Conditions: Plaque Psoriasis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 80
Healthy volunteers: no

Brief summary:
To evaluate the efficacy of etanercept in adults with moderate to severe plaque psoriasis who have failed therapy with apremilast (Otezla).

Detailed description:
This is a multicenter, open-label, single-arm, phase 4, estimation study in adults with plaque psoriasis (PsO) who have failed apremilast. The study will consist of a screening period of up to 45 days, a 24-week treatment period with study visits every 4 weeks, and a 30-day follow-up period for safety. Etanercept dosing will follow the recommended label dosing for adults with plaque psoriasis.

Arms:
arm 1: Participants received etanercept 50 mg subcutaneously twice weekly for 12 weeks followed by 50 mg once weekly for an additional 12 weeks.

Interventions: intervention 1: Etanercept
Intervention descriptions: intervention 1: Administered subcutaneously twice weekly for 12 weeks then once weekly for an additional 12 weeks.

Protocol document:
Prot_000.pdf: 
 
 
 
Product:  Etanercept 
Protocol Number:  20150252 
Date:  5 February 2016 
Page 1 of 61 
CONFIDENTIAL 
 
 
Title:  Open Label Study to Evaluate the Efficacy of Etanercept Treatment in 
Subjects With Moderate to Severe Plaque Psoriasis Who Have Failed Therapy 
With Apremilast  
Amgen Protocol Number (Etanercept) 20150252 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 
91320-1799 
 
United States Address 
1-805-447-1000 
Key Sponsor Contact(s): 
  
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 
  
Email: 
 
Date: 
5 February 2016 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1-800-77-AMGEN. 
PPD
PPD
PPD


 
 
 
Product:  Etanercept 
Protocol Number:  20150252 
Date:  5 February 2016 
Page 2 of 61 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled, Open Label Study to Evaluate the Efficacy of 
Etanercept Treatment in Subjects With Moderate to Severe Plaque Psoriasis Who Have 
Failed Therapy With Apremilast, dated 5 February 2016, and agree to abide by all 
provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 


 
 
 
Product:  Etanercept 
Protocol Number:  20150252 
Date:  5 February 2016 
Page 3 of 61 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  Open Label Study to Evaluate the Efficacy of Etanercept Treatment in Subjects With 
Moderate to Severe Plaque Psoriasis Who Have Failed Therapy With Apremilast  
Study Phase:  4 
Indication:  Plaque Psoriasis (PsO) 
Primary Objective:  To evaluate the efficacy of etanercept at week 12 as measured by a 75% 
improvement in Psoriasis Area and Severity Index (PASI 75) in adult subjects with moderate to 
severe plaque PsO who have failed therapy with apremilast (Otezla) 
Secondary Objectives:  To evaluate the effect of treatment with etanercept on other efficacy 
endpoints (PASI, Static Physician’s Global Assessment [sPGA], Body Surface Area [BSA]), and 
patient reported outcomes (PRO), including Psoriasis Symptom Inventory (PSI), Patient 
Assessment of Treatment Satisfaction, and Dermatology Life Quality Index (DLQI) 
Safety Objective:  To evaluate the safety and tolerability of etanercept in apremilast failures  
Hypotheses:  A formal hypothesis will not be tested in this study.  This study will estimate the 
proportion of subjects with PsO who achieve a PASI 75 after 12 weeks of treatment with 
etanercept following failure of treatment with apremilast. 
Primary Endpoint:  PASI 75 at week 12 
Secondary Endpoints:   
• 
PASI 75 at all other visits 
• 
PASI 50 and 90 at all visits 
• 
Percent PASI improvement at all visits 
• 
sPGA of 0 or 1 at all visits 
• 
sPGA of 0, 1, or 2 at all visits 
• 
sPGA at all visits 
• 
One and two grade improvement in sPGA at all visits 
• 
Percent BSA improvement at all visits 
• 
PSI and component scores at all visits 
• 
Patient Assessment of Treatment Satisfaction at week 12 and 24 
• 
Improvement in DLQI at week 12 and 24 
Safety Endpoints: 
• 
Adverse events 
• 
Laboratory assessments 
Study Design:  This is a multicenter, open-label, single-arm, phase 4, estimation study in 
subjects with PsO who have failed apremilast.  Approximately 80 subjects will be enrolled in the 
study of which at least 10 subjects (and not to exceed 20) will be enrolled for reasons of 
intolerability to apremilast in the investigator’s opinion. The remaining 60 to 70 subjects will be 
enrolled for reasons of primary or secondary failure to apremilast in the investigator’s opinion. 
The study will consist of a screening period of up to 45 days, a 24-week treatment period with 
study visits every 4-weeks, and a 30-day follow-up period for safety. Etanercept dosing will follow 
the recommended label dosing for subjects with PsO. 
Sample Size:  Approximately 80 subjects will be enrolled in the study. 
Summary of Subject Eligibility Criteria: The study seeks to enroll male and female subjects   
(≥ 18 years of age) with moderate to severe plaque PsO defined by BSA ≥ 10%, sPGA ≥ 3, and 
PASI ≥ 10 at screening and baseline who have failed therapy with apremilast either because of 
failure to achieve adequate response, loss of adequate response or intolerability in the opinion of 


 
 
 
Product:  Etanercept 
Protocol Number:  20150252 
Date:  5 February 2016 
Page 4 of 61 
CONFIDENTIAL 
 
 
the investigator. Female subjects of childbearing potential must have a negative serum 
pregnancy test within 4 weeks from starting etanercept and a negative urine pregnancy test at 
baseline. For a full list of eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2.  
Investigational Product:  Etanercept will be supplied in a single-use prefilled 1.0 mL syringe as 
a sterile, clear and colorless, preservative-free solution for subcutaneous injection.  Each 
single-use prefilled syringe contains 0.98 mL of 50 mg/mL etanercept. Etanercept will be provided 
with  4 syringes to a pack. 
Amgen Investigational Product Dosage and Administration:  Etanercept dosing will follow the 
recommended label dosing for patients with PsO: 50 mg subcutaneously twice weekly for 
12 weeks followed by 50 mg once weekly for the additional 12 weeks.  
Procedures:  Written informed consent must be obtained from all subjects before any screening 
procedures are performed. The following procedures will occur per the Schedule of Assessments:  
medical and medication history, physical exam, vital signs, height and weight, tuberculosis 
testing, hepatitis testing, urinalysis, assessment of the sPGA score, PASI score and assessment 
of involved BSA. Blood samples will be collected for hematology, chemistry, and for all females 
(except those who have had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy, 
or who are at least 2 years postmenopausal) to conduct a serum pregnancy test. The treatment 
period will be 24 weeks in duration with study visits every 4 weeks. Baseline evaluations will be 
performed on day 1 of treatment before subjects receive the first dose of etanercept. The 
following procedures will be performed at baseline (day 1) and during the treatment period: 
interim physical exam, vital signs, weight , PASI, BSA, sPGA, blood samples, urinalysis (day 1 
only) and urine pregnancy tests when required per schedule of assessments. PROs will be 
collected at day 1 and during the treatment period. Adverse events, disease related events, 
serious adverse events and changes in concomitant medications will be recorded throughout the 
treatment period. Investigational product will be dispensed at baseline and every 4 weeks.up to 
week 20. Approximately 30 days after the last dose of etanercept, subjects will receive a final 
safety follow-up phone call to confirm the status of any ongoing and/or new disease related 
events or serious adverse events. The overall study design is described by a study schema at the 
end of this synopsis section. 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:  This is an open-label single-arm study. Ninety five percent 
confidence intervals and p-values for estimated response rates will be generated for descriptive 
purposes only. The full analysis set includes all subjects who received at least one dose of 
investigational product during the study. All safety and efficacy endpoints will be analyzed using 
the full analysis set. For the primary analysis of all efficacy endpoints, missing efficacy data will 
be imputed using last observation carried forward method. A sensitivity analysis will be performed 
using observed cases. There will be no interim analysis. 
For a full description of statistical analysis methods, refer to Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
 
