65 
1. 
OBJECTIVES 
1.1 
Primary 
• 
To assess the injection site pain associated with a modified formulation of 
etanercept compared to the currently marketed etanercept in adult subjects with 
either rheumatoid arthritis (RA) or psoriatic arthritis (PsA) as measured by a 
visual analog scale (VAS) 
1.2 
Secondary 
• 
To describe the injection site pain by disease indication 
1.3 
Safety 
• 
To evaluate the safety of etanercept 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Rheumatoid arthritis is a chronic, systemic, autoimmune, inflammatory arthropathy of 
unknown etiology.  Symptoms include joint stiffness, pain, and swelling that can 
progress to deformities and loss of function of both small and large joints.  Rheumatoid 
arthritis occurs worldwide in approximately 1% of adults of all races.  Disease onset 
occurs most often between the ages 20 and 60 years, with peak occurrences at 40 to 
45 years.  The prevalence of RA increases with age in both sexes, and prevalence is 
higher in women than men, with a ratio of approximately 2.5 (Alamanos et al, 2006). 
PsA is a chronic inflammatory disorder of the peripheral joints and axial skeleton that 
occurs in 7% to 34% of patients with psoriasis ([PsO] 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 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 PsO, PsA 
can present without skin changes.  Radiographic features include joint erosions, joint 
space loss, osteolysis that may cause penciling of the phalanx, and periostitis.  Psoriatic 
arthritis can lead to permanent destruction of joints and functional disabilities. 
2.2 
Amgen Investigational Product 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 RA 
and PsO.  Elevated levels of TNF alpha (α) are found in involved tissues and fluids of 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 14 of 65 
patients with RA, PsA, ankylosing spondylitis, and PsO.  Two distinct receptors for TNF, 
a 55-kilodalton protein and a 75-kilodalton protein, 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 extracellular ligand-binding 
portion of the human 75-kilodalton TNF receptor linked to the Fc portion of human 
immunoglobulin G1.  Etanercept inhibits binding of TNFα and TNF beta ([β] lymphotoxin 
alpha ) to cell surface TNF receptors, rendering TNF biologically inactive.  In the United 
States (US) and Canada, etanercept is currently indicated for the treatment of:  
1) moderately to severely active RA, alone or in combination with methotrexate; 
2) moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 
2 and older in the US and 4 to 17 years in Canada; 3) PsA alone or in combination with 
methotrexate; 4) active ankylosing spondylitis; and 5) adult patients with chronic 
moderate to severe plaque PsO who are candidates for systemic therapy or 
phototherapy. 
Refer to the specific section of the Etanercept Investigators’ Brochure, or the product 
label for additional information related to the physical, chemical, and pharmaceutical 
properties and formulation(s). 
2.3 
Rationale 
Injection-related pain can often contribute to the poor compliance of drug administration.  
It is believed that route of administration, physical and chemical attributes of injected 
drug products, and the physical attributes of needles used to administer these drugs play 
a role in injection pain associated with drug administration (Flanagan et al, 2007; 
Laursen et al, 2006; Palmon et al, 1998; Robb and Kanji, 2002).  Alleviation of injection 
site pain can occur through modification of the solution composition.  An etanercept 
modified formulation with minor excipient changes has been developed in an attempt to 
reduce the injection site pain related to its administration.  The modified etanercept 
50 mg/mL liquid formulation designed for use in this study is similar to the currently 
marketed etanercept product and has been shown in a single dose study to reduce 
injection-related pain.  This study is designed to investigate the injection site pain of the 
modified formulation in comparison with currently marketed formulation of etanercept.   
This will be a multicenter, randomized, double-blind, 2-sequence, 2-period crossover 
study to assess the injection site pain associated with the etanercept modified 
formulation in RA and PsA subjects naïve to etanercept.  Injection site pain will be 
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measured by a 100 mm VAS specifically designed to query these data.  The VAS scores 
will be collected immediately (ie, within 30 seconds after injection) after subcutaneous 
administration to assess injection site pain.  A difference of 13 to 16 mm on the VAS is 
considered to be clinically meaningful (Gallagher et al, 2002) in a setting of acute pain.  
Both internal and published data on clinicaltrials.gov have demonstrated that patients 
with RA, in general, report injection site pain with lower intensity as compared to healthy 
volunteers.  RA and PsA were the indications chosen for this study as prior studies with 
this formulation were in healthy volunteers.  These are of the most common indications 
for which etanercept is prescribed.  These populations use the same dosing interval of 
etanercept, which allows them both to be included in this study.  Additionally, including 
both populations allows the results of this study to be applied in a broader context for the 
medical community. 
Prior internal studies have demonstrated that attenuation of the injection site pain 
response occurs with repeated injection of investigational product.  This study will collect 
data using 2 doses in a crossover design.  This will leverage the efficiencies afforded by 
the cross over while minimizing the effects of long term attenuation.   
These subjects are candidates for initiating etanercept for sustained treatment and will 
be able to initiate dosing in this study and then continue with commercially available 
etanercept treatment after completing the study.  This is anticipated to mitigate the 
potential challenges with enrollment. 
2.4 
Clinical Hypotheses 
The primary hypothesis of this study is that the modified etanercept formulation will be 
associated with less injection site pain compared to the currently marketed etanercept 
formulation. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
This is a phase 3b, multicenter, randomized, double-blind, 2-period, 2-sequence 
crossover study in subjects with RA or PsA who are naive to etanercept.  The study will 
evaluate injection site pain associated with the current formulation of etanercept and the 
modified formulation of etanercept immediately after injection of each formulation. 
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Subjects will be randomized in a 1:1 ratio to receive each etanercept formulation in 1 of 
2 crossover treatment sequences.  Subjects randomized to the first treatment sequence 
(ie, sequence AB) will receive 1 dose of the current formulation (ie, treatment A) during 
the first study period, followed by a second visit 1 week later during the second study 
period at which time subjects will receive 1 dose of the modified formulation 
(ie, treatment B).  Subjects randomized to the second treatment sequence will undergo 
the same procedures but will receive investigational product in the opposite order 
(ie, sequence BA).  At each study visit subjects will inject the blinded treatment and 
immediately (ie, within 30 seconds of injection) record the associated injection site pain 
using the VAS.  A total of 112 subjects will be enrolled with 56 subjects in each 
treatment sequence, stratified by disease indication (RA or PsA).  A minimum of 20 PsA 
subjects will be enrolled. 
After study completion subjects may continue with commercially available etanercept.  
The study will consist of a screening period of up to 14 days, a treatment period of 
2 weeks and a 30-day safety follow-up period.  
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 30 sites in the US will participate in this study.  
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”. 
A total of 112 subjects are expected to enroll in this study with 56 subjects in each 
treatment sequence.  Subjects will be randomly assigned in a blinded manner to 1 of 
2 crossover sequences.  The sample size accounts for 5% withdrawal or dropout.  
Refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects who withdraw or removed from the study will not be replaced.  Subjects who 
dropout after the first injection will not be replaced by new subjects. 
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3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
After signing the informed consent, subjects should be enrolled within 14 days.  The 
planned length of participation in the study for an individual a subject is as follows: 
• 
Up to a 14 day screening period 
• 
2-week treatment period 
• 
30 day post treatment safety follow-up 
3.5.2 
End-of-Study 
Primary Completion:  The time when the last subject is assessed for the purposes of 
final collection of data for the primary analysis (ie, last subject completes Study Visit 2).  
End-of-Study:  The time when the last subject is assessed for evaluation in the study 
(ie, last subject completes safety follow-up). 
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).  This log may be completed and updated via an Interactive Voice Response 
(IVR)/Interactive Web Response (IWR) system.   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion and Exclusion Criteria  
4.1.1 
Inclusion Criteria  
101 
Subject has provided informed consent before initiation of any study-specific 
activities/procedures 
102 
Male or female subject is ≥ 18 years of age at time of signing the informed 
consent form 
103 
Subject has a diagnosis of RA or PsA and indicated for treatment with etanercept 
per the current label, based on investigator judgment 
104 
Subject is naïve to etanercept   
105 
Subject is able to self-inject etanercept 
4.1.2 
Exclusion Criteria  
RA Related 
201 
Subject is diagnosed with Felty’s syndrome (RA, splenomegaly and 
granulocytopenia) 
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Skin Disease Related 
202 
Subject has active erythrodermic, pustular, guttate PsO, or medication induced 
PsO, or other skin conditions at the time of screening visit (eg, eczema) that 
would interfere with evaluations of the effect of investigational product on PsO for 
those subjects with PsA 
Other Medical Conditions 
203 
Subject has a history of clinically significant skin allergies (eg, frequent rashes) 
204 
Subject has a history of alcoholic hepatitis, nonalcoholic steatohepatitis, or 
immunodeficiency syndromes, including Human Immunodeficiency Virus 
infection 
205 
Subject has any active infection (including chronic or localized infections) for 
which anti-infectives were indicated within 4 weeks before screening 
206 
Subject has had a serious infection, defined as requiring hospitalization or 
intravenous anti-infectives within 8 weeks before first dose of investigational 
product 
207 
Subject had a prosthetic joint infection within 5 years of screening or native joint 
infection within 1 year of screening. 
208 
Subject has known alcohol addiction or dependency, uses alcohol daily, or has 
current substance use or abuse. 
209 
Subject has positive hepatitis B surface antigen, hepatitis B core antibody 
(confirmed by hepatitis B DNA test) or hepatitis C virus antibody serology at 
screening, or a positive medical history for hepatitis B or C. (Subjects with a 
history of hepatitis B vaccination without history of hepatitis B are allowed to 
enroll) 
210 
Subject has any active malignancy, including evidence of cutaneous basal, 
squamous cell carcinoma, or melanoma. 
211 
Subject has a history of malignancy within the last 5 years EXCEPT for cases 
that have been treated and considered cured specifically involving cutaneous 
basal or squamous cell carcinoma (non-melanoma skin cancers), cervical 
carcinoma in situ or breast ductal carcinoma in situ  
212 
Subject has known history of active tuberculosis 
213 
Subject has a positive test for tuberculosis during screening defined as either: 
• 
positive purified protein derivative ([PPD] ≥ 5 mm of induration at 48 to 72 hours 
after test is placed) 
OR 
• 
positive Quantiferon test 
• 
Subjects with a positive PPD and a history of Bacillus 
Calmette-Guérin vaccination are allowed with a negative Quantiferon 
test. 
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• 
Subjects with a positive PPD test (without a history of Bacillus 
Calmette-Guérin vaccination) or subjects with a positive or 
indeterminate Quantiferon test are allowed if they have ALL of the 
following: 
 
