Clinical trial NCT03082729
Conditions: Psoriasis Cardiovascular Diseases
Sponsor: University of Pennsylvania
Start date: 2017-04-24; Completion date: 2021-08-17
Enrollment: 70 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the VIP-A study is to determine the effect of apremilast on aortic vascular inflammation, cardiometabolic biomarkers and body composition in patients with moderate-severe psoriasis.

Detailed description:
The primary objectives of this study are to determine the effect of apremilast on aortic vascular inflammation, cardiometabolic biomarkers and body composition in patients with moderate-severe psoriasis. Fluorodeoxyglucose (FDG) - positron emission tomography (PET)/computed tomography (CT) will be used to assess vascular inflammation, with multi-volumetric product, tissue-to-background ratio and total atherosclerotic burden, and body composition via volumetric quantification. This is a year-long, single arm, open label study.

Arms: arm 1: Apremilast (Otezla), 30mg oral tablet twice per day for 52 weeks. Single arm, open label study.
Interventions: intervention 1: Apremilast
Intervention descriptions: intervention 1: Apremilast (brand name Otezla) is a medication for the treatment of certain types of psoriasis and psoriatic arthritis.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A PHASE IV, OPEN LABEL STUDY OF THE EFFECTS OF 
APREMILAST ON VASCULAR INFLAMMATION AND 
CARDIOMETABOLIC FUNCTION IN PSORIASIS 
 
 
Principal Investigator: 
Joel M. Gelfand MD, MSCE 
 
University of Pennsylvania Department of Dermatology 
Perelman Center for Advanced Medicine 
3400 Civic Center Boulevard 
7th Floor, South Tower #730 
Philadelphia, PA 19104 
Phone: 215-614-0635 
Fax: 215-615-3127 
 
 
Joel.Gelfand@pennmedicine.upenn.edu 
 
Co-Investigator:  
 
Joy Wan MD, MSCE 
University of Pennsylvania Department of Dermatology 
Perelman Center for Advanced Medicine 
3400 Civic Center Boulevard 
7th Floor, South Tower #773 
Philadelphia, PA 19104 
Phone: 215-615-2937 
Fax: 215-615-3127 
 
 
 
 joywan@pennmedicine.upenn.edu 
 
Regulatory Sponsor:  
Joel M. Gelfand MD, MSCE 
 
University of Pennsylvania Department of Dermatology 
Perelman Center for Advanced Medicine 
3400 Civic Center Boulevard 
7th Floor, South Tower #730 
Philadelphia, PA 19104  
Phone: 215-614-0635 
Fax: 215-615-3127 
 
 
Joel.Gelfand@pennmedicine.upenn.edu 
 
Funding Source: 
Amgen Corporation 
110 Allen Rd 
Basking Ridge, NJ  07920 
Phone: 908-860-4000 
 
Investigational Product: 
 
Apremilast (Otezla)  
Protocol Number: 
 
Amgen Number: 
826652  
 
 
 20207136  
ClinicalTrials.gov Number:          NCT03082729 


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Initial version:  7-21-2016  
 
Amended:   
 v7.04-03-2017 
 
Amended:       v8.05-15-2017  
  
Amended:       v9 07-14-2017 
 
Amended:       v10: 10-09-17 
 
 
Amended:   
v11: 07-18-19 
 
 
Amended: 
v12: 08-18-2020 
 
Amended 
v13:10.01.2021  
 
Current: 
v14:12.13.21 
 
 


