Conditions: Psoriatic Arthritis
Keywords: Psoriatic Arthritis CC-10004 MRI apremilast
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 123
Healthy volunteers: no

Brief summary:
This study is designed to assess the efficacy of apremilast, either in monotherapy or with stable methotrexate, on imaging outcomes in adults with active psoriatic arthritis with less than 5 years of disease duration (since diagnosis), and who are naïve to biologic therapies.

Detailed description:
This study consists of 3 phases:

* Screening Phase - up to 4 weeks
* Single-arm, Open-label Treatment Phase - Weeks 0 to 48

  * Participants will receive apremilast 30 mg BID (after a 5-day titration period) for the entire duration of this phase.
  * MRI of the most affected hand and whole body MRI (WB-MRI) will be performed at weeks 0, 24, and 48.
  * The hand with the greater inflammatory burden of swollen joints and/or dactylitis will be considered as the most affected hand. If both hands are equally affected, the dominant hand will be designated as the index hand.
* Observational Follow-up Phase - 4 Weeks

  * All participants who complete the study or discontinue early will participate in the 4-week Post-Treatment Observational Follow-up Phase.

Arms:
arm 1: Participants will receive apremilast 30 mg twice a day for 48 weeks.

Interventions: intervention 1: Apremilast
Intervention descriptions: intervention 1: Tablets for oral administration

Protocol document:
Prot_002.pdf: 
EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
1
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
TITLE PAGE
A PHASE 4, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE IMPACT OF 
APREMILAST (CC-10004) ON MRI OUTCOMES IN 
SUBJECTS WITH PSORIATIC ARTHRITIS
PROTOCOL NUMBER:
CC-10004-PSA-014
DATE FINAL:
14 AUG 2018
DATE AMENDMENT No. 1 FINAL:
21 SEP 2018
DATE AMENDMENT No. 2 FINAL:
12 FEB 2019
DATE AMENDMENT No. 3 FINAL:
17 MAY 2019
DATE AMENDMENT No. 4 FINAL:
04 MAY 2020
EudraCT NUMBER:
2018-002748-10
IND NUMBER:
101761
NCT No.
NCT03783026
SPONSOR NAME/ADDRESS:
Amgen Inc,
Amgen Center Dr, Thousand Oaks, CA 
91320
USA
Confidentiality Notice 
This document contains confidential information of Amgen. 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. If you have questions regarding how this document may be used 
or shared, call the Amgen Medical Information number: 1- 800-77-AMGEN 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
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Confidential and Proprietary
2
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
MEDICAL MONITOR/EMERGENCY CONTACT INFORMATION 
Contact 
Information 
Global
Name:
 MD
Title:
Medical Director Global Development
Amgen Inc.
Address: 
Amgen Inc,
Amgen Center Dr, Thousand Oaks, CA 91320
USA
Phone:
E-mail:
Note: Only call Amgen Medical Information, if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls. 
Amgen Medical Information: 1- 800-77-AMGEN (1 800-772-6436)
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
[See appended electronic signature page]
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, Vice President and Head of Immunology &Fibrosis Clinical 
Development
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable. 
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable. NOTE: Signed by Celgene based on Approval from Amgen 
Therapeutic Head 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Amgen representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
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CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
PROTOCOL SUMMARY
Study Title
A Phase 4, Multicenter, Single-Arm, Open-Label Study to Evaluate the Impact of Apremilast 
(CC-10004) on MRI Outcomes in Subjects with Psoriatic Arthritis
Indication
Psoriatic arthritis (PsA) is a heterogeneous inflammatory rheumatologic disorder characterized 
by peripheral arthritis, affecting 6% to 39% of patients suffering from psoriasis. PsA is classified 
as a seronegative spondyloarthropathy (SpA) because it shares certain features with other 
conditions included in that group. Indeed, spinal involvement has been reported in approximately 
50% of patients with PsA. In addition, PsA is associated with enthesitis and dactylitis, which are 
extra-articular features common to SpA. Finally, the majority of patients with PsA are negative 
for the rheumatoid factor (Gladman, 2005; Kruithof, 2005).
Apremilast (CC-10004) is an oral phosphodiesterase enzyme (PDE) inhibitor. It is highly 
selective for PDE4, which is the dominant PDE in inflammatory cells. Through inhibiting PDE4, 
apremilast elevates intracellular cyclic adenosine monophosphate levels, leading to a partial 
inhibition of the production of many pro-inflammatory mediators, as well as an increase in some 
anti-inflammatory mediators. A recent study in subjects with PsA indicated that apremilast was 
associated with reductions in tumor necrosis factor–α (TNF-α), interleukin (IL)-17, IL-23, IL-6, 
IL-8, macrophage inflammatory protein-1β, and monocyte chemoattractant protein 1, as well as
increases in anti-inflammatory mediators, including IL-10 and the IL-1 receptor antagonist
(Schafer, 2015). It is believed, therefore, that apremilast exerts its therapeutic benefits through 
the modulation of multiple inflammatory pathways.  
Following a comprehensive clinical development program, apremilast has been approved for the 
treatment of PsA and it is under clinical investigation for the treatment of Behçet’s syndrome and 
inflammatory bowel disease. 
Apremilast has been shown to be efficacious in halting inflammation and reducing signs and 
symptoms of PsA, as well as improving physical function (Cutolo, 2016; Edwards, 2016; 
Kavanaugh, 2014; Nash, 2018). A question that remains to be addressed is whether apremilast 
can impact the structural progression of the disease. In addition, the extent of its structure 
modifying effects remains to be characterized using axial PsA specific imaging techniques and 
methodologies.  
Magnetic resonance imaging (MRI) has gained importance as a promising tool for early 
diagnosis and increasing acceptance as an outcome measure in clinical trials of different 
inflammatory arthritides. It is highly sensitive (Althoff, 2007; Braun, 2004; Hermann, 2005; 
Hermann, 2006) and superior to conventional radiography in depicting inflammatory bone 
lesions of the peripheral arthritis and axial skeleton. Moreover, it can detect soft tissue 
inflammation, bone erosion, and proliferation. As such, this study is designed to assess the 
efficacy of apremilast on MRI outcomes in subjects with active PsA, with less than 5 years of 
disease duration (since diagnosis), and who are naïve to biologic therapies.
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
7
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Objectives
Primary Objective

To evaluate the efficacy of apremilast 30 mg twice per day (BID) on inflammation 
indices, assessed by MRI of the hand
Secondary Objectives

To evaluate the efficacy of apremilast 30 mg BID on imaging outcomes associated 
with structural progression, assessed by MRI of the hand

To evaluate the efficacy of apremilast 30 mg BID on disease activity and 
functionality, assessed by clinical outcomes

To evaluate the efficacy of apremilast 30 mg BID on inflammation indices of 
peripheral arthritis and enthesitis, total (sum of arthritis and enthesitis) and separately, 
assessed by whole-body MRI (WB-MRI) 

To evaluate the efficacy of apremilast 30 mg BID on PsAID-12

To evaluate the safety and tolerability of apremilast 30 mg BID 
Exploratory Objectives
Study Design
This is a Phase 4, single-arm, multicenter, open-label study to evaluate the impact of apremilast 
(CC-10004) either in monotherapy or with stable methotrexate (MTX) on MRI outcomes in 
subjects with active PsA with up to 5 years of disease duration (since diagnosis). 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
8
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Approximately 120 subjects will receive apremilast 30 mg BID, after a 5-day titration period, 
with or without stable MTX. All subjects will be permitted to take nonsteroidal anti-
inflammatory drugs (NSAIDs) and/or low-dose oral glucocorticoids (prednisone ≤ 10 mg/day or 
equivalent) throughout the study. The NSAIDs and low-dose oral glucocorticoids must be on a 
stable regimen for at least 4 weeks prior to baseline. MTX (≤25 mg/week) will be permitted if 
duration of treatment is ≥6 months and on a stable regimen for at least 3 months prior to 
baseline. In addition, the stable doses of MTX, NSAIDs, and low-dose glucocorticoids must be 
continued from Day 1 through the Week 24 Visit. Change in doses, increase or decrease, and/or 
discontinuation will not be allowed except for safety reasons or for lack of availability. After the 
Week 24 Visit, the doses of MTX, NSAIDs, or glucocorticoids may be adjusted as clinically 
required.
This is a 56-week study comprising of 3 phases:

Screening Phase – up to 4 weeks

Single-arm, Open-label Treatment Phase – Weeks 0 to 48

120 subjects will receive apremilast 30 mg BID (after a 5-day titration period) for 
the entire duration of this phase.

All subjects who complete the study or discontinue early will participate in the 4-
week Post-treatment Observational Follow-up Phase. Henceforth, this will be referred 
to as the Observational Follow-up Phase.
The study will be conducted in compliance with International Council for Harmonisation Good 
Clinical Practice guidelines.
Study Population
The study population will consist of male or female subjects, ≥ 18 years of age, with active PsA 
with up to 5 years of disease duration, who have not been previously treated with TNF blockers 
or other biologic disease-modifying antirheumatic drugs (DMARDs). Prior treatment with 2 non-
biologic conventional synthetic DMARDs (csDMARDs) is permitted. Subjects who are taking 
MTX (≤25 mg/week) for at least 6 months and on stable doses for at least 3 months will be 
allowed to maintain such treatment. Subjects who are still taking a csDMARD at the time of 
screening must discontinue their treatment at least one day prior to their Baseline Visit (ie, Visit 
2; Day 1), except for those subjects taking MTX, leflunomide, and cyclosporine. Subjects taking 
MTX at screening who do not meet the criteria above will require a 28 day-washout. Subjects 
taking leflunomide will require a 12-week washout or treatment with cholestyramine in 
accordance with the leflunomide prescribing label (ie, 8 g cholestyramine 3 times daily for 11 
days). Subjects taking cyclosporine at screening will require a 28 day-washout to participate in 
the study. Subjects who have been previously treated with more than 2 csDMARD or any 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
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Confidential and Proprietary
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biologic treatment for rheumatic or dermatologic diseases will not be allowed to participate in 
the study. At screening, subjects must have a documented diagnosis of PsA based on the
Classification Criteria for Psoriatic Arthritis (CASPAR), with disease duration ≥ 3 months and 
≤5 years. In addition, subjects must have ≥3 swollen (out of 76) AND ≥ 3 tender (out of 78) 
joints, with hand involvement (defined as ≥ 1 swollen joint or dactylitis [each clinically active 
joint of a dactylitic digit is counted as one joint]), and at least 1 active enthesitis site (either one 
of the Spondyloarthritis Research Consortium of Canada or Leeds Enthesitis Index sites) at 
screening. Subjects may or may not have axial involvement in conjunction with peripheral PsA. 
Length of Study
Subjects will spend up to a total of 56 weeks in this study: up to 4 weeks in the Screening Phase, 
48 weeks in the open-label active treatment phase, and 4 weeks in the Observational Follow-up 
Phase. 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary, and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Apremilast will be provided in blister cards for a 5-day titration period. Dose titration cards will 
be provided at Week 0 to all subjects. 
After the 5-day titration, subjects will be required to take one 30 mg tablet twice daily (morning 
and evening), approximately 12 hours apart, with or without food. All subjects will receive 
apremilast supplied in high-density polyethylene bottles until the end of study or early 
discontinuation. 
Overview of Key Efficacy Assessments
Overview of Efficacy Assessments on Imaging
The following will be used for assessing clinical efficacy on MRI outcomes:

Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Magnetic 
Resonance Imaging Score (PsAMRIS)

WB-MRI generated indices, such as WB-MRI inflammation indices of peripheral 
arthritis and enthesitis, the Canada-Denmark and the Spondyloarthritis Research 
Consortium of Canada (SPARCC) Magnetic Resonance Imaging Scoring Indices for 
the axial involvement (Krabbe, 2017; Maksymowych, 2005), the Hip Inflammation 
Magnetic Resonance Imaging Scoring System (HIMRISS) (Maksymowych, 2016), 
the Knee Inflammation Magnetic Resonance Imaging Scoring System (KIMRISS)
(Jaremko, 2017), and the OMERACT Heel Enthesitis Magnetic Resonance Imaging 
Scoring System
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
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CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Overview of Clinical Efficacy Assessments
The following will be used for assessing clinical efficacy:

76 Swollen Joint and 78 Tender Joint Score

Clinical Disease Activity Index for Psoriatic Arthritis (c-DAPSA)

Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Assessment
(Maksymowych, 2009)

Leeds Enthesitis Index (LEI)

Leeds Dactylitis Index (LDI)

Psoriatic Arthritis Disease Activity Score (PASDAS) (Coates, 2014)

Patient’s (Subject’s) and Physician’s (Evaluator’s) Global Assessment of Disease 
Activity

Subject’s Pain Assessment 

Health Assessment Questionnaire–Disability Index (HAQ-DI)

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), for subjects deemed 
to have PsA spondylitis by the investigator and with BASDAI item 2 ≥ 4 at baseline
Overview of Subject-reported Outcomes
The following will be used for assessing health-related quality of life, impact of disease, fatigue, 
and work productivity:

Psoriatic Arthritis Impact of Disease 12-domain questionnaire (PsAID-12)
Overview of Key Safety Assessments
The following will be used for assessing safety:

Adverse events/

Physical examination, vital signs, weight

Clinical laboratory evaluations
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
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Confidential and Proprietary
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Statistical Methods
Sample size calculation for this single-arm study was based on the confidence interval (CI) 
approach. Efficacy parameters including MRI, clinical, and subject-reported outcomes will be 
analyzed descriptively and 95% CIs will be provided as appropriate. Safety analyses will be 
performed for all subjects who receive at least one dose of study medication.
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
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Confidential and Proprietary
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CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................20
1.1.
Disease Background ...............................................................................................20
1.1.1.
Psoriatic Arthritis....................................................................................................20
1.2.
Compound Background ..........................................................................................20
1.2.1.
Apremilast..............................................................................................................20
1.2.2.
Key Findings from Clinical Studies ........................................................................21
1.2.2.1.
Efficacy..................................................................................................................22
1.2.2.2.
Safety.....................................................................................................................29
1.3.
Rationale ................................................................................................................34
1.3.1.
Study Rationale and Purpose ..................................................................................34
1.3.1.1.
Unmet Medical Need..............................................................................................34
1.3.1.2.
Magnetic Resonance Imaging (MRI) in PsA and Study Rationale...........................34
1.3.2.
Rationale for the Study Design ...............................................................................36
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................37
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................38
3.
OVERALL STUDY DESIGN ................................................................................44
3.1.
Study Design ..........................................................................................................44
3.2.
Study Duration for Subjects....................................................................................46
3.3.
End of Trial ............................................................................................................46
4.
STUDY POPULATION.........................................................................................47
4.1.
Medical and Disease History ..................................................................................47
4.2.
Number of Subjects ................................................................................................47
4.3.
Inclusion Criteria....................................................................................................47
4.4.
Exclusion Criteria...................................................................................................48
5.
TABLE OF EVENTS.............................................................................................51
6.
PROCEDURES......................................................................................................56
6.1.
Screening Period.....................................................................................................56
6.2.
Treatment Period ....................................................................................................57
6.2.1.
End of Treatment/Early Termination Visit ..............................................................58
Approved 
 
 


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6.3.
Observational Follow-up Period .............................................................................59
6.3.1.
Safety Follow-up ....................................................................................................59
6.4.
Efficacy Assessments .............................................................................................59
6.4.1.
Magnetic Resonance Imaging (MRI) ......................................................................59
6.4.2.
MRI of the Most Affected Hand .............................................................................60
6.4.3.
WB-MRI ................................................................................................................60
6.4.3.1.
Definition of WB-MRI Indices ...............................................................................60
.........................................................60
.........................................................60
6.4.5.
Clinical Efficacy Assessments ................................................................................61
6.4.5.1.
Joint Assessments...................................................................................................61
6.4.5.2.
Subject and Evaluator’s Global Assessments of Disease Activity............................62
6.4.5.3.
Subject’s Pain Numeric Rating Scale......................................................................62
6.4.5.4.
HAQ-DI .................................................................................................................62
.......................................................................63
..................................................63
6.4.5.7.
Enthesitis................................................................................................................63
6.4.5.8.
Dactylitis ................................................................................................................64
6.4.5.9.
Clinical Disease Activity Index for Psoriatic Arthritis (c-DAPSA)..........................64
6.4.5.10.
Psoriatic Arthritis Disease Activity Score (PASDAS).............................................64
6.4.5.11.
PASI and BSA........................................................................................................65
6.4.5.12.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ............................65
6.5.
Safety Assessments.................................................................................................65
6.5.1.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential ...............65
6.5.2.
Vital Signs, Height and Weight...............................................................................66
6.5.3.
Complete/Limited Physical Examination ................................................................66
6.5.4.
Psychiatric Evaluation ............................................................................................66
6.5.5.
Diarrhea, Nausea and Vomiting ..............................................................................66
6.5.6.
Tuberculosis ...........................................................................................................67
6.5.7.
Clinical Laboratory Evaluations..............................................................................67
6.5.8.
Adverse Events.......................................................................................................67
6.6.
Biomarkers .............................................................................................................68
Approved 
 
 


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6.7.
Subject-reported Outcomes.....................................................................................68
6.7.1.
Psoriatic Arthritis Impact of Disease 12-domain Questionnaire (PsAID-12)............68
......................................................68
......68
................69
................69
7.
DESCRIPTION OF STUDY TREATMENTS........................................................70
7.1.
Description of Investigational Product(s)................................................................70
7.2.
Treatment Administration and Schedule .................................................................70
7.2.1.
Overdose ................................................................................................................70
7.3.
Method of Treatment Assigned...............................................................................71
7.4.
Packaging and Labeling..........................................................................................71
7.5.
Investigational Product Accountability and Disposal ..............................................71
7.5.1.
Dosing....................................................................................................................72
7.5.1.1.
Study Medication Dispensing and Counting ...........................................................72
7.6.
Investigational Product Compliance........................................................................72
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................73
8.1.
Permitted Concomitant Medications and Procedures...............................................73
8.2.
Concomitant Medications Not Recommended ........................................................74
8.3.
Prohibited Concomitant Medications and Procedures..............................................75
8.4.
Required Concomitant Medications and Procedures................................................75
9.
STATISTICAL CONSIDERATIONS ....................................................................76
9.1.
Overview................................................................................................................76
9.2.
Study Population Definitions ..................................................................................76
9.3.
Sample Size and Power Considerations...................................................................76
9.4.
Background and Demographic Characteristics........................................................76
9.5.
Subject Disposition.................................................................................................76
9.6.
Efficacy Analysis....................................................................................................77
9.6.1.
Primary Endpoint....................................................................................................77
9.6.2.
Secondary Endpoints ..............................................................................................77
Approved 
 
 


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9.6.3.
Exploratory Endpoints............................................................................................77
9.7.
Safety Analysis.......................................................................................................77
9.8.
Other Topics...........................................................................................................78
9.8.1.
Investigational Product Compliance (Tablets).........................................................78
9.8.2.
Concomitant Therapy .............................................................................................78
9.8.3.
Steering Committee ................................................................................................78
10.
ADVERSE EVENTS..............................................................................................79
10.1.
Monitoring, Recording, and Reporting of Adverse Events ......................................79
10.1.1.
Monitoring, Recording, and Reporting AEs of Diarrhea..........................................79
10.2.
Evaluation of Adverse Events.................................................................................80
10.2.1.
Seriousness.............................................................................................................80
10.2.2.
Severity/Intensity....................................................................................................81
10.2.3.
Causality ................................................................................................................82
10.2.4.
Duration .................................................................................................................82
10.2.5.
Action Taken..........................................................................................................82
10.2.6.
Outcome.................................................................................................................82
10.3.
Abnormal Laboratory Values..................................................................................82
10.4.
Pregnancy...............................................................................................................83
10.4.1.
Collection of Pregnancy and Infant Health Information ..........................................83
10.4.2.
Male Subjects With Partners Who Become Pregnant ..............................................84
10.4.3.
Collection of Lactation Information........................................................................84
10.5.
Reporting of Serious Adverse Events......................................................................84
10.5.1.
Safety Queries ........................................................................................................85
10.6.
Expedited Reporting of Adverse Events..................................................................85
11.
DISCONTINUATIONS .........................................................................................87
11.1.
Treatment Discontinuation......................................................................................87
11.2.
Study Discontinuation ............................................................................................87
12.
EMERGENCY PROCEDURES.............................................................................88
12.1.
Emergency Contact.................................................................................................88
12.2.
Emergency Identification of Investigational Products .............................................88
13.
REGULATORY CONSIDERATIONS...................................................................89
13.1.
Good Clinical Practice............................................................................................89
Approved 
 
 