no symptoms per tuberculosis worksheet provided by Amgen 
 
documented history of a completed course of adequate 
prophylaxis (completed treatment for latent tuberculosis) per 
local standard of care before the start of investigational 
product 
 
no known exposure to a case of active tuberculosis after most 
recent prophylaxis 
214 
Subject has 1 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 
before randomization 
• 
uncontrolled hypertension 
• 
severe chronic pulmonary disease (eg, requiring oxygen therapy) 
• 
multiple sclerosis or any other demyelinating disease 
• 
major chronic inflammatory disease or connective tissue disease other than RA 
or PsA (eg, fibromyalgia, systemic lupus erythematosus with the exception of 
secondary Sjögren’s syndrome, etc.) 
Excluded Medications 
215 
Subject has used biologic disease modifying agent ≤ 3 months before screening 
216 
If subject is receiving continuous treatment with acetaminophen, non-steroidal 
anti-inflammatory drug or tramadol, hydrocodone, oxycodone, codeine, and/or 
propoxyphene and the dose is within 4 hours before study visit and dose is not 
stable for ≥ 2 weeks before first dose of investigational product 
217 
For subjects not on continuous analgesics, subject has taken the following within 
4 hours before screening:  acetaminophen, non-steroidal anti-inflammatory 
drugs, 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 before screening. 
218 
Subject has received live vaccines ≤ 4 weeks before first dose of investigational 
product 
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Laboratory Abnormalities 
219 
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 (or 125 × 109/L)  
• 
White blood cell count < 3000/mm3 (or 3.0 × 109/L) 
• 
Absolute neutrophil count < 1500/mm3 (1.5 × 109/L) 
220 
Estimated creatinine clearance < 50 mL/min (Cockcroft-Gault formula, calculated 
value to be provided to sites) 
221 
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. 
Other 
222 
Subject is currently receiving treatment in another investigational device or drug 
study, or < 30 days since ending treatment on another investigational device or 
drug study(s). 
223 
Other investigational procedures while participating in this study 
224 
Females who are pregnant or breastfeeding, or planning to become pregnant or 
breastfeed during treatment and/or within 4 weeks after the last dose of 
etanercept 
225 
Females of child-bearing potential with a positive pregnancy test (assessed by a 
serum pregnancy test during screening and a urine pregnancy test at baseline) 
226 
Females of child-bearing potential who are unwilling to practice true sexual 
abstinence (refrain from heterosexual intercourse) or unwilling to use 1 of the 
following effective birth control methods during treatment and for an additional 
4 weeks after the last dose of etanercept (refer to Section 6.8 for specific 
contraception methods and definition of child-bearing potential):  
• 
hormonal contraceptives in pill, implant, injection, or patch form;  
• 
Intrauterine device 
• 
Intrauterine hormonal-releasing system  
• 
bilateral tubal ligation/occlusion  
• 
male partner with confirmed vasectomy on semen analysis  
• 
sexual abstinence 
• 
two barrier method  
227 
Subject previously has enrolled in this study 
228 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
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229 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Patient 
Reported Outcomes) to the best of the subject’s and investigator’s knowledge 
230 
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. 
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).  
Subjects must personally sign and date the IRB/IEC and Amgen approved informed 
consent form before commencement of study-specific activities/procedures.   
Upon completion of the screening period the subject is evaluated by the investigator and 
providing the subject continues to meet the inclusion/exclusion criteria, the subject is 
subsequently eligible to be enrolled in the study and either randomized or assigned to a 
treatment regimen. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the 14-day screening period for the study receives a 
unique subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned by IVR/IWR.  This 
number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject.  This number will not necessarily 
be the same as the randomization number assigned for the study.  If a subject has not 
met all eligibility criteria at the end of the 14-day window, the subject will be registered as 
a screen fail.  Screen failed subjects may be eligible for re-screening once. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
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5.1 
Randomization/Treatment Assignment 
Subjects will be randomized in a 1:1 ratio to receive each etanercept formulation in 1 of 
2 crossover treatment sequences and will be stratified by indication.  Subjects 
randomized to the first treatment sequence (ie, sequence AB) will receive 1 dose of the 
current formulation (ie, treatment A) during the first study period, followed by a second 
visit 1, week later during the second study period at which time subjects will receive 
1 dose of the modified formulation (ie, treatment B).  Subjects randomized to the second 
treatment sequence will undergo the same procedures but will receive investigational 
product in the opposite order (ie, sequence BA).  At each study visit, subjects will inject 
the blinded treatment and immediately (ie, within 30 seconds of injection) record the 
associated injection site pain using the VAS.   
The randomization will be performed via IVR/IWR system on-study day 1.   
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.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The investigator is strongly encouraged to contact the Amgen Clinical Trial Manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event (ie, unblinding).   
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products and/or Medical Devices 
The Amgen Investigational Products used in this study includes  etanercept and 
SureClick auto injector device.   
Note:  Non-investigational medical device(s) (ie, medical device[s]not under study) or 
products will be described in Section 6.5. 
The Investigational Product Instruction Manual, a document external to this protocol, 
contains detailed information regarding the storage, preparation, destruction, and 
administration of etanercept.  
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6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product Etanercept 
Etanercept will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.  The solution of etanercept is clear 
and colorless.  Etanercept will be supplied in a single-use SureClick autoinjector as a 
sterile, preservative-free solution for subcutaneous injection.  Each single-use SureClick 
autoinjector contains 0.98 mL of 50 mg/mL etanercept in either the currently marketed 
formulation (Treatment A) or a modified formulation (Treatment B). 
6.2.1.1 
Dosage, Administration, and Schedule 
All injections of etanercept will be administered by the subject as a subcutaneous 
injection at the study site on the scheduled dose day.  The subject must demonstrate to 
the site staff that he or she is competent to correctly administer the subcutaneous doses.  
Supplies of etanercept will be dispensed to subjects during the study visit.   
Each dose of etanercept will consist of the complete contents of 1 SureClick 
autoinjector.  If the first injection site occurs on the thigh, the second injection site 
should be performed on the contralateral limb.  If the injection occurs in the abdomen, 
the first injection should be on either the right or left half of the abdomen with the second 
injection occurring on the opposite side of the abdomen.  Each dose will follow the 
recommended label dosing for subjects with RA and PsA: 50 mg weekly (scheduled 
approximately 7 days apart).  Throughout the entire study, administration of etanercept 
should occur on the scheduled day; however, if unavoidable, it may be given earlier or 
later as long as the dose is not within 3 days of the previous or next scheduled dose.  If 
the dosing window is missed, that dose should be skipped.  Etanercept is to be taken the 
day of a study visit in the presence of the investigator or designee. 
The volume (full, partial, or none), dose date, and box number of etanercept are to be 
recorded on each subject’s CRF. 
The effects of overdose of etanercept are not known.  Please refer to the US Prescribing 
Information or the Etanercept Investigator’s Brochure for the most recent safety 
information. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin [TBL]) and/or international normalized ratio (INR) and/or 
signs/symptoms of hepatitis (as described below) may meet the criteria for withholding 
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or permanent discontinuation of Amgen investigational product or other protocol-required 
therapies as specified in the Guidance for Industry Drug-Induced Liver Injury:  
Premarketing Clinical Evaluation, July 2009). 
6.3.1 
Criteria for Permanent Discontinuation of Etanercept Due to 
Potential Hepatotoxicity 
Etanercept should be discontinued permanently and the subject should be followed 
according to the recommendations in Appendix A (Additional Safety Assessment 
Information) for possible drug-induced liver injury (DILI), if ALL of the criteria below are 
met: 
• 
TBL > 2 x ULN or INR > 1.5 
• 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3 × ULN 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− 
hepatobiliary tract disease 
− 
viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus, Herpes Simplex Virus, Varicella, toxoplasmosis, and 
Parvovirus) 
− 
right sided heart failure, hypotension or any cause of hypoxia to the liver 
causing ischemia 
− 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal 
and dietary supplements, plants and mushrooms   
− 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
Syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir) 
− 
alpha-one antitrypsin deficiency 
− 
alcoholic hepatitis 
− 
autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
nonalcoholic Fatty Liver Disease including Steatohepatitis  
− 
non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, the investigator should determine (based on 
subject population and/or severity of the hepatotoxicity or event) if etanercept and other 
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protocol-required therapies should be withheld or permanently discontinued, as deemed 
appropriate for the safety of the subject. 
6.3.2 
Criteria for Conditional Withholding of Etanercept due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of etanercept 
outlined above and have no underlying liver disease, and eligibility criteria requiring 
normal transaminases and TBL at baseline or subjects with underlying liver disease and 
baseline abnormal transaminases, the following rules are recommended for withholding 
of etanercept:  
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation 
Any 
> 8 × ULN at any time 
Any 
> 5 × ULN but < 8 × ULN for ≥ 2 weeks 
Any 
> 5 × ULN but < 8 × ULN and unable to adhere to 
enhanced monitoring schedule 
Any 
> 3 × ULN with clinical signs or symptoms that is 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, and jaundice). 
• 
OR: TBL > 3 × ULN at any time 
• 
OR: ALP > 8 × ULN at any time 
Etanercept should be withheld pending investigation into alternative causes of DILI.  If 
etanercept is withheld, the subject is to be followed according to recommendations in 
Appendix A for possible DILI.  Rechallenge may be considered if an alternative cause for 
impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and the 
laboratory abnormalities resolve to normal or baseline.   
6.3.3 
Criteria for Rechallenge of Etanercept After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then etanercept should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation 
should never be rechallenged. 
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6.4 
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 6.7. 
Concomitant therapies are to be collected from baseline (day 1) through the end of 
treatment. 
For concomitant therapies being taken for RA and PsA, collect therapy name, indication, 
dose, unit, frequency, route, start date, and stop date.  For other medications being 
taken collect therapy name, indication, start date and stop date. 
6.5 
Medical Devices 
The following medical device, SureClick, will be used in this study and provided by 
Amgen.  Additional details for each medical device is to be provided in the 
Investigational Product Instruction Manual.   
6.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Concerns or irregularities about the packaging, appearance or usage of the SureClick or 
other Amgen provided protocol-required product (ie, etanercept) in this study are to be 
reported to Amgen within 24 hours of discovery or notification of the concern or 
irregularity. 
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 Investigational Product Instruction Manual. 
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6.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Subjects are prohibited from receiving the following therapies during Treatment Phase of 
this study: 
• 
Any other investigational agents 
• 
Any commercially available biologic agent for treatment RA or PsA (other than 
investigational product) 
• 
Analgesics including acetaminophen, non-steroidal anti-inflammatory drugs, 
hydrocodone, codeine, tramadol, propoxyphene (within 4 hours of study visit) and/or 
oxycodone (within 24 hours of study visit) 
• 
Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or 
other alkylating agents 
• 
Fumarates 
• 
Hydroxyurea 
• 
Live vaccines (eg, measles, mumps, and rubella; varicella; intranasal flu) 
6.8 
Contraceptive Requirements 
6.8.1 
Female Subjects  
Female subjects of childbearing potential must agree to use an acceptable method of 
contraception during treatment and for an additional 4 weeks after the last dose of 
etanercept.   
Acceptable methods of effective contraception include: Hormonal (Combined estrogen 
and progestogen or progesterone-only hormonal contraception given via oral, 
intravaginal, transdermal, injectable, or implantable route); Intrauterine device; 
Intrauterine hormonal-releasing system; Bilateral tubal occlusion/ligation; Vasectomized 
partner (provided that partner is the sole sexual partner of the female participant who is 
of childbearing potential and that the vasectomized partner has received medical 
assessment of the surgical success); Sexual abstinence (defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence must be evaluated in relation to the 
duration of the trial and the preferred and usual lifestyle of the subject).  Two barrier 
methods (1 by each partner) and the female partner must use spermicide (if spermicide 
is commercially available) with the barrier method the male must use a condom (latex or 
other synthetic material) and the female may select either a diaphragm, cervical cap or 
contraceptive sponge.  A female condom is not an option because there is a risk of 
tearing when both partners use a condom.   
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Females not of childbearing potential are defined as:  Any female who has had a 
hysterectomy, OR bilateral salpingectomy, OR bilateral oophorectomy, OR is 
postmenopausal.  Post-menopausal females are: 
• 
Age > 55 years with cessation of menses for 12 or more months  
• 
Age < 55 years but no spontaneous menses for at least 2 years 
• 
Age < 55 years and spontaneous menses within the past 1 year, but currently 
amenorrheic (eg, spontaneous or secondary to hysterectomy), AND with 
follicle-stimulating hormone levels > 40 IU/L, or postmenopausal estradiol levels 
< 5 ng/dL, or according to the definition of "postmenopausal range" for the laboratory 
involved. 
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.   
6.8.2 
Unacceptable Methods of Birth Control for Male and Female 
Subjects 
Birth control methods that are considered unacceptable in clinical studies include:  
periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method. 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 will 
be performed after obtaining a signed informed consent form.   
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.   
Any missed visits, tests not done, or examinations that are not conducted must be 
reported as such on the CRFs.  Subsequent study visits should resume on the original 
schedule.  Missed assessments at prior visits should not be duplicated at subsequent 
visits. 
7.1 
Schedule of Assessments 
 
