Conditions: Arthritis, Psoriatic
Keywords: Oligoarthritis PsA Apremilast Oral tablet Background therapy Standard of care
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 310
Healthy volunteers: no

Brief summary:
This clinical study will test the effects of a drug called apremilast in oligoarticular psoriatic arthritis with less than 5 years of disease duration. In previous studies, apremilast has been shown to be safe and efficacious in reducing signs and symptoms of psoriatic arthritis, as well as improving physical function. This study will compare the effects of apremilast to placebo on psoriatic arthritis subjects in which the number of affected joints is limited (greater than 1 but less or equal to 4). About 285 patients worldwide will take part in this study.

Detailed description:

Arms:
arm 1: Subjects will take ORAL tables of apremilast for up to 48 weeks (30 mg twice daily). Subjects may also receive stable doses of background therapy (standard or care) with NSAIDs, glucorticosteroids and 1 csDMARD as permitted by protocol. After wk. 24, subjects may change the dose /type of permitted Psoriatic Arthritis medications arm 2: Subjects will take placebo for up to 24 weeks (twice daily). Subjects may also receive stable doses of background therapy ( standard of care) with NSAIDs, glucocorticosteroids and 1 csDMARD as permitted by protocol. After wk 24, subjects may change the dose /type of permitted PsA medications.

Interventions: intervention 1: Apremilast (CC-10004) intervention 2: Apremilast (CC-10004) Placebo
Intervention descriptions: intervention 1: Subjects randomized to apremilast will receive dose-titration for the initial 5 days. Apremilast subjects will receive "dummy" titration at wk. 16 (for early escape subjects) and again at week 24 to maintain the blinding of the original treatment assignments. Investigational product (IP) will be dispensed in blinded dose cards until Week 28. Thereafter, IP will be dispensed in open-label bottles. intervention 2: Subjects randomized to placebo will receive "dummy" dose-titration for the initial 5 days. Placebo subjects who meet the criteria for early escape at wk. 16 may receive apremilast beginning at wk. 16 and will receive active titration. Remaining placebo subjects will receive active dose titration at week 24. Beginning at wk 24 all subjects will be dispensed active apremilast. Investigational product will be dispensed in blinded dose cards until Week 28. to maintain the blinding of the original treatment assignments. Thereafter, IP will be dispensed in open-label bottles

Protocol document:
Prot_000.pdf: 
Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
1 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
TITLE PAGE 
A PHASE 4, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF APREMILAST (CC-10004) 
IN SUBJECTS WITH EARLY, OLIGOARTICULAR 
PSORIATIC ARTHRITIS DESPITE INITIAL STABLE 
TREATMENT WITH EITHER NSAIDS AND/OR  1 
CONVENTIONAL SYNTHETIC DMARD 
 
PROTOCOL NUMBER: 
 
CC-10004-PSA-013 
DATE FINAL: 
 
09 JUL 2018  
AMENDMENT 1 DATE FINAL: 
 
05 FEB 2019 
AMENDMENT 2 DATE FINAL: 
 
17 MAY 2019 
AMENDMENT 3 DATE FINAL 
 
04 MAY 2020 
AMENDMENT 4 DATE FINAL 
 
03 FEB 2021 
AMENDMENT 5 DATE FINAL 
 
12 JUL 2021 
EudraCT NUMBER: 
 
2018-002735-26 
IND NUMBER: 
 
101761 
NCT NUMBER 
 
NCT03747939 
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 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
2 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
 
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)  
 
 
 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Signature of Site Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Site Principal Investigator 
Institution Name:____________________________________ 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
3 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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. 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
4 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
PROTOCOL SUMMARY 
Study Title 
A phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of apremilast (CC-10004) in subjects with early, oligoarticular 
psoriatic arthritis despite initial stable treatment with either non-steroidal anti-inflammatory 
drugs (NSAIDs) and/or 1 conventional synthetic disease-modifying antirheumatic 
drugs (DMARD). 
Indication 
Psoriatic arthritis (PsA) is a heterogeneous inflammatory rheumatologic disorder characterized 
by inflammatory 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 up to 
50 of patients with PsA. In addition, PsA is associated with enthesitis and dactylitis, which are 
common to SpA. Finally, the majority of patients with PsA are negative for rheumatoid factor 
(RF) (Gladman, 2005; Kruithof, 2005; Roberts, 1976). 
Asymmetrical oligoarthritis sometimes involving distal interphalangeal (DIP) joints, is a frequent 
form of PsA (Ritchlin, 2017). Despite this, very little is known with respect to the burden of 
disease and the appropriate management of patients with asymmetrical oligoarthritis. Indeed, 
there is a paucity of data on the treatment of patients with oligoarthritis since published clinical 
trials focus on polyarticular forms of the disease. Likewise, treatment recommendations tend to 
also focus on polyarticular forms (Gossec, 2016). Knowledge regarding the efficacy of drugs in 
oligoarticular forms would be of great value to clinicians. 
Standard classification criteria of ‘oligoarticular PsA’ for use in clinical studies remain to be 
established. In recent studies, patients with  4 active joint counts (tender and/or swollen) at 
baseline were classified as oligoarticular (Coates, 2013; Helliwell, 2007; Jones, 1994; Kane, 
2003). Using this definition, the proportion of subjects with oligoarthritis appears to range from 
14 to 63, the higher values being observed in patients with shorter disease duration. It is 
believed that the evolution of the disease, from oligoarthritis to polyarthritis, accounts for the 
lower proportion of patients with oligoarthritis in populations with longer disease duration. 
Indeed, results from the long-term follow-up of PsA cohorts, including subjects with short 
articular symptoms duration ( 24 months), showed that about two third of subjects presenting 
with an oligoarthritic disease at baseline evolved into the polyarticular sub-type over time 
(Jones, 1994). In addition, treatments with conventional synthetic DMARDs (csDMARDs) were 
associated with the reclassification of subjects, from polyarthritic at the initial clinical 
presentation into oligoarthritic at follow-up (Kane, 2003). Such oligoarticular patients may be 
associated with residual joints that are less responsive to treatment when compared to patients 
with recent onset of oligoarthritis. Taken together, these observations suggest that patients with 
oligoarticular form of PsA but with long standing disease duration and previous response to 
anti-rheumatic treatments may be less sensitive to further improvement after additional therapies 
than earlier populations who are mainly csDMARDs-naive. Therefore, the current study will 
enroll subjects with short disease duration and limited exposure to prior NSAIDs and/or 
csDMARDs. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
5 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 (cAMP) 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 TNF-, IL-17, IL-23, IL-6, IL-8, MIP-1, and 
MCP-1, as well as increases in anti-inflammatory mediators, including IL-10 and the IL-1 
receptor antagonist. It is believed, therefore, that apremilast exerts its therapeutic benefits 
through the modulation of multiple inflammatory pathways (Schafer, 2015).   
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.  
Apremilast has been shown to be safe and efficacious in reducing signs and symptoms of PsA, as 
well as improving physical function (Cutolo, 2016; Edwards, 2016; Kavanaugh, 2014; Nash, 
2018). Like most agents, the clinical development program of apremilast was restricted to 
subjects with  3 swollen and  3 tender joints at baseline. This allowed for a limited proportion 
of subjects with asymmetric oligoarthritis at study entry. Consequently, the safety and efficacy of 
apremilast in patients with oligoarthritis remains to be further investigated.  
The current study is designed to evaluate the benefit:risk profile of apremilast in subjects with an 
early diagnosis of PsA ( 5 years since signs and symptoms began), presenting with 
oligoarthritis, despite initial stable treatments with either NSAIDs and/or  1  csDMARD 
(methotrexate [MTX] or sulfasalazine [SSZ]). 
Objectives 
Primary Objective 
 To evaluate the efficacy of apremilast 30 mg BID  NSAIDs and/or csDMARDs vs. 
Placebo  NSAIDs and/or csDMARDs in subjects with early oligoarticular PsA, 
assessed by modified MDA (MDA-Joints). 
Secondary Objectives  
 To evaluate the impact of treatment with apremilast 30 mg BID  NSAIDs and/or 
csDMARDs vs. Placebo  NSAIDs and/or csDMARDs on disease activity in subjects 
with early oligoarticular PsA, 
 To evaluate the impact of apremilast 30 mg BID  NSAIDs and/or csDMARDs vs. 
Placebo  NSAIDs and/or csDMARDs on patient reported outcomes (PROs) in 
subjects with early oligoarticular PsA, 
 To evaluate the safety and tolerability of apremilast 30 mg BID  NSAIDs and/or 
csDMARDs vs. Placebo  NSAIDs and/or csDMARDs in subjects with early 
oligoarticular PsA. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
6 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Exploratory Objectives 
Study Design 
This is a Phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy, safety and tolerability of apremilast (CC-10004) in subjects with 
early ( 5 years since signs and symptoms began) oligoarticular PsA (according to 
Classification Criteria for Psoriatic Arthritis [CASPAR] criteria), despite treatment with 
either NSAIDs and/or  2 csDMARD. Approximately 285 subjects will be randomized (2:1) to 
apremilast 30 mg BID or placebo. Treatment assignment will be stratified via an Interactive Web 
Response System (IWRS) based on concomitant use of glucocorticosteroids at baseline (yes/no) 
and prior/concomitant use of a csDMARD, either MTX or SSZ, (ie, csDMARD-naïve; 
csDMARD use prior to baseline [treatment not continued]; or csDMARD use prior to and 
concomitant at baseline). The number of subjects who are csDMARD-naïve is targeted to 
comprise up to 50  of the subjects enrolled in the study. Given that this is a phase 4 study, all 
subjects are required to meet the existing apremilast regulatory labeling conditions specific to the 
countries where enrollment will take place (eg, Food and Drug Administration [FDA], European 
Medicines Agency [EMA], Health Canada). There is no planned protocol extension following 
the end of the study.  
Subjects will be enrolled in this study if they received  2 prior csDMARD for the treatment of 
PsA. All subjects will be permitted to take NSAIDs and/or low-dose oral glucocorticosteroids 
(prednisone  10 mg/day or equivalent) throughout the study. The NSAIDs and low-dose oral 
glucocorticosteroids must be administered as a stable regimen for at least 2 weeks and 4 weeks 
prior to the Baseline Visit, respectively. A maximum of 1 concomitant use of csDMARD will be 
permitted if the subject is on a stable regimen for at least 3 months prior to the Baseline Visit. 
Stable doses of glucocorticosteroids, NSAIDs, and a csDMARD must be continued from the 
Baseline Visit through the Week 24 Visit. During this phase of the study, any change in dose, 
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 glucocorticosteroids, NSAIDs, or 
csDMARDs may be adjusted as clinically required.  
Subjects with prior exposure to biologic DMARD (bDMARD) and/or JAK-inhibitors will not be 
allowed in the study.  
This is a 56-week study. Subjects will have up to 4 weeks in the Screening Phase, followed by 
24 weeks in the Double-blind, Placebo-controlled Treatment Phase, which provides an 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
7 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
opportunity for “early escape” at Week 16. At the Week 24 Visit, subjects will be offered to 
enter the Active-treatment Extension Phase. All subjects enrolled in the Extension Phase will 
receive treatment with apremilast (30 mg BID) until the end of the study (ie, up to the Week 48 
Visit) or until early discontinuation.  
Beginning at the Week 28 Visit, all subjects in the Extension Phase will be dispensed open-label 
apremilast (30 mg BID) in high-density polyethylene (HDPE) bottles. The original treatment 
assignments (apremilast 30 mg BID or placebo) will remain blinded until the end of the study 
(Section 3.1). Subjects may also discontinue at any time during the study. 
The study will consist of 4 phases: 
 Screening Phase – up to 4 weeks 
 Randomized, Double-blind, Placebo-controlled Treatment Phase – Weeks 0 to 24. 
Henceforth, this will be referred to as the Placebo-controlled Phase.  
– Subjects will be randomly assigned in a 2:1 ratio to either apremilast 30 mg BID 
or placebo.  Subjects randomized to apremilast will be dose-titrated in a blinded 
fashion.  
– Dose titration is described in Study Treatments, Section 7.2 and Section 7.3. 
– Early Escape: Subjects with no improvement in SJC (sentinel joints) at Week 16 
are eligible for early escape, at the discretion of the Investigator and will receive 
apremilast 30 mg BID. The joints monitored for early escape must be the 
“sentinel joints” (ie, the joints affected at baseline).   
– Placebo-treated subjects who escape early will be transitioned to apremilast 30 
mg BID in a blinded fashion via an Interactive Web Response System (IWRS), 
while apremilast-treated subjects will remain on their original treatment 
assignment. Placebo-treated subjects will be dose-titrated in a blinded fashion. 
– All subjects who complete this 24-week treatment phase will have the option to 
enter the Active-treatment Extension Phase.  
 Active-treatment Extension Phase – Week 24 to Week 48. Henceforth, this will be 
referred to as the Extension Phase.  
– All subjects will receive apremilast 30 mg BID until the completion of the study 
(ie, up to the Week 48 Visit). The remaining placebo-treated subjects will be 
dose-titrated in a blinded fashion. 
– Beginning at the Week 28 Visit, all subjects in the Extension Phase will be 
dispensed open-label apremilast (30 mg BID) as described in Study Treatments 
and Section 7.3. 
 Post-treatment Observational Follow-up Phase – up to 4 weeks. Henceforth this will 
be referred to as the Observational Follow-up Phase. 
– All subjects who complete the Placebo-controlled Phase, the Extension Phase or 
prematurely discontinued from the study will participate in the 4-week 
Observational Follow-up Phase.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
8 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
– The Observational Follow-up Visit should be performed 4 weeks after the last 
dose of investigational product (IP) ( 7 days). 
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) Good Clinical Practice (GCP). 
Study Population 
The study population will consist of male or female subjects,  18 years of age at the time of 
signing the informed consent form (ICF), with early ( 5 years since signs and symptoms 
began) oligoarthritis ( 1 swollen joint [SJ] but  4 SJs, and  1 tender joint [TJ] but  4 TJs at 
the Screening Visit and confirmed prior to randomization at the Baseline Visit), despite prior 
treatment with either NSAIDs (stable  2 weeks prior to the Baseline Visit) and/or  2 
csDMARD (stable regimen for  3 months prior to the Baseline Visit) for the treatment of PsA. 
See Inclusion Criteria, Section 4.2 and Permitted Concomitant Medications, Section 8.1 for 
details describing allowed PsA medications and dosing regimens. At Screening, subjects must 
have a documented diagnosis of PsA, based on the CASPAR, with a disease duration since 
diagnosis  3 months and  5 years. Subjects with prior exposure to biologic DMARD 
(bDMARD) and/or JAK-inhibitors will not be allowed in the study. 
No adjustment to NSAIDs or csDMARD dosing regimens will be allowed until Week 24. 
Between Week 24 and Week 48, dosing of concomitant medications may be adjusted as 
clinically required. The complete list of Inclusion and Exclusion criteria can be found in 
Section 4.2 and Section 4.3, respectively. Additional allowed PsA medications (including 
glucocorticosteroids, MTX and SSZ) and dosing regimens are described in Section 8.1. 
Length of Study  
Subjects will spend up to a total of 56 weeks in this study, up to 28 days (approximately, 
4 weeks) in the Screening Phase, 24 weeks in the Placebo-controlled Phase, 24 weeks in the 
Extension 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 
Eligible subjects will enter the Placebo-controlled Phase at the Baseline Visit. Subjects will be 
assigned randomly to apremilast 30 mg twice daily (BID) or placebo BID. Subjects are to take 
investigational product (IP), as designated in the treatment card, twice daily (morning and 
evening, approximately 12 hours apart, with or without food). 
With the aim to mitigate potential dose-related side effects associated with apremilast, such as 
headache and gastrointestinal (GI) disturbances, apremilast-treated subjects will be dose-titrated 
from 10 mg BID to 20 mg BID to 30 mg BID over the first 5 days of treatment (Table 14). 
Subjects assigned to placebo will receive 10-, 20-, and 30-mg placebo tablets in blister cards 
(treatment cards) which are identical in appearance to the corresponding strength apremilast 
tablets. Apremilast will be provided in blister cards as either 10 mg, 20 mg or 30 mg tablets. The 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
9 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
5-day titration period will also be initiated for the placebo arm after the following visits: the 
Baseline, Week 16 (early escape), and Week 24. The original treatment assignments (apremilast 
30 mg BID or placebo) will remain blinded throughout the study. 
At the Week 16 Visit, subjects with no improvement in SJC (sentinel joints) at Week 16 are 
eligible for early escape, at the discretion of the Investigator and will receive early escape 
treatment with apremilast 30 mg BID. The joints monitored for early escape must correspond to 
those affected at the Baseline Visit (sentinel joints). Refer to Section 4.2; Inclusion 6. Subjects 
will receive the following treatment: 
o Subjects who were randomized to apremilast (30 mg BID) at the Baseline Visit will 
continue to take apremilast 30 mg BID. 
o Subjects who were randomized to placebo at the Baseline Visit will be switched to 
receive apremilast (30 mg BID) and will be dose-titrated as described above.   
After the Week 24 Visit, subjects will be offered to enter the Active treatment Extension Phase. 
All subjects enrolled in the Extension Phase will receive treatment with apremilast (30 mg BID) 
until the end of the study (ie, up to the Week 48 Visit) or until early discontinuation. Placebo 
subjects will be dose titrated. All subjects will receive treatment cards of identical appearance to 
maintain the blinding of the original treatment assignments (apremilast 30 mg BID or placebo). 
Beginning at the Week 28 Visit, after placebo-treated subjects have completed the blinded 
titration period, all subjects in the Extension Phase will be dispensed open-label apremilast (BID) 
in high-density polyethylene (HDPE) bottles. Subjects must be clearly instructed to follow 
dosing instructions. The original treatment assignments (apremilast 30 mg BID or placebo) will 
remain blinded until the end of the study (Section 3.1). Subjects may also discontinue at any time 
during the study. 
Overview of Key Efficacy Assessments 
The following will be used for assessing efficacy: 
 Modified Minimal Disease Activity (MDA-Joints) 
➢ Based on achieving 1 swollen joint count (SJC) and  1 tender joint count (TJC; 
66/68 SJ/TJ counts), plus 3 out of 5 of the following cut-off values: Body Surface 
Area (BSA)  3, Patient pain assessment (Visual analog scale [VAS])  15, 
Patient global assessment of disease activity (VAS)  20, HAQ  0.5, Tender 
entheseal points  1 (Based on the Leeds Enthesitis Index - LEI).  
 Swollen and Tender Joint Counts 
 Evaluator’s (Physician’s) Global Assessments of Disease Activity on VAS scale 
 Patient’s (Subject’s) Global Assessments of Disease Activity on VAS  
 Patient’s (Subject’s) Pain Assessment on VAS  
 Health Assessment Questionnaire – Disability Index (HAQ-DI)  
 The Leeds Enthesitis Index (LEI) 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
10 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
 
 Number of digits affected by dactylitis 
 Clinical Disease Activity in Psoriatic Arthritis (cDAPSA) remission score 
(cDAPSA4) or low disease activity score (4cDAPSA13). cDAPSA calculation 
based on SJC, TJC (66/68 SJ/TJ counts), Patient pain assessment (VAS) and Patient 
global assessment of disease activity (VAS).  
 Measure of Very Low Disease Activity (VLDA) defined as achieving 1 SJC and 1 
TJC (66/68 SJ/TJ counts), plus all 5 of the following cut-off values: BSA  3, 
Patient pain assessment (VAS)  15, Patient global assessment of disease activity 
(VAS)  20, HAQ  0.5, Tender entheseal points  1 (based on the Leeds Enthesitis 
index - LEI) 
 Psoriatic Arthritis Disease Activity Score (PASDAS) to assess good or moderate 
response.  
 Plaque psoriasis assessment by Body Surface Area (BSA) 
Overview of Patients’ Reported Outcomes  
The following will be used for assessing health-related quality of life: 
 Psoriatic Arthritis Impact of Disease 12 questions (PsAID-12) questionnaire 
 