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13.2.
Investigator Responsibilities ...................................................................................89
13.3.
Subject Information and Informed Consent.............................................................90
13.4.
Confidentiality........................................................................................................90
13.5.
Protocol Amendments.............................................................................................90
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................90
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................91
13.8.
Termination of the Study ........................................................................................91
14.
DATA HANDLING AND RECORDKEEPING.....................................................92
14.1.
Data/Documents .....................................................................................................92
14.2.
Data Management...................................................................................................92
14.3.
Record Retention....................................................................................................92
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................94
15.1.
Study Monitoring and Source Data Verification......................................................94
15.2.
Audits and Inspections............................................................................................94
15.3.
Product Complaint..................................................................................................94
15.3.1.
How to Report a Product Complaint to Amgen: ......................................................95
16.
PUBLICATIONS ...................................................................................................96
17.
REFERENCES.......................................................................................................97
18.
APPENDICES......................................................................................................103
APPENDIX A.
TABLE OF ABBREVIATIONS..................................................................104
APPENDIX B.
THE CLASSIFICATION CRITERIA FOR PSORIATIC ARTHRITIS 
(CASPAR) CRITERIA.........................................................................................108
APPENDIX C.
JOINT ASSESSMENT ................................................................................109
APPENDIX D.
NUMERICAL RATING SCALES...............................................................110
APPENDIX E.
DISABILITY INDEX OF THE HEALTH ASSESSMENT 
QUESTIONNAIRE (HAQ-DI).............................................................................111
APPENDIX F.
LEEDS ENTHESITIS INDEX (LEI)............................................................114
APPENDIX G.
THE SPONDYLOARTHRITIS RESEARCH CONSORTIUM OF 
CANADA (SPARCC) ENTHESITIS INDEX.......................................................115
APPENDIX H.
LEEDS DACTYLITIS INDEX (LDI)..........................................................116
APPENDIX I.
PSORIASIS AREA SEVERITY INDEX (PASI)...........................................118
APPENDIX J.
BATH ANKYLOSING SPONDYLITIS DISEASE ACTIVITY INDEX 
(BASDAI) ............................................................................................................119
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
17
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
APPENDIX K.
THE EULAR PSORIATIC ARTHRITIS IMPACT OF DISEASE 12 
DOMAINS (PSAID-12) QUESTIONNAIRE .......................................................120
.............................125
..............126
.............130
......135
APPENDIX P.
PSORIATIC ARTHRITIS MAGNETIC RESONANCE IMAGING 
SCORING SYSTEM (PSAMRIS)........................................................................137
APPENDIX Q.
WHOLE-BODY (WB)–MRI ASSESSMENTS............................................138
...............................................................139
APPENDIX S.
BLISTER CARD CONFIGURATION FOR THE TITRATION 
PERIOD...............................................................................................................142
APPENDIX T.
CONTRACEPTION EDUCATION .............................................................143
APPENDIX U.
SAMPLE SERIOUS ADVERSE EVENT REPORT FORM ........................144
APPENDIX V.
PREGNANCY NOTIFICATION FORM.....................................................147
APPENDIX W.
LACTATION NOTIFICATION FORM .....................................................148
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
18
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
LIST OF TABLES
Table 1:
Apremilast Phase 3 and 3b Studies .........................................................................21
Table 2:
Primary (ACR20) and Major Secondary Endpoints of Studies 
CC-10004-PSA-002 (Palace 1), CC-10004-PSA-003 (Palace 2), and 
CC-10004-PSA-004 (Palace 3) (Full Analysis Set).................................................22
Table 3:
Primary and Major Secondary Endpoints of Study CC-10004-PSA-005 (Full 
Analysis Set) ..........................................................................................................24
Table 4:
Summary of Secondary Efficacy Endpoints Related to Enthesitis and 
Dactylitis at Week 16 (FAS; LOCF) .......................................................................25
Table 5:
ACR 20/50/70 Responses at Weeks 16 and 24 During the Placebo-controlled 
Period in Study CC-10004-PSA-006 (FAS; NRI) ...................................................26
Table 6:
HAQ-DI Score (0 to 3) Change From Baseline at Weeks 16 and 24 (FAS; 
MMRM).................................................................................................................27
Table 7:
Gladman Enthesitis Index Change From Baseline at Weeks 16 and 24 
During the Placebo-controlled Period in Subjects With Pre-existing 
Enthesopathy (FAS; MMRM).................................................................................28
Table 8:
Treatment-emergent Adverse Events Reported in 2% of Subjects in Any 
Treatment Group, First 16 Weeks of Exposure (Studies CC-10004-PSA-002, 
CC-10004-PSA-003, CC-10004-PSA-004, and CC-10004-PSA-005; 
Subjects As Treated)...............................................................................................30
Table 9:
Treatment-emergent Serious Adverse Events Reported in >1 Subject in Any 
Treatment Group, First 16 Weeks of Exposure (Studies CC-10004-PSA-002, 
CC-10004-PSA-003, CC-10004-PSA-004, and CC-10004-PSA-005; 
Subjects As Treated)...............................................................................................31
Table 10:
Frequency of Common AEs Over 208 Weeks of Exposure .....................................32
Table 11:
Study Objectives.....................................................................................................38
Table 12:
Study Endpoints .....................................................................................................39
Table 13:
Table of Events.......................................................................................................51
Table 14:
Treatment Schema for Dose Titration at Baseline ...................................................70
Table 15:
Abbreviations and Specialist Terms......................................................................104
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
19
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................45
.................62
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
20
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
1.
INTRODUCTION
1.1.
Disease Background 
1.1.1.
Psoriatic Arthritis
Psoriatic arthritis (PsA) is a heterogeneous inflammatory rheumatologic disorder characterized 
by inflammatory arthritis, enthesitis, dactylitis and spondylitis, affecting 6% to 39% of the 
patients suffering from psoriasis. 
The exact prevalence of PsA is unknown. Estimates of incidence vary from 0.3% to 1% of the 
population. Disease onset typically occurs between the ages of 30 and 55 years, and affects both 
genders equally (Gladman, 2005).
PsA is classified as a seronegative spondyloarthropathy (SpA) because it shares certain features 
with other conditions included in that group. Indeed, spinal involvement has been reported in 
approximately 50% of patients with PsA. In addition, PsA is associated with enthesitis and 
dactylitis, which are extra-articular features common to SpA. Finally, the majority of patients 
with PsA are negative for the rheumatoid factor (RF) (Gladman, 2005; Kruithof, 2005).
Recent studies have challenged the assertion that PsA is a more benign disease than rheumatoid 
arthritis (RA). There is an increasing body of evidence that suggests that PsA patients experience 
progressive joint destruction over a relatively short period of time. The results from these studies 
indicate that PsA is erosive and deforming in nearly half of the patients, with joint damage 
appearing in the first years of disease onset. Other investigators later confirmed that 41% of the 
patients developed erosive disease within 2 years of onset of symptoms (Helliwell, 2015).
PsA is also associated with a high burden of disease. PsA has been shown to have a similar 
impact on physical function, quality of life (QoL) and ability to work as RA. When compared to 
patients with psoriasis alone, patients with PsA had a further diminished QoL. Lastly, PsA was 
associated with a significantly higher (60%) risk of mortality than that of the general population; 
the risk increased with increasing severity of the disease (Gladman, 2008; Rosen, 2012; Sokoll, 
2001). 
1.2.
Compound Background 
1.2.1.
Apremilast
Apremilast (CC-10004) is an oral phosphodiesterase enzyme (PDE) inhibitor. It is highly 
selective for PDE4, which is the dominant PDE in inflammatory cells. Through inhibiting PDE4, 
apremilast elevates intracellular cyclic adenosine monophosphate levels, leading to a partial 
inhibition of the production of many pro-inflammatory mediators, as well as an increase in some 
anti-inflammatory mediators. Indeed, a recent study in subjects with PsA indicated that 
apremilast was associated with reductions in tumor necrosis factor–(TNF-), interleukin (IL)-
17, IL-23, IL-6, IL-8, macrophage inflammatory protein-1β, and monocyte chemoattractant 
protein 1, as well as increases in anti-inflammatory mediators, including IL-10 and the IL-1 
receptor antagonist (Schafer, 2015). It is believed, therefore, that apremilast exerts its therapeutic 
benefits through the modulation of multiple inflammatory pathways. 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
21
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Following a comprehensive clinical development program, apremilast has been approved for the 
treatment of PsA and psoriasis. It is under clinical investigation for the treatment of Behçet’s 
syndrome and inflammatory bowel disease. 
Whether apremilast can impact the structural progression of PsA has yet to be addressed. In 
addition, the extent of its effects on axial imaging parameters remains to be characterized in 
subjects with axial PsA.  
1.2.2.
Key Findings from Clinical Studies
The safety and efficacy of apremilast for the treatment of PsA were demonstrated in a 
comprehensive clinical development program. Subjects enrolled in Phases 3 and 3b studies 
included disease-modifying antirheumatic drug (DMARD)-naïve, DMARDs-experienced, 
biologic-naïve, and biologic-experienced subjects 
The results from these studies 
indicated that apremilast is safe and effective, both as monotherapy and in combination with 
conventional synthetic DMARDs (csDMARDs). 
Table 1:
Apremilast Phase 3 and 3b Studies
Study
Population
Treatment Arms
Subjects 
Randomized Who 
Received 1 Dose 
of Study Medication
PALACE 1/
CC-10004-PSA-
002
csDMARD- and/or 
biologic-experienced
Apremilast 20 mg/30 mg BID + 
concomitant csDMARDs vs. 
PBO + concomitant 
csDMARDs
504
PALACE 2/
CC-10004-PSA-
003
csDMARD- and/or 
biologic-experienced
Apremilast 20 mg/30 mg BID + 
concomitant csDMARDs vs. 
PBO + concomitant 
csDMARDs
484
PALACE 3/
CC-10004-PSA-
004
csDMARD- and/or 
biologic-experienced 
with > 1 psoriatic skin 
lesion > 2 cm
Apremilast 20 mg/30 mg BID + 
concomitant csDMARDs vs. 
PBO + concomitant 
csDMARDs
505
PALACE 4/
CC-10004-PSA-
005
csDMARD-naïve and 
biologic-naïve
Apremilast monotherapy vs. 
PBO
527
ACTIVE/
CC-10004-PSA-
006
Maximum 1 prior 
csDMARD, biologic-
naïve
Apremilast monotherapy vs. 
PBO
219
BID = twice daily; csDMARD = conventional synthetic disease-modifying antirheumatic drug; PBO = placebo; vs = versus.
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
22
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
1.2.2.1.
Efficacy
1.2.2.1.1. Efficacy Data From Phase 3 Studies CC-10004-PSA-002 (Palace 1), 
CC-10004-PSA-003 (Palace 2), and CC-10004-PSA-004 (Palace 3) Through 
Week 24 in Subjects With Prior csDMARDs and/or Biologic DMARDs
Apremilast was first evaluated in 3 multicenter, randomized, double-blinded, placebo-controlled,
Phase 3 pivotal studies (Studies CC-10004-PSA-002 [Palace 1], CC-10004-PSA-003 [Palace 2], 
and CC-10004-PSA-004 [Palace 3]) (Cutolo, 2016; Edwards, 2016; Kavanaugh, 2014). The 
studies were similarly designed. Adult subjects with active PsA (≥ 3 swollen and ≥ 3 tender 
joints) despite prior csDMARD and/or biologic TNF therapy were enrolled in the studies (TNF 
blockers efficacy failures were limited to < 10% of subjects). Subjects were excluded if they had 
previously failed > 3 agents for PsA or > 1 TNF inhibitor. Stable baseline concomitant 
methotrexate (MTX [≤ 25 mg/week]), sulfasalazine (SSZ [≤ 2 g/day]), leflunomide (LEF [≤ 20 
mg/day]), low-dose oral glucocorticoids (equivalent to ≤ 10 mg of prednisone a day), and/or 
nonsteroidal anti-inflammatory drugs (NSAIDs) were allowed during the trials. 
In the 3 pivotal studies, 1493 subjects were randomized equally to placebo (N = 496), apremilast 
(APR) 20 twice per day (BID) (N = 500), or APR 30 BID (N = 497). Placebo subjects whose 
tender and swollen joint counts (TJC and SJC, respectively) had not improved by 20% were re-
randomized 1:1 in a blinded fashion to either apremilast 20 mg or 30 mg twice daily at Week 16, 
while apremilast subjects remained on their initial treatment. 
All 3 studies achieved their primary endpoint (Table 2); a statistically significantly higher 
percentage of subjects in the APR 30 BID treatment group achieved the primary endpoint of 
American College of Rheumatology (ACR) 20 at Week 16 compared with placebo. Apremilast 
was also associated with statistically significant improvements in physical function and 
improvements in skin manifestations at Weeks 16 and 24 among subjects with body surface area 
(BSA) for psoriasis ≥ 3 % at baseline.
Table 2:
Primary (ACR20) and Major Secondary Endpoints of Studies
CC-10004-PSA-002 (Palace 1), CC-10004-PSA-003 (Palace 2), and 
CC-10004-PSA-004 (Palace 3) (Full Analysis Set)
Study CC-10004-PSA-002
Study CC-10004-PSA-003
Study CC-10004-PSA-004
Placebo
N = 168
APR 30 BID
N = 168
Placebo
N = 159
APR 30 BID
N = 162
Placebo
N = 169
APR 30 BID
N = 167
ACR 20 – NRI
  Week 16 n (%)
32 (19.0)
64 (38.1)
30 (18.9)
52 (32.1)
31 (18.3)
68 (40.7)
  Week 24 n (%)
22 (13.1) 
59 (35.1)***
25 (15.7)
40 (24.7)*
26 (15.4)
52 (31.3)***
ACR 50 – NRI
  Week 16 n (%)
10 (6.0)
27 (16.1)**
8 (5.0)
17 (10.5)
14 (8.3) 
25 (15.0)
  Week 24 n (%)
7 (4.2)
32 (19.0)***
14 (8.8)
19 (11.7)
13 (7.7)
27 (16.2)*
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
23
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Table 2:
Primary (ACR20) and Major Secondary Endpoints of Studies 
CC-10004-PSA-002 (Palace 1), CC-10004-PSA-003 (Palace 2), and 
CC-10004-PSA-004 (Palace 3) (Full Analysis Set) (Continued)
Study CC-10004-PSA-002
Study CC-10004-PSA-003
Study CC-10004-PSA-004
Placebo
N = 168
APR 30 BID
N = 168
Placebo
N = 159
APR 30 BID
N = 162
Placebo
N = 169
APR 30 BID
N = 167
ACR 70 – NRI
  Week 16 n (%)
2 (1.2)
7 (4.2)
1 (0.6)
2 (1.2)
4 (2.4)
6 (3.6)
  Week 24 n (%)
1 (0.6)
17 (10.1)***
5 (3.1)
4 (2.5)
6 (3.6)
9 (5.4)
HAQ – LOCFa
  Week 16 
mean change from 
Baseline (SE)b
-0.086 
(0.0360)
-0.244 
(0.0364)**
-0.053 
(0.0358)**
-0.193 
(0.0354)
-0.065 
(0.0335)
-0.192 
(0.0339)**
  Week 24 
mean change from 
Baseline (SE)b
-0.076 
(0.0369)
-0.258 
(0.0371)***
-0.085 
(0.0377)
-0.206 
(0.0372)*
-0.053 
(0.0350)
-0.192 
(0.0353)**
BSA > 3 at 
Baseline
Placebo
N = 68
APR 30 BID
N = 82
Placebo
N = 74
APR 30 BID
N = 77
Placebo
N = 89
APR 30 BID
N = 90
PASI 50 – LOCF
  Week 16 n (%)
11 (16.2)
36 (43.9)***
10 (13.5)
33 (42.9)***
22 (24.7)
38 (42.2)*
  Week 24 n (%)
12 (17.6)
41 (50.0)***
11 (14.9)
35 (45.5)***
22 (24.7)
39 (43.3)**
PASI 75 – LOCF
  Week 16 n (%)
3 (4.4)
18 (22.0)**
2 (2.7)
17 (22.1)***
7 (7.9)
20 (22.2)**
  Week 24 n (%)
3 (4.4)
17 (20.7)**
3 (4.1)
21 (27.3)***
10 (11.2)
23 (25.6)**
ACR 20/50/70 = American College of Rheumatology 20%/50%/70% response; APR = apremilast; BID = twice daily; 
BSA = body surface area; DMARD = disease-modifying antirheumatic drugs; HAQ-DI = Health Assessment Questionnaire 
Disability Index (HAQ-DI score:  0 = best, 3 = worst; measures the subject’s ability to perform the following: dress/groom, arise, 
eat, walk, reach, grip, maintain hygiene, and maintain daily activity); LOCF = last observation carried forward; NRI = non-
responder imputation; PASI 50/75 = 50%/75% or greater improvement in the Psoriasis Area and Severity Index; SE = standard 
error.
***p < 0.001 for apremilast versus placebo.  **p < 0.01 for apremilast versus placebo.  *p < 0.05 for apremilast versus placebo.
a Subjects with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included.
b Least-squares mean (SE) and p-value based on an analysis of covariance model for the change from baseline at the respective 
time point, with treatment group and baseline DMARD use as factors, and (for Study PSA-004 only) involvement of ≥3% 
BSA with psoriasis at baseline as factors, and the baseline value as a covariate.
For subjects who discontinued from the study prior to Week 16, the last available postbaseline value observed prior to 
discontinuation was carried forward to Weeks 16 and 24. For subjects who entered early escape (EE) at Week 16 or who did not 
enter EE but discontinued from the study between Weeks 16 and 24, the last available postbaseline value observed prior to EE or 
discontinuation, respectively, was carried forward to Week 24. Missing values for subjects who did not discontinue or enter EE 
were imputed using the latest available postbaseline value prior to the visit in question. Subjects who did not have sufficient data
(observed or imputed) for a determination of response status at the respective visits were counted as non-responders.
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
24
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
1.2.2.1.2. Efficacy Data From Phase 3 Study CC-10004-PSA-005 (Palace 4) Through Week 
24 in Subjects Naïve to csDMARDs and Biologic DMARDs
The efficacy of apremilast in subjects naïve to csDMARDs therapy was investigated in a 
multicenter, randomized, double-blinded, placebo-controlled Phase 3 study (CC-10004-PSA-005 
[Palace 4]) (Wells, 2013). Subjects enrolled had a diagnosis of PsA for 3 months and active 
disease (defined by ≥3 swollen and ≥3 tender joints). Previous treatment with csDMARDs or 
biologics was not allowed. Subjects could receive stable doses of prednisone (equivalent to 
≤10 mg/day) and/or NSAIDs. The use of other csDMARDs, including MTX, SSZ, LEF, or 
biologics was prohibited during the trial. Subjects were randomized 1:1:1 to placebo, APR 20 
BID, or APR 30 BID treatment groups.  
In total, 527 subjects were randomized to the placebo (n = 176), APR 20 BID (n = 175), or APR 
30 BID (n = 176) group. Subjects whose TJCs and SJCs had not improved by ≥20% at Week 16 
were required to enter the early escape (EE) to blinded active treatment. Placebo subjects who 
met the EE criteria were re-randomized 1:1 in a blinded fashion to APR 20 BID or APR 30 BID. 
Apremilast subjects remained on their initial treatment.  
A statistically significantly higher percentage of subjects in the APR 30 BID treatment group 
achieved the primary endpoint of ACR 20 at Week 16 compared with placebo (Table 3). 
Apremilast was also associated with statistically significant improvements in physical function 
and improvements in skin manifestations at Weeks 16 and 24 among subjects with BSA for 
psoriasis ≥ 3% at baseline. 
Table 3:
Primary and Major Secondary Endpoints of Study CC-10004-PSA-005 (Full 
Analysis Set)
Study CC-10004-PSA-005
Placebo
N = 176
APR 30 BID
N = 176
ACR 20 – NRI
 Week 16 n (%)
28 (15.9)
54 (30.7)**
 Week 24 n (%)
23 (13.1)
43 (24.4)***
ACR 50 – NRI
 Week 16 n (%)
8 (4.5)
20 (11.4)*
 Week 24 n (%)
11 (6.3)
22 (12.5)*
ACR 70 – NRI
 Week 16 n (%)
2 (1.1)
7 (4.0)
 Week 24 n (%)
7 (4.0)
8 (4.5)
HAQ - LOCFa
 Week 16 
  mean change from Baseline (SE)b
0.012 (0.0350)
-0.205 (0.0350)***
 Week 24 
  mean change from Baseline (SE)b
0.012 (0.0370)
-0.207 (0.0369)***
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
25
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Table 3:
Primary and Major Secondary Endpoints of Study CC-10004-PSA-005 (Full 
Analysis Set) (Continued)
Study CC-10004-PSA-005
BSA ≥3 at Baseline
Placebo
N = 93
APR 30 BID
N = 103
PASI 50 – LOCF
 Week 16 n (%)
18 (19.4)
51 (46.8)***
 Week 24 n (%)
23 (24.7)
53 (48.6)***
PASI 75 – LOCF
 Week 16 n (%)
10 (10.8)
29 (26.6)**
 Week 24 n (%)
11 (11.8)
28 (25.7)*
ACR 20/50/70 = American College of Rheumatology 20%/50%/70% response; APR = apremilast; BID = twice daily; 
BSA = body surface area; DMARD = disease-modifying antirheumatic drugs; HAQ-DI = Health Assessment Questionnaire 
Disability Index; LOCF = last observation carried forward; NRI = non-responder imputation; PASI 50/75 = 50%/75% or greater 
improvement in the Psoriasis Area and Severity Index; SE = standard error. 
***p < 0.001 for apremilast versus placebo.  **p < 0.01 for apremilast versus placebo.  *p < 0.05 for apremilast versus placebo.
a Subjects with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included.
b Least-squares mean (SE) and p-value based on an analysis of covariance model for the change from baseline at the respective 
time point, with treatment group and baseline DMARD use as factors, and (for Study PSA-004 only) involvement of ≥3% 
BSA with psoriasis at baseline as factors, and the baseline value as a covariate.
Health Assessment Questionnaire–Disability Index (HAQ-DI) score:  0 = best, 3 = worst; 
measures the subject’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, 
maintain hygiene, and maintain daily activity.
For subjects who discontinued from the study prior to Week 16, the last available postbaseline 
value observed prior to discontinuation was carried forward to Weeks 16 and 24. For subjects 
who entered EE at Week 16 or who did not enter EE but discontinued from the study between 
Weeks 16 and 24, the last available postbaseline value observed prior to EE or discontinuation, 
respectively, was carried forward to Week 24. Missing values for subjects who did not 
discontinue or enter EE were imputed using the latest available postbaseline value prior to the 
visit in question. Subjects who did not have sufficient data (observed or imputed) for a 
determination of response status at the respective visits were counted as non-responders.
Improvements in enthesitis and dactylitis among subjects with baseline enthesitis and/or 
dactylitis at baseline are shown in Table 4. 
Table 4:
Summary of Secondary Efficacy Endpoints Related to Enthesitis and 
Dactylitis at Week 16 (FAS; LOCF)
Secondary Endpoints
Placebo
N = 176
APR 30 BID
N = 176
MASES mean change from baseline (SE) 
-0.5 (0.24)
-1.5 (0.25)**
MASES = 0 n (%)
22 (19.1)
41 (36.9)**
Dactylitis mean change from baseline (SE) 
-1.0 (0.25)
-1.7 (0.26)*
Dactylitis score = 0 n (%)
30 (33.3)
34 (40.5)
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
26
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
APR = apremilast; BID = twice daily; FAS = Full Analysis Set; LOCF = last observation carried forward; MASES = 
Maastricht Ankylosing Spondylitis Enthesitis Score; SE = standard error. 
MASES evaluated only subjects with pre-existing enthesopathy (N = 115 and 111 for placebo and APR 30 BID, 
respectively).
Dactylitis score evaluated only in subjects in pre-existing dactylitis (N = 90 and 84 for placebo and APR 30 BID, 
respectively).
Note: **p < 0.01 for apremilast versus placebo. *p < 0.05 for apremilast versus placebo.  
1.2.2.1.3. Efficacy Data From Phase 3 CC–10004-PSA-006 (ACTIVE) Through Week 24 
in Subjects With an Inadequate Response to 1 csDMARDs and Who Received 
Apremilast Monotherapy
The rapid onset of efficacy of apremilast monotherapy in biologic-naïve subjects who had 
received ≤1 csDMARDs was demonstrated in the ACTIVE study (CC-10004-PSA-006) (Nash, 
2018), a Phase 3b multicenter, parallel-group study with 1 active treatment; overall treatment 
duration was 2 years. The study randomized 219 patients (APR 30 mg, n=110; placebo [PBO],
n=109). At Week 16 (time of the primary endpoint), all subjects whose improvement was < 10% 
in both tender and swollen joint counts were eligible to enroll into an EE to active treatment with 
apremilast 30 mg BID. After 24 weeks of treatment, all subjects entered the active-treatment 
phase, in which they received apremilast 30 mg BID. 
A separation in the proportion of ACR20 responders to APR versus PBO was noted at Week 2 
(16.4% versus 6.4%; P=0.0252), the first Post-baseline Visit. Early onset of response to APR 
was observed across clinical assessments, with improvements in the Disease Activity Score 
(DAS)-28 C-reactive protein (CRP), SJC, HAQ-DI, enthesitis, and morning stiffness severity. 
Dactylitis and skin responses were not assessed in CC-10004-PSA-006.
A statistically significantly greater proportion of subjects in the APR 30 BID treatment group 
achieved the primary endpoint of ACR 20 response at Week 16 compared to placebo. A 
nominally significantly greater proportion of subjects in the APR 30 BID treatment group 
achieved an ACR 50 or ACR 70 response at Week 16 than in the placebo group (Table 5). 
Significant reduction in PsA disease activity/manifestations versus placebo was also 
demonstrated by changes in DAS-28 (CRP) (P<0.0001), SJC (P≤0.0001), and HAQ-DI (Table 
6).
Table 5:
ACR 20/50/70 Responses at Weeks 16 and 24 During the Placebo-controlled 
Period in Study CC-10004-PSA-006 (FAS; NRI)
Study CC-10004-PSA-006
Placebo
N = 109
APR 30 BID
N = 110
ACR 20
  Week 16 n (%)
22 (20.2)
42 (38.2)**
  Week 24 n (%)
27 (24.8)
48 (43.6)**
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
27
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Table 5:
ACR 20/50/70 Responses at Weeks 16 and 24 During the Placebo-controlled 
Period in Study CC-10004-PSA-006 (FAS; NRI) (Continued)
Study CC-10004-PSA-006
Placebo
N = 109
APR 30 BID
N = 110
ACR 50
  Week 16 n (%)
5 (4.6)
20 (18.2)**
  Week 24 n (%)
12 (11.0)
22 (20.0)
ACR 70
  Week 16 n (%)
0 (0.0)
7 (6.4)*
  Week 24 n (%)
5 (4.6)
8 (7.3)
ACR 20/50/70 = American College of Rheumatology 20%/50%/70%; APR = apremilast; BID = twice daily; 
FAS = Full Analysis Set; NRI = non-responder imputation.
Note:  **p < 0.01 for apremilast versus placebo.  *p < 0.05 for apremilast versus placebo.  
Table 6:
HAQ-DI Score (0 to 3) Change From Baseline at Weeks 16 and 24 (FAS; 
MMRM)
Visit
Treatment Group
na
Change From Baseline
LS Mean (SE)b
Week 16
  Placebo
109
-0.055 (0.0513)
  APR 30 BID
109
-0.205 (0.0523)*
Week 24
  Placebo
109
-0.169 (0.0581)
  APR 30 BID
109
-0.273 (0.0572)
APR = apremilast; BID = twice daily; DMARD = disease-modifying antirheumatic drug; EE = early escape; FAS = 
Full Analysis Set; HAQ-DI = Health Assessment Questionnaire – Disability Index; LS = least-squares; 
MMRM = mixed-effects model of repeated measures; SE = standard error.
a Subjects with a baseline value and at least 1 postbaseline value (after exclusion of data for EE subjects) during the 
Placebo-controlled Phase are included in the MMRM analysis.
b The LS mean (SE) and 2-sided p-value are based on an MMRM analysis for the change from baseline, with 
treatment group, time, treatment-by-time interaction, and previous DMARD use and baseline oral glucocorticoids
(prednisone or equivalent) use as factors and the baseline value as a covariate. An unstructured covariance matrix 
that is homogeneous across treatment groups was used. The p-values in italics are < 0.05 and are considered 
nominally significant, as hierarchical testing was stopped after the first secondary endpoint.
Among subjects with enthesitis at baseline, significant improvements from baseline in Gladman 
Enthesitis Index (GEI) score were observed with APR 30 mg (-1.1) versus placebo (-0.4) at 
Week 2 (P=.0354), as well as at Weeks 16 and 24 (Table 7).
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
28
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
In addition, numerically greater proportions of subjects treated with APR 30 mg (48.2%) 
compared to placebo (33.3%) achieved GEI scores of 0 at Week 24.
Table 7:
Gladman Enthesitis Index Change From Baseline at Weeks 16 and 24 During 
the Placebo-controlled Period in Subjects With Pre-existing Enthesopathy 
(FAS; MMRM)
Treatment Group
na
Change From Baseline
Week 16
LS Mean (SE)b
Week 24
LS Mean (SE)b
Placebo
48
-0.4 (0.26)
-0.5 (0.27)
APR 30 BID
49
-1.5 (0.26)**
-1.5 (0.26)**
APR = apremilast; BID = twice daily; DMARD = disease-modifying antirheumatic drug; EE = early escape; FAS = 
Full Analysis Set; GEI = Gladman Enthesitis Index; LS = least squares; MMRM = mixed-effects model for repeated 
measures; SE = standard error. 
a Subjects with a baseline value and at least 1 postbaseline value at or prior to the respective visits are included.
b The LS mean and 2-sided p-value is based on an MMRM analysis for the change from baseline, with treatment 
group, time, treatment-by-time interaction, and previous DMARD use and baseline oral glucocorticoids 
(prednisone or equivalent) use as factors and the baseline value as a covariate. An unstructured covariance matrix 
that is homogeneous across treatment groups was used. The p-values in italics are < 0.05 and are considered 
nominally significant, as hierarchical testing was stopped after the first secondary endpoint.
Note: **p < 0.01 for apremilast versus placebo. For subjects who EE at Week 16, data obtained after EE are 
excluded from the MMRM analysis. The GEI is a count from 0 to 6. A higher count represents greater enthesitis 
burden, and a negative change from baseline indicates improvement. Pre-existing enthesopathy was defined as 
subjects who had a baseline GEI score of greater than 0. Joints temporarily or permanently inaccessible at baseline 
were excluded from joint count. For other unassessed joints at baseline, the joint assessment at the Screening Visit, 
if assessed, was used as the baseline assessment; otherwise, the joint was excluded from joint count. The last 
observed joint assessment (at baseline or postbaseline) is used for joints unassessed at the time point.
1.2.2.1.4. Long-term Efficacy Data From Phase 3 Study CC-10004-PSA-002 (Palace 1)
The 5-year efficacy of apremilast in subjects with active PsA despite prior csDMARD and/or 
biologic anti-TNF therapy was assessed using data from the Phase 3 Study CC-10004-PSA-002 
(Palace 1) (TNF blockers efficacy failures were limited to < 10% of subjects). Data were based 
on observed analyses from subjects who received apremilast 30 mg BID and who were still 
attending study visits. 
ACR20/50/70 responses were achieved by 71.7%, 48.6%, and 28.4% of subjects, respectively,
attending the Week 260 Visit (Kavanaugh, 2018). Psoriasis Area and Severity Index (PASI) 50 
and 75 were achieved by 69.4% and 46.9% of subjects, respectively. At Week 260, 61.5% of the 
subjects achieved HAQ-DI improvements >0.3, which corresponds to the minimal clinically 
important difference (MCID) (Mease, 2004).
Apremilast was also associated with sustained responses and improvements in enthesitis and 
dactylitis among subjects still attending study visits. At 5 years, 54.5% of subjects achieved a 
Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 80% achieved a dactylitis count 
of 0.
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
29
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
1.2.2.1.5. Long-term Efficacy Data From Phase 3 Study CC-10004-PSA-005 (Palace 4) in 
csDMARD-naïve Subjects
The long-term efficacy profile of APR monotherapy in DMARD-naïve subjects was reported for 
208 weeks. ACR20/50/70 responses were achieved by 68.2%, 43.4%, and 23.1% of subjects, 
respectively, attending the Week 208 Visit (Wells, 2017). PASI 50 and 75 were achieved by 
67.6% and 40.5%. At Week 208, half of the subjects achieved HAQ-DI improvements greater 
than 0.3, which corresponded to the MCID (Mease, 2004).
Apremilast monotherapy was also associated with sustained responses and improvements in 
enthesitis and dactylitis among subjects still attending study visits. 
1.2.2.1.6. Long-term Efficacy Data From Phase 3 Study CC-10004-PSA-006 (ACTIVE) 
In biologic-naïve PsA subjects who may have had exposure to 1 prior csDMARD, sustained 
improvements were observed with the continued exposure to apremilast in monotherapy among 
subjects still attending study visits through Week 52: ACR20/50/70 responses were achieved by 
63.3%, 32.4%, and 14.0% respectively (Nash, 2018); also, 45.6% achieved HAQ-DI 
improvements >0.3, which corresponded to the MCID (Mease, 2004). It is noteworthy that
62.8% of subjects who were initially randomized to receive APR 30 mg with baseline enthesitis 
(GEI >0) achieved a GEI of 0 at Week 52.
1.2.2.2.
Safety
1.2.2.2.1. Pooled Safety 16-Week Data From Phase 3 Studies CC-10004-PSA-002 (Palace 
1), CC-10004-PSA-003 (Palace 2), CC-10004-PSA-004 (Palace 3), and 
CC-10004-PSA-005 (Palace 4)
The safety data from the Palace 1, 2, 3, and 4 studies were pooled and summarized for the first 
16 weeks of exposure to placebo or apremilast (Celgene, 2017; Wells, 2013). The analyses 
conducted on the apremilast population included subjects started on apremilast at baseline and 
subjects switched from placebo to apremilast at Weeks 16 or 24. Analysis included all data 
during the time subjects were exposed to apremilast, regardless of the time apremilast exposure 
started.
Approximately half of the subjects (50.7%) experienced 1 treatment-emergent adverse event 
(TEAE) during the first 16 weeks of exposure to apremilast. The incidence of TEAE was higher 
among subjects who received apremilast than placebo (42.9%) (Table 8). The most frequently 
reported TEAEs were diarrhea, nausea, headache, and upper respiratory tract infection. The 
subject incidence of diarrhea, nausea, and headache was higher in the APR 30 BID group than in 
the APR 20 BID group, suggesting a dose effect. 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
30
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Table 8:
Treatment-emergent Adverse Events Reported in 2% of Subjects in Any 
Treatment Group, First 16 Weeks of Exposure (Studies CC-10004-PSA-002, 
CC-10004-PSA-003, CC-10004-PSA-004, and CC-10004-PSA-005; Subjects 
As Treated)
Preferred Term
a
Weeks 0 to 16
First 16 Weeks of Apremilast Treatment
b
Placebo 
Subjects
n (%)
(N = 671)
APR 20 BID
n (%)
(N = 972)
APR 30 BID
n (%)
(N = 973)
APR Total
n (%)
(N = 1945)
Any TEAE
288 (42.9)
470 (48.4)
516 (53.0)
986 (50.7)
Diarrhea
17 (2.5)
86 (8.8)
128 (13.2)
214 (11.0)
Nausea
26 (3.9)
71 (7.3)
114 (11.7)
185 (9.5)
Headache
24 (3.6)
53 (5.5)
77 (7.9)
130 (6.7)
Upper Respiratory Tract 
Infection 
16 (2.4)
42 (4.3)
37 (3.8)
79 (4.1)
Vomiting
5 (0.7)
17 (1.7)
29 (3.0)
46 (2.4)
Nasopharyngitis
12 (1.8)
28 (2.9)
17 (1.7)
45 (2.3)
Hypertension
15 (2.2)
17 (1.7)
25 (2.6)
42 (2.2)
Dyspepsia
8 (1.2)
21 (2.2)
19 (2.0)
40 (2.1)
Abdominal Pain Upper
1 (0.1)
19 (2.0)
18 (1.8)
37 (1.9)
AE = adverse event; APR = apremilast; BID = twice daily; MedDRA = Medical Dictionary for Regulatory 
Activities; TEAE = treatment-emergent adverse event.
a Preferred terms are coded using MedDRA Version 14 and are presented in descending order of subject incidence 
in the APR Total group. A subject with multiple occurrences of an AE is counted only once in the AE category.
b The first 16 weeks of exposure are included regardless of when apremilast exposure started.
Treatment-emergent AEs were predominantly mild or moderate in severity. The most frequently 
reported TEAEs (ie, diarrhea, nausea, upper respiratory tract infection, and headache) were 
primarily mild in severity. Severe diarrhea was reported by 1 (0.1%) subject in the placebo 
group, 4 (0.4%) in the APR 20 BID group, and 3 (0.3%) in the APR 30 BID group. Severe 
nausea was reported by 0 subjects in the placebo group, 2 (0.2%) in the APR 20 BID group, and 
3 (0.3%) in the APR 30 BID group. Severe headache was reported by 1 (0.1%) subject in the 
placebo group, 2 (0.2%) in the APR 20 BID group, and 1 (0.1%) in the APR 30 BID group. No 
events of severe upper respiratory tract infection were reported in any treatment group. 
Treatment with apremilast was associated with an increase in adverse reactions of depression. 
During the 0-to-16-week placebo-controlled period of Palace 1, 2, and 3, 1.0% (10/998) of 
subjects treated with apremilast reported depression or depressed mood and 0.8% (4/495) treated 
with placebo.
Body weight was measured routinely in Studies CC-10004-PSA-002, CC-10004-PSA-003, 
CC-10004-PSA-004, and CC-10004-PSA-005. At the end of the placebo-controlled period, 
median (mean) weight change from baseline was 0.00 (0.13) kg in the placebo group, -0.50 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
31
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
(-1.05) kg in the APR 20 BID group, and -0.60 (-0.97) kg in the APR 30 BID group. Weight loss 
> 5% was observed in 2.1% of subjects in the placebo group, 4.7% in the APR 20 BID group, 
and 4.9% in the APR 30 BID group. 
Serious TEAEs were reported for 22 (3.3%) subjects who received placebo and 44 (2.3%) who 
received apremilast during the first 16 weeks of exposure (Table 9). The incidence of serious 
adverse events (SAEs) was comparable across treatment groups, ie, 3.3% of subjects in the 
placebo group, 2.4% in APR 20 BID group, and 2.2% in the APR 30 BID group.
Table 9:
Treatment-emergent Serious Adverse Events Reported in >1 Subject in Any 
Treatment Group, First 16 Weeks of Exposure (Studies CC-10004-PSA-002, 
CC-10004-PSA-003, CC-10004-PSA-004, and CC-10004-PSA-005; Subjects 
As Treated)
Preferred Term
a
Weeks 0 to 
16
First 16 Weeks of Apremilast Treatment
b
Placebo
n (%)
(N = 671)
APR 20 BID
n (%)
(N = 972)
APR 30 BID
n (%)
(N = 973)
APR Total
n (%)
(N = 1945)
Any SAE
22 (3.3)
23 (2.4)
21 (2.2)
44 (2.3)
Atrial Fibrillation
0
0
2 (0.2)
2 (0.1)
Acute Myocardial Infarction
1 (0.1)
2 (0.2)
0
2 (0.1)
Deep Vein Thrombosis
0
0
2 (0.2)
2 (0.1)
Myocardial Ischemia
0
2 (0.2)
0
2 (0.1)
Psoriatic Arthropathy
3 (0.4)
1 (0.1)
1 (0.1)
2 (0.1)
Hypertensive Crisis
2 (0.3)
0
1 (0.1)
1 (0.1)
Pancreatitis Acute
2 (0.3)
0
0
0
AE = adverse event; APR = apremilast; BID = twice daily; MedDRA = Medical Dictionary for Regulatory 
Activities; SAE = serious adverse event.
a Preferred terms are coded using MedDRA Version 14 and are presented in descending order of subject incidence 
in the APR Total group and then alphabetically. A subject with multiple occurrences of an AE is counted only 
once in the AE category.
b The first 16 weeks of exposure are included regardless of when apremilast exposure started.
During the first 16 weeks, 1 death was reported in Study PSA-002 (Palace 1). The event occurred 
in a subject randomized to the APR 20 BID treatment group, who died due to multi-organ failure 
on Day 73 of the study. The subject was diagnosed with anemia due to vitamin B12 deficiency 
before the first dose of apremilast and was receiving concomitant MTX for the treatment of PsA.
The death certificate indicated that the direct cause of death was “multiple organ failure,” 
specifying that severe B12 deficiency anemia led to the event of multiple organ failure.
TEAEs leading to drug withdrawal were reported in 3.6% of subjects in the placebo group, 4.5% 
in the APR 20 BID group, and 5.2% in the APR 30 BID group. The most frequently reported 
TEAEs leading to withdrawal of apremilast were diarrhea, nausea, and headache. Among 
subjects who were taking placebo, the most frequently reported TEAEs that led to drug 
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
32
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
withdrawal were diarrhea and nausea. There was no evidence of an increased incidence of 
TEAEs leading to drug withdrawal with continued apremilast treatment when the incidence rate 
was adjusted for exposure.
1.2.2.2.2. Long-term Safety Data From CC-10004-PSA-006 (ACTIVE), CC-10004-PSA-
002 (Palace 1), CC-10004-PSA-003 (Palace 2) and CC-10004-PSA-004 (Palace 3)
The long-term safety of apremilast monotherapy in subjects who had received ≤1 csDMARD 
was assessed in the ACTIVE study over a period of 52 weeks (Nash, 2018). The overall 
incidence of adverse events (AEs) in the placebo-controlled period was generally similar for 
APR monotherapy and placebo. The most commonly reported AEs (≥5% of pts) with APR 
versus placebo were nasopharyngitis (8.3% versus 6.4%, respectively), nausea (8.3% versus
1.8%), headache (7.3% versus 3.7%), hypertension (6.4% versus 6.4%), and diarrhea (subject- or 
investigator-reported) (14.7% versus 11.0%); using a protocol-defined characterization of 
diarrhea (≥2 watery/liquid stools/day), overall incidence was lower for APR and placebo (11.0% 
and 8.3%). Serious AEs were lower with APR than placebo (2.8% versus 4.6%). No 
opportunistic infections, reactivations of tuberculosis (TB), or cases of marked depression were 
seen. In general, no increase was seen in AE incidence/severity with longer-term exposure to 
APR up to 52 weeks. Apremilast was generally well tolerated.
The long-term safety of apremilast, with or without concomitant csDMARDs, over 4 years was 
assessed in a pooled analysis of the Palace 1, 2, and 3 studies (Mease, 2017). Results from this 
analysis suggested a favorable and consistent safety profile over time. Importantly, the frequency 
of gastrointestinal AEs decreased with longer exposure to apremilast, and the frequency of other 
common AEs either decreased or remained stable with prolonged exposure (Table 10). The rates 
of infections did not increase over time, nor did the data indicate a need for specific laboratory 
monitoring. Treatment with apremilast was associated with an increase in adverse reactions of 
depression; 0.3% (4/1441) of subjects treated with apremilast discontinued treatment due to 
depression or depressed mood versus 0 placebo-treated subjects (0/495). Depression was 
reported as serious in 0.2% (3/1441) of subjects exposed to apremilast versus 0 placebo-treated 
subjects (0/495). Two subjects who received placebo committed suicide versus 0 apremilast-
treated subjects. Importantly, the rates of depression remained low over time. 
Table 10:
Frequency of Common AEs Over 208 Weeks of Exposure
Weeks 
0 to ≤52
Weeks 
> 52 to ≤104
Weeks 
> 104 to ≤156
Weeks 
> 156 to ≤208
Subjects, n (%)
APR30
N=721
APR30
n=520
APR30
n=443
APR30
n=401
≥1 AE
524 (72.7)
316 (60.8)
284 (64.1)
234 (58.4)
≥1 SAE
47(6.5)
35 (6.7)
40 (9.0)
28 (7.0)
AE leading to drug withdrawal
56 (7.8)
13 (2.5)
7 (1.6)
7 (1.7)
Death
0 (0.0)
1
§ (0.2)
0 (0.0)
2
‡,║(0.5)
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
33
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
Table 10:
Frequency of Common AEs Over 208 Weeks of Exposure (Continued)
Weeks 
0 to ≤ 52
Weeks 
> 52 to ≤ 104
Weeks 
> 104 to ≤ 156
Weeks 
> 156 to ≤ 208
Subjects, n (%)
APR30
N=721
APR30
n=520
APR30
n=443
APR30
n=401
AEs in ≥5% of subjects, n (%)
Diarrhea
112 (15.5)
20 (3.8)
12 (2.7)
4 (1.0)
Nausea
108 (15.0)
11 (2.1)
10 (2.3)
3 (0.7)
Headache
75 (10.4)
17 (3.3)
12 (2.7)
7 (1.7)
Upper respiratory tract infection
60 (8.3)
27 (5.2)
24 (5.4)
21 (5.2)
Nasopharyngitis
41 (5.7)
31 (6.0)
20 (4.5)
26 (6.5)
AE = adverse event; APR30 = apremilast 30 mg twice daily; SAE = serious adverse event.
* Includes all subjects who received APR during the time interval relative to the start of APR treatment. §Motor 
vehicle accident on Day 489. ‡Cerebrovascular accident on Day 1,330 in a 69-year-old man, considered unrelated 
to study drug; subject had history of myocardial infarction, atrial fibrillation, and cerebrovascular accident. 
║Stroke on Day 1,224 in a 58-year-old woman, considered unrelated to study drug; subject had a history of chronic 
ischemic heart disease, hypertension, alcoholism, and atrial fibrillation. 
Most AEs were mild or moderate in severity. Rates were very low for major cardiac events, 
malignant neoplasms, and serious opportunistic infections. It is noteworthy that systemic 
opportunistic infections did not occur with long-term exposure to apremilast. Marked laboratory 
abnormalities were infrequent, and most returned to baseline values with continued treatment.
In a pooled analysis of Palace 1, 2, 3, and 4 (Celgene, 2017) for subjects receiving long-term 
treatment with APR 30 BID, the median (mean) weight change from baseline was -1.00 (-1.25) 
kg and -1.30 (-1.68) kg, respectively, at Week 52, and -1.00 (-1.70 kg) and -2.00 (-2.14) kg at 
Week 78. At the end of treatment, weight loss > 5% was observed in 14.8% of subjects receiving 
apremilast 20 mg BID and 16.5% receiving apremilast 30 mg BID. Overall, no overt clinical 
consequences were seen with the weight loss observed with apremilast.
The 5-year safety of apremilast was evaluated in a long-term analysis of the Palace 1 study 
(Kavanaugh, 2018). No new safety concerns were identified. For subjects entering the fifth year 
of apremilast 30 mg BID exposure, AEs occurring in ≥5% were upper respiratory tract infection, 
nasopharyngitis, and urinary tract infection; most AEs were mild or moderate in severity. 
Apremilast 30 mg BID continued to demonstrate a favorable safety profile and was generally 
well tolerated.
Please refer to the Investigator Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP).
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
34
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
1.3.1.1.
Unmet Medical Need 
In 2016, the European League Against Rheumatism and the Group for Research and Assessment 
of Psoriasis and Psoriatic Arthritis (GRAPPA) published updated recommendations for the 
management of PsA. The GRAPPA recommendations are based on the following goals of 
therapy: 1) To achieve the lowest possible level of disease activity; 2) To optimize functional 
status and improve QoL, and prevent structural damage, and 3) To avoid or minimize 
complications, both from untreated active disease and from therapy. 
Apremilast has been extensively investigated for the treatment of PsA. It is associated with 
improvements in clinical outcomes across several core PsA domains, physical function and QoL.
However, its impact on imaging outcomes associated with structural progression in patients with 
PsA remains to be determined. In addition, the extent of its effects on axial parameters remains 
to be characterized in subjects with axial PsA.
Importantly, recent studies have failed to demonstrate substantial radiographic progressions in 
most PsA subjects studied over short periods of time (Gladman, 1995a; Gladman, 1995b; 
Queiro-Silva, 2003). These studies enrolled subjects who were at high risk for structural disease 
progression, such as patients with 3 swollen joints, elevated CRP, and evidence of erosive 
disease of peripheral joints at baseline. Subjects were treated with biologics or Janus kinase 
(JAK) inhibitors, or were receiving placebo. Taken together, the limited amount of radiographic 
progression observed in these studies may reflect a change in the expression of the disease over 
time, which can be explained by improvements in the care of PsA. This may also highlight the 
limitations of conventional radiographic imaging to assess structural changes.
1.3.1.2.
Magnetic Resonance Imaging (MRI) in PsA and Study Rationale
Magnetic resonance imaging (MRI) has gained importance as a promising tool for early 
diagnosis and increasing acceptance as an outcome measure in clinical trials of different 
inflammatory arthritides (Ostergaard, 2009; Weber, 2007; Weber, 2009). It is highly sensitive
(Althoff, 2007; Braun, 2004; Hermann, 2005; Hermann, 2006) and superior to conventional 
radiography in depicting inflammatory bone lesions of peripheral arthritis and the axial skeleton. 
Moreover, it can detect soft tissue inflammation, bone erosion, and proliferation. Since there is 
lack of ionizing radiation, an MRI is also well suited for young patients and repetitive follow-up 
exams.
Results from studies in RA indicate that bone marrow edema (BME) is a predictor of erosive 
progression. A similar relationship is also suggested in PsA (Poggenborg, 2015c). Indeed, a close 
relationship between erosions and BME was found in a cross-sectional MRI study of erosive PsA 
patients. These data suggest that BME is a “forerunner” of structural joint damage in PsA (Tan, 
2009). In a 48-week longitudinal study of PsA patients, BME detected by MRI predicted 
subsequent erosive progression as detected by computed tomography (relative risk of erosion 
progression of 10 [95% CI, 2.1-49] versus joints without BME) (Poggenborg, 2014).
Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
Apremilast
Protocol CC-10004-PSA-014
Amgen Inc.
Confidential and Proprietary
35
CC-10004-PSA-014 Amendment 4 Final: 04 May 2020
The potential use of MRI to monitor treatment outcomes has encouraged research in this field. In 
2015, the Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Magnetic 
Resonance Imaging Score (PsAMRIS) was validated in a randomized placebo-controlled trial 
with 40 subjects who received placebo or abatacept for 6 months. The results showed numerical 
improvements in the inflammatory variables of PsAMRIS, with high responsiveness, especially 
for synovitis and tenosynovitis, during abatacept but not placebo therapy. The scoring system
(Glinatsi, 2015) assesses metacarpophalangeal, proximal interphalangeal, and distal 
interphalangeal joints of fingers 2 to 5, quantifying synovitis (score 0-3), flexor tenosynovitis 
(score 0-3), periarticular inflammation (absent or present), bone edema (score 0-3), bone erosion 
(score 0-10), and bone proliferation/enthesophytes (absent or present). The PsAMRIS is a new 
outcome measure for clinical trials (Coates, 2012). The scoring system provides an objective 
measure of disease activity, being able to identify responses earlier than clinical assessments. 
Poggenborg, et al (Poggenborg, 2014) showed that MRI is useful in quantifying improvements in 
tenosynovitis, synovitis, and osteitis after treatment with an anti-TNF agent. In contrast, in the 
same trial, MRI scores of periarticular inflammation did not change significantly after 24 weeks.
As a result, the impact of apremilast on the PsAMRIS composite score of BME, synovitis, and 
tenosynovitis was chosen as the primary endpoint of this study, due to its sensitivity to change in 
response to treatment.
Dynamic contrast-enhanced MRI (DCE-MRI) is a distinct MRI technique that quantifies the 
patterns of enhancement within pre-determined regions of interest, after injection of intravenous 
contrast agent (Cimmino, 2012). Such dynamic imaging allows the capture of the tissue 
vascularity and quantifies the inflammation in the studied joint. It has been validated in RA for 
measuring inflammation, but has been used less frequently in studies in PsA. It seems to be a 
sensitive tool to assess inflammation in PsA, correlating significantly with PsAMRIS total 
inflammation score (Poggenborg, 2012). In this study, DCE-MRI will be performed in the most 
affected hand as an optional assessment. Furthermore, we aim to compare standard MRI and 
DCE-MRI for monitoring inflammation, determining differences in responsiveness between 
both. 
Undoubtedly, physical examination is the basis of clinical evaluation. Nevertheless, the routine 
clinical exam, especially of enthesitis, is often inconclusive, making the decision to initiate or 
adapt therapy very difficult. Therefore, more objective methods demonstrating inflammation at 
tendons, ligaments, and fascia at their insertion in bone and/or the adjacent soft tissue are needed
(Poggenborg, 2015a). However, standard MRI can only be used to scan a small anatomical area 
at a time. This is a limitation when assessing PsA, which has a heterogeneous phenotype, being 
diverse and widespread in terms of disease manifestations. Whole-body MRI (Althoff, 2007)
(WB-MRI) is a promising method for improving enthesitis assessment by evaluating all entheses 
from “head-to-toe” in one examination (Mager, 2009; Meaney, 2010). A prospective, cross-
sectional pilot study of patients with PsA (n=18) and axial SpA (n=18) by Poggenborg and 
colleagues showed that enthesitis can be detected on WB-MRI, with moderate agreement 
between WB-MRI and clinical examination at the entheseal level (Poggenborg, 2015a). It is 
important to emphasize that, although clinical examination is considered the gold standard, 
previous studies have documented a moderate reliability of clinical assessment among 
rheumatologists with expertise in SpA. This undoubtedly contributes to the lack of association 
with MRI findings (Gladman, 2007). Poggenborg’s study showed that enthesitis was frequently 
Approved 
 