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Table 1.  Schedule of Assessments 
 
Screening 
Double-blind Treatment Period 
Safety 
Follow-up/EOS 
Days 
-14 to -1 
1 (± 3 days) 
8 (± 3 days) 
38 (+ 7 days)a 
GENERAL & SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
Demographic data 
X 
 
 
 
Registration via IVR/IWR 
X 
 
 
 
Eligibility criteria 
X 
 
 
 
Medical history 
X 
 
 
 
Medication history 
X 
 
 
 
Concomitant medications 
X 
X 
X 
 
Adverse eventsb 
X 
X 
X 
 
Serious adverse eventsb 
X 
X 
X 
X 
Physical examinationc 
X 
X 
X 
 
Vital signs 
X 
X 
X 
 
Weight 
X 
 
 
 
Height 
X 
 
 
 
Chest x-ray (if needed)d 
X 
 
 
 
LABORATORY ASSESSMENTS 
Serum pregnancy teste 
X 
 
 
 
Pregnancy test (urine)e 
 
X 
 
 
Hematology profile 
X 
 
 
 
Chemistry profile 
X 
 
 
 
Tuberculosis testingf 
X 
 
 
 
Hepatitis B and C serologiesg 
X 
 
 
 
DOSING 
Investigational product dispensation (etanercept) 
 
X 
X 
 
DISEASE ASSESSMENTS 
Physician global assessment of disease activity  
(VAS 0-100) 
X 
X 
X 
 
SUBJECT ASSESSMENTS (Reported Outcomes) 
Injection site pain (VAS 0-100) 
 
X 
X 
 
Footnotes defined on next page. 
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EOS = end-of-study, IVR = interactive voice response, IWR = interactive web response, PPD = purified protein derivative, TNF = tumor necrosis factor, VAS = Visual 
Analog Scale 
a Thirty days (+ 7 days) after their last dose of etanercept, subjects will be contacted by phone by the study staff to follow-up on any continuing serious adverse events 
and inquire about the emergence of any new serious adverse events. 
b Adverse events and serious adverse events are collected from signing the informed consent form.  Adverse device effects are included in the collection of adverse 
events.  Adverse events are collected through the end of treatment period. 
c A full physical examination will be completed at the screening visit.  Subsequent physical examinations will be conducted per standard of care to monitor for any 
changes. 
d Only for subjects with a positive tuberculosis test (ie, positive PPD or positive or indeterminate Quantiferon). 
e For all females, unless at least 2 years postmenopausal or postmenopausal status has been confirmed or history of hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. 
f Subjects will receive either a PPD test or Quantiferon test at screening.  National guidelines should be followed for appropriate tuberculosis screening in the setting of 
anti-TNF therapy.  
g Subjects positive for hepatitis B core antibody may require additional testing for hepatitis B DNA by polymerase chain reaction. 
 