The following will be used for assessing safety: 
 Adverse events 
 Physical examination, vital signs, weight 
 Clinical laboratory evaluations 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
11 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Statistical Methods  
Assuming a 15 dropout rate during the Randomized, Placebo-controlled, Double-blind 
Treatment Phase, a sample size of approximately
 for the active and placebo groups, 
respectively, will have 80 power to detect a true 15 difference (30 versus 15) in the 
proportions of subjects achieving the modified MDA between the treatment groups, using a chi-
square test with a two-sided significance level of 0.05. The primary efficacy endpoint, proportion 
of subjects who achieve the modified MDA at Week 16, between the treatment groups will be 
compared using a Cochran-Mantel-Haenszel (CMH) test, controlling for concomitant use of 
glucocorticosteroids at baseline (yes/no) and use of a csDMARD (csDMARD-naïve; csDMARD 
use prior to baseline; or csDMARD use prior to and concomitant at baseline). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
12 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL SUMMARY ...............................................................................................................4 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Disease Background ...................................................................................................19 
1.1.1. 
Psoriatic Arthritis ........................................................................................................19 
1.2. 
Compound Background ..............................................................................................20 
1.2.1. 
Key Findings from Clinical Studies ...........................................................................21 
1.2.1.1. 
Efficacy .......................................................................................................................22 
1.2.1.2. 
Safety ..........................................................................................................................31 
1.3. 
Rationale .....................................................................................................................36 
1.3.1. 
Study Rationale and Purpose ......................................................................................36 
1.3.1.1. 
Unmet Medical Need ..................................................................................................36 
1.3.1.2. 
Rationale for the Study Design ...................................................................................36 
1.3.1.3. 
Rationale for Dose, Schedule, and Regimen Selection ..............................................36 
1.3.1.4. 
Rationale for Choice of Comparator Compounds ......................................................37 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................38 
3. 
OVERALL STUDY DESIGN ....................................................................................44 
3.1. 
Study Design ...............................................................................................................44 
3.2. 
Study Duration for Subjects ........................................................................................47 
3.3. 
End of Trial .................................................................................................................47 
4. 
STUDY POPULATION .............................................................................................48 
4.1. 
Number of Subjects ....................................................................................................48 
4.2. 
Inclusion Criteria ........................................................................................................48 
4.3. 
Exclusion Criteria .......................................................................................................49 
5. 
TABLE OF EVENTS .................................................................................................51 
6. 
PROCEDURES ..........................................................................................................56 
6.1. 
Screening Period .........................................................................................................56 
6.2. 
Treatment Period ........................................................................................................58 
6.2.1. 
End of Treatment ........................................................................................................58 
6.3. 
Observational Follow-up ............................................................................................59 
6.3.1. 
Safety Follow-up ........................................................................................................59 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
13 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
6.4. 
Efficacy Assessments .................................................................................................60 
6.4.1. 
Modified Minimal Disease Activity–Joints (MDA-Joints) and its 
Components ................................................................................................................60 
6.4.1.1. 
Joint Assessment .........................................................................................................60 
6.4.1.2. 
Patient’s Global Assessments of Disease Activity .....................................................60 
6.4.1.3. 
Patient’s Pain Visual Analogue Scale .........................................................................60 
6.4.1.4. 
HAQ-DI ......................................................................................................................61 
6.4.1.5. 
Enthesitis: Leeds Enthesitis Index ..............................................................................61 
6.4.1.6. 
BSA.............................................................................................................................61 
6.4.1.7. 
Physician’s Global Assessments of Disease Activity .................................................61 
6.4.2. 
Enthesitis: 
 .........................................................................................61 
6.4.3. 
Dactylitis .....................................................................................................................62 
6.4.4. 
Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) ............................62 
6.4.5. 
Psoriatic Arthritis Disease Activity Score (PASDAS) ...............................................62 
6.4.6. 
High sensitivity C-reactive Protein .............................................................................62 
6.5. 
Safety Assessments .....................................................................................................63 
6.5.1. 
Serum and Urine Pregnancy Tests for Females of Childbearing Potential ................63 
6.5.2. 
Vital Signs, Height and Weight ..................................................................................63 
6.5.3. 
Complete/Limited Physical Examination ...................................................................63 
6.5.4. 
Psychiatric Evaluation ................................................................................................64 
6.5.5. 
Diarrhea, Nausea and Vomiting .................................................................................64 
6.5.6. 
Tuberculosis ................................................................................................................65 
6.5.7. 
Clinical Laboratory Evaluations .................................................................................65 
6.5.8. 
Adverse Events ...........................................................................................................65 
6.6. 
Patient Reported Outcomes or Quality of Life or Health Economics ........................65 
6.6.1. 
The PsA Impact of Disease 12-Item (PsAID-12) Questionnaire ................................66 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
14 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
7. 
DESCRIPTION OF STUDY TREATMENTS ..........................................................68 
7.1. 
Description of Investigational Product(s) ...................................................................68 
7.2. 
Treatment Administration and Schedule ....................................................................68 
7.3. 
Method of Treatment Assignment ..............................................................................70 
7.4. 
Packaging and Labeling ..............................................................................................70 
7.5. 
Investigational Product Accountability and Disposal .................................................71 
7.6. 
Study Medication Dispensing and Counting ..............................................................71 
7.7. 
Investigational Product Compliance ...........................................................................71 
7.8. 
Overdose .....................................................................................................................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 ................................................74 
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 .....................................................................................................77 
9.6. 
Efficacy Analysis ........................................................................................................77 
9.6.1. 
Efficacy Evaluation for the Placebo-Controlled, Double-Blind Treatment 
Phase ...........................................................................................................................77 
9.6.2. 
Multiplicity .................................................................................................................77 
9.6.3. 
Primary Efficacy Endpoint .........................................................................................77 
9.6.4. 
Secondary Endpoints ..................................................................................................78 
9.6.5. 
Active-Treatment Phase. .............................................................................................78 
9.7. 
Safety Analysis ...........................................................................................................78 
9.8. 
Interim Analysis ..........................................................................................................78 
9.9. 
Other Topics ...............................................................................................................79 
9.9.1. 
Investigational Product Compliance (Tablets) ...........................................................79 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
15 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
9.9.2. 
Concomitant Therapy .................................................................................................79 
10. 
ADVERSE EVENTS..................................................................................................80 
10.1. 
Monitoring, Recording and Reporting of Adverse Events .........................................80 
10.1.1. 
Monitoring, Recording and Reporting AEs of Diarrhea ............................................80 
10.2. 
Evaluation of Adverse Events ....................................................................................80 
10.2.1. 
Seriousness .................................................................................................................81 
10.2.2. 
Severity/Intensity ........................................................................................................82 
10.2.3. 
Causality .....................................................................................................................83 
10.2.4. 
Duration ......................................................................................................................83 
10.2.5. 
Action Taken ..............................................................................................................83 
10.2.6. 
Outcome ......................................................................................................................83 
10.3. 
Abnormal Laboratory Values .....................................................................................83 
10.4. 
Pregnancy ...................................................................................................................84 
10.4.1. 
Collection of Pregnancy and Infant Health Information ............................................84 
10.4.2. 
Male Subjects With Partners Who Become Pregnant ................................................85 
10.4.3. 
Collection of Lactation Information ...........................................................................85 
10.5. 
Reporting of Serious Adverse Events .........................................................................85 
10.5.1. 
Safety Queries .............................................................................................................86 
10.6. 
Expedited Reporting of Adverse Events .....................................................................86 
11. 
DISCONTINUATIONS .............................................................................................88 
11.1. 
Treatment Discontinuation .........................................................................................88 
11.2. 
Study Discontinuation ................................................................................................88 
12. 
EMERGENCY PROCEDURES ................................................................................89 
12.1. 
Emergency Contact .....................................................................................................89 
12.2. 
Emergency Identification of Investigational Products ...............................................89 
13. 
REGULATORY CONSIDERATIONS......................................................................90 
13.1. 
Good Clinical Practice ................................................................................................90 
13.2. 
Investigator Responsibilities .......................................................................................90 
13.3. 
Subject Information and Informed Consent ...............................................................91 
13.4. 
Confidentiality ............................................................................................................91 
13.5. 
Protocol Amendments ................................................................................................91 
13.6. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval .....................................................................................................................91 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
16 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
13.7. 
Ongoing Information for Institutional Review Board/ Ethics Committee .................92 
13.8. 
Termination of the Study ............................................................................................92 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................93 
14.1. 
Data/Documents .........................................................................................................93 
14.2. 
Data Management .......................................................................................................93 
14.3. 
Record Retention ........................................................................................................93 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................95 
15.1. 
Study Monitoring and Source Data Verification ........................................................95 
15.2. 
Audits and Inspections ................................................................................................95 
15.3. 
Product Complaint ......................................................................................................95 
15.3.1. 
How to Report a Product Complaint to Amgen: ........................................................96 
16. 
PUBLICATIONS .......................................................................................................97 
17. 
REFERENCES ...........................................................................................................98 
18. 
APPENDICES ..........................................................................................................102 
Appendix A: Table of Abbreviations ........................................................................................102 
Appendix B: The CASPAR Criteria .........................................................................................106 
Appendix C: Modified Minimal Disease Activity (MDA-Joints) Assessment .........................107 
Appendix D: Joint Assessment - 68 and 66 Joint Counts .........................................................108 
Appendix E: Visual Analog Scale .............................................................................................110 
Appendix F: Disability Index of the Health Assessment Questionnaire (HAQ-DI) .................111 
Appendix G: Leeds Enthesitis Index (LEI) ...............................................................................113 
Appendix H: Body Surface Area (BSA) ...................................................................................114 
Appendix K: C-Disease Activity index for Psoriatic Arthritis (cDAPSA) ...............................117 
Appendix L: Psoriatic Arthritis Disease Activity Score (PASDAS) ........................................118 
Appendix N: The PsA Impact of Disease 12-Item (PsAID-12) Questionnaire ........................120 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
17 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Appendix T: Blister Card Configurations .................................................................................135 
Appendix W: Sample Serious Adverse Event Report Form .....................................................139 
Appendix X: Pregnancy Notification Form ..............................................................................142 
Appendix Y: Lactation Notification Form ................................................................................143 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
18 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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) ...................................................23 
Table 3: 
Primary and Major Secondary Endpoints of Study CC-10004-PSA-005 (Full 
Analysis Set) ...............................................................................................................26 
Table 4: 
Summary of Secondary Efficacy Endpoints Related to Enthesitis and 
Dactylitis at Weeks 16 (FAS; LOCF), Study CC 10004 PSA-005 ............................27 
Table 5: 
ACR 20/50/70 Responses at Weeks 16 and 24 During the Placebo-
Controlled Period (FAS; NRI), CC-10004-PSA-006 .................................................29 
Table 6: 
HAQ-DI Score (0 to 3) Change From Baseline at Weeks 16 and 24 (FAS; 
MMRM) ......................................................................................................................29 
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) ....................................................................................30 
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) ....................................................................................................32 
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) ....................................................................................................33 
Table 10: Frequency of Common AEs Over 208 Weeks of Exposure .......................................35 
Table 11: Study Objectives .........................................................................................................38 
Table 12: Study Endpoints ..........................................................................................................39 
Table 13: Table of Events ...........................................................................................................51 
Table 14: Treatment of Schema for Dose Titration at Baseline .................................................69 
Table 15: Treatment Schema for Dose Titration at Week 16 (Early Escape) or Week 24 .........69 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................46 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
19 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
1. 
INTRODUCTION 
1.1. 
Disease Background 
1.1.1. 
Psoriatic Arthritis 
Psoriatic arthritis (PsA) is a heterogeneous inflammatory rheumatologic disorder characterized 
by inflammatory 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 up to 
50 of patients with PsA. In addition, PsA is associated with enthesitis and dactylitis, which are 
features common to SpA. Finally, the majority of patients with PsA are negative for rheumatoid 
factor (RF) (Gladman, 2005; Kruithof, 2005; Roberts, 1976). Moll and Wright described five 
subgroups of PsA (Moll, 1973). These include distal interphalangeal (DIP) joint only, 
asymmetrical oligoarthritis, polyarthritis, spondylitis and arthritis mutilans. Among these five 
subtypes, asymmetrical oligoarthritis sometimes involving distal interphalangeal (DIP) joints, is 
a frequent form of PsA (Ritchlin, 2017). Very little is known with respect to the burden of 
disease, the performance of different measurement tools and the appropriate management of 
patients with oligoarthritis. Indeed, there is a paucity data on the treatment of patients with 
oligoarthritis, one reason being that published clinical trials focus on polyarticular forms of the 
disease. In addition, treatment recommendations tend to focus on polyarticular forms (Gossec, 
2016). Knowledge regarding the efficacy of drugs in oligoarticular forms would be of great value 
to clinicians. 
Standard classification criteria for use in clinical studies remain to be established. In recent 
studies, patients with  4 active joint counts (tender and/or swollen) at baseline were classified as 
oligoarthritic (Coates, 2013; Helliwell, 2007; Jones, 1994; Kane, 2003). Use of this definition in 
different studies, indicated that the proportion of subjects with oligoarthritis ranges from 14 to 
63, the higher values being observed in patients with shorter disease duration. It is believed 
that the evolution of the disease, from oligoarthritis to polyarthritis, accounts for the lower 
proportion of patients with oligoarthritis in populations with longer disease duration. Indeed, 
results from the long-term follow-up of PsA cohorts, including subjects with short articular 
symptoms duration ( 24 months), showed that about two-thirds of subjects presenting with an 
oligoarthritic disease at baseline evolved into the polyarticular sub-type over time (Jones, 1994). 
In addition, treatments with conventional synthetic DMARDs (csDMARDs) were associated 
with the reclassification of subjects, from polyarthritic at the initial clinical presentation into 
oligoarthritic at follow-up (Kane, 2003). Such oligoarticular patients may be associated with 
residual joints that are less responsive to treatment when compared to patients with recent onset 
of oligoarthritis. Taken together, these observations suggest that patients with oligoarticular form 
of PsA but with long standing disease duration and previous response to anti-rheumatic 
treatments may be less sensitive to further improvement after additional therapies than earlier 
populations who are mainly csDMARDs-naive. As a result, the current study will enroll subjects 
with short disease duration and limited exposure to prior nonsteroidal anti-inflammatory drugs 
(NSAIDs) and/or csDMARDs. 
Results from the GRACE cohort (GRAPPA Composite Exercise) highlight the burden of disease 
of patients with oligoarthritis. The GRACE cohort enrolled 503 PsA patients, out of which 266 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
20 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
(53) were classified with oligoarthritis. This subpopulation of patients reported other aspects of 
the disease, such as enthesitis (34 of the patients) and dactylitis (12 of patients). Limited skin 
involvement was observed in these patients, as shown by a median Psoriasis Area and Severity 
Index (PASI) score of 1.2 points. Noteworthy, when comparing subjects with mono/oligoarthritis 
to polyarthritis, subjects with mono/oligoarthritis were associated with lower levels of 
inflammation and lower proportions of subjects with erosive disease at follow-up (Lindqvist, 
2008). 
The results from the Tight Control of Psoriatic Arthritis (TICOPA) trial in patients with early 
and treatment-naive PsA allowed for the comparison of outcomes measures between subjects 
with oligoarthritis and polyarthritis. Patients with oligoarthritis were more likely to achieve 
minimal disease activity (MDA) as defined by Coates, et al (Coates, 2010) than those with 
polyarticular disease. Conversely, a significantly greater proportion of subjects with polyarthritis 
achieved 20 improvement in the American College of Rheumatology ACR criteria (ACR 20) 
when compared with those with oligoarthritis (Coates, 2016). Further analyses of the TICOPA 
trial has shown that both Psoriatic Arthritis Disease Activity Score (PASDAS) and Composite 
Psoriatic Disease Activity Index have limited ability to distinguish effects of therapy in the 
subgroup of study patients with oligoarthritis (Coates, 2017). The value of the Clinical Disease 
Activity in Psoriatic Arthritis score (cDAPSA) [without measuring C-reactive protein], alone or 
in comparison to the MDA, has not been extensively studied in this subset of PsA patients. 
The limited performance of ACR20 response criteria reported in the TICOPA trial are inherent to 
the baseline level of disease activity associated with patients with oligoarthritis. This is partially 
explained by the limited discriminative ability of the ACR20 response criteria to report 20 
changes in populations with limited number of joint counts at baseline. For example, for a 
subject with 1 SJ and 1 TJ at baseline, a 20 improvement would correspond to a 0.2 reduction 
in 1 swollen joint (SJ) and 1 tender joint (TJ). This is not assessable by clinical palpation, 
making this endpoint less desirable for the studied population. As a result, the primary endpoint 
of the current study will be based on a modification of the MDA.  
1.2. 
Compound Background  
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 (cAMP) 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 TNF-, IL-17, IL-23, IL-6, IL-8, MIP-1, and 
MCP-1, as well as increases in anti-inflammatory mediators, including IL-10 and the IL-1 
receptor antagonist. It is believed, therefore, that apremilast exerts its therapeutic benefits 
through the modulation of multiple inflammatory pathways (Schafer, 2015).  
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.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
21 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP). 
1.2.1. 
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 DMARD-naive, DMARDs-experienced, biologic-naive, and biologic-experienced 
subjects (Table 1). The results from these studies indicated that apremilast is safe and effective, 
both as monotherapy and in combination with 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-naive and 
biologic-naive 
Apremilast monotherapy vs. 
PBO 
527 
ACTIVE/ 
CC-10004-PSA
-006 
Maximum 1 prior 
csDMARD, biologic-
naive 
Apremilast monotherapy vs. 
PBO 
219 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
22 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
1.2.1.1. 
Efficacy 
1.2.1.1.1. 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]; (Kavanaugh, 2014; Cutolo, 2016; Edwards, 2016). The 
studies were similarly designed. Adult patients with active PsA ( 3 swollen and  3 tender 
joints) despite prior csDMARD and/or biologic tumor necrosis factor (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 concomitant methotrexate (MTX) ( 25 mg/week), sulfasalazine (SSZ [ 2 g/day]), 
leflunomide (LEF [ 20 mg/day]), low-dose oral corticosteroids (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 patients were randomized equally to placebo (N  496), apremilast 
(APR) 20 twice daily (BID (N  500), or APR 30 BID (N  497). Placebo patients whose tender 
and swollen joints counts 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 patients 
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 
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 Week 
16 and 24 among subjects with body surface area (BSA) for psoriasis  3  at baseline. 
Detailed information can be found in the Investigator’s Brochure (IB). 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
23 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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)* 
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) ** 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
24 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 
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; HAQ-DI  Health Assessment Questionnaire Disability Index; PASI 50/75  
50/75 or greater improvement in the Psoriasis Area and Severity Index; LOCF  last observation carried 
forward; NRI  nonresponder imputation; PASI 50/75  50/75 or greater improvement in the Psoriasis Area and 
Severity Index; SE  standard error. 
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. 
Note: ***p  0.001 for apremilast versus placebo. **p  0.01 for apremilast versus placebo. *p  0.05 for apremilast 
versus placebo. 
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 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. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
25 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
1.2.1.1.2. Efficacy Data From Phase 3 Study CC-10004-PSA-005 (Palace 4) Through 
Week 24 in Subjects Naive to csDMARDs and Biologic DMARDs 
The efficacy of apremilast in subjects naive to csDMARDs therapy was investigated in a 
multicenter, randomized, double-blinded, placebo-controlled Phase 3 study (CC-10004-PSA-005 
[Palace 4]; Wells, 2018). 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 tender and swollen joint counts 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 Week 16 and 24 among subjects with BSA for 
psoriasis  3 at baseline.  
Detailed information can be found in the IB. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
26 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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)*** 
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; HAQ-DI  Health Assessment Questionnaire Disability Index; PASI 50/75  50/75 or greater 
improvement in the Psoriasis Area and Severity Index; LOCF  last observation carried forward; NRI  nonresponder 
imputation; SE  standard error.  
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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
27 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Note: ***p  0.001 for apremilast versus placebo. **p  0.01 for apremilast versus placebo. *p  0.05 for apremilast versus 
placebo. 
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 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. 
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 Weeks 16 (FAS; LOCF), Study CC 10004 PSA-005 
Secondary Endpoints 
Placebo 
N  176 
APR 30 BID 
N  176 
MASES change from baseline, LS mean (SE)  
-0.5 (0.24) 
-1.5 (0.25)** 
MASES  0, n () 
22 (19.1) 
41 (36.9)** 
Dactylitis change from baseline, LS mean (SE)  
-1.0 (0.25) 
-1.7 (0.26)* 
Dactylitis count  0, n () 
30 (33.3) 
34 (40.5) 
APR  apremilast; BID  twice daily; FAS  Full Analysis Set; LOCF  last observation carried forward; LS  least 
squares; 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.   
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
28 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
1.2.1.1.3. 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-naive patients 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; 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 vs PBO was noted at Week 2 
(16.4 vs 6.4; P  0.0252), the first post-baseline visit. Early onset of response to APR was 
observed across clinical assessments, with improvements in DAS-28 (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 reductions in PsA disease activity/manifestations vs placebo were also demonstrated 
by changes in DAS-28 (CRP) (P  0.0001), SJC (P  0.0001), and HAQ-DI (Table 6). 
Detailed information can be found in the IB. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
29 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 5: 
ACR 20/50/70 Responses at Weeks 16 and 24 During the Placebo-Controlled 
Period (FAS; NRI), CC-10004-PSA-006  
 
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)** 
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  nonresponder 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. n with non-missing values were 103 and 91 for Placebo and 
APR 30 BID at Week 16, and 63 and 76 at Week 24, respectively. 
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 corticosteroids (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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
30 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Among patients with enthesitis at Baseline, significant improvements from Baseline in Gladman 
Enthesitis Index (GEI) score were observed with APR 30 mg (-1.1) vs placebo (-0.4) at Week 2 
(P.0354), as well as at Weeks 16 and 24 (Table 7). 
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) 
Visit 
 
Treatment Group 
na 
Change From Baseline 
Week 16 
LS Mean (SE)b 
Week 24 
LS Mean (SE)b 
Placebo 
51 
-0.4 (0.26) 
-0.5 (0.27) 
APR 30 BID 
56 
-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. n 
with non-missing values were 48 and 49 for Placebo and APR 30 BID at Week 16, and 29 and 41 at Week 24, 
respectively. 
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 corticosteroids 
(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 unassessable 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. 
1.2.1.1.4. 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 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
31 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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. 
1.2.1.1.5. Long-term Efficacy Data From Phase 3 Study CC-10004-PSA-005 (Palace 4) in 
csDMARD-naive patients 
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.  
1.2.1.1.6. Long-term Efficacy Data From Phase 3 Study CC-10004-PSA-006 (ACTIVE)  
In biologic-naive PsA patients 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 
67.1, 36.7, and 21.3.0 respectively; also, 45.6 achieved HAQ-DI improvements  0.35, 
which corresponded to the MCID. 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 (Nash, 2018). 
1.2.1.2. 
Safety 
1.2.1.2.1. 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.  
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
32 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 Terma 
Weeks 0 to 16 
First 16 Weeks of Apremilast Treatmentb 
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 
patients treated with apremilast reported depression or depressed mood and 0.8 (4/495) treated 
with placebo. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
33 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 
(-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 Terma 
Weeks 0 to 
16 
First 16 Weeks of Apremilast Treatmentb 
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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
34 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 
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. 
1.2.1.2.2. 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 patients who had received  1 csDMARD 
was assessed in the ACTIVE study over a period of 52 weeks (Nash, 2018). The overall 
incidence of AEs in the placebo-controlled period was generally similar for APR monotherapy 
and placebo. The most commonly reported AEs ( 5 of patients) with APR vs placebo were 
nasopharyngitis (8.3 vs 6.4, respectively), nausea (8.3 vs 1.8), headache (7.3 vs 3.7), 
hypertension (6.4 vs 6.4), and diarrhea (patient- or investigator-reported) (14.7 vs 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 vs 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 patients treated with apremilast discontinued treatment due to depression or 
depressed mood vs 0 placebo-treated patients (0/495). Depression was reported as serious in 
0.2 (3/1441) of patients exposed to apremilast vs 0 placebo-treated patients (0/495). Two 
patients who received placebo committed suicide vs 0 apremilast-treated patients. Importantly, 
the rates of depression remained low over time.  
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
35 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 10: 
Frequency of Common AEs Over 208 Weeks of Exposure 
APR-Exposure 
Period* 
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) 
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) 
APR30  apremilast 30 mg BID; AE  adverse event; n/m  number of subjects with 1 occurrence of the abnormality at any 
time point/number of subjects with 1 post-baseline value; ULN  upper limit of normal. 
Note: *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  53 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, 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
36 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 IB for detailed information concerning the available pharmacology, 
toxicology, drug metabolism, clinical studies, and adverse event profile of the investigational 
product (IP). 
1.3. 
Rationale 
1.3.1. 
Study Rationale and Purpose 
1.3.1.1. 
Unmet Medical Need  
Apremilast has been shown to be safe and efficacious in reducing signs and symptoms of PsA, as 
well as improving physical function (Cutolo, 2016; Edwards, 2016; Kavanaugh, 2014; 
Nash, 2018). Like most agents, the clinical development program of apremilast was restricted to 
subjects with 3 swollen and tender joints at baseline. This allowed for a limited proportion of 
subjects with asymmetric oligoarthritis at study entry. Consequently, the safety and efficacy of 
apremilast in patients with oligoarthritis remains to be further investigated.  
The current study is designed to evaluate the benefit: risk profile of apremilast in subjects with 
an early diagnosis of PsA ( 5 years since signs and symptoms began), presenting with 
oligoarthritis despite concurrent stable treatments with either NSAIDs and/or  1 csDMARD. 
1.3.1.2. 
Rationale for the Study Design 
Analyses in PsA subjects with oligoarthritis (defined by different combinations of limited 
numbers of swollen and tender joints) in five Phase 3 PsA studies (PSA-002, PSA-003, 
PSA-004, PSA-005 and PSA-006) indicated that in patients with oligoarticular PsA, apremilast 
30 mg BID was associated with a numerically greater proportion of subjects achieving the 
modified MDA (MDA-joint) at week 16 compared with placebo. In addition, results from the 
apremilast development program demonstrated that responses to apremilast improve over a 
period of up to 24 weeks when compared to placebo. Therefore, the 24-week, double-blind, 
placebo-controlled treatment period with frequent visits and assessments will provide adequate 
time to reasonably assess the onset of action of, and durability of, response to apremilast in 
achieving the modified MDA (MDA-Joints). The joints monitored for early escape must 
correspond to those affected at the Baseline Visit (sentinel joints). 
The Active-treatment Extension Phase (24 weeks) will allow for the investigation of the 
long-term efficacy, safety and tolerability of apremilast  concomitant therapies for the treatment 
of patients with oligoarthritis. In addition, this period will allow for the investigation of the 
impact of apremilast  concomitant therapies after a course of placebo  NSAIDs and/or 
 1 csDMARDs.  
1.3.1.3. 
Rationale for Dose, Schedule, and Regimen Selection  
The dosing regimen and dose of apremilast is based on the approved dosing regimen and dose of 
apremilast for the treatment of PsA.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
37 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
After a dose titration over a 5-day period, an oral dose of apremilast 30 mg BID will be given to 
all subjects randomized or enrolled to receive apremilast. 
1.3.1.4. 
Rationale for Choice of Comparator Compounds  
The comparator of this study is Placebo. This will allow for the assessment of the risk / benefit of 
apremilast.  
To allow for the treatment of oligoarticular PsA, apremilast  NSAIDs and/or  1csDMARDs 
will be compared to placebo  NSAIDs and/or  1 csDMARDs. Stable low doses of 
glucocorticoids (prednisone  10 mg/day or equivalent) will be allowed. Indeed, it is understood 
that several patients with oligoarthritis are managed with NSAIDs and/or csDMARDs. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
38 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 BID  NSAIDs and/or csDMARDs vs. Placebo  NSAIDs and/or 
csDMARDs in subjects with early oligoarticular psoriatic arthritis (PsA), 
assessed by modified MDA (MDA-Joints). 
Secondary Objective(s) 
 To evaluate the impact of treatment with apremilast 30 mg BID  NSAIDs 
and/or csDMARDs vs. Placebo  NSAIDs and/or csDMARDs on disease 
activity in subjects with early oligoarticular PsA. 
 To evaluate the impact of apremilast 30 mg BID  NSAIDs and/or 
csDMARDs vs. Placebo  NSAIDs and/or csDMARDs on patient-reported 
outcomes (PROs) in subjects with early oligoarticular PsA. 
 To evaluate the safety and tolerability of apremilast 30 mg BID  NSAIDs 
and/or csDMARDs vs. Placebo  NSAIDs and/or csDMARDs in subjects 
with early oligoarticular PsA.  
Exploratory Objective(s) 
The exploratory objectives are: 
 csDMARDs  Conventional synthetic disease-modifying antirheumatic drugs; cDAPSA  Clinical 
disease activity in psoriatic arthritis (without measuring C-reactive protein); 
NSAIDs 
 Nonsteroidal anti-inflammatory drugs; MDA  Minimal disease activity; HAQ-DI  Health Assessment Questionnaire 
Disability Index; PGA  Physician’s Global Assessment of Disease activity; PRO  Patient-reported outcome; 
PsAID  Psoriatic Arthritis Impact of Disease (questionnaire). 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
39 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 12: 
Study Endpoints 
Endpoint 
Name 
Description 
Timeframe 
Efficacy Endpoints at Week 16: Double-Blind Placebo-Controlled Treatment Phase 
Primary 
MDA-Joints 
Proportion of subjects who achieve a clinical state of minimal disease activity 
defined MDA-Joints. Subjects must achieve  1 SJC and TJC, plus 3 out of 5 
of the remaining cut-off values (BSA  3; Patient pain (VAS)  15; Patient 
global disease activity (VAS)  20; HAQ0.5; Tender entheseal points  1 
(based on Leeds Enthesitis Index - LEI).  
Week 16 
Secondary  
 
cDAPSA remission or low 
disease activity 
Proportion of subjects who achieve remission (defined by clinical disease 
activity in psoriatic arthritis [DAPSA]  4 score) or low disease activity 
(defined by cDAPSA  4 but  13 score). 
Week 16 
Swollen Joint Count (SJC)  1  Proportion of subjects with SJC  1.  
Week 16 
Tender Joint Count (TJC)  1  
Proportion of subjects with TJC  1.  
Week 16 
Patient's global assessment of 
disease activity  
Proportion of subjects whose global assessment of disease activity score  20 
in the visual analogue scale (VAS).  
Week 16 
Patient's assessment of pain 
Proportion of subjects whose assessment of pain score  15 in VAS. 
Week 16 
PsAID-12 
Change from Baseline in the Psoriatic Arthritis Impact of Disease 12-item for 
clinical trials (PsAID-12) questionnaire.  
Week 16 
PASDAS good and moderate 
response 
Proportion of patients achieving a good or moderate response in PASDAS 
score.  
Week 16 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
40 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 12: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
Exploratory Efficacy Endpoints: Evaluated for the Duration of the Study: 
(Double-Blind Placebo-Controlled Treatment Phase and/or the Active-treatment Phase) 
Exploratory 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
41 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 12: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
Exploratory Efficacy Endpoints: Evaluated for the Duration of the Study: 
(Double-Blind Placebo-Controlled Treatment Phase and/or the Active-treatment Phase) 
Exploratory 
(Continued) 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
42 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 12: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
Exploratory Efficacy Endpoints: Evaluated for the Duration of the Study: 
(Double-Blind Placebo-Controlled Treatment Phase and/or the Active-treatment Phase) 
Exploratory 
(Continued) 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
43 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 12: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
Exploratory 
(Continued) 
Safety 
Endpoints 
Safety Endpoints: Evaluated throughout the duration of the study: 
Adverse events 
Type, frequency, severity, and relationship of adverse events (AEs) to investigational 
product (IP). 
Throughout the duration of 
the study 
Discontinuation due to 
AEs 
Number of subjects who discontinue IP due to any AE. 
Throughout the duration of 
the study 
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. 
Throughout the duration of 
the study 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
44 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
3. 
OVERALL STUDY DESIGN  
3.1. 
Study Design 
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. 
This is a Phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy, safety and tolerability of apremilast (CC-10004) in subjects with 
early ( 5 years since signs and symptoms began) oligoarticular PsA (according to 
Classification Criteria for Psoriatic Arthritis [CASPAR] criteria) despite treatment with 
either NSAIDs and/or  2 csDMARD.  Subjects must also meet the following criteria:  1 SJ but 
 4 SJ, and  1 TJ but  4 TJ at the Screening Visit and confirmed prior to randomization at the 
Baseline Visit. 
Given that this is a phase 4 study, all subjects are required to meet the existing apremilast 
regulatory labeling conditions specific to the countries where enrollment will take place (eg, 
Food and Drug Administration [FDA], European Medicines Agency [EMA], Health Canada]. 
There is no planned protocol extension following the end of the study.  
Approximately 285 subjects will be randomized in a 2:1 ratio to either apremilast 30 mg BID or 
identically appearing placebo, with approximately 
 subjects assigned to the active treatment 
group and approximately 
 subjects assigned to receive placebo. Treatment assignment will be 
stratified via an Interactive Web Response System (IWRS) based on concomitant use of 
glucocorticosteroids at baseline (yes/no) and prior/concomitant use of a csDMARD, either MTX 
or SSZ (ie, csDMARD-naïve; csDMARD use prior to baseline [treatment not continued]; or 
csDMARD use prior to and concomitant at baseline). The number of subjects who are 
csDMARD-naïve is targeted to comprise up to 50  of the subjects enrolled in the study. 
This is a 56-week study. Subjects will have up to 4 weeks in the Screening Phase, followed by 
24 weeks in the Double-blind, Placebo-controlled Treatment Phase, which provides an 
opportunity for “early escape” at Week 16, allowing subjects to receive treatment with 
apremilast 30 mg BID beginning at Week 16. At the Week 24 Visit, all subjects will be offered 
entry into the Active-treatment Extension Phase. Subjects enrolled in the Extension Phase will 
receive treatment with apremilast (30 mg BID) until the end of the study (ie, up to the Week 48 
Visit) or until early discontinuation.  
Beginning at the Week 28 Visit, all subjects in the Extension Phase will be dispensed open-label 
apremilast (30 mg BID) in high-density polyethylene (HDPE) bottles (Section 7.3). Subjects, 
Investigators and persons responsible for the ongoing conduct of the study will continue to be 
blinded to the original treatment assignment. Subjects must be clearly instructed to follow dosing 
instructions. Subjects may discontinue at any time during the study.  
After all subjects complete the Week 24 Visit (or discontinue prematurely from the study), 
selected members of the Amgen study team who do not have direct interaction with subjects will 
be unblinded for the analysis of the Week 24 data. These persons may include but are not limited 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
45 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
to the following: Therapeutic Area Head, Study Lead, Medical Director and the Statistician. The 
results from these analyses may be published prior to the end of the study. 
Subjects, Investigators and persons responsible for the ongoing conduct of the study will 
continue to be blinded to the original treatment assignment until the end of the study. These 
persons are those individuals that have direct interaction with subjects and/or subject 
assessments, and may include but are not limited to the following: Clinical Trial Manager, Data 
Manager, Clinical Research Associates (Amgen and External Partners) and Site Monitors.  
This is a 56-week study which will consist of 4 phases:  
 Screening Phase – up to 4 weeks 
 Randomized, Double-blind, Placebo-controlled Treatment Phase – Weeks 0 to 24. 
Henceforth, this will be referred to as the Placebo-controlled Phase.  
o Subjects will be randomly assigned in a 2:1 ratio to either apremilast 30 mg BID 
or placebo.  Subjects randomized to apremilast will be dose-titrated in a blinded 
fashion.  
o Dose titration is described in Study Treatments, Section 7.2. and Section 7.3. 
o Subjects with no improvement in SJC (sentinel joints) at Week 16 are eligible for 
early escape, at the discretion of the Investigator and will receive apremilast 
30 mg BID. The joints monitored for early escape must be the “sentinel joints” 
(ie, the joints affected at baseline). 
o Placebo-treated subjects who escape early will be transitioned to apremilast 
30 mg BID in a blinded fashion via an Interactive Web Response System (IWRS), 
while apremilast-treated subjects will remain on the original treatment assigned at 
baseline. Placebo-treated subjects will be dose-titrated in a blinded fashion. 
o All subjects who complete this 24-week treatment phase will have the option to 
enter the Active-treatment Extension Phase.  
 Active-treatment Extension Phase – Week 24 to Week 48. Henceforth, this will be 
referred to as the Extension Phase.  
o All subjects will receive apremilast 30 mg BID until the completion of the study 
(ie, up to the Week 48 Visit). All remaining placebo-treated subjects will be 
dose-titrated in a blinded fashion. 
o Beginning at the Week 28 Visit, all subjects in the Extension Phase will be 
dispensed open-label apremilast (30 mg BID) as described in Study Treatments 
and Section 7.3. 
 Post-treatment Observational Follow-up Phase – up to 4 weeks. Henceforth this will be 
referred to as the Observational Follow-up Phase.  
o All subjects who complete the Placebo-controlled Phase or the Extension Phase or 
discontinue early will participate in the 4-week Observational Follow-up Phase.  
o The Observational Follow-up visit should be performed 4 weeks after the last 
dose of IP ( 7 days). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
46 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Figure 1: Overall Study Design 
 
 
* – Subjects with no improvement in SJC (sentinel joints) at Week 16 are eligible for early escape, at the discretion of the Investigator. 
 