 


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observed, mostly occurring at the greater femoral trochanter, supraspinatus, and Achilles tendon 
insertions. Moreover, by performing WB-MRI, it may be possible to differentiate between 
enthesitis and fibromyalgia, enabling the rheumatologist to choose the appropriate treatment
(Weckbach, 2011).
Involvement of the axial skeleton is a characteristic feature of spondyloarthritis (SpA). It is 
present in between 25% (early disease and clinical assessment only) and 75% (late disease and 
sophisticated imaging) of PsA patients, with an impact as great as that seen in ankylosing 
spondylitis (Jadon, 2017). MRI is widely accepted as the most sensitive imaging modality to 
detect early inflammatory lesions of the axial skeleton (Weber, 2008). WB-MRI is capable of 
detecting axial involvement in PsA patients, because it evaluates multiple possible areas of 
involvement in a single procedure. WB-MRI has been validated against standard MRI for 
scoring acute inflammatory lesions in the sacroiliac joints of 32 SpA patients with established 
and active disease (30 had primary ankylosing spondylitis and 2 had Crohn’s disease, all 
fulfilling the modified New York criteria) (Weber, 2009). Results showed a strong correlation 
and comparable reliability for the detection of inflammatory lesions. 
Thus, although relatively new, WB-MRI is a very promising tool for the assessment of disease 
activity and damage in PsA, with significant potential as a measure of the overall burden of the 
disease (Ostergaard, 2017; Poggenborg, 2015b). As a result, WB-MRI will be used in the current 
study to assess the impact of apremilast on MRI parameters of axial joints in subjects with 
suspected axial PsA. Its impact on entheses and peripheral joints will also be investigated.
The concept that MRI more accurately identifies clinically relevant synovitis than clinical 
assessment is well established. One hypothesis for why MRI might be a useful predictive 
biomarker for clinical response is that some patients may have elevated disease activity measures 
driven by comorbid conditions, rather than solely by active joint inflammation (Baker, 2017).
Conversely, patients with greater MRI-detected activity might be expected to have a big 
proportion of their clinical disease activity explained by active PsA. Finally, since the evidence 
for the prognostic value of MRI in PsA is still scarce (Mathew, 2017), this study intends to 
investigate the correlation between specific imaging features and structural progression in this 
population.
1.3.2.
Rationale for the Study Design
Psoriatic arthritis may vary from a mild nonprogressive oligoarthritis to severe polyarticular 
disease, with great disability and reduced quality of life.  These diverse clinical manifestations 
undermine general predictions regarding outcomes. Although PsA has been historically 
conceived as a more benign arthropathy, in some patients it follows a particularly aggressive and 
deforming course. Hence, early diagnosis and treatment may have a significant beneficial effect 
on the natural course of this disease.
This study is designed to determine the impact of apremilast on imaging outcomes, assessed by 
both MRI of the most affected hand and WB-MRI, in biologic-naïve subjects with active PsA, 
with ≥ 3 months and ≤ 5 years of disease duration, who had inadequate response to 2 or less 
csDMARDs. The purpose of the single-arm design of this trial is to obtain preliminary evidence 
of the impact of apremilast on MRI outcomes and structural progression of the disease. 
Approved 
 
 


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A placebo-controlled study was not deemed necessary since current evidence in the literature 
shows that inflammation, as assessed by MRI, is not expected to significantly improve without 
an intervention in PsA. Moreover, a comparison arm with methotrexate was not pursued as the 
efficacy of MTX in PsA has not been convincingly proven in a randomized placebo-controlled 
trial. 
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
After a dose titration over a 5-day period, an oral dose of apremilast 30 mg BID will be given to 
all subjects. This is the approved dosing regimen of apremilast for the treatment of PsA.
In the Phase 3 PsA studies, a statistically significantly greater proportion of subjects in the 
apremilast 30 mg BID treatment group achieved the primary endpoint of ACR 20 response at 
Week 16 versus placebo. The statistically significant ACR 20 responses observed at Week 16 
were maintained at Week 24 in the APR 30 BID group in all 3 pivotal studies. Therefore, the 24-
week treatment period with frequent visits and assessments will provide adequate time to 
reasonably assess the effect of apremilast on clinical parameters and subject-reported outcomes, 
but especially on inflammatory and bony lesions classically associated with PsA, as assessed by 
MRI. This is also consistent with the design of clinical trials that evaluated the effect of biologic 
drugs in subjects with PsA through MRI assessments that have selected their primary endpoints 
at Week 24 in order to assess efficacy. The long-term effects of apremilast will be evaluated at 
Week 48. Indeed, results from the above-mentioned studies indicate that a longer follow-up is 
needed to detect changes in erosions with MRI.
Approved 
 
 


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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 11:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the efficacy of apremilast 30 mg twice a day (BID) on 
inflammation indices, assessed by magnetic resonance imaging (MRI) of the hand.
Secondary Objective(s)
The secondary objectives of the study are to evaluate:

The efficacy of apremilast 30 mg BID on imaging outcomes associated with structural progression, 
assessed by MRI of the hand.

The efficacy of apremilast 30 mg BID on disease activity and functionality, assessed by clinical 
outcomes

The efficacy of apremilast 30 mg BID on inflammation indices of peripheral arthritis and enthesitis, 
total (sum of arthritis and enthesitis) and separately, assessed by whole-body MRI (WB-MRI)

The efficacy of apremilast 30 mg BID on The European League Against Rheumatism Psoriatic 
Arthritis Impact of Disease 12 domains (PsAID-12)

The safety and tolerability of apremilast 30 mg BID 
Exploratory Objective(s)
Approved 
 
 


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Table 12: Study Endpoints
Endpoint
Name
Description
Time Frame
Primary
Psoriatic Arthritis Magnetic 
Resonance Imaging Score
(PsAMRIS) Inflammation Score 
of bone marrow edema [BME] + 
synovitis + tenosynovitis
Change from baseline in the 
composite score of BME, synovitis,
and tenosynovitis assessed by 
PsAMRIS
Week 24
Secondary
Efficacy
PsAMRIS Inflammation Score of 
BME + Synovitis + Tenosynovitis
Change from baseline in the 
composite score of BME, synovitis, 
and tenosynovitis assessed by 
PsAMRIS
Week 48
PsAMRIS BME + Synovitis
Change from baseline in the 
composite score of BME and 
synovitis assessed by PsAMRIS
Week 24
Week 48
PsAMRIS Total Inflammation 
Score (BME + Synovitis + 
Tenosynovitis + Periarticular 
Inflammation)
Change from baseline in the 
PsAMRIS total inflammation score
Week 24
Week 48
PsAMRIS BME
Change from baseline in BME 
assessed by PsAMRIS
Week 24
Week 48
PsAMRIS Synovitis
Change from baseline in synovitis 
assessed by PsAMRIS
Week 24
Week 48
PsAMRIS Tenosynovitis
Change from baseline in 
tenosynovitis assessed by PsAMRIS
Week 24
Week 48
PsAMRIS Periarticular 
Inflammation
Change from baseline in periarticular 
inflammation assessed by PsAMRIS
Week 24
Week 48
PsAMRIS Total Damage Score
(erosion + bone proliferation)
Change from baseline in the 
PsAMRIS total damage score
(erosion + bone proliferation)
Week 24
Week 48
PsAMRIS Erosion
Change from baseline in bone erosion 
assessed by PsAMRIS
Week 24
Week 48
PsAMRIS Bone Proliferation
Change from baseline in bone 
proliferation/enthesophytes assessed 
by PsAMRIS
Week 24
Week 48
Swollen Joint Count (SJC)
Change from baseline in the SJC
Week 24
Week 48
Tender Joint Count (TJC)
Change from baseline in the TJC
Week 24
Week 48
Approved 
 
 


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Table 12:
Study Endpoints (Continued)
Endpoint
Name
Description
Time Frame
Clinical Disease Activity Index 
for Psoriatic Arthritis (c-DAPSA)
Change from baseline in the c-
DAPSA Score
Week 24
Week 48
Spondyloarthritis Research 
Consortium of Canada 
(SPARCC)
Change from baseline in SPARCC, in 
subjects with preexisting 
enthesopathy
Week 24
Week 48
Leeds Enthesitis Index (LEI)
Change from baseline in the LEI, in 
subjects with preexisting 
enthesopathy
Week 24
Week 48
Enthesitis improvement to 0
Proportion of subjects with baseline 
enthesitis whose enthesitis improves 
to 0
Week 24
Week 48
Leeds Dactylitis Index (LDI)
Change from baseline in the LDI, in 
subjects with preexisting dactylitis
Week 24
Week 48
Dactylitis improvement to 0
Proportion of subjects with baseline 
dactylitis whose tender dactylitis 
count improves to 0
Week 24
Week 48
Psoriatic Arthritis Disease 
Activity Score (PASDAS)
Change from baseline in the PASDAS
Week 24
Week 48
Evaluator’s Global Assessment of 
Disease Activity
Change from baseline in the 
evaluator’s global assessment of 
disease activity
Week 24
Week 48
Subject’s Global Assessment of 
Disease Activity
Change from baseline in the subject’s 
global assessment of disease activity
Week 24
Week 48
Subject’s Assessment of Pain
Change from baseline in the subject’s 
assessment of pain
Week 24
Week 48
Health Assessment 
Questionnaire-Disability Index 
(HAQ-DI)
Change from baseline in physical 
function (HAQ-DI score)
Week 24
Week 48
WB-MRI Peripheral Enthesitis
Inflammation Index
Change from baseline in the 
peripheral enthesitis inflammation 
index assessed by WB-MRI
Week 24
Week 48
WB-MRI Peripheral Joints 
Inflammation Index
Change from baseline in peripheral 
joints inflammation index assessed by 
WB-MRI
Week 24
Week 48
WB-MRI Total Peripheral 
Inflammation Index
Change from baseline in the total 
peripheral (joints and enthesitis) 
inflammation index assessed by WB-
MRI
Week 24
Week 48
Approved 
 
 


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Table 12:
Study Endpoints (Continued)
Endpoint
Name
Description
Time Frame
BASDAI
Change from baseline in the BASDAI 
(for subjects deemed to have PsA 
spondylitis by the investigator and 
with BASDAI item 2 ≥4 at baseline)
Week 24
Week 48
The European League Against 
Rheumatism Psoriatic Arthritis 
Impact of Disease 12 domains 
(PsAID-12)
Change from baseline in the PsAID-
12
Week 24
Week 48
Safety
The following parameters will be evaluated throughout the duration of the study:
Adverse events (AEs)
Type, frequency, severity and 
relationship of AEs to study 
medication
-
Discontinuation due to AEs
Number of subjects who discontinue 
study medication due to any AE
-
Clinically significant changes in 
physical examination, vital signs, 
and/or laboratory findings
Frequency of clinically significant 
changes in physical examination, vital 
signs, and/or laboratory findings
-
Exploratory
Approved 
 
 


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Table 12:
Study Endpoints (Continued)
Endpoint
Name
Description
Time Frame
Approved 
 
 


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Table 12:
Study Endpoints (Continued)
Endpoint
Name
Description
Time Frame
Approved 
 
 


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3.
OVERALL STUDY DESIGN
3.1.
Study Design
The study will be conducted in compliance with the International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements. For all regions, the local 
Regulatory Label must be followed. 
This is a Phase 4, multicenter, single-arm, open-label study to evaluate the impact of apremilast,
either in monotherapy or with stable MTX, on MRI outcomes in subjects with active PsA with 
up to 5 years of disease duration (since diagnosis).
Approximately 120 subjects will receive apremilast 30 mg BID, after a 5-day titration period,
with or without stable MTX. All subjects will be permitted to take NSAIDs and/or low-dose oral 
glucocorticoids (prednisone ≤ 10 mg/day or equivalent) throughout the study. The NSAIDs and 
low-dose oral glucocorticoids must be on a stable regimen for at least 4 weeks prior to baseline. 
MTX (≤25 mg/week) will be permitted if treatment duration is ≥6 months and on a stable 
regimen for at least 3 months prior to baseline. In addition, the stable doses of MTX, NSAIDs,
and low-dose glucocorticoids must be continued from Day 1 through the Week 24 Visit. Change 
in doses, increase or decrease, and/or discontinuation will not be allowed, except for safety 
reasons or for lack of availability. After the Week 24 Visit, the doses of MTX, NSAIDs, or 
glucocorticoids may be adjusted as clinically required.
This is a 56-week study which will consist of 3 phases, as shown in Figure 1:

Screening Phase – up to 4 weeks

Single-arm, Open-label Treatment Phase – Weeks 0 to 48

120 subjects will receive apremilast 30 mg BID (after a 5-day titration period) for 
the entire duration of this phase

All subjects who complete the study or discontinue early will participate in the 4-
week Post-treatment Observational Follow-up Phase. Henceforth, this will be referred 
to as the Observational Follow-up Phase.
Approved 
 
 


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Figure 1:
Overall Study Design
                           Wk -4            Wk 0      Wk 8      Wk 16         Wk 24            Wk 36               Wk 48         Wk 52
                                                                                            Primary Endpoint
BID = twice daily; MTX = methotrexate; Wk = Week. 
Apremilast 30 mg BID with or without
MTX
Screening
Follow-up
 
Approved 
 
 


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3.2.
Study Duration for Subjects 
Subjects who complete the study will spend up to a total of 56 weeks in this study:

Up to 4 weeks in the Screening Phase

Weeks 0 to 48 (ie, 48 weeks) in the Open-label, Single-arm, Treatment Phase

4 weeks in the Observational Follow-up Phase 
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study completion is defined as the date of the last visit of the last subject in this clinical study.
Study completion for an individual subject is defined as reaching Visit 7/48 weeks of treatment, 
and finishing the Observational Follow-up Visit at Week 52. A subject not meeting this 
definition is considered under early discontinuation (see Section 6.3). For the purpose of 
analyses, study completion for an individual subject is defined as reaching the Week 48 Visit.
Approved 
 
 


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4.
STUDY POPULATION
Subjects must meet all inclusion criteria (Section 4.3) and must not have any of the conditions 
specified in the exclusion criteria (Section 4.4) to qualify for participation in the study. The 
subject’s source documents must support his/her qualifications for the study (eg, if a female 
subject does not require pregnancy testing and birth control because of a hysterectomy, the date 
of the hysterectomy must be included in the medical history).
4.1.
Medical and Disease History
Relevant medical history should be recorded, including smoking and alcohol history, as well as 
previous relevant surgeries. Disease history should include history of psoriasis and PsA. 
4.2.
Number of Subjects 
Approximately 120 subjects will be enrolled worldwide. 
4.3.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1.
Males or females, aged ≥ 18 years at time of consent
2.
For all regions, the local Regulatory Label for treatment with apremilast must be followed. 
For example, subjects in the EU must have had inadequate response or intolerance to a prior 
csDMARD. 
3.
Must understand and voluntarily sign an informed consent document prior to any study 
related assessments/procedures being conducted
4.
Able to adhere to the study visit schedule and other protocol requirements
5.
Have a documented diagnosis of PsA of ≥ 3 months AND ≤5 years in duration, meeting the 
CASPAR criteria for PsA (Appendix B, Taylor, 2006) at the time of Screening Visit
6.
Have ≥ 3 swollen AND ≥ 3 tender joints, with hand involvement (defined as ≥ 1 swollen 
joint or dactylitis [each clinically active joint of a dactylitic digit is counted as one joint]).
7.
Have at least 1 active enthesitis site (one of the SPARCC or LEI sites)
8.
Must not have been treated previously with a TNF blocker or other biologic drug for PsA 
treatment
9.
Must not have been treated with more than 2 csDMARDs
10. Subjects taking csDMARDs, with the exception of MTX, cyclosporine, or LEF (see Section
4.4, Exclusion Criterion 18, 19 and 20), do not require a washout period. However, they 
must discontinue the csDMARD treatment at least one day prior to their Baseline Visit (ie, 
Visit 2, Day 1)
11. Subjects who have been previously treated with MTX for < 6 months and who are not on 
stable doses for at least 3 months will require a 28-day washout prior to the Baseline Visit 
(ie, Visit 2, Day 1) to participate in the study
Approved 
 
 


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12. Subjects who have been previously treated with LEF will require a 12-week washout prior 
to the Baseline Visit (ie, Visit 2, Day 1), or treatment with cholestyramine, per LEF
prescribing label (ie, 8 g cholestyramine 3 times daily for 11 days)
13. Subjects who have been previously treated with cyclosporine will require a 28-day washout 
prior to the Baseline Visit (ie, Visit 2, Day 1) to participate in the study
14. If taking MTX (≤25 mg/week), continuity of treatment will be allowed if duration of 
treatment is ≥ 6 months and on a stable dose for at least 3 months prior to the Baseline Visit 
(ie, Visit 2, Day 1)
15. If taking oral glucocorticoids, must be on a stable dose of prednisone ≤ 10 mg/day or 
equivalent for at least 4 weeks prior to the Baseline Visit (ie, Visit 2, Day 1)
16. If taking NSAIDs or narcotic analgesics, must be on stable dose for at least 4 weeks prior to 
Baseline Visit (ie, Visit 2, Day 1) 
17. A female of childbearing potential (FCBP)† must have a negative pregnancy test at 
screening and baseline. While on IP and for at least 28 days after taking the last dose of IP, a
FCBP who engages in activity in which conception is possible must use one of the approved 
contraceptive§ options described below:
Option 1: Any one of the following highly effective methods: hormonal contraception (oral, 
injection, implant, transdermal patch, vaginal ring); intrauterine device; tubal ligation; or 
partner’s vasectomy; 
OR
Option 2: Male or female condom (latex condom or non-latex condom NOT made out of 
natural [animal] membrane [for example, polyurethane]); PLUS one additional barrier 
method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) 
contraceptive sponge with spermicide.
Note: Option 2 may not be acceptable as a highly effective contraception option in all 
countries, per local guidelines/recommendations.
† An FCBP is defined as a sexually mature female who 1) has not undergone a hysterectomy (the surgical 
removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 
consecutive months).
§ The female subject’s chosen form of contraception must be effective by the time the female subject is 
screened into the study (for example, hormonal contraception should be initiated at least 28 days before 
screening).
18. Must be in general good health (except for PsA) as judged by the investigator, based on 
medical history, physical examination, and clinical laboratories. (Note: The definition of 
good health means a subject does not have uncontrolled significant comorbid conditions).
4.4.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1.
Contraindication to MRI examination including, but not limited to, intracranial metal 
clips, heart pacemakers, insulin pumps, implanted hearing aids, neurostimulators, metal 
hip replacements, profound claustrophobia or inability to lie in the MRI machine in an 
Approved 
 
 


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appropriate position to obtain quality images, history of hypersensitivity to gadolinium 
contrast agent
2.
Severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by 
the Cockroft–Gault equation), which would prevent the use of gadolinium enhancement
3.
History of clinically significant (as determined by the investigator) cardiac, endocrine, 
pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or 
other major uncontrolled disease
4.
Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study 
5.
Prior history of suicide attempt at any time in the subject’s lifetime prior to signing the 
informed consent, or major psychiatric illness requiring hospitalization within the last 3 
years prior to signing the informed consent.
6.
Pregnant or breast feeding
7.
Active substance abuse or a history of substance abuse within 6 months prior to screening
8.
History of allergy or hypersensitivity to any component of the IP
9.
History of rare hereditary problems of galactose intolerance, lapp lactase deficiency or 
glucose-galactose malabsorption
10.
History of positive human immunodeficiency virus (HIV), or congenital or acquired 
immunodeficiency (eg, Common Variable Immunodeficiency Disease)
11.
Active tuberculosis or a history of incompletely treated tuberculosis
12.
Bacterial infections requiring treatment with oral or injectable antibiotics, or significant 
viral or fungal infections, within 4 weeks of screening. Any treatment for such infections 
must have been completed and the infection cured, at least 4 weeks prior to screening and 
no new or recurrent infections prior to the Baseline Visit
13.
Malignancy or history of malignancy or myeloproliferative or lymphoproliferative 
disease within the past 3 years, except for treated (ie, cured) basal cell or squamous cell 
in situ skin carcinomas
14.
Major surgery (including joint surgery) within 8 weeks prior to screening or planned 
major surgery within 6 months following Baseline Visit
15.
Rheumatic autoimmune disease other than PsA, including, but not limited to: systemic 
lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or 
fibromyalgia
16.
Prior history of or current inflammatory joint disease other than PsA (eg, gout, reactive 
arthritis, RA, ankylosing spondylitis, Lyme disease), which confounds the ability to 
interpret data from the study
17.
Prior treatment with any biologic DMARD
18.
Prior treatment with more than 2 csDMARDs
Approved 
 
 


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19.
Use of the following systemic therapy(ies) within 28 days of the Baseline Visit (ie, Visit 
2, Day 1): cyclosporine or other calcineurin inhibitors, glucocorticoids exceeding 10 mg 
daily prednisone equivalent, as well as mycophenolate
20.
Use of MTX within 4 weeks of the Baseline Visit (ie, Visit 2, Day 1), unless subject is on 
stable doses for at least 3 months and total treatment duration with MTX is ≥6 months
21.
Use of LEF within 12 weeks of the Baseline Visit (ie, Visit 2, Day 1), unless subject has 
taken cholestyramine, 8 g three times daily 11 days after stopping LEF
22.
Previous treatment with a JAK inhibitor (including tyk2 inhibitor)
23.
Prior treatment with apremilast, or participation in a clinical study involving apremilast
24.
Use of intra-articular (IA) glucocorticoid injection within 8 weeks before the Baseline 
Visit (ie, Visit 2, Day 1). 
25.
Use of any investigational drug within 4 weeks of the Baseline Visit, or 5 
pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer)
Approved 
 
 


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5.
TABLE OF EVENTS
Table 13: Table of Events
Early 
Termination j
Observational 
Follow-up
Visit Number
1
Screening
2
Baseline
3
4
5
6
7
Assessments
performed for 
Early 
Termination
8 (or 
subsequent 
to Early 
Termination 
Visit)
Week
Days -28 to 0
0
8
(+/-1 
week)
16
(+/-1 week)
24
(+/-1 
week)
36
(+/-1
week)
48
(+/-1
week)
-
Week 52 or 4 
weeks (+/-1 
week) after 
Early 
Termination)
Study Entry and General 
Assessments
Informed Consent
x
-
-
-
-
-
-
-
-
Demographics
x
-
-
-
-
-
-
-
-
Medical History
x
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
x
x
-
-
-
-
-
-
-
Prior/concurrent Medications
x
x
x
x
x
x
x
x
x
Prior/concurrent Procedures
x
x
x
x
x
x
x
x
x
Biomarkers and Safety Assessments
Vital Signs
x
x
x
x
x
x
x
x
-
Height
x
-
-
-
-
-
-
-
-
 
Approved 
 
 


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Table 13:
Table of Events (Continued)
Early 
Termination j
Observational 
Follow-up
Visit Number
1
Screening
2
Baseline
3
4
5
6
7
Assessments
performed for 
Early 
Termination
8 (or 
subsequent 
to Early 
Termination 
Visit)
Week
Days -28 to 0
0
8 
(+/-1 
week)
16
(+/-1 week)
24
(+/-1 
week)
36
(+/-1 
week)
48
(+/-1 
week)
-
Week 52 or 4 
weeks (+/-1 
week) after 
Early 
Termination)
Weight 
x
x
x
x
x
x
x
x
-
Assessment of Diarrhea
-
x
x
x
x
x
x
x
-
Complete Physical Exam a
x
-
-
-
x
-
x
x
-
Limited Physical Exam a
-
x
x
x
-
x
-
-
-
Complete Blood Count
x
x
x
x
x
x
x
x
-
Serum Chemistries
x
x
x
x
x
x
x
x
-
Hemoglobin A1c
-
x
-
-
x
-
x
x
-
Urinalysis
x
x
-
-
x
-
x
x
-
Pregnancy Test c (FCBP only)
x
x
-
-
-
-
x
x
-
Contraception Education d
x
x
-
-
-
-
-
-
-
Adverse Events e
x
x
x
x
x
x
x
x
x
Efficacy Assessments
Tender Joint Count (0-78)
x
x
x
x
x
x
x
x
-
Swollen Joint Count (0-76)
x
x
x
x
x
x
x
x
-
Subject Global Assessment of 
Disease Activity
x
x
x
x
x
x
x
x
-
 
Approved 
 
 


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Table 13:
Table of Events (Continued)
Early 
Termination j
Observational 
Follow-up
Visit Number
1
Screening
2
Baseline
3
4
5
6
7
Assessments
performed for 
Early 
Termination
8 (or 
subsequent 
to Early 
Termination 
Visit)
Week
Days -28 to 0
0
8 
(+/-1 
week)
16
(+/-1 week)
24
(+/-1 
week)
36
(+/-1 
week)
48
(+/-1 
week)
-
Week 52 or 4 
weeks (+/-1 
week) after 
Early 
Termination)
Evaluator Global Assessment
of Disease Activity 
-
x
x
x
x
x
x
x
-
Subject Assessment of Pain 
x
x
x
x
x
x
x
x
-
HAQ-DI
-
x
x
x
x
x
x
x
-
c-DAPSA (for eligibility) f
x
x
-
-
-
-
-
-
-
SPARCC
x
x
x
x
x
x
x
x
-
LEI
x
x
x
x
x
x
x
x
-
Dactylitis Assessment g
x
x
x
x
x
x
x
x
-
BSA
x
x
-
-
x
-
x
x
-
BASDAI h
-
x
x
-
x
-
x
x
-
MRI of the Most Affected Hand i
-
x
-
-
x
-
x
x
-
Whole-body MRI i
-
x
-
-
x
-
x
x
-
 
Approved 
 
 


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Table 13:
Table of Events (Continued)
Early 
Termination j
Observational 
Follow-up
Visit Number
1
Screening
2
Baseline
3
4
5
6
7
Assessments
performed for 
Early 
Termination
8 (or 
subsequent 
to Early 
Termination 
Visit)
Week
Days -28 to 0
0
8 
(+/-1 
week)
16
(+/-1 week)
24
(+/-1 
week)
36
(+/-1 
week)
48
(+/-1 
week)
-
Week 52 or 4 
weeks (+/-1 
week) after 
Early 
Termination)
SRO
-
PsAID-12
-
x
x
-
x
-
x
x
-
Dosing
-
Dispense Investigational Product
-
x
x
x
x
x
-
-
-
Investigational Product 
Accountability
-
-
x
x
x
x
x
x
-
; ACR = American College of Rheumatology; BASDAI = Bath Ankylosing Spondylitis Activity Index; BSA = body surface area; c-
DAPSA = Clinical Disease Activity Index for Psoriatic Arthritis; CRP = C-reactive protein; 
; 
 
 FCBP = female of childbearing potential; HAQ-DI = Health Assessment Questionnaire – Disability Index; IP = investigational product; LDI = 
Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MRI = magnetic resonance imaging; PASI = Psoriasis Area and Severity Index;
 
PsA = psoriatic arthritis; PsAID = PsA Impact of Disease; 
; SPARCC = Spondyloarthritis 
Research Consortium of Canada; SRO = Subject-reported Outcomes; 
.
a During the Observational Follow-up Visit, a complete or limited physical exam may be done at the discretion of the study physician, although not required as per protocol.
b High-sensitivity CRP will also be performed as one of the efficacy assessments.
c An FCBP† must have a negative pregnancy test at screening and baseline. Serum beta human chorionic gonadotropin (β-hCG) pregnancy test will be performed at screening, and 
urine β-hCG pregnancy test will be performed at baseline. Urine pregnancy test will be performed to assess subject eligibility within 72 hours prior to the first administration of 
IP (negative results required for dispensing IP). Pregnancy tests should be performed if the FCBP subject has missed a menstrual period or the contraception method has
changed. At the last treatment visit, or in case of early termination, a serum β-hCG pregnancy test will be performed.
d See Section 4.3 and Appendix T.
 