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7.2 
General Study Procedures  
7.2.1 
Screening Period 
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After signing the written 
informed consent form, sites will register the subject in IVRS/IWRS and screen the 
subject in order to assess eligibility for participation.  The screening window is 14 days.  
If a subject has not met all eligibility criteria at the end of the 14-day window, the subject 
will be registered as a screen fail.  Screen fail subjects may be eligible for re-screening 
one time. 
7.2.2 
Re-screening 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen once.  Re-screen subjects must first be registered as screen 
failed in IVRS/IWRS and subsequently registered as re-screened.  Subjects will retain 
the same subject identification number assigned at the original screening.  Once the 
subject is registered as re-screened, a new 14-day screening window will begin.  If the 
re-screening period begins more than 14 days after the original signing of the informed 
consent form, all screening procedures, including informed consent must be repeated.  If 
the re-screening occurs less than 14 days after the original signing of the informed 
consent, then only those criteria that were originally failed are required to be repeated.  
The PPD test, chest x-ray, and Quantiferon will not need to be repeated for re-screen 
subjects if negative at the original screening.  However, subjects screen-failing for and 
not meeting the tuberculosis testing inclusion criterion are not permitted to rescreen. 
7.2.3 
Treatment Period 
Visits will occur per the Schedule of Assessments during the treatment period from 
screening through week 2.  Study visits may be completed within ± 3 days of the target 
visit date.  Prior to enrollment, subject eligibility must be confirmed with screening 
procedures.  Subjects satisfying eligibility requirements will be enrolled.  The date of the 
first dose of investigational product is defined as day 1.  All subsequent doses and study 
visits will be scheduled based on the day 1 date. 
The procedures completed during the 2-week treatment period are those listed in 
Table 1.  Etanercept is to be administered after all assessments have been done for all 
visits with the exception of the VAS subject injection site pain assessment.  
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7.2.4 
Safety Follow-up/End-of-Study 
Thirty  days (+ 7 days) after their last dose of etanercept, subjects will be contacted by 
phone by the study staff to follow-up on any continuing serious adverse events and 
inquire about the emergence of any new serious adverse events. 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures for required 
timepoints. 
7.3.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed. 
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.   
7.3.3 
Medical History 
The investigator or designee will collect a complete medical history from 5 years before 
enrollment through the first dose of etanercept, which will be recorded in the medical 
history CRF.  Medical history will include information on the subject’s concurrent medical 
conditions.  Diagnosis dates for RA or PsA will also be collected. 
7.3.4 
Medication History 
A complete history of RA or PsA medications starting at the time of diagnosis and up to 
screening will be recorded on the CRF.  This information will include medication name, 
indication, dose, unit, frequency, route, start date and stop date.  All other medications 
taken within 3 months before screening will be collected, including medication name, 
indication, dose, unit, frequency, route, start date and stop date. 
7.3.5 
Physical Examination 
The screening physical examination will be a complete physical examination.  Breast, 
genital, and rectal examinations are not required at any study visit unless specific 
evaluation is warranted.  Physical examination findings at screening should be recorded 
in the medical and surgical history CRF.  
The physical examination at subsequent study visits will consist of a musculoskeletal 
examination for RA and PsA subjects along with a skin examination for PsA subjects per 
standard of care.  Examination findings should be recorded on the appropriate CRF 
(eg, medical history, event).  Any clinically significant changes in musculoskeletal or skin 
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examinations throughout the study, per the investigator’s opinion, should be recorded on 
the event CRF. 
7.3.6 
Physical Measurements 
Height should be measured in inches without shoes.  Weight should be measured in 
pounds without shoes. 
7.3.7 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position possible.  The position selected for a subject should be the same 
throughout the study and documented on the vital signs CRF.  The temperature location 
selected for a subject should be the same throughout the study and documented on the 
vital signs CRF.  If abnormalities are found and they are considered an adverse event, 
record on the event summary page. 
7.3.8 
Chest Radiograph 
Subjects with a positive PPD test without a history of Bacillus Calmette-Guerin 
vaccination or subjects with a positive or indeterminate Quantiferon test will require a 
chest radiograph including posterior-anterior and lateral views performed within 
3 months before the first dose of investigational product.  The radiograph report should 
be read by a radiologist or per local requirement and the report must be reviewed by the 
investigator before enrollment of the subject. 
7.3.9 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events observed by the investigator or reported by 
the subject will be collected at all study visits. 
7.3.10 
Concomitant Medications 
Concomitant medications are to be collected from baseline through the treatment period.  
For concomitant medications, collect therapy name, indication, dose, unit, frequency, 
route, start date and stop date.  Concomitant medications include over-the-counter 
products and vitamins administered while the subject is on-study. 
7.3.11 
Injection Site Pain Score 
The injection site pain score is an assessment of the severity of the subject’s injection 
site pain and will be completed by the subject immediately after the administration of the 
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etanercept dose (ie, within 30 seconds) using a VAS (Appendix D [English version or 
Appendix E [Spanish version]).  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 VAS has been specifically designed to capture injection site 
associated pain. 
7.3.12 
Physician Global Assessment of Disease Activity (PGA) 
The global assessment of the subject’s overall RA or PsA disease activity will be 
assessed by the principal investigator or sub investigator for the study by completion of a 
VAS.  The PGA will be completed -at screening, and on day 1 and day 8 before 
investigational product administration.  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.  
7.3.13 
Laboratory Assessments 
All laboratory samples will be processed and sent to the central laboratory with the 
exception of urine pregnancy and PPD, which will be done by the site staff, and 
Quantiferon, which 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, hepatitis C antibody, hepatitis B surface antigen and core antibody, and any 
other laboratory tests required.  The results of this testing will be maintained in the 
source documents at the site.  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, and other testing to be conducted on 
blood and urine samples are listed below.  Although not specifically listed, additional 
components, abnormal, and/or atypical cells will also be reported if present. 
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Table 2.  Laboratory Analyte Listing 
Central Lab  
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 
AST (SGOT) 
ALT (SGPT) 
Central Lab 
Hematology 
RBC 
RBC Morphology 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Neutrophil ANC 
Central Lab 
Other Labs 
Hepatitis B 
surface antigen 
total 
Hepatitis B core 
antibody 
Hepatitis B virus 
DNA by 
polymerase 
chain reaction 
Hepatitis C 
antibody 
Serum beta 
hCGa 
 
Local Lab 
Other Labs 
Urine 
pregnancy 
Local/Central 
Lab 
Other Labs 
Tuberculosis 
testingb 
 
Abbreviations: ALT = alanine aminotransferase, ANC = absolute neutrophil count, AST = aspartate 
aminotransferase, BUN = blood urea nitrogen, hCG = human chorionic gonadotropin, PPD = purified 
protein derivative, RBC = red blood cell, SGOT = serum glutamic oxaloacetic transaminase, 
SGPT = serum glutamic-pyruvic transaminase, WBC = white blood count. 
a All female subjects except those who are confirmed surgically sterile or at least 2 years postmenopausal or 
per the definition in Section 6.8.  
b Subjects must receive either a PPD test or Quantiferon testing at screening. 
7.3.14 
Tuberculosis Testing 
7.3.14.1 
Purified Protein Derivative (PPD) 
All subjects who have never received Bacillus Calmette-Guerin vaccination must receive 
a PPD test before enrollment in the study.  The test must be read by a trained licensed 
healthcare professional 48 to 72 hours after the test material is placed intradermally 
under the skin.  PPD test kits will not be provided by the sponsor and must be procured 
locally. 
7.3.14.2 
Quantiferon 
Subjects with a positive PPD test and a history of Bacillus Calmette-Guerin vaccination 
will require Quantiferon testing.  If testing is performed by central laboratory then refer to 
the central laboratory manual for instructions on sample collection, processing, and 
shipping of samples. 
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7.3.15 
Urine Pregnancy Test 
All females, except those who are confirmed to be of non-childbearing potential (refer to 
Section 6.8 for this criteria), must have a negative urine pregnancy test at day 1, before 
administering the first dose of etanercept.  Urine pregnancy tests will be performed 
locally at each site.  The central laboratory will provide the urine pregnancy tests. 
7.3.16 
Hepatitis B and C Status 
The following should be followed for the determination of hepatitis B and C status: 
• 
if hepatitis B and/or hepatitis C status is known to be positive by serology no 
additional laboratory testing procedures are required 
• 
if hepatitis B and/or hepatitis C status is not known to be positive by serology, the 
following laboratory testing is required: 
o hepatitis B surface antigen  
 