Abbreviations: BID  twice daily; csDMARD  conventional synthetic disease-modifying antirheumatic drug; MDA  Minimal Disease Activity; NSAIDs  
non-steroidal anti-inflammatory drug. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
47 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
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 24 (ie, 24 weeks) in the Placebo-controlled Phase 
 Weeks 24 to 48 (ie, 24 weeks) in the Extension Phase  
 Weeks 48 to 52 (ie, 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 48 weeks of treatment and 
completion of the Observational Follow-up Visit (Week 52), 4 weeks after the last dose of IP 
( 7 days). A subject not meeting this definition is considered an early discontinuation subject 
(Section 6.2.1). For the purpose of analysis, study completion for an individual subject is defined 
as reaching the Week 48 Visit.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
48 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
4. 
STUDY POPULATION 
4.1. 
Number of Subjects  
Approximately 285 subjects will be enrolled worldwide.  
4.2. 
Inclusion Criteria 
Subjects must satisfy the following criteria to be enrolled in the study: 
1. Subject is a male or female,  18 years at time of consent. 
2. Subjects must understand and voluntarily sign an informed consent document prior to any 
study related assessments/procedures being conducted. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements. 
4. Subject must have signs and symptoms of PsA  5 years duration at the time of the 
Screening Visit. 
5. Subject meets the CASPAR (Appendix B) criteria for PsA at the Screening Visit. 
6. Subject must have a total number of swollen joints greater than 1 and equal or less than 4 
( 1 but  4 swollen joints) at the Screening Visit and confirmed prior to randomization at 
the Baseline Visit. 
7. Subject must have a total number of tender joints greater than 1 and equal or less than 4 ( 1 
but  4 tender joints) at Screening and confirmed prior to randomization at the Baseline Visit. 
8. Subjects taking oral glucocorticosteroids must be on a stable dose of prednisone  10 mg/day 
or equivalent for at least 4 weeks prior to the Baseline Visit (Section 8.1). 
9. 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.  
10. Subjects taking 1 protocol-allowed csDMARD (methotrexate [MTX] or sulfasalazine [SSZ]) 
to treat PsA may enter the study provided that the treatment is taken at a stable dose for at 
least 3 months prior to the Baseline Visit. See Permitted Medications (Section 8.1) for details 
describing dose criteria.  
11. Subjects exposed to MTX or SSZ and stopped treatment due to intolerance or due to safety 
reasons may enter the study provided that treatment was stopped within at least 4 days of the 
Baseline Visit. 
12. Subjects taking NSAIDs may enter the study provided that the dose is stable for at least 
2 weeks prior to the Baseline Visit. Subjects may discontinue NSAIDs at any time up to and 
including the Baseline Visit, prior to study randomization. 
13. Females of childbearing potential (FCBP)† must have a negative pregnancy test at Screening 
and the Baseline Visit. While on investigational product and for at least 28 days after taking 
the last dose of investigational product, FCBP who engage in activity in which conception is 
possible must use one of the approved contraceptive§ options described below: 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
49 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Option 1: Any one of the following highly effective methods: hormonal 
contraception (oral, injection, implant, transdermal patch, vaginal ring); 
intrauterine device (IUD); 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/regulations. 
 
† A female of childbearing potential 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). 
14. Must be in general good health (except for psoriatic arthritis) 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). 
 
4.3. 
Exclusion Criteria 
The presence of any of the following will exclude a subject from enrollment: 
1. Prior use of  2 csDMARD to treat PsA. 
2. Prior exposure to a JAK-inhibitor, including tyk2 inhibitors and/or a biologic DMARD. 
3. Use of intra-articular (IA) or intra-muscular (IM) glucocorticoid injection within 8 weeks 
before the Baseline Visit. 
4. Use of leflunomide within 12 weeks of randomization. Subjects who stopped leflunomide 
and completed 11 days of treatment with cholestyramine (8 g, 3 x daily) prior to the 
Baseline Visit may enter the study. 
5. Prior use of cyclosporine.  
6. Prior treatment with apremilast, or participation in a clinical study, involving apremilast. 
7. Use of any investigational drug within 4 weeks of the Baseline Visit, or 5 
pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer). 
8. History of clinically significant or uncontrolled disease (as determined by the 
Investigator), which places the subject at unacceptable risk if he/she were to participate in 
the study. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
50 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
9. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study. Subjects with a 
creatinine clearance level less than 30 mL/min (estimated by the Cockcroft–Gault 
equation) will be considered to have severe renal impairment and will be excluded from 
the study. 
10. 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. 
11. Pregnant or breast feeding. 
12. Active substance abuse or a history of substance abuse within 6 months prior to 
Screening. 
13. History of allergy or hypersensitivity to any component of the investigational product. 
14. History of positive human immunodeficiency virus (HIV), or congenital or acquired 
immunodeficiency (eg, Common Variable Immunodeficiency Disease). 
15. Active tuberculosis or a history of incompletely treated tuberculosis. 
16. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant 
viral or fungal infections, within 1 week of Screening. Any treatment for such infections 
must have been completed and the infection cured, at least 1 week prior to Screening and 
no new or recurrent infections prior to the Baseline Visit. 
17. 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.  
18. Major surgery (including joint surgery) within 8 weeks prior to the Screening Visit or 
planned major surgery within 6 months following the Baseline Visit. 
19. Rheumatic autoimmune disease other than PsA, including, but not limited to: systemic 
lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, 
polymyositis, or fibromyalgia. 
20. Prior history of or current inflammatory joint disease other than PsA (eg, gout, reactive 
arthritis, rheumatoid arthritis [RA], ankylosing spondylitis, Lyme disease), which 
confounds the ability to interpret data from the study. 
21. Erythrodermic, guttate, or generalized pustular psoriasis at randomization. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
51 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
5. 
TABLE OF EVENTS 
Table 13: 
Table of Events 
 
Screening 
Placebo-controlled Phase 
 
Extension Phase 
 
Early 
Termination 
Visit 
Observational 
Follow-up- 
Phase 
Visit Number 
1 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
Early 
Termination 
10 
Week (Visit Window) 
-28 Days 
Week 0  
4 
(3 days) 
12 
( 3 days) 
16a 
(3 days) 
24b 
(3 days) 
28c 
(3 days) 
40 
( 1 week) 
48 
(1 week)) 
ETd 
Obs. Follow-up 
Visite 
4 wks after the 
last dose of IP 
( 7 days) 
Informed consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical History/PsA 
History 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Smoking and alcohol intake 
history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion/Exclusion Criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety and Laboratory 
Assessments  
 
 
 
 
 
 
 
 
 
 
 
Vital Signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
Weight g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Diarrhea assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
52 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 13: 
Table of Events (Continued) 
 
Screening 
Placebo-controlled Phase 
Extension Phase 
Early 
Termination 
Visit 
Observational 
Follow-up- 
Phase 
Visit Number 
1 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
Early 
Termination 
10 
Week (Visit Window) 
-28 Days 
Week 0  
4 
(3 days) 
12 
( 3 days) 
16a 
(3 days) 
24b 
(3 days) 
28c 
(3 days) 
40 
( 1 week) 
48 
(1 week)) 
ETd 
Obs. Follow-up 
Visite 
4 wks after the 
last dose of IP 
( 7 days) 
Complete Physical 
Examination 
X 
- 
- 
- 
- 
X 
- 
- 
X 
X 
- 
Limited Physical 
Examination 
- 
X 
X 
X 
X 
- 
X 
X 
- 
- 
- 
Laboratory Evaluations 
(including high sensitivity 
C-reactive protein and 
urinalysis)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Rheumatoid Factor 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Pregnancy Test for Females 
of Child Bearing Potential 
(FCBP) and Contraception 
Education h 
X 
X 
- 
- 
- 
- 
- 
- 
X 
X 
- 
Adverse Events i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Efficacy 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
Tender Joint Count (0-68) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Swollen Joint Count (0-66) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Physician’s Global 
Assessment of  
Disease Activity (VAS) 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Patient’s Global Assessment 
 of Disease Activity (VAS) 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
53 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 13: 
Table of Events (Continued) 
 
Screening 
Placebo-controlled Phase 
Extension Phase 
Early 
Termination 
Visit 
Observational 
Follow-up- 
Phase 
Visit Number 
1 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
Early 
Termination 
10 
Week (Visit Window) 
-28 Days 
Week 0  
4 
(3 days) 
12 
( 3 days) 
16a 
(3 days) 
24b 
(3 days) 
28c 
(3 days) 
40 
( 1 week) 
48 
(1 week)) 
ETd 
Obs. Follow-up 
Visite 
4 wks after the 
last dose of IP 
( 7 days) 
Patient’s Assessment of Pain 
(VAS) 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Dactylitis 
 j 
X 
Enthesitis assessment-
 LEI 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
HAQ-DI 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
BSA 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
PROs/QOLs 
 
 
 
 
 
 
 
 
 
 
 
PsAID-12 
X 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
54 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
Table 13: 
Table of Events (Continued) 
 
Screening 
Placebo-controlled Phase 
Extension Phase 
Early 
Termination 
Visit 
Observational 
Follow-up- 
Phase 
Visit Number 
1 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
Early 
Termination 
10 
Week (Visit Window) 
-28 Days 
Week 0  
4 
(3 days) 
12 
( 3 days) 
16a 
(3 days) 
24b 
(3 days) 
28c 
(3 days) 
40 
( 1 week) 
48 
(1 week)) 
ETd 
Obs. Follow-up 
Visite 
4 wks after the 
last dose of IP 
( 7 days) 
Health Economics Assessment 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
- 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
Return/Count Study Drug 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
BID  twice daily; BSA  Body Surface Area;
 FCBP  Females of Child Bearing Potential; HAQ-DI  Health Assessment 
Questionnaire – Disability Index; IP  Investigational Product;
LEI  Leeds Enthesitis Index;
Obs. 
Follow-up Visit  Observational Follow-up Visit; PROs  Patient Reported Outcomes; PsAID  PsA Impact of Disease;
 
 QOL  Quality of Life;
VAS  Visual 
Analog Scale;
 
a At the Week 16 Visit, subjects with no improvement in SJC (sentinel joints) at Week 16 are eligible for early escape, at the discretion of the Investigator and will receive 
treatment with apremilast 30 mg BID. The joints monitored for early escape must correspond to those affected at the Baseline Visit (sentinel joints).  
b All subjects who complete the Week 24 Visit will enter Extension Phase and receive apremilast 30 mg BID. The original treatment assignments (apremilast 30 mg BID or 
placebo) will remain blinded until the end of the study. 
c Beginning at the Week 28 Visit, all subjects in the Extension Phase will be dispensed open-label apremilast (30 mg BID) in high-density polyethylene (HDPE) bottles. Subjects 
must be clearly instructed to follow dosing instructions.  
d Subjects who discontinue the study prior to the Week 48 Visit, will have an Early Termination (ET). 
 
 
e The Observational Follow-up Visit will be conducted 4 weeks after the last dose of IP (± 7 days). 
f If an on site study visit is replaced with a telemedicine assessment, vital signs will not be measured. 
g If an on site study visit is replaced with a telemedicine assessment, the subject’s weight will not be measured. 
h Females of childbearing potential (FCBP) will have a serum pregnancy test done at the Screening Visit and at the Week 48 Visit (or Early Termination Visit). The urine 
pregnancy test collected at the Baseline Visit must be assessed prior to study randomization. The Investigator must educate all FCBP about the options for and correct use of 
contraceptive methods at the Screening and Baseline Visits and at any time when a subject’s contraceptive measures or ability to become pregnant change. An unscheduled 
pregnancy test should be administered if the subject has missed a menstrual period or at the discretion of the Investigator per country specific guidelines. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
55 
CC-10004-PSA-013 Amendment 5 Final: 12 July 2021 
i Details pertaining to the monitoring and collection of adverse events are included in Section 10. Information about specific safety assessments are provided in Section 6.5. 
j For the dactylitis assessment at Screening, only a binary evaluation is needed (yes/no). 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
56 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
6. 
PROCEDURES 
The following procedures will be conducted as outlined in Table 13, the Table of Events. 
6.1. 
Screening Period 
Following the signing of the informed consent form (ICF), 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. 
The following evaluations will be performed at the frequency specified in Table 13, Table of 
Events: 
 Demographics include year of birth, sex, race, and ethnicity-if allowed by local 
regulations, will be collected. 
 Smoking and alcohol intake history 
 Complete medical history including all relevant medical conditions diagnosed, and 
occurring prior to the Screening Visit, should also be recorded. 
 PsA history will be collected. 
 Prior and concomitant medication evaluation including all medications (prescription and 
nonprescription, including vitamins) taken by the subject up to  28 days prior to the 
Screening Visit should be recorded.  All medications taken by the subject at any time 
during the study must also be recorded. Other key medications and therapies, such as 
previous treatment for tuberculosis or relevant diseases, should also be recorded. 
 Prior and concomitant PsA-related medications: 
o All medications for PsA and oligoarthritis taken by the subject are to be recorded 
in the subject’s source document prior to study randomization. 
o Careful attention must be taken when randomizing a subject in IWRS regarding a 
subject’s use of glucocorticosteroids and DMARDs. This includes use prior to 
study randomization and at the time of study randomization at the Baseline Visit. 
o PsA medications and all other medications must also be recorded in the eCRF 
according to the CRF guidelines.  
o Contraindicated PsA medications: 
▪ For this protocol, contraindication to PsA medications will refer to those 
subjects who have a pre-existing medical condition where administration 
of the medication is not possible since the treatment could cause harm to 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
57 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
the subject, resulting in the subject NOT TAKING the medication. For 
subjects who meet this criterion, this information must be recorded in the 
source document along with the pre-existing medical condition that 
prevented the subject from receiving the treatment. The pre-existing 
medical condition must also be reported the eCRF. 
 Prior and concomitant procedures including all procedures occurring  28 days before the 
Screening Visit must be collected. 
 Vital signs 
 Height and weight 
 Chest X-ray is not required per protocol but may be done at the discretion of the 
Investigator or according to local regulations and guidelines. 
 Diarrhea assessment (Section 6.5.5)  
 Complete physical examination (recorded in the source document) 
 Laboratory evaluations will be performed by a central laboratory and are described in 
Section 6.5.7 and are listed below: 
o Hematology panel   
o Chemistry panel 
o Urinalysis 
▪ Microscopic urinalysis (epithelial cells, red blood cells [RBCs], white 
blood cells [WBCs], crystals, bacteria, and casts) will be performed only if 
the urinalysis is abnormal. 
o High sensitivity C-reactive Protein (hsCRP) 
o Rheumatoid factor 
 Adverse event evaluation (continuously) 
 SJC and TJC assessment 
 Pregnancy test is required for all female subjects of childbearing potential.  Serum beta 
human chorionic gonadotropin -hCG pregnancy test will be performed at the Screening 
Visit. 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 will be performed by the Investigator at screening for all FCBP 
about the options for and correct use of contraceptive methods at the Screening and 
Baseline Visits and at any time when a FCBP’s contraceptive measures or ability to 
become pregnant changes. 
o A pregnancy test should be performed if the FCBP subject has missed a menstrual 
period or the contraception method has changed 
o Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
58 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
6.2. 
Treatment Period  
The Treatment Period includes the Placebo-controlled Phase and the Extensions Phase. 
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 28 days of signing the ICF.  The following evaluations will be performed at the 
frequency specified in Table 13. In addition, at the discretion of the investigator, an Unscheduled 
Visit may be performed to evaluate subject safety and efficacy as needed. 
 Concomitant medications evaluation 
 Concomitant procedures evaluation 
 Limited or complete physical examination (source documented only) as described in 
Table 13. During the Extension Phase, limited physical exam may be done at the 
discretion of the Investigator. 
 Vital signs 
 Diarrhea assessment (Section 6.5.5)  
 Weight (Section 6.5.2) 
 Hematology panel  
 Chemistry panel 
 hsCRP 
 Urinalysis 
 Microscopic urinalysis (epithelial cells, RBCs, WBCs, crystals, bacteria, and 
casts) will be performed only if the urinalysis is abnormal. 
 Adverse event evaluation (continuously) 
 Efficacy assessments (see Section 6.4) 
 Patient reported outcomes (PROs), Quality of Life (QOL) assessments and Health 
Economics (Section 6.6) 
 Urine pregnancy testing will be done for FCBP prior to dosing at the Baseline Visit. 
Serum beta human chorionic gonadotropin -hCG pregnancy test will be performed at 
the Week 48 Visit 
 IP dispensing and accountability 
6.2.1. 
End of Treatment 
An end of treatment (EOT) evaluation 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.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
59 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
The following evaluations will be performed as specified in Table 13, Table of Events: 
 Complete physical examination (source documented only) 
 Vital signs 
 Weight 
 Diarrhea assessment (Section 6.5.5) 
 Concomitant medications evaluation 
 Concomitant procedures evaluation 
 Subject reported outcomes or quality of life 
 Adverse event evaluation  
 Hematology panel 
 Chemistry panel 
 hsCRP 
 Urinalysis  
 Microscopic urinalysis (epithelial cells RBCs, WBCs, crystals, bacteria, and 
casts) will be performed only if the urinalysis is abnormal. 
 Serum beta human chorionic gonadotropin -hCG pregnancy test will be performed for 
FCBP. 
 Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted.  
 Efficacy Assessments (Section 6.4) 
 PROs (Quality of Life (QOL) assessments and Health Economics (Section 6.6) 
 Return/count of study drug  
6.3. 
Observational Follow-up 
6.3.1. 
Safety Follow-up 
All subjects will be followed for 28 days after the last dose of apremilast for AE reporting, as 
well as SAEs made known to the Investigator at any time following the protocol-required 
reporting period or after end of study , as described in Section 10. 
The following evaluations will be performed at the Observational Follow-up Visit, or if 
necessary via telephone contact, as specified in Table 13, Table of Events: 
 Concomitant medications evaluation 
 Concomitant procedures evaluation 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
60 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 Adverse event (non-serious and serious) evaluation 
6.4. 
Efficacy Assessments 
The following assessments will be conducted as outlined in Table 13, Table of Events. Subject 
questionnaires and clinician assessments will be reported using electronic data capture. These 
data will be entered directly into the ERT tablet. 
6.4.1. 
Modified Minimal Disease Activity–Joints (MDA-Joints) and its Components  
For this study, the MDA-Joints (Appendix C) is used as the primary endpoint and is defined as 
Tender Joint Counts (TJC)  1 and Swollen Joint Counts (SJC)  1 plus 3 of any of the 5 criteria: 
1) patient’s global VAS on a 100-mm scale  20, 2) patient pain VAS on a 100-mm scale  15, 
3) physical function [HAQ-DI]  0.5, 4) enthesitis count  1 (based on the Leeds Enthesitis 
Index) and 5) psoriasis Body Surface Area (BSA)  3.  Joint assessment to be based on 66 
swollen joints and 68 tender joints (see Section 6.4.1.1). Assessment of the joint counts will be 
performed by the evaluator, however, calculation of the MDA-Joints will be done 
programmatically. 
6.4.1.1. 
Joint Assessment 
A modified joint count that includes the distal interphalangeal joints of the fingers and toes (the 
“68 tender and 66 swollen” joint scores; (Appendix D) will be performed at every visit. 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 or intra-muscular glucocorticoid (allowed only after Week 24 
assessments are completed, and up to the Week 48 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. 
6.4.1.2. 
Patient’s Global Assessments of Disease Activity 
The Patient’s (Subject’s) Global Assessments of Disease Activity (Appendix E) is an assessment 
of how active a subject’s psoriatic arthritis was on average during the last week. The subject will 
be asked to place a vertical line on a visual analogue scale (VAS) on which the left-hand 
boundary represents the lowest level of disease activity and the right-hand boundary represents 
the highest. Distance from the mark to the left-hand boundary will be recorded in millimeters, 
except when calculating cDAPSA score, where the distance will be calculated in centimeters. 
6.4.1.3. 
Patient’s Pain Visual Analogue Scale  
The pain visual analogue scale (VAS) is the subject’s assessment of how much pain he/she had, 
on average, last week in his/her joints due to PsA.  The subject will be asked to place a vertical 
line on a VAS on which the left-hand boundary represents “no pain,” and the right-hand 
boundary represents “pain as severe as can be imagined” (Appendix E). The distance from the 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
61 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
mark to the left-hand boundary will be recorded in millimeters, except when calculating 
cDAPSA score, where the distance will be calculated in centimeters. 
6.4.1.4. 
HAQ-DI 
The HAQ-DI (Appendix F; 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). 
6.4.1.5. 
Enthesitis: Leeds Enthesitis Index 
In the evaluation of MDA-Joints, enthesitis will be assessed by the Leeds Enthesitis Index (LEI) 
(Appendix G; Healy, 2008). 
For the LEI, pain will be assessed at the following entheses (tendon insertions): Lateral 
epicondyle humerus (left/right (L/R)); Medial condyle femur (L/R); Achilles tendon insertion 
into calcaneum (L/R). The LEI ranges from 0 to 6. 
6.4.1.6. 
BSA 
BSA (Appendix H) is a measurement of involved skin. The overall BSA affected by psoriasis is 
estimated based on the palm area of the subject’s hand (entire palmar surface or “handprint”), 
which equates to approximately 1 of total body surface area. All subjects will have their BSA 
assessed by the Evaluator.  
6.4.1.7. 
Physician’s Global Assessments of Disease Activity  
The Physician’s (Evaluator’s) Global Assessments of Disease Activity is an assessment of how 
active a subject’s psoriatic arthritis was on average during the last week. For the Physician’s 
(Evaluator’s) Global Assessments of Disease Activity, evaluator should mark a single vertical 
mark on a 100-mm VAS (see Appendix E), with zero representing the lowest level of disease 
activity or pain and 100 representing the highest. The distance from the mark to the left-hand 
boundary of the scale will be recorded in millimeters (Appendix E, Felson, 1995). 
6.4.2. 
Enthesitis: 
 
In addition to assessment by the Leeds Enthesitis Index (Section 6.4.1.5), enthesitis will also be 
assessed using the 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
62 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
6.4.3. 
Dactylitis 
Dactylitis assessment will be done at screening, only a binary evaluation is needed (yes/no). 
 