Approved 
 
 


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e See Section 6.5.8.
f At screening (and to be confirmed at baseline), c-DAPSA will be calculated, for eligibility. Half of the subjects must have moderate disease activity or below. Eligibility for each 
patient will be confirmed by IWRS.
g For dactylitis assessment at screening, only a binary evaluation is needed (yes/no). As per inclusion criteria, subjects must have ≥ 3 swollen AND ≥ 3 tender joints, with hand 
involvement (defined as ≥1 swollen joint OR dactylitis). For the subsequent visits, LDI is needed.
h BASDAI will be performed for all subjects.
i The clinical and the MRI assessments should be performed on the same day, with the MRI scans always performed after the clinical visit. Exceptionally, MRI scans can be 
performed within 7 days after the clinical assessments. The baseline MRI must be performed within 7 days after the first administration of IP. The subsequent MRIs should be 
performed at Week 24 + 7 days and Week 48 + 7 days.
j As per protocol, in case of early termination, the site must perform all due assessments, including the MRI scans, to the best of its ability. Early termination MRI assessments 
will not be performed if the previous MRI scans have been done within the last 8 weeks before the early termination visit.
 
Approved 
 
 


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6.
PROCEDURES
The following procedures will be conducted as outlined in the Table of Events, Section 5.
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days of first dosing unless noted otherwise below. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Safety laboratory analyses and all assessments will be performed centrally. Screening laboratory 
values must demonstrate subject eligibility, but may be repeated within the screening window, if 
necessary.
Chest radiography can be performed at the investigator’s discretion, however it is not required as 
per protocol.
The following will be performed at screening as specified in the Table of Events, after informed 
consent has been obtained:

Inclusion/Exclusion criteria

Medical history (including specific information regarding diagnosis and additional 
needed details)

Demographics (include year of birth, sex, race, and ethnicity-if allowed by local 
regulations)

Prior disease therapies: includes surgery, systemic or any other therapy for the subject’s 
disease

Complete medical history (all relevant medical conditions diagnosed/ occurring prior to 
screening should also be included)

Prior and concomitant procedures (including all procedures occurring ≤ 28 days before 
screening)

Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
screening, except for those taken for disease)

Complete physical examination (can be source documented only), height, weight and 
BSA

c-DAPSA (for eligibility, to be confirmed at Baseline Visit). Half of the subjects must 
have moderate disease activity or below

SPARCC, LEI and dactylitis assessment (for eligibility, to be confirmed at Baseline 
Visit)

Vital signs (including blood pressure, temperature, and heart rate)
Approved 
 
 


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
Hematology panel including complete blood count (CBC) with differential, including red 
blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count (with 
differential), and platelet count

Chemistry panel including sodium, potassium, calcium, chloride, blood urea nitrogen
(BUN), creatinine, creatinine clearance, glucose, albumin, total protein, alkaline 
phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic pyruvic 
transaminase (ALT/SGPT) and lipid profile

Urinalysis 

Pregnancy test is required for all FCBP subjects. Serum beta human chorionic 
gonadotropin (β-hCG) pregnancy test will be performed at screening. Urine pregnancy 
test will be performed to assess subject eligibility within 72 hours prior to the first 
administration of IP (negative results required for dispensing IP)

Contraception education: counseling about pregnancy precautions and the potential risks 
of fetal exposure must be conducted (see Section 4.3)

Adverse event assessment begins when the subject signs the informed consent form.
6.2.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 28 days of signing the informed consent form (ICF).
The following will be performed at the frequency specified in the Table of Events, Table 13. 

Inclusion/Exclusion criteria

Concomitant medications evaluation

Concomitant procedures evaluation

Physical examination 

Vital signs

Weight (see Section 6.5.2)

Hematology panel including complete blood count (CBC) with differential and platelet 
count

Chemistry panel 

Hemoglobin A1c
Approved 
 
 


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
Urinalysis 

Subject-reported outcomes 

Adverse event evaluation (continuously)

Assessment of diarrhea (see Section 6.5.5)

Efficacy assessments, including MRI (see Section 6.4)

Pregnancy test (prior to dosing on Day 1 and as specified in the Table of Events)

A pregnancy test should be performed if the FCBP subject has missed a menstrual period 
or the contraception method has changed

Contraception education: counseling about pregnancy precautions and the potential risks 
of fetal exposure must be conducted (see Section 4.3)

Dispensing IP

IP accountability
6.2.1.
End of Treatment/Early Termination Visit
An Early Termination Visit will be performed for subjects who are withdrawn from treatment for 
any reason, as soon as possible, after the decision to permanently discontinue treatment has been 
made. 
The following will be performed as specified in the Table of Events:

Complete physical examination (source documented only), weight

Vital signs 

Concomitant medications evaluation

Concomitant procedures evaluation

Subject-reported outcomes

Adverse event/Serious Adverse Event evaluation/assessment

Assessment of diarrhea

Hematology panel including complete blood count (CBC) with differential and platelet

Chemistry panel

Hemoglobin A1c

Urinalysis 

Serum β-hCG (for FCBP subjects)

Efficacy assessments, including MRI

IP accountability
Approved 
 
 


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6.3.
Observational Follow-up Period
6.3.1.
Safety Follow-up
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as any 
SAEs made known to the Investigator at any time following the protocol-required reporting 
period or after end of study t, as described in Section 10.1. Safety assessments are specified in 
the Table of Events, Table 13.
6.4.
Efficacy Assessments
The following assessments will be conducted as outlined in the Table of Events, Section 5.
6.4.1.
Magnetic Resonance Imaging (MRI)
The MRI assessments will be conducted following the procedures outlined in the MRI manual, at 
scheduled visits according to Section 5 (Table of Events). The clinical and the MRI assessments 
should be performed on the same day, with the MRI scans always performed after the clinical 
visit. Exceptionally, MRI scans can be performed within 7 days after the clinical assessments. 
The baseline MRI must be performed within 7 days after the first administration of IP. The 
subsequent MRIs should be performed at Week 24 + 7 days and Week 48 + 7 days. All MRI 
visits should be scheduled well in advance to allow for proper planning. In addition, it is 
recommended to schedule 2 MRI visits (an initial and a repeat visit) for each MRI time point in 
order to be assured of a high-quality MRI scan at each protocol-specified time point. The initial 
and repeat MRI visits should be scheduled approximately 7 to 14 days apart to allow enough 
time for confirmation of quality scans from the initial MRI. If the initial MRI scans are of 
acceptable quality, then the scheduled repeat MRI session can be canceled.
All MRI technicians will receive training on specific MRI positioning and joint placement, 
further details of which are provided in the Study Procedures Manual. The MRI technician will 
ensure the quality of each MRI prior to the subject leaving the radiology facility.
The adjudication of the results, when two readers are involved, will be done through the 
consensus procedure between the two readers. The readers will be able to share the screen and 
discuss the data, then amend the final scoring. All data, the original and the consented results 
will be recorded and stored in the imaging database and later incorporated into the clinical 
database to be available for statistical analysis. 
Approved 
 
 


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Refer to Appendix P, Appendix Q and
for details of MRI indices.
For more detailed information on the specific procedures and the consistent acquisition of MRI 
images, see the MRI Manual. 
6.4.2.
MRI of the Most Affected Hand
The OMERACT PsAMRIS is a validated scoring system that assesses metacarpophalangeal, 
proximal interphalangeal, and distal interphalangeal joints of fingers 2 to 5, evaluating synovitis 
(score 0-3), flexor tenosynovitis (score 0-3), periarticular inflammation (absent or present), bone 
edema (score 0-3), bone erosion (score 0-10) and bone proliferation/enthesophytes (absent or 
present). It will be obtained by MRI of the most affected hand (Appendix P).
6.4.3.
WB-MRI 
Selected peripheral joints and entheses, the sacroiliac joints (SIJ) and the spine will be assessed 
by WB-MRI (Appendix Q). 
Selected peripheral joints will be scored at each side (right and left) for synovitis and BME, 
including glenohumeral, acromioclavicular, sternoclavicular, hip and knee. Selected entheses 
will be scored bilaterally for entheseal BME and entheseal soft tissue inflammation. The entheses 
will include supraspinatus tendon insertion at humerus, ischial tuberosity, pubic symphysis, 
greater femoral trochanter, tendon insertions at the knee, calcaneal Achilles tendon insertion and 
plantar fascia insertion. 
The final WB-MRI assessment protocol will be developed based on the prevalent 
recommendations by the OMERACT MRI in arthritis working group at the time of reading 
initiation. The final detailed MRI manual will be available before any reading starts.
6.4.3.1.
Definition of WB-MRI Indices
WB-MRI indices will be constructed to assess synovitis, BME, and soft tissue inflammation per 
regions, including pre-specified entheses and peripheral joints, SIJ and the spine.
The final list of WB-MRI indices may be updated based on the prevalent knowledge, including 
recommendations by the OMERACT MRI in arthritis working group, at the time of reading 
initiation. The final detailed imaging charter with a reading manual will be available before any 
reading starts.
Approved 
 
 


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6.4.5.
Clinical Efficacy Assessments 
6.4.5.1.
Joint Assessments
A modified ACR joint count that includes the distal interphalangeal joints of the fingers and toes 
(the “78 tender and 76 swollen” joint scores; Appendix C) will be performed at every visit. The 
joints to be evaluated are illustrated in Figure 2. Joint tenderness and swelling will be noted as 
“present” or “absent,” with no quantitation of severity. 
In case of digit(s) with dactylitis, each joint of the affected digit must be evaluated for tenderness 
and swelling.
Joints that are swollen or tender should be marked with a tick. 
In the event that a joint is injected with intra-articular glucocorticoid (allowed only after Week 
24 assessments are completed, and up to the Week 36 Visit), this joint should be marked by an 
“X” and won’t be assessed if the study visit occurs within 4 weeks (28 days) of the intra-articular 
(IA) injection. 
In order to maintain consistency throughout the study, the same evaluator should perform the 
joint assessments for a given subject at a study site at each study visit.
Approved 
 
 


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6.4.5.2.
Subject and Evaluator’s Global Assessments of Disease Activity
The Patient’s (Subject’s) and Physician’s (Evaluator’s) Global Assessments of Disease Activity 
are assessments of how active a subject’s PsA was on average during the past week. Both, 
subjects and evaluators should mark the box with an X on a 0- to-10-unit numeric rating scale 
(NRS), on which the left-hand box of 0 represents “not active,” and the right-hand box represents 
“very active” (Appendix D; Felson, 1995; Sieper, 2009).
6.4.5.3.
Subject’s Pain Numeric Rating Scale 
The pain NRS is the subject’s assessment of how much pain he/she had, on average, during the 
past week in his/her joints due to PsA. The subject will be asked to mark the box with an X on a 
0- to 10-unit NRS, on which the left-hand box of 0 represents “no pain,” and the right-hand box 
represents the “pain as bad as you can imagine” (Appendix D; Felson, 1995; Sieper, 2009;
Hjermstad, 2011).
6.4.5.4.
HAQ-DI
The HAQ-DI (Appendix E; Fries, 1980) is a 20-question, self-administered instrument that 
measures the subject’s functional ability on a 4-level difficulty scale (0 to 3, with 0 representing 
normal or no difficulty; and 3 representing an inability to perform). Eight categories of 
functioning are included: dressing, rising, eating, walking, hygiene, reach, grip, and usual 
activities (Bruce, 2003). This scale is sensitive to change and is a good predictor of future 
disability (Aletaha, 2006).
Approved 
 
 


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6.4.5.7.
Enthesitis
Enthesitis, or the inflammation of the sites where tendons or ligaments insert into the bone, is a 
prominent clinical manifestation in subjects with PsA. In this study, 2 clinical indices will be 
used to evaluate entheseal inflammation. The Leeds Enthesitis Index (Appendix F; Healy, 
2008b) will be assessed through physical examination of the following sites. Tenderness (yes/no) 
will be assessed at 6 sites of tendon insertions (0-6) as depicted below: 

Lateral epicondyle, left and right

Medial femoral condyle, left and right

Achilles tendon insertion, left and right
Tenderness on physical examination is recorded as either present (1) or absent (0) for each of the 
6 sites, for an overall score range of 0 to 6. Higher count represents a greater enthesitis burden.
The SPARCC Enthesitis Index (Appendix G) will be assessed through physical examination of 
the following sites:

Medial epicondyle (left/right [L/R])

Lateral epicondyle (L/R)

Supraspinatus insertion into greater tuberosity of humerus (L/R)

Greater trochanter (L/R)

Quadriceps insertion into superior border of patella (L/R)

Patellar ligament insertion into inferior pole of patella or tibial tubercle (L/R)

Achilles tendon insertion into calcaneum (L/R)

Plantar fascia insertion into calcaneum (L/R)
Tenderness on examination is recorded as either present (1) or absent (0) for each of the 16 sites, 
for an overall score range of 0–16. Higher count represents greater enthesitis burden.
Approved 
 
 


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6.4.5.8.
Dactylitis
Dactylitis (“sausage digit”) is characterized by the swelling of the entire finger or toe. It will be 
assessed using the Leeds Dactylitis Index (LDI) (Appendix H; Helliwell, 2005).
The score is a function of finger circumference and tenderness, assessed and summed across all 
dactylitic digits.
6.4.5.9.
Clinical Disease Activity Index for Psoriatic Arthritis (c-DAPSA)
The c-DAPSA is a measure of PsA disease activity, associated with functional and structural 
outcomes (Aletaha, 2017). It will be performed programmatically by summing four disease 
activity variables: TJC and SJC, subject global and pain assessment. Cut-offs for cDAPSA are:

≤4: remission

> 4 and ≤13: low disease activity

> 13 and ≤27: moderate disease activity

> 27: high disease activity. 
6.4.5.10.
Psoriatic Arthritis Disease Activity Score (PASDAS)
The PASDAS is a weighted index comprising assessments of joints, function, acute phase 
response, QoL, and patient and physician visual analogue scores (VAS) (Coates, 2014). 
Note: This study does not utilize VASs, but rather NRSs. The patient’s and physician’s global 
assessment of disease activity captured on a NRS will be multiplied by a factor of 10 to derive 
the VAS, used to calculate PASDAS.
The calculation of the PASDAS will be performed programmatically using the formula below:
PASDAS =(((0.18×√physician global VAS)+(0.159×√patient global 
VAS)−(0.253×√SF36−PCS)+(0.101×LN (SJC +1))+(0.048×LN (TJC +))+(0.23×LN (Leeds 
enthesitis count+1))+(0.377 LN (dactylitis count+1))+(0.102× LN (CRP+1))+2)*1.5.
CRP = C-reactive protein; LN = natural logarithm; PCS = physical component summary scale of SF36; SF36 = 
Medical Outcomes Study Short Form-36; SJC = swollen joint count; TJC = tender joint count; VAS = visual 
analogue scale. All VAS scores are 0–100 mm. Swollen joint count is 66 joints, and tender joint count 68. 
The score range of the PASDAS is 0–10, with worse disease activity represented by higher 
scores. Response criteria for the Psoriatic Arthritis Disease Activity Score (PASDAS) is detailed 
below.
Approved 
 
 


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6.4.5.12.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI is a composite score based on a subject self-administered survey of six questions 
using a 0- to 10-unit NRS that assesses the subject’s five major symptoms relevant to 
spondyloarthropathies: 1) fatigue; 2) spinal pain; 3) peripheral joint pain/swelling; 4) areas of 
localized tenderness; 5) morning stiffness severity upon wakening; 6) morning stiffness duration 
upon wakening (Appendix J; Calin, 1999; Sieper, 2009). The subject will be asked to mark with 
an X a 0- to 10-unit NRS for each of the six questions. To give each of the five symptoms equal 
weighting, the mean of the two scores relating to morning stiffness is taken. The resulting 0 to 50 
score is divided by 5 to give a final 0 to 10 BASDAI score. A BASDAI score of 4 or greater is 
considered to be indicative of active disease.
6.5.
Safety Assessments
In addition to daily safety monitoring conducted by investigators and individual study personnel, 
AEs, serious adverse events (SAEs), discontinuations and laboratory findings will be reviewed 
internally by the study team at Amgen. 
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
The following assessments will be conducted as outlined in the Table of Events, Section 5.
6.5.1.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential 
A serum pregnancy test with a sensitivity of ≤ 15 mIU/mL will be required for FCBP subjects at 
screening, at the last treatment visit or the Early Termination Visit for subjects who discontinue 
Approved 
 
 


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before Week 48 Visit. Urine pregnancy test will be performed on all FCBP subjects at the 
Baseline Visit at the site. Urine pregnancy test kit will be provided by the central laboratory.
Pregnancy tests should be performed if the FCBP subject has missed a menstrual period or the 
contraception method has changed.
In addition to the assessments specified in Section 5, the Investigator will follow country 
guidelines regarding the monitoring of pregnancy testing at any scheduled or unscheduled visit 
and will document the test result in the source document.  At the discretion of the Investigator, a 
serum pregnancy may be done.
6.5.2.
Vital Signs, Height and Weight
Vital signs, including temperature, pulse, and seated blood pressure, will be taken during the 
visits indicated in Section 5, Table of Events. Height will be measured and recorded at screening; 
weight will be measured and recorded at every visit.
In the event of unexplained and clinically significant weight loss, subjects should be evaluated and
discontinuation of study treatment should be considered by the investigator.
6.5.3.
Complete/Limited Physical Examination
A complete physical examination includes evaluations of skin, nasal cavities, eyes, ears, lymph 
nodes, and respiratory, cardiovascular, gastrointestinal, neurological, and musculoskeletal 
systems. A complete physical examination is done at screening and other designated visits as 
indicated in Section 5. A limited physical examination includes evaluations of skin, lymph 
nodes, and respiratory, cardiovascular, and musculoskeletal systems. A limited physical 
examination is done at Baseline Visit and other designated visits as indicated in Section 5.
6.5.4.
Psychiatric Evaluation
Treatment with apremilast is associated with an increase in adverse reactions of depression. 
Before using apremilast in subjects with a history of depression and/or suicidal thoughts or 
behavior, the investigator should carefully weigh the risks and benefits of treatment with 
apremilast in such patients. Subjects should be advised of the need to be alert for the emergence 
or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur 
to contact the Investigator. 
If a patient suffers from new or worsening psychiatric symptoms, or suicidal ideation or suicidal
attempt is identified, it is recommended to discontinue study treatment (see Section 11).
6.5.5.
Diarrhea, Nausea and Vomiting
Apremilast has been associated with AE reports of diarrhea in clinical trials. Most diarrhea 
events were of mild or moderate severity and reported within the first 2 weeks of treatment, 
usually resolving within 4 weeks without medical intervention.
Diarrhea is the passage of three or more loose or liquid stools per day, or more frequently than is 
normal for the individual (World Health Organization [WHO], 2013). Following the definition of 
diarrhea by the WHO and taking a more conservative approach, the AE of diarrhea in this 
protocol is defined as having two or more watery/liquid stools in a day. 
Approved 
 
 


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To better characterize diarrhea and to distinguish similar events coding to the Medical Dictionary 
of Regulatory Activities (MedDRA) preferred term of diarrhea, subjects reporting diarrhea or 
similar events (eg, frequent bowel movements, loose bowels, etc.) will be asked whether they 
have had two or more watery/liquid stools in a day. Subjects who respond “yes” to this question 
will be further asked how often, on average, have they experienced two or more watery/liquid 
stools in a day. Subjects who respond “no” to the question will not be asked any further 
questions.
There have been post-marketing reports of severe diarrhea, nausea and vomiting associated with 
the use of apremilast. Most events occurred within the first few weeks of treatment. In some 
cases, patients were hospitalized. 
Subjects 65 years of age or older and those taking medications that can lead to volume depletion 
or hypotension may be at a higher risk of complications. Subjects should be monitored for the 
occurrence of severe diarrhea, nausea and vomiting.  If subjects develop severe diarrhea, nausea 
and vomiting, discontinuation of treatment with study treatment may be necessary (see 
Section 11).
6.5.6.
Tuberculosis 
After an extensive clinical development program, there is no current evidence that apremilast has 
the potential to activate latent TB. Therefore, no TB testing will be done in this protocol. 
Investigators can test for TB if clinically indicated, using the site’s local or country specific 
guidelines. If the subject has active or latent TB, he/she should be treated according to local 
guidelines. Subjects who require TB treatment at any time during the study must be 
discontinued. 
6.5.7.
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed by the central laboratory, and as indicated in 
Section 5. Clinical laboratory evaluations include: RF, CBC (RBC count, hemoglobin, 
hematocrit, WBC count and differential, absolute WBC counts, platelet count); serum 
chemistries (total protein, albumin, calcium, phosphorous, glucose, triglycerides, total 
cholesterol [TC], total and direct bilirubin, alkaline phosphatase, AST, ALT], sodium, potassium, 
chloride, bicarbonate [carbon dioxide, CO2], BUN, creatinine, creatinine clearance, lactate 
dehydrogenase [LDH], and magnesium);
; hemoglobin A1c (HbA1c); and urinalysis 
(specific gravity, pH, glucose, ketones, protein, blood, bilirubin, leukocyte esterase, nitrite, and 
urobilinogen). Urinalysis will be performed by the central laboratory; microscopic urinalysis 
(epithelial cells, RBC, WBC, and casts) will be performed only if the urinalysis is abnormal. 
6.5.8.
Adverse Events
All subjects will be monitored for adverse events (AEs) during the study. Assessments may 
include monitoring of any or all the following parameters: the subject’s clinical symptoms, 
laboratory, pathological, radiological, or surgical findings; physical examination findings; or 
other appropriate tests and procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent to 
28 days after the last dose of IP. AEs and SAEs will be recorded on the AE page of the case 
report form (CRF), the paper SAE reporting form (SAEs) and in the subject’s source documents. 
Approved 
 
 


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All SAEs must be reported to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of the event using the paper Serious Adverse Event Report Form by facsimile/email 
of the paper SAE Report Form directly to Amgen Global Patient Safety
Details of AE/SAE reporting can be found in Section 10 of the protocol.
It should be noted that worsening of a subject’s PsA should be considered as worsening of 
disease under study and should not be captured as an adverse event.
6.6.
Biomarkers
6.7.
Subject-reported Outcomes
The following assessments will be conducted as outlined in the Table of Events, Section 5.
6.7.1.
Psoriatic Arthritis Impact of Disease 12-domain Questionnaire (PsAID-12)
The PsAID is a validated score reflecting the impact of disease in PsA. The PsAID-12 is a 12-
item, self-administered questionnaire that reflects the impact of PsA from the perspective of the 
patient. It is composed of 12 physical and psychological domains. Each domain is rated from 0 to 
10 with a different weighting. The total score is divided by 20. The final score has a range from 0 
(best status) to 10 (worst status) with a cut-off of 4 (Appendix K; Gossec, 2014).
Approved 
 
 


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Approved 
 
 


EDMS Doc. Number: 24688121 - 22800536
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
The chemical name of apremilast (CC-10004) is N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl] acetamide.  
Apremilast will be provided by Amgen Inc. and labelled appropriately as IP for this study.  
Apremilast will be provided as 10, 20, or 30 mg tablets in blister cards for dose titration 
purposes.  Apremilast will also be provided as 30 mg tablets in high-density polyethylene 
(HDPE) bottles (approximately 80 tablets) with child-resistant caps.  The apremilast dosing 
schedule and dose adjustments to be followed for this study are described in Section 7.2. Please 
refer to the IB for more details on approved indications, known precautions, warnings, and 
adverse reactions of apremilast. 
Additional information may be included on the label as needed or applicable. Label(s) for IP will 
contain information as required per local health authority.
7.2.
Treatment Administration and Schedule
Tablets will be taken by mouth twice daily, in the morning (AM) and in the evening (PM), 
approximately 12 hours apart, with no food restrictions. To mitigate potential gastrointestinal 
(GI) adverse events, dose titration shall be implemented over a 5-day period (Table 14). At the 
Week 0 Visit, subjects will be dispensed a blister card with 10, 20, and 30 mg apremilast tablets 
for the dose titration. Subjects will be dispensed bottles with 30 mg apremilast tablets at 
designated visits.
Table 14:
Treatment Schema for Dose Titration at Baseline
Week 0
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
10 mg
-
10 mg
10 mg
10 mg
20 mg
20 mg
20 mg
20 mg
30 mg
30 mg
30 mg
Pictures of the blister card configurations are shown in Appendix S. Since dose modifications are 
not permissible in this study, if a subject develops severe renal impairment (creatinine clearance 
of less than 30 mL per minute estimated by the Cockroft–Gault equation), interruption of study 
medication is required.
7.2.1.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP(s) only.
Therefore, for a drug to be subject to the overdose definition it must be both required and an
investigational drug. In this study the only required and investigational drug is apremilast and 
there is no control arm drug, hence overdose definition will apply to only apremilast. Other 
required or optional non-study drugs intended for prophylaxis of certain side effects, etc, are 
excluded from this definition.
Approved 
 
 


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Overdose for this protocol, on a per dose basis, is defined as ingestion of 4 or more 30 mg 
apremilast tablets in any 24-hour period whether by accident or intentionally. On a schedule or 
frequency basis, an overdose is defined as dosing more than 4 times during any 24-hour period. 
Adverse Events associated with an overdose must be collected on the Adverse Events page of the
CRF (see Section 10) for all overdosed subjects, but the overdose itself is not considered an AE.
7.3.
Method of Treatment Assigned
After the informed consent is signed, subjects will be assigned a subject identification number 
using a centralized interactive web response system (IWRS). At the Baseline Visit, a centralized 
schema will be applied to assign subjects who meet the inclusion and none of the exclusion 
criteria to receive apremilast 30 mg BID, after a 5-day titration period. In addition, half of the 
subjects must have moderate disease activity or below, as assessed by c-DAPSA.
During the study visits, the pharmacy or authorized study personnel at the investigational site 
will dispense coded IP kits in accordance with the identification number assigned by the IWRS. 
7.4.
Packaging and Labeling
For the titration period, apremilast will be supplied by Amgen Inc. to the principal investigator as 
blister cards. For the remaining of the study, apremilast 30 mg tablets will be supplied in HDPE 
bottles with child-resistant caps.
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
7.5.
Investigational Product Accountability and Disposal 
The investigator, or designee, is responsible for taking an inventory of each shipment of 
apremilast received, and comparing it with the accompanying apremilast shipping order/packing 
list. 
The Investigator(s) or designee(s) will verify the accuracy of the information on the form, sign 
and date it, retain a copy in the study file, and record the information in the IRT.
Investigational product will be stored per the storage conditions identified on the drug label. At 
the study site, all IP will be stored in a locked, safe area to prevent unauthorized access.
Amgen (or designee) will review with the Investigator and relevant site personnel the process for 
investigational product return, disposal and/or destruction including responsibilities for the site 
versus Amgen (or designee). 
Approved 
 
 


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7.5.1.
Dosing
7.5.1.1.
Study Medication Dispensing and Counting
After the informed consent is signed, subjects will be assigned a subject identification number 
using a centralized interactive web response system (IWRS). At the Baseline Visit, a centralized 
schema will be applied to assign subjects who meet the inclusion and none of the exclusion 
criteria to receive apremilast 30 mg tablets. Study medication will be dispensed as specified in 
Section 5, Table of Events. The tear-off label from each blister card should be pasted into the 
drug accountability document in each subject’s record. Subjects must be instructed to return all 
previously issued empty blister card(s), empty study drug bottle(s) and/or unused study 
medication at the time that new medication is issued. A detailed record of tablets issued and 
returned at each visit must be maintained in the subject’s record.
During the study visits, the pharmacy or authorized study personnel at the investigational site 
will dispense coded IP kits in accordance with the number assigned by the IWRS. 
7.6.
Investigational Product Compliance
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP. Investigational product will be dispensed as noted in the Table of Events, 
Section 5. The subjects will be instructed to return the IP containers, including any unused 
medication, to the study site at each visit for tablet counts and reconciliation. Subjects will be 
asked whether they have taken their IP as instructed at each study visit. Any problems with IP 
compliance will be reviewed with the subject. If the subject misses 4 or more consecutive days 
of dosing, Amgen must be contacted to decide whether dosing should resume or whether the 
subject should be terminated from the Treatment Phase of the study, and enter into the 
Observational Follow-up Phase.
Gross compliance problems (eg, missing 4 or more consecutive days of dosing or taking less 
than 75% of the doses between study visits) should be discussed with Amgen. Compliance is 
defined as taking between 75% and 120% of dispensed IP.
Approved 
 
 


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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
All medications and therapies being taken/used by the subject up to 30 days prior to the 
Screening Visit (Visit 1) or at any time during the study should be recorded. Prior medications 
for the treatment of PsA must be recorded at any time. Other key medications and therapies, such 
as previous treatment for TB or relevant diseases, should be recorded.  
All medications and therapies, including physical therapy, for PsA and their reasons for 
discontinuation, should be recorded. The stop dates for all medications and therapies prohibited 
in the study should be recorded. Additional instructions can be found in the CRF Completion 
Guidelines.
8.1.
Permitted Concomitant Medications and Procedures
All medications (prescription and non-prescription), treatments and therapies taken by the 
subject from screening throughout their entire participation in the study, including those initiated 
prior to the start of the study, must be recorded on the subject’s source document and on the 
appropriate page of the CRF. The dose, unit, frequency, route, indication, the date the medication 
was started and the date the medication was stopped (if not ongoing) must be recorded. Subjects 
may continue receiving standard of care therapy (eg, folic acid for those on MTX) if not 
explicitly prohibited as per protocol. The following concomitant medications and procedures are 
permitted: 

Oral glucocorticoids, (on a stable dose of prednisone ≤ 10 mg/day or equivalent for at 
least 4 weeks prior to Baseline Visit [ie, Day 1]).

Note: The stable dose of glucocorticoids must be continued and maintained from Day 
1 through the Week 24 Visit. Change in doses, increase or decrease, and/or 
discontinuation of glucocorticoids will not be allowed except for safety reasons or for 
lack of availability. After the Week 24 Visit, the dose of glucocorticoids may be 
adjusted as clinically required.

MTX (≤25 mg/week, if total treatment duration is ≥ 6 months and on a stable dose
for at least 3 months prior to baseline).

At Week 12, subjects will be allowed to receive IA glucocorticoids, administration of 
up to 2 injections of ≤ 40 mg triamcinolone hexacetonide or equivalent (each joint). 

NSAIDs or narcotic analgesics (must be on a stable dose for at least 4 weeks prior to
the Baseline Visit [ie, Day 1]).

Note: The stable dose of NSAIDs or narcotic analgesics must be continued and 
maintained from Day 1 through the Week 24 Visit. Change in doses, increase or 
decrease, and/or discontinuation of NSAIDs or narcotic analgesics will not be 
allowed except for safety reasons or for lack of availability. After the Week 24 Visit, 
the dose of NSAIDs or narcotic analgesics may be adjusted as clinically required.

NSAIDs or narcotic analgesics that are administered on an as needed basis (PRN) 
should be recorded on the Prior/Concomitant Medications page of the CRF. 

Loperamide and antidiarrheal drugs with antisecretory effect (eg, racecadotril).
Approved 
 
 


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
Low dose aspirin (acetylsalicylic acid, up to 325 mg per day) for cardiovascular 
prophylaxis.

Birth control medications/barrier methods for FCBP subjects.

Low-potency topical glucocorticoids (or locally available equivalent) as background 
therapy for treatment of psoriasis on the face, axillae and groin in accordance with the 
manufacturers’ suggested usage during the course of the study.  

Coal tar shampoo and/or salicylic acid scalp preparations on scalp psoriasis lesions. 

A nonmedicated skin emollient (eg, Eucerin® cream) for body psoriasis lesions only.
Medications for conditions other than PsA and psoriasis, which are not prohibited in Section 8.2, 
are permitted and must be recorded in the subject’s source documents and as a concomitant 
medication on the CRF.
The following therapy will be permitted after the Week 24 Visit for subjects with worsening 
arthritic symptoms of PsA:

Change of NSAID type and/or dose

Administration of no more than 40 mg intramuscular (IM) or intra-articular (IA)
glucocorticoid (triamcinolone hexacetonide or equivalent) at a single visit, up to 
Week 36, not to exceed two glucocorticoid IM and/or IA administrations in any 6 
month-interval. Injected joints should not be counted during the visits that will take 
place within 4 weeks of the intra-articular injection.

Short course (≤ 2 weeks) of low-dose oral glucocorticoids (prednisone ≤ 10 mg/day 
or equivalent), to be completed up to Week 36 and not to exceed one course in a 6-
month interval
In order to minimize the impact on ongoing efficacy assessments, the investigator should use the 
least intensive regimen to ameliorate the subject’s worsening PsA symptoms. After Week 24, if 
subjects experience a decrease in PsA clinical disease activity, the investigator may opt to taper 
the background treatment; however, only one agent may be reduced or tapered at any one time. 
After the first agent’s taper has been completed (not required to be zero), the dose must be stable 
for at least 4 weeks prior to starting the taper of the next agent. Subjects are recommended to 
have a reduction of background therapy in the following order: first MTX, second 
glucocorticoids and third NSAIDs or other pain medication. If clinically indicated, the 
investigator may opt to reduce the medications in a different order. Any further 
questions/concerns regarding dose reductions can be discussed with the Sponsor.
All other prohibited medications listed in Section 4.4 (Exclusion Criteria) and Section 8.2
(Prohibited Concomitant Medications and Procedures) remain in effect through the end of the 
subject’s participation in the study.
8.2.
Concomitant Medications Not Recommended
It has been observed that co-administration with strong cytochrome P450 3A4 (CYP3A4) 
enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of apremilast, which 
may result in a loss of efficacy of apremilast. Therefore, the use of strong CYP3A4 enzyme 
Approved 
 
 


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inducers (eg, rifampicin, phenobarbital, carbamazepine, phenytoin and St. John’s Wort) with 
study treatment is not recommended.
8.3.
Prohibited Concomitant Medications and Procedures
The following concomitant medications and concomitant procedures are prohibited, except as 
permitted in Section 8.1.