if results are hepatitis B surface antigen positive, no additional 
testing is necessary 
o hepatitis B Core Antibody  
 
if results are hepatitis B core antibody positive but negative for 
hepatitis B surface antigen, additional testing is necessary for 
hepatitis B virus DNA by polymerase chain reaction  
o hepatitis C virus antibody  
• 
if results are hepatitis C virus antibody positive, no additional testing is necessary 
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, device 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, adverse events, disease related events, and device related events, as 
applicable.  The investigator must document the change to the Schedule of 
Assessments (Table 1) and the level of follow-up that is agreed to by the subject (eg, in 
person, by telephone/mail, through family/friends, in correspondence/communication 
with other physicians, from review of the medical records).   
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Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
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, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time before study completion.    
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) 
• 
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 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical study 
subject.  The event does not necessarily have a causal relationship with study treatment.  
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The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on-study, 
is not considered an adverse event.   
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject requests to 
withdraw from protocol-required therapies or the study due to an adverse event, refer to 
Section 8.1 for additional instructions on the procedures recommended for safe 
withdrawal from protocol-required therapies or the study.  All adverse events will be 
summarized as described below based on the safety analysis set, overall, by indication, 
treatment arm, and by period. 
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease related event such as worsening of symptoms of RA or PsA is to be reported 
as a serious adverse event if: 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a subject with the same underlying condition, or 
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• 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
• 
and the event meets at least 1 of the serious criteria. 
All adverse events of malignancies should be classified as serious adverse events. 
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 
Safety Event Reporting Procedures  
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after signing of the informed consent 
form through the end of treatment period are reported using the Event CRF. 
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 etanercept and SureClick device, study 
procedures/study activities, and 
• 
Action taken. 
The adverse event grading scale used will be the Common Toxicity Criteria.  The 
grading scale used in this study is described in Appendix A.  If the severity of an 
adverse event changes from the date of onset to the date of resolution, record as 
a single event with the worst severity on the Event CRF. 
The investigator must assess whether the adverse event is possibly related to the 
etanercept and SureClick device.  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 etanercept and SureClick device?   
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The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last day of the dosing interval or end-of-study, 
whichever is later are recorded in the subject’s medical record and are submitted to 
Amgen.  A shorter or longer safety follow-up interval can be utilized following 
consultation with the Amgen Global Safety Officer and are recorded in the subject’s 
medical record and are submitted to Amgen.  All serious adverse events must be 
submitted to Amgen within 24 hours following the investigator’s knowledge of the event 
via the Event CRF.   
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet /electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the eSerious Adverse Event Contingency Report Form, the data must be entered into 
the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
the etanercept and SureClick device.  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 etanercept and SureClick device? 
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The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and Good 
Clinical Practice (GCP).  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end-of-study.  However, these serious 
adverse events can be reported to Amgen.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical study cases for the purposes of expedited 
reporting.  
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9.2.1.4 
Serious Adverse Events That Are Not To Be Reported By The 
Sponsors To Regulatory Agencies In An Expedited Manner 
The study population involved will have an increased burden of comorbidities, which are 
commonly associated with PsA and RA and may lead to serious adverse events that do 
not need to be reported in an expedited manner.  This includes any serious adverse 
event attributed to worsening of PsA and RA.  These serious adverse events will be 
monitored with routine pharmacovigilance on an ongoing basis. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking etanercept report the pregnancy to Amgen Global Patient Safety as 
specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur 4 weeks after the last dose of etanercept.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.  If a male 
subject's female partner becomes pregnant, the investigator should discuss obtaining 
information regarding the birth outcome and health of the infant from the pregnant 
partner.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur 4 weeks after the last dose of protocol-required therapies.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 43 of 65 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Change in injection site pain score between the current formulation and the 
modified formulation as measured by the VAS  
10.1.1.2 
Safety Endpoints 
• 
Adverse events 
10.1.2 
Analysis Sets 
The primary analysis set will include all subjects who received the dose of investigational 
product during each study period and who completed the injection site pain score during 
each study period.  The primary endpoint will be evaluated based on this primary 
analysis set. 
The safety analysis set will include all subjects who received at least 1 dose of 
investigational product during the study.  All safety endpoints will be evaluated using the 
safety analysis set. 
10.1.3 
Covariates and Subgroups 
The following subgroup analyses will be performed to assess their influence on the 
primary endpoint, overall, by indication, by randomization sequence, and by period: 
• 
Age (< 65, ≥ 65) 
• 
Sex (male, female) 
• 
Baseline PGA (< median, ≥ median) 
• 
Prior biologic use (yes, no) 
• 
Other subgroups may be evaluated as necessary 
10.1.4 
Handling of Missing and Incomplete Data  
Subjects who dropout after the first injection will not be replaced by new subjects.  
Subjects will be included in the safety analysis, but not in the efficacy analysis as 
described in Section 10.1.2.   
10.2 
Sample Size Considerations 
The primary objective of the study is to compare the injection site pain from the modified 
formulation of etanercept with that from the currently marketed etanercept.   
CONFIDENTIAL 
 
 
 
 
 


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Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 45 of 65 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 5.2 and Section 9.2.1.2).  
10.4 
Planned Analyses 
10.4.1 
Primary Analyses 
The primary analysis, will be conducted at the end of the study for the primary endpoint.  
The purpose will be to test the null hypothesis of no difference in injection site pain 
scores between the 2-etanercept formulations. 
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
The primary analysis of the primary endpoint will be conducted using the primary 
analysis set.  Analysis of covariance will be used to compare the difference in injection 
site pain score within subjects receiving etanercept in the currently marketed formulation 
and in the modified formulation, with the disease indication (RA or PsA) and the 
treatment as factors, adjusting for period effect and sequence effect.  Descriptive 
statistics will also be presented for the primary endpoint for the subgroups listed in 
Section 10.1.1.1 and Section 10.1.3.  
Safety endpoints will be analyzed using the safety analysis set.   
Descriptive statistics for continuous variables, consists of number of observations, mean, 
standard error and/or SD, median, 25th percentile (Q1), 75th percentile (Q3), minimum, 
maximum, and for categorical variables, the number of observations, frequency, and 
percentage will be presented.  Subject disposition, demographics, baseline 
characteristics, and safety information will be summarized.  There will be no adjustment 
for multiplicity and no imputation techniques for missing values.  All analyses will be 
based on observed data. 
10.5.2 
Primary Efficacy Endpoint 
As state above, analysis of covariance will be used to compare the difference in injection 
site pain score between subjects receiving etanercept in the current marketed 
formulation and in the modified formulation, with the disease indication (RA or PsA) and 
the treatment as factors, adjusting for period effect and sequence effect.  Sensitivity 
analyses may be performed for the primary endpoint for subjects who complete the 
injection site pain score per protocol.  In addition, the difference in injection site pain 
score will be evaluated by disease indication, using descriptive statistics.   
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
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Date:  30 March 2017 
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10.5.3 
Safety Endpoints 
All safety endpoints will be analyzed using 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. 
Adverse events will be coded using the most current version of the Medical Dictionary 
for Regulatory Activities version 19.0 or later.  Events of interest and hospitalizations will 
be tabulated by treatment group.  Subgroup analyses will be presented for all adverse 
events. 
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 Clinical Trial Manager to the 
investigator.  The written informed consent form is to be prepared in the language(s) of 
the potential subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
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Product:  Enbrel 
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Date:  30 March 2017 
Page 47 of 65 
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 approval/IRB and IEC renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with governmental/ International Council for Harmonisation (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 
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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 multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an Investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen before implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen.   
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. 
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In this study, the IVR/IWR system captures the following data points and these are 
considered source data:  subject identification, enrollment date, investigational product 
dispensation date, and investigational product box number dispensed.  
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
Non-investigational product(s) and or medical device(s) documentation, as 
applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
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. 
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In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
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 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 or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the CRF, the data queries, and agrees with the 
content. 
Amgen (or designee) will perform Self-Evident Corrections to obvious data errors in the 
clinical study database.  The Self-Evident Corrections will be documented in the CRF 
instructions available in the EDC system.  Examples of obvious data errors that may be 
corrected by Amgen (or designee) include deletion of obvious duplicate data (ie, the 
same results sent twice with the same date with different visit, [eg, week 4 and early 
termination]) and updating a specific response if the confirming datum is provided in the 
“other, specify” field (eg, for race, reason for ending study).  
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subject’s not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw 
before 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.   
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12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors 2013 Recommendations for 
the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals, which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
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12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
Alamanos Y, Youlgari PV, et al.  Incidence and prevalence of rheumatoid arthritis, based 
on the 1987 American College of Rheumatology criteria: a systematic review.  Semin 
Arthritis Rheum.  2006;36:182-188. 
Biondi Oriente C, Scarpa R, et al P. Psoriasis and psoriatic arthritis.  Dermatological and 
rheumatological co-operative clinical report.  Acta Derm Venereol.  
1989;146(suppl):69-71. 
Espinoza L, Zakraoui L, et al. Psoriatic arthritis: clinical response and side effects to 
methotrexate therapy.  J Rheum.  1992;19:872-877. 
Amgen.  Etanercept Investigator’s Brochure.  Thousand Oaks, CA.   
Flanagan T, Wahl MJ, et al. Size doesn't matter: needle gauge and injection pain.  
Gen Dent.  2007;55:216-217. 
Gallagher EJ, Bijur PE, et al. Reliability and validity of a visual analog scale for acute 
abdominal pain in the ED. Am J Emerg Med. 2002;20:287-290. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 
Publication.  2013. http://www.icmje.org/ 
Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life 
assessment.  Dermatol Clin.  1996;14:485-496. 
Laursen T, Hansen B, et al. Pain perception after subcutaneous injections of media 
containing different buffers.  Basic Clin Pharmacol Toxicol.  2006;98:218-221. 
Palmon SC, Lloyd LT, et al.  The effect of needle gauge and lidocaine pH on pain during 
intradermal injection.  A & A. 1998;86:379-381. 
Robb D, Kanji Z. Comparison of two needle sizes for subcutaneous administration of 
enoxaparin: effects on size of hematomas and pain on injection.  Pharmacotherapy.  
2002;22:1105-1106. 
Scarpa R, Oriente P, et al. Psoriatic arthritis in psoriatic patients.  Br J Rheumatol.  
1984;23:246-250. 
Shbeeb M, Uramoto KM, et al.  The epidemiology of psoriatic arthritis in Olmsted 
County, Minnesota, USA, 1982-1991.  J Rheum.  2000;27:1247-1250. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Toxicity Criteria version 4.0  is available at the following link: 
http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.3 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 6.3 or who experience AST or ALT elevations > 3 x ULN or 2-fold increases 
above baseline values for subjects with elevated values before drug are to undergo a 
period of “close observation” until abnormalities return to normal or to the subject’s 
baseline levels.   
Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2 × ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL.  The following are to be considered depending on the clinical situation: 
− 
Complete blood count (CBC) with differential to assess for eosinophilia 
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− 
Serum total immunoglobulin G, Anti-nuclear antibody (ANA), Anti Smooth Muscle 
Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
− 
Serum acetaminophen (paracetamol) levels 
− 
A more detailed history of:  
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
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 
− 
Viral serologies 
− 
CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
Hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs. 
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Appendix B.  Electronic Serious Event Contingency Form 
 