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3 
Table of Contents 
List of Abbreviations .......................................................................................................................... 6 
Study Summary: ................................................................................................................................... 7 
1. 
Background and Study Rationale ...................................................................................... 8 
1.1 
Background and Relevant Literature ....................................................................................... 8 
1.2 
Name and Description of the Investigational Product: Apremilast ............................ 9 
1.3 
Non-clinical Data ............................................................................................................................... 9 
1.4 
Clinical Data to Date ........................................................................................................................ 9 
1.4.1 Human Pharmacokinetics ............................................................................................................. 9 
1.4.2 
Clinical Studies in Adults ........................................................................................................................ 10 
1.4.3 
Clinical Studies in Children ................................................................................................................... 10 
1.5 
Dose Rationale ................................................................................................................................ 10 
1.6 
Potential Risk .................................................................................................................................. 11 
2 
Study Objectives ......................................................................................................................... 11 
2.1 
Primary Objectives........................................................................................................................ 11 
2.2 
Secondary Objectives ................................................................................................................. 11 
3 
Investigational Plan ................................................................................................................... 11 
3.1 
General Design ............................................................................................................................... 11 
3.1.1 
Screening Phase ........................................................................................................................................ 13 
3.1.2 
Study Intervention Phase ....................................................................................................................... 13 
3.2 
Study Endpoints ............................................................................................................................ 13 
3.2.1 
Primary Study Endpoints........................................................................................................................ 13 
3.2.2 
Secondary Study Endpoints ................................................................................................................. 13 
3.2.3 
Primary Safety Endpoints ...................................................................................................................... 14 
4 
Study Population and Duration of Participation............................................................ 14 
4.1 
Inclusion Criteria ........................................................................................................................... 14 
4.2 
Exclusion Criteria .......................................................................................................................... 15 
4.3 
Subject Recruitment ..................................................................................................................... 16 
4.4 
Duration of Study Participation ............................................................................................... 16 
4.5 
Total Number of Subjects and Sites ...................................................................................... 16 
4.6 
Vulnerable Populations ............................................................................................................... 17 
5 
Study Drug ..................................................................................................................................... 17 
5.1 
Description ....................................................................................................................................... 17 
5.2 
Intervention Regimen .................................................................................................................. 17 
5.3 
Receipt ............................................................................................................................................... 17 
5.4 
Storage ............................................................................................................................................... 17 
5.5 
Preparation and Packaging ....................................................................................................... 17 
5.6 
Administration and Accountability ........................................................................................ 17 
5.7 
Subject Compliance Monitoring .............................................................................................. 18 
. 
18 
5.8 
Return or Destruction of Investigational Product ........................................................... 18 
6 
Study Procedures ....................................................................................................................... 18 
6.1 
Screening (Day -30 to Day -1) ................................................................................................... 18 
6.2 
Study Intervention Phase ........................................................................................................... 18 
6.2.1 
Visit 1 / Baseline Visit (Day 0) ............................................................................................................. 18 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 
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6.2.2 
Visit 2 / Week 4 Visit (Day 28 +/- 7 days) ...................................................................................... 19 
6.2.3 
Visit 3 / Week 8 Visit (Day 56 +/- 7 days) ...................................................................................... 19 
6.2.5 
Visit 5 / Week 16 Visit (Day 112 +/- 7 days) ................................................................................. 19 
6.2.6 
Visit 6 / Week 28 Visit (Day 196 +/- 7 days) ................................................................................. 20 
6.2.7 
Visit 7 / Week 40 Visit (Day 280 +/- 7 days) ................................................................................. 20 
6.2.8 
Visit 8 / Week 52/EOS Visit (Day 364 +/- 7 days) ..................................................................... 20 
6.3 
Unscheduled Visits ....................................................................................................................... 21 
6.4 
Subject Withdrawal ....................................................................................................................... 21 
6.5 
Early Termination Visits ............................................................................................................. 21 
7 
Statistical Plan ............................................................................................................................. 21 
7.1 
Primary Endpoint ........................................................................................................................... 21 
7.2 
Secondary Endpoints .................................................................................................................. 21 
7.3 
Sample Size and Power Determination ................................................................................ 22 
7.4 
Statistical Methods ....................................................................................................................... 22 
7.4.1 
Baseline Data ............................................................................................................................................... 22 
7.4.2 
Safety Analysis ............................................................................................................................................ 23 
7.5 
Subject Population(s) for Analysis ........................................................................................ 23 
8 
Safety and Adverse Events .................................................................................................... 23 
8.1 
Definitions......................................................................................................................................... 23 
8.1.1 
Adverse Event ............................................................................................................................................. 23 
8.1.2 
Serious Adverse Event ............................................................................................................................ 23 
8.2 
Recording of Adverse Events .................................................................................................. 24 
8.3 
Relationship of AE to Study ...................................................................................................... 24 
8.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated 
Problems ....................................................................................................................................................... 24 
8.4.1 
Follow-up report .......................................................................................................................................... 26 
8.4.2 
Investigator reporting: notifying Amgen .......................................................................................... 26 
Investigator Reporting: Notifying the Penn IRB .......................................................................... 26 
9.1 
Stopping Rules ............................................................................................................................... 27 
9.2 
Medical Monitoring ....................................................................................................................... 27 
9.2.1 
Data and Safety Monitoring Plan ....................................................................................................... 27 
10 
Study Administration, Data Handling and Record Keeping ................................. 28 
10.1 Confidentiality ................................................................................................................................. 28 
10.2 Data Collection and Management .......................................................................................... 28 
10.3 Records Retention ........................................................................................................................ 29 
11 
Study Monitoring, Auditing, and Inspecting ................................................................ 29 
11.1 Auditing and Inspecting ............................................................................................................. 29 
12 
Ethical Considerations ......................................................................................................... 29 
12.1 Risks ................................................................................................................................................... 29 
12.2 Benefits .............................................................................................................................................. 30 
12.3 Risk Benefit Assessment ........................................................................................................... 30 
12.4 Informed Consent Process / HIPAA Authorization ......................................................... 30 
13 
Study Finances ........................................................................................................................ 30 
13.1 Funding Source .............................................................................................................................. 30 
13.2 Conflict of Interest......................................................................................................................... 30 
13.3 Subject Stipends or Payments ................................................................................................ 30 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 
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14 
Publication Plan ....................................................................................................................... 31 
15 
References ................................................................................................................................. 31 
16 
Attachments ..................................................................................................................................... 35 
16.1 Appendix A - Apremilast Prescribing Information .......................................................... 35 
16.2 Appendix B -  Informed Consent ............................................................................................ 35 
16.3 Appendix C - Study Flow Chart ............................................................................................... 35 
16.4 Appendix D - Dermatology Life Quality Index (DLQI) .................................................... 35 
16.5 Appendix E - Sample Preparation and Handling ............................................................. 35 
16.6 Appendix F - Data Safety and Management Plan ............................................................ 35 
 