6.4.4. 
Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) 
The cDAPSA score (Appendix K) is based on the numerical summation of 4 disease activity 
variables: tender and swollen joints, patient global and pain assessments on a 10 cm Visual 
Analogue Scale (VAS) (Appendix E). Proposed cut-offs for cDAPSA 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. Evaluation of components of cDAPSA is described 
above. The calculation of the cDAPSA will be performed programmatically. 
6.4.5. 
Psoriatic Arthritis Disease Activity Score (PASDAS) 
The PASDAS (Helliwell, 2014; Appendix L) is a weighted index comprising assessments of 
joints, function, acute-phase response, quality of life (QOL), and patient and physician by VAS. 
The calculation of the PASDAS will be performed programmatically using the formula below: 
PASDAS  ((0.18 x Physician global VAS)  (0.159 x Patient global VAS) – (0.253 x 
SF36 – PCS)  (0.101 x LN (Swollen joint count  1))  (0.048 x LN (Tender joint count  
1))  (0.23 x LN (Leeds Enthesitis Count  1))  (0.377 x LN (Dactylitis count  1))  (0.102 
x LN (CRP  1)) 2)*1.5. 
Note: LN  natural logarithm, PCS  physical component summary scale of SF36, CRP  C-
reactive protein in mg/l, SF36  Medical Outcomes Study Short Form-36. 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. Definition of 
good or moderate response is detailed in Appendix L. 
6.4.6. 
High sensitivity C-reactive Protein 
High sensitivity C-reactive protein (hsCRP) and rheumatoid factor will be performed at a central 
laboratory along with the other clinical laboratory assessments described in Section 6.5.7. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
63 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 
by the study team. The review follows the Council for International Organizations for Medical 
Sciences, Working Group VI (CIOMS VI) recommendations.  
The study will be conducted in compliance with the ICH of Technical Requirements for 
Registration of Pharmaceuticals for Human Use/GCP and applicable regulatory requirements. 
The following assessments will be conducted as outlined in Table 13, Table of Events. 
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 and the Week 48 Visit (or at the Early Termination Visit for subjects who prematurely 
discontinue from the study). Urine pregnancy test will be performed on all FCBP subjects at the 
Baseline Visit, prior to randomization. A 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 Table 13, 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 Table 13, Table of Events. Height will be measured and recorded at Screening; 
weight will also 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 
(assessment of joints and spine) systems. A complete physical examination is done at Screening 
and other designated visits as indicated in Table 13, Table of Events. A limited physical 
examination includes evaluations of skin, lymph nodes, and respiratory, cardiovascular, and 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
64 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
musculoskeletal systems. A limited physical examination is done at the Baseline Visit and other 
designated visits as indicated in Table 13. 
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 subject suffers from new or worsening psychiatric symptoms, or if suicidal ideation or 
suicidal attempt is identified, it is recommended to discontinue the subject participation to the 
study (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.  
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. This data will be reported via electronic data capture in the ERT tablet. If an AE is 
identified by the Investigator, the AE and respective attributes will be reported in the clinical 
database. If the AE meets serious criteria, it must be reported to Amgen Global Patient Safety 
(see Section 10.5). 
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 subjects 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 a subject develops severe 
diarrhea, nausea and vomiting, discontinuation of study treatment may be necessary (see 
Section 11). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
65 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 as indicated in 
Table 13, Table of Events. These include complete blood count (red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count and differential, absolute WBC counts, 
platelet count) and serum chemistries (total protein, albumin, calcium, phosphorous, glucose, 
triglycerides, total cholesterol [TC], total bilirubin, alkaline phosphatase, aspartate 
aminotransferase [AST; serum glutamic-oxaloacetic transaminase, SGOT], alanine 
aminotransferase [ALT; serum glutamic pyruvic transaminase, SGPT], sodium, potassium, 
chloride, bicarbonate [carbon dioxide, CO2], blood urea nitrogen, creatinine, creatinine clearance 
[estimated by the Cockcroft–Gault equation], lactate dehydrogenase [LDH], and magnesium); 
rheumatoid factor; high-sensitivity C-reactive protein (hsCRP), 
urinalysis (specific gravity, pH, glucose, ketones, protein, blood, bilirubin, leukocyte esterase, 
nitrite, and urobilinogen. Microscopic urinalysis (epithelial cells, red blood cells [RBCs], white 
blood cells [WBCs], crystals, bacteria, 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 of 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. Adverse events and serious adverse events (SAEs) will be 
recorded on the AE page of the electronic case report form (eCRF), the paper SAE reporting 
form (SAEs) and in the subject’s source documents. All SAEs must be reported to Amgen 
Global Patient Safety immediately (ie, within 24 hours of the Investigator’s knowledge of the 
event) by recording on the CRF and completing the paper SAE Report Form which is sent 
directly to Amgen Global Patient Safety by facsimile or email. 
Details of AE reporting can be found in Section 10 of the protocol. It should be noted that 
worsening of a subject’s psoriatic arthritis should be considered as worsening of disease under 
study and should not be captured as an adverse event. 
 
6.6. 
Patient Reported Outcomes or Quality of Life or Health Economics 
Questionnaires will be performed and as indicated in Table 13, Table of Events. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
66 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
6.6.1. 
The PsA Impact of Disease 12-Item (PsAID-12) Questionnaire 
The PsAID-12 Questionnaire (Appendix N; Gossec, 2014) 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  4.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
67 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
68 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 and placebo will be provided as identically appearing by the Sponsor and labeled 
appropriately as investigational product for this study. In addition, tablets (both apremilast and 
placebo) required for dose titration cards will also be provided. 
Please refer to the IB for more details on approved indications, known precautions, warnings, 
and adverse reactions of apremilast. 
The apremilast dosing schedule to be followed for this study is described in Section 7.2.  
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 (see Table 14). 
At the Week 0 (ie, initial randomization), Week 16 (ie, for Early Escape subjects), and Week 24 
(ie, Active-treatment Phase) visits, subjects will be dispensed blister cards with 10, 20, and 
30 mg apremilast tablets or identically appearing placebo for the dose titration. Subjects will be 
dispensed blister cards containing 30 mg apremilast tablets or identically appearing placebo at 
designated visits (Table 13). Beginning at the Week 28 Visit, subjects will be dispensed open 
label bottles with 30 mg apremilast tablets. Pictures of the blister card configurations are shown 
in Appendix T. Dose modifications are not permissible in this study. Apremilast and placebo 
tablets (oral IP) are identical in appearance. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
69 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 
Table 14: 
Treatment of Schema for Dose Titration at Baseline 
Dose 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Group 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Placebo 
(dummy 
titration) 
10 mg 
placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
30 mg 
apremilast 
(titration) 
10 mg 
apremilast  
20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg 
apremilast  
20 mg placebo 
 30 mg 
placebo 
10 mg 
apremilast  
20 mg placebo 
 30 mg 
placebo 
10 mg 
apremilast 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
 
 
Table 15: 
Treatment Schema for Dose Titration at Week 16 (Early Escape) or Week 24 
Dose 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Group 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Placebo to 
30 mg 
apremilast 
(titration) 
10 mg 
apremilast  
20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg 
apremilast  
20 mg placebo 
 30 mg 
placebo 
10 mg 
apremilast  
20 mg placebo 
 30 mg 
placebo 
10 mg 
apremilast 
 20 mg 
placebo 
 30 mg 
placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
apremilast  
30 mg placebo 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
30 mg 
apremilast 
(dummy 
titration)  
10 mg 
placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
10 mg placebo 
 20 mg 
placebo 
 30 mg 
apremilast 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
70 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
7.3. 
Method of Treatment Assignment 
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 in a 2:1 ratio to receive either apremilast 30 mg tablets or placebo. The IWRS will 
stratify the randomized subjects by their use of glucocorticosteroids (yes/no) and use of a 
csDMARD: (csDMARD-naïve; csDMARD use prior to baseline; or csDMARD use prior to and 
concomitant at baseline). 
Subjects who are randomized to apremilast at baseline will be dose-titrated during their first 
week of active treatment (see Section 7.2), while subjects who are randomized to placebo will 
receive identically appearing placebo titration cards while continuing to receive their assigned 
dose of placebo BID.  
Subjects with no improvement in the swollen joint count at Week 16 are eligible for early 
escape. The joints monitored for early escape must correspond to those affected at baseline 
(sentinel joints). To maintain the study blind, placebo-treated subjects who escape early will be 
transitioned in a blinded fashion via an IWRS to apremilast 30 mg BID and apremilast-treated 
subjects will remain blinded on their original treatment assignment. Placebo subjects will be 
dose-titrated during their first week of active treatment (see Section 7.2), while subjects who 
were already on apremilast 30 mg BID will receive identically appearing placebo titration cards 
while continuing to receive their assigned dose of apremilast 30 mg BID.  
At the Week 24 Visit, subjects will be offered to enter a 24-week Active - treatment Extension 
Phase (Extension Phase). All subjects enrolled in the Extension Phase will receive treatment with 
apremilast (30 mg BID) until the completion of the study (ie, up to the Week 48 Visit) or until 
early discontinuation. Placebo subjects will be dose titrated (5-day titration period). All subjects 
will receive treatment cards of identical appearance to maintain the blinding of the original 
treatment assignments (apremilast 30 mg BID or placebo). 
Beginning at the Week 28 Visit, the next scheduled study visit following the placebo titration 
period, all subjects in the Extension Phase will be dispensed open-label apremilast (30 mg BID) 
in high-density polyethylene (HDPE) bottles. Subjects must be clearly instructed to follow 
dosing instructions. 
Designated study personnel at the investigational sites will be assigned password protected, 
coded identification numbers, which give them authorization to log into the IWRS to randomize 
subjects. The system will present a menu of questions by which the study personnel will identify 
the subject and confirm eligibility. When all questions have been answered, the IWRS will 
assign a randomization identification number. Confirmation of the randomization will be sent via 
fax to the investigational site, Amgen and/or its representative. 
During the study visits, the pharmacy or authorized study personnel at the investigational site 
will dispense coded IP kits in accordance with the randomization number assigned by the IWRS.  
7.4. 
Packaging and Labeling 
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 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
71 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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. 
All IP, including placebo and apremilast tablets, will be supplied by Amgen Inc. to the principal 
Investigator as blister cards during the Placebo-controlled Phase. 
Starting at the Week 28 Visit, apremilast 30 mg tablets will be supplied in HDPE bottles with 
child-resistant caps. 
7.5. 
Investigational Product Accountability and Disposal  
The Investigator, or designee, is responsible for taking an inventory of each shipment of oral IP 
received, and comparing it with the accompanying IP 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 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). 
7.6. 
Study Medication Dispensing and Counting 
After the subject has satisfied all inclusion and exclusion criteria, study medication will be 
dispensed as specified in Table 13, 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. 
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). 
7.7. 
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 Table 13, Table of 
Events. 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 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 the Observational 
Follow-up Phase. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
72 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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. 
7.8. 
Overdose 
Overdose, as defined for this protocol, applies to protocol-required dosing of the investigational 
product(s) (IPs) 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 the control arm drug (ie, placebo), hence overdose definition will apply to 
only apremilast (or matching placebo). Other required or optional non-study drugs intended for 
prophylaxis of certain side effects, etc, are excluded from this definition. 
Overdose for this protocol, on a per dose basis, is defined as ingestion of 4 or more 30 mg 
apremilast (or matching placebo) 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 
eCRF (see Section 10) for all overdosed subjects, but the overdose itself is not considered an AE. 
If the AE associated with the overdose meets seriousness criteria, it must also be reported to 
Amgen Global Patient Safety using the paper SAE report form (see Section 10.5). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
73 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
8. 
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 eCRF. 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. Additional instructions can be found in the 
electronic Case Report Form (eCRF) Completion Guidelines.  
8.1. 
Permitted Concomitant Medications and Procedures 
The following concomitant medications and procedures are permitted during the study:  
 Oral glucocorticosteroids are to be taken on a stable dose up to the Week 24 Visit: 
o Prednisone  10 mg/day (or prednisolone equivalent) for at least 4 weeks prior to 
the Baseline Visit must be continued and maintained through the Week 24 Visit 
(change in dose and/or discontinuation are not allowed except for safety reasons 
or for lack of availability). 
 NSAIDs (and/or narcotic analgesics) are allowed during the study, provided that the 
NSAIDs are taken on a stable dose for at least 2 weeks prior to the Baseline Visit. 
o The stable dose of NSAIDs or narcotic analgesics must be continued and 
maintained from the Baseline Visit 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. 
o NSAIDs or narcotic analgesics that are administered on an as needed basis (PRN) 
should be recorded on the Prior/Concomitant Medications page of the eCRF.  
 csDMARDs –  
o Only 1 csDMARD (MTX or SSZ) for the treatment of PsA is permitted during the 
first 24 weeks of the study, provided that the treatment is taken on a stable dose 
 3 months prior to the Baseline Visit.  
o Subjects exposed to MTX or SSZ and stopped treatment due to intolerance or due 
to safety reasons may enter the study provided that treatment was stopped within 
at least 4 days of the Baseline Visit  
 The allowed dose for permitted csDMARDs are: MTX (oral or parenteral) 
 25 mg /week; SSZ (oral)  3 gm/daily 
 Low-dose aspirin (acetylsalicylic acid, up to 325 mg per day) for cardiovascular 
prophylaxis.  
 Loperamide and antidiarrheal drugs with antisecretory effect (eg, racecadotril). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
74 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 A nonmedicated skin emollient (eg, Eucerin cream) for body psoriasis lesions only.  
After the Week 24 Visit, changes in the following therapy will be permitted as clinically required 
for subjects with worsening arthritic symptoms of PsA: 
 Change of NSAID type and/or dose 
 Parenteral glucocorticoids are allowed, provided that the following criteria are met: 
o Administration of no more than 40 mg intra-articular (IA) or intra-muscular (IM) 
glucocorticosteroid (triamcinolone hexacetonide or equivalent) injection at a single 
visit.  
o Injected joints should not be counted during the visits that will take place within 4 
weeks of the intra-articular injection. Joints should be marked with an X. 
o Intra-articular injection should not be performed after week 44 visit (ie, 4 weeks 
prior to study end). 
 Oral glucocorticosteroids may be adjusted as clinically required 
o Short course ( 2 weeks) of oral corticosteroids, including a Medrol Dosepak, not to 
exceed one course in any 6-month interval  
 Non-biologic DMARDs: methotrexate ( 25 mg/week), sulfasalazine ( 3 gm/day), 
leflunomide ( 20 mg/day), hydroxychloroquine ( 400 mg/day), chloroquine 
( 600 mg/day). 
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 has been tapered (not required to be zero), the dose must be 
stable for at least 4 weeks prior to tapering the next agent. Subjects are recommended to have a 
reduction of background therapy in the following order (when applicable): First csDMARD, 
second glucocorticosteroids 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.  
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. 
8.2. 
Concomitant Medications Not Recommended 
It has been observed that coadministration with strong cytochrome P450 3A4 (CYP3A4) enzyme 
inducers, 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 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 during the 
study as noted below: 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
75 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 Use of 1 csDMARD prior to Week 24 
 Prior use of tofacitinib or any other JAK-inhibitor 
 Use of any biologic DMARD.   
 Use of leflunomide within 12 weeks of randomization. Subjects who stopped 
leflunomide and completed 11 days of treatment with cholestyramine (8 g TID) prior 
to the Baseline Visit may enter the study. Leflunomide may be initiated 
( 20 mg/day) after Week 24. 
 Prior use of cyclosporine  
 Use of DMARDs other than MTX or SSZ for the treatment of PsA, except for MTX 
( 25 mg/week), or SSZ ( 3 gm daily), prior to Week 24. 
 Use of intra-articular (IA) and intra-muscular (IM) glucocorticoid injection within 
8 weeks before the Baseline Visit. Use of IA and IM injections may be administered 
after Week 24 as discussed in Section 8.1. 
8.4. 
Required Concomitant Medications and Procedures 
There are no required concomitant medications or procedures. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
76 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Overview  
The primary efficacy analysis of the proportion of subjects achieving the modified MDA 
(MDA-Joints) at Week 16 and the secondary analyses will be performed after all subjects 
complete the placebo-controlled period (Week 0 to 24) or terminate early prior to Week 24 visit. 
Additional analyses will be performed after the final database lock when all subjects complete 
the study or terminate early. 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 unblinding of the treatment assignment 
for the 24-week, placebo-controlled, double-blind treatment phase of the study or any analysis 
procedures are conducted, whichever is earlier.  
9.2. 
Study Population Definitions 
The Full Analysis Set (FAS) will consist of all subjects who are randomized. Efficacy analyses 
will be primarily based on the FAS and subjects will be included in the treatment group to which 
they are randomized. 
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 during the 24-week placebo-controlled 
treatment period. The final determination of major protocol violations will be made prior to the 
unblinding of treatment assignment and will be documented. The PP analyses will be based on 
the PP population and subjects will be included in the treatment group for the treatment they 
actually receive. 
The Safety population will consist of all subjects who receive at least one dose of study 
medication. The safety analyses will be based on the safety population and subjects will be 
included in the treatment group for the treatment they actually receive. 
9.3. 
Sample Size and Power Considerations 
Sample size estimation was based on the results from integrated analyses of subpopulation data 
from five Phase 3 studies (PSA-002, PSA-003, PSA-004, PSA-005, and PSA-006). Assuming a 
15 dropout rate during the randomized, placebo-controlled, double-blind treatment phase, a 
sample size of approximately 
 for the Apremilast 30 mg BID and placebo groups, 
respectively, will have 80 power to detect a true 15 difference (30 versus 15) in the 
proportions of subjects achieving the modified MDA (MDA-Joints) between the Apremilast 
30 mg BID and placebo groups, using a chi-square test with a two-sided significance level of 
0.05.  
9.4. 
Background and Demographic Characteristics 
Subjects’ 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 summarized using frequency tabulations. Treatment 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
77 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
history (including oral glucocorticosteroid, NSAIDs, and csDMARD use) will be summarized 
using frequency distributions.  
9.5. 
Subject Disposition 
Subject disposition (counting of analysis populations; and subjects enrolled, randomized, and 
completing or discontinuing in 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. 
9.6. 
Efficacy Analysis 
9.6.1. 
Efficacy Evaluation for the Placebo-Controlled, Double-Blind Treatment Phase 
The analyses of efficacy endpoints will be primarily based on the FAS. In addition, supportive 
analyses using the Per Protocol population will also be conducted for the primary endpoint.  
Efficacy results will be considered statistically significant after consideration of the control of 
multiplicity, as specified in Section 9.6.2. Two-sided p-values and confidence intervals (CIs) will 
be reported, and all statistical tests will be conducted at the significance level of 0.05. 
9.6.2. 
Multiplicity 
Statistical tests for comparing the apremilast 30 mg BID and placebo will be conducted for the 
primary endpoint and the secondary efficacy endpoints as listed in Section 2. 
The multiplicity of the analyses performed for the primary and selected secondary efficacy 
endpoints will be adjusted using a sequential test procedure to preserve the family-wise type I 
error rate. The hierarchy order of the selected secondary endpoints to be followed in the 
sequential test procedure will be specified in the statistical analysis plan (SAP). 
It should be noted that the above multiplicity control will only be conducted for the primary 
endpoint and the key secondary endpoints that are evaluated in the randomized, placebo-
controlled, double-blind treatment phase. 
9.6.3. 
Primary Efficacy Endpoint 
The primary efficacy endpoint, proportion of subjects who achieve the modified MDA 
(MDA-Joints) at Week 16, between the Apremilast 30 mg BID and placebo groups will be 
compared using a Cochran-Mantel-Haenszel test, controlling for concomitant use of 
glucocorticosteroids at baseline (yes/no) and use of a csDMARD: (csDMARD-naïve; csDMARD 
use prior to baseline; or csDMARD use prior to and concomitant at baseline). 
Subjects who have discontinued prior to Week 16 due to lack of efficacy or adverse event will be 
treated as non-responders in the analysis; and the multiple imputation methodology will be 
utilized to impute the data for subjects whose modified MDA at Week 16 is missing for a reason 
other than lack of efficacy or adverse event. Sensitivity analyses will be performed using the 
non-responder imputation for subjects who have discontinued prior to Week 16, or do not have 
sufficient information for a definitive determination of the modified MDA (MDA-Joints) status 
at Week 16.  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
78 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
9.6.4. 
Secondary Endpoints 
For the secondary endpoints, the analyses of binary responses in the placebo-controlled phase 
will be similar to the analysis of the primary endpoint. That is, a Cochran-Mantel-Haenszel test 
adjusted for concomitant use of glucocorticosteroids at baseline (yes/no) and use of a 
csDMARD: (csDMARD-naïve; csDMARD use prior to baseline; or csDMARD use prior to and 
concomitant at baseline) will be used to compare the response rates between the apremilast 
30 mg BID and the placebo groups.  
A mixed-effect model of repeated measures (MMRM) will be used to analyze the continuous 
endpoints. The MMRM model will use change from baseline as the dependent variable and 
include treatment group, time, treatment-by-time interaction, use of glucocorticosteroids (yes/no) 
and use of a csDMARD (csDMARD-naïve; csDMARD use prior to baseline; or csDMARD use 
prior to and concomitant at baseline) as factors, and baseline value as a covariate. Time will be 
treated as a categorical variable in the MMRM model.  
All analyses on endpoints including joint counts will be performed on those joints that are 
affected at baseline (defined as sentinel joints). 
 
 
9.6.5. 
Active-Treatment Phase.  
Efficacy endpoints beyond Week 24 will be summarized using descriptive statistics for 
continuous variables and frequency tabulation for discrete variables.  
9.7. 
Safety Analysis 
The safety analyses will be performed using the safety population as defined in Section 9.2. 
Adverse events will be classified using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) classification system. All adverse events will be summarized by system organ class 
and preferred term; in addition, by severity and relationship to investigational product separately. 
Adverse events leading to death, if any, or to discontinuation from treatment, serious adverse 
events, and study drug-related adverse events 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 pretreatment 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 pretreatment 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, as appropriate.  
9.8. 
Interim Analysis 
Not applicable. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
79 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
9.9. 
Other Topics 
9.9.1. 
Investigational Product Compliance (Tablets) 
Investigational product record information will be summarized. Overall compliance will be 
estimated by the proportion of subjects who take between 75 and 120 of the intended 
quantity of IP. 
9.9.2. 
Concomitant Therapy 
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations. The Anatomical Therapeutic Chemical coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations. Separate data summaries of background medications will be provided. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
80 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 an investigational product 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 7.8 for the definition of overdose.)  Any sequela of 
an accidental or intentional overdose of an investigational product which meets the definition of 
an adverse event, should be reported as an AE on the CRF.  If the sequela of an overdose meets 
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 of IP 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 completing the paper SAE Report Form which is sent to 
Amgen Global Patient Safety by facsimile/email. 
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. Please refer to Section 10.2 for further details on how to record such AEs. 
10.2. 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to:  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
81 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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. 
 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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
82 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
If an AE is considered serious the AE page 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 the IP, action taken regarding the IP, 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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
83 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
10.2.3. 
Causality 
The Investigator must determine the relationship between the administration of the IP 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 IP as a result of each AE, as applicable (eg, 
discontinuation, interruption, or dose reduction of IP, 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 to be an AE if the abnormality: 
 Results in discontinuation from the study; 
 Requires treatment, modification/ interruption of IP 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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
84 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 -subunit of human chorionic 
gonadotropin [-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 X).  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 SAEs. 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 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
85 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 Y) 
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 subject’s 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 for an SAE requires the reporting of 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 IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) and any 
SAE made known to the Investigator at any time following the protocol-required reporting 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
86 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
period or after end of study.  Serious adverse events occurring prior to treatment (after signing 
the ICF) are to be collected/recorded/reported.  
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. 
The SAE is recorded within the CRF and reported directly to Amgen Global Patient 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.  
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 SAE 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 W). 
 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 SAE 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 SAE Report Form (refer to Appendix W). 
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.  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 purpose of regulatory reporting, Amgen Global Patient Safety will determine the 
expectedness of events suspected of being related to apremilast based on the Investigator 
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 (EEA), Amgen or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
87 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Committees concerned, suspected unexpected serious adverse reactions (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 investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.   
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 SAE 
Report Form, paper Pregnancy Notification Form and/or paper Lactation Notification Form 
(Appendix W, Appendix X, Appendix Y). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
88 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
11. 
DISCONTINUATIONS 
11.1. 
Treatment Discontinuation 
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s): 
 Adverse event(s) 
 Withdrawal by subject 
 Death 
 Lost to follow-up 
 Lack of efficacy 
 Non-compliance with study drug 
 Study terminated by Sponsor 
 Pregnancy 
 Death 
 Protocol deviation 
 Other (to be specified on the CRF) 
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents. 
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 
 Loss 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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
89 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 
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 
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor. However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject.  
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation. 
Emergency unblinding should only be performed by the Investigator through the Integrated 
Response Technology (IRT) by using an emergency unblinding personal identification number 
(PIN), and the Investigator should call IRT for unblinded dose information. Beginning at Week 
24 all subjects will be dispensed apremilast with titration in blinded treatment cards (Sections 7.3 
and 7.4). However, subjects will receive open-label apremilast at beginning at Week 28 until the 
end of the study, or until early discontinuation. Therefore, IP will be identified on the package 
labeling beginning at Week 28. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
90 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 informed consent 
form (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. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
91 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 for 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 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
92 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
93 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 investigational product 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 SOPs. This 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 CRFs (if paper) and 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). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
94 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
95 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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, a 
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, 
investigational product 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 (eg, FDA, 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-