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Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 60 of 65 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 61 of 65 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 62 of 65 
Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 63 of 65 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 64 of 65 
Appendix D.  Subject Injection Site Pain Perception Assessment (English Version) 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 65 of 65 
Appendix E.  Subject Injection Site Pain Perception Assessment (Spanish Version) 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 1 of 6 
Amendment 1 
Protocol Title:  A Multicenter, Randomized, Double-blind, Crossover Study to 
Assess the Injection Site Pain Associated With a Modified Etanercept Formulation 
in Adult Subjects With Either Rheumatoid Arthritis or Psoriatic Arthritis 
 
Amgen Protocol Number 20140339 
 
Amendment Date: 
30 March 2017 
Rationale: 
This protocol is being amended to: 
• 
Recategorize study phase from phase 4 to phase 3b 
• 
Update sample size based on 8 mm as an updated estimation of true effect size 
• 
Make editorial updates and correct administrative errors throughout protocol 
CONFIDENTIAL 
 
 
 
 


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Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 3 of 6 
Section:  Protocol Synopsis, Study Design, Paragraph 2 
Replace: 
A total of 90 subjects will be enrolled with 45 subjects in each treatment sequence, 
stratified by disease indication (RA or PsA).  A minimum of 20 PsA subjects will be 
enrolled, therefore enrollment of RA subjects will be limited to 70 subjects. 
With: 
A total of 112 subjects will be enrolled with 56 subjects in each treatment sequence, 
stratified by disease indication (RA or PsA).  A minimum of 20 PsA subjects will be 
enrolled. 
Section:  Protocol Synopsis, Sample Size 
Replace: 
The proposed sample size of 90 (ie, 45 per sequence treatment arm with at least 
10 subjects with PsA) would provide approximately 42 subjects for each sequence 
treatment arm at the completion of the study, assuming an early termination or dropout 
rate of 5% for each sequence treatment arm over the course of the study. 
With: 
The proposed sample size of 112 (ie, 56 per sequence treatment arm with at least 
10 subjects with PsA) would provide approximately 53 subjects for each sequence 
treatment arm at the completion of the study, assuming an early termination or dropout 
rate of 5% for each sequence treatment arm over the course of the study. 
Section:  Protocol Synopsis, Amgen Investigational Product Dosage and Administration, 
Paragraph 2 
Replace: 
If the first injection site occurs on the arm or leg, the second injection site should be 
performed on the contralateral limb. 
With: 
If the first injection site occurs on the thigh, the second injection site should be 
performed on the contralateral limb. 
CONFIDENTIAL 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 4 of 6 
Section:  Study Design and Treatment Schema 
Replace: 
 
With: 
 
Section:  3.1 Study Design, Paragraph 3 
Replace: 
A total of 90 subjects will be enrolled with 45 subjects in each treatment sequence, 
stratified by disease indication (RA or PsA).  A minimum of 20 PsA subjects will be 
enrolled, therefore enrollment of RA subjects will be limited to 70 subjects. 
CONFIDENTIAL 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 5 of 6 
With: 
A total of 112 subjects will be enrolled with 56 subjects in each treatment sequence, 
stratified by disease indication (RA or PsA).  A minimum of 20 PsA subjects will be 
enrolled. 
Section:  3.3 Number of Subjects, Paragraph 2 
Replace: 
A total of 90 subjects are expected to enroll in this study with 45 subjects in each 
treatment sequence. 
With: 
A total of 112 subjects are expected to enroll in this study with 56 subjects in each 
treatment sequence. 
Section:  6.2.1.1 Dosage, Administration, and Schedule, Paragraph 2 
Replace: 
If the first injection site occurs on the arm or leg, the second injection site should be 
performed on the contralateral limb. 
With: 
If the first injection site occurs on the thigh, the second injection site should be 
performed on the contralateral limb. 
Section:  6.2.1.1 Dosage, Administration, and Schedule, Paragraph 3 
Delete: 
The volume (full, partial, or none), dose date, dose time, and box number of etanercept 
are to be recorded on each subject’s CRF. 
Section:  9.2.1.1 Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria, Paragraph 3 
Add: 
The adverse event grading scale used will be the Common Toxicity Criteria.  The 
grading scale used in this study is described in Appendix A.  If the severity of an 
adverse event changes from the date of onset to the date of resolution, record as 
a single event with the worst severity on the Event CRF. 
CONFIDENTIAL 
 
 
 
 


Product:  Enbrel 
Protocol Number:  20140339 
Date:  30 March 2017 
Page 6 of 6 
Section:  10.2 Sample Size Considerations, Paragraph 2 
Replace: 
The proposed sample size of 90 (ie, 45 per sequence treatment arm with at least 
10 subjects with PsA) would provide approximately 42 subjects for each sequence 
treatment arm at the completion of the study, assuming an early termination or dropout 
rate of 5% for each sequence treatment arm over the course of the study. 
With: 
The proposed sample size of 112 (ie, 56 per sequence treatment arm with at least 
10 subjects with PsA) would provide approximately 53 subjects for each sequence 
treatment arm at the completion of the study, assuming an early termination or dropout 
rate of 5% for each sequence treatment arm over the course of the study. 
Section:  10.2 Sample Size Considerations, Paragraph 6 
Replace: 
Therefore, a conservative effect size of 9 mm was used for this study. 
With: 
Therefore, a conservative effect size of 8 mm was used for this study. 
Section:  10.2 Sample Size Considerations, Paragraph 7 
Replace: 
Therefore, the sample size of 42 per arm was calculated to have more than 90% power 
to detect a difference in means of 9 mm in the injection site pain score between the 
2 formulations with corresponding SD of 25 using a t-test (crossover Analysis of 
Variance) with a 2-sided significance level of 0.05. 
With: 
Therefore, the sample size of 53 per arm was calculated to have more than 90% power 
to detect a difference in means of 8 mm in the injection site pain score between the 
2 formulations with corresponding SD of 25 using a t-test (crossover Analysis of 
Variance) with a 2-sided significance level of 0.05. 
CONFIDENTIAL 
 
 
 
 