DMARDs (conventional synthetic or biologic) for treatment of PsA, except for MTX
(≤ 25 mg/week) if on stable dose at least 3 months prior to Baseline Visit and with 
total treatment duration ≥ 6 months.  

Treatment with IA glucocorticoids outside the time points specified in Section 8.1, or 
administration of more than 2 injections of ≤ 40 mg triamcinolone hexacetonide or 
equivalent (each joint) 
8.4.
Required Concomitant Medications and Procedures
There are no required concomitant medications or procedures.
Approved 
 
 


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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This section outlines the statistical analysis strategy for the data collected in the study. A detailed 
Statistical Analysis Plan (SAP), including data handling and imputation rules, will be prepared 
and finalized before database lock or any analysis procedures are conducted. 
9.2.
Study Population Definitions
The Full Analysis Set (FAS) will consist of all subjects who are enrolled in the study. Among the 
FAS, specific analysis populations will be defined in detail in the SAP.
The Per Protocol (PP) population will consist of all subjects who receive at least one dose of 
study medication and have no major protocol deviations during the first 24-week period. The 
final determination of major protocol deviation criteria will be made prior to the database lock 
and will be documented.
The Safety population will consist of all subjects who received at least one dose of study 
medication.  
9.3.
Sample Size and Power Considerations
While no MRI data are available for apremilast, assumptions used for the sample size calculation 
are primarily derived from the literature (Glinatsi, 2015). With an approximate 20% dropout rate, 
a sample size of 120 is required to produce a two-sided 95% confidence interval, for the 
expected change from baseline in the composite score of BME, synovitis, and tenosynovitis, with 
a distance from the mean to the limit equal to 1.24, assuming the standard deviation is 6.2.
9.4.
Background and Demographic Characteristics
Subject’s age, weight, height and other continuous demographic and baseline characteristics will 
be summarized using descriptive statistics (mean, standard deviation, minimum and maximum), 
while gender, race, and other categorical variables will be summarized with frequency 
tabulations. Medical history data will be classified using the MedDRA classification system and 
summarized using frequency tabulations by system organ class and preferred term. Treatment 
history (including previous csDMARD and investigational agents) will be summarized using 
frequency tabulations. The Anatomical Therapeutic Chemical (ATC) coding scheme of the 
World Health Organization (WHO) will be used to group medications into relevant categories 
for these tabulations.
9.5.
Subject Disposition
Subject disposition (subjects enrolling into and completing or discontinuing from the study, 
along with primary reason for discontinuation) will be summarized using frequency and percent 
by study phase. A summary of subjects enrolled by site will be provided. Protocol deviations will 
be summarized using frequency tabulations.
Approved 
 
 


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9.6.
Efficacy Analysis
9.6.1.
Primary Endpoint
The primary endpoint, change from baseline in the composite score of BME, synovitis, and 
tenosynovitis assessed by PsAMRIS at Week 24, will be analyzed descriptively. The 95% 
confidence interval will be provided for the mean change, and the composite score over time will 
be presented graphically.
9.6.2.
Secondary Endpoints
All secondary efficacy endpoints listed in Section 2 will be analyzed descriptively, with 
summary statistics for continuous endpoints and frequency distribution for binary endpoints. The 
95% confidence intervals will also be provided. Separate analyses for the responders and non-
responders will also be performed for each imaging endpoint. The PsAMRIS will also be 
analyzed separately based on the presence or absence of different imaging parameters at 
baseline. In addition, data will be reported based on the proportion of subjects above or below 
the smallest detectable changes (SDC).
9.6.3.
Exploratory Endpoints
9.7.
Safety Analysis
The safety analyses will be performed using the safety population as defined in Section 10.2.
Adverse events will be classified using the MedDRA classification system. All adverse events 
will be summarized by system organ class and preferred term; in addition, also by severity 
separately. Adverse events leading to death or to discontinuation from treatment, serious adverse 
events, study drug-related adverse events, and events of interest will be summarized separately. 
A subject having the same event more than once will be counted only once using the maximum 
severity.
Laboratory data will be summarized by visit descriptively (mean, standard deviation, median, 
minimum, and maximum). Number and percentage of subjects with marked laboratory 
abnormalities will be provided. In addition, shift tables showing the number of subjects with 
values low, normal, and high based on the normal ranges pre-treatment versus post-treatment 
will be provided. 
Vital sign measurements, including weight, will be summarized by visit descriptively. In 
addition, shift tables showing the number of subjects with values low, normal, and high based on 
the normal reference ranges pre-treatment versus post-treatment will be provided.
To account for the exposure to the study medication, the exposure adjusted incidence rate will 
also be calculated for adverse events and marked laboratory abnormalities. 
Approved 
 
 


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9.8.
Other Topics
9.8.1.
Investigational Product Compliance (Tablets)
Study medication information will be summarized and subject listings will be provided. 
Compliance will be estimated by the proportion of subjects who take between 75% and 120% of 
the intended quantity of study medication.
9.8.2.
Concomitant Therapy
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations. The ATC coding scheme of the WHO will be used to group medications into 
relevant categories for these tabulations. Separate data summaries of background medications 
will be provided.
9.8.3.
Steering Committee 
Guidance in protocol development and interpretation of data analysis will be provided by a 
scientific steering committee (SSC). Details for the SSC are pre-specified in a separate SSC 
charter.
Approved 
 
 


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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording, and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded on 
the AE/SAE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to apremilast should be reported as an AE. Overdose, 
accidental or intentional, whether or not it is associated with an AE, should be reported on the 
overdose CRF. (See Section 7.2.1 for the definition of overdose.) Any sequela of an accidental or 
intentional overdose of an IP which meets the definition of an adverse event should be reported 
as an AE on the CRF. If the sequelae of an overdose meet serious criteria, then it must be marked 
as serious on the CRF and the paper SAE Report form. The overdose itself should not be 
reported as an AE.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for apremilast overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study. Assessments may include monitoring of 
any or all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests 
and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose, as well as any SAEs made known to the Investigator at any time 
following the protocol-required reporting period or after end of study will also be reported for 
these subjects. All adverse events (serious/non-serious) will be recorded on the CRF, the paper 
SAE Report form (SAEs) and in the subject’s source documents. All SAEs must be reported to 
Amgen Global Patient Safety within 24 hours of the Investigator’s knowledge of the event by 
recording on the CRF and using the paper Serious Adverse Event Report Form by 
facsimile/email of the paper SAE Report Form directly to Amgen Global Patient Safety.
10.1.1.
Monitoring, Recording, and Reporting AEs of Diarrhea
The PDE4 inhibitors, including apremilast, have been associated with AE reports of diarrhea. To 
better characterize and understand all reported AEs of diarrhea, further information will be 
collected as described in Section 5, in the Table of Events. Please refer to Section 10.1 for further 
details on how to record such AEs.
Approved 
 
 


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10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death;

Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration. However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
Approved 
 
 


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
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the paper SAE Report 
Form must be completed. All SAEs must be reported to Amgen Global Patient Safety within 24 
hours of the Investigator’s knowledge by submitting the paper SAE report form via 
facsimile/email directly to Amgen Global Patient Safety.
For each AE, the Investigator will provide information on severity, start and stop dates, 
relationship to apremilast, action taken regarding apremilast, and outcome.
10.2.2.
Severity/Intensity
For each AE, the Investigator must assess the severity/ intensity of the event. 
Mild

Asymptomatic or mild symptoms; clinical or diagnostic observations only

Intervention not indicated

Activities of daily life (ADLs) minimally or not affected

No or minimal intervention/therapy may be required 
Moderate 

Symptom(s) cause moderate discomfort

Local or noninvasive intervention indicated

More than minimal interference with ADLs but able to carry out daily social and 
functional activities.

Drug therapy may be required
Severe (could be non-serious or serious) 

Symptoms causing severe discomfort/pain

Symptoms requiring medical/surgical attention/intervention

Interference with ADLs including inability to perform daily social and functional 
activities (eg, absenteeism and/or bed rest)

Drug therapy is required
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious,” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
Approved 
 
 


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10.2.3.
Causality
The Investigator must determine the relationship between the administration of apremilast and 
the occurrence of an AE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event. “Reasonable possibility” means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for each AE based on currently available information.
Causality is to be reassessed and provided as additional information becomes available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional non-
IP that has not been manufactured or provided by Amgen, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For each AE, the Investigator will provide a record of the start and stop dates of the event.
10.2.5.
Action Taken
The Investigator will report the action taken with apremilast as a result of each AE, as applicable 
(eg, discontinuation or interruption, as appropriate) and report if concomitant and/or additional 
treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for each AE.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of dose, or any other therapeutic 
intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity or is an exacerbation or worsening of an existing 
condition.
Approved 
 
 


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Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as the AE. If the abnormality was not a part of a diagnosis or 
syndrome, then the laboratory abnormality should be recorded as the AE. If possible, the 
laboratory abnormality should be recorded as a medical term and not simply as an abnormal 
laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in a female subject of childbearing potential 
are immediately reportable events.  
10.4.1.
Collection of Pregnancy and Infant Health Information
Pregnancies and suspected pregnancies (including elevated β-subunit of human chorionic
gonadotropin [β-hCG] or positive pregnancy test in a female subject of childbearing potential
regardless of disease state) occurring while the subject is on IP, or within 28 days of the subject’s
last dose of IP, must be reportable within 24 hours. Investigational product is to be discontinued 
immediately and the subject instructed to return any unused portion of the IP to the investigator. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Amgen
Global Patient Safety immediately by facsimile, email or other appropriate method, using the 
Pregnancy Notification Form or approved equivalent form (refer to Appendix V).  The 
Pregnancy Notification Form must be submitted to Amgen Global Patient Safety within 24 hours 
of learning of a subject’s pregnancy. (Note:  Sites are not required to provide any information on 
the Pregnancy Notification Form that violates the country or regions local privacy laws). 
After obtaining the female subject’s signed consent for release of pregnancy and infant health 
information, the investigator will collect pregnancy and infant health information and complete 
the pregnancy questionnaire for any female subject who becomes pregnant while taking IP 
through 28 days of the subject’s last dose of IP. This information will be forwarded to Amgen 
Global Patient Safety. Generally, infant follow-up will be conducted 12 months after the birth of 
the child (if applicable).         
The female subject may be referred to an obstetrician-gynecologist or another appropriate
healthcare professional for further evaluation.
The Investigator will follow the female subject until completion of the pregnancy and must
notify Amgen Global Patient Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome).
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious
criteria, it must be reported as an SAE to Amgen Global Patient Safety using the paper Serious 
Adverse Event Report Form within 24 hours of the Investigator’s knowledge of the event. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to
causality, as an SAE. In addition, any infant death after 28 days that the Investigator suspects is
related to in utero exposure to the IP should also be reported as an SAE to Amgen Global Patient 
Approved 
 
 


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Safety by facsimile, email, or other appropriate method within 24 hours of the Investigator’s 
knowledge of the event, using the paper SAE Report form. 
10.4.2.
Male Subjects With Partners Who Become Pregnant 
In the event a male subject fathers a child during treatment, and for an additional 28 days after 
discontinuing IP, the information will be recorded on the Pregnancy Notification Form (refer to 
Appendix V). The form must be submitted to Amgen Global Patient Safety with 24 hours of the 
investigator’s/site’s awareness of the pregnancy (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions local 
privacy laws). 
The investigator will attempt to obtain a signed consent for release of pregnancy and infant 
health information directly from the pregnant female partner to obtain additional pregnancy 
information.   
After obtaining the female partner’s signed consent for release of pregnancy and infant health 
information the investigator will collect pregnancy outcome and infant health information on the 
pregnant partner and her baby and complete the pregnancy questionnaires. This information will 
be forwarded to Amgen Global Patient Safety.     
Generally, infant follow-up will be conducted up to 12 months after the birth of the child (if 
applicable). 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.
10.4.3.
Collection of Lactation Information 

Investigator will collect lactation information on any female subject who breastfeeds 
while taking IP through 28 days post last dose of IP.  

Information will be recorded on the Lactation Notification Form (refer to Appendix W) 
and submitted by facsimile or email to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.

Study treatment will be discontinued if female subject breastfeeds during the study.

With the female subjects signed consent for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while taking 
IP through 28 days after discontinuing IP.       
10.5.
Reporting of Serious Adverse Events
Any AE that meets any seriousness criterion must be reported as an SAE within 24 hours of the 
Investigator’s knowledge of the event. This instruction pertains to initial SAE reports as well as 
any follow-up reports.
This requirement applies to all SAEs (regardless of relationship to apremilast) that occur during 
the study (from the time the subject signs informed consent until 28 days after the last dose of 
apremilast) and any SAE made known to the Investigator at any time following the protocol-
required reporting period or after end of study. Serious adverse events occurring prior to 
treatment (after signing the ICF) are to be collected/recorded/reported.
Approved 
 
 


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All SAEs must be reported directly to Amgen Global Patient Safety within 24 hours of the 
Investigator’s knowledge of the event by facsimile or email via the paper Serious Adverse Event 
Report form, in addition, ensuring the event is recorded on the CRF as well.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Amgen and the IRB/EC.
Serious Adverse Event Reporting transmitted via paper Serious Adverse Event Report 
Form: 

Facsimile transmission of the Serious Adverse Event Report Form is the preferred 
method to transmit this information. If facsimile is unavailable, the email method to 
transmit this information is acceptable (refer to Appendix U).    

In rare circumstances and in the absence of facsimile equipment, this form may be sent 
via email, or notification by telephone is acceptable with a copy of the Serious Adverse 
Event Report Form in English language sent by overnight mail or courier service.     

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting timeframes.  

Once the study has ended, serious adverse events (regardless of causality) should be 
reported to Amgen Global Patient Safety if the investigator becomes aware of them and 
may use the paper Serious Adverse Event Report Form (refer to Appendix U).    
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated/generated from Amgen Global Patient Safety 
to the site via Amgen’s safety query paper process or other appropriate method. Pertaining, to 
urgent queries (eg, missing causality assessment), these may be handled by phone, facsimile or 
email.  
10.6.
Expedited Reporting of Adverse Events
For the purposes of regulatory reporting, Amgen Global Patient Safety will determine the 
expectedness of events suspected of being related to apremilast, based on the investigator’s
brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area, Amgen or its authorized representative will 
report in an expedited manner to Regulatory Authorities and Ethics Committees concerned, 
SUSARs in accordance with Directive 2001/20/EC and the Detailed Guidance on collection, 
verification and presentation of adverse reaction reports arising from clinical trials on IPs for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
Approved 
 
 


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Amgen or its authorized representative shall notify the Investigator of the following information:

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Amgen and the IRB/EC. (See Section 14.3 for record retention 
information).
Amgen Global Patient Safety Contact Information (fax/email):
For Amgen Global Patient  Safety contact information, please refer to your site’s  paper Serious 
Adverse Event Report Form, paper Pregnancy Notification Form and/or paper Lactation 
Notification Form (Appendix V, Appendix U, Appendix W).
Approved 
 
 


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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the IP
(apremilast):

Adverse event(s)

Lack of efficacy

Non-compliance with study drug

Withdrawal of consent

Study termination by sponsor

Lost to follow-up

Pregnancy

Death

Protocol deviation

Other (to be specified on the CRF)
Subjects have the right to withdraw from the study at any time and for any reason. The reason for
discontinuation should be recorded in the CRF and in the source documents.
When a subject discontinues from treatment, the Investigator will make every attempt possible to 
have the subject evaluated at the Early Termination Visit within 4 days of the last intake of 
investigational product.
The decision to discontinue a subject from treatment can be taken at any time and remains the 
responsibility of the treating physician, which will not be delayed or refused by the Sponsor.
However, prior to discontinuing a subject, the Investigator may contact the Medical Monitor and 
forward appropriate supporting documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the
study:

Screen failure

Adverse event

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF and in the source 
documents.
Approved 
 
 


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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the investigator should use their medical judgement to provide 
appropriate medical care of clinical trial subjects. The Investigator may also contact the 
responsible Clinical Research Physician/Medical Monitor or designee by telephone at the 
number(s) listed on the Emergency Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, the investigator may also contact the Amgen Medical Information number at 1- 800-77-
AMGEN (1 800-772-6436). The representatives are responsible for obtaining your call-back 
information and contacting the on-call /contract research organization Medical Monitor, who will 
then contact you promptly.
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
Approved 
 
 


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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Amgen, its authorized representative, and 
Investigator abide by GCP, as described in ICH Guideline E6 and in accordance with the general 
ethical principles outlined in the Declaration of Helsinki. The study will receive approval from 
an IRB/EC prior to commencement. The Investigator will conduct all aspects of this study in 
accordance with applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations. Amgen staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Amgen information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an ICF and are 
screened for entry into the study. Subjects who fail screening must have the reason(s) recorded in 
the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Amgen on public registry websites) is considered Amgen confidential 
information. Only information that is previously disclosed by Amgen on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement. Amgen protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Amgen. Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Amgen for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Amgen will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
Approved 
 
 


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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Amgen affirms the subject’s right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Amgen requires 
the Investigator to permit Amgen ’s representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Amgen Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval.
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Amgen or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Approved 
 
 


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Amgen or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Amgen and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Amgen reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Amgen has the right to discontinue a single site at any time during 
the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
Approved 
 
 


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14.
DATA HANDLING AND RECORDKEEPING
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the IP are complete, accurate, filed and retained. Examples of source 
documents include hospital records; clinic and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiche; x-ray film and reports; and records kept at the pharmacy, and the laboratories, as 
well as copies of CRFs or CD-ROM.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Amgen standard 
operating procedures (SOPs). These data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Amgen , and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in the 
study, curriculum vitae, and their signatures;

Copies of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, etc.); 

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
Approved 
 
 


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The Investigator must notify Amgen if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.
The Investigator must obtain approval in writing from Amgen prior to destruction of any records. 
If the Investigator is unable to meet this obligation, the Investigator must ask Amgen for 
permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
Approved 
 
 


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Amgen or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Amgen ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting. Prior to enrolling subjects into the study, an
Amgen representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, IP
storage area, CRFs, subject’s source documents, and all other study documentation will be 
inspected/reviewed by the Amgen representative in accordance with the Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff. Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified. Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Quality, Compliance & Audit, Learning & 
Performance unit exists within Amgen.  Representatives of this unit will conduct audits of 
clinical research activities in accordance with Amgen SOPs to evaluate compliance with Good 
Clinical Practice guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (egg, Food and Drug Administration 
[FDA], European Medicines Agency [EMA], Health Canada) and company authorized 
representatives. The Investigator should make every effort to be available for the audits and/or 
inspections. If the Investigator is contacted by any regulatory authority regarding an inspection, 
he/she should contact Amgen immediately.
15.3.
Product Complaint
A product complaint (PC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product or device after they are released for distribution to 
market or clinic by either Amgen or by distributors, and partners with whom Amgen 
manufactures the material.  This includes any drugs, devices, or combination products 
provisioned and/or repackaged/modified by Amgen.  Drugs or devices include investigational 
product.  Any product complaints associated with an investigational product, or non-
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investigational products or devices supplied by Amgen are to be reported according to the 
instructions provided in the Investigational Product Instruction Manual or equivalent. 
If you become aware of a suspected PC, you are obligated to report the issue within 24 hours of 
discovery or notification of the concern or irregularity.  Amgen requires notification of any 
concern or irregularity at any stage of the study.
15.3.1.
How to Report a Product Complaint to Amgen:  
Complete Amgen’s paper Clinical Product Complaint Intake Form and email the form to the 
following Amgen email address: 
Clinical-Complaint-Intake@amgen.com
Approved 
 
 


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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Amgen on public registry websites, is considered 
Amgen confidential information and is not to be used in any publications. Amgen protocol-
related information proposed for use in a publication must be submitted to Amgen for review and 
approval and should not be utilized in a publication without express written approval from 
Amgen, or as described in the Clinical Trial Agreement.
Amgen will ensure Amgen -sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 2 and Phase 3 clinical studies, and any other study results of significant 
medical importance. This also includes results relating to investigational medicines whose 
development programs have been discontinued.
Study results may also be presented at one or more medical congresses and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for authorship will be in alignment with ICMJE authorship criteria and be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis and contribution to abstract, presentation 
and/or publication development.
Approved 
 
 


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17.
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Approved 
 
 


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Approved 
 
 


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2011;77(1):149-55.
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Wells AF, Edwards CJ, Adebajo AO, Kivitz AJ, Bird P, Shah K, et al. Apremilast in the 
treatment of DMARD-naive psoriatic arthritis patients: results of a phase 3 randomized, 
controlled trial (PALACE 4) [abstract L4]. Arthritis Rheum. 2013;65(10 Suppl12):3320-1.
Wells AF, Edwards CJ, Kivitz AJ, Bird P, Nguyen D, Paris M, et al. Long-tern (4-year) efficacy 
and safety of apremilast monotherapy in DMARD-naive subjects with active psoriatic arthritis 
[abstract]. Arthritis Rheumatol. 2017;69 Suppl 10:Abstract 601.
World Health Organization. Diarrhoea. [Internet]. Available from
http://www.who.int/topics/diarrhoea/en/. Accessed November 27, 2013.
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18.
APPENDICES
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APPENDIX A. TABLE OF ABBREVIATIONS
Table 15:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ACR
American College of Rheumatology
ADL
Activity of daily life
AE
Adverse event
ALT
Alanine aminotransferase
APR
Apremilast
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
β-hCG
Serum beta human chorionic gonadotropin
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BID
Twice per day
BME 
Bone marrow edema
BSA
Body surface area
BUN
Blood urea nitrogen
CASPAR
Classification Criteria for Psoriatic Arthritis
CBC
Complete blood count
c-DAPSA
Clinical Disease Activity Index for Psoriatic Arthritis
CI
Confidence interval
CRF
Case report form
CRP
C-reactive protein
csDMARD
Conventional synthetic disease-modifying antirheumatic drug
DAS
Disease Activity Score
DEMRIQ
Dynamic Contrast-enhanced MRI Quantification
DMARD
Disease-modifying antirheumatic drug
EC
Ethics Committee
EDC
Electronic data capture
EE
Early escape
EULAR
European League Against Rheumatism
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Table 15:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
FAS
Full Analysis Set
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEI
Gladman Enthesitis Index
GRAPPA
Group for Research and Assessment of Psoriasis and Psoriatic Arthritis
HAQ-DI
Health Assessment Questionnaire–Disability Index
HDPE
High-density polyethylene
HIMRISS
Hip Inflammation Magnetic Resonance Imaging Scoring System
HLA
Human leukocyte antigen
IA
Intra-articular
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IL
Interleukin
IM
Intramuscular
IP
Investigational product
IRB
Institutional Review Board
IWRS
Interactive web response system
JAK
Janus kinase
KIMRISS
Knee Inflammation Magnetic Resonance Imaging Scoring System
LDI
Leeds Dactylitis Index
LEF
Leflunomide 
LEI
Leeds Enthesitis Index
LOCF
Last observation carried forward
L/R
Left/right
MCID
Minimal clinically important difference
MedDRA
Medical Dictionary for Regulatory Activities
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Table 15:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
MRI
Magnetic resonance imaging
MTX
Methotrexate
NRI
Non-responder imputation
NRS
Numeric rating scale
NSAID
Nonsteroidal anti-inflammatory drug
OMERACT
Outcome Measures in Rheumatology
PASDAS
Psoriatic Arthritis Disease Activity Score
PASI
Psoriasis Area and Severity Index
PBO
Placebo
PDE
Phosphodiesterase enzyme
PP
Per protocol
PC
Product Complaint
PsA
Psoriatic arthritis
PsAID-12
Psoriatic Arthritis Impact of Disease 12-domain questionnaire 
PsAMRIS
Psoriatic Arthritis Magnetic Resonance Imaging Score
QoL
Quality of life
RA
Rheumatoid arthritis
RBC
Red blood cell
RF
Rheumatoid factor
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SIJ
Sacroiliac joint
SJC
Swollen joint count
SOP
Standard operating procedure
SpA
Spondyloarthropathy
SPARCC
Spondyloarthritis Research Consortium of Canada
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Table 15:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
SRO
Subject-reported outcomes
SSC
Scientific steering committee
SSZ
Sulfasalazine
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TJC
Tender joint count
TNF
Tumor necrosis factor
VAS
Visual analog scale
vs
versus
WBC
White blood cell 
WB-MRI
Whole-body magnetic resonance imaging
WHO
World Health Organization
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APPENDIX B. THE CLASSIFICATION CRITERIA FOR PSORIATIC 
ARTHRITIS (CASPAR) CRITERIA
To meet the CASPAR1 criteria, a patient must have inflammatory articular disease (joint, spine, 
or entheseal) with ≥ 3 points from the following 5 categories:
1. Evidence of current psoriasis, a personal history of psoriasis, or a family history of 
psoriasis.

Current psoriasis is defined as psoriatic skin or scalp disease present today as judged 
by a rheumatologist or dermatologist. 2

A personal history of psoriasis is defined as a history of psoriasis that may be 
obtained from a patient, family physician, dermatologist, rheumatologist, or other 
qualified health care provider.

A family history of psoriasis is defined as a history of psoriasis in a first- or second-
degree relative according to patient report.
2. Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis 
observed on current physical examination.
3. A negative test result for the presence of rheumatoid factor by any method except latex 
but preferably by enzyme-linked immunosorbent assay or nephelometry, according to the 
local laboratory reference range.
4. Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis 
recorded by a rheumatologist.
5. Radiographic evidence of juxta-articular new bone formation, appearing as ill-defined 
ossification near joint margins (but excluding osteophyte formation) on plain radiographs 
of the hand or foot.
                                               
1 The CASPAR criteria have specificity of 98.7% and sensitivity of 91.4%.
2 Current psoriasis is assigned a score of 2; all other features are assigned a score of 1 
(from Taylor, 2006).
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APPENDIX D. NUMERICAL RATING SCALES
Subject’s Assessment of Pain
Subject’s Global Assessment of Disease Activity
Evaluator’s Global Assessment of Disease Activity
Adapted from Felson, 1995.
Pain As Bad As 
You Can Imagine
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APPENDIX E. DISABILITY INDEX OF THE HEALTH ASSESSMENT 
QUESTIONNAIRE (HAQ-DI)
In this section we are interested in learning how your illness affects your ability to function in daily life. Please 
feel free to add any comments on the back of this page.
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
DRESSING & GROOMING
Are you able to:
Without
ANY
Difficulty
With
SOME
Difficulty
With
MUCH
Difficulty
UNABLE
To Do
- Dress yourself, including tying shoelaces and 
doing buttons?
_____
_____
_____
_____
- Shampoo your hair?
_____
_____
_____
_____
ARISING
Are you able to:
- Stand up from a straight chair?
_____
_____
_____
_____
- Get in and out of bed?
_____
_____
_____
_____
EATING
Are you able to:
- Cut your meat?
_____
_____
_____
_____
- Lift a full cup or glass to your mouth?
_____
_____
_____
_____
- Open a new milk carton?
_____
_____
_____
_____
WALKING
Are you able to:
- Walk outdoors on flat ground?
_____
_____
_____
_____
- Climb up five steps?
_____
_____
_____
_____
Please check any AIDS OR DEVICES that you usually use for any of these activities:
_____ Cane
_____ Devices used for dressing (button hook, zipper 
pull, long handled shoe horn, etc.)
_____ Walker
_____ Built up or special utensils
_____ Crutches
_____ Special or built up chair
_____ Wheelchair
_____ Other (Specify:______________________)
Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
_____ Dressing and Grooming
_____ Eating
_____ Arising
_____ Walking
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Please check the response which best describes your usual abilities OVER THE PAST 
WEEK:
HYGIENE
Are you able to:
Without
ANY
Difficulty
With
SOME
Difficulty
With
MUCH
Difficulty
UNABLE
To Do
- Wash and dry your body?
_____
_____
_____
_____
- Take a tub bath?
_____
_____
_____
_____
- Get on and off the toilet?
_____
_____
_____
_____
REACH
Are you able to:
- Reach and get down a 5-pound object
(such as a bag of sugar) from just above 
your head?
_____
_____
_____
_____
- Bend down to pick up clothing from the 
floor?
_____
_____
_____
_____
GRIP
Are you able to:
- Open car doors?
_____
_____
_____
_____
- Open jars which have been previously 
opened?
_____
_____
_____
_____
- Turn faucets on and off?
_____
_____
_____
_____
ACTIVITIES
Are you able to:
- Run errands and shop?
_____
_____
_____
_____
- Get in and out of a car?
_____
_____
_____
_____
- Do chores such as vacuuming or 
yardwork?
_____
_____
_____
_____
Please check any AIDS OR DEVICES that you usually use for any of these activities:
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_____ Raised toilet seat
_____ Bathtub bar
_____ Bathtub seat
_____ Long-handled appliances for reach
_____ Jar opener (for jars
_____ Long-handled appliances in bathroom
previously opened)
_____ Other (Specify: 
______________________)
Please check any categories for which you usually need HELP FROM ANOTHER 
PERSON:
_____ Hygiene
_____ Gripping and opening things
_____ Reach
_____ Errands and chores
We are also interested in learning whether or not you are affected by pain because of your 
illness.
How much pain have you had because of your illness IN THE PAST WEEK:
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE SEVERITY OF THE PAIN.
NO
PAIN
0
___________________________________________________________
SEVERE
PAIN
100
Source: Bruce, 2003.
STANFORD-RA (MAY99 - Phase 31) – English, USA
HAQ-DI - United States/English - Mapi.
HAQ-DI_AU1.0-eng-USori.doc
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APPENDIX F.
LEEDS ENTHESITIS INDEX (LEI)
Leeds Enthesitis Index (Healy, 2008b):
Enthesitis is measured by physical examination of the following joints. Tenderness (yes/no) will 
be assessed at 6 sites of tendon insertions (0-6) as depicted below: 

Lateral epicondyle, left and right

Medial femoral condyle, left and right

Achilles tendon insertion, left and right
Tenderness on physical examination is recorded as either present (1) or absent (0) for each of the 
6 sites, for an overall score range of 0 to 6. Higher count represents a greater enthesitis burden.
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APPENDIX G. THE SPONDYLOARTHRITIS RESEARCH 
CONSORTIUM OF CANADA (SPARCC) ENTHESITIS 
INDEX
Entheseal sites examined include:

Medial epicondyle (left/right [L/R])

Lateral epicondyle (L/R)

Supraspinatus insertion into greater tuberosity of humerus (L/R)

Greater trochanter (L/R)

Quadriceps insertion into superior border of patella (L/R)

Patellar ligament insertion into inferior pole of patella or tibial tubercle (L/R)

Achilles tendon insertion into calcaneum (L/R)