 
 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 
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List of Abbreviations 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
cAMP 
Cyclic adenosine monophosphate 
CBC 
Complete blood count 
Cmax 
Maximum serum concentration 
CMP 
Complete metabolic profile 
CRF 
Case report form 
CRP 
C-reactive protein 
CYP 
Cytochrome 
CV 
Cardiovascular 
DCERN 
Dermatology Clinical Effectiveness Research Network 
DICOM 
Digital Imaging and Communication in Medicine 
DLQI 
Dermatology Life Quality Index 
ECG 
12-lead electrocardiogram 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
FDG 
[18F]-fluorodeoxyglucose 
HDL 
High-density lipoprotein 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 
IDS 
Investigational Drug Services at the University of Pennsylvania 
IRB 
Institutional Review Board 
IL 
Interleukin 
MRHD 
Maximum Recommended Human Dose 
NIH 
National Institutes of Health 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PASI 
Psoriasis Area and Severity Index 
PASI-## 
Reduction of Psoriasis Area and Severity Index by ## (percent) 
PDE4 
Phosphodiesterase -4 
Penn IRB 
Institutional Review Board of the University of Pennsylvania 
PET/CT 
Positron emission tomography / computed tomography 
PGA 
Physician Global Assessment 
PHI 
Protected health information 
PI 
Principle Investigator 
SAE 
Serious adverse event 
SD 
Standard deviation 
SUV 
Standard uptake value 
TAB 
Total atherosclerosis burden 
TB 
Tuberculosis 
TBR 
Tissue-to-background ratio 
Th1 
T helper cell type 1 
Th17 
T helper cell type 17 
Tmax 
Time to reach maximum concentration 
TNF 
Tumor necrosis factor 
VAS 
Visual analog scale 
WBC 
White blood cell 
 