5: 20 March 2015   
 


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Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 6 of 61 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BIW 
twice a week 
BSA 
body surface area 
cAMP 
cyclic adenosine monophosphate 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
defined as the first day that protocol-specified investigational product 
is administered to the subject 
DILI 
Drug-induced liver injury  
DLQI 
Dermatology Life Quality Index 
EDC 
electronic data capture 
ET 
early termination 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
EOS 
End of Study (for individual subject) 
End of Study (end of trial) defined as the time when the last subject is assessed or receives an 
intervention for evaluation in the study.  
GRAPPA 
Group for Research and Assessment of Psoriasis and Psoriatic 
Arthritis 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/ independent ethics committee 
IVR 
Interactive Voice Response, telecommunication technology that is 
linked to a central computer in real time as an interface to collect and 
process information.  
IWR 
Interactive Web Response, web based technology that is linked to a 
central computer in real time as an interface to collect and process 
information.  
kD 
kilodalton 
LT-α 
lymphotoxin alpha 
PASI 
Psoriasis Area and Severity Index 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 7 of 61 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
PDE4 
phosphodiesterase 4 
PPD 
tuberculin purified protein derivative 
PRO 
Patient Reported Outcomes 
PSI 
Psoriasis Symptom Inventory 
PsO 
psoriasis 
PUVA 
Psoralen plus ultraviolet light A 
Serum beta-HCG 
Serum beta human chorionic gonadotropin 
QW 
Once a week 
RA 
rheumatoid arthritis 
sPGA 
Static Physician’s Global Assessment  
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies). (ICH 
Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
TBL 
total bilirubin 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
UVA 
ultraviolet light A 
UVB 
ultraviolet light B 
 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 8 of 61 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 5 
Study Glossary ................................................................................................................ 6 
1. 
OBJECTIVES ....................................................................................................... 12 
1.1 
Primary ..................................................................................................... 12 
1.2 
Secondary ................................................................................................. 12 
1.3 
Safety ........................................................................................................ 12 
2. 
BACKGROUND AND RATIONALE ...................................................................... 12 
2.1 
Disease ..................................................................................................... 12 
2.2 
Apremilast (OTEZLA) Background .......................................................... 12 
2.3 
Amgen Investigational Product Background:  Etanercept .......................... 13 
2.4 
Rationale ................................................................................................... 14 
2.5 
Clinical Hypotheses ................................................................................... 14 
3. 
EXPERIMENTAL PLAN ........................................................................................ 14 
3.1 
Study Design ............................................................................................. 14 
3.2 
Number of Sites ........................................................................................ 15 
3.3 
Number of Subjects ................................................................................... 15 
3.4 
Replacement of Subjects .......................................................................... 15 
3.5 
Estimated Study Duration .......................................................................... 15 
3.5.1 
Study Duration for Subjects ....................................................... 15 
3.5.2 
End of Study .............................................................................. 15 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 15 
4.1 
Inclusion and Exclusion Criteria ................................................................ 16 
4.1.1 
Inclusion Criteria ........................................................................ 16 
4.1.2 
Exclusion Criteria ...................................................................... 17 
5. 
SUBJECT ENROLLMENT .................................................................................... 20 
5.1 
Treatment Assignment .............................................................................. 21 
6. 
TREATMENT PROCEDURES .............................................................................. 21 
6.1 
Investigational Product .............................................................................. 21 
6.1.1 
Amgen Investigational Product: Etanercept ............................... 21 
6.1.1.1 
Dosage, Administration, and Schedule .................... 21 
6.2 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 22 
6.2.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product Due to Potential Hepatotoxicity ............. 23 
6.2.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product Due to Potential Hepatotoxicity ............. 23 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 9 of 61 
CONFIDENTIAL 
 
 
6.2.3 
Criteria for Rechallenge of Amgen Investigational 
Product After Potential Hepatotoxicity ....................................... 24 
6.3 
Concomitant Therapy ................................................................................ 24 
6.4 
Medical Devices ........................................................................................ 25 
6.5 
Product Complaints ................................................................................... 25 
6.6 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 25 
7. 
STUDY PROCEDURES ....................................................................................... 26 
7.1 
Schedule of Assessments ......................................................................... 27 
7.2 
General Study Procedures ........................................................................ 30 
7.2.1 
Screening .................................................................................. 30 
7.2.2 
Re-screening ............................................................................. 30 
7.2.3 
Treatment .................................................................................. 30 
7.2.4 
Safety Follow-up/End of Study .................................................. 31 
7.3 
Description of Study Procedures ............................................................... 31 
7.3.1 
Informed Consent ...................................................................... 31 
7.3.2 
Demographic Data..................................................................... 31 
7.3.3 
Physical Examination and Medical History ................................ 31 
7.3.4 
Medication History ..................................................................... 31 
7.3.5 
Physical Measurements ............................................................ 32 
7.3.6 
Vital Signs ................................................................................. 32 
7.3.7 
Chest Radiograph ..................................................................... 32 
7.3.8 
Adverse Events and Disease Related Events ............................ 32 
7.3.9 
Concomitant Medications .......................................................... 32 
7.3.10 
Subject Diary for Study Drug Administration .............................. 32 
7.3.10.1 
Distribution and Instruction ...................................... 32 
7.3.10.2 
Collection and Review ............................................. 33 
7.3.11 
Disease Assessments ............................................................... 33 
7.3.11.1 
PASI ........................................................................ 33 
7.3.11.2 
BSA Involvement ..................................................... 33 
7.3.11.3 
sPGA ...................................................................... 33 
7.3.12 
Patient Reported Outcomes ...................................................... 34 
7.3.12.1 
Psoriasis Symptom Inventory .................................. 34 
7.3.12.2 
Patient Assessment of Treatment 
Satisfaction ............................................................. 34 
7.3.12.3 
Dermatology Life Quality Index ............................... 34 
7.4 
Laboratory Assessments ........................................................................... 34 
7.4.1 
Tuberculosis Testing ................................................................. 35 
7.4.1.1 
PPD ........................................................................ 35 
7.4.1.2 
Quantiferon ............................................................. 35 
7.4.2 
Urine Pregnancy Test ................................................................ 35 
7.5 
Sample Storage and Destruction ............................................................... 36 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 10 of 61 
CONFIDENTIAL 
 
 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 37 
8.1 
Subjects’ Decision to Withdraw ................................................................. 37 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 38 
8.3 
Reasons for Removal From Treatment, or Study ...................................... 38 
8.3.1 
Reasons for Removal From Treatment ...................................... 38 
8.3.2 
Reasons for Removal From Study ............................................. 38 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 38 
9.1 
Definition of Safety Events ........................................................................ 38 
9.1.1 
Disease Related Events ............................................................ 38 
9.1.2 
Adverse Events ......................................................................... 39 
9.1.3 
Serious Adverse Events ............................................................ 40 
9.2 
Safety Event Reporting Procedures .......................................................... 40 
9.2.1 
Reporting Procedures for Disease Related Events .................... 40 
9.2.2 
Adverse Events ......................................................................... 41 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 41 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 42 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 43 
9.2.2.4 
Serious Adverse Events That Are not to be 
Reported In an Expedited Manner ........................... 43 
9.3 
Pregnancy and Lactation Reporting .......................................................... 43 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 44 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 44 
10.1.1 
Study Endpoints ........................................................................ 44 
10.1.1.1 
Primary Endpoint ..................................................... 44 
10.1.1.2 
Secondary Endpoints .............................................. 44 
10.1.1.3 
Safety Endpoints ..................................................... 44 
10.1.2 
Analysis Sets ............................................................................. 45 
10.1.3 
Covariates and Subgroups ........................................................ 45 
10.2 
Sample Size Considerations ..................................................................... 45 
10.2.1 
Planned Analysis ....................................................................... 46 
10.2.2 
Primary Analysis ........................................................................ 46 
10.2.3 
Sensitivity Analysis .................................................................... 46 
10.3 
Planned Methods of Analysis .................................................................... 46 
10.3.1 
General Considerations ............................................................. 46 
10.3.2 
Efficacy Endpoints ..................................................................... 46 
10.3.3 
Safety Endpoints ....................................................................... 47 
11. 
REGULATORY OBLIGATIONS ............................................................................ 47 
11.1 
Informed Consent ...................................................................................... 47 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 11 of 61 
CONFIDENTIAL 
 