SAP_001.pdf: 
Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 1
STATISTICAL ANALYSIS PLAN
A Multicenter, Randomized, Double-blind, Crossover Study to Assess the Injection 
Site Pain Associated With a Modified Etanercept Formulation in Adult Subjects 
With Either Rheumatoid Arthritis or Psoriatic Arthritis
Protocol Number:
20140339
Version:
1.0
Date:
31 May 2017
Authors:
PPD
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IRUSXUSRVHVRISRVWLQJRQFOLQLFDOWULDOVJRY


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 2
Table of Contents
Table of Abbreviations.....................................................................................................4
1.
Introduction.............................................................................................................5
2.
Objectives...............................................................................................................5
2.1
Primary .......................................................................................................5
2.2
Secondary...................................................................................................5
2.3
Safety..........................................................................................................5
3.
Study Overview ......................................................................................................5
3.1
Study Design...............................................................................................5
3.1.1
Study Schema.............................................................................7
3.2
Sample Size................................................................................................8
4.
Study Endpoints and Covariates.............................................................................9
4.1
Study Endpoints..........................................................................................9
4.1.1
Primary Endpoint.........................................................................9
4.1.2
Safety Endpoint...........................................................................9
4.2
Planned Covariates and Subgroups............................................................9
5.
Hypotheses and/or Estimations ..............................................................................9
6.
Definitions...............................................................................................................9
7.
Analysis Subsets ..................................................................................................12
7.1
Primary Analysis Set .................................................................................12
7.2
Safety Analysis Set ...................................................................................12
8.
Interim Analysis and Early Stopping Guidelines....................................................12
9.
Data Screening and Acceptance...........................................................................12
9.1
General Principles.....................................................................................12
9.2
Data Handling and Electronic Transfer of Data .........................................12
9.3
Handling of Missing and Incomplete Data .................................................12
9.4
Detection of Bias.......................................................................................12
9.5
Outliers .....................................................................................................13
9.6
Distributional Characteristics.....................................................................13
9.7
Validation of Statistical Analyses...............................................................13
10.
Statistical Methods of Analysis..............................................................................13
10.1
General Principles.....................................................................................13
10.2
Subject Accountability ...............................................................................13
10.3
Important Protocol Deviations ...................................................................13
10.4
Demographic and Baseline Characteristics...............................................14
10.5
Primary Analyses ......................................................................................14
10.6
Other Analyses .........................................................................................14


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 3
10.7
Safety Analyses ........................................................................................14
10.7.1
Adverse Events and Disease Related Events............................14
10.7.2
Laboratory Test Results ............................................................15
10.7.3
Physical Examination ................................................................15
10.7.4
Vital Signs .................................................................................15
10.7.5
Exposure to Investigational Product ..........................................15
10.7.6
Exposure to Concomitant Medication ........................................15
11.
Appendices...........................................................................................................16
List of Appendices
Appendix A.  Imputation Rules for Partial or Missing Stop Dates...................................17
Appendix B.  Visual Analog Scale..................................................................................18
Appendix C.  Code Fragment ........................................................................................19


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 4
Table of Abbreviations
Abbreviation or Term
Definition/Explanation
CRF
Case Report Form
EDC
Electronic Data Capture
Interactive Voice Response (IVR)
Telecommunication technology that is linked to a 
central computer in real time as an interface to collect 
and process information.
Interactive Web Response (IWR)
Web based technology that is linked to a central 
computer in real time as an interface to collect and 
process information.
PsA
Psoriatic Arthritis
RA
Rheumatoid Arthritis
VAS
Visual Analog Scale
PGA
Physician Global Assessment
SD
standard deviation
Q1
Quartile 1, 25th Percentile
Q3
Quartile 3, 75th Percentile
MedDRA
Medical Dictionary for Regulatory Activities
CTCAE
Common Terminology Criteria for Adverse Events


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 5
1.
Introduction
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for Etanercept Phase 3b
Study 20140339 dated 30 March 2017. The scope of this plan includes the final analysis
that is planned and will be executed by the Biostatistics department.
2.
Objectives
2.1
Primary

To assess the injection site pain associated with a modified formulation of 
etanercept compared to the currently marketed etanercept in adult subjects 
with either rheumatoid arthritis (RA) or psoriatic arthritis (PsA) as measured 
by a visual analog scale (VAS)
2.2
Secondary

To describe the injection site pain by disease indication
2.3
Safety

To evaluate the safety of etanercept
3.
Study Overview
3.1
Study Design
This is a phase 3b, multicenter, randomized, double-blind, 2-period, 2-sequence 
crossover study in subjects with RA or PsA who are naive to etanercept. The study will 
evaluate injection site pain associated with the current formulation of etanercept and the 
modified formulation of etanercept immediately after injection of each formulation.
Subjects will be randomized in a 1:1 ratio to receive each etanercept formulation in 1 of 
2 crossover treatment sequences. Subjects randomized to the first treatment sequence 
(ie, sequence AB) will receive 1 dose of the current formulation (ie, treatment A) during 
the first study period, followed by a second visit 1 week later during the second study 
period at which time subjects will receive 1 dose of the modified formulation 
(ie, treatment B). Subjects randomized to the second treatment sequence will undergo 
the same procedures but will receive investigational product in the opposite order 
(ie, sequence BA). At each study visit subjects will inject the blinded treatment and 
immediately (ie, within 30 seconds of injection) record the associated injection site pain 
using the VAS. A total of 112 subjects will be enrolled with 56 subjects in each treatment 
sequence, stratified by disease indication (RA or PsA). A minimum of 20 PsA subjects 
will be enrolled, therefore enrollment of RA subjects will be limited to 92 subjects. 


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 6
After study completion subjects may continue with modifiedly available etanercept. The 
study will consist of a screening period of up to 14 days, a treatment period of 2 weeks 
and a 30-day safety follow-up period.


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 7
3.1.1
Study Schema
The overall study design is described as follows:
Abbreviations: QW = every week


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 8
3.2
Sample Size
The primary objective of the study is to compare the injection site pain from the modified 
formulation of etanercept with that from the currently marketed formulation of etanercept.
The proposed sample size of 112 (ie, 56 per sequence treatment arm with at least 
10 subjects with PsA) would provide approximately 53 subjects for each sequence 
treatment arm at the completion of the study, assuming an early termination or dropout 
rate of 5% for each sequence treatment arm over the course of the study. Subjects who 
drop out after the first injection will not be replaced by new subjects. 
The sample population will be comprised of subjects with RA or PsA; the estimated 
injection site pain score for subjects with PsA is assumed to be similar to those with RA. 
There are no data assessing injection site pain in subjects with either RA or PsA on any 
of the etanercept currently marketed or modified formulations. Given that RA subjects in 
non-etanercept studies have lower absolute injection site pain scores compared with 
healthy volunteers, the effect size between the formulations is expected to be smaller 
compared to that seen with healthy volunteers, in addition to expected attenuation at the 
second injection. Therefore, a conservative effect size of 8 mm was used for this study. 
Therefore, the sample size of 53 per arm was calculated to have more than 90% power 
to detect a difference in means of 8 mm in the injection site pain score between the 
2 formulations with corresponding SD of 25 using a 2-sided t-test (crossover analysis of 
variance) with a significance level of 0.05.
CCI


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 9
4.
Study Endpoints and Covariates
4.1
Study Endpoints
4.1.1
Primary Endpoint

Change in injection site pain score between the current formulation and the 
modified formulation as measured by the VAS
4.1.2
Safety Endpoint

Adverse events
4.2
Planned Covariates and Subgroups
The disease indication will be adjusted as the straitification factor when analyzing the 
primary endpoint.
The following subgroup analyses will be performed to assess their influnce on the 
primary endpoint:

Age (< 65, ≥65)

Sex (male, female)

Baseline PGA (< median, ≥median)

Baseline PGA (< 66.7 mm, ≥ 66.7 mm)

Prior biologic use (yes, no)

Other subgroups may be evaluated as necessary
5.
Hypotheses and/or Estimations
The primary hypothesis of this study is that the modified etanercept formulation will be 
associated with less injection site pain compared to the currently marketed etanercept 
formulation.
6.
Definitions
Injection Site Pain Visual Analog Scale (VAS) 
The injection site pain score is an assessment of the severity of the subject’s injection 
site pain and will be completed by the subject immediately after the administration of the 
etanercept dose (ie, within 30 seconds) using a visual analog scale. 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 VAS has been specifically 
designed to capture injection site associated pain.