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
96 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
97 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
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. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
98 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
17. 
REFERENCES 
Aletaha D, Smolen JS. The definition and measurement of disease modification in inflammatory 
rheumatic diseases. Rheum Dis Clin North Am. 2006;32(1):9-44, vii. 
Annual Scientific Meeting of the American College of Rheumatology; 10/2011; Chicago, IL; 
November 4-9, 20112011. p. S153. 
Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of its history, issues, 
progress, and documentation. J Rheumatol. 2003;30(1):167-78. 
Coates LC, FitzGerald O, Gladman DD, McHugh N, Mease P, Strand V, et al. Reduced joint 
counts misclassify patients with oligoarticular psoriatic arthritis and miss significant numbers of 
patients with active disease. Arthritis Rheum. 2013;65(6):1504-9. 
Coates LC, Helliwell PS. Methotrexate Efficacy in the Tight Control in Psoriatic Arthritis Study. 
J Rheumatol. 2016;43(2):356-61. 
Coates LC, Mahmood F, Emery P, Conaghan PG, Helliwell PS. The dynamics of response as 
measured by multiple composite outcome tools in the TIght Control of inflammation in early 
Psoriatic Arthritis (TICOPA) trial. Ann Rheum Dis. 2017;76(10):1688-92. 
Coates LC, Cook R, Lee A, Chandran V, Gladman D. Frequency, predictors, and prognosis of 
sustained minimal disease activity in an observational psoriatic arthritis cohort. Arthritis Care & 
Research, 2010,62, (7): 970–976. 
Cutolo M, Myerson GE, Fleischmann R, Liote F, Diaz-Gonzalez F, Van den Bosch F, et al. A 
phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of 
the PALACE 2 trial. J Rheumatol. 2016;43(9):1724-34. 
Edwards CJ, Blanco FJ, Crowley J, Birbara CA, Jaworski J, Aelion J, et al. Apremilast, an oral 
phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a 
phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis. 2016;75(6):1065-73. 
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College 
of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis 
Rheum. 1995;38(6):727-35. 
Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. 
Arthritis Rheum. 1980;23(2):137-45. 
Gladman D, Antoni C, Mease P, Clegg D, Nash P. Psoriatic arthritis: epidemiology, clinical 
features, course and outcome. Ann Rheum Dis 2005;64(Suppl II):ii14–ii17. doi: 
10.1136/ard.2004.032482. 
Gossec L, de Wit M, Kiltz U, Braun J, Kalyoncu U, Scrivo R, et al. A patient-derived and 
patient-reported outcome measure for assessing psoriatic arthritis: elaboration and preliminary 
validation of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire, a 13-country 
EULAR initiative. Ann Rheum Dis. 2014;73(6):1012-9. 
Gossec L, Smolen JS, Ramiro S, De Wit M, Cutolo M, Dougados M, et al. European League 
Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with 
pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75(3):499-510. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
99 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Healy PJ, Helliwell PS. Measuring clinical enthesitis in psoriatic arthritis: assessment of existing 
measures and development of an instrument specific to psoriatic arthritis. Arthritis Rheum. 
2008;59(5):686-91. 
Helliwell PS, Firth J, Ibrahim GH, Melsom RD, Shah I, Turner DE. Development of an 
assessment tool for dactylitis in patients with psoriatic arthritis. J Rheumatol. 2005;32(9):1745-
50. 
Helliwell PS, Porter G, Taylor WJ. Polyarticular psoriatic arthritis is more like oligoarticular 
psoriatic arthritis, than rheumatoid arthritis. Ann Rheum Dis. 2007;66 (1):113-7. 
Helliwell PS, FitzGerald O, Fransen J. Composite disease activity and responder indices for 
psoriatic arthritis: a report from the GRAPPA, 2013 meeting on development of cutoffs for both 
disease activity states and response.  J Rheumatol 2014, 41;1212-1217. 
Jones SM, Armas JB, Cohen MG, Lovell CR, Evison G, McHugh NJ. Psoriatic arthritis: 
outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J 
Rheumatol. 1994;33(9):834-9. 
Kane D, Stafford L, Bresnihan B, FitzGerald O. A classification study of clinical subsets in an 
inception cohort of early psoriatic peripheral arthritis--'DIP or not DIP revisited'. Rheumatology 
(Oxford). 2003;42(12):1469-76. 
Kavanaugh A, Gladman DD, Gomez-Reino JJ, Hall S, Lespessailles E, Mease PJ, et al. 
Durability of apremilast response through 5 years of treatment of subjects with psoriatic arthritis 
[abstract]. Presented at the Annual Meeting of the American Academy of Dermatology; February 
16-20, 2018, San Diego, CA. 
Kavanaugh A, Gladman DD, Gomez-Reino JJ, Hall S, Lespessailles E, Mease PJ, et al. 
Durability of apremilast response through 5 years of treatment in subjects with psoriatic arthritis 
[poster 6336]. Annual Meeting of the American Academy of Dermatology; February 16-20, 
2018, San Diego, CA. 
Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD, et al. 
Treatment of psoriatic arthritis in a phase 3 randomized, placebo-controlled trial with apremilast, 
an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6):1020-6. 
Kruithof E, Baeten D, De Rycke L, Vandooren B, Foell D, Roth J, Cañete J, Boots A, Veys M, 
De Keyser F. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, 
resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther. 2005, 
7:R569-R580 (DOI 10.1186/ar1698). 
Lindqvist UR, Alenius GM, Husmark T, Theander E, Holmstrom G, Larsson PT. The Swedish 
early psoriatic arthritis register--2-year followup: a comparison with early rheumatoid arthritis. J 
Rheumatol. 2008;35(4):668-73. 
Maksymowych WP, Mallon C, Morrow S, Shojania K, Olszynski WP, Wong RL, et al. 
Development and validation of the Spondyloarthritis Research Consortium of Canada 
(SPARCC) Enthesitis Index. Ann Rheum Dis. 2009;68(6):948-53. 
Mease, PJ, et al. How much improvement in functional status is considered important by patients 
with active psoriatic arthritis: applying the outcome measures in rheumatoid arthritis clinical 
trials (omeract) group guidelines. EULAR, 2004, LI SAT0015. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
100 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Mease PJ, Gladman DD, Davenport EK, Zhou X, Guerette B, Teng L, et al. Improvements in 
work productivity with up to 104 weeks of apremilast monotherapy: results from a phase 3b, 
randomized, controlled study in biologic-naive subjects with active psoriatic arthritis [abstract]. 
Arthritis Rheumatol. 2017;69(suppl 10):602. 
Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum. 1973;3(1):55-78. 
Nash P, Ohson K, Walsh J, Delev N, Nguyen D, Teng L, et al. Early and sustained efficacy with 
apremilast monotherapy in biological-naive patients with psoriatic arthritis: a phase IIIB, 
randomised controlled trial (ACTIVE). Ann Rheum Dis. 2018;77:690-8. 
Pham,T. Patient acceptable symptomatic state (PASS). Joint Bone Spine 76 (2009) 321e323. 
Reilly MC, Gooch KL, Wong RL, Kupper H, van der Heijde D. Validity, reliability and 
responsiveness of the Work Productivity and Activity Impairment Questionnaire in ankylosing 
spondylitis. Rheumatology (Oxford). 2010;49(4):812-9. 
Ritchlin CT, Colbert RA, Gladman DD. Psoriatic Arthritis. N Engl J Med. 2017;376(10):957-70. 
Roberts ME, Wright V, Hill AG, Mehra AC. Psoriatic arthritis. Follow-up study. Ann Rheum 
Dis. 1976;35(3):206-12. 
Schafer PH, Chen P, Fang L, Wang A, Chopra R. The pharmacodynamic impact of apremilast, 
an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in 
patients with psoriatic arthritis: substudy results from a phase III, randomized, placebo-
controlled trial (PALACE 1). J Immunol Res. 2015;2015:906349. doi: 10.1155/2015/. 
Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification criteria 
for psoriatic arthritis: development of new criteria from a large international study. Arthritis 
Rheum. 2006;54(8):2665-73. 
The EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3):199-208. 
Tubach F, Pham T, Skomsvoll JF, Mikkelsen K, Bjorneboe O, Ravaud P, et al. Stability of the 
patient acceptable symptomatic state over time in outcome criteria in ankylosing spondylitis. 
Arthritis Rheum. 2006;55(6):960-3. 
van Vollenhoven R F, Cifaldi MA, Saurabh R; Chen N, Weisman M H. Improvement in work 
place and household productivity for patients with early rheumatoid arthritis treated with 
adalimumab plus methotrexate: work outcomes and their correlations with clinical and 
radiographic measures from a randomized controlled trial companion study. American College 
of Rheumatology 2010,62, (2) 226–234. 
Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Med Care. 1992;30(6):473-83. 
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. 
Arthritis Rheumatol. 2018;69 (suppl 10):601. 
Wolf, F, et al. The American College of Rheumatology preliminary diagnostic criteria for 
fibromyalgia and measurement of symptom severity. Arthritis Care Res 62(5):600-610, 2010. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
101 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
World Health Organization. Diarrhoea. Available at http://www.who.int/topics/diarrhoea/en/. 
Accessed November 27, 2013. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
102 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
18. 
APPENDICES 
Appendix A: Table of Abbreviations 
Abbreviation or 
Specialist Term 
Explanation 
ACR20/50/70 
American College of Rheumatology 20/50/70 response 
improvement 
ADL 
Activity of daily life  
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
ANC 
Absolute neutrophil count 
APR 
Parmalat  
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
-hCG 
-subunit of human chorionic gonadotropin 
bDMARD 
Biologic disease-modifying antirheumatic drug 
BID 
Twice daily 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
cAMP 
Cyclic adenosine monophosphate 
CASPAR 
Classification Criteria for Psoriatic Arthritis 
CBC 
Complete blood count 
cDAPSA 
Clinical disease activity in psoriatic arthritis (without measuring C-
reactive protein [CRP]) 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration of drug 
CNS 
Central nervous system 
CRO 
Contract research organization 
CRF 
Case report form 
CRP 
C-reactive protein 
csDMARD 
Conventional synthetic disease-modifying antirheumatic drug: 
antirheumatic drugs designed in a traditional way, such as methotrexate or 
sulfasalazine 
CT 
Computed tomography 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
103 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Abbreviation or 
Specialist Term 
Explanation 
DIP 
Distal interphalangeal 
DLT 
Dose-limiting toxicity 
DMARD 
Disease-modifying antirheumatic drug 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EE 
Early escape 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EOT 
End of treatment 
FAS 
Full analysis set  
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEI 
Gladman Enthesitis Index 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IL 
Interleukin  
IM 
Intra-muscular 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Integrated Response Technology 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
104 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Abbreviation or 
Specialist Term 
Explanation 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
LEF 
Leflunomide 
LEI 
Leeds Enthesitis Index 
LVEF 
Left ventricular ejection fraction 
LOCF 
Last observation carried forward 
LS mean 
Least squares mean 
MASES 
Maastricht Ankylosing Spondylitis Enthesitis Score 
MCID 
Minimal clinically important difference 
MDA 
Minimal disease activity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIP 
Macrophage inflammatory protein 
MMRM 
Mixed-effects model for repeated measures 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MTX 
Methotrexate 
MUGA 
Multi-gated acquisition 
NCI 
National Cancer Institute 
NRI 
Nonresponder imputation 
NSAID 
Nonsteroidal anti-inflammatory drug 
PSAID 
Psoriatic Arthritis Impact of Disease  
PASDAS 
Psoriatic Arthritis Disease Activity Score 
PASI 50/70 
 50/75 improvement in the Psoriasis Area and Severity Index 
PBO 
Placebo  
PDE 
Phosphodiesterase enzyme 
PRO 
Patient-reported outcome 
PsA 
Psoriatic arthritis 
PsAID 
Psoriatic arthritis impact of disease 
PC 
Product Complaint  


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
105 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Abbreviation or 
Specialist Term 
Explanation 
QOL 
Quality of life 
RBC 
Red blood cell count 
RF 
Rheumatoid factor 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Steering committee 
SE 
Standard error 
SGOT 
Serum glutamic oxaloacetic transaminase  
SGPT 
Serum glutamic pyruvic transaminase 
SJC 
Swollen joint count 
SOP 
Standard operating procedure 
SpA 
Seronegative spondyloarthropathy 
SSZ 
Sulfasalazine  
SUSAR 
Suspected unexpected serious adverse reaction 
T½  
Half-life 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TB 
Tuberculosis  
TID 
Three times daily 
TJC 
Tender joint count 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VAS 
Visual analog scale 
VLDA 
Very low disease activity 
Vss 
Volume of distribution 
WBC 
White blood cell count 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
106 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 
Appendix B: The CASPAR Criteria 
To meet the CASPAR1 (Classification criteria for Psoriatic Arthritis) 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 juxtaarticular 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). 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
107 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix C: Modified Minimal Disease Activity (MDA-Joints) Assessment 
To meet the mMDA-Joints criteria, a patient must achieve  1 SJC and TJC, plus 3 out of 5 of 
the following cut-off values: 
1. Patient’s global disease activity (VAS, 0-100 mm)  20 
2. Patient’s pain (VAS, 0-100 mm)  15 
3. HAQ  0.5 
4. Tender entheseal points  1 (Based on the Leeds Enthesitis Index - LEI)  
5. BSA  3 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
108 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix D: Joint Assessment - 68 and 66 Joint Counts 
 
68 Joint Score: Upper Extremity Joint Counts 
Please write in the appropriate code for every joint using the Pain/Tenderness and Swelling Codes. 
Pain/Tenderness Codes 
Swelling Codes 
N  No pain/tenderness 
N  No swelling 
Y  Pain/tenderness 
Y  Swelling 
ND  Not Done 
ND  Not Done 
Joints that are swollen and tender should be marked with a tick. If a joint is injected with intra-
articular glucocorticoid, this joint should be marked by an X for the next 4 weeks 
 
Joints 
Right Side 
Left Side 
Pain/Tenderness 
Swelling 
Pain/Tenderness 
Swelling 
Y    N    ND 
Y    N    ND 
Y    N    ND 
Y    N    ND 
Temporomandibular 
 
 
 
 
Sternoclavicular 
 
 
 
 
Acromioclavicular 
 
 
 
 
Shoulder 
 
 
 
 
Elbow 
 
 
 
 
Wrist 
 
 
 
 
MCP 1 
 
 
 
 
MCP 2 
 
 
 
 
MCP 3 
 
 
 
 
MCP 4 
 
 
 
 
MCP 5 
 
 
 
 
PIP 1 
 
 
 
 
PIP 2 
 
 
 
 
PIP 3 
 
 
 
 
PIP 4 
 
 
 
 
PIP 5 
 
 
 
 
DIP 2 
 
 
 
 
DIP 3 
 
 
 
 
DIP 4 
 
 
 
 
DIP 5 
 
 
 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
109 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix D: Joint Assessment – 68 and 66 Joint Counts (Continued) 
 
68 Joint Score:  Lower Extremity Joint Counts 
Please write in the appropriate code for every joint using the Pain/Tenderness and Swelling Codes. 
Pain/Tenderness Codes 
Swelling Codes 
N  No pain/tenderness 
N  No swelling 
Y  Pain/tenderness 
Y  Swelling 
ND  Not Done 
ND Not Done 
 
 
Joints 
Right Side 
Left Side 
Pain/Tenderness 
Swelling 
Pain/Tenderness 
Swelling 
Y    N    ND 
Y    N    ND 
Y    N    ND 
Y    N    ND 
Hip 
 
 
 
 
Knee 
 
 
 
 
Ankle 
 
 
 
 
Mid-tarsal 
 
 
 
 
MTP 1 
 
 
 
 
MTP 2 
 
 
 
 
MTP 3 
 
 
 
 
MTP 4 
 
 
 
 
MTP 5 
 
 
 
 
PIP 1 
 
 
 
 
PIP 2 
 
 
 
 
PIP 3 
 
 
 
 
PIP 4 
 
 
 
 
PIP 5 
 
 
 
 
 
 


Apremilast
Protocol CC-10004-PSA-013
Amgen Inc.
Confidential and Proprietary
110
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021
Appendix E:
Visual Analog Scale
Scales depicted below are on 0-100 mm scale. Note that for the cDAPSA (Appendix K), both 
;(0+):G9':/+4:G925('299+993+4:5,/9+'9+):/</:?'4*;(0+):G999+993+4:5,'/4
scales will be on 0-10 cm scale. 
Evaluators Global Assessment of Disease Activity
+!*0)* %*0)#&#))))$%*& ))* , *.
+!*0) Assessment of Pain
From Felson, 1995.


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
111 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix F: Disability Index of the Health Assessment Questionnaire 
(HAQ-DI)  
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
112 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix F: Disability Index of the Health Assessment Questionnaire  
(HAQ-DI) (Continued)  
 
Source: Bruce, 2003. 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
113 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix G: Leeds Enthesitis Index (LEI)  
Leeds Enthesitis Index: 
Enthesitis is measured by physical examination of the joints below. Tenderness will be assessed 
at the following entheses (tendon insertions) as depicted below:  
1. Lateral epicondyle humerus, left and right 
2. Medial condyle femur, left and right 
3. Achilles tendon insertion into calcaneum, 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. 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
114 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix H: Body Surface Area (BSA) 
BSA is a measure of involved skin. The overall BSA affected by psoriasis is estimated based on 
the palm area of the subject’s hand (entire palmar surface or “handprint”), which equates to 
approximately 1 of the total body surface area. 
Tutorial is available at http://www.pasitraining.com/bsa_score/ 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
115 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
116 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
117 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix K: C-Disease Activity index for Psoriatic Arthritis (cDAPSA)  
The cDAPSA score assesses four domains (Tender Joint Counts [TJC] and Swollen Joint Counts 
[SJC] using 66/68 joints count, patient’s global VAS on a 10-cm scale, patient’s pain VAS on a 
10-cm scale. The cDAPSA is calculated by summing swollen  tender joint counts  patient pain 
 patient global assessments. 
The cDAPSA score can be used to effectively separate the disease states of remission (REM), 
low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) 
by specific cutpoints detailed below: 
REM: cDAPSA4; LDA: 4cDAPSA13; MDA: 13cDAPSA27; HDA: cDAPSA27. 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
118 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix L: Psoriatic Arthritis Disease Activity Score (PASDAS) 
The PASDAS is a weighted index comprising assessments of joints, physical function, acute-
phase response, patient and physician global assessment of the disease, enthesitis and dactylitis. 
It is represented by the formula: 
PASDAS  ((0.18 x Physician global VAS)  (0.159 x Patient global VAS) – (0.253 x SF36 
– PCS)  (0.101 x LN (Swollen joint count  1))  (0.048 x LN (Tender joint count  1))  (0.23 
x LN (Leeds Enthesitis Count  1))  (0.377 x LN (Dactylitis count  1))  (0.102 x LN (CRP  
1))2)*1.5 
CRP  C-reactive protein in mg/l, LN  natural logarithm, SF36  Medical Outcomes Study 
Short Form-36, SF36-PCS  physical component summary scale of SF36. 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.  
Definition of good or moderate response is detailed in the table below: 
Response criteria for the Psoriatic Arthritis Disease Activity Score (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 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
119 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
120 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix N: The PsA Impact of Disease 12-Item (PsAID-12) Questionnaire 
The PsAID-12 Questionnaire (Gossec, 2014) 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.  
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:  
 
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: 
 
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 
None 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
Extreme 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
121 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix N: The PsA Impact of Disease 12-Item (PsAID-12) Questionnaire 
(Continued) 
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 (ie, resting at night) you felt due to 
your psoriatic arthritis during the last week:  
 
8. Coping  
Considering your psoriatic arthritis overall, how well did you cope (manage, deal, make do) with 
your psoriatic arthritis during the last week?   
 
 
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 
Very 
well 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Very 
poorly 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
122 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix N: The PsA Impact of Disease 12-Item (PsAID-12) Questionnaire 
(Continued) 
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: 
 
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. 
 
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 
None 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extreme 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
123 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix N: The PsA Impact of Disease 12-Item (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). 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
124 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
125 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
126 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
127 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
128 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
129 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
130 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
131 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
132 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
133 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
134 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
135 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix T: Blister Card Configurations 
 
 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
136 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix T: Blister Card Configurations (Continued) 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
137 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
138 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
139 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix W: Sample Serious Adverse Event Report Form 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
140 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix W: Sample Serious Adverse Event Report Form (Continued) 
 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
141 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix W: Sample Serious Adverse Event Report Form (Continued) 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
142 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix X: Pregnancy Notification Form 


Apremilast 
Protocol CC-10004-PSA-013 
 
Amgen Inc. 
Confidential and Proprietary 
143 
CC-10004-PSA-013 Amendment 4 Final: 12 July 2021 
Appendix Y: Lactation Notification Form 


Product:  Apremilast 
Protocol Number:  20200058 
Date:  12 July 2021 
Page 1 of 9 
Amgen Proprietary - Confidential 
Confidential 
 
Amendment 5 
Protocol Title:  A PHASE 4, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF APREMILAST (CC-10004) IN SUBJECTS WITH 
EARLY, OLIGOARTICULAR PSORIATIC ARTHRITIS DESPITE INITIAL STABLE 
TREATMENT WITH EITHER NSAIDS AND/OR  1 CONVENTIONAL SYNTHETIC 
DMARD 
 
Amgen Protocol Number Apremilast CC-1004-PSA-013 20200058 
EudraCT Number:  2018-002735-26 
IND Number:  101761 
NCT Number:  NCT03747939 
 
Amendment Date: 
12 July 2021 
Rationale: 
The rationale of this protocol amendment is to include following updates: 
 
To update the total number of subjects to be randomized in the study in all the 
sections wherever applicable. 
 
To update the inclusion criteria to update language as symptoms of psoriatic 
arthritis (PsA) with oligoarthritis by any criteria with no minimum time 
constraint. 
 
To update the study rationale to include subjects with early diagnosis of PsA 
( 5 years since signs and symptoms began). 
 
To update the exclusion criteria for prior use of 2 conventional synthetic 
disease-modifying antirheumatic drugs. 
 
To update the exclusion criteria to change the bacterial infections requiring 
treatment within 1 week of Screening. 
 
To update the table of events table to include  7 days for observational 
follow-up visit. 
 
To update the statistical sample size of approximately 
 for the 
active and placebo groups. 


Apremilast 
Summary of Changes CC-10004-PSA-013 
Amgen Inc. 
Amgen Proprietary - Confidential 
Confidential and Proprietary 
1 
    CC-10004-PSA-013 Amendment 4 Final: 03 February 2021 
– SUMMARY OF CHANGES – 
A PHASE 4, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF APREMILAST 
(CC-10004) IN SUBJECTS WITH EARLY, OLIGOARTICULAR 
PSORIATIC ARTHRITIS DESPITE INITIAL STABLE 
TREATMENT WITH EITHER NSAIDS AND/OR  1 
CONVENTIONAL SYNTHETIC DMARD 
AMENDMENT NO. 4 
INVESTIGATIONAL PRODUCT (IP): 
 
Apremilast 
PROTOCOL NUMBER: 
 
CC-10004-PSA-013 
ORIGINAL DATE: 
 
09 JUL 2018  
AMENDMENT 1 DATE 
 
05 FEB 2019 
AMENDMENT 2 DATE: 
 
17 MAY 2019  
AMENDMENT 3 DATE: 
 
04 MAY 2020 
AMENDMENT 4 DATE: 
 
03 FEB 2021 
EudraCT NUMBER: 
 
2018-002735-26 
IND NUMBER:  
 
101761 
NCT NUMBER 
 
NCT03747939 
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. 
 
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 
Amgen Medical Information:  1- 800-77-AMGEN (1 800-772-6436) 


Apremilast 
Summary of Changes CC-10004-PSA-013 
Amgen Inc. 
Amgen Proprietary - Confidential 
Confidential and Proprietary 
2 
    CC-10004-PSA-013 Amendment 4 Final: 03 February 2021 
JUSTIFICATION FOR AMENDMENT 
 
The purpose for this amendment is to better reflect clinical practice and facilitate enrollment.  The 
following changes were made to the protocol, dated 03 February 2021: 
 
Change the primary endpoint to week 16, which is closer to the timeframe in which clinicians 
assess efficacy in clinical practice 
 
Change inclusion criteria 10, a main reason for screen failure, to remove requirement that 
treatment with a maximum of 1 csDMARD (methotrexate or sulfasalazine) begin  6 months 
prior to Baseline to allow for concomitant use of 1 csDMARD if the subject is on a stable 
regimen for at least 3 months prior to the Baseline Visit 
 
Change exclusion criteria 1, another main reason for screen failure, to allow prior use of 
1 csDMARD to treat other conditions like psoriasis other than the study indication (PsA) 
 
Change the early diagnosis period from  3 months and  24 months to  3 months and 
 5 years to be consistent with Study CC-10004-PSA-014, an imaging study on joint impact 
of PsA in the early stages of the disease.  This alignment between studies will ensure a more 
robust clinical and imaging data set in early PsA. 
 
Change timepoints in secondary efficacy endpoints to include Week 16 instead of Week 24 
 
This amendment also includes minor clarifications and corrections to the following sections: 
o 
Section 1.2.1:  Key Findings from Clinical Studies 
o 
Figure 1:  Overall Study Design 
o 
Table 12:  Study Endpoints 
o 
Table 13:  Table of Events 
o 
Section 6.4:  Efficacy Assessments 
o 
Section 6.4.3:  Dactylitis 
o 
Section 6.5.5:  Diarrhea, Nausea and Vomiting 
o 
Section 7.8:  Overdose 
o 
Section 8.1:  Permitted Concomitant Medications and Procedures 
 
Grammatical and typographical changes were made throughout the protocol. 
 


EDMS Doc. Number: 24688746 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Amgen Inc.
Confidential and Proprietary
1
CC-10004-PSA-013 Amendment 3 Final:  04 May 2020
TITLE PAGE
– SUMMARY OF CHANGES –
A PHASE 4, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF APREMILAST (CC-
10004) IN SUBJECTS WITH EARLY, OLIGOARTICULAR 
PSORIATIC ARTHRITIS DESPITE INITIAL STABLE TREATMENT 
WITH EITHER NSAIDS AND/OR ≤ 1 CONVENTIONAL 
SYNTHETIC DMARD
AMENDMENT NO. 3
INVESTIGATIONAL PRODUCT (IP):
Apremilast
PROTOCOL NUMBER:
CC-10004-PSA-013
ORIGINAL DATE:
09 JUL 2018 
AMENDMENT No. 2 DATE:
17 MAY 2019 
AMENDMENT No. 3 DATE:
04 MAY 2020
EudraCT NUMBER:
2018-002735-26
IND NUMBER: 
101761
NCT NUMBER
NCT037479396
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.
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
Amgen Medical Information: 1- 800-77-AMGEN (1 800-772-6436)


EDMS Doc. Number: 24688746 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Amgen Inc.
Confidential and Proprietary
2
CC-10004-PSA-013 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 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. NOTE: Signed by Celgene based on Approval from 
Amgen Therapeutic Head


EDMS Doc. Number: 24688746 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Amgen Inc.
Confidential and Proprietary
3
CC-10004-PSA-013 Amendment 3 Final:  04 May 2020
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.
Additional updates include changes to the following sections:

Section 8.1 Permitted Medications: Correction: “Oral glucocorticosteroids are to be taken on a 
stable dose: prednisone ≤ 10 mg/day (or prednisolone equivalent) for at least 4 weeks prior to the 
Baseline Visit”. The text previous stated “at least 2 weeks prior to the Baseline Visit”. This is 
correctly stated in Inclusion Criteria #8.
The amendment also includes minor clarifications and corrections to align with Amgen 
process:

Section 7.5 Investigational Product Accountability

Section 15.2 Audits and Compliance 

Section 16 Publications. 


EDMS Doc. Number: 23739869 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Celgene Corporation
Confidential and Proprietary
1
CC-10004-PSA-013 Amendment # 2 Final: 17 May 2019
TITLE PAGE
– SUMMARY OF CHANGES –
A PHASE 4, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP 
STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF APREMILAST (CC-10004) IN SUBJECTS WITH 
EARLY, OLIGOARTICULAR PSORIATIC ARTHRITIS 
DESPITE INITIAL STABLE TREATMENT WITH 
EITHER NSAIDS AND/OR ≤ 1 CONVENTIONAL 
SYNTHETIC DMARD
AMENDMENT NO. 2
INVESTIGATIONAL PRODUCT (IP):
Apremilast
PROTOCOL NUMBER:
CC-10004-PSA-013
ORIGINAL DATE:
09 JUL 2018 
AMENDMENT No. 2 DATE:
17 MAY 2019
EudraCT NUMBER:
2018-002735-26
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: 23739869 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Celgene Corporation
Confidential and Proprietary
2
CC-10004-PSA-013 Amendment # 2 Final: 17 May 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
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: 23739869 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PSA-013 Amendment # 2 Final: 17 May 2019
1.
JUSTIFICATION FOR AMENDMENT
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 the trial. 
The IB will be submitted to all sites and clearly identified as the RSI in the clinical trial 
application (CTA) package. 
All references in the protocol that include “approved product labeling” and “Prescribing 
Information” were removed throughout the following sections of the protocol: 

Section 1.2; 

Section 1.2.1.1.1; 

Section 1.2.1.1.2; 

Section 1.2.1.1.3; 

Section 1.2.2.2,

Section 7.1.
Exclusion criteria #2 updated to include prior exposure to tyk2 inhibitors as a prohibited 
medication. 
The amendment also includes several other minor clarifications and corrections:

Section 8.1 Permitted Medications. Intramuscular glucocorticosteroids was deleted.