 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 48 
11.3 
Subject Confidentiality ............................................................................... 48 
11.4 
Investigator Signatory Obligations ............................................................. 49 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 49 
12.1 
Protocol Amendments and Study Termination .......................................... 49 
12.2 
Study Documentation and Archive ............................................................ 49 
12.3 
Study Monitoring and Data Collection ....................................................... 50 
12.4 
Investigator Responsibilities for Data Collection ........................................ 51 
12.5 
Language .................................................................................................. 52 
12.6 
Publication Policy ...................................................................................... 52 
12.7 
Compensation ........................................................................................... 52 
13. 
REFERENCES ..................................................................................................... 53 
14. 
APPENDICES ...................................................................................................... 54 
 
List of Tables 
Table 1.  Schedule of Assessments
 
 ............................................................................... 28
Table 2.  Analyte Listing
 
 ................................................................................................ 35
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information
 
 ................................................ 55
Appendix B.  Sample Electronic Adverse Event Contingency Report Form
 
 ................... 57
Appendix C.  Pregnancy and Lactation Notification Worksheets
 
 .................................... 60
 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 12 of 61 
CONFIDENTIAL 
 
 
1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the efficacy of etanercept at week 12 as measured by a 75% improvement 
in Psoriasis Area and Severity Index (PASI 75) in adult subjects with moderate to severe 
plaque (PsO) who have failed therapy with apremilast (Otezla®).  
1.2 
Secondary 
To evaluate the effect of treatment with etanercept on other efficacy endpoints (PASI, 
Static Physician’s Global Assessment [sPGA], Body Surface Area [BSA]), and patient 
reported outcomes (PRO), including Psoriasis Symptom Inventory (PSI), Patient 
assessment of Treatment Satisfaction, and Dermatology Life Quality Index (DLQI). 
1.3 
Safety 
To evaluate the safety and tolerability of etanercept in apremilast failures. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
PsO is a chronic, often severe, autoimmune dermatologic condition that affects 
approximately 2% of the world’s population (Menter et al, 2008). Moderate to severe 
plaque PsO is, for most patients, a chronic, life-long condition. Current therapies include 
topical agents (eg, corticosteroids, vitamin D3), phototherapy, oral systemic therapies 
(eg, apremilast, methotrexate, cyclosporine) and biologics (eg, etanercept, infliximab, 
adalimumab, ustekinumab and secukinumab). Many patients nevertheless remain 
untreated, fail to respond or lose response to therapy over time, or suffer from toxicities 
associated with systemic medication or phototherapy. 
2.2 
Apremilast (OTEZLA) Background 
Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for 
cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased 
intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its 
therapeutic action in psoriasis patients is not well defined. OTEZLA (apremilast) is 
indicated for the treatment of patients with moderate to severe plaque PsO who are 
candidates for phototherapy or systemic therapy. Refer to the specific section of the 
product label for additional information. 
The safety of apremilast was assessed in 1426 subjects with psoriasis in 3 randomized, 
double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque 
PsO who were candidates for phototherapy or systemic therapy. Subjects were 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 13 of 61 
CONFIDENTIAL 
 
 
randomized to receive apremilast 30 mg twice daily or placebo twice daily. Titration was 
used over the first 5 days.  Subjects ranged in age from 18 to 83 years, with an overall 
median age of 46 years.  Diarrhea (17%), nausea (17%), and upper respiratory tract 
infection (9%) were the most commonly reported adverse reactions. The most common 
adverse reactions leading to discontinuation for subjects taking apremilast were nausea 
(1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis 
who discontinued treatment due to any adverse reaction was 6.1% for subjects treated 
with apremilast 30 mg twice daily and 4.1% for placebo-treated subjects. Severe 
worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following 
discontinuation of treatment with apremilast (Otezla prescribing information, 2014). 
Two multicenter, randomized, double-blind, placebo-controlled trials (Studies PSOR-1 
and PSOR-2) enrolled a total of 1257 subjects 18 years of age and older with moderate 
to severe plaque PsO.  Study PSOR-1 enrolled 844 subjects and Study PSOR-2 
enrolled 413 subjects. In both studies, subjects were randomized 2:1 to Otezla 30 mg 
BID or placebo for 16 weeks. Clinical Response at Week 16 in the PSOR-1 and PSOR-2 
studies was as follows: 
• 
PSOR-1 
- 
33.1% achieved PASI 75 with apremilast vs. 5.3% with placebo 
- 
21.7% achieved sPGA clear (0) or almost clear (1) with apremilast vs. 3.9% with 
placebo 
• 
PSOR-2 
- 
28.8% achieved PASI 75 with apremilast vs. 5.8% with placebo 
- 
20.4% achieved sPGA clear (0) or almost clear (1) with apremilast vs. 4.4% with 
placebo 
2.3 
Amgen Investigational Product Background:  Etanercept 
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 PsO.  
Elevated levels of TNF are found in involved tissues and fluids of patients with 
rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and PsO. Two distinct 
receptors for TNF, a 55 kilodalton (kD) protein (p55) and a 75 kD protein (p75), exist 
naturally as monomeric molecules on cell surfaces and in soluble forms. Biological 
activity of TNF is dependent upon binding to either cell surface TNF receptor. 
Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding 
portion of the human 75 kD TNF receptor linked to the Fc portion of human 


 
 
 
Product:  Etanercept  
Protocol Number:  20150252 
Date:  5 February 2016   
Page 14 of 61 
CONFIDENTIAL 
 
 
immunoglobulin G1. Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha 
[LT-α]) to cell surface TNF receptors, rendering TNF biologically inactive. 
Etanercept is indicated in the United States for the treatment of : 1) moderately to 
severely active RA 2) moderately to severely active polyarticular juvenile idiopathic 
arthritis in patients aged 2 and older; 3) psoriatic arthritis; 4) active ankylosing 
spondylitis; and, 5) adult patients with chronic moderate to severe plaque PsO who are 
candidates for systemic therapy or phototherapy. 
Refer to the specific section of the Investigator’s Brochure, or the product label for 
additional information related to the physical, chemical, and pharmaceutical properties 
and formulation(s). 
2.4 
Rationale 
Limited data is available on the efficacy and tolerability of etanercept in patients with 
inadequate response to apremilast.  This study will evaluate the use of etanercept in 
subjects with inadequate response to apremilast for reasons of either primary failure, 
secondary failure or intolerability.  There is a current trend of Dermatologists adopting 
the use of apremilast as an oral therapy option for psoriasis. Despite the convenient 
administrative route, it is anticipated that there may be a growing population of active 
psoriasis patients who will need to be switched or require additional therapy for reasons 
of failure to respond to apremilast or intolerance to apremilast. This study aims to 
characterize the response to etanercept in this population.  There is also a need to better 
understand patient oriented measures in psoriasis patients, and this study seeks to 
characterize PRO including a novel instrument termed the PSI, in response to 
etanercept treatment. 
2.5 
Clinical Hypotheses 
A formal hypothesis will not be tested in this study. This study will estimate the 
proportion of subjects with PsO who achieve a PASI 75 after 12 weeks of treatment with 
etanercept following failure of treatment with apremilast. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multicenter, open-label, single-arm, phase 4 estimation study in subjects with 
PsO who have failed apremilast. Approximately 80 subjects will be enrolled in the study, 
among which at least 10 subjects (and not to exceed 20) will be enrolled for reasons of 
intolerability to apremilast in the investigator’s opinion. The remaining 60 to 70 subjects 


 
 
 
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will be enrolled for reasons of primary or secondary failure to apremilast in the 
investigator’s opinion.  The study consists of up to a 45 day screening period, a 24-week 
treatment period with study visits every 4 weeks and a 30-day follow-up period for 
safety. Etanercept dosing will follow the recommended label dosing for patients with 
plaque PsO. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 20 sites in North America 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”. Approximately 
80 subjects will be enrolled. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The planned length of participation in the study for an individual subject is approximately 
8 months. This includes up to a 45-day screening period, a 24-week treatment period 
and a safety follow-up phone call 30-days after the last dose of etanercept.  
3.5.2 
End of Study 
The end of study (end of trial) is defined as the time when the last subject is assessed or 
receives an intervention for evaluation in the study. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  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).   