Plantar fascia insertion into calcaneum (L/R)
Tenderness on examination is recorded as either present (1) or absent (0) for each of the 16 sites, 
for an overall score range of 0–16. Higher count represents greater enthesitis burden.
The video describing the approach to the physical exam can be seen at www.carearthritis.com 
under “Physician Tools”.
Source: Maksymowych, 2009.
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APPENDIX H. LEEDS DACTYLITIS INDEX (LDI)
The LDI (Healy, 2008a; Helliwell, 2005) measures the ratio of the circumference of the affected 
digit to the circumference of the digit on the opposite hand or foot, using a minimum difference 
of 10% to define a dactylitic digit. The ratio of circumference is multiplied by a tenderness score.
Affected fingers are marked on a diagram displaying fingers and toes. Circumferences of the 
affected and contralateral fingers are then measured around the proximal phalanx, as close as 
possible to the web space, using either a measuring tape or a pre-calibrated loop. 
The clinician then squeezes the affected fingers with moderate pressure and documents the 
patient’s response: 0 = no tenderness, 1 = tender, 2 = tender and winces, and 3 = tender and 
withdraws. 
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APPENDIX H.
LEEDS DACTYLITIS INDEX (LDI) (CONTINUED)
The ratio of circumference between an affected finger and the contralateral unaffected finger is 
recorded. If both sides are affected, the circumference of the affected finger is compared to 
normative data supplied in a table. The tenderness score (0-3) for a finger with dactylitis is 
recorded, and a total score is generated for each finger. If multiple fingers are affected, each 
score is added together to produce a total for the patient.
In addition, as part of the LDI, number of affected digits will be evaluated. Each digit on the 
hands and feet will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis 
score is the sum of the individual scores for each digit.
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APPENDIX J.
BATH ANKYLOSING SPONDYLITIS DISEASE 
ACTIVITY INDEX (BASDAI)
Please check the box that represents your answer. (i.e. 
)
All questions refer to the last 7 days.
1. How would you describe your overall level of fatigue/tiredness?
0
1
2
3
4
5
6
7
8
9
10
       none
                                                                                                                very severe
2. How would you describe your overall level of neck, back or hip pain resulting from AS?
0
1
2
3
4
5
6
7
8
9
10
       none
                                                                                                                very severe
3. How would you describe your overall level of pain/swelling in joints other than the 
neck, back or hips?
0
1
2
3
4
5
6
7
8
9
10
       none
                                                                                                                very severe
4. How would you describe your overall level of discomfort from any areas tender to the 
touch or pressure?
0
1
2
3
4
5
6
7
8
9
10
       none
                                                                                                                very severe
5. How would you describe your overall level of morning stiffness from the time you wake 
up?
0
1
2
3
4
5
6
7
8
9
10
       none
                                                                                                                very severe
6. How long does your morning stiffness last from the time you wake up?
0
1
2
3
4
5
6
7
8
9
10
0    
hr
1 
hr
2 or more 
hrs
Source: Calin, 1999; Sieper, 2009.
BASDAI © Andrei Calin, 1994. All Rights Reserved
BASDAI - United States/English - Version of 09 Dec 15 - Mapi.
ID051206/ BASDAI_TS1.0_eng-US2.doc
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APPENDIX K. THE EULAR PSORIATIC ARTHRITIS IMPACT OF 
DISEASE 12 DOMAINS (PSAID-12) QUESTIONNAIRE 
The PsAID-12 questionnaire is a 12-item, self-administered questionnaire that reflects the impact 
of PsA from the perspective of the patient. It is composed of 12 physical and psychological 
domains. Each domain is rated from 0 to 10 with a different weighting. The total score is divided 
by 20. The final score has a range from 0 (best status) to 10 (worst status), with a cut-off of 4. 
The outputs of the PsAID calculation should be printed and added to the source documents.
We want you to indicate how much your psoriatic arthritis impacts your health. Please tell us 
how you have been feeling this last week. 
1. Pain 
Circle the number that best describes the pain you felt due to your psoriatic arthritis during the 
last week:
2. Fatigue 
Circle the number that best describes the overall level of fatigue due to your psoriatic arthritis 
you have experienced during the last week: 
3. Skin problems 
Circle the number that best describes the skin problems including itching you felt due to your 
psoriatic arthritis during the last week: 
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
No 
fatigue
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Totally 
exhausted
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
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APPENDIX K: THE EULAR PSORIATIC ARTHRITIS IMPACT OF 
DISEASE 12 DOMAINS (PSAID-12) QUESTIONNAIRE 
(CONTINUED)
4. Work and/or leisure activities 
Circle the number that best describes the difficulties you had to participate fully in work and/or 
leisure activities due to your psoriatic arthritis during the last week:
5. Functional capacity 
Circle the number that best describes the difficulty you had in doing daily physical activities due 
to your psoriatic arthritis during the last week: 
6. Discomfort 
Circle the number that best describes the feeling of discomfort and annoyance with everyday 
tasks due to your psoriatic arthritis during the last week:
7. Sleep disturbance 
Circle the number that best describes the sleep difficulties (i.e., resting at night) you felt due to 
your psoriatic arthritis during the last week: 
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
No 
difficulty
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme 
difficulty
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
No 
difficulty
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme 
difficulty
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APPENDIX K: THE EULAR PSORIATIC ARTHRITIS IMPACT OF 
DISEASE 12 DOMAINS (PSAID-12) QUESTIONNAIRE 
(CONTINUED)
8. Coping 
Considering your psoriatic arthritis overall, how well did you cope (manage, deal, make do) with 
your psoriatic arthritis during the last week?  
9. Anxiety, fear and uncertainty 
Circle the number that best describes the level of anxiety, fear and uncertainty (for example 
about the future, treatments, fear of loneliness) due to your psoriatic arthritis you have 
experienced during the last week: 
10. Embarrassment and/or shame
Considering your psoriatic arthritis overall, circle the number that best describes the level of 
embarrassment and/or shame due to your appearance experienced during the last week:
11. Social participation
Circle the number that best describes the difficulties you had to participate fully in social 
activities (including relationships with family and/or people very close to you) due to your 
psoriatic arthritis during the last week:
Very 
well
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Very 
poorly
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
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APPENDIX K: THE EULAR PSORIATIC ARTHRITIS IMPACT OF 
DISEASE 12 DOMAINS (PSAID-12) QUESTIONNAIRE 
(CONTINUED)
12. Depression
Circle the number that best describes the level of depression due to your psoriatic arthritis you 
have experienced during the last week:
THANK YOU FOR ANSWERING THIS QUESTIONNAIRE
Source: Gossec, 2014.
None
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme
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APPENDIX K: THE EULAR PSORIATIC ARTHRITIS IMPACT OF 
DISEASE 12 DOMAINS (PSAID-12) QUESTIONNAIRE 
(CONTINUED)
PsAID-12 SCORING AND CALCULATION RULES 
The PsAID is calculated based on 12 NRS questions. Each NRS is assessed as a number between 
0 and 10. 
Calculators and translations are available at 
http://www.eular.org/index.cfm?framePage=/st_com_clinical_tools.cfm.
1. Calculation  
PsAID final value = 
(PsAID1 (pain) NRS value (range 0-10) x 3) 
+ (PsAID2 (fatigue) NRS value (range 0-10) x 2) 
+ (PsAID3 (skin) NRS value (range 0-10) x 2) 
+ (PsAID4 (Work and/or leisure activities) NRS value (range 0-10) x 2) 
+ (PsAID5 (function) NRS value (range 0-10) x 2) 
+ (PsAID6 (discomfort) NRS value (range 0-10) x 2) 
+ (PsAID7 (sleep) NRS value (range 0-10) x 2) 
+ (PsAID8 (coping) NRS value (range 0-10) x 1) 
+ (PsAID9 (anxiety) NRS value (range 0-10) x 1) 
+ (PsAID10 (embarrassment) NRS value (range 0-10) x 1) 
+ (PsAID11 (social life) NRS value (range 0-10) x 1) 
+ (PsAID12 (depression) NRS value (range 0-10) x 1) 
The total is divided by 20. Thus, the range of the final PsAID value is 0-10, where 
higher figures indicate worse status. 
2. Missing data imputation 
If one of the 12 NRS values composing the PsAID is missing, the imputation is as follows:
a.
calculate the mean value of the 11 other (non-missing) NRS values (range, 0-10)
b. impute this value for the missing NRS value
c.
then, calculate the PsAID score as explained above. 
If 2 or more of the NRS values are missing, the PsAID score is considered a missing value 
(no imputation).
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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APPENDIX P.
PSORIATIC ARTHRITIS MAGNETIC RESONANCE 
IMAGING SCORING SYSTEM (PSAMRIS)
Source: Glinatsi, 2015.
Approved 
 
 


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APPENDIX Q. WHOLE-BODY (WB)–MRI ASSESSMENTS
The final WB-MRI assessment protocol will be developed based on the prevalent 
recommendations by the OMERACT MRI in arthritis working group at the time of reading 
initiation. The final detailed MRI manual will be available before any reading starts.
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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APPENDIX S.
BLISTER CARD CONFIGURATION FOR THE 
TITRATION PERIOD
The blister card figure displayed below is an approximate representation of the actual blister 
card, which may not have the exact number of extra tablets. Subjects must be instructed to use 
tablets from the blister card through the first 31 days and then switch to the bottle.
Approved 
 
 


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APPENDIX T. CONTRACEPTION EDUCATION
The risks to a fetus or to a nursing child from apremilast are not known at this time. Results of 
the animal and in vitro studies can be found in the IB.
All females of childbearing potential3 must use one of the approved contraceptive options as 
described in Section 4.3 while on IP and for at least 28 days after administration of the last dose 
of the IP. The female subject’s chosen form of contraception must be effective by the time the 
female subject is screened for the study (for example, hormonal contraception should be initiated 
at least 28 days before screening).
At screening and at baseline, and at any time during the study, when an FCBP’s contraceptive 
measures or ability to become pregnant changes, the investigator (or a representative as a study 
nurse) will educate the subject regarding contraception options and the correct and consistent use 
of effective contraceptive methods in order to successfully prevent pregnancy.
                                               
3 A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 
consecutive months). A tubal ligation alone is not sufficient to qualify a female as of non-childbearing potential.
Approved 
 
 


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APPENDIX U. SAMPLE SERIOUS ADVERSE EVENT REPORT FORM 
Approved 
 
 


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APPENDIX U:
SAMPLE SERIOUS ADVERSE EVENT REPORT FORM
(CONTINUED)
Approved 
 
 


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APPENDIX U:
SAMPLE SERIOUS ADVERSE EVENT REPORT FORM
(CONTINUED)
Approved 
 
 


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APPENDIX V. PREGNANCY NOTIFICATION FORM 
Approved 
 
 


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APPENDIX W. LACTATION NOTIFICATION FORM 
Approved 
 
 


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Amendment # 3 Final: 04 May 2020
TITLE PAGE
– SUMMARY OF CHANGES –
A PHASE 4, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE IMPACT OF 
APREMILAST (CC-10004) ON MRI OUTCOMES IN 
SUBJECTS WITH PSORIATIC ARTHRITIS
AMENDMENT NO. 4
INVESTIGATIONAL PRODUCT (IP):
Apremilast
PROTOCOL NUMBER:
CC-10004-PSA-014
ORIGINAL DATE:
14 AUG 2018
AMENDMENT No. 1 DATE:
21 SEP 2018
AMENDMENT No. 2 DATE:
12 FEB 2019
AMENDMENT No. 3 DATE:
17 MAY 2019
AMENDMENT No. 4 DATE:
04 MAY 2020
EudraCT NUMBER:
2018-002748-10
IND NUMBER: 
101761
NCT NUMBER
NCT03783026
Contact Information: 
Name:
, MD
Title:
Medical Director Global Development
Amgen Inc.
Address: 
Amgen Inc,
Amgen Center Dr, Thousand Oaks, CA 91320
USA
Phone:
E-mail:
Note: Only call Amgen Medical Information, if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls.
Amgen Medical Information: 1- 800-77-AMGEN (1 800-772-6436)


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Amendment # 3 Final: 04 May 2020
Confidentiality Notice 
This document contains confidential information of Amgen. 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. If you have 
questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: 1- 800-77-AMGEN


EDMS Doc. Number: 24688121 - 22995811
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Amendment # 3 Final: 04 May 2020
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, Vice President and Head of Immunology &Fibrosis Clinical 
Development
Printed Name of CelgeneTherapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable. NOTE: Signed by Celgene based on Approval from 
Amgen Therapeutic Head 


EDMS Doc. Number: 24688121 - 22995811
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Amendment # 3 Final: 04 May 2020
1.
JUSTIFICATION FOR AMENDMENT
The purpose of this amendment is to update the change in Sponsor, as well as key contact and 
emergency information, and to update safety reporting and product complaints to align with 
Amgen processes.

All references to “Celgene Corporation” were removed and replaced with “Amgen Inc” 
and “Celgene” changed to “Amgen” throughout the protocol. 

Cover Pages were updated with Amgen contact information

Section 10 Monitoring and Reporting of Adverse Events was updated to align with 
Amgen Global Drug Safety processes. 

Section 10.4 Pregnancy was modified according to the Amgen Global Drug Safety 
process:
o
Collection of Pregnancy Information and Infant Health Information
o
Collection of information: Male Subjects with Partners Who Become Pregnant 
o
Collection of Lactation Information

Section 10.5 Reporting of Serious Adverse Events was updated to include instructions for 
paper reporting of SAEs 

Section 12.1 Emergency Contact was updated with Amgen emergency contact 
information.

Section 15.3 Product Complaint Section added
The amendment also includes minor clarifications and corrections to align with Amgen 
process:

Section 7.5-Investigational Product Accountability

Section 15.2Audits and Compliance 

Section 16 Publications. 


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CC-10004-PSA-014 Amendment 3 Final: 17 May 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 3
A PHASE 4, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE IMPACT OF 
APREMILAST (CC-10004) ON MRI OUTCOMES IN
SUBJECTS WITH PSORIATIC ARTHRITIS
INVESTIGATIONAL PRODUCT (IP):
Apremilast
PROTOCOL NUMBER:
CC-10004-PSA-014
ORIGINAL DATE:
14 AUG 2018
AMENDMENT No. 1 DATE:
21 SEP 2018
AMENDMENT No. 2 DATE:
12 FEB 2019
AMENDMENT No. 3 DATE:
17 MAY 2019
EudraCT NUMBER:
2018-002748-10
IND NUMBER: 
101761
Contact Information: 
Name:
Title:
Medical Director
Address: 
PPDI
900 Perimeter Park Drive
Morrisville, NC 27560
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 23759493 - 22995811
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CC-10004-PSA-014 Amendment 3 Final: 17 May 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, Executive Director, Inflammation and Immunology
Global Medical Affairs Rheumatology
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


EDMS Doc. Number: 23759493 - 22995811
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CC-10004-PSA-014 Amendment 3 Final: 17 May 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

All references to “approved product labeling” and “prescribing information” were 
removed.
Based on comments from Health Authorities, there should be one reference safety 
information (RSI) for a trial. Therefore, Celgene clarifies that the investigator brochure 
(IB) is the identified RSI for this trial. The IB will be submitted to all sites and clearly 
identified as the RSI in the clinical trial application (CTA) package. 
Revised sections: 

Section 1.2.2.2.2; 

Section 7.1.

Exclusion criteria #22 updated to include prior exposure to a tyk2 inhibitor, as prohibited 
medication. 
The amendment also includes several other minor clarifications and corrections:

References to the 
were corrected to reflect the appropriate nomenclature of such subject-reported outcome 
questionnaire.
Revised sections: 

Protocol Summary;

Table of Contents;

Table 12; 

Section 5 (Table 13);

Section 6.7.4;

Appendix A;


The BASDAI questionnaire will be performed for all subjects, at the timepoints specified 
as per the Table of Events.
Revised sections: 

Section 5 (Table 13, footnote h).

Quality of Life abbreviature (QoL) was removed from the text in all the instances it was
placed together with “subject-reported outcomes”, for clarity and consistency across 
different sections of the protocol.
Revised sections: 

Section 6.2;


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
Section 6.2.1;

Section 6.7.

The word “electronic” was deleted in all the instances it was displayed right before the 
word CRF.
Revised sections: 

Section 7.2.1;

Section 8;

Section 8.1;

Section 10.1;

Section 10.2.1;

Section 14.2.

The following abbreviations were inserted: EDC, LOCF, NRI, SRO, vs.
Revised section: 

Appendix A.

CASPAR Criteria replaced with a corrected version that includes an additional footnote. 
Revised section: 

Appendix B.

Protocol number updated from CC-10004-PsA-014 to CC-10004-PSA-014 for 
consistency purposes.
Revised sections: 

Headers and footers throughout the document and the protocol title on Title Page.


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TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 2
A PHASE 4, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE IMPACT OF 
APREMILAST (CC-10004) ON MRI OUTCOMES IN
SUBJECTS WITH PSORIATIC ARTHRITIS
INVESTIGATIONAL PRODUCT (IP):
Apremilast
PROTOCOL NUMBER:
CC-10004-PsA-014
ORIGINAL DATE:
14 AUG 2018
AMENDMENT No. 1 DATE:
21 SEP 2018
AMENDMENT No. 2 DATE:
12 FEB 2019
EudraCT NUMBER:
2018-002748-10
IND NUMBER: 
101761
Contact Information: 
Name:
Title:
Medical Director
Address: 
PPDI
900 Perimeter Park Drive
Morrisville, NC 27560
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 23509971 - 22995811
Apremilast
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CC-10004-PsA-014 Amendment 2 Final: 12 Feb 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, Executive Director, Inflammation and Immunology
Global Medical Affairs Rheumatology
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


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1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Medical Monitor/Emergency Contact Information text was modified.
Change made to reflect PPD’s (clinical research organization) responsible personnel.
Revised section: Medical Monitor/Emergency Contact Information

Deleted text: “Detailed information can be found in the Investigator’s Brochure (IB)”
As this is a Phase 4 study, approved product labeling or the IB (depending on regional 
regulations) should be used as the reference for additional information on apremilast 
in this approved indication. Since selected countries, as per local regulations, will 
have the product label as the main document for additional information on apremilast, 
the reference to IB in isolation was deleted.
Revised sections: 
-
1.2.2.1.1, Efficacy Data From Phase 3 Studies CC-10004-PSA-002 (Palace 1), 
CC-10004-PSA-003 (Palace 2), and CC-10004-PSA-004 (Palace 3) Through 
Week 24 in Subjects With Prior csDMARDs and/or Biologic DMARDs
-
1.2.2.1.2, Efficacy Data From Phase 3 Study CC-10004-PSA-005 (Palace 4) 
Through Week 24 in Subjects Naïve to csDMARDs and Biologic DMARDs
-
1.2.2.1.3, Efficacy Data From Phase 3 CC–10004-PSA-006 (ACTIVE) Through 
Week 24 in Subjects With an Inadequate Response to 1 csDMARDs and Who 
Received Apremilast Monotherapy

Added text: “/approved product labeling”
As this is a Phase 4 study, approved product labeling or the IB (depending on regional 
regulations) should be used as the reference for additional information on apremilast
in this approved indication.
Revised sections: 
-
Section 1.2.2.2.2, Long-term Safety Data From CC-10004-PSA-006 (ACTIVE), 
CC-10004-PSA-002 (Palace 1), CC-10004-PSA-003 (Palace 2) and 
CC-10004-PSA-004 (Palace 3)
-
Appendix T, Contraception Education

A note was added to inclusion criterion #17.
Addition to highlight that option 2 may not be considered as highly effective 
contraceptive measures in all countries.
Revised section: Section 4.3 Inclusion Criteria

In exclusion criterion #1, “history of hypersensitivity to gadolinium contrast agent” 
was added. In exclusion criterion #8, the word “hypersensitivity” was added. 


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Exclusion criterion #9 was added: “History of rare hereditary problems of galactose 
intolerance, lapp lactase deficiency or glucose-galactose malabsorption”.
Additions made to comply with requests from European Health Authorities.
Revised section: Section 4.4 Exclusion Criteria

The Table of Events was updated to reflect: Weight will be captured at every visit; 
 
 
.
Weight will now be captured at every visit to comply with the requested from 
European Health Authorities. Other changes made for consistency with other sections 
of the protocol.
Revised section: Section 5, Table of Events (Table 13)

Demographics: “initials” deleted; “date” substituted by “year” of birth, for 
consistency with CRF; Contraception Education: reference to Section 4.3 and 
Appendix T were added; Urinalysis: “a urine dipstick may be used” deleted; 4) 
Chemistry panel: “creatinine clearance added. Changes made for consistency with 
other sections of the protocol.
Revised section: Section 6.1, Screening Period

Weight: reference to Section 6.5.2 was added; Assessment of diarrhea: reference to 
Section 6.5.5 was added; Contraception Education: reference to Section 4.3 and 
Appendix T were added; Urinalysis: “a urine dipstick may be used” deleted; 
Chemistry panel: “creatinine clearance added; “MRI assessments” moved to same 
bullet point as “Efficacy assessments” for consistency with protocol sections.
Revised section: Section 6.2, Treatment Period

Added “End of Treatment” for compliance with protocol template; Urinalysis: “a 
urine dipstick may be used” deleted; “MRI assessments” moved to same bullet point 
as “Efficacy assessments” for consistency with protocol sections.
Revised section: Section 6.2.1 Early termination/End of Treatment

Cut-offs for cDAPSA put in bullet points for clarity.
Revised section: Section 6.4.5.9, Clinical Disease Activity Index for Psoriatic 
Arthritis (cDAPSA)

Text was revised to delete reference to SMT, for consistency with wording in Phase 4 
protocols across Rheumatology and Dermatology, as approved by Safety team.
Revised section: Section 6.5, Safety Assessments

A paragraph was added to reference country guidelines for pregnancy testing.
Revised section: Section 6.5.1, Serum and Urine Pregnancy Tests for FCBP


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
Weight will now be captured at every visit. A paragraph was added for consideration 
of study treatment discontinuation of study treatment in the event of unexplained and 
clinically significant weight loss.
Revised section: Section 6.5.2, Vital Signs, Height and Weight 

A paragraph was added as a recommendation for study treatment discontinuation in 
the event of new/worsening psychiatric symptoms or suicidal ideation/attempt.
Addition made to comply with European Health Authorities’ requests.
Revised section: Section 6.5.4, Psychiatric Evaluation

A section dedicated to “Diarrhea, Nausea and Vomiting” was added, including a 
statement that “discontinuation of study treatment may be necessary if severe 
diarrhea, nausea and vomiting occur”.
Addition made to comply with European Health Authorities requests.
Revised section: Section 6.5.5, Diarrhea, Nausea and Vomiting

Text revised to add “creatinine clearance”.
Revised section: Section 6.5.7, Clinical Laboratory Evaluations

Text revised to reflect new safety gateway process, as agreed upon by the Safety 
team. Paragraphs referencing diarrhea were moved to newly created section 6.5.5 
“Diarrhea, Nausea and Vomiting”.
Revised section: Section 6.5.8, Adverse Events

“Concomitant Medications Not Recommended” section was added.
Addition was made to comply with European Health Authorities, for consistency with 
apremilast’s label. 
Revised section: Section 8.2, Concomitant Medications Not Recommended

The word “violation” was substituted by “deviation” for compliance with current 
SOP.
Revised section: Section 9.2, Study Population Definitions

Text was revised to reflect new safety gateway process, as agreed upon by the Safety 
team.
Revised section: Section 10, Adverse Events (10.1, 10.4, 10.5, 10.5.1)

Text was revised to reflect subjects’ right to withdraw from the study (and proper 
documentation), as well as the importance of early termination assessments.
Revised section: Section 11.1, Treatment Discontinuation

HAQ-DI questionnaire was updated to display validated version used in the eRT 
tablet which the subjects will be responding to.
Revised section: Appendix E, Health Assessment Questionnaire–Disability Index 
(HAQ-DI)


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CC-10004-PsA-014 Amendment 2 Final: 12 Feb 2019

A paragraph was added to reference the evaluation of the number of affected digits,
for completion and consistency between Phase 4 PsA protocols.
Revised section: Appendix H, Leeds Dactylitis Index (LDI)

The BASDAI questionnaire was updated to display validated version used in the eRT 
tablet subjects will be responding to.
Revised section: Appendix J, Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI)

Questions 9, 10 and 11 had the text near the NRS extremes revised, to display the 
exact language in the validated version of the questionnaire, which is used in the eRT 
tablet subjects will be responding to. Also, Scoring and Calculation Rules were
updated to display PsAID-12 accurate multiplying factors for each domain, as agreed 
upon by Biostats team.
Revised section: Appendix K, Psoriatic Arthritis Impact of Disease 12-domain 
questionnaire (PsAID-12)

A paragraph was added to clarify that the figure displayed is an approximate 
representation of the actual blister card and to better explain the transition from blister 
card to bottle.
Revised section: Appendix S, Blister Card Configuration for the Titration Period


EDMS Doc. Number: 22995988 - 22995811
Apremilast
Summary of Changes CC-10004-PsA-014-MOSAIC™
Celgene Corporation
Confidential and Proprietary
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CC-10004-PsA-014-MOSAIC™
Amendment 1 Final: 21 Sep 2018 
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 1
A PHASE 4, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE IMPACT OF 
APREMILAST (CC-10004) ON MRI OUTCOMES IN
SUBJECTS WITH PSORIATIC ARTHRITIS
INVESTIGATIONAL PRODUCT (IP):
Apremilast
PROTOCOL NUMBER:
CC-10004-PsA-014-MOSAIC™
ORIGINAL DATE:
14 AUG 2018
AMENDMENT No. 1 DATE:
21 SEP 2018
EudraCT NUMBER:
2018-002748-10
IND NUMBER: 
101761
Contact Information: 
Name:
, MD
Title:
Medical Director
Address: 
Celgene Corporation
86 Morris Avenue
Summit, NJ `07901 USA
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 22995988 - 22995811
Apremilast
Summary of Changes CC-10004-PsA-014-MOSAIC™
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CC-10004-PsA-014-MOSAIC™
Amendment 1 Final: 21 Sep 2018 
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, Executive Director, Inflammation and Immunology
Global Medical Affairs Rheumatology
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


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CC-10004-PsA-014-MOSAIC™
Amendment 1 Final: 21 Sep 2018 
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

14-3-3 eta biomarker was deleted from the protocol since it will no longer be part of 
the study, due to feasibility issues. Revised Sections: Section 2, Section 5, Section 6.2 
and Section 6.6.

Section 6.4.1 was revised to specify the timeframes within which the Magnetic 
Resonance Imaging (MRI) assessments should be performed.

Section 10.5.1 was revised to reflect the current safety language.

Appendix S was revised to better represent this study’s design (open label, single-arm 
trial). The blister card configuration for the titration period was replaced by a card 
with no placebo.

SAP_003.pdf: 
Amgen 
Statistical Analysis Plan 
Protocol: CC-10004-PsA-014 
Date: 12-MAY-2022 
Amgen Proprietary - Restricted
Confidential and Proprietary 
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Confidential Clinical Trials 
STATISTICAL ANALYSIS PLAN 
A PHASE 4, MULTICENTER, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE 
THE IMPACT OF APREMILAST (CC-10004) ON MRI OUTCOMES IN SUBJECTS 
WITH PSORIATIC ARTHRITIS 
INVESTIGATIONAL PRODUCT (IP): 
Apremilast 
PROTOCOL NUMBER: 
CC-10004-PsA-014
DATE FINAL: 
12-MAY-2022
SAP Version Status: 
1.0 
Prepared by: 
Amgen 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, 
except to the extent necessary to obtain informed consent, may not be disclosed to 
another party unless such disclosure is required by law or regulations.  Persons to 
whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
NCT Number: NCT03783026
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


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HISTORY OF AMENDMENT(S) 
Amendment 
number 
Date of 
amendment 
Significant amendments and 
rationales 
Impact to statistical 
analysis and descriptions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
INTRODUCTION ........................................................................................................9 
3. 
STUDY OBJECTIVES ..............................................................................................10 
3.1. 
Primary Objective .......................................................................................................10 
3.2. 
Secondary Objectives .................................................................................................10 
3.3. 
Exploratory Objectives ...............................................................................................10 
4. 
INVESTIGATIONAL PLAN .....................................................................................12 
4.1. 
Overall Study Design and Plan ...................................................................................12 
4.2. 
Study Endpoints ..........................................................................................................13 
4.2.1. 
Efficacy Endpoints ......................................................................................................13 
4.2.2. 
Safety Endpoints .........................................................................................................16 
4.2.3. 
Health-related Quality of Life Endpoints ...................................................................17 
4.2.4. 
Derivations of Efficacy Endpoints..............................................................................17 
4.2.5. 
Derivations of Safety Endpoints .................................................................................40 
4.3. 
Sample Size and Power ..............................................................................................41 
5. 
GENERAL STATISTISTICAL CONSIDERATIONS ..............................................42 
5.1. 
Reporting and Analysis Conventions .........................................................................42 
5.2. 
Definition of Analysis Populations .............................................................................42 
5.2.1. 
Full Analysis Set .........................................................................................................42 
5.2.2. 
Modified Intent to Treat (mITT) .................................................................................42 
5.2.3. 
Per-protocol Population ..............................................................................................42 
5.2.4. 
Safety Population ........................................................................................................43 
5.3. 
Analysis Periods .........................................................................................................43 
5.4. 
Baseline Definitions ....................................................................................................43 
5.5. 
Time Points .................................................................................................................43 
6. 
STATISTICAL METHODOLOGY FOR EFFICACY ..............................................46 
6.1. 
Analysis of Primary Efficacy Endpoint ......................................................................46 
6.2. 
Analyses of Secondary Efficacy Endpoints ................................................................46 
6.2.1. 
Analyses of Binary Secondary Endpoints ..................................................................46 
6.2.2. 
Analyses of Continuous Secondary Endpoints ...........................................................47 


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6.3. 
Analyses of Exploratory Efficacy Endpoints .............................................................47 
6.4. 
Subgroup Analysis ......................................................................................................47 
7. 
INTERIM ANALYSIS ...............................................................................................49 
8. 
SUMMARY OF SUBJECT DISPOSITION ..............................................................50 
9. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................51 
9.1. 
Demographics .............................................................................................................51 
9.2. 
Baseline or Disease Characteristics ............................................................................51 
9.3. 
Medical History ..........................................................................................................54 
9.4. 
Prior Medications ........................................................................................................54 
9.5. 
Prior Procedures ..........................................................................................................54 
10. 
STUDY TREATMENTS AND EXTENT OF EXPOSURE......................................55 
10.1. 
Treatment Duration .....................................................................................................55 
10.2. 
Treatment Compliance ................................................................................................55 
11. 
PROTOCOL DEVIATIONS/VIOLATIONS .............................................................57 
12. 
SAFETY ANALYSIS ................................................................................................58 
12.1. 
Adverse Events ...........................................................................................................58 
12.1.1. 
Overall Summary of Adverse Events .........................................................................59 
12.1.2. 
All TEAEs ..................................................................................................................59 
12.2. 
Adverse Events of Special Interest .............................................................................61 
12.3. 
Clinical Laboratory Evaluations .................................................................................61 
12.4. 
Vital Sign Measurements and Weight ........................................................................62 
12.5. 
Physical Examination .................................................................................................62 
12.6. 
Concomitant Medications/Procedures ........................................................................62 
12.6.1. 
Concomitant Medications ...........................................................................................62 
12.6.2. 
Concomitant Procedures .............................................................................................63 
13. 
REFERENCES ...........................................................................................................64 
APPENDIX A1 ..............................................................................................................................65 
1. 
GUIDELINE OF PARTIALLY MISSING DATE IMPUTATION ..........................65 
1.1 
Adverse Events ...........................................................................................................65 
1.2 
Prior/Concomitant Medications and Procedures ........................................................65 
1.3 
Medical History ..........................................................................................................66 
1.4 
Treatment Duration .....................................................................................................66 


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2. 
MARKED ABNORMALITIES CRITERIA ..............................................................67 
....................................................................69 


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1. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
APR  
Apremilast 
AST 
Aspartate aminotransferase (SGOT) 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BID 
Twice per day 
BME 
Bone marrow edema 
BSA 
Body surface area 
CASPAR  
Classification Criteria for Psoriatic Arthritis 
CBC 
Complete blood count 
c-DAPSA 
Clinical Disease Activity Index for Psoriatic Arthritis 
CI 
Confidence interval 
CRP 
Clinical Research Physician 
DAS 
Disease Activity Score 
DCE-MRI 
Dynamic Contrast-enhanced MRI 
eCRF 
Electronic case report form 
EGA 
Evaluator’s Global Assessment of Disease activity 
ET 
Early Termination 
EULAR 
European League Against Rheumatism 
FAS 
Full Analysis Set 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEI 
Gladman Enthesitis Index 


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GRAPPA 
Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 
HbA1c 
Glycated hemoglobin 
HAQ-DI  
Health Assessment Questionnaire Disability Index 
hsCRP 
High sensitivity C-reactive protein 
IP 
Investigational product 
LDI 
Leeds Dactylitis Index. 
LEI 
Leeds Enthesitis Index 
L/R 
Left/right 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent to treat 
MRI 
Magnetic resonance imaging 
MTX 
Methotrexate 
NR 
Non-responder 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
PASDAS 
Psoriatic Arthritis Disease Activity Score 
PGA 
Patient’s Global Assessment of Disease activity 
PP 
Per Protocol 
PsA 
Psoriatic arthritis 
PsAID-12 
Psoriatic Arthritis Impact of Disease 12-domain questionnaire 
PsAMRIS 
Psoriatic Arthritis Magnetic Resonance Imaging Score 
QoL 
Quality of life 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SJC 
Swollen joint count 


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SOP 
Standard operating procedure 
SPARCC 
Spondyloarthritis Research Consortium of Canada Enthesitis 
TEAE 
Treatment-emergent adverse event 
TJC 
Tender joint account 
WBC 
White blood cell  
WB-MRI 
Whole-body magnetic resonance imaging 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
Wk 
Week 
 


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2. 
INTRODUCTION  
This statistical analysis plan (SAP) describes the analyses and data presentations for Amgen’s 
protocol CC-10004-PSA-014 “A Phase 4, Multicenter, Single-Arm, Open-Label Study to 
Evaluate the Impact of Apremilast (CC-10004) On MRI Outcomes in Subjects with Psoriatic 
Arthritis”.  This SAP contains definitions of analysis populations, derived variables and 
statistical methods for the efficacy and safety analyses. The efficacy and safety analyses will be 
based on the final database locked at the completion of the study.  
In this SAP, the term “treatment group” refers to the apremilast 30 mg BID group. The term 
“APR” refers to the apremilast. 
This SAP provides a more technical and detailed elaboration of the statistical analyses, as 
outlined and/or specified in the CC-10004-PSA-014 study protocol amendment 4 dated May 4, 
2020. All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.3 or 
higher. 
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of apremilast 30 mg twice a day 
(BID) on inflammation indices, assessed by magnetic resonance imaging (MRI) of the hand. 
3.2. 
Secondary Objectives 
The secondary objectives of the study are to evaluate: 
 The efficacy of apremilast 30 mg BID on imaging outcomes associated with structural 
progression, assessed by MRI of the hand 
 The efficacy of apremilast 30 mg BID on disease activity and functionality, assessed by 
clinical outcomes 
 The efficacy of apremilast 30 mg BID on inflammation indices of peripheral arthritis and 
enthesitis, total (sum of arthritis and enthesitis) and separately, assessed by whole-body MRI 
(WB-MRI)  
 The efficacy of apremilast 30 mg BID on The European League Against Rheumatism 
Psoriatic Arthritis Impact of Disease 12 domains (PsAID-12) 
 The safety and tolerability of apremilast 30 mg BID 
3.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 4, single-arm, multicenter, open-label study to evaluate the impact of apremilast 
(CC-10004), either in monotherapy or with stable methotrexate (MTX) on MRI outcomes in 
subjects with active PsA with up to 5 years of disease duration (since diagnosis).  
Approximately 120 subjects will receive apremilast 30 mg BID, after a 5-day titration period, 
with or without stable MTX. All subjects will be permitted to take nonsteroidal anti-
inflammatory drugs (NSAIDs) and/or low-dose oral glucocorticoids (prednisone ≤ 10 mg/day or 
equivalent) throughout the study. The NSAIDs and low-dose oral glucocorticoids must be on a 
stable regimen for at least 4 weeks prior to baseline. MTX (≤ 25 mg/week) will be permitted if 
duration of treatment is ≥ 6 months and on a stable regimen for at least 3 months prior to 
baseline. In addition, the stable doses of MTX, NSAIDs, and low-dose glucocorticoids must be 
continued from Day 1 through the Week 24 Visit. Change in doses, increase or decrease, and/or 
discontinuation will not be allowed except for safety reasons or for lack of availability. After the 
Week 24 Visit, the doses of MTX, NSAIDs, or glucocorticoids may be adjusted as clinically 
required. 
This is a 56-week study comprised of 3 phases: 
 Screening Phase – up to 4 weeks 
 Single-arm, Open-label Treatment Phase – Weeks 0 to 48 
 120 subjects will receive apremilast 30 mg BID (after a 5-day titration period) for 
the entire duration of this phase. 
 Observational Follow-up Phase – 4 Weeks 
 All subjects who complete the study or discontinue early will participate in the 4-
week Post-Treatment Observational Follow-up Phase.  
The study schematic is presented in Figure 1. 
 