 
 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 
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Study Summary: 
 
Title 
A Phase IV, Open label Study of the Effects of Apremilast on Vascular 
Inflammation and Cardiometabolic function in Psoriasis 
Short Title 
Vascular Inflammation in Psoriasis-Apremilast (VIP-A) 
IRB Number 
826652 
Protocol Number 
97509210 
Phase 
Phase IV 
Methodology 
Single arm, open label, self-controlled trial 
Study Duration 
Up to 30 day screening period, treatment period of 52 weeks per subject 
Study Center(s) 
Multicenter within the Dermatology Clinical Effectiveness Research Network 
(DCERN). The lead site and coordinating center is the University of 
Pennsylvania. 
Objectives 
The primary objectives of this study are to determine the effect of apremilast 
on aortic vascular inflammation, cardiometabolic biomarkers and body 
composition in patients with moderate-severe psoriasis. FDG-PET/CT will be 
used to assess vascular inflammation, with multi-volumetric product, tissue-
to-background ratio and total atherosclerotic burden, and body composition 
via volumetric quantification. 
Number of Subjects 
70 patients 
Main Inclusion and 
Exclusion Criteria 
Males and females 18 years of age and older with moderate to severe plaque 
psoriasis defined by ≥10% Body Surface Area affected and Psoriasis Area 
and Severity Index ≥12. Subjects must be candidates for systemic therapy 
and have active psoriasis despite treatment with topical agents. 
Study Product: 
 
Apremilast tablets, oral 
Day 1: 10 mg in AM 
Day 2: 10 mg AM and PM 
Day 3: 10 mg AM and 20 mg PM 
Day 4: 20 mg AM and PM 
Day 5: 20 mg AM and 30 mg PM 
Day 6: 30 mg PO BID 
Day 7-week 52: 30 mg PO BID 
Duration of 
administration 
52 weeks 
Reference therapy 
Not applicable 
Endpoints 
The primary endpoints to be measured in this study include: change from 
baseline in total vascular inflammation of the aorta, as assessed on FDG-
PET/CT, and change in cardiometabolic biomarkers at week 16.  
 
The secondary endpoints to be measured are change in  vascular 
inflammation between week 52 and earlier time points, change from baseline 
in cardiometabolic biomarkers at other time points (week 4, 8, 12, 52), 
volumetric changes in visceral and subcutaneous adipose tissue, changes in 
physician reported outcomes (PASI, PGA), changes in patient reported 
outcomes (DLQI, pruritus VAS) and safety endpoints.   
Statistical 
Methodology 
Descriptive statistics, Wilcoxon signed rank tests, multivariable linear 
regression, and exploratory analyses will be conducted 
Safety Evaluations 
 
Monitoring for adverse events and serious adverse events 
 
Vital signs, physical examination 
 
Laboratory assessments (e.g., hematology, chemistry)  
 
 
 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 
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1. BACKGROUND AND STUDY RATIONALE 
1.1 
Background and Relevant Literature  
Psoriasis is a common T-helper cell type 1 (Th1) and type 17 (Th17) mediated inflammatory disease, 
affecting 2-3% of the population.1-3 Over 7.5 million Americans have been diagnosed with psoriasis and 
about 1 million have moderate to severe disease requiring systemic treatments.4 Despite the broad array 
of therapeutic options, about 70% of patients with severe psoriasis affecting ≥10% body surface area (BSA) 
are not receiving treatment to control their disease.5 It is now increasingly recognized that psoriasis, like 
rheumatoid arthritis and systemic lupus erythematosus, is a systemic inflammatory disorder and not only a 
disorder limited to the skin.6 In support of this, increasing evidence identifies psoriasis, particularly severe 
disease, as an independent risk factor for diabetes mellitus, dyslipidemia, myocardial infarction, stroke, and 
cardiovascular (CV) mortality.7-20 
 