Section 8.1 Permitted Medications. NSAIDs and/or narcotic analgesics text updated 
for clarity.

Section 8.1 Permitted Medications. Text updated to clarify that only 1 csDMARD is 
allowed during the first 24 weeks of the study. The first 24 weeks of the study was 
added.

Section 8.1 Permitted Medications. Text updated to clarify that after the Week 24 
Visit, changes in therapy will be permitted as clinically required for subjects with 
worsening arthritic symptoms of PsA. The word required was added.

References. Citation for Kruithof was updated with the abbreviated version.

Appendix B CASPAR Criteria. Appendix was replaced with a corrected version of 
the criteria that includes an additional footnote.


EDMS Doc. Number: 23430026 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Celgene Corporation
Confidential and Proprietary
1
CC-10004-PSA-013 Amendment 1 Final: 05 Feb 2019
TITLE PAGE
– SUMMARY OF CHANGES –
A PHASE 4, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP 
STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF APREMILAST (CC-10004) IN SUBJECTS WITH 
EARLY, OLIGOARTICULAR PSORIATIC ARTHRITIS 
DESPITE INITIAL STABLE TREATMENT WITH 
EITHER NSAIDS AND/OR ≤ 1 CONVENTIONAL 
SYNTHETIC DMARD
AMENDMENT NO. 1
INVESTIGATIONAL PRODUCT (IP):
Apremilast 
PROTOCOL NUMBER:
CC-10004-PSA-013
ORIGINAL DATE:
09 JUL 2018
AMENDMENT No. 1 DATE:
05 FEB 2019
EudraCT NUMBER:
2018-002735-26
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: 23430026 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Celgene Corporation
Confidential and Proprietary
2
CC-10004-PSA-013 Amendment 1 Final: 05 Feb 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
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: 23430026 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PSA-013 Amendment 1 Final: 05 Feb 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes noted below were made based on Health Authority comments and to align 
with the approved label for apremilast:

Section 4.3 Exclusion Criteria; Clarification of Exclusion #8 and addition of Exclusion 
#9 (laboratory abnormalities) modified to add severe renal disease as a significant 
laboratory abnormality.

Section 6.5.7 Clinical Laboratory Evaluations; Creatinine clearance added to support 
Exclusion Criteria #9.

Section 6.5.2: Vital Signs, Height and Weight; Section modified to clarify treatment 
discontinuation for severe weight loss. Weight will be added to every visit. The following 
sections were also revised:
o
Section 5 Table of Events; Weight assessment increased to be done at every visit
to support modification of Section 6.5.2.
o
Section 6.3.1 Safety Follow-up Period; Weight added.

Section 6.5.4: Psychiatric Evaluation; Section was modified to clarify study
discontinuation for psychiatric symptoms.

Section 6.5.5: Diarrhea, Nausea and Vomiting; Section was added to clarify treatment 
discontinuation for severe symptoms of diarrhea, nausea and vomiting.

Section 8.2 Concomitant Medications Not Recommended; Section added to align with 
guidance provided in the label regarding co-administration of strong cytochrome P450 
3A4 enzyme inducers with apremilast.
Significant changes noted below were made based on Health Authority comments:

Section 4.2 Inclusion Criteria #13; Updated to clarify that contraception, Option 2, may 
not be acceptable as a highly effective contraception option in all countries per local 
guidelines/regulations.

Section 6.5.1 Serum and Urine Pregnancy Tests for Females of Childbearing Potential; 
Section modified to clarify that additional visits (unscheduled visits) may be done to 
monitor pregnancy testing.
The amendment also includes several other minor clarifications and corrections:

Medical Monitor / Emergency Contact Information; Updated with the PPD Medical 
Monitor names.

The protocol was modified to update the International Conference on Harmonization with
International Council for Harmonisation.

Section 1.2 Compound Background; As this is a Phase 4 study, approved product 
labeling or the Investigator brochure (depending on regional regulations) should be used 
as the reference for additional information on apremilast in this approved indication.


EDMS Doc. Number: 23430026 - 23431284
Apremilast
Summary of Changes CC-10004-PSA-013
Celgene Corporation
Confidential and Proprietary
4
CC-10004-PSA-013 Amendment 1 Final: 05 Feb 2019

Section 4.2 Inclusion Criteria #11; Clarification to the wording of discontinuation criteria 
for sulfasalazine and methotrexate. Also, update was made in Section 8.1 Permitted 
Concomitant Medications and Procedures.

Section 4.3 Exclusion Criteria #3; Intra-muscular glucocorticosteroids added. Also,
updates were made in Section 8.1 Permitted Concomitant Medications and Section 8.3 
Prohibited Concomitant Medications and Procedures.

Section 6.5.7 Clinical Laboratory Evaluations; “dipstick urinalysis” was deleted to align 
with the Laboratory Manual. The updates were also made in Section 6 Procedures: 
(Sections 6.1, 6.2, 6.2.1) and Table 13.

Section 6.1 Screening Period Demographics; Date of birth deleted to align with current 
clinical database.

Section 10 Adverse Events; Updated with the revised language for electronic data capture 
of safety data (“Safety Gateway”).

Appendix N PSA Impact of Disease 12-Item (PsAID-12) Questionnaire; Calculations and 
Section 9 updated per statistician’s request.

Appendix T Blister Card Configuration; Treatment cards replaced with the corrected 
image.

SAP_001.pdf: 
Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 1 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Statistical Analysis Plan 
 
Protocol Title: 
Phase 4, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate 
the efficacy and safety of apremilast (CC-10004) in 
subjects with early, oligoarticular psoriatic arthritis 
despite initial stable treatment with either non-
steroidal anti-inflammatory drugs (NSAIDs) and/or  
1 conventional synthetic disease-modifying 
antirheumatic drugs (csDMARD) 
Short Protocol Title: 
Not Applicable 
Protocol Number: 
20200058 
NCT Number: 
NCT03747939 
Authors: 
 
 
Sponsor: 
AMGEN INC. 
One Amgen Center Drive, Thousand Oaks, CA 
91320, United States 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
07 February 2023 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
07FEB2023 
Not Applicable 
 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 2 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Table of Contents 
Table of Contents ............................................................................................................ 2 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 9 
2.1 
Objectives and Endpoints/Estimands .......................................................... 9 
2.2 
Hypotheses and/or Estimations ................................................................. 17 
3. 
Study Overview .................................................................................................... 17 
3.1 
Study Design ............................................................................................. 17 
3.2 
Sample Size .............................................................................................. 19 
3.3 
Adaptive Design ........................................................................................ 19 
4. 
Covariates and Subgroups ................................................................................... 20 
4.1 
Planned Covariates ................................................................................... 20 
4.2 
Subgroups ................................................................................................. 20 
5. 
Definitions ............................................................................................................. 20 
5.1 
Derivations of Efficacy/ Health-related Quality of Life Endpoints ............... 20 
5.1.1 
Modified Minimal Disease Activity–Joints (MDA-Joints) ............. 20 
5.1.2 
Joint Assessment ...................................................................... 21 
5.1.3 
Patient’s Global Assessments of Disease Activity ..................... 22 
5.1.4 
Patient’s Pain Visual Analogue Scale ........................................ 22 
5.1.5 
Data resource: Pain VAS is entered by the patient via 
tablets provided by ERT. HAQ-DI .............................................. 22 
5.1.6 
Enthesitis: Leeds Enthesitis Index ............................................. 23 
5.1.7 
BSA ........................................................................................... 24 
5.1.8 
Physician’s Global Assessments of Disease Activity ................. 24 
5.1.9 
Enthesitis: 
 ........................................................ 24 
5.1.10 
Dactylitis .................................................................................... 24 
5.1.11 
Clinical Disease Activity Index for Psoriatic Arthritis 
(cDAPSA) .................................................................................. 25 
5.1.12 
Psoriatic Arthritis Disease Activity Score (PASDAS) .................. 25 
5.1.15 
The PsA Impact of Disease 12-Item (PsAID-12) 
Questionnaire ............................................................................ 26 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 3 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
5.2 
Derivations of Safety Endpoints ................................................................ 30 
5.2.1 
Treatment-emergent Adverse Events Leading to Drug 
Withdrawal, Leading to Drug Interruption, and Leading 
to Death, and Drug-related Treatment-emergent 
Adverse Events ......................................................................... 31 
5.3 
Baseline Definitions ................................................................................... 31 
5.4 
Time Points ............................................................................................... 31 
5.5 
Analysis Phases/Period ............................................................................. 32 
6. 
Analysis Sets ........................................................................................................ 34 
6.1 
Full Analysis Set........................................................................................ 34 
6.2 
Safety Analysis Set ................................................................................... 34 
6.3 
Per Protocol Set(s) .................................................................................... 34 
6.4 
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) ........................................................................................................ 34 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 35 
6.6 
Interim Analyses Set(s) ............................................................................. 35 
6.7 
Study-specific Analysis Sets...................................................................... 35 
6.7.1 
Apremilast Subjects as Randomized or Transitioned 
Population  ................................................................................ 35 
6.7.2 
Apremilast Subjects as Treated Population ............................... 35 
7. 
Planned Analyses ................................................................................................. 35 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 35 
7.2 
Primary Analysis ....................................................................................... 35 
7.3 
Final Analysis ............................................................................................ 36 
8. 
Data Screening and Acceptance ........................................................................... 36 
8.1 
General Principles ..................................................................................... 36 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 36 
8.3 
Handling of Missing and Incomplete Data ................................................. 36 
8.3.1 
Adverse Events ......................................................................... 36 
8.3.2 
Prior/Concomitant Medications/Procedures ............................... 38 
8.3.3 
Medical History .......................................................................... 39 
8.4 
Detection of Bias ....................................................................................... 39 
8.5 
Outliers ..................................................................................................... 40 
8.6 
Distributional Characteristics ..................................................................... 40 
8.7 
Validation of Statistical Analyses ............................................................... 40 
9. 
Statistical Methods of Analysis.............................................................................. 40 
9.1 
General Considerations ............................................................................. 40 
9.1.1 
Reporting and Analysis Conventions ......................................... 40 
9.1.2 
Statistical Methodology for Efficacy ........................................... 41 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 4 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
9.1.3 
Multiplicity .................................................................................. 42 
9.2 
Subject Accountability ............................................................................... 42 
9.3 
Important Protocol Deviations ................................................................... 43 
9.4 
Demographic and Baseline Characteristics ............................................... 43 
9.4.1 
Demographics ........................................................................... 44 
9.4.2 
Baseline or Disease Characteristics .......................................... 44 
9.4.3 
Medical History .......................................................................... 47 
9.4.4 
Prior and Concomitant Procedures ............................................ 47 
9.4.5 
Prior and Concomitant Medications ........................................... 47 
9.5 
Efficacy Analyses ...................................................................................... 49 
9.5.1 
Analyses of Primary Efficacy Endpoint ...................................... 49 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 51 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 52 
9.6 
Safety Analyses ........................................................................................ 54 
9.6.1 
Analyses of Primary Safety Endpoint ......................................... 54 
9.6.2 
Adverse Events ......................................................................... 55 
9.6.3 
Adverse Events of Special Interest ............................................ 57 
9.6.4 
Laboratory Test Results ............................................................ 57 
9.6.5 
Vital Signs ................................................................................. 59 
9.6.6 
Physical Measurements ............................................................ 59 
9.6.7 
Electrocardiogram ..................................................................... 59 
9.6.8 
Antibody Formation ................................................................... 59 
9.6.9 
Exposure to Investigational Product .......................................... 59 
9.6.10 
Exposure to Non-investigational Product ................................... 61 
9.6.11 
Exposure to Other Protocol-required Therapy ........................... 61 
9.7 
Other Analyses ......................................................................................... 61 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 61 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 61 
9.7.3 
Analyses of Health Economic Endpoints ................................... 61 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 61 
10. 
Changes From Protocol-specified Analyses.......................................................... 62 
11. 
Literature Citations / References ........................................................................... 62 
12. 
Prioritization of Analyses....................................................................................... 62 
13. 
Data Not Covered by This Plan............................................................................. 62 
14. 
Appendices ........................................................................................................... 63 
Appendix A.  Analytical Windows .......................................................................... 64 
Appendix B.  Marked Abnormality Criteria ............................................................ 66 
 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 5 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
List of Tables 
Table 1. Response criteria for the PASDAS .................................................................. 26 
Table 2. Imputation Rules for Partially Missing AE Start Dates for Subjects 
Who Were Treated with Apremilast Initially ............................................. 37 
Table 3. Imputation Rules for Partially Missing AE Start Dates for Subjects 
Who Were Treated with Placebo Initially ................................................. 38 
Table 4. Normal Ranges for Shift Table ......................................................................... 59 
Table 5. Table for Visit Mapping for by Time Point Analysis .......................................... 64 
Table 6. Marked Abnormalities Criteria .......................................................................... 66 
 
List of Figures 
No table of figures entries found. 
 
 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 6 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
Adverse Event 
ATC 
Anatomical Therapeutical Chemical 
ATC 
Anatomical-Therapeutic-Chemical 
BID 
Twice Daily 
BSA 
Body Surface Area (%) Affected by Psoriasis 
cDAPSA 
Clinical Disease Activity in Psoriatic Arthritis 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRF or eCRF 
(electronic) Case Report Form 
CRO 
Contract Research Organization  
CRP 
C-Reactive Protein  
csDMARD 
Conventional Synthetic Disease-Modifying Antirheumatic Drugs  
CSR 
Clinical Study Report  
EAIR 
Exposure-Adjusted Incidence Rate 
EE 
Early Escape  
ERT 
eResearchTechnology, Inc  
GSO-DM 
Global Study Operations-Data Management 
GSP 
Global Statistical Programming  
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
hsCRP 
High Sensitivity C-Reactive Protein  
IA 
Intra-Articular  
IP 
Investigational Product 
IPDs 
Important Protocol Deviations 
IWRS 
Interactive Web Response System  
L/R 
Left/Right  
LEI 
Leeds Enthesitis Index 
LN 
Natural Logarithm 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 7 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
LS Mean 
Least Squares Mean 
MAR 
Missing At Random    
MCID 
Minimal Clinically Important Differences  
MDA 
Minimal Disease Activity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect Model for Repeated Measures 
MNAR 
Missing Not At Random 
MTX 
Methotrexate 
NR 
Non-Responder  
NRI 
Non-responder Imputation  
NRS 
Numeric Rating Scale 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
PASDAS 
Proportion Of Patients Achieving A Good Or Moderate 
Response  
PD 
Pharmacodynamic 
PP 
Per-Protocol (Set) 
PROs 
Patient-Reported Outcomes  
PsA 
Psoriatic Arthritis  
PsAID-12 
Psoriatic Arthritis Impact Of Disease 12-Item For Clinical Trials  
PT 
Preferred Term 
QOL 
Quality Of Life  
SAP 
Statistical Analysis Plan 
SD  
Standard Deviation 
SI 
Standard International (unit) 
SJC 
Swollen Joint Count  
SOC 
System Organ Class 
sPGA 
static Physician Global Assessment 
SSZ 
Sulfasalazine 
TEAE 
Treatment-emergent Adverse Event 
TJC 
Tender Joint Count  
VAS 
Visual Analogue Scale 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 8 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
VLDA 
Very Low Disease Activity 
WHODD 
World Health Organization Drug Dictionary 
 
 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 9 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol CC-10004-PSA-013 amendment 5 
for study 20200058, AMG407 dated 12 July 2021. The scope of this plan includes the 
primary analysis and the final analysis that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified. 
The SAP will be finalized and signed prior to the unblinding of the Week 24 database 
which will be the primary analysis database. All statistical analyses detailed in this SAP 
will be conducted using SAS® Version 9.4 or higher. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of 
apremilast 30 mg BID  NSAIDs 
and/or csDMARDs vs. Placebo  
NSAIDs and/or csDMARDs in 
subjects with early oligoarticular 
psoriatic arthritis (PsA), assessed 
by modified MDA (MDA-Joints). 
 
Proportion of subjects who 
achieve a clinical state of minimal 
disease activity (MDA-Joints) at 
Week 16, which is defined as 
achieving SJC  1 and TJC  1 
(based on sentinel joints), plus 3 
out of the following 5 criteria: 
o Psoriasis BSA  3%;  
o Patient pain (VAS)  15;  
o Patient global disease 
activity (VAS)  20;  
o HAQ-DI  0.5;  
o Tender entheseal points 
 1 (based on Leeds 
Enthesitis Index - LEI) 
Secondary 
 
To evaluate the impact of 
treatment with apremilast 30 mg 
BID  NSAIDs and/or csDMARDs 
vs. Placebo NSAIDs and/or 
csDMARDs on disease activity in 
 
cDAPSA remission or low disease 
activity: Proportion of subjects 
who achieve remission (defined 
by clinical disease activity in 
psoriatic arthritis [cDAPSA] ≤ 4 
score) or low disease activity 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 10 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
subjects with early oligoarticular 
PsA. 
(defined by cDAPSA > 4 but ≤ 13 
score) at week 16. 
 
Swollen Joint Count (SJC)  1: 
Proportion of subjects with SJC 
 1 at week 16, based on sentinel 
joints. 
 
Tender Joint Count (TJC)  1 : 
Proportion of subjects with TJC 
 1 at week 16, based on sentinel 
joints. 
 
Patient's global assessment of 
disease activity: Proportion of 
subjects whose global 
assessment of disease activity 
score  20 in the visual analogue 
scale (VAS) at week 16. 
 
Patient's assessment of pain: 
Proportion of subjects whose 
assessment of pain score  15 in 
VAS at week 16. 
 
PASDAS good and moderate 
response: Proportion of patients 
achieving a good or moderate 
response in PASDAS score 
(Table 1) at week 16. 
 
To evaluate the impact of 
apremilast 30 mg BID  NSAIDs 
and/or csDMARDs vs. Placebo  
NSAIDs and/or csDMARDs on 
patient-reported outcomes (PROs) 
in subjects with early oligoarticular 
PsA. 
 
PsAID-12: Change from Baseline 
in the Psoriatic Arthritis Impact of 
Disease 12-item for clinical trials 
(PsAID-12) questionnaire at week 
16. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 11 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
To evaluate the safety and 
tolerability of apremilast 30 mg 
BID  NSAIDs and/or csDMARDs 
vs. Placebo  NSAIDs and/or 
csDMARDs in subjects with early 
oligoarticular PsA 
 
Adverse events: Type, frequency, 
severity, and relationship of 
adverse events (AEs) to 
investigational product (IP). 
 
Discontinuation due to AEs: 
Number of subjects who 
discontinue IP 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 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 12 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 13 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 14 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 15 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 16 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 17 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
2.2 
Hypotheses and/or Estimations 
The primary hypothesis for this study is: Apremilast  NSAIDs and/or csDMARDs is 
superior to placebo  NSAIDs and/or csDMARDs in subjects with early oligoarticular 
psoriatic arthritis as measured by proportion of subjects achieving MDA-Joints. 
H0: the difference in proportion of subjects who achieved a clinical state of minimal 
disease activity (MDA-Joints) at Week 16 in apremilast and in that of placebo = 0. 
H1: the difference in proportion of subjects who achieved a clinical state of minimal 
disease activity (MDA-Joints) at Week 16 in apremilast and in that of placebo ≠ 0. 
3. 
Study Overview 
3.1 
Study Design 
This Phase 4 multicenter, randomized, placebo-controlled, double-blind study is 
designed to evaluate the efficacy, safety and tolerability of apremilast over 48 weeks of 
treatment in approximately 285 subjects with early oligoarticular psoriatic arthritis. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 18 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
subjects will be randomized in a 2:1 ratio to either apremilast 30 mg BID or identically 
appearing placebo via an Interactive Web Response System (IWRS).  
Randomization to apremilast arm or placebo arm will be stratified by concomitant use of 
glucocorticosteroids at baseline (yes/no) and prior/concomitant use of a csDMARD, 
either MTX or SSZ, (i.e., csDMARD-naïve; csDMARD use prior to baseline [treatment 
not continued]; or csDMARD use prior to and concomitant at baseline). The number of 
subjects who are csDMARD-naïve is targeted to comprise up to 50 % of the subjects 
enrolled in the study. There is no planned protocol extension following the end of the 
study. 
This is a 56-week study which will consist of 4 phases:  
 
Screening Phase – up to 4 weeks 
 
(Randomized, Double-blind) Placebo-controlled (Treatment) Phase – Weeks 0 to 
24.  
o Stratified randomization (2:1 ratio to either apremilast 30 mg BID or 
placebo). 
o Dose-titrated. 
o Subjects with no improvement in SJC (based on sentinel joints, i.e., the 
joints affected at baseline) at Week 16 are eligible for Early Escape (EE), 
at the discretion of the Investigator; Placebo-treated subjects who escape 
early will be transitioned to apremilast 30 mg BID in a blinded fashion via 
IWRS, while apremilast-treated subjects will remain on the original 
treatment assigned at baseline. 
o The patients remaining on placebo will be transitioned to apremilast 30 
mg BID at Week 24. 
o All subjects who complete this 24-week treatment phase will have the 
option to enter the Active-treatment Extension Phase.  
 
(Active-treatment) Extension Phase – Week 24 to Week 48. 
o Beginning at Week 24 Visit, all subjects in the Extension Phase will be 
dispensed open-label apremilast (30 mg BID). 
o All subjects will receive apremilast 30 mg BID until the completion of the 
study (i.e., up to Week 48 Visit) 
 
(Post-treatment) Observational Follow-up Phase – up to 4 weeks. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 19 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
o All subjects who complete the Placebo-controlled Phase or the Extension 
Phase or discontinue early will participate in the 4-week Observational 
Follow-up Phase.  
o The Observational Follow-up visit should be performed 4 weeks after the 
last dose of IP. 
The study schematic is presented in the following figure: 
 
3.2 
Sample Size 
Sample size estimation was based on the results from integrated analyses of 
subpopulation data from five Phase 3 studies (PSA-002, PSA-003, PSA-004, PSA-005, 
and PSA-006). Assuming a 15% dropout rate by the primary endpoint, a sample size of 
for the Apremilast 30 mg BID and placebo groups, respectively, will have 
80% power to detect a true 15% difference (30% versus 15%) in the proportions of 
subjects achieving the modified MDA (MDA-Joints) between the Apremilast 30 mg BID 
and placebo groups, using a chi-square test with a two-sided significance level of 0.05. 
The calculation was implemented using nQuery 7.0. 
3.3 
Adaptive Design 
Not Applicable. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 20 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Covariates includes but not be limited to baseline value for each measured endpoint. 
4.2 
Subgroups 
To determine whether the treatment effect is consistent across various subgroups, the 
primary analysis of the primary endpoint will be repeated for each category, as 
appropriate, of the following classification variables: 
Subgroups 
• 
Sex (male, female) 
• 
Race (White, non-White) 
• 
Age (< 65, ≥ 65 years) 
• 
Baseline weight (< 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥ 100 kg) 
• 
Region (North America, Europe, Rest of the World [including Russia]) 
• 
Baseline glucocorticosteroid use (yes, no) 
• 
Prior/concomitant use of csDMARD, either MTX or SSZ, (naïve, prior use only,  
prior and concomitant use)  
• 
Prior use of csDMARD (yes, no) 
• 
Concomitant use of csDMARD (yes, no). 
The subgroup categories proposed above for the individual demographic and baseline 
parameters may be adjusted as appropriate. Additionally, the MDA-Joints response 
rates at Week 16 will be described graphically with forest plots by subgroup. 
5. 
Definitions 
5.1 
Derivations of Efficacy/ Health-related Quality of Life Endpoints 
Baseline definition for all efficacy endpoints is given in Section 5.3. Change from 
baseline is calculated as on-treatment value minus the baseline value. Handling of time 
points is described in Section 5.4. 
5.1.1 
Modified Minimal Disease Activity–Joints (MDA-Joints) 
For this study, the MDA-Joints (Appendix C of Protocol) is the primary endpoint and is 
defined as Tender Joint Counts (TJC) ≤ 1 and Swollen Joint Counts (SJC) ≤ 1 plus 3 of 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 21 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
the following 5 criteria: 1) psoriasis Body Surface Area (BSA) ≤ 3%, 2) patient pain VAS 
on a 100-mm scale ≤ 15, 3) patient’s global assessment on a 100-mm scale ≤ 20,  4) 
physical function [HAQ-DI] ≤ 0.5, and 5) enthesitis count ≤ 1 based on the Leeds 
Enthesitis Index. Joint assessment will be based on 66 swollen joints and 68 tender 
joints. Assessment of tenderness and swelling of the individual joints will be performed 
by the evaluator; however, calculation of the MDA-Joints will be done programmatically. 
Data resource: each component is entered by the physician or the subject via tablets 
provided by eResearchTechnology, Inc (ERT). The binary value of meeting MDA-Joints 
criteria or not is calculated in the analysis dataset. 
5.1.2 
Joint Assessment 
TJC or SJC will be derived from the joint assessments entered by the physician via 
tablets provided by ERT. Joint assessment for tenderness and swelling will be 
performed for 68 and 66 joints (Appendix D of Protocol), respectively, at every visit. Joint 
tenderness and swelling will be noted in the following categories, with no quantitation of 
severity, as shown on the tablet.  
- Pain/Tenderness Only 
- Swelling Only 
- Pain/Tenderness and Swelling 
- Permanently Not Assessable 
- Temporarily Not Assessable Due to IA Injection 
- Temporarily Not Assessable - Other  
In the event that a joint is injected with intra-articular (IA) glucocorticoid (allowed only 
after week 24 assessments are completed, and up to the Week 48 Visit), this joint 
should be marked as “Temporarily Not Assessable Due to IA Injection” if the study visit 
occurs within 4 weeks (28 days) of the 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. 
As a joint assessment may be recorded as “temporarily not assessable” or “permanently 
not assessable”, the following data handling rules will be applied to handle the data in 
the calculation of SJC and TJC. 
 
Joints temporarily or permanently not assessable at baseline are excluded from 
joint count throughout the study. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 22 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
For other un-assessed joints at baseline, the joint assessment at the screening 
visit, if assessed, is used as the baseline assessment; otherwise, the joint is 
excluded from joint count throughout the study. 
 