 


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Figure 1: 
Overall Study Design 
 
   Wk -4            Wk 0      Wk 8      Wk 16         Wk 24              Wk 36               Wk 48         Wk 52 
 
 
 
 
                                                                                         
                                                                  Primary Endpoint 
 
BID = twice daily; MTX = methotrexate; Wk = Week.  
4.2. 
Study Endpoints 
Efficacy and safety endpoints are listed in Sections 4.2.1 through 4.2.2, respectively. Derivations 
of select efficacy and safety endpoints are described in Sections 4.2.4 and 4.2.5, respectively. 
4.2.1. 
Efficacy Endpoints 
The following sections provide the efficacy endpoints as specified in the protocol.  
4.2.1.1. 
Primary Efficacy Endpoint  
The primary endpoint of the study is the change from baseline in the composite score of bone 
marrow edema (BME), synovitis, and tenosynovitis assessed by Psoriatic Arthritis Magnetic 
Resonance Imaging Score (PsAMRIS) at Week 24. 
4.2.1.2. 
Secondary Efficacy Endpoints 
 Change from baseline in the composite score of BME, synovitis, and tenosynovitis 
assessed by PsAMRIS at Week 48. 
 Change from baseline in the composite score of BME and synovitis assessed by 
PsAMRIS at Weeks 24 and 48. 
 Change from baseline in the PsAMRIS total inflammation score (BME, synovitis, 
tenosynovitis and periarticular inflammation) at Weeks 24 and 48. 
 Change from baseline in BME assessed by PsAMRIS at Weeks 24 and 48. 
 Change from baseline in synovitis assessed by PsAMRIS at Weeks 24 and 48. 
 Change from baseline in tenosynovitis assessed by PsAMRIS at Weeks 24 and 48. 
 Change from baseline in periarticular inflammation assessed by PsAMRIS at Weeks 24 
and 48. 
Apremilast 30 mg BID with or without 
MTX 
Screening 
Follow-up 


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 Change from baseline in the PsAMRIS total damage score (erosion + bone proliferation) 
at Weeks 24 and 48. 
 Change from baseline in bone erosion assessed by PsAMRIS at Weeks 24 and 48. 
 Change from baseline in bone proliferation/enthesophytes assessed by PsAMRIS at 
Weeks 24 and 48. 
 Change from baseline in the Swollen Joint Count (SJC) at Weeks 24 and 48. 
 Change from baseline in the Tender Joint Count (TJC) at Weeks 24 and 48. 
 Change from baseline in the Clinical Disease Activity Index for Psoriatic Arthritis (c-
DAPSA) Score at Weeks 24 and 48. 
 Change from baseline in Spondyloarthritis Research Consortium of Canada (SPARCC), 
in subjects with preexisting enthesopathy at Weeks 24 and 48. 
 Change from baseline in the Leeds Enthesitis Index (LEI), in subjects with preexisting 
enthesopathy at Weeks 24 and 48. 
 Proportion of subjects with baseline enthesitis whose enthesitis improves to 0 at Weeks 
24 and 48. 
 Change from baseline in the Leeds Dactylitis Index (LDI), in subjects with preexisting 
dactylitis at Weeks 24 and 48. 
 Proportion of subjects with baseline dactylitis whose tender dactylitis count improves to 0 
at Week 24 and 48. 
 Change from baseline in the Psoriatic Arthritis Disease Activity Score (PASDAS) at 
Weeks 24 and 48. 
 Change from baseline in the evaluator’s global assessment of disease activity at Weeks 
24 and 48. 
 Change from baseline in the subject’s global assessment of disease activity at Weeks 24 
and 48. 
 Change from baseline in the subject’s assessment of pain at Weeks 24 and 48. 
 Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI 
score) at Weeks 24 and 48. 
 Change from baseline in the peripheral enthesitis inflammation index assessed by WB-
MRI at Weeks 24 and 48. 
 Change from baseline in peripheral joints inflammation index assessed by WB-MRI at 
Weeks 24 and 48. 
 Change from baseline in the total peripheral (joints and enthesitis) inflammation index 
assessed by WB-MRI at Weeks 24 and 48. 


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 Change from baseline in the Bath Ankylosing Spondylitis Disease Activity Index 
BASDAI (for subjects deemed to have PsA spondylitis by the investigator and with 
BASDAI item 2 ≥ 4 at baseline) at Weeks 24 and 48. 
 Change from baseline in the PsAID-12 at Weeks 24 and 48. 
4.2.1.3. 
Exploratory Efficacy Endpoints 


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4.2.2. 
Safety Endpoints 
The follow safety parameters will be evaluated throughout the duration of the study: 
 Adverse events (AEs) 
o Type, frequency, severity and relationship of adverse events to study medication 
o Number of subjects who discontinue study medication due to any adverse event 
 Deaths 
 Laboratory evaluations 
o Laboratory marked abnormalities (refer to Appendix A1.2) 
o Observed value and change from baseline over time in continuous laboratory 
parameters 
o Shifts from baseline to post-baseline time points and to the worst post-baseline 
value in terms of low/normal/high/both low and high in laboratory parameters, as 
appropriate 
 Vital signs and weight 


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o Observed value and change from baseline over time in vital signs (weight, 
temperature, pulse, and blood pressure) 
o Shifts from baseline to post-baseline time points, and to the worst post-baseline 
value in terms of normal/abnormal in pulse and blood pressure (normal ranges are 
defined as: 60-100 beats/minute for pulse, 90-140 mmHg for systolic blood 
pressure, 35.5-37.9 C for temperature, and 60-90 mmHg for diastolic blood 
pressure) 
o Observed value, change and percent change from baseline over time in weight 
4.2.3. 
Health-related Quality of Life Endpoints 
All endpoints related to the health-related quality of life (shown below) are included in the 
efficacy endpoints above. 
 
Table 1: Health-related Quality of Life Endpoints 
Secondary 
The European League Against 
Rheumatism Psoriatic Arthritis 
Impact of Disease 12 domains 
(PsAID-12) 
Change from baseline in the PsAID-12 
Week 24 
Week 48 
Exploratory 
Exploratory 
Exploratory 
Exploratory 
4.2.4. 
Derivations of Efficacy Endpoints 
The definition of baseline, applicable to all continuous efficacy endpoints, is given in Section 
5.4. Change from baseline is calculated as on-treatment value minus the baseline value. Handling 
of time points is described in Section 5.5. 
4.2.4.1. 
Magnetic Resonance Imaging (MRI) 
In this study, the
 
 
 


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The MRI assessments will be conducted following the procedures outlined in the MRI manual, 
and must be performed on the same day of or within 7 days after the clinical visit. Therefore, the 
baseline MRI could be performed 7 days after the first administration of IP. The subsequent 
MRIs should be performed at Week 24 + 7 days and Week 48 + 7 days. All MRI visits should be 
scheduled well in advance to allow for proper planning. In addition, it is recommended to 
schedule 2 MRI visits (an initial and a repeat visit) for each MRI time point to ensure a high-
quality MRI scan at each protocol-specified time point. The initial and repeat MRI visits should 
be scheduled approximately 7 to 14 days apart. If the initial MRI scans are of acceptable quality, 
then the scheduled repeat MRI session can be canceled. Maximum two repeated MRI scans can be 
scheduled. All images will be read regardless of deviations in acquisition window. 
4.2.4.2. 
MRI of the Most Affected Hand 
The conventional MRI assessment will be performed at baseline, Week 24, Week 48 and ET 
visit on the hand with the greater inflammatory burden of swollen joints and/or dactylitis. If both 
hands are equally affected, the dominant hand will be designated as the index hand.  
4.2.4.3. 
PsAMRIS 
The Outcome Measures in Rheumatology Clinical Trial (OMERACT) Psoriatic Arthritis 
Magnetic Resonance Imaging Score (PsAMRIS) is a validated scoring system used to assess the 
images from the MRI of the most affected hand.  
OMERACT PsAMRIS assesses metacarpophalangeal (MCP), proximal interphalangeal (PIP), 
and distal interphalangeal (DIP) joints of fingers 2 to 5, and evaluates synovitis (score 0-3), 
flexor tenosynovitis (score 0-3), periarticular inflammation (absent or present), bone edema 
(score 0-3), bone erosion (score 0-10) and bone proliferation/enthesophytes (absent or present).  
All MRI readings are performed by two radiologists blinded to visit sequence and the patients. 
The adjudication of the results, when two readers are involved, will be done through the 
consensus procedure between the two readers. The readers will be able to share the screen and 
discuss the data, then amend the final scoring. The adjudication might involve the original 
reading and repeat reading. The adjudication score is considered as final assessment score and 
used for analysis. The intent of adjudication is to verify those cases that will have the greatest 
impact on results.  
For more detailed information on the specific procedures and the consistent acquisition of MRI 
images, please refer to the Imaging Charter. The handling of missing data in PsAMRIS will be 
discussed in Section 4.2.4.4. 
4.2.4.3.1. Synovitis  
Synovitis is to be scored 0-3 at MCP, PIP and DIP joints of fingers 2 to 5. Grading scale:  score 0 
is normal, while score 1–3 is mild, moderate, severe, respectively. A total of 12 joints in the most 
affected hand are evaluated, the maximum possible score is 36.  


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4.2.4.3.2. Flexor Tenosynovitis 
Flexor tenosynovitis is to be scored 0-3 at the same 12 joint regions as evaluated for synovitis. 
The maximal thickness of enhancing/bright signal tenosynovium is to be assessed as follows: 0: 
none; 1: < 1/2 tendon thickness; 2: ≥ 1/2 and < 1 tendon thickness; 3: ≥ 1 tendon thickness. Like 
the synovitis score in Section 4.2.4.3.1, the maximum possible score is 36. 
4.2.4.3.3. Periarticular Inflammation 
Periarticular inflammation is to be scored 0–1 separately at volar and dorsal aspects of the same 
12 joint regions as evaluated for synovitis and flexor tenosynovitis. Grading scale: 0: absent; 1: 
present. Thus, the maximum possible score is 24. 
4.2.4.3.4. BME score assessed by PsAMRIS 
Bone marrow edema score, the bone edema score from PsAMRIS, is assessed on a scale of 0-3, 
based on the proportion of bone with edema, compare to the “assessed bone volume”, judged on 
all available images; where 0: no edema; 1: 1–33% of bone oedema; 2: 34–66% of bone oedema; 
3: 67–100% of bone oedema (as per RAMRIS1). A total of 12 joint regions are evaluated, and as 
each joint has proximal and distal components, thus the maximum possible score is 72. 
4.2.4.3.5. Bone Erosion 
Bone erosion is assessed on a scale of 0-10, based on the proportion of eroded bone compared to 
the “assessed bone volume,” judged on all available images: 0: no erosion; 1: 1–10% of bone 
eroded; 2: 11–20%, etc. The “assessed bone volume” is from the articular surface (or its best 
estimated position if absent) to a depth of 1 cm (as per RAMRIS1).  A total of 12 joints in the 
most affected hand are evaluated and each joint has proximal and distal components; the 
maximum possible score is 240. 
4.2.4.3.6. Bone Proliferation 
Bone proliferation is to be scored 0–1 at MCP, PIP, and DIP joints of fingers 2 to 5. Grading 
scale: 0: absent; 1: present. Thus, the maximum possible score is 12. 
4.2.4.3.7. Inflammation Score of BME, Synovitis and Tenosynovitis 
To give each of the three symptoms equal weighting, the inflammation score of BME, synovitis 
and tenosynovitis is the 
 
The maximum possible score is 216. 
4.2.4.3.8. Composite Score of BME and Synovitis 
The composite score of BME and synovitis is the 
 like the 
inflammation score estimation in Section 4.2.4.3.7. The maximum possible score is 144. 
4.2.4.3.9. Total Inflammation Score    
The total inflammation score consists of BME, synovitis, tenosynovitis and periarticular 
inflammation. The total inflammation score is computed as 
 


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. The maximum possible score is 
288. 
4.2.4.3.10. Total Damage Score   
The total damage score consists of erosion score and bone proliferation score. To give these 2 
symptoms equal weights, the total damage score is 
 
 The maximum possible score is 480.  
4.2.4.3.11. Smallest Detectable Change (SDC)  
To maintain objectivity in the evaluation of imaging, two different readers will evaluate all time 
points for a given subject. All time points for a subject will be presented in arbitrary order. The 
reviewers will have no knowledge of the time point chronological sequence, subject identity.  
4.2.4.4. 
Handling of Missing Data in PsAMRIS 
4.2.4.4.1. Handling of Missing Individual Joint Evaluation in PsAMRIS 
PsAMRIS readings between the two readers will be adjudicated by the consensus method.  For 
more detailed information on the adjudication of MRI images, please refer to the Imaging 
Charter. Missing or unclassifiable readings for individual joint/location evaluations will be 
imputed by the following guideline:  
 
 


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4.2.4.4.2. Handling of Missing PsAMRIS Total Score Assessment 
If a subject does not have any results within the visit window (referred to Section 4.2.4.1), the 
PsAMRIS results for this subject will be considered as missing at the time point, no imputation is 
needed and the detailed statistical analysis will be described in section 6.1  
4.2.4.5. 
Whole Body-MRI (WB-MRI) 
Selected peripheral joints and entheses, 
 will be assessed 
by WB-MRI.  
For completed details on the reading, scoring, and review process, please refer details in the 
Imaging Charter. 
The parameters for WB-MRI are listed below: 
• 
SPARCC spine and sacroiliac joint indices 
• 
MRI inflammation indices of peripheral arthritis and enthesitis 
 
 
 


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Figure 4: Areas to be scored for the Peripheral Arthritis and 
Enthesitis.  


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 The range of total synovitis joints is 0-249, the range of total osteitis joints is 0-288, the range of 
total osteitis entheses is 0-102, and the range of total STI is 0-99. 


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4.2.4.8. 
Handling of Missing 
  
If a subject does not have any results within the visit window (referred to Section 4.2.4.1), the 
 results for this subject will be considered as missing at the time point, no imputation 
is needed and the detailed statistical analysis will be described in section 6.1. 
4.2.4.9. 
Tender and Swollen Joint Counts 
For tender and swollen joint counts, a joint assessment will be recorded as “Temporarily Not 
Assessable Due to IA Injection” (TNA-IA), “Permanently Not Assessable” (PNA), “Temporarily 
Not Assessable – Other” (TNA-O), “Tender Only”, “Swollen Only”, or “Tender and Swollen”. 
In this section, the term “assessed” refers to the joints that are “Tender Only”, “Swollen Only”, 
or “Tender and Swollen”. 
The approaches below used to handle joints at screening, baseline and post-baseline visits will be 
applied, unless otherwise specified. 
Table 3: TJC and SJC Handling method 
Visit 
Scenarios 
Handling method 
Screening Visit 
The joint is assessable  
Count it into the number of tender/swollen joints 
The joint is PNA 
Exclude it from joint count throughout the study 
The joint is TNA-IA or 
TNA-O 
Exclude it from joint count at screening visit 
Baseline Visit 
The joint is assessable  
Count it into the number of tender/swollen joints 
The joint is TNA-IA or 
PNA or TNA-O  
Exclude it from joint count throughout the study (both 
baseline and post-baseline visits) 
Post-Baseline 
Visit 
The joint is assessable at 
both baseline and post-
baseline visit 
Count it into the number of tender/swollen joints 
The joint is TNA-IA or 
PNA or TNA-O 
The last observed joint assessment (including baseline 
and post-baseline assessment) will be carried forward 
to this visit 
After applying these data handling rules, TJC will be calculated by adding the number of tender 
joints with outcomes of ‘Tender Only' or ‘Tender and Swollen’. SJC will be calculated by adding 


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the number of joints with outcomes of 'Swollen Only' or ‘Tender and Swollen’. TJC and SJC will 
be derived based on all the joints (76 joints for swellingness and 78 joints for tenderness). 
Data resource: Joint assessment is entered by evaluator via site pad provided by eRT. 
Swollen Joint Count/Tender Joint Count over 48 weeks based on all joints will be presented 
graphically. Proportion of Subjects with Swollen Joint Count/Tender Joint Count <=1 Over 48 
Weeks will be plotted. 
4.2.4.10. Subject’s Pain Numeric Rating Scale 
The pain Numeric Rating Scale (NRS) is the subject’s assessment of how much pain he/she had, 
on average, in the previous week in his/her joints due to Psoriatic Arthritis (PsA). The subject 
will be asked to mark the box with an X on a 0- to 10-unit NRS on which the left-hand box of 0 
represents “No Pain,” and the right-hand box of 10 represents “Pain As Bad As You Can 
Imagine”.  This value will be used as a numerical result. 
Data resource: Subject’s pain score is entered by patient via site pad provided by ERT. 
Patient’s assessment of pain over 48 weeks will be presented graphically. 
4.2.4.11. Patient’s Global Assessments of Disease Activity (PGA) 
The Patient’s (Subject’s) Global Assessments of Disease Activity is an assessment of how active 
a subject’s PsA was on average during the previous week. Subject will select a number from a 0- 
to 10-unit NRS on which the 0 represents “Very Well” and 10 represents “Very Poor”.   
Data resource: PGA is entered by patient via site pad provided by ERT. 
4.2.4.12. Evaluator’s Global Assessments of Disease Activity (EGA) 
The Evaluator’s Global Assessment (EGA) is an assessment of how active a subject’s arthritis 
today. Evaluator will select a number from a 0- to 10-unit NRS on which the 0 represents “No 
Arthritis Activity” and 10 represents “Extreme Active Arthritis”.   
Data resource: EGA is entered by evaluator via site pad provided by ERT. 
4.2.4.13. Clinical Disease Activity Index for Psoriatic Arthritis (c-DAPSA) Score 
The c-DAPSA is a measure of PsA disease activity, associated with functional and structural 
outcomes (Aletaha, 2017).  The c-DAPSA score is computed using the following formula: 
c-DAPSA = TJC68 + SJC66 + PGA + Pain, 
where the TJC68 is the 68-tender joint count (0-68), the SJC66 is the 66-swollen joint count (0-
66), PGA is the patient (subject) global assessment of disease activity (0-10 NRS), and Pain is 
the subject’s pain numeric rating scale (0-10 NRS).  
10 joints (CMC and DIP 2-5 joints on left and right side) will be excluded from TJC78 and 
SJC76. See Figure 5 for the schematic diagram. 


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Figure 5: Schematic diagram of 68 tenders and 66 swollen joint assessment
 
The c-DAPSA score ranges from 0 to 154, and it will be set to missing if any of the 4 
components is missing. A higher score indicates greater disease activity. Proposed cut off for c-
DAPSA are a score ≤ 4 for remission, a score > 4 and ≤ 13 for low disease activity, > 13 and 
≤ 27 for moderate disease activity and >27 for high disease activity. The proportion of subjects 
who achieve PSA remission, low disease activity, moderate disease activity and high disease 
activity will be summarized. 
c-DAPSA score over 48 weeks will be tabulated and presented graphically. 
4.2.4.14. Enthesitis 
Enthesitis or the inflammation of the sites where tendons or ligaments insert into the bone, is a 
prominent clinical manifestation in subjects with PsA. In this study, Spondyloarthritis Research 
Consortium of Canada (SPARCC) and Leeds Enthesitis Index (LEI) will be used to evaluate 
entheseal inflammation. The details about SPARCC and LEI are mentioned in Sections 
4.2.4.14.1 and 4.2.4.14.2. 
Pre-existing SPARCC enthesopathy is defined as subjects who have a baseline SPARCC score 
greater than 0. Pre-existing LEI enthesopathy is defined as subjects who have a baseline LEI 
score greater than 0. The subjects with baseline SPARCC enthesitis is defined as the subjects 
whose baseline SPARCC scores greater than 0. The subjects with baseline LEI enthesitis is 
defined as the subjects whose baseline LEI scores greater than 0Spondyloarthritis Research 
Consortium of Canada (SPARCC) 


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The SPARCC Enthesitis Index will be assessed through physical examination of the following 
sites: 
 Medial epicondyle (left/right [L/R]) 
 Lateral epicondyle (L/R) 
 Supraspinatus insertion into greater tuberosity of humerus (L/R) 
 Greater trochanter (L/R) 
 Quadriceps insertion into superior border of patella (L/R) 
 Patellar ligament insertion into inferior pole of patella or tibial tubercle (L/R) 
 Achilles tendon insertion into calcaneum (L/R) 
 Plantar fascia insertion into calcaneum (L/R) 
Tenderness on examination is recorded as either present (1) or absent (0) for each of the 16 sites, 
for an overall score range of 0–16. Higher count represents greater enthesitis burden. 
Similar to the tender and swollen joint assessments, the SPARCC assessment may be not done or 
the joints may be recorded as “Temporarily Not Assessable” or “Permanently Not Assessable”, 
thus the approaches of dealing with not done assessment and handling joints that are not 
assessable will be employed (see Section 4.2.4.9 for details). 
Data resource: SPARCC questionnaire is entered by evaluator via site pad provided by ERT.  
4.2.4.14.1. Leeds Enthesitis Index (LEI) 
The Leeds Enthesitis Index will be assessed through physical examination of the following sites. 
Tenderness (yes/no) will be assessed at 6 sites of tendon insertions (0-6) as depicted below:  
 Lateral epicondyle, left and right 
 Medial femoral condyle, left and right 
 Achilles tendon insertion, left and right 
Tenderness on physical examination is recorded as either present (1) or absent (0) for each of the 
6 sites, for an overall score range of 0 to 6. Higher count represents a greater enthesitis burden. 
Similar to the tender and swollen joint assessments, the LEI assessment may be not done, or the 
joints may be recorded as “Temporarily Not Assessable” or “Permanently Not Assessable”, thus 
the approaches of dealing with assessments that are not completed and handling of joints that are 
not assessable will be employed (see Section 4.2.4.9 for details). 
Data resource: LEI is entered by evaluator via site pad provided by ERT. 
LEI score over 48 weeks will be presented graphically. 
4.2.4.15. Dactylitis 
Dactylitis (“sausage digit”) is characterized by the swelling of the entire finger or toe. It will be 
assessed using the Leeds Dactylitis Index (LDI) (Helliwell, 2005). 


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4.2.4.15.1. Leeds Dactylitis Index (LDI)  
In this study, the dactylitis will be assessed by LDI, which is a function of finger circumference 
and tenderness (0 = No Tenderness, 1 = Tender, 2 = Tender and wince, 3 = Tender and 
withdraw).  
In addition, as part of the LDI, number of affected digits will be evaluated. Each digit on the 
hands and feet will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis 
score is the sum of the individual scores for each digit. 
The dactylitis score for individual affected finger or toe is defined as below. 
[(Circumference of involved digit/circumference of contralateral digit – 1) *100] *Tenderness 
Score. 
Preexisting dactylitis will be defined as subjects who have a baseline LDI score greater than 0 . 
A higher score indicates greater disease activity. 
Data resource: LDI is entered by evaluator via site pad provided by ERT. 
4.2.4.16.  Psoriatic Arthritis Disease Activity Score (PASDAS) 
The PASDAS is a weighted index comprised of assessments of joints, function, acute phase 
response, QoL, and patient and physician visual analogue scores (VAS) (Coates, 2014).  
Note: This study does not utilize VASs, but rather NRSs. The patient’s and physician’s global 
assessment of disease activity captured on a NRS will be multiplied by a factor of 10 to derive 
the VAS, used to calculate PASDAS. 
The calculation of the PASDAS will be performed programmatically using the formula below: 
PASDAS =[(0.18×√physician global VAS)+(0.159×√patient global 
VAS)−(0.253×√SF36−PCS)+(0.101×LN (SJC66 +1))+(0.048×LN (TJC68 +1))+(0.23×LN 
(Leeds enthesitis count+1))+(0.377 LN (dactylitis count+1))+(0.102× LN (CRP+1)+2)]*1.5. 
CRP = C-reactive protein; LN = natural logarithm; PCS = physical component summary scale of SF36; SF36 = 
Medical Outcomes Study Short Form-36; SJC = swollen joint count; TJC = tender joint count; VAS = visual 
analogue scale. All VAS scores are 0–100 mm. Swollen joint count is 66 joints, and tender joint count 68.  
Note: SJC66 and TJC68 will be used in the derivation of PASDAS, refer section 4.2.4.13. If one 
or more components are missing, then PASDAS is set to be missing. The score range of the 
PASDAS is 0–10, with worse disease activity represented by higher scores. Response criteria for 
the Psoriatic Arthritis Disease Activity Score (PASDAS) is detailed in Table 4. PASDAS Score 
Over 48 Weeks will be presented graphically.  
 
 


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Table 4: Response criteria for PASDAS 
 
 
 
Improvement 
Final PASDAS Score 
≥ 1.6 
< 1.6 BUT > 0.8 
≤0.8 
≤ 3.2 
1 
2 
3 
>3.2 but <5.4 
2 
2 
3 
≥ 5.4 
2 
3 
3 
1: good response; 2: moderate response; 3: poor response 
4.2.4.17. Health Assessment Questionnaire-Disability Index (HAQ-DI) Score 
The HAQ-DI is composed of 20 items in 8 categories (Dressing and Grooming, Arising, Eating, 
Walking, Hygiene, Reach, Grip, Activities). Each category has 2 or 3 items. For each item, there 
are 4 response options: without any difficulty, with some difficulty, with much difficulty, and 
unable to do (scored 0-3, respectively). The HAQ-DI score will be set to missing if a subject 
does not have values for at least 6 of the 8 categories.  
Computing the HAQ-DI Score will follow the 2 steps below: 
1. Find the highest score for each category. If use of aids/devices and/or help from another 
person are indicated, adjust the highest score for the associated category by increasing a 
lower score, which is between 0 and 2, to represent underlying disability more accurately. 
For example, if use of aids/devices and/or help from another person are indicated, adjust 
the highest score to 2 if the highest score is a 0 or a 1 If the highest score is 2 or 3, retain 
the value. 
2. Sum the highest scores from all categories answered and divide it by the number of 
categories answered (must be a minimum of 6) to obtain an HAQ-DI score of 0-3 
(3=worst functioning). 
Please note, only one score will be calculated per HAQ-DI assessment. 
If the “other” category is checked on the HAQ-DI assessment, then this is expected to be an aide 
not associated for any of the existing categories, thus this will be excluded from the HAQ-DI 
score calculation. 
Data resource: HAQ-DI is entered by the patient via site pad provided by ERT.  
Change from baseline in HAQ-DI score over 48 weeks will be presented graphically. 
4.2.4.18. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score 
The BASDAI consists of 6 questions to assess 5 major symptoms (fatigue, spinal pain, peripheral 
joint pain/swelling, areas of localized tenderness, and morning stiffness), with each answered on 
a 0- to 10-unit NRS. To give each of the 5 symptoms equal weighting, the mean of the two 


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scores relating to morning stiffness (questions 5 and 6) is taken. Each of the other 4 questions 
counts as 1 item by itself. The final BASDAI score is defined by calculating the mean of the 5 
items. The BASDAI score ranges from 0 to 10, with higher scores reflecting greater disease 
activity. In case any of the scores for questions 1-4 is missing, or the scores for both questions 5 
and 6 are missing, the BASDAI score will be set to missing. In case of a missing score for either 
question 5 or 6, the score for the other question answered will be used as the mean of questions 5 
and 6. 
Data resource: BASDAI is entered by patient via site pad provided by ERT. 
BASDAI score over 48 weeks will be presented graphically. 
4.2.4.19. Psoriatic Arthritis Impact of Disease 12-domain Questionnaire (PsAID-12) 
The PsAID consists of 12 physical and psychological domains and is based on 0- to 10-unit 
NRS. Each domain is rated as a number between 0 and 10. The final PsAID score is the sum of 
each domain with different weighting and divided by 20 as below.  
Final PsAID value =[ (PsAID1 (pain) NRS value (range 0-10) x 3)  
+ (PsAID2 (fatigue) NRS value (range 0-10) x 2)   
+ (PsAID3 (skin) NRS value (range 0-10) x 2)   
+ (PsAID4 (work and/or leisure activities) NRS value (range 0-10) x 2)   
+ (PsAID5 (function) NRS value (range 0-10) x 2)   
+ (PsAID6 (discomfort) NRS value (range 0-10) x 2)   
+ (PsAID7 (sleep) NRS value (range 0-10) x 2)   
+ (PsAID8 (coping) NRS value (range 0-10) x 1)   
+ (PsAID9 (anxiety) NRS value (range 0-10) x 1)  
+ (PsAID10 (embarrassment and/or shame) NRS value (range 0-10) ×1) 
+ (PsAID11 (social life) NRS value (range 0-10) x 1) 
+ (PsAID12 (depression) NRS value (range 0-10) x 1)]/20 
The final score has a range from 0 (best status) to 10 (worst status) with a cut-off of 4 (Gossec, 
2014). 
If one of the 12 domains composing the PsAID is missing, it will be imputed by the mean value 
of the 11 non-missing NRS scores. If two or more of the domains are missing, the final PsAID 
score will be considered as missing. 
Data resource: PsAID-12 is entered by patient via site pad provided by ERT. 
PsAID-12 score over 48 weeks will be presented graphically.  


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4.2.5. 
Derivations of Safety Endpoints 
Baseline definition for all safety endpoints is given in Section 5.4. Change from baseline is 
calculated as on-treatment value minus the baseline value. Handling of time points is described 
in Section 5.5. 
4.2.5.1. 
Treatment-Emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as any AE that begins or worsens on or 
after the date of the first dose of investigational product (IP) and no later than 28 days after the 


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last dose of IP for subjects who have completed the study or have discontinued early by the time 
of database cut. 
If the treatment-emergent status of an AE is unclear due to a missing/incomplete start date, it will 
always be considered treatment-emergent, unless shown otherwise by data. Date imputation rules 
for partially missing AE start dates are described in Appendix A1 1.1. 
4.2.5.2. 
Treatment-emergent Adverse Events Leading to Drug Withdrawal, Leading to 
Drug Interruption, and Leading to Death, and Drug-related Treatment-
emergent Adverse Events 
A TEAE leading to drug withdrawal is a TEAE for which the investigator indicates that the 
action taken with respect to IP is withdrawn permanently (action taken on AE eCRF is recorded 
as “DRUG WITHDRAWN”). A TEAE leading to drug interruption is a TEAE for which the 
investigator indicates that the action taken with respect to IP is drug interrupted. A TEAE leading 
to death is a TEAE for which the outcome is fatal. Relationship to IP is based on the 
investigator's causality judgment; that is, a drug-related AE is an AE indicated by the 
investigator to have a suspected relationship to IP. 
4.3. 
Sample Size and Power  
While no MRI data are available for apremilast, assumptions used for the sample size calculation 
are primarily derived from the literature (Glinatsi, 2015). With an approximate 20% dropout rate, 
a sample size of 120 is required to produce a two-sided 95% confidence interval, for the 
expected change from baseline in the composite score of BME, synovitis, and tenosynovitis, with 
a distance from the mean to the limit equal to 1.24, assuming the standard deviation is 6.2. 


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5. 
GENERAL STATISTISTICAL CONSIDERATIONS  
5.1. 
Reporting and Analysis Conventions 
Summary statistics for continuous variables include sample size (n), mean, standard deviation 
(SD), median, minimum, the 25th (Q1) and 75th (Q3) percentiles, and maximum. All mean and 
median values will be formatted to one more decimal place than the measured value. SD values 
will be formatted to two more decimal places than the measured value. Minimum and maximum 
values will be presented to the same number of decimal places as the measured value.  
Frequency summary for categorical variables includes number and percentage. All percentages 
will be rounded to one decimal place, unless presenting two decimal places is necessary when 
the percentages are very small. Number and percentage values will be presented as xx (xx.x%).  
All analysis and summary tables will have the population sample size for the treatment in the 
column heading. P-values (2 sided) will be presented with 4 decimal places. All laboratory data 
except for hs-CRP will be reported using standard international (SI) units; hs-CRP will be 
reported in mg/dL. 
Change from baseline will be calculated as (post-baseline minus baseline value).  
Percent (%) change from baseline will be calculated as (post-baseline minus baseline value) 
divided by (baseline value), then multiply by 100. If a baseline value is zero, the percent change 
from baseline value will be excluded from the summaries. 
Subject data listings will be provided to support the tables and graphs will be provided for 
selected parameters. 
5.2. 
Definition of Analysis Populations 
5.2.1. 
Full Analysis Set 
The Full Analysis Set (FAS) will be the primary population for efficacy analyses. The FAS will 
consist of all subjects who are enrolled in the study. Subjects who are enrolled but do not receive 
any dose of IP will be excluded from FAS. 
5.2.2. 
Modified Intent to Treat (mITT) 
The mITT will consist of all subjects who are in FAS, have baseline and at least one postbaseline 
of primary efficacy endpoint PsAMRIS. mITT might be the population for the sensitivity 
analysis for the primary efficacy endpoint if needed.  
5.2.3. 
Per-protocol Population 
The Per Protocol (PP) population will consist of all subjects who receive at least one dose of 
study medication and have no major protocol violations which might affect primary efficacy 
endpoint. The final determination of major protocol violation criteria will be made prior to the 
database lock and will be documented. 