 
 
 
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4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Male or female subject is ≥ 18 years of age at time of screening. 
103 
Subject is a candidate for systemic therapy or phototherapy in the opinion of the 
investigator. 
104 
Subject has moderate to severe plaque PsO with involved BSA ≥ 10%, 
PASI ≥ 10 and sPGA ≥ 3 at screening and baseline. 
105 
Subject is currently receiving treatment with apremilast for moderate to severe 
plaque PsO or subject has discontinued treatment with apremilast for PsO within 
the past 3 months prior to screening.   
106 
Subject has failed therapy with apremilast for moderate to severe plaque PsO 
defined as either (1) failure to achieve adequate clinical response in the opinion 
of the investigator, (2) loss of adequate clinical response in the opinion of the 
investigator or (3) intolerability to apremilast in the opinion of the investigator.  A 
total of at least 10 and no more than 20 subjects may be enrolled for 
intolerability.   
107 
Subject has received at least 4 weeks of apremilast treatment for moderate to 
severe plaque PsO (this only applies for subjects who are qualifying by failure to 
achieve adequate clinical response or loss of adequate clinical response; this 
does not apply for subjects who are qualifying by intolerability to apremilast). 
108 
Subject has not had significant known weight increase or decrease (≥ 10%) 
during apremilast treatment. 
109 
Subject is < 264 lbs at screening and baseline. 
110 
Subject has a negative test for hepatitis B surface antigen, hepatitis B core 
antibody and hepatitis C antibody. 
111 
Subject has no known history of tuberculosis. 
112 
Subject has a negative test for tuberculosis during screening defined as either: 
• 
negative tuberculin purified protein derivative (PPD) (< 5 mm of induration at 
48 to 72 hours after test is placed) OR 
• 
negative Quantiferon test 
Subjects with a positive PPD and a history of Bacillus Calmette-Guérin 
vaccination are allowed with a negative Quantiferon test. 
Subjects with a positive PPD test (without a history of Bacillus Calmette-Guérin 
vaccination) or subjects with a positive or indeterminate Quantiferon test are 
allowed if they have ALL of the following: 
• 
no symptoms per tuberculosis worksheet provided by Amgen Inc. 
• 
documented history of a completed course of adequate treatment or 
prophylaxis per local standard of care prior to the first dose of etanercept 


 
 
 
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• 
no known exposure to a case of active tuberculosis after most recent 
prophylaxis 
• 
no evidence of active tuberculosis on chest radiograph within 3 months prior 
to the first dose of etanercept 
113 
Subject if female and not at least 2 years postmenopausal or history of 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, has a negative 
serum pregnancy test ≤ 4 weeks from starting etanercept and a negative urine 
pregnancy test at baseline (day 1). 
114 
Subject or designee must have the ability to inject etanercept subcutaneously. 
4.1.2 
Exclusion Criteria 
Skin disease related 
201 
Subject has active erythrodermic, pustular, guttate psoriasis, or medication-
induced psoriasis, or other skin conditions at the time of the screening visit 
(eg,eczema) that would interfere with evaluations of the effect of investigational 
product on PsO. 
Other Medical Conditions 
202 
Subject has one or more significant concurrent medical conditions per          
investigator judgment, including the following: 
• 
poorly controlled diabetes 
• 
chronic kidney disease stage IIIb, IV, or V 
• 
symptomatic heart failure (New York Heart Association class II, III, or IV) 
• 
myocardial infarction or unstable angina pectoris within the past 12 months 
prior to randomization 
• 
uncontrolled hypertension 
• 
severe chronic pulmonary disease (eg, requiring oxygen therapy) 
• 
multiple sclerosis or any other demyelinating disease 
• 
liver disease  
• 
anemia 
• 
major chronic inflammatory disease or connective tissue disease other than 
psoriasis and/or psoriatic arthritis (eg, systemic lupus erythematosus with the 
exception of secondary Sjogren’s syndrome) 
203 
Subject has active malignancy, including evidence of cutaneous basal or 
squamous cell carcinoma or melanoma, Merkel cell carcinoma, or history of 
cancer (other than fully resected and surgically cured cutaneous basal cell and 
squamous cell carcinoma) within 5 years before the first dose of investigational 
product. If malignancy occurred more than 5 years ago, documentation of 
disease-free state since treatment is required. 
204 
Subject has known history of alcoholic hepatitis, non-alcoholic steatohepatitis or 
hepatitis B or C or immunodeficiency syndromes including Human 
Immunodeficiency Virus infection. 


 
 
 
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205 
Subject has any condition that, in the opinion of the investigator, might cause the 
study to be detrimental to the subject. 
206 
Subject has any active infection (including chronic or localized infections) for 
which anti-infectives were indicated within 4 weeks prior to the first dose of 
investigational product. 
207 
Subject has a serious infection, defined as requiring hospitalization or 
intravenous anti-infectives within 8 weeks before screening. 
208 
Subject has any condition that could, in the opinion of the investigator, 
compromise the subject’s ability to give written consent and/or comply with the 
study procedures, such as a history of substance abuse or a psychiatric condition 
including suicidal ideation/attempt.  
Washouts and Disallowed Medications 
209 
Subject has used any of the following therapies within 2-weeks prior to the first 
dose of etanercept: 
• 
Ultraviolet light B (UVB) therapy 
• 
Topical preparations of cyclosporine, a vitamin A or D analog, or a calcineurin 
inhibitor 
• 
Topical steroids (exception: upper mid-strength or lower potency topical 
steroids are permitted on the scalp, axillae, and groin at the discretion of the 
investigator) 
210 
Subject has used any of the following therapies within 4-weeks prior to the first 
dose of etanercept: 
• 
Ultraviolet light A (UVA) with or without Psoralen (PUVA) therapy 
• 
Oral retinoids 
• 
Intravenous or oral calcineurin inhibitors 
• 
Anthralin 
• 
Any other systemic psoriasis therapy (eg, cyclosporine, azathioprine, 
fumarates, hydroxyurea and thioguanine), including oral or parenteral 
corticosteroids 
• 
Cyclophosphamide 
• 
Sulfasalazine 
• 
Methotrexate 
211 
Subject has used a biologic agent for PsO AND either: 
• 
Did not have a documented satisfactory response as defined by sPGA 0 or 1 
or clear or almost clear or the equivalent in the opinion of the investigator.  
Subjects who had a satisfactory response to a biologic for psoriasis and then 
lost satisfactory response are allowed, unless the biologic was etanercept.   
OR 
• 
Subject had a clinically significant adverse event (eg, serious infection, 
neurologic event, malignancy, hematologic event, or any other adverse event 
that the investigator feels might cause this study to be detrimental to the 
subject). 