For joints that become either temporarily or permanently not assessable at a 
post-baseline visit, the last observed joint assessment (including baseline and 
post-baseline assessments) will be used for that visit. 
After applying these data handling rules, TJC will be calculated by adding the number of 
joints with outcomes of 'Pain/Tenderness Only' or 'Pain/Tenderness and Swelling'. SJC 
will be calculated by adding the number of joints with outcomes of 'Swelling Only' or 
'Pain/Tenderness and Swelling'. TJC and SJC will be derived based on the sentinel 
joints and all joints (66 joints for swelling and 68 joints for tenderness). 
5.1.3 
Patient’s Global Assessments of Disease Activity 
The Patient’s (Subject’s) Global Assessments of Disease Activity (Appendix E of 
Protocol) is an assessment of how active a subject’s psoriatic arthritis was on average 
during the last week. The subject will be asked to place a vertical line on a visual 
analogue scale (VAS) on which the left-hand boundary represents the lowest level of 
disease activity and the right-hand boundary represents the highest. Distance from the 
mark to the left-hand boundary will be recorded in millimeters, except when calculating 
cDAPSA score, where the distance will be calculated in centimeters. 
Data resource: This VAS is entered by the patient via tablets provided by ERT.  
5.1.4 
Patient’s Pain Visual Analogue Scale  
The pain in visual analogue scale (VAS) (Appendix E of Protocol) is the subject’s 
assessment of how much pain he/she had, on average, last week in his/her joints due to 
PsA. The subject will be asked to place a vertical line on a VAS on which the left-hand 
boundary represents “no pain” and the right-hand boundary represents “pain as severe 
as can be imagined”. The distance from the mark to the left-hand boundary will be 
recorded in millimeters, except when calculating cDAPSA score, where the distance will 
be calculated in centimeters. 
5.1.5 
Data resource: Pain VAS is entered by the patient via tablets 
provided by ERT. HAQ-DI 
The HAQ-DI (Appendix F of Protocol) 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 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 23 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
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. This scale is sensitive to change and is a good predictor of 
future disability. 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 tablets provided by ERT.  
5.1.6 
Enthesitis: Leeds Enthesitis Index 
In the evaluation of MDA-Joints, enthesitis will be assessed by the Leeds Enthesitis 
Index (LEI) (Appendix G of Protocol). 
For the LEI, pain will be assessed at the following 6 entheses (tendon insertions) sites: 
Lateral epicondyle humerus (left/right (L/R)); Medial condyle femur (L/R); and Achilles 
tendon insertion into calcaneum (L/R). Tenderness at each site is quantified on a 
dichotomous basis: 0 means nontender and 1 means tender. The LEI ranges from 0 to 
6. 
Data resource: LEI is entered by the physician via tablets provided by ERT.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 24 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
5.1.7 
BSA 
BSA (Appendix H of Protocol) is a measurement of involved skin. The overall BSA 
affected by psoriasis is estimated based on the palm area of the subject’s hand (entire 
palmar surface or “handprint”), which equates to approximately 1% of total body surface 
area. All subjects will have their BSA assessed by the Evaluator. 
Data resource: BSA is entered by the physician via tablets provided by ERT.  
5.1.8 
Physician’s Global Assessments of Disease Activity  
The Physician’s (Evaluator’s) Global Assessments of Disease Activity is an assessment 
of how active a subject’s psoriatic arthritis was on average during the last week. For the 
Physician’s (Evaluator’s) Global Assessments of Disease Activity, evaluator should mark 
a single vertical mark on a 100-mm VAS, with zero representing the lowest level of 
disease activity or pain and 100 representing the highest. The distance from the mark to 
the left-hand boundary of the scale will be recorded in millimeters. 
Data resource: This VAS is entered by the physician via tablets provided by ERT.  
5.1.9 
Enthesitis
 
In addition to assessment by the Leeds Enthesitis Index, enthesitis will also be assessed 
using the 
 
5.1.10 
Dactylitis 
Dactylitis assessment will be done at screening, only a binary evaluation is needed 
(yes/no). 
 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 25 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
5.1.11 
Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) 
The cDAPSA score (Appendix K of Protocol) is based on the numerical summation of 4 
disease activity variables: tender and swollen joints, subject’s (patient’s) global 
assessments of disease activity (SGA) and Subject’s assessment of pain on a 10 cm 
Visual Analogue Scale (VAS).  
cDAPSA = SJC(66)+TJC(68)+SGA(VAS 0-10 cm)+Pain(VAS 0-10 cm), with range of 0-
154, and it will be set to missing if any of the 4 components is missing. A higher score 
indicates greater disease activity. Disease activity based on cDAPSA will be categorized 
as remission if cDAPSA ≤ 4, low disease activity if 4 < cDAPSA ≤ 13, moderate disease 
activity if 13 < cDAPSA ≤ 27, and high disease activity if cDAPSA > 27. The calculation 
of the cDAPSA will be performed programmatically. 
5.1.12 
Psoriatic Arthritis Disease Activity Score (PASDAS) 
The PASDAS (Appendix L of Protocol) is a weighted index comprising assessments of 
joints, function, acute-phase response, quality of life (QOL), and patient and physician by 
VAS. The calculation of the PASDAS will be performed programmatically using the 
formula below: 
PASDAS  ((0.18 x Physician global VAS)  (0.159 x Patient global VAS) – (0.253 x 
SF36–PCS)  (0.101 x LN (Swollen joint count  1))  (0.048 x LN (Tender joint count  
1))  (0.23 x LN (Leeds Enthesitis Count  1))  (0.377 x LN (Dactylitis count  1))  
(0.102 x LN (CRP  1) 2))*1.5. 
Note: LN = natural logarithm, SF36 = Medical Outcomes Study Short Form-36, SF36-
PCS = physical component summary scale of SF36, CRP = C-reactive protein in mg/L. 
High sensitivity C-reactive protein (hsCRP) and rheumatoid factor will be analyzed at a 
central laboratory. 
All VAS scores are 0–100 mm. Swollen joint count is based on 66 joints, and tender joint 
count based on 68 joints. The score range of the PASDAS is 0–10, with worse disease 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 26 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
activity represented by higher scores. If CRP is reported as below detection limit, then 
the value of detection limit will be used for PASDAS calculation.  
If one or more components are missing, then PASDAS is set to be missing. 
Table 1. Response criteria for the PASDAS 
Final PASDAS Score 
Improvement 
≥ 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 
 
5.1.15 
The PsA Impact of Disease 12-Item (PsAID-12) Questionnaire 
The PsAID-12 Questionnaire (Appendix N of Protocol) 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.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 27 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Final PsAID-12 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 ≤ 4 
representing patient-acceptable symptom state. (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 captured via tablets provided by ERT.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 28 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 29 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 30 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
5.2 
Derivations of Safety Endpoints 
Baseline definition for all safety endpoints is given in Section 5.3. Change from baseline 
is calculated as on-treatment value minus the baseline value. Handling of time points is 
described in Section 5.4. 
Treatment-emergent Adverse Event 
An AE is a treatment-emergent AE (TEAE) if the AE start date is 
 
on or after the date of the first dose of investigational product (IP) and no later 
than 28 days after the last dose of IP for subjects who have completed the study 
or have discontinued early by the time of database cut, or 
 
on or after the date of the first dose of IP for subjects who are ongoing at the time 
of database cut 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 31 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
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 Section 8.3.1 
5.2.1 
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 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. 
5.3 
Baseline Definitions 
For both efficacy and safety analyses in the Placebo-controlled Phase, baseline will be 
the last value measured prior to or on the day of the first dose of IP. 
For safety analyses in Apremilast-exposure Period, baseline will be the last value 
measured prior to or on the first apremilast dose date. 
5.4 
Time Points 
Time points in all efficacy 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 
phase/period 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. Only scheduled visit will be used for time point analysis.  
 
 Early Termination Visit 
A value from the Early Termination Visit (for a discontinued subject) will be mapped 
to the subsequent scheduled visit for that parameter after the last visit the subject 
has completed. 
Note that each measurement collected at the Early Termination Visit will only be mapped 
to the next scheduled visit for that measurement. For example, SF-36 is scheduled to be 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 32 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
collected at Week 16/Visit 5, Week 24/Visit 6, and Week 48/Visit 9. If a subject 
discontinued after Week 24/Visit 6, then the SF-36 Early Termination data would be 
mapped to Week 48/Visit 9, not Visit 7. 
Analysis visits in safety analyses are based on the remapped visits/study weeks using 
the visit mapping algorithm (Appendix A), which may or may not be the same as the 
visits/study weeks as recorded in the database. 
5.5 
Analysis Phases/Period 
For the purposes of data analysis and reporting, below analysis phases/period for post-
baseline data are defined: the Placebo-controlled Phases (through Week 24 and through 
Week 16) and the Apremilast-exposure Period.  
The start and stop dates of each analysis phases/period are defined below, unless 
otherwise defined for a specific analysis or summary. Analyses for a specific period will 
include all data occurring, measured or collected (based on date of occurrence or 
measurement, or date of specimen collection, as appropriate) between the start and stop 
dates (inclusive or exclusive, depending on the data type) of that analysis phases/period. 
The specific rules for including or excluding the start and stop dates, depending on the 
data type, are also given below. 
 
Placebo-controlled Phase through Week 24: 
- Start date: The date of the first dose of IP. 
- Stop date: 
▪ 
The date of the first Week 16/Visit 5 dose for placebo-treated 
subjects who escape early at Week 16/Visit 5 and take at least 
one dose of IP dispensed at that visit, or 
▪ 
The date of the first Week 24/Visit 6 dose for subjects who 
complete Week 24/Visit 6, except for placebo-treated subjects 
who escape early, or 
▪ 
For all other subjects (i.e., subjects who discontinue prior to Week 
24/Visit 6, with the exception of placebo-treated subjects who 
discontinue after early escape and has taken at least one dose of 
IP dispensed at Week 16/Visit 5), the date of the last study visit 
(including the Early Termination Visit and the Observational 
Follow-up Visit; i.e., all data after the start date will be included) for 
efficacy analyses, or 28 days after the last dose of IP or the date 
of death (if applicable), whichever comes first, for safety analyses. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 33 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
Placebo-controlled Phase through Week 16: 
- Start date: The date of the first dose of IP. 
- Stop date: 
▪ 
The date of the first Week 16/Visit 5 dose for placebo-treated 
subjects who escape early at Week 16/Visit 5 and take at least 
one dose of IP dispensed at that visit, or 
▪ 
The last non-missing Week 16/Visit 5 date for subjects who 
complete Week 16/Visit 5, except for placebo-treated subjects 
who escape early, or 
▪ 
For all other subjects (i.e., subjects who discontinue prior to Week 
16/Visit 5), the date of the last study visit (including the Early 
Termination Visit and the Observational Follow-up Visit; i.e., all 
data after the start date will be included) for efficacy analyses, or 
28 days after the last dose of IP or the date of death (if 
applicable), whichever comes first, for safety analyses. 
 
For the Placebo-controlled Phases, the start date is exclusive, and the stop date is 
inclusive for efficacy analyses, and safety analyses of laboratory, vital signs, weight, and 
ECG data. For AE analyses, the start date is inclusive, the stop date under the first 2 
bullets is exclusive and the stop date under the third bullet is inclusive. 
 
Apremilast-exposure Period: 
- Start date: 
▪ 
The date of the first dose of apremilast after being randomized (at 
Week 0/Visit 2) or escaped/transitioned (at Week 16/Visit 5 or 
Week 24/Visit 6) to an apremilast dose group. 
- Stop date: 
▪ 
For efficacy analyses, the date of the last study visit available in 
the database (including the Early Termination Visit and the 
Observational Follow-up Visit; i.e., all data after the start date of 
the Apremilast-exposure Period will be included), or 
▪ 
For safety analyses, 28 days after the last dose of apremilast or 
the date of death (if applicable), whichever comes first, for 
subjects who have completed the study or have discontinued early 
by the time of database cut. For ongoing subjects, the data cutoff 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 34 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
date for safety analyses of laboratory, vital signs, weight, and 
ECG data, and AE analyses. 
For the Apremilast-exposure Period, the start date is exclusive and the stop date is 
inclusive for efficacy analyses, and safety analyses of laboratory, vital signs, weight, and 
ECG data. For AE analyses, both the start and stop dates are inclusive. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all subjects who are randomized as specified 
in the protocol. Subjects who are randomized in error and do not receive any dose of IP 
will be excluded from FAS.  Efficacy analyses for the Placebo-controlled Phase will be 
primarily based on the FAS and subjects will be included in the treatment group to which 
they are randomized. 
6.2 
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who receive at least one dose of 
study medication. The safety analyses for the Placebo-controlled Phase will be based on 
the Safety Analysis Set and subjects will be included in the treatment group for the 
treatment they actually receive. For most subjects this will be the treatment group to 
which they are randomized. Subjects who take an IP that differs from the assigned one, 
according to the randomization schedule, for the entire Placebo-controlled Phase will be 
included in the treatment group corresponding to the IP they actually received. Subjects 
received at least one dose of apremilast in the Placebo-controlled Phase will have their 
actual treatment arm as apremilast. 
6.3 
Per Protocol Set(s) 
The Per Protocol (PP) Set will consist of all subjects who are randomized and receive at 
least one dose of study medication and have no major protocol deviations during the 
Placebo-controlled Phase that will have a major impact on the assessment of the 
primary endpoint. The final determination of major protocol deviations will be made prior 
to the unblinding of treatment assignment and will be documented. The PP analyses in 
the Placebo-controlled Phase will be based on the PP population and subjects will be 
included in the treatment group for the treatment they are randomized. 
6.4 
Health-related Quality-of-Life or Health Economics Analyses Set(s) 
Not applicable. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 35 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
Not applicable. 
6.6 
Interim Analyses Set(s) 
Not applicable. 
6.7 
Study-specific Analysis Sets 
6.7.1 
Apremilast Subjects as Randomized or Transitioned Population  
The efficacy analyses for the Apremilast-exposure period that include data from the 
placebo-controlled and active-treatment extension phases will be based on the subjects 
as randomized or transitioned population, which will include all FAS subjects who are 
randomized (at Week 0) or escaped/transitioned (at Week 16 or Week 24) to apremilast. 
The data summaries will be tabulated by the group subjects are randomized to (i.e., 
separately for subjects who are randomized to apremilast or placebo at Week 0).   
6.7.2 
Apremilast Subjects as Treated Population  
Safety analyses for the Apremilast-exposure Period will be based on the apremilast 
subjects as treated, which will include all subjects who are treated with apremilast from 
Week 0 or transitioned to apremilast at Week 16 or Week 24. Subjects’ safety data 
during the Apremilast-exposure Period will be included. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis will be conducted. 
7.2 
Primary Analysis 
After all subjects have completed the Week 24 Visit (or discontinued from the study), a 
Week 24 database restriction will be performed, the primary data analysis will be 
conducted. However, unblinded data will only be made available to selected Sponsor 
and Contract Research Organization (CRO) team members involved with analysis of the 
data.  All other Sponsor, site, and CRO personnel directly involved with the conduct of 
the study, will remain blinded to treatment assignments until the final database lock at 
the conclusion of the study. 
The primary analysis will present data from the completed placebo-controlled phase of 
the study, including the primary, secondary endpoints at Week 16, and
 
 and safety results up to week 24. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 36 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
7.3 
Final Analysis 
At the end of the study, after all subjects have completed or have been discontinued 
from the Apremilast Extension Phase (Weeks 24 to 48) and the Observational Follow-up 
Phase, the final analysis will be performed. The scope of the final analysis is the 
evaluation of the long-term efficacy and safety data. A final Clinical Study Report will be 
generated. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data and will be processed by Amgen Global Statistical programming (GSP) 
to be used in the planned analyses.  This study will use the RAVE database, the efficacy 
endpoint data received from Clario (formerly ERT), IWRS data from Endpoint and 
Laboratory data from LabCorp (formerly Covance). 
8.3 
Handling of Missing and Incomplete Data 
8.3.1 
Adverse Events 
Partially missing AE start dates will be imputed in the ADaM dataset for AEs. 
Adverse Events  
Partially missing AE start dates 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.  
 
Subjects who were treated with apremilast at Week 0/Visit 2  
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.  
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose 
of IP as “DIP/MIP/YIP”. The following table gives the imputation rules for partially missing 
AE start dates for subjects who were treated with apremilast initially.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 37 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Table 2. Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (Both month and day are missing) 
1 
YEvent < YIP 
12/31/YEvent 
2 
Otherwise 
Max(day of first dose of IP, 1/1/YEvent) 
Partially missing date includes both year and month (Only day is missing) 
1 
YEvent < YIP, or (YEvent = YIP 
and MEvent <MIP) 
Last date of MEvent/YEvent 
2 
Otherwise, i.e., YIP < YEvent, 
or (YIP =YEvent and MIP≤ 
MEvent) 
Max (date of first dose of IP, 
1/MEvent/YEvent) 
 
Subjects who were treated with placebo at Week 0/Visit 2  
The principle of the imputation rules for subjects who were treated with placebo initially 
and started apremilast treatment at Week 16 or Week 24 is to consider the AE starting 
on or after the date of the first dose of apremilast, if possible; if the partially missing start 
date suggests that it is prior to the date of the first dose of apremilast, the AE will be 
considered starting on or after the date of the first dose of IP, if possible. 
The following are 4 scenarios considered in the imputation rules: 
1. The partially missing AE start date suggests the date is prior to the date of the 
first dose of IP: impute it by the latest possible date (determined by the non-
missing field of the date);  
2. The partially missing AE start date suggests the date is after the date of the first 
dose of apremilast: impute it by the earliest possible date (determined by the 
non-missing field of the date);  
3. The partially missing AE start date is in the same year (if both month and day are 
missing), or the same year/month (if only day is missing) of the first dose of 
apremilast: impute it by the date of the first dose of apremilast;  
4. The partially missing AE start date suggests the date is no earlier than the date 
of the first dose of IP but prior to the date of the first dose of apremilast: impute it 
by the date of the first dose of IP, or the earliest possible date (determined by the 
non-missing field of the date), whichever occurs later.  
 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 38 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Let an AE start date be represented as “DEvent/MEvent/YEvent”, the date of the first dose of 
IP as “DIP/MIP/YIP”, and the date of the first dose of apremilast following Week 24 or early 
escape date as “DAPR/MAPR/YAPR”. The following table gives the imputation rules for 
partially missing AE start dates. 
Table 3. Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Placebo Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (Both month and day are missing) 
1 
YEvent < YIP 
12/31/YEvent 
2 
YEvent > YAPR 
1/1/YEvent 
3 
YEvent = YAPR 
Date of first dose of apremilast 
4 
Otherwise, i.e., YIP ≤ YEvent< 
YAPR 
Max (date of first dose of IP, 1/1/YEvent) 
Partially missing date includes both year and month (Only day is missing) 
1 
YEvent < YIP, or (YEvent = YIP 
and MEvent <MIP) 
Last date of MEvent/YEvent 
2 
YEvent > YAPR, or (YEvent = YAPR 
and MEvent > MAPR) 
1/MEvent/YEvent 
3 
YEvent = YAPR and MEvent = 
MAPR 
Date of first dose of apremilast 
4 
Otherwise, i.e., YIP < YEvent < 
YAPR, or (YIP = YEvent < YAPR 
and MIP ≤ MEvent),  
or  
(YIP = YEvent = YAPR and MIP ≤ 
MEvent < MAPR), or (YIP < YEvent 
= YAPR and MEvent < MAPR) 
Max (date of first dose of IP, 
1/MEvent/YEvent) 
 
 
8.3.2 
Prior/Concomitant Medications/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 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 39 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
imputed by the rule below is after the stop date, then the start date will be imputed with 
the stop date. 
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 with the latest 
possible date given the non-missing field(s) of the date. 
8.3.3 
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.  If this imputation results in a medical treatment start date is 
on or after the informed consent date, then the incomplete medical treatment start date 
will be assigned as one day before earliest recorded informed consent date. If the end 
date is complete with no missing year, month, or day, and the partially missing start date 
imputed by the rule above is after the end date, then the start date will be imputed with 
the end date. 
8.4 
Detection of Bias 
This study has been designed to minimize potential bias by the use of randomization of 
subjects into treatment groups and the use of blinding. Other factors that may bias the 
results of the study include: 
 
Major protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints. 
 
Subject level unblinding before the primary analysis database lock and formal 
unblinding. 
Important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints will be tabulated in the Clinical Study Report (CSR).  
Any unblinding of individual subjects prior to formal unblinding of the study will be 
documented in the CSR. The impact of such unblinding on the results observed will be 
assessed.  
Additional sensitivity analyses will be performed to assess the impact of potential biases 
on the primary endpoint if needed. If any sensitivity analyses are required to evaluate 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 40 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
potential biases in the study’s conclusions, then the sources of the potential biases and 
results of the sensitivity analyses will be documented in the CSR.   
8.5 
Outliers 
Extreme data points will be identified during the blinded review of the data prior to 
primary analysis database lock. Such data points will be reviewed with clinical data 
management to ensure accuracy. The primary analyses will include outliers in the data. 
Sensitivity analyses that exclude outliers may be undertaken if extreme outliers for a 
variable are observed.  
8.6 
Distributional Characteristics 
Distributional assumptions for the primary and secondary endpoints will be assessed If 
the assumptions are not met, then alternative methods will be utilized. The use of 
alternative methods will be fully justified in the CSR. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
9.1.1 
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 each treatment group in the 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 41 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
column heading. P-values (2 sided) will be presented with 4 decimal places. All 
laboratory data will be reported using standard international (SI) units. 
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. 
The analyses involving stratification factors (use of glucocorticosteroid at baseline and 
use of a csDMARD) will be primarily based on the stratification factors recorded in IWRS 
at the randomization. Similarly, EE status, as recorded in the IWRS, will be used in all 
derivations/analyses. 
Subject data listings will be provided to support the tables and graphs for selected 
parameters. 
9.1.2 
Statistical Methodology for Efficacy 
For the Placebo-controlled Phase, treatment outcomes between APR 30 mg BID and 
placebo will be compared primarily using the FAS. Supportive analysis of the primary 
endpoint (MDA-joints at Week 16) will use the PP.  
For efficacy analyses, data obtained after the day of the first Week 16/Visit 5 dose for 
subjects who escape early at Week 16/Visit 5 and take at least one dose of IP dispensed 
at that visit will be excluded from the placebo-controlled summaries through Week 
24/Visit 6, unless otherwise specified. 
The null and alternative hypotheses for the treatment comparisons can be described as 
follows: 
H0: 𝑝𝑎𝑝𝑟𝑒𝑚𝑖𝑙𝑎𝑠𝑡 =  𝑝𝑝𝑙𝑎𝑐𝑒𝑏𝑜        vs.        H1: 𝑝𝑎𝑝𝑟𝑒𝑚𝑖𝑙𝑎𝑠𝑡 ≠  𝑝𝑝𝑙𝑎𝑐𝑒𝑏𝑜, 
Where p stands for the parameter in comparison, e.g., proportion of subjects achieving 
MDA-Joints. 
Efficacy results will be considered statistically significant after incorporating the strategy 
for controlling the family-wise Type 1 error rate as described in Section 9.1.3, Multiplicity. 
All statistical tests will be conducted at the α = 0.05 (2-sided) level. That is, 2-sided p-
values and 2-sided confidence intervals (CIs) for intended point estimates will be 
reported. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 42 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Analyses of the long-term data that include the Placebo-Controlled Phase and the 
Active-treatment Extension Phase will be based on Apremilast Subjects as Randomized 
population. 
9.1.3 
Multiplicity 
Among statistical tests for the comparisons between the apremilast 30 mg BID and 
placebo groups, the multiplicity of the analyses performed for the primary and  
secondary efficacy endpoints will be adjusted using a sequential test procedure to 
preserve the family-wise type I error rate. The secondary efficacy endpoints and the 
hierarchical order of the endpoints in the sequential testing will follow those listed in 
Section 2.1  
The sequential test procedure will be conducted as follows: 
 
Formal statistical tests will be carried out sequentially for selected endpoints, 
starting with the primary endpoint and then the secondary endpoints by the order 
same as presented in Section 2.1  
 
At each step in the sequential testing, statistical significance for a specific 
endpoint will be claimed only if the p-value for the test is less than 0.05, and the 
p-values for the tests of all previous endpoints in the hierarchy order are also less 
than 0.05. 
 