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5.2.4. 
Safety Population 
The Safety population will consist of all subjects who received at least one dose of study 
medication. 
5.3. 
Analysis Periods 
In this study, the analysis periods are divided into open label treatment period and observational 
follow-up period below. 
 Open label treatment period – Week 0 to Week 48 
This period starts on the day after the first IP is dispensed (Visit 2/Week 0), and stops on 
either: (1) the completion date of treatment period collected in the eCRF; or (2) the early 
termination date of treatment period collected in the eCRF; or (3) the last known study 
date if the subject is lost to follow-up. 
 Observational follow-up period – 4 weeks 
Subjects who complete the study or early terminate from the study, will be followed up 
for 28 days after the Visit 7/Week 48 or Early Termination visit. The period starts at the 
end date of treatment period + 1 and stops on either (1) the completion date of follow-up 
period in eCRF; (2) the last known study date if the subject is lost to follow-up.  
For efficacy analysis, only the open-label treatment period will be used.  
For safety analysis, the open-label treatment period and observational follow-up period will be 
included into the data summary. 
5.4. 
Baseline Definitions 
For all MRI assessments (MRI of the most affected hand, WB-MRI, and 
), the 
baseline is defined as nominal baseline result from IAG. For other assessments related to 
efficacy endpoints and baseline disease characteristics, the baseline is defined as the last value 
measured on or before the day of the first dose of IP.  
For safety analyses, the baseline is defined as the last value measured on or before the day of the 
first dose of IP. 
5.5. 
Time Points 
Time points in all analyses are based on the visits/study weeks as recorded in the database. 
Appropriate dates (e.g., date of measurement or date of specimen collection) will first be used to 
ensure only data (including data from scheduled, unscheduled and discontinuation) measured or 
collected within the specific analysis period (Section 5.3) are included, and then the visits/study 
weeks as recorded in the database will be used to assign one value (possibly missing) to each 
time point at the subject level according to the following rules: 
Scheduled Visits 
 If the value at a scheduled visit is missing but a value is available at an associated 
unscheduled visit, the value from the associated unscheduled visit will be used for the 


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study week. If values from more than one associated unscheduled visit (e.g., Visits 8.01 
and 8.02) are available, then the one from the first associated unscheduled visit (e.g., 
Visit 8.01) will be used for the study week. 
 If the value at a scheduled visit is missing and there is no value available from an 
associated unscheduled visit, the value at the study week will be missing. 
 Please note that unscheduled visits are recorded to one general visit code. The visit 
numbering for unscheduled visits will be re-numbered based on the unscheduled visit 
date (and time) comparison to the schedule visit date (and time). If the unscheduled 
record falls in between two scheduled visits, the re-numbered value will be assigned. For 
example, if the unscheduled visit date is “on or after visit 1” AND “prior to visit 2”, then 
the re-numbered value will be 1.01. If there are multiple unscheduled visits in that 
interval, the unscheduled visit date (and time) will be used to ordered the re-number 
values like 1.01, 1.02, 1.03, so on. 
Early Termination Visit 
 A value from the early termination visit will be mapped to the next scheduled visit after 
the last visit the subject has completed. 
Unscheduled Visit 
 Please note that only vital signs, local lab data, central lab data and procedures MRI will 
have unscheduled visits and each unscheduled visit will be recorded to one specific visit 
code.  
Analysis Visit Window for Safety Data 
For safety analyses, all available values obtained between 2 planned visits including unscheduled 
measurements will be pooled to the analysis visit window according to the following definition: 
Table 2: Analysis visit window for Safety Data 
Visit Number 
Visit Name 
Target Day 
Analysis Window for Safety Data 
1 
Screening (1) 
<1 
<1 
2 
Baseline (2) 
1 
1 
3 
Week 8 (3) 
56 
[2, 84] 
4 
Week 16 (4) 
112 
[85, 140] 
5 
Week 24 (5) 
168 
[141, 210] 
6 
Week 36 (6) 
252 
[211, 294] 
7 
Week 48 (7) 
336 
[295, 350] 


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For multiple measurements in the same visit category, the value measured nearest to the target 
day will be assigned to the visit; if they are at the same distance to the target day, the latest one 
will be used. 
For the efficacy data, no analysis window will be mapped, and the nominal visit will be used.  
 


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6. 
STATISTICAL METHODOLOGY FOR EFFICACY 
The analyses of efficacy endpoints will be primarily based on the FAS. In addition, supportive 
analyses using the Per Protocol population and mITT might be conducted for the primary and the 
key secondary efficacy endpoints.  
6.1. 
Analysis of Primary Efficacy Endpoint 
The primary endpoint of the study is the change from baseline to Week 24 in the composite score 
of BME, synovitis, and tenosynovitis assessed by PsAMRIS.  
Descriptive statistics of the baseline, post-baseline, change from baseline and percent change 
from baseline values will also be presented by the scanner type and the combination of both 
scanner types for the FAS. 
The boxplots of change from baseline of primary efficacy endpoint over week 48 will be 
presented graphically. 
Sensitivity analyses 
The supportive/sensitivity analyses of the primary endpoint will be performed with the same 
analysis model based on PP population and mITT population.  
6.2. 
Analyses of Secondary Efficacy Endpoints 
The secondary efficacy endpoints are divided into binary and continuous endpoints. 
6.2.1. 
Analyses of Binary Secondary Endpoints 
The binary secondary endpoints list is presented below: 
 Proportion of subjects with baseline Leeds Enthesitis Index (LEI) whose LEI improves to 
0 at Week 24 and Week 48 


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 Proportion of subjects with baseline SPARCC whose SPARCC improves to 0 at Week 24 
and Week 48 
 Proportion of subjects with baseline dactylitis whose tender dactylitis count improves to 0 
at Week 24 and Week 48 
For these binary endpoints, the number and percentages of subjects will be summarized by 
baseline and post-baseline visits, and the two-sided 95% Clopper-Pearson confidence intervals 
will be provided for the proportion. In addition, the proportion will be presented graphically. The 
number of subjects with missing values at each visit will be provided in a separate category.  
6.2.2. 
Analyses of Continuous Secondary Endpoints 
Due to the impact from MRI scanner type, the statistical method for the continuous secondary 
endpoints assessed by all MRI assessments (MRI of the most affected hand, WB-MRI, and DCE-
MRI) will be different from other continuous secondary endpoints. 
6.2.2.1. 
Analyses of Continuous Secondary Endpoints Assessed by MRI 
The analyses of secondary endpoints assessed by all MRI assessments will be performed in a 
manner similar as the primary analysis for primary endpoint (refer to Section 6.1) due to the 
impact from scanner type and baseline score and time. 
 
 
6.2.2.2. 
Analyses of Other Continuous Secondary Endpoints 
Descriptive statistics (n, mean, SD, median, Q1, Q3, min, max) for observed values and changes 
from baseline (including percent changes from baseline, if needed) will be presented at specified 
time points among subjects who have both values at baseline and the time point of interest. In 
addition, two-sided 95% CIs based on normal distribution for mean changes (and percent 
changes from baseline) will be provided at each time point of interest. In addition, data will be 
reported based on the proportion of subjects above or below the smallest detectable changes 
(SDC). 
6.3. 
Analyses of Exploratory Efficacy Endpoints 
6.4. 
Subgroup Analysis 
To determine whether the treatment effect is consistent across various subgroups, the primary 
endpoint will be provided, where feasible, within each category of the following classification 
variables (subcategories under a specific category of a variable, where applicable, are indicated 
in brackets): 
Demographic subgroups 


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 Sex (male, female) 
 Age (< 65, ≥ 65 years) 
 Baseline weight (< 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥ 100 kg) 
 Baseline BMI (< 25, ≥ 25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40, ≥ 40 kg/m2) 
 Region (North America, Europe, Rest of the World [including Russia]) 
 Prior glucocorticosteroid use (yes, no) 
 Prior use of MTX (Yes/No) 
 Concomitant use of MTX (Yes/No)  
Baseline disease subgroups 
  Duration of PsA (≥3 months to ≤ 2, > 2 to ≤ 5 years) 
The consistency of the treatment effect across subgroups will be assessed in the context of the 
primary methods used for the analyses with the entire FAS.  
 
 


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7. 
INTERIM ANALYSIS 
No interim analysis will be conducted. 
At the end of the study, after all subjects have completed the treatment period or early 
terminated, the final analysis will be performed, and a final clinical study report will be 
generated. 


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8. 
Summary of Subject Disposition 
The number of subjects screened, the number and percentage of subjects, who complete 
screening, who do not complete screening, and who are screen failure among all subjects 
screened, and the eligibility criteria failed will be summarized. The above percentages will be 
based on the number of subjects screened.   
For this single-arm, open-label study, the number and percentage of subjects who enroll, receive 
at least one dose of IP, complete, and discontinue, and the number and percentage of primary 
reasons for discontinuation (except for the observational follow-up) will be summarized. The 
number and percentage of subjects who enter/complete the observational follow-up, will also be 
provided. The primary reasons for discontinuation are collected in the study disposition eCRF 
and will be summarized with the following categories: 
 Adverse event(s) 
 Lack of efficacy 
 Non-compliance with study drug 
 Withdrawal by subject 
 Study terminated by sponsor 
 Lost to follow-up 
 Pregnancy 
 Death 
 Protocol deviation 
 Other  
The number and percentage of subjects included in the FAS, mITT, PP, and safety populations 
will be summarized; the percentages will be based on the number of subjects enrolled. A listing 
of subjects excluded from the analysis populations, with the reasons for exclusions, will be 
provided. 
The number and percentage of subjects by region, country, and study site will be tabulated based 
on the FAS. 


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9. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively for the FAS. Each 
relevant characteristic will be assessed descriptively in table format; no statistical hypothesis 
tests will be performed on these characteristics.   
For summaries (number and percentage) of categorical variables in demographics, baseline 
disease characteristics, and alcohol and tobacco use, an “unknown” category may be added (in 
addition to the categories specified below) to account for missing data as appropriate. 
9.1. 
Demographics 
Summary statistics will be provided for the following continuous variables as appropriate: 
 Age (years) 
 Weight (kg) 
 Height (cm) 
 Body mass index (BMI; kg/m2) 
Number and percentage will be provided for the following categorical variables as appropriate: 
 Age category (< 65, ≥ 65 years; < 40, 40 to < 65, 65 to < 75, 75 to < 85, ≥ 85 years) 
 Sex (male, female) 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islanders, White, Other) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 Region (North America, Europe, Rest of the World [including Russia]) 
 Weight category (< 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥ 100 kg) 
 BMI category (< 25, 25 to < 30, 30 to < 35, 35 to < 40,  40 kg/m2) 
9.2. 
Baseline or Disease Characteristics 
Summary statistics will be provided for the following continuous variables as appropriate: 
 Duration of PsA (from the date of diagnosis to the date of informed consent; years) 
 Psoriasis body surface area (BSA; %) 
 Inflammation score of BME, synovitis, and tenosynovitis assessed by PsAMRIS 
 Composite score of BME and synovitis assessed by PsAMRIS 
 BME score assessed by PsAMRIS 
 Synovitis score assessed by PsAMRIS 


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 Tenosynovitis score assessed by PsAMRIS 
 Periarticular inflammation score assessed by PsAMRISTotal Inflammation score 
 Total damage score (bone erosion + bone proliferation) assessed by PsAMRIS 
 Bone erosion score assessed by PsAMRIS 
 Bone proliferation score assessed by PsAMRIS 
 Tender joint count 
 Swollen joint count 
 C-DAPSA score 
 SPARCC score 
 SPARCC score (for subjects with pre-existing enthesopathy) 
 LEI score 
 LEI score (for subjects with pre-existing enthesopathy) 
 LDI score 
 LDI score (for subjects with pre-existing dactylitis) 
 PASDAS score 
 Physician global assessment of disease activity (0-10 NRS) 
 Subject global assessment of disease activity (0-10 NRS) 
 Subject assessment of pain (0-10 NRS) 
 HAQ-DI score 
 Peripheral enthesitis inflammation index assessed by WB-MRI 
 Peripheral joints inflammation index assessed by WB-MRI 
 Total peripheral (joints and enthesitis) inflammation index assessed by WB-MRI 
 BASDAI score (for subjects deemed to have PsA spondylitis by the investigator and with 
BASDAI item 2 ≥ 4 at baseline) 
 PsAID-12 score 


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Number and percentage will be provided for the following categorical variables (subcategories 
under a specific category of a variable, where applicable, are indicated in square brackets) as 
appropriate: 
 Baseline use of methotrexate (MTX) (yes, no) 
 Psoriasis BSA ≥ 3% (yes, no) 
 Prior use of NSAIDs 
 Prior use of low-dose oral glucocorticoids (prednisone ≤ 10 mg/day or equivalent) 
 Prior use of narcotic analgesics (yes, no) 
 Rheumatoid factor (normal, high) 
 Pre-existing SPARCC enthesopathy (yes, no) 
 Pre-existing LEI enthesopathy (yes, no) 
 Pre-existing dactylitis (yes, no) 
 PsA spondylitis assessed by investigator (yes, no) 


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 BASDAI iterm 2 ≥ 4 (yes, no) 
 PsA spondylitis assessed by investigator and BASDAI iterm 2 ≥ 4 (yes, no) 
 Prior csDMARD usage (yes, no) 
 Prior biologic treatment (yes, no) 
 C-DAPSA (<=4, >4 to <=13, >13 to <=27, >27) 
 As based on the trial design (Section 4.1) and permitted concomitant medications and 
procedures from protocol, MTX (≤ 25 mg/week) will be permitted if treatment duration is 
≥ 6 months and on a stable regimen for at least 3 months prior to baseline. The NSAIDs, 
narcotic analgesics and low-dose oral glucocorticoids (prednisone ≤ 10 mg/day or 
equivalent) must be on a stable regimen for at least 4 weeks prior to baseline. Thus, 
baseline use of MTX is defined as MTX (≤ 25 mg/week) used as a stable regimen for at 
least 3 months before the first dose of IP. For the NSAIDs, narcotic analgesics and low-
dose oral glucocorticoids medications, the baseline use of these medications are defined 
as medications used as a stable regimen for at least 4 weeks before the first dose of IP. 
9.3. 
Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA; Version 21.0). A frequency summary (number and percentage) of medical history 
will be presented by system organ class (SOC), and preferred term (PT).  
9.4. 
Prior Medications  
Prior medications will be collected from prior and concomitant medications and history of 
psoriatic arthritis medications panels in the CRF pages. The prior medications are defined as 
medications that were taken before the first dose of IP. The Anatomical Therapeutic Chemical 
(ATC) coding scheme of the World Health Organization Drug Dictionary (WHODD; Version 
March 2018) will be used to group prior medications and history of psoriatic arthritis 
medications into relevant categories. Frequency summaries will be provided by ATC 2 level, and 
standardized medication name for the FAS population. 
9.5. 
Prior Procedures 
Prior procedures are defined as the procedures that occurred before the first dose of IP. The prior 
procedures will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
Version 21.0). Frequency summaries of prior procedures will be provided for the FAS 
population by SOC, and PT.    
 


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10. 
Study Treatments and Extent of Exposure 
Overall treatment duration will be summarized using descriptive statistics. Individual subject 
listings will be provided to support the tables. 
10.1. 
Treatment Duration 
Summary statistics for treatment duration (in weeks), as well as a frequency summary of 
treatment duration categories (e.g., < 8 weeks, ≥ 8 to < 16 weeks, etc.) will be summarized for 
FAS and safety population. A subject data listing of study drug exposure will be also provided. 
Treatment duration (in weeks) will be calculated as (the date of the last dose of IP - the date of 
first dose of IP +1)/7 and rounded to one decimal place. The specific definitions of the first and 
last dose dates are given below: 
 First dose date: the date of the first dose of IP at Visit 2/ Week 0. 
 Last dose date: 
o The date of last dose of IP captured at Visit 7/Week 48 or Early Termination 
Visit, whichever occurred first. 
o The date prior to Visit 7/Week 48, if the date of last dose of IP is unknown at 
Visit 7/Week 48 
o The date prior to Early Termination Visit, if the date of last dose of IP is unknown 
at Early Termination Visit 
o The last known study date if the subject is lost to follow-up 
Imputation rules for partially or completely missing last dose date is specified in Appendix A1 1. 
10.2. 
Treatment Compliance  
Treatment compliance (%) will be calculated for each subject based on the number of tablets 
dispended and the number of tablets returned at each visit (except Visit 1). Treatment 
compliance will be summarized. 
The treatment compliance (%) for each subject is calculated as below: 
(100* the total number of tablets taken)/ the intended total number of tablets that should have 
been taken over the same period 
Where the total number of tablets taken = the total number of tablets dispensed – the total 
number of tablets returned. The intended total number of tablets that should have been taken over 
the same period is [(last dose date in the period-first dose date in the period)+1]*2 – 1 since the 
patient only took one dose at study day 1.  
 
Please note that treatment compliance will not be calculated for subjects who have only the 
dispense record at Visit 2/Week 0 and no other drug accountability records. 


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Additionally, the number and percentage of subjects will be summarized by compliance categories 
(e.g., < 75%, ≥ 75% to ≤ 120%, and > 120%). A subject data listing of drug accountability records 
will be provided. 


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11. 
Protocol Deviations/Violations 
The protocol deviations or violations will be identified and assessed by clinical research 
physician (CRP) or designee throughout all study periods. A list of protocol deviations and 
important protocol deviations for all subjects for final analysis will be defined and finalized prior 
to the beginning of any data analyses or the final database lock, whichever occurred first. This 
listing will also identify which subjects are to be excluded from the per-protocol population.    
Protocol deviations and important protocol deviations will be summarized for all subjects and 
FAS population. Summary tables showing the number and percent of subjects with at least one 
protocol deviation and important protocol deviations and by each category of protocol deviations 
and important protocol deviations will be provided. Summary of protocol deviations related to 
COVID-19 control measures will be provided. Listings of subjects with protocol deviations and 
important protocol deviations will also be provided. 
 
 


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12. 
SAFETY ANALYSIS  
Safety will be evaluated via descriptive statistics and point estimates. Safety summaries will be 
provided based on all the subjects in the safety population . Individual subject listings will be 
provided to support the summary tables. 
For the analyses of AEs and marked abnormalities, the following point estimates are provided, 
unless otherwise specified: 
 Subject incidence: Subject incidence (i.e., percentage [%] used in a frequency summary) 
is defined as the number of subjects with the specific event divided by the number of 
subjects included in the analysis, multiplied by 100. Subjects with multiple occurrences 
of a specific event in a defined exposure interval will be counted only once in the 
numerator. 
 Exposure-adjusted incidence rate (EAIR) per 100 subject-years: The EAIR per 100 
subject-years is defined as 100 times the number of subjects with the specific event 
divided by the total exposure time (in years) among subjects included in the analysis. 
Subjects with multiple occurrences of the specific event in a defined exposure interval 
will be counted only once in the numerator. The exposure time for a subject without the 
specific event is the treatment duration, whereas the exposure time for a subject with the 
specific event is the treatment duration up to the start date (inclusive) of the first 
occurrence of the specific event. The total exposure time in years is calculated by 
dividing the sum of exposure time in days over all subjects included in the analysis by 
364. The EAIR per 100 subject-years is interpreted as the expected number of subjects 
with at least one occurrence of the specific event per 100 subject-years of exposure to the 
IP. 
In summaries of continuous variables with summary statistics by time point, values for baseline, 
time point, and change from baseline will be summarized at each time point for subjects who 
have values at both baseline and the specific post-baseline time point. Frequency summaries of 
shifts from baseline to post-baseline time points will be provided for subjects who have values at 
both baseline and each individual specific post-baseline time point. In addition to the scheduled 
visits, shift summaries will also be provided from baseline to the end of period and to the worst 
value in a specific post-baseline period. 
12.1. 
Adverse Events 
AEs will be coded according to the MedDRA Version 21.0. Unless otherwise specified, AEs will 
be summarized by SOC and PT, with SOCs presented in the standard international order and PTs 
within each SOC in descending order of subject incidence. 


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A subject data listing of all AEs (including TEAEs and non-TEAEs) will be provided. 
12.1.1. 
Overall Summary of Adverse Events 
An overall summary of the following AE categories will be provided: 
 Any TEAE 
 Any drug-related TEAE 
 Any severe TEAE  
 Any serious TEAE 
 Any serious drug-related TEAE 
 Any TEAE leading to drug interruption 
 Any TEAE leading to drug withdrawal 
 Any TEAE leading to death 
12.1.2. 
All TEAEs 
Summarization of all TEAEs by the following categories will be provided as appropriate: 
 Any TEAEs (by SOC and PT, and by PT only) 
 Any TEAEs by exposure interval (≤1, > 1 to ≤ 4, > 4 to ≤ 12, > 12) 
 Any TEAEs by age category (<65, ≥ 65 years) andgender 
 Any TEAEs by prior methotrexate use (Yes/No) 
 Any TEAE by concomitant methotrexate use (Yes/No) 
For the summary of any TEAEs by exposure interval, the AE data will be handled per the 
following rules, unless otherwise specified. 
 An event with a start date falling into an exposure interval is considered a new event for 
that interval.  
 Each subject is counted once for either subject incidence or EAIR for each applicable 
specific TEAE in each exposure interval where an event started.  
 The denominator of a subject incidence is the number of subjects with treatment duration 
exceeding the lower bound of the particular exposure interval, while the denominator of 
an EAIR is the sum of the exposure time during the exposure interval (up to the first 
event start date for subjects with at least one event starting in the interval) among the 
same number of subjects as in the denominator of the corresponding subject incidence. 


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Summarization of the TEAEs with the following specifications will be provided as appropriate: 
 Most frequent TEAEs (≥ 5%; by SOC and PT, and by PT only in descending order of 
subject incidence) 
 Most frequent TEAEs by onset interval and event duration (for special interest of PTs: 
Diarrhoea, Headache, Nasopharyngitis, Nausea, Hypertension, and Upper respiratory 
tract infection) 
 Any drug-related TEAEs (by SOC and PT) 
 Any drug-related TEAEs by exposure interval (refer to Section 12.1.2) 
 Any serious TEAEs (by SOC and PT) 
 Any serious TEAEs by exposure interval (refer to Section 12.1.2) 
 Any serious TEAEs by age category (<65, ≥ 65 years) and gender 
 Any serious drug-related TEAEs (by SOC and PT) 
 Any serious drug-related TEAEs by exposure interval (refer to Section 12.1.2) 
 TEAEs by maximum severity (by SOC and PT) 
 Any TEAEs leading to study drug withdrawal (by SOC and PT) 
 Any TEAEs leading to study drug withdrawal by age category (<65, ≥ 65 years) and 
gender 
 Any TEAEs leading to study drug withdrawal by prior use of psoriatic arthritis 
medications 
 Any TEAE leading to study drug withdrawal by concomitant use of psoriatic arthritis 
medications  
 Any TEAEs leading to study drug interruption (by SOC and PT) 
 Any TEAEs leading to death (by SOC and PT) 
For drug-related TEAEs, the relationship of an AE to IP is recorded on the Adverse Events - 
Serious Adverse Events eCRF page as “NOT SUSPECTED” and “SUSPECTED”. Adverse 
events with missing relationship to IP will be assessed as drug-related. 
For TEAEs by maximum severity, if a subject reports multiple occurrence of a specific event 
within a specific analysis period, the subject will be counted only once by the maximum severity 
(mild, moderate, severe, or, if needed, missing). If a subject reports multiple TEAEs within an 
SOC, the subject will be counted only once for that SOC at the maximum severity. If the severity 


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is missing for one or more of the occurrences/TEAEs, the maximum severity of the remaining 
occurrences will be used. If the severity is missing for all the occurrences/TEAEs, the subject 
will be counted only once in the “missing” category of severity.  
In addition, subject data listings for serious AEs (both TEAEs and non-TEAEs), TEAEs leading 
to drug withdrawal, and deaths will be provided. 
12.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) include diarrhea.  
Protocol defined diarrhea AEs, referring to events with 2 or more watery or liquid stools in a 
day, will be captured on the site pad by ERT. Duration and frequency of the individual diarrhea 
will be captured. The diarrheas reported on the site pad will need to be reconciled with the events 
captured on Medidata’s RaveX EDC platform. 
Frequencies (Daily, 5 – 6 days per week, 2 – 4 days per week, once every other week to once a 
week) of these events will be summarized.  
A listing of AESIs will be also provided. 
12.3. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be available from the central laboratory and include: 
 Hematology: complete blood count (CBC) (red blood cell [RBC] count, hemoglobin, 
hematocrit, white blood cell [WBC] count and differential, absolute WBC counts, platelet 
count).  
 Serum chemistries: total protein, albumin, calcium, phosphorous, glucose, triglycerides, 
total cholesterol [TC], total and direct bilirubin, alkaline phosphatase, AST, ALT], 
sodium, potassium, chloride, bicarbonate [carbon dioxide, CO2], blood urea nitrogen 
[BUN], creatinine, lactate dehydrogenase [LDH], and magnesium. 
 Urinalysis: specific gravity, pH, glucose, ketones, protein, blood, bilirubin, leukocyte 
esterase, nitrite, and urobilinogen; if urinalysis is abnormal, microscopic urinalysis 
(epithelial cells, RBC, WBC, and casts) will be performed.  
Summary statistics of observed values and changes from baseline in hematology and serum 
chemistry parameters will be provided over time. Frequency summaries (shift tables) of shifts 
from baseline to post-baseline time points and to the worst post-baseline value, in terms of 
low/normal/high/both low and high, will be provided for hematology and serum chemistry 
parameters. Subject data listings of all laboratory data, including urinalysis, will be provided.  
Summary of the categories of laboratory marked abnormalities will be provided based on the 
marked abnormalities criteria. Subject incidence and EAIR for each abnormality will be 
calculated based on subjects with a baseline value and at least one post-baseline value for criteria 


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requiring baseline or subjects with at least one post-baseline value for criteria not requiring 
baseline.  
A separate summary of laboratory marked abnormalities will also be presented by categories of 
subjects with normal values at baseline and subjects with abnormal values at baseline. To the 
purpose of these summaries, subjects with abnormal (normal) values at baseline are defined as 
those whose baseline value is low (not low) for criteria concerning low values and those whose 
baseline value is high (not high) for criteria concerning high values; both low and high are 
relative to the laboratory normal range.  
A subject data listing of laboratory marked abnormalities will be provided. In the listing, all 
recordings of a lab analyte will be displayed for the subject if that subject has one or more 
marked abnormalities for the test.  
For comorbid conditions of interest or a subgroup of subjects, summary statistics of relevant 
laboratory parameters over time may be provided. A subject listing will be also provided for all 
available pregnancy test results. 
12.4. 
Vital Sign Measurements and Weight 
For vital signs and weight, summary statistics (n, mean, standard deviation, median, minimum, 
the 25th (Q1) and 75th (Q3) percentiles, maximum, percent change from baseline for weight 
only) of observed and change from baseline values will be presented.  
For vital signs (excluding weight), Frequency summaries (shift tables) of shifts from baseline to 
post-baseline or worst post-baseline values (low/normal/high/both low and high) during the 
treatment in below, within and above the normal ranges will be displayed in cross–tabulations.  
For weight, change and percent change from baseline to the end of the study will be presented, as 
well as by baseline BMI and baseline weight categories. 
12.5. 
Physical Examination 
Physical examination findings will be captured as medical history (screening) or abnormal 
physical examination findings will be reported as adverse events and will be reported in those 
summaries. 
12.6. 
Concomitant Medications/Procedures 
Concomitant medications and procedures will be summarized for the safety population. Subject 
data listings for concomitant medications and procedures will be also provided.  
12.6.1. 
Concomitant Medications 
Concomitant medications are defined as medications that administered on or after the first dose 
of the IP or those started prior to the first dose of the IP but stopped on or after the date of the 
first dose of IP, or recorded as ongoing. The Anatomical Therapeutical Chemical (ATC) coding 
scheme of the World Health Organization Drug Dictionary (WHODD; Version March 2018) will 


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be used to group medications into relevant categories. A frequency summary of concomitant 
medications will be provided by ATC2 level and standardized medication name. 
12.6.2. 
Concomitant Procedures 
Concomitant procedures are defined as procedures that were done on or after the first dose of the 
IP or those started prior to the first dose of the IP but stopped on or after the date of the first dose 
of IP, or recorded as ongoing. Concomitant procedures will be coded according to MedDRA 
Version 21.0. A frequency summary of concomitant procedures will be provided by SOC and 
preferred term. 
 
 
 
 


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13. 
REFERENCES 
Aletaha D, Alasti F, Smolen JS. Disease activity states of the DAPSA, a psoriatic arthritis 
specific instrument, are valid against functional status and structural progression. Ann Rheum 
Dis. 2017;76(2):418-21. 
Glinatsi D, Bird P, Gandjbakhch F, Mease PJ, Boyesen P, Peterfy CG, et al. Validation of the 
OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) for the hand and 
foot in a randomized placebo-controlled trial. J Rheumatol. 2015;42(12):2473-9. 
 
 


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APPENDIX A1  
Following are the general conventions for various computations and imputations for references. 
Users may need to consult with study team for specific study practices or regulatory guidelines. 
1. Guideline of Partially Missing Date Imputation 
1.1 Adverse Events 
The principle of the imputation rules for subjects who were treated with apremilast initially is to 
treat the AE as treatment-emergent, i.e., occurring on or after the date of the first dose of IP, if 
possible.  
Partially missing AE start date will be imputed in the ADaM dataset for AEs, but partially 
missing AE end dates will not be imputed in the same dataset. If the AE end date is complete 
with no missing year, month, or day, and the partially missing start date imputed by the rules 
below is after the AE end date, then the start date will be imputed by the AE end date. 
The following scenarios are considered in the imputation rules: 
 If AE start day is missing, and AE start month and year are not missing:  
o If AE start year and month are the same as the year and month of first dose, then 
impute AE start day using the day of first dose date.  
o If AE start date is less than the first dose date, then impute AE start day using the 
last day of AE start month. 
o If AE start date is greater than the first dose date, then impute AE start day using 
the first day of AE start month. 
 If both AE start month and day are missing, and AE start year is not missing: 
o If AE start year is less than the year of first dose, then impute AE start date using 
the last day of the AE start year. 
o If AE start year is equal to the year of first dose, then impute AE start date using 
the first dose date. 
o If AE start year is greater than the year of first dose, then impute AE start date 
using the first day of the AE start year.  
1.2 Prior/Concomitant Medications and Procedures 
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset for 
prior/concomitant medications/procedures.  
For prior/concomitant medications, if the stop date is complete with no missing year, month, or 
day, and the partially missing start date imputed by the rule below is after the stop date, then the 
start date will be imputed by the stop date. 


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Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date. 
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date. 
1.3 Medical History 
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history (for the purposes of calculating durations of PsA and psoriasis). The 16th of the month 
will be used to impute a partially missing start date that has only the day missing, and July 1st 
will be used to impute a partially missing start date that has both the month and day missing. 
 
1.4 Treatment Duration 
Partially or completely missing last dose dates will be imputed in the ADaM dataset for 
treatment duration. When partially missing last dose date is available, set last dose date to the 
maximum of [the earliest possible date given the non-missing field(s) of last dose date, the 
minimum of (the latest possible date given the non-missing field(s) of last dose date, last known 
date in database, first non-missing Early Termination (ET) visit date)] When last dose date is 
completely missing, set last dose date to the minimum of (last known date in database, first non-
missing Early Termination (ET) visit date) Last known date in database is defined as maximum 
of (last visit date, lab, vital signs, AE start or end dates, concomitant medications start or end 
dates, concomitant procedure date, last dose date from 'Disposition- Treatment' page, treatment 
exposure start date or end date where doses were completely or partially taken, death date). 
 
 


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2. Marked Abnormalities Criteria 
Table 8: Marked Abnormalities Criteria 
Category / Analyte 
SI Units   Criteria  
Chemistry/ 
ALT/AST 
U/L 
3*ULN 
   Alanine Aminotransferase (SGPT) 
U/L 
3*ULN  
 
   Albumin 
kg/m3 
<25 
   Alkaline Phosphatase 
U/L 
> 400 
   Aspartate Aminotransferase   
   (SGOT) 
U/L 
3*ULN 
   Bilirubin 
µmol/L 
> 1.8xULN  
Bilirubin and  
ALT/AST 
 
umol/L 
U/L 
(ALT or AST > 3xULN) and 
bilirubin > 2xULN 
   Blood Urea Nitrogen 
mmol/L 
>15 
   Calcium  
 
mmol/L 
1. < 1.8 
2. > 3.0 
   Cholesterol 
mmol/L 
> 7.8 
   Creatinine  
µmol/L  
> 1.7*ULN 
   Glucose 
mmol/L 
1. < 2.8 
2. > 13.9 
 
 
 
   Lactate Dehydrogenase 
U/L 
> 3*ULN 
   Magnesium 
mmol/L 
> 1.2 
 
   Phosphate 
mmol/L 
1. < 0.64 
2. >1.6 
   Potassium 
mmol/L 
1. < 3.0 
2. > 5.5 
   Sodium 
mmol/L 
1. < 130 
2. > 150 
   Urate 
umol/L 
Male: > 590; Female: > 480 
Hematology/ 
   Basophils  
10^9/L 
> 3 
   Eosinophils 
10^9/L 
1. > 0.8 
2. Increase ≥ 100% and value > 0.8 


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Category / Analyte 
SI Units   Criteria  
   Hematocrit 
Ratio 
1. < 0.27 
2. Male: > 0.55; Female: > 0.50 
   Hemoglobin 
g/dL 
1. Male: < 10.5 or Female < 8.5 
2. Male: > 18.5 or Female > 17 
   Hemoglobin A1C 
% 
> 9 
   Leukocytes 
10^9/L  
< 1.5 
   Lymphocytes 
10^9/L 
< 0.8 
   Neutrophils 
10^9/L 
< 1 
 
   Platelets 
10^9/L 
1. < 75 
2. > 600 
ULN = upper limit of normal  


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