 
 
 
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212 
Subject has used interleukin 12/23 inhibitors within 6 months of the first dose of 
etanercept or has used other biologic therapies for psoriasis within 3 months 
prior to the first dose of etanercept. 
213 
Subject has used a biologic agent for PsO after discontinuing apremilast 
treatment. 
214 
While receiving apremilast treatment or after discontinuing apremilast,            
subject had a clinically significant adverse event (eg, serious infection,           
neurologic event, malignancy, hematologic event, psychiatric adverse event such 
as depression or suicidal ideation/attempt) or any other adverse event that the 
investigator feels might cause this study to be detrimental to the subject. 
215 
Subject has used a live vaccine within 1 month prior to the first dose of 
etanercept. 
Laboratory Abnormalities 
216 
Subject has laboratory abnormalities at screening, including: 
• 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
≥ 1.5x the upper limit of normal (ULN) 
• 
Serum total bilirubin (TBL) ≥ 1.5 mg/dL  
• 
Hemoglobin < 11 g/dL 
• 
Platelet count < 125,000/mm3 
• 
White blood cell count < 3,000 cells/mm3 
• 
Absolute neutrophil count (ANC) < 1,500/mm3 
• 
Estimated creatine clearance < 50 mL/min (Cockroft-Gault formula, calculated 
value to be provided to sites) 
217 
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, will interfere with the interpretation of the study results, or might cause the 
study to be detrimental to the subject. 
Other 
218 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies). Other investigational procedures while participating in this study 
are excluded. 
219 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
220 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, PROs) to 
the best of the subject and investigator’s knowledge. 
221 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 


 
 
 
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222 
Female subject is not willing to use acceptable method(s) of effective 
contraception during study treatment and for an additional 4 weeks after the last 
dose of etanercept (except those who have had a hysterectomy, bilateral 
salpingectomy or bilateral oophorectomy, or who are at least 2 years 
postmenopausal).  
Note:  Additional medications given during treatment with etanercept may 
increase the length of time that subjects must avoid becoming pregnant or 
breastfeeding after the last dose of study drugs. The investigator is to discuss 
these changes with the subject if applicable. 
223 
Subject is pregnant or breast feeding, or planning to become pregnant or 
breastfeed during the study treatment and through 4 weeks after the last dose of 
etanercept.  
Note:  Additional medications given during treatment with etanercept may 
increase the length of time that subjects must avoid becoming pregnant or 
breastfeeding after the last dose of study drugs. The investigator is to discuss 
these changes with the subject if applicable. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the IRB/IEC and Amgen approved informed 
consent form before commencement of study-specific activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned by IVR/IWR system. 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.  Subjects who are unable to complete or meet 
eligibility on initial screening will be permitted to re-screen twice (see Section 7.2.2). 
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 
Treatment Assignment 
All subjects enrolled in the study will be assigned open-label etanercept treatment. The 
treatment assignment date is to be documented in the subject’s medical record and on 
the enrollment CRF. 
6. 
TREATMENT PROCEDURES 
The Amgen Investigational Product(s) used in this study include(s): etanercept.  
The investigational medical device used in this study include(s): prefilled syringe 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of etanercept.  
6.1 
Investigational Product 
6.1.1 
Amgen Investigational Product: Etanercept 
Etanercept will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures. Etanercept will be supplied in a 
single-use prefilled 1.0 mL syringe as a sterile, preservative-free solution for 
subcutaneous injection. The solution of etanercept is clear and colorless and is 
formulated at pH 6.3 ± 0.2.  Each single-use prefilled syringe contains 0.98 mL of 
50 mg/mL etanercept in a formulation consisting of 100 mM Sodium Chloride, 25 mM 
sodium phosphate, 25 mM L-Arginine-HCL, and 1% sucrose.  Etanercept will be 
provided in packs with 4 syringes. 
6.1.1.1 
Dosage, Administration, and Schedule 
Etanercept dosing will follow the recommended label dosing for patients with PsO: 
50 mg subcutaneously, twice weekly for 12 weeks followed by 50 mg subcutaneously 
once weekly (for the additional 12 weeks).  
Each dose of etanercept will consist of the complete contents of 1 pre-filled syringe. 
Injections should occur in the thigh, abdomen or outer area of the upper arm.  The 
injection site should be rotated with each dose. 
During the first 12 weeks of the study, subjects will receive 2 doses of etanercept per 
week (eg, on Monday and Thursday).  During the second 12 weeks of the study, 
subjects will receive 1 dose of etanercept per week (scheduled approximately 7 days 
apart). Throughout the entire trial, 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 2 days of the next scheduled dose. If the dosing window is missed, 


 
 
 
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that dose should be skipped. Subsequent doses of etanercept should resume on the 
original schedule. If etanercept is to be taken the day of a study visit, it must be taken 
after the study visit has occurred. 
Injections of etanercept will be administered by the subject or a caregiver. The individual 
administering the dose must demonstrate to the site staff that he or she is competent to 
correctly administer the subcutaneous doses. The first dose of etanercept must be 
administered at the study site. All subsequent doses will be administered at the subject’s 
location on the scheduled dose day. Supplies of etanercept will be dispensed to subjects 
for administration at home. The subject will be instructed in appropriate handling and 
storage of used and unused syringes.   
The dose, start date, stop date, dose time and box number of etanercept are to be 
recorded on each subject’s CRF.  
The effects of overdose of etanercept are not known.  
There may not be any adjustment of etanercept dosage other than the protocol-specified 
reduction from 50 mg twice weekly for the first 12 weeks of the study to 50 mg once 
weekly for the second 12 weeks. 
Please refer to the US Prescribing Information or the Etanercept Investigator’s Brochure 
for the most recent safety information.  
6.2 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, TBL, and/or international normalized ratio [INR] and/or signs/symptoms of 
hepatitis) as described below may meet the criteria for withholding or permanent 
discontinuation of Amgen investigational product or other protocol-required therapies as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009. 


 
 
 
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6.2.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product 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 > 2x 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 
< 1.5x ULN 
> 3x ULN 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
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, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if etanercept should be withheld or permanently 
discontinued, as deemed appropriate for the safety of the subject.  
6.2.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product 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 


 
 
 
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transaminases and TBL < 1.5x ULN at baseline or subjects with underlying liver disease 
and baseline abnormal transaminases, the following rules are recommended for 
withholding of Amgen investigational product and other protocol-required therapies:  
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).   
• 
OR: TBL > 3x ULN at any time 
• 
OR: ALP > 8x ULN at any time 
Etanercept should be withheld pending investigation into alternative causes of DILI.  If 
investigational product(s) 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 
(Section 6.2.3). 
6.2.3 
Criteria for Rechallenge of Amgen Investigational Product 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 (as 
described in Section 6.2.1) should never be rechallenged. 
6.3 
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 6.6. 
Concomitant therapies are to be collected in the CRF from baseline (day 1) through the 
end of treatment. 


 
 
 
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For concomitant therapies being taken for PsO, 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. 
6.4 
Medical Devices 
The following medical device: prefilled syringe will be used in this study and provided by 
Amgen.  Additional details for each medical device is to be provided in the IPIM.    
Other medical devices, which are not considered test articles, may be used in the 
conduct of this study as part of standard care.  These devices that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices.   
6.5 
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) or device(s) provisioned and/or repackaged /modified by 
Amgen.  Drug(s) or device(s) includes etanercept and prefilled syringe. 
Any product complaint(s) associated with an investigational product or device supplied 
by Amgen are to be reported according to the instructions provided in the IPIM. 
6.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Proscribed medications during this study include the following: 
• 
Any biologic immune modulator (other than etanercept), including but not limited to 
alefacept, anakinra, adalimumab, infliximab, secukinumab, ustekinumab 
• 
Apremilast 
• 
Azathioprine 
• 
Cyclophosphamide 
• 
Cyclosporine 
• 
Fumarates 
• 
Hydroxyurea 
• 
Leflunomide 
• 
Live vaccines (eg, measles, mumps, and rubella; varicella; intranasal flu) 


 
 
 
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• 
Methotrexate 
• 
Mycophenolate mofetil 
• 
Oral or parenteral corticosteroids including intramuscular or intra-articular 
administration (the use of otic, nasal, or inhaled corticosteroids within recommended 
doses is allowed) 
• 
Oral retinoids 
• 
Sulfasalazine 
• 
Systemically administered calcineurin inhibitors 
• 
Tofacitinib 
• 
Any other systemic therapy for psoriasis 
• 
Any investigational therapy 
• 
Thioguanine 
• 
Topical steroids (exception: upper mid-strength or lower potency topical steroids are 
permitted on the scalp, axillae, and groin at the discretion of the investigator) 
• 
Topical vitamin A or D analog preparations, or anthralin 
• 
Topical cyclosporine or other calcineurin inhibitors 
• 
PUVA therapy 
• 
UVA therapy 
• 
UVB therapy 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 
(Schedule of Assessments) can only be performed after obtaining informed consent.  
This includes any discontinuation of the subject’s medication for the purpose of 
participation in this study. 
All study visits should be scheduled from day 1 (date of the first dose of etanercept) of 
the study.  It is very important to attempt to perform study procedures and obtain 
samples at the precise timepoints stipulated in Table 1.  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 in Table 1.  
With the exception of the screening and re-screen visits, all study procedures for a visit 
should be completed on the same day.  Any missed visits, tests not done, or 
examinations that are not conducted must be reported as such on the CRFs.  
Subsequent study visits should resume on the original schedule.  Missed assessments 
at prior visits should not be duplicated at subsequent visits.  