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 10
The 100 mm VAS is commonly used in such studies and has been shown to correlate 
well with categorical pain scales. A difference of 13 to 16 mm on the VAS is considered 
to be clinically meaningful (Gallagher et al, 2002) in a setting of acute pain.
Physician Global Assessment of Disease Activity (PGA)
The global assessment of the subject’s overall RA or PsA disease activity will be 
assessed by the principal investigator or sub investigator for the study by completion of a 
VAS. The PGA will be completed -at screening, and on day 1 and day 8 before 
investigational product administration. 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.
Enrollment
A subject is considered enrolled once randomized to treatment. 
Randomization Date 
The date the subject was assigned a randomization number. 
Study Day 1
Study day 1 is defined as the first day of administration of investigational product after 
enrollment. The day prior to Study Day 1 is considered Day -1. For subjects that is not 
dosed, Study Day 1 is defined as the randomization date.
Study Day
Post-study day 1: study day = (date – date of Study Day 1) + 1 
Pre-study day 1: study day = (date – date of Study Day 1)
End of Follow-up
When the last subject completes the last protocol-specified assessment in the study
End of Study (EOS)
When the last subject is assessed or receives an intervention for evaluation in the study
(ie, last subject completes safety follow-up)
End of Study (primary completion)
When the last subject is assessed or receives an intervention for the purposes of final 
collection of data for the primary analysis (ie, last subject completes Study Visit 2)


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 11
Amgen Proprietary - Internal Use Only
Investigation Product
The term ‘investigational product’ is used in reference to etanercept, either the modified 
formulation or the modified formulation
Serious Adverse Event
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: Serious Adverse Event (SAE) 

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 in-patient hospitalization” if the 
event necessitated an in-patient admission to a health care facility. If an investigator 
considers an event to be clinically important, but it does not meet any of the serious 
criteria, the event could be classified as a serious adverse event under the criterion of 
“other medically important serious event.” Examples of such events could include 
allergic bronchospasm, convulsions, blood dyscrasias, drug-induced liver injury 
(see Appendix A in protocol for drug-induced liver injury reporting criteria), or events that 
necessitate an emergency room visit, outpatient surgery, or urgent intervention. Since 
the criteria for the CTCAE grading scale differs from the regulatory criteria for serious 
adverse events, if adverse events correspond to grade 4 “life threatening” CTCAE 
grading scale criteria (eg, laboratory abnormality reported as grade 4 without 
manifestation of life threatening status), it will be left to the investigator’s judgment to 
also report these abnormalities as serious adverse events. For any adverse event that 
applies to this situation, comprehensive documentation of the event’s severity status 
must be recorded in the subject’s medical record.
Treatment Emergent Adverse Event
A treatment-emergent adverse event is any adverse event that begins or worsens after 
the initial dose of investigational product and before the end of study. The severity of 
each adverse event will be graded using the CTCAE version 4.0 criteria, to be consistent 
with the version used for all etanercept studies. Adverse events will be coded using 
MedDRA (version 19.0 or later).


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 12
7.
Analysis Subsets
7.1
Primary Analysis Set
The primary analysis set will include all subjects who received the dose of investigational 
product during each study period and who completed the injection site pain score during 
each study period. The primary endpoint will be evaluated using the primary analysis 
set.   
7.2
Safety Analysis Set
The safety analysis set will include all subjects who received at least 1 dose of 
investigational product during the study. All safety endpoints will be evaluated using the 
safety analysis set.
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.
9.2
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE
database. 
9.3
Handling of Missing and Incomplete Data
The following imputation for missing or incomplete data will be performed if required: 
Incomplete dates for adverse event and concomitant medication will be imputed as 
described in Appendix A.
Subjects who drop out after the first injection will not be replaced by new subjects.
These subjects will be included in the safety analysis set, but not in the primary analysis
set.
9.4
Detection of Bias
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each treatment 
group. The clinical study team will identify and document the criteria for important 
protocol deviations. 


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 13
9.5
Outliers
Outlier data will not be excluded, unless for any specific reason(s) that could be justified. 
9.6
Distributional Characteristics
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
9.7
Validation of Statistical Analyses
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures. 
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System.
10.
Statistical Methods of Analysis
10.1
General Principles
Descriptive statistics for continuous variables, consists of number of observations, mean, 
standard error and/or SD, median, 25th percentile (Q1), 75th percentile (Q3), minimum, 
maximum, and for categorical variables, the number of observations, frequency, and 
percentage will be presented. Subject disposition, demographics, baseline 
characteristics, and safety information will be summarized. There will be no adjustment 
for multiplicity and no imputation techniques for missing values. All analyses will be 
based on observed data.
10.2
Subject Accountability
A summary of subject disposition with discontinuation reasons, and etanercept 
completion and discontinuation will be provided. A list of subjects who withdraw early will 
be provided. It will include the reason and timing of the withdrawal. Similarly, the reason 
any subject is excluded from an analysis set will also be provided. In addition, significant 
known protocol deviations will be noted for individual subjects.
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. Eligibility deviations are defined 


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 14
in the protocol. The final IPD list is used to produce the Summary of IPDs table and the 
List of Subjects with IPDs.
10.4
Demographic and Baseline Characteristics
Age, race, sex, height, weight, baseline PGA, prior biologic use and indication will be 
summarized for all the subjects enrolled.
10.5
Primary Analyses 
A mixed effects analysis of variance model will be used for the primary endpoint. 
Treatment, period, sequence and disease indication (RA or PsA) will be evaluated as 
fixed effects, and subject nested within sequence will be included as a random effect.
The modified formulation of etanercept will be used as the test treatment and current
formulation of etanercept as the reference treatment. 
The null hypothesis that there is no difference of injection site pain between the current 
and modified formulation will be tested and p-value will be provided. The least square 
mean of the injection site pain score and the difference between the formulations will be 
estimated and the corresponding 2-sided 95% CI will be provided..
10.6
Other Analyses
The descriptive statistics will be provided for the injection site pain score for overall and 
by indication and formulation.
Sensitivity analyses will be performed for the primary endpoint for subjects in the primary 
analysis set, excluding the subject(s) with injection(s) administrated without warming the 
investigation product to the required temperature.
Subgroup analyzes will be conducted for the primary endpoint with the subgroups 
defined in Section 4.2.
10.7
Safety Analyses
10.7.1
Adverse Events and Disease Related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 or later will be 
used to code all events categorized as adverse events (AEs) to a system organ class 
and a preferred term.  The severity of each adverse event will be graded using CTCAE 
version 4.0 criteria.
The subject incidence of AEs will be summarized for all treatment-emergent AEs, 
serious AEs, AEs leading to withdrawal of investigational product, fatal AEs.


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 15
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 adverse events will be tabulated by 
system organ class, preferred term, and grade in descending order of frequency.
Adverse events (such as injection site reactions) occuring during different periods of the 
treatment may be examined to evaluate the safety and tolerability of a current 
formulation versus the modified formulation of etanercept.
10.7.2
Laboratory Test Results
Drug-induced liver injury will be assessed by evaluating subjects for Hy’s Law in the 
study period.  Hy’s law lab value criteria is defined as aspartate amino transferase or 
alanine amino transferase > 3 times upper limit of normal (ULN), total bilirubin > 2 times 
ULN, and alkaline phosphatase < 2 times ULN assessed within 7 days.  Subjects who 
meet these criteria on study will be further evaluated to assess whether there exist 
underlying conditions or concomitant medications which can explain the elevation in 
laboratory analytes.
Individual chemistry, hematology laboratory data will not be listed unless any safety 
issue arises.
10.7.3
Physical Examination
The physical examination results will not be listed unless any safety issue arises.
10.7.4
Vital Signs
The vital signs results will not be listed unless any safety issue arises.
10.7.5
Exposure to Investigational Product
The formulation, period, administration site, laterality, quantity and reason of dose 
change/withheld (if available) of each investigational product administration will be listed 
for each subject. In addition a listing of the unique manufacturing lot numbers, and a 
listing of the subjects administered each manufacturing lot number will be provided.
10.7.6
Exposure to Concomitant Medication
All medications will be coded using the WHOdrug dictionary. Concomitant medication 
will not be listed or summarized unless any safety issues arise.


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 16
11.
Appendices


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 17
Appendix A.  Imputation Rules for Partial or Missing Stop Dates
We are using the following imputation rules:
1. For the start date
a.
If the month is missing, impute Janurary
b.
If the day is missing, impute the 1
c.
If both the month and day are missing, impute Janurary 1. 
2. For the stop date
a.
If the month is missing, impute December
b.
If the day is missing, impute the last day of the month
c.
If both month and day are missing, impute December 31.
3. If the stop date is entirely missing, assume the event or medication is ongoing. If 
a partial or complete stop date is present and the ‘ongoing’ or ‘continuing’ box is 
checked, then it will be assumed that the AE or concomitant medication stopped 
and the stop date will be imputed, if partial.
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month. If an imputed stop date based on abive 
rule is on or after the end of study (EOS) date, the EOS date should be used as the 
imputed stop date.


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 18
Appendix B.  Visual Analog Scale


Product:  Enbrel
Statistical Analysis Plan:  20140339
Date: 31 May 2017
Page 19
Appendix C.  Code Fragment
CCI