Once a p-value is 0.05 or greater for the testing of a specific endpoint, only the 
tests for the preceding endpoints will be considered statistically significant; the 
testing for this and the subsequent endpoints will not be considered statistical 
significance and the nominal p-values will be reported. 
Of note, the above multiplicity control will only be conducted for the primary endpoint and 
the secondary endpoints that are evaluated in the Placebo-controlled Phase. 
9.2 
Subject Accountability 
The number of subjects screened, randomized, receiving IP, and completing the study 
will be summarized. 
Subject disposition will be tabulated by treatment arm and study phase.  Reasons for 
discontinuation will be summarized.  
The number and percent of subjects randomized will be tabulated by the stratification 
factors. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 43 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to primary analysis database lock.  These definitions of IPD categories, 
subcategory codes, and descriptions will be used during the course of the study. 
Eligibility deviations are defined in the protocol. 
The protocol deviations/violations will be identified and assessed by clinical research 
physician or designee throughout all study periods. The protocol deviations/violations for 
a particular analysis will be defined prior to unblinding of the database. For example, the 
analysis for the primary endpoint will be based on the 24-week database and definitions 
of major protocol deviations/violations that may affect the analysis will be determined 
prior to unblinding of the 24-week database. The protocol deviations/violations will be 
summarized by treatment arm for the FAS for the double-blind, Placebo-controlled  
Phase (up through Week 24, regardless of early escape status). Additional summaries 
will be provided based on Apremilast Subjects as Randomized through Week 52 (Weeks 
0-52). 
A list of protocol deviations/violations for all subjects will be provided by the Clinical 
Research Physician and/or through a standardized algorithm prior to the primary 
analysis database lock and unblinding. Among these protocol deviations, those that may 
have impact on treatment efficacy will also be determined prior to the primary analysis 
database lock and used to identify which subjects are to be removed from the Per 
Protocol Set . These protocol deviation data will be integrated into the clinical database. 
Additionally, protocol deviations and important protocol deviations related to COVID-19 
will be summarized. 
9.4 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively by 
treatment group using the FAS. In addition, demographics and baseline disease 
characteristics will also be summarized for subjects who escape early, subjects who do 
not escape early and subjects who discontinue early. The comparability of the treatment 
groups for each relevant characteristic will be assessed descriptively in table format; no 
statistical hypothesis tests will be performed on these characteristics. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 44 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
9.4.1 
Demographics 
Demographic characteristics including age, sex, race, ethnicity, geographic region, 
weight (kg) and height (cm), etc. (please refer to CRF for available variables) will be 
summarized. 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum, etc.).  Categorical variables  will be 
summarized with counts and percentages. 
Summary statistics will be provided by treatment group for the following continuous 
variables: 
 
Age (years) 
 
Weight (kg) 
 
Height (cm) 
 
 
Number and percentage will be provided by treatment group for the following categorical 
variables where sufficient numbers allow: 
 
Age category (< 65, ≥ 65 years; < 40, ≥ 40 to < 65, ≥ 65 to < 75, ≥ 75 to < 85, ≥ 
85 years, if appropriate) 
 
Sex (male, female) 
 
Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islanders, White, Not Collected or Unknown) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
 
Region (North America, Europe, Rest of the World [including Russia]) 
 
Weight category (< 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥ 100 kg) 
 
 
Most variables will be used as recorded on the CRF. 
The demographics summary will include the frequencies of alcohol history (current user, 
past user, never used), and smoking status (current user, past user, never used). 
9.4.2 
Baseline or Disease Characteristics 
Summary statistics will be provided by treatment group for all relevant baseline 
characteristics continuous variables, such as the following: 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 45 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
Duration of PsA (from the date of diagnosis to the date of informed consent; 
months) 
 
Baseline prednisone (or equivalent) dose (mg/day) 
 
Concomitant Methotrexate dose (mg/week) 
 
Concomitant Sulfasalazine does (g/day) 
 
cDAPSA 
 
Swollen joint count (66 joints) 
 
Tender joint count (68 joints) 
 
Patient’s global assessment of disease activity (0 to 100 mm VAS) 
 
Patient’s assessment of pain (0 to 100 mm VAS) 
 
PsAID-12 
 
HAQ-DI score and categories 
 
Physician’s global assessment of disease activity (0 to 100 mm VAS) 
 
LEI in subjects with pre-existing enthesopathy 
 
PASDAS 
 
Psoriasis BSA 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 46 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
hsCRP (mg/L) 
Number and percentage will be provided by treatment group for all relevant 
categorical variables, such as the following (subcategories under a specific category 
of a variable, where applicable): 
 
Baseline glucocorticosteroid use (yes, no) in IWRS and in actual data, if different 
 
Prior/concomitant use of a csDMARD, either MTX or SSZ, (csDMARD-naïve; 
csDMARD use prior to baseline; or csDMARD use prior to and concomitant at 
baseline) in IWRS and in actual data, if different 
 
Prior use csDMARD (yes, no) 
 
Concomitant use of csDMARD (yes, no) 
 
Tender joint count (2, 3, 4) 
 
Swollen joint count (2, 3, 4) 
 
Swollen or tender joint count (2, 3, 4, 5, 6, 7, 8) 
 
Swollen and tender joint count (0, 1, 2, 3, 4) 
 
cDAPSA (≤ 4 for remission, > 4 and ≤ 13 for low disease activity, > 13 and ≤ 27 
for moderate disease activity, and > 27 for high disease activity) 
 
Patient’s global assessment of disease activity VAS (≤20, >20) 
 
Patient’s assessment of pain VAS (≤15, >15) 
 
PsAID-12 (≤ 4, > 4) 
 
PASDAS (≤3.2,  >3.2 to < 5.4, ≥ 5.4) 
 
HAQ-DI (≤0.5, > 0.5) 
 
LEI (= 0, > 0) 
 
LEI (≤1, >1) 
 
Psoriasis BSA (≤3%, >3%) 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 47 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
9.4.3 
Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA, version 25.1 or later). A frequency summary (number and 
percentage) of medical history will be presented by treatment group, system organ class 
(SOC), and preferred term (PT).  
 
9.4.4 
Prior and Concomitant Procedures 
The prior and concomitant procedures will be coded using the MedDRA, version 25.1 or 
higher. Frequency summaries of prior procedures for Full Analysis Set, and concomitant 
procedures for Safety Analysis Set will be provided by treatment group, SOC and PT. 
Prior procedures are defined as procedures or surgeries that were started before the first 
dose of IP (regardless of they ended before the first dose of IP). Prior procedures that 
continue or occur after the first dose of IP will also be reported as concomitant 
procedures.  
Concomitant procedures will be similarly analyzed as concomitant medications in the 
next section. 
 
9.4.5 
Prior and Concomitant Medications 
The Anatomical Therapeutical Chemical (ATC) coding scheme of the World Health 
Organization Drug Dictionary (WHODD version March 2020 or later) will be used to 
group medications into relevant categories. Frequency summaries of prior medications 
for Full Analysis Set and concomitant medications for Safety Analysis Set will be 
provided by treatment group, ATC2 level, and standardized medication name. 
Prior medications are defined as those started before the first dose of IP (whether or not  
ended before the first dose of IP). Prior medications that continue after the first dose of 
IP will be also reported as concomitant medications.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 48 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Concomitant medications and procedures will be summarized differently for each 
phase/period of the study.  The concomitant medication for the Placebo-controlled 
Phase will be summarized by treatment group using the Safety Analysis Set.  The 
concomitant medication for the Apremilast-exposure Period will be summarized by a 
total group only of those who were treated with apremilast (irrespective of when the 
apremilast exposure starts [at Week 0, 16, or 24]).  In addition, to account for possible 
resumption/initiation of non-study medications treating PsA during the Observational 
Follow-up Phase, concomitant medications will be summarized for the Observational 
Follow-up Phase based on all subjects who entered the phase. 
A concomitant medication for the Placebo-controlled Phase is defined as a non-study 
medication that meets either one of the following 2 criteria: 
1. Is started on or after the date of the first dose of IP, and  
- before the date of the first Week 16/Visit 5 dose for placebo-treated subjects 
who escape early at Week 16/Visit 5 and take at least one dose of IP 
dispensed at that visit, or 
- before the date of the first Week 24/Visit 6dose for subjects who complete 
Week 24/Visit 6 dose, except for placebo-treated subjects who escape early, 
or  
- on or before the date of the last study visit (including the Early Termination 
Visit and excluding any unscheduled visits associated with the Early 
Termination Visit and the Observational Follow-up Visit) for all other subjects 
(i.e., subjects who discontinue prior to Week 24/Visit 6, with the exception of 
placebo-treated subjects who discontinue after early escape and have taken 
at least one dose of IP dispensed at Week 16/Visit 6). 
2. Is started before the date of the first dose of IP, and stopped on or after the date 
of the first dose of IP, or recorded as ongoing. 
A concomitant medication for the Apremilast-exposure Period is defined as a non-study 
medication that meets either one of the following 2 criteria: 
1. is started on or after the date of the first dose of apremilast after being 
randomized (at Week 0/Visit 2) or escaped/transitioned (at Week 16/Visit 5 or Week 
24/Visit 6) to apremilast dose group and stopped on or before the date of the last 
study visit (including the Early Termination Visit and excluding any unscheduled 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 49 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
visits associated with the Week 48/Visit 9 and the Early Termination Visit, and the 
Observational Follow-up Visit) for subjects who have completed the study or have 
discontinued early, or on or before the data cutoff date for ongoing subjects. 
2. is started before the date of the first dose of apremilast after being randomized or 
escaped/transitioned to apremilast dose, and stopped on or after the date of the first 
dose of apremilast, or recorded as ongoing. 
A concomitant medication for the Observational Follow-up Phase is defined as a non-
study medication that meets either one of the following 2 criteria: 
1. is started after the date of the Week 48/Visit 9 (for subjects who have completed 
the study) or the Early Termination Visit (for subjects who have discontinued early), 
but no later than 28 days after the last dose of IP in the study. 
2. is started on or before the date of the Week 48/Visit 9 (for subjects who have 
completed the study) or the Early Termination Visit (for subjects who have 
discontinued early), and stopped after this date, or recorded as ongoing. 
 
9.5 
Efficacy Analyses  
9.5.1 
Analyses of Primary Efficacy Endpoint 
The primary efficacy endpoint, proportion of subjects who achieve the modified MDA 
(MDA-Joints) at Week 16, will be compared between the Apremilast 30 mg BID group 
and placebo group using the Cochran-Mantel-Haenszel (CMH) test, controlling for use of 
glucocorticosteroids at baseline (yes/no) and use of a csDMARD (naïve, prior use only, 
or prior and concomitant use). Unadjusted group responder rates, unadjusted treatment 
differences in proportions, and adjusted treatment differences in proportions using the 
weighted average of the treatment differences across the strata with the CMH weights, 
along with the associated 2-sided 95% CIs using a normal approximation to the 
weighted average and the 2-sided p-values from the CMH tests, will be provided. 
Apremilast will be declared efficacious if the test result for the comparison is statistically 
significant in favor of Apremilast. 
Subjects who have discontinued prior to Week 16 due to lack of efficacy or adverse 
event will be treated as non-responders in the analysis; and the multiple imputation 
methodology will be utilized, as appropriate, to impute the data for subjects whose 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 50 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
modified MDA at Week 16 is missing for a reason other than lack of efficacy or adverse 
event.  
The combination of non-responder imputation of some subjects and the multiple 
imputation of the rest of missing values at Week 16 is to address the Missing Not At 
Random (MNAR) nature of missing values at the analysis time point. The detailed data 
handling and analysis follow the procedures below: 
Step 1. Censor or apply NRI (non-responder imputation) per different scenario 
 
(Censoring) After applying Early Termination Visit data, missing Week 16 values 
remain as missing for patients discontinued prior to Week 16 due to other 
reasons 
 
 (NRI) Set non-responder (NR) to subjects discontinued prior to Week 16 due to 
o Lack of efficacy 
o Adverse event 
Step 2. Implement multiple imputation, with 40 iterations (using fully conditional 
specification to impute the missing modified MDA generated from Step 1). 
Step 3. Calculate statistics on each imputation iteration from Step 2. 
Step 4. Combine results from Step 3. 
The overall p-value will be derived from the CMH test that is normalized via the Wilson-
Hilferty transformation (Wilson & Hilferty, 1931; Goria, 1992). 
Sensitivity analysis 
Subjects with no response data to determine the response status at all assessment 
timepoints will be excluded.   
The effect of protocol compliance will be studied by repeating the primary analysis using 
the PP population, according to the treatment subjects actually receive and the 
stratification factors subjects’ medication data show. 
In order to investigate the impact of the imputation method used for the primary analysis, 
a sensitivity analysis will be performed using the non-responder imputation for subjects 
who have discontinued prior to Week 16, or do not have sufficient information for a 
definitive determination of the modified MDA (MDA-Joints) status at Week 16. The 
responder analysis using the CMH model as in the primary analysis will be repeated. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 51 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
To examine the robustness of the results obtained from the primary analysis based on 
the CMH method, a sensitivity analysis will be implemented using logistic regression. 
The responder analysis based on the logistic regression model will include treatment 
group, concomitant use of glucocorticosteroids at baseline (yes/no), and use of 
csDMARD (naïve, prior use only, or prior and concomitant use) as factors.  This analysis 
will be based on the FAS data set used for the primary analysis with non-responder 
imputation along with the MI.  
 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
For the secondary endpoints, the missing data of the binary response parameters will be 
imputed using the non-responder imputation (NRI) and MI, as appropriate. The binary 
responses in the Placebo-controlled Phase will be analyzed using the CMH method, 
adjusted for use of glucocorticosteroids at baseline (yes/no) and use of a csDMARD 
(naïve, prior use only, or prior and concomitant use).  
A mixed-effect model of repeated measures (MMRM) will be used to analyze the 
continuous endpoints. Because of the nature of the MMRM method, data from all 
timepoints during the Placebo-controlled Phase will be included in the model. Data 
obtained after early escape for subjects who escape early at Week 16 will be set to 
missing. Change from baseline will be analyzed using the MMRM approach with 
treatment group, time, treatment-by-time interaction, use of glucocorticosteroids 
(yes/no), use of csDMARD (naïve, prior use only, or prior and concomitant use) as 
factors, and baseline value as a covariate. Time will be treated as a categorical variable 
in the MMRM model. An unstructured covariance matrix will be used to model the within 
subject covariance. If the MMRM model using an unstructured covariance matrix fails to 
converge with the default Newton-Raphson algorithm, the Fisher scoring algorithm or 
other appropriate methods can be used to provide initial values of the covariance 
parameters. In the rare event that none of the above methods yields convergence, a 
structured covariance such as heterogeneous Toeplitz and Toeplitz structures will be 
used to model the correlation among repeated measurements. In this case, the empirical 
option will be used because the sandwich variance-covariance estimator is 
asymptotically consistent. Within-group least-squares (LS) mean changes from baseline, 
the associated standard errors (SEs) and 2-sided 95% CIs, treatment differences in LS 
mean changes from baseline at Week 16 and the associated 2-sided 95% CIs and 2-


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 52 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
sided p-values will be obtained from the MMRM model and will be provided in the 
summary table. 
All analyses on endpoints including joint counts will be performed on those joints that are 
affected at baseline (defined as sentinel joints).   
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 53 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 54 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint 
Safety will be evaluated via descriptive statistics and point estimates. Unless otherwise 
specified, all safety analyses described in this section will be performed for both the 
Placebo-controlled and Apremilast-exposure Phases (Section 5.5). 
Safety analyses for the Placebo-controlled Phase will be based on the safety population 
and presented by treatment group (apremilast 30 mg BID and placebo); the data 
included are up to Week 16/Visit 5 for placebo-treated subjects who early escape and up 
to Week 24/Visit 6 for all other subjects. For the Apremilast-exposure Period, the 
analyses will be based on the apremilast subjects as treated population and include data 
from Day 1 of apremilast exposure, irrespective of when the apremilast exposure starts 
(at Week 0, 16, or 24). For both the Placebo-controlled Phase and the Apremilast-
exposure Period, the data included will be up to 28 days after the last dose of IP or the 
date of death (if applicable), whichever comes first, for subjects who discontinue 
prematurely. 
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. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 55 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
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 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. 
- Total exposure time: 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 
365.25 days. 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. If the subject experiences an event which 
starts on the first dose of the phase/period, the exposure time of that subject for 
that event is 1 day. 
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 phase/period and to the worst value, including 
scheduled and unscheduled visits, in a specific post-baseline phase/period. 
 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term with SOCs presented in the standard international order and PTs within 
SOCs will be presented in descending order of subject incidence. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, drug-related treatment-emergent adverse events, severe adverse 
events, serious adverse events, adverse events leading to discontinuation of 
investigational product ,fatal adverse events and adverse events of interest.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 56 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
A subject data listing of all AEs (including TEAEs and non-TEAEs) will be provided. 
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 
Summarization of the following AE categories will be provided: 
 
Any TEAE (by SOC and PT, and by PT only) 
 
Common TEAE (subject incidence ≥ 5% by SOC and PT, and by PT only) 
 
Any serious TEAE (by SOC and PT) 
 
Any non-serious TEAE (by SOC and PT) 
 
Any drug-related TEAE (by SOC and PT) 
 
Any serious drug-related TEAE (by SOC and PT) 
 
TEAEs by maximum severity (by SOC and PT) 
 
Any TEAE leading to study drug withdrawal (by SOC and PT) 
 
Any TEAE leading to study drug interruption (by SOC and PT) 
 
Any TEAE leading to death (by SOC and PT), if applicable 
If a subject reports multiple occurrences of a specific event within a specific analysis 
phase/period, the subject will be counted only once by the maximum severity (mild, 
moderate, severe, and, if needed, missing). If the severity is missing for one or more of 
the occurrences, the maximum severity of the remaining occurrences will be used. If the 
severity is missing for all occurrences, the subject will be counted only once in the 
“missing” category of severity. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 57 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
The relationship of an AE to IP is recorded on the AE CRF page as “not suspected” and 
“suspected”. Adverse events recorded as “suspected” or with missing relationship to IP 
will be assessed as drug-related. 
Summaries about selected TEAEs will also be provided by onset day and the event 
duration.  
New events of all TEAEs by exposure interval will be summarized for the Placebo-
controlled Phase (≤ 1, > 1 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12, > 12 weeks) and the Apremilast-
exposure Period (≤ 1, > 1 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12, > 12 to ≤ 16, > 16 to ≤ 28, > 28 
to ≤ 40, > 40 weeks). An event with a start date falling into an exposure interval is 
considered a new event for that interval. Each subject is counted once in the numerator 
of a subject incidence 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. 
All TEAEs will be summarized by age, sex, glucocorticosteroid use at baseline and 
prior/concomitant use of csDMARD. Subgroups of glucocorticosteroid use at baseline 
and prior/concomitant use of csDMARD will be based on the actual data, not by the data 
from IWRS. 
If there are deaths, a listing will be provided. 
9.6.3 
Adverse Events of Special Interest 
AESIs include protocol defined diarrhea AEs, which refers to events with two or more 
watery or liquid stools in a day, will be captured on the tablet by ERT. Frequency of the 
individual diarrhea will be captured.  
Frequencies (Daily, 5 - 6 days per week, 2 - 4 days per week, once every other week to 
once a week, once a month or less) of these events will be summarized.  
The summaries will be generated for the Placebo-controlled Phase, and for the 
Apremilast-exposure Period. 
9.6.4 
Laboratory Test Results 
Summary statistics of observed values and changes from baseline in laboratory 
parameters will be provided by time points. For each hematology and chemistry analyte, 
frequency summaries of shifts from baseline to post-baseline time points and to the 
worst post-baseline value during each treatment phase will be provided. The low, 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 58 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
normal, and high categories of laboratory values used in the shift will be based on the 
laboratory normal range.  
Laboratory marked abnormalities will be summarized based on the criteria in marked 
abnormalities criteria (Appendix B). 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 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. Subject data listings of all 
laboratory data, including urinalysis, will be provided. 
Clinical laboratory evaluations will be available from the central laboratory and include: 
 
Hematology: complete blood count (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 bilirubin, alkaline phosphatase, aspartate 
aminotransferase [AST; serum glutamic-oxaloacetic transaminase, SGOT], 
alanine aminotransferase [ALT; serum glutamic-pyruvic transaminase, SGPT], 
sodium, potassium, chloride, bicarbonate [carbon  dioxide, CO2], blood urea 
nitrogen, creatinine, creatinine clearance [estimated by the Cockcroft–Gault 
equation], lactate dehydrogenase [LDH], magnesium 
 
Dipstick urinalysis: specific gravity, pH, glucose, ketones, protein, blood, bilirubin, 
leukocyte esterase, nitrite, and urobilinogen. Dipstick urinalysis will be performed 
by the central laboratory; if the dipstick urinalysis is abnormal then a microscopic 
urinalysis (epithelial cells, RBC, WBC, and casts) will be performed.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 59 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
A subject listing will be provided for all available pregnancy test results. 
 
9.6.5 
Vital Signs 
For vital signs (temperature, pulse, and blood pressure) and weight, summary statistics 
(n, mean, standard deviation, median, minimum, the 25th (Q1) and 75th (Q3) 
percentiles, and maximum) of observed and change from baseline values will be 
presented. For vital signs (excluding weight), shift from baseline to each post-baseline 
visit, to worst (low/normal/high/both low and high) and to end of phase/period in below, 
within and above the normal ranges will be displayed in cross–tabulations for the 
Placebo-controlled Phase and for the Apremilast-exposure Period for parameters 
included in below Table 4. For weight, change from baseline (and percent change from 
baseline) to end of phase/period will be presented, as well as by baseline 
 and 
baseline weight categories. 
Table 4. Normal Ranges for Shift Table 
Vital Sign Parameter 
Normal Ranges 
Pulse 
60 – 100 beats/minutes 
Systolic blood pressure 
90 – 140 mmHg 
Diastolic blood pressure 
60 – 90 mmHg 
 
 
9.6.6 
Physical Measurements 
Physical examination findings will be captured as medical history at screening. Abnormal 
physical examination findings post Screening will be reported as adverse events and will 
be reported in the summaries. 
9.6.7 
Electrocardiogram 
Not applicable.  
9.6.8 
Antibody Formation 
Not applicable. 
9.6.9 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. Compliance to each IP will also be summarized.  


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 60 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Treatment duration will be summarized by treatment group for the Placebo-controlled 
Phase using the safety population. 
Summary statistics for treatment duration (in weeks), as well as a frequency summary of 
treatment duration categories (e.g., < 4, ≥ 4 - < 8 weeks, etc.) and exposure categories 
(e.g., ≥ 1 day, ≥ 4, ≥ 8 weeks, etc.), will be provided. 
Treatment duration (in weeks) is calculated as (the date of the last dose of IP – the date 
of the first dose of IP + 1) / 7 and rounded to one decimal place.  
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 the last dose date is completely missing, set the last dose date to the minimum of 
(the 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, clinical efficacy 
assessment date, lab, vital signs, AE start or end dates, concomitant medications start 
or end dates, concomitant procedure date, treatment exposure start date or end date 
where doses were completely or partially taken, death date). 
The specific definitions of the first and last dose dates for the Placebo-controlled Phase 
and Apremilast-exposure Period are given below: 
 
Placebo-controlled Phase: 
- First dose date: The date of the first dose of IP. 
- Last dose date: 
▪ 
the date prior to Week 16/Visit 5 for placebo-treated subjects who escape 
early at Week 16/Visit 5 and take at least one dose of IP dispensed at 
that visit, or 
▪ 
the date prior to Week 24/Visit 6 for subjects who complete Week 24/Visit 
6 dose, except for placebo-treated subjects who escape early  
▪ 
For all other subjects (i.e., subjects who discontinue prior to Week 24/Visit 
6), the date of the last dose of IP in the study. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 61 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
 
Apremilast-exposure Period: 
- First dose date: 
▪ 
The date of the first dose of apremilast after being randomized (at Week 
0/Visit 2) or transitioned (at Week 16/Visit 5 or Week 24/Visit 6) to 
apremilast. 
- Last dose date: 
▪ 
The date of the last dose of apremilast. 
 
The treatment compliance (in %) for each subject will be computed as 100 times the 
total number of tablets taken (the total number of tablets dispensed minus the total 
number of tablets returned) over the analysis phase or period divided by the intended 
total number of tablets that should have been taken over the same phase or period. 
Summary statistics for compliance (%) will be provided by treatment arm for each 
analysis phase or period. Frequency summary tables of compliance will also be 
presented with the following categories: < 75%, ≥ 75% - ≤120%, and > 120%. 
9.6.10 
Exposure to Non-investigational Product  
Not applicable. 
9.6.11 
Exposure to Other Protocol-required Therapy 
Not applicable.  
 
9.7 
Other Analyses 
Not applicable 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Not applicable. 
9.7.2 
Analyses of Clinical Outcome Assessments 
Not applicable. 
9.7.3 
Analyses of Health Economic Endpoints 
Not applicable. 
9.7.4 
Analyses of Biomarker Endpoints 
Not applicable. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 62 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
10. 
Changes From Protocol-specified Analyses 
During the development of this document, it was realized that the analysis for endpoint 
 
specified in section 2, Table 12 of the protocol is a typing error and that 
 
 is desired. The protocol has not been amended for 
this. The changes will be documented in the Clinical Study Report. 
11. 
Literature Citations / References 
Goria, M.N. 1992. On the forth root transformation of chi-square. Australian Journal of 
Statistics, 34 (1), 55-64.   
Rubin D.B. 1987. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
and Sons. 
Ware J E., Kosinski M, Keller S D, 1994. SF-36 physical and mental health summary 
scales: a user's manual, Boston : Health Institute, New England Medical Center. 
Wilson, E.B., Hilferty, M.M. 1931. The distribution of chi-squared. Proceedings of the 
National Academy of Sciences, Washington, 17, 684–688. 
12. 
Prioritization of Analyses 
Not applicable. 
13. 
Data Not Covered by This Plan 
Not applicable. 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 63 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
14. 
Appendices 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 64 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Appendix A.  Analytical Windows 
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. In the event of multiple measurements of the same test in the same 
window, the value measured nearest to the target day will be selected to the window; if 
they are at the same distance to the target day, the latest one will be used. If the value at 
a scheduled visit is missing and there is no value available within the time window based 
on the study day, the value at the study week will be missing.    
Table 5. Table for Visit Mapping for by Time Point Analysis 
Visit 
Target Day 
Analysis Time Window 
 for Safety Data  
Screening (1) 
<1 
<1 
Baseline (2) 
1 
1 
Week 4 (3) 
29 
[2, 56] 
Week 12 (4) 
85 
[57, 98] 
Week 16 (5) 
113 
[99, 140] 
Week 24 (6) 
169 
[141, 182] 
Week 28 (7) 
197 
[183, 238] 
Week 40 (8) 
281 
[239, 308] 
Week 48 (9) 
337 
≥309 
 Target Day = Visit date – Drug start date + 1. 
For Placebo-controlled Phase, target day and relative window are relative to the first 
dose of IP. 
The Apremilast-exposure Period encompasses all apremilast-exposure data, 
irrespective of when the apremilast exposure starts (at Week 0, 16, or 24).  The 
scheduled study weeks for subjects who are originally randomized to the placebo group 
and transitioned to apremilast at Week 16/Visit 5 (due to early escape) or Week 24/Visit 
6 will be adjusted to reflect the study weeks relative to the transition (i.e., study weeks on 
apremilast), and mapped to the (unadjusted) scheduled study weeks.  Adjusted study 
weeks on apremilast will align with scheduled study weeks specified in the protocol. 
This simple mapping will be ordered first as “minus 16” or “minus 24” from the scheduled 
visit depending on when the subject started apremilast, and then re-aligned to the 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 65 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
protocol scheduled visit.  Scheduled weeks are: 0, 4, 12, 16, 24, 28, 40, 48; Placebo 
subjects who early escaped: 0, 8, 12, 24, 32; placebo subjects who transitioned at week 
24: 0, 4, 16, 24.  The records related to Week 8 are realigned to Week 4, 32 to Week 28. 
 
 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 66 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
  
 
Appendix B.  Marked Abnormality Criteria 
Table 6. Marked Abnormalities Criteria 
Category 
Analyte (Unit)  
 Criteria  
Chemistry 
Alanine Aminotransferase (U/L)  
> 3×ULN   
   
Albumin (g/L)   
< 30  
    
Alkaline Phosphatase (U/L) 
> 400 
    
ALT/AST (U/L) 
ALT or AST > 3×ULN 
   
Aspartate Aminotransferase 
(U/L) 
> 3×ULN 
     
Bilirubin (µmol/L) 
> 2×ULN   
 
Bilirubin (umol/L) and ALT/AST 
(U/L) 
Bilirubin > 2×ULN and (ALT or AST > 
3×ULN)   
    
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. > 1.60    
    
Potassium (mmol/L) 
1. < 3.0  
2. > 5.5      
   
Sodium (mmol/L)   
1. < 130   
2. > 150   
    
Triglycerides (mmol/L)   
> 3.4     
    
Urate (umol/L) 
Male: > 590; Female: > 480    
Hematology   
Hemoglobin (g/L)   
1.  Male: < 105; Female: < 85 
2.  Male: > 185; Female: > 170 


Product:  AMG407  
Protocol Number:  20200058 
Date:  07 February 2023 
Page 67 of 67 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Category 
Analyte (Unit)  
 Criteria  
 
Basophils (10^9/L) 
> 3 
 
Eosinophils (10^9/L) 
1. > 0.8 
2. Increase ≥ 100% and value > 0.8 
 
Hematocrit (Ratio) 
1.  < 0.27  
2.  Male: > 0.55; Female: > 0.50  
    
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 
    
Hemoglobin A1C (%)   
> 9