 
 
 
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Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling procedures. 
7.1 
Schedule of Assessments   


 
 
 
 
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Table 1.  Schedule of Assessments 
 
Screening 
Treatment Period 
Safety Follow-up 
Period 
Study Visit 
Up to 
45 days 
Day 1 
(baseline) 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24/ 
ET 
30-day (phone call) 
(EOS) 
General and Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
 
Disease related events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease Assessments 
PASI 
X 
X 
X 
X 
X 
X 
X 
X 
 
sPGA 
X 
X 
X 
X 
X 
X 
X 
X 
 
Involved BSA 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Reported Outcomes 
PSIb 
 
X 
X 
X 
X 
X 
X 
X 
 
Patient Assessment of Treatment 
Satisfaction 
 
X 
 
 
X 
 
 
X 
 
DLQI 
 
X 
 
 
X 
 
 
X 
 
Laboratory Assessments 
Hematology profile 
X 
X 
 
 
X 
 
 
X 
 
Chemistry profile 
X 
X 
 
 
X 
 
 
X 
 
Hepatitis C virus antibody 
X 
 
 
 
 
 
 
 
 
Hepatitis B virus surface antigen and 
core antibody  
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
Pregnancy testc 
X 
X 
 
 
 
 
 
X 
 
Tuberculosis testing 
X 
 
 
 
 
 
 
 
 
Investigational Product  
Investigational product dispensation 
 
X 
X 
X 
X 
X 
X 
 
 
Subject Diary 
 
Subject diary dispensation/collection 
 
X 
X 
X 
X 
X 
X 
X 
 
Footnotes defined on next page 


 
 
 
 
Product:  Etanercept 
Protocol Number:  20150252 
Date:  5 February 2016   
Page 29 of 61 
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PASI= Psoriasis Area and Severity Index; sPGA = Static Physician’s Global Assessment; BSA = Body Surface Area; PSI = Psoriasis Symptom Inventory;  
DLQI = Dermatology Life Quality Index; ET: early termination; EOS: end of study 
a Screening physical exam will be a full physical exam; subsequent exams will be interim exams to monitor for any changes. 
b PSI to be completed at home at weeks 1, 2, and 3 as well as at each visit indicated. 
c Pregnancy test to be performed for all women except those of non-reproductive potential (ie, those who have had a hysterectomy, bilateral salpingectomy or 
ophorectomy, or who are at least 2 years postmenopausal). Serum pregnancy test at screening must be performed ≤ 4 weeks from the first dose of etanercept; Urine 
pregnancy test will be performed at baseline and Week 24 or ET visit.  


 
 
 
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7.2 
General Study Procedures  
The procedures performed at each study visit are outlined above in Table 1.  Details 
regarding each type of procedure are provided in subsequent sub-sections.   
Refer to the applicable supplemental central laboratory, IVR/IWR system, IPIM, and 
study manuals for detailed collection and handling procedures.   
7.2.1 
Screening 
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy. After signing the written 
informed consent form, site will register the subject in IVR/IWR and screen the subject in 
order to assess eligibility for participation. The screening window is up to 45 days. If a 
subject has not met all eligibility criteria at the end of the 45-day window, the subject will 
be registered as a screen fail. Screen fail subjects may be eligible for re-screening twice 
as described in Section 7.2.2.  
7.2.2 
Re-screening 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen twice. Re-screen subjects must first be registered as screen failed 
in IVRS/IWRS system 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 45-day screening window will begin.  If the 
re- screening period begins more than 30 days after the original signing of the informed 
consent form, all screening procedures, including informed consent must be repeated. If 
the re-screening occurs less than 30 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 re-screen. 
7.2.3 
Treatment  
Visits will occur per the Schedule of Assessments (Table 1) during the treatment period 
from day 1 (baseline) through week 24. On-study visits may be completed within 
± 5 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 etanercept is defined as day 1 (baseline). All subsequent 
doses and study visits will be scheduled based on the day 1 date. 


 
 
 
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Etanercept is to be administered at the site after all assessments have been done for all 
visits that will include dosing. Subjects ending the study prior to week 24 will be asked to 
complete the unscheduled early termination (ET) visit assessments which are the same 
as those listed in the Schedule of Assessments under Week 24/ET.  
7.2.4 
Safety Follow-up/End of Study 
Approximately 30 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 or disease related events and inquire about the emergence of any new serious 
adverse events or disease related 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 
Physical Examination and Medical History 
Physical examination should be completed as per standard of care.   Physical 
examination findings should be recorded on the appropriate CRF (eg, medical history, 
event). Any clinically significant changes in physical exam throughout the study, per the 
investigator’s opinion, should be recorded on the event CRF. 
The Investigator or designee will collect a complete medical and surgical history that 
started within 5 years prior to enrollment  through the first dose of etanercept. In addition 
to the medical history above, PsO history must date back to the original diagnosis. 
Medical history will include information on the subject’s concurrent medical conditions. 
Record all findings on the medical history CRF. 
7.3.4 
Medication History 
A complete history of psoriasis medications (including apremilast) starting at the time of 
diagnosis and up to screening will be recorded on the CRF. This information will include 
therapy name, indication, dose, unit, frequency, route, start date and stop date. All other 


 
 
 
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medications taken within 3 months prior to screening will be collected, including therapy 
name, indication, dose and start date and stop date. 
7.3.5 
Physical Measurements 
Height in inches and weight in pounds should be measured without shoes.  
7.3.6 
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 CRF. 
7.3.7 
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 prior to 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 prior to enrollment of the subject. 
7.3.8 
Adverse Events and Disease Related Events 
Adverse events, serious adverse events and disease related events observed by the 
investigator or reported by the subject will be collected as per Section 9. 
7.3.9 
Concomitant Medications 
Concomitant medications are to be collected from baseline (day 1) through the end of 
treatment as described in Section 6.3.   
7.3.10 
Subject Diary for Study Drug Administration 
7.3.10.1 
Distribution and Instruction 
All subjects should be able to complete entries in the subject diary in English or have a 
designee who can do so for the subject. All subjects will complete a diary which is 
dispensed per the schedule of assessments. Site staff must instruct the subject on 
accurate and complete documentation in the diary, which serves as a source document. 


 
 
 
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Subjects will complete the diary after each dose administered, including the first dose 
self-administered in the clinic. Subject is to record the date, time, dose of etanercept 
injection, injection site, etanercept box ID, any concomitant medications taken, and 
adverse events. 
7.3.10.2 
Collection and Review 
Subjects will return the diary at each study visit. . Site staff will review the diary with the 
subject to confirm the subject accurately reported all required information, including 
adverse events and concomitant medications, and will clarify entries, as necessary. Site 
staff will enter the data into the CRF. 
7.3.11 
Disease Assessments 
The assessor who performs the following assessments will be a licensed healthcare 
professional who has been certified as trained by Amgen standard training material for  
PASI, sPGA and BSA provided by Amgen OR who has been previously certified as 
trained with the standard training material provided by Amgen or by organizations such 
as Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 
(documentation of certification must be provided to Amgen).  If possible, each subject 
should have their assessments done by the same assessor throughout the study. If 
necessary, study visits may be rescheduled within the specified window “(± 3 days) to 
accommodate when the specific assessor will be available. 
7.3.11.1 
PASI 
PASI score (0 to 72) is a calculation of plaque qualities, including induration, erythema, 
and desquamation, and the area involved with psoriasis. The assessor will score plaque 
qualities (0 to 4) and area of involvement (0 to 6) for each of 4 body areas: head and 
neck, upper extremities, trunk, and lower extremities. Higher scores indicate more 
severe and/or extensive psoriasis. The PASI worksheet will be signed and dated by the 
PASI assessor and maintained in the subject’s source documents. 
7.3.11.2 
BSA Involvement 
The involved BSA numerical score (0% to 100%) is completed by the same assessor 
performing the sPGA assessment and will be used to measure the physician’s 
assessment of the proportion of the subject’s total BSA involved with psoriasis. 
7.3.11.3 
sPGA 
The sPGA is designed to evaluate the physician’s global assessment of the subject’s 
psoriasis based on severity of induration, scaling, and erythema.  The sPGA is assessed 


 
 
 
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on a scale of 0 to 5.  It is important that each subject have their sPGA assessments 
done by the same assessor throughout the study.   
7.3.12 
Patient Reported Outcomes 
7.3.12.1 
Psoriasis Symptom Inventory  
The subject will be asked to rate the severity of their psoriasis signs and symptoms on 
an 8-item questionnaire (itch, redness, scaling, burning, stinging, cracking, flaking, pain).  
Each item is scored from 0 (not at all severe) to 4 (very severe).  A 7-day recall period 
will be utilized and the PSI will be completed by the subject on paper version at baseline 
and weeks 1, 2, 3 and then at each visit. 
7.3.12.2 
 Patient Assessment of Treatment Satisfaction 
The subject will be asked to check a box (from “very dissatisfied” to “very satisfied”) to 
indicate his or her level of satisfaction with the medication’s control of psoriasis.  The 
response scale is adapted from the Medical Outcomes Study: Patient Satisfaction 
Survey. 
7.3.12.3 
Dermatology Life Quality Index 
Health related quality of life will be evaluated using the DLQI, a skin disease-specific 
instrument that has been validated for use in patients with psoriasis 
(Finlay and Khan, 1994).  
7.4 
Laboratory Assessments 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory with the exception of urine pregnancy and PPD. The central laboratory will be 
responsible for all screening and on-study serum chemistry, hematology, serum 
pregnancy, urinalysis, hepatitis C antibody, hepatitis B surface antigen and core 
antibody, and any other laboratory tests required. Urine pregnancy and PPD testing will 
be performed locally at each site. 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 etanercept administration (if etanercept is to be administered on the same day as 
a study visit) at the time points outlined in the Schedule of Assessments (Table 1). The 
date and time of sample collection will be recorded in the source documents at the site.  
Specific analytes for serum chemistry, hematology, urinalysis, and other testing to be 
conducted on blood and urine samples are below (Table 2).  


 
 
 
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Table 2.  Analyte Listing 
Sodium 
Chemistry 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN 
Creatininea 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
Specific gravity 
Urinalysis 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Leukocyte esterase 
Ketones 
Microscopic (Reflex 
testing if abnormal) 
Red blood cells 
Hematology and 
Differential 
Red blood cell 
morphology 
Hemoglobin 
Hematocrit 
Platelets 
White blood cell 
Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
• 
Monocytes 
Serum beta hCGb 
Other Labs 
Hepatitis B surface 
antigen and Hepatitis 
B core antibody 
Hepatitis C virus 
antibody 
Quantiferonc 
a Estimated creatine clearance will be calculated using the Cockroft-Gault formula. 
b For all women, unless at least 2 years postmenopausal or history of hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy. If a pregnancy is suspected, additional pregnancy testing may be performed at 
the discretion of the investigator. 
c If applicable 
7.4.1 
Tuberculosis Testing 
All subjects must receive either a PPD or Quantiferon test at screening per the Inclusion 
Criteria.  PPD testing should be performed unless contraindicated.   
7.4.1.1 
PPD 
The PPD 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. 
7.4.1.2 
Quantiferon 
If a subject does not receive a PPD test, then a Quantiferon test must be performed per 
the Inclusion Criteria.  Please refer to the central laboratory manual for instructions on 
sample collection, processing, and shipping of samples (if applicable).    
7.4.2 
Urine Pregnancy Test 
Urine pregnancy tests will be performed locally at each site.  All women, except those of 
non-reproductive potential (ie, those who have had a hysterectomy, bilateral 


 
 
 
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salpingectomy, or bilateral oophorectomy, or who are at least 2 years postmenopausal), 
must take a urine pregnancy test at baseline.  The central laboratory will provide the 
urine pregnancy tests.  Urine pregnancy tests must be given prior to dispensing 
investigational product.    
7.5 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
inflammatory conditions, the dose response and/or prediction of response to etanercept, 
and characterize aspects of the molecule (eg, mechanism of action/target, metabolites).  
Results from this analysis are to be documented and maintained, but are not necessarily 
reported as part of this study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of exploratory studies are not placed in the subject’s 
medical record and are not to be made available to the subject, members of the family, 
the personal physician, or other third parties, except as specified in the informed 
consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 


 
 
 
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The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 1) and 
collection of data, including endpoints and adverse events.  The investigator must 
document the change to the Schedule of Assessments (Table 1) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   


 
 
 
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8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From 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, lost to follow-up) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  Disease related events for the purposes 
of this study include worsening of the skin symptoms associated with PsO.  Such events 
do not meet the definition of an Adverse Event unless assessed to be more severe than 
expected for the subject’s condition.  


 
 
 
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Disease Related Events and/or Disease Related Outcomes that do not qualify as 
Serious Adverse Events:  
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease Related Event.  
• 
Death due to the disease under study is to be recorded on the Event CRF. 
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the investigational product(s)/study treatment protocol required therapies and 
disease worsening, this must be reported as an Adverse Event or Serious Adverse 
Event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease (eg, 
diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
An adverse device effect is any adverse event related to the use of a medical device. 
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device.  
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   


 
 
 
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9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease related event as described above 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 patient with the same underlying condition, or 
• 
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 above. 
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 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Reporting Procedures for Disease Related Events 
The investigator is responsible for ensuring that all Disease Related Events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
medicinal product(s)/study treatment/protocol-required therapies through the safety 
follow-up (ie, 30 days after the last dose of etanercept) are reported using the Event 
CRF.  Additionally, the investigator is required to report a fatal Disease Related Event on 
the Event CRF.   


 
 
 
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Events assessed by the investigator to be related to the investigational medicinal 
product(s)/study treatment/protocol-required therapies, and determined to be serious, 
require reporting of the event on the Event CRF.  
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product 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 
• 
Action taken 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.  The grading scale used in this study is described 
in Appendix A.  The investigator must assess whether the adverse event is possibly 
related to the investigational product.  This relationship is indicated by a “yes” or “no” 
response to the question:  Is there a reasonable possibility that the event may have been 
caused by the investigational product?   
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Adverse Event 
Summary CRF. 
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. 


 
 
 
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The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent  through the 30-day safety follow-up period 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.   
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
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. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the 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. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 


 
 
 
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in compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.2.2.4 
Serious Adverse Events That Are not to be Reported In an 
Expedited Manner  
The study population involved will have an increased burden of comorbidities which are 
commonly associated with psoriasis 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 hypertension, obesity, type 2 diabetes, metabolic syndrome, myocardial 
infarction, angina, coronary artery disease, cerebrovascular accident, peripheral 
vascular disease, depression and anxiety. These serious adverse events will be 
monitored with routine pharmacovigilance on an ongoing basis.  
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
through 4-weeks after the end of treatment with etanercept.  


 
 
 
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The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).   
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through 
4 weeks after the end of treatment with etanercept.  
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C). 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
PASI 75 at week 12 
10.1.1.2 
Secondary Endpoints 
• 
PASI 75 at all other visits 
• 
PASI 50 and 90 at all visits 
• 
Percent PASI improvement at all visits 
• 
sPGA of 0 or 1 at all visits 
• 
sPGA of 0, 1, or 2 at all visits 
• 
sPGA at all visits 
• 
One and two grade improvement in sPGA at all visits 
• 
Percent BSA improvement at all visits 
• 
PSI total and component scores at all visits 
• 
Patient Assessment of Treatment Satisfaction at week 12 and 24 
• 
Improvement in DLQI at week 12 and 24 
10.1.1.3 
Safety Endpoints 
• 
Adverse events 
• 
Laboratory assessments 


 
 
 
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10.1.2 
Analysis Sets 
The full analysis set is all subjects who received at least one dose of investigational 
product during the study.  All safety and efficacy endpoints will be analyzed using the full 
analysis set. 
10.1.3 
Covariates and Subgroups 
The following predictors and subgroup analyses may be performed to assess their 
influence on the primary endpoint: 
• 
Body mass index (≤ 35 kg/m2  or > 35 kg/m2) 
• 
Body Weight (≤ median, > median) 
• 
Age (<65, ≥ 65) 
• 
Gender (male vs.  female) 
• 
Race (white, non-white) 
• 
Ethnicity (Hispanic or Latino, Non-Hispanic or Latino) 
• 
Baseline PASI score (≤ median, > median) 
• 
Baseline BSA with psoriasis involvement (%) (≤ median, > median) 
• 
History of psoriatic arthritis (yes, no) 
• 
Baseline sPGA score (3, 4 or 5) 
10.2 
Sample Size Considerations 
This study will estimate the proportion of subjects with PsO who achieve a PASI 75 after 
12 weeks of treatment with etanercept following failure of treatment with apremilast.   
In recent etanercept studies, the 12-week PASI 75 response rate for etanercept was 
~50 to 60%.  The assumed response for a population with failure of treatment with 
apremilast is 40%.  In placebo-controlled phase 3 studies, the PASI 75 placebo 
response rate was ~5% in subjects with moderate to severe plaque PsO.  Therefore, in 
this single-arm study if the lower bound of the 95% confidence interval for the proportion 
of PASI 75 response is above 10%, we can safely conclude that in spite of limitations of 
a single-arm study (ie, regression to the mean and/or placebo effect), the etanercept 
effect is real. 
The sample size of 80 is more than adequate to achieve a half-width of less than 15% 
for the 95% confidence interval for the proportion of subjects who achieve a PASI 75 
response, assuming a sample proportion of 40% and a lower bound of the confidence 
interval above 10%.   


 
 
 
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In a phase 3, randomized, double-blind, placebo-controlled apremilast trial, 17% of 
subjects reported diarrhea and/or nausea.  Of the 80 subjects enrolled, 60 subjects will 
be enrolled for reasons of primary or secondary failure to apremilast in the investigator’s 
opinion. In addition, between 10 and 20 (up to 25%) will be enrolled for reasons of 
intolerability to apremilast in the investigator’s opinion.   
10.2.1 
Planned Analysis 
10.2.2 
Primary Analysis 
The primary analysis for all efficacy endpoints will be performed using the full analysis 
set. Missing values will be imputed using last observation carried forward method. 
Summary statistics will be generated as well as confidence intervals and p-values. No 
multiplicity adjustments will be made for the p-values. 
No interim analysis is planned for this study. 
10.2.3 
Sensitivity Analysis 
A sensitivity analysis will be performed using observed cases. 
10.3 
Planned Methods of Analysis  
10.3.1 
General Considerations 
This is an open-label single-arm study. 95% confidence intervals and p-values for 
estimated response rates will be generated for descriptive purposes only. 
The final analysis will be performed after all subjects have completed the week 24 
assessments and all data through week 24 and the 30-day safety follow-up (EOS) have 
been finalized. Subject disposition, demographics, and baseline disease characteristics 
will be summarized descriptively for all subjects. 
10.3.2 
Efficacy Endpoints 
The primary analysis for all efficacy endpoints will be performed using the full analysis 
set. Missing values will be imputed using last observation carried foraward method. 
Summary statistics will be generated as well as confidence intervals and p-values.  
For efficacy analyses, all categorical endpoints will be summarized using number and 
percentage of subjects. In addition to being summarized using number and percentage 
of subjects, ordinal categorical endpoints will also be summarized using number of 
observations, mean, standard error, standard deviation, median, minimum, and 
maximum. All continuous endpoints will be summarized using number of observations, 
mean, standard error, standard deviation, median, minimum, and maximum. 
Subgroup analysis may be considered as described in Section 10.1.3. 


 
 
 
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10.3.3 
Safety Endpoints 
Safety endpoints will be summarized descriptively based on the full 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, and significant 
treatment-emergent adverse events will be provided.  
Subject incidence of disease related events and fatal disease related events will be 
tabulated by system organ class and preferred term. 
Laboratory parameters and vital signs will be summarized by study visit. Shift tables of 
the worst on-study laboratory toxicity based on CTCAE version 4.0 relative to baseline 
will be tabulated. Subject listings of grades 3 and 4 laboratory toxicities will be provided.  
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 Clinical Study Manager to the investigator.  
The written informed consent document is to be prepared in the language(s) of the 
potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form  is to be signed and personally dated by the 


 
 
 
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subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
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.   
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 


 
 
 
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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 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, 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 ID, enrollment date, investigational product 
dispensation date and investigational product box number dispensed. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data).  In this study, PROs 
noted in Schedule of Assessments will be considered as source document.  
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 (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
Non-investigational product(s) and or medical device(s) 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 Amgen 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. 


 
 
 
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The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global R&D Compliance and Audit (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 electronic data 
capture 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 trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.   
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 


 
 
 
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stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 1), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication of  
Scholarly Work in Medical Journals (International Committee of Medical Journal Editors, 
2013, updated 2014), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work 
are appropriately investigated and resolved.  Authors should meet conditions 1, 2, 3 
and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
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 
Etanercept Investigator’s Brochure. Thousand Oaks, CA. Amgen Inc. 
Enbrel (etanercept) Prescribing Information, Thousand Oaks, CA, Amgen Inc. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994;19:210–216. 
International Committee of Medical Journal Editors, Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals 2013: 
http://www.icmje.org/ 
Menter A, Gottlieb A, Feldman SR et al. Guidelines of care for the management of 
psoriasis and psoriatic arthritis. Section 1. Overview of psoriasis and guidelines of care 
for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-50. 
Otezla Prescribing Information. Summit, NJ. Celgene Corporation. 


 
 
 
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14. 
APPENDICES 


 
 
 
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Appendix A.  Additional Safety Assessment Information 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 is available 
at the following location: 
Adverse Event Grading Scale 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments  
To facilitate appropriate monitoring for signals of drug induced liver injury (DILI), cases of 
concurrent AST or ALT and TBL and/or INR elevation according to the criteria specified 
in Section 
Reporting 
6.2 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 the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
All subjects in whom investigational product is withheld (either permanently or 
conditionally) due to potential DILI as specified in Section 
Additional Clinical Assessments and Observation 
6.2.1 and 6.2.2 or who 
experience AST or ALT elevations > 3 x ULN are to undergo a period of “close 
observation” until abnormalities return to normal or to the subject’s baseline levels.  
Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
− 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 


 
 
 
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− 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody, Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 to assess for 
autoimmune hepatitis 
− 
Obtain serum acetaminophen (paracetamol) levels 
− 
Obtain a more detailed history of:  
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
• 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all investigational 
product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 


 
 
 
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Appendix B.  Sample Electronic Adverse Event Contingency Report Form 
 


 
 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


 
 
 
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