The pathophysiology of psoriasis is characterized by inflammation with increased antigen presentation and 
lymphocyte activity and up-regulation of Th1/Th17 cytokines. Serum levels of inflammatory markers, 
including C-reactive protein (CRP) and tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-18, IL-12, IL-17 
and IL-22 are chronically increased in patients with psoriasis and correlate with psoriasis severity.21-27 
Elevated levels of cytokines including IL-6 and TNF-α, cell adhesion molecules, and downstream acute-
phase reactants such as CRP and fibrinogen have been associated with increased cardiovascular 
risk.14,17,28-35 The role of Th17 cells in atherogenesis remains less clear, however, with evidence suggesting 
both pro- and anti-atherogenic effects.36,37 It is evident, however, that, in general, systemic inflammation in 
psoriasis shares similar pathophysiology with atherosclerotic cardiovascular disease.6,38-40 
 
A preliminary study on experimentally induced in vivo inflammation revealed that robust activation of TNF-
α and IL-6 is followed by a systemic insulin-resistant state, metabolic dyslipidemia and decreased high-
density lipoprotein (HDL) function.41 Dysfunction of three inter-related pathways have been shown in 
patients with psoriasis: 1) Pro-atherogenic lipoprotein profiles (reduced HDL, elevated triglycerides, and 
increased small dense low-density lipoprotein particles),42,43 2) impaired macrophage cholesterol efflux and 
reverse cholesterol transport,44,45 and 3) inflammation-induced adipose and metabolic dysfunction (increase 
in leptin and insulin, and decrease in adiponectin).41,46 These data suggested potential biologic links to 
vascular inflammation and accelerated CV disease development. 
 
An innovative method to investigate the systemic inflammatory burden of psoriasis is with [18F]-
fluorodeoxyglucose (FDG) positron emission tomography / computed tomography (PET/CT). FDG-PET/CT 
is a validated imaging technique that enables highly sensitive and precise measurements of inflammation 
in vivo.47 FDG uptake in arterial walls reflects metabolic activity of inflammatory cells, particularly 
macrophages, within atherosclerotic lesions.48 In a pilot study, it was observed that psoriasis is associated 
not only with clinically observed inflammation in the skin, but also foci of subclinical inflammation within the 
liver, joints, tendons, and aorta that were not explained by traditional cardiovascular risk factors or co-
morbidities.49 Moreover, increasing severity of skin disease in psoriasis is associated with increasing 
severity of aortic vascular inflammation50. Since vascular inflammation on FDG-PET/CT strongly predicts 
future major vascular events and is responsive to even short term interventions for traditional CV risk 
factors, 51-55 it may also serve as a useful marker for evaluating vascular inflammation and, thus, 
cardiovascular risk in response to psoriasis treatments. 
 
Cyclic adenosine monophosphate (cAMP) is a key modulator of immune cell responses and is 
predominantly regulated by phosphodiesterase 4 (PDE4). Apremilast is an oral selective PDE4 inhibitor 
that is FDA approved for the treatment of psoriasis (see section 1.2). PDE4 inhibition down-regulates the 
inflammatory response by reducing the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-23, and 
other pro-inflammatory cytokines, while increasing anti-inflammatory cytokines, such as IL-1056,57.  cAMP 
also plays an important role in regulation of macrophage inflammatory responses, and PDE4 inhibition has 
been shown to dramatically decrease the inflammatory response of macrophages58. 
 
Macrophages play an important role in the pathogenesis of atherosclerosis, contributing at all stages59. 
Macrophages ingest lipoproteins, transforming them into cholesterol-laden foam cells. These foam cells 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 
9 
persist in plaques and promote disease progression60. They represent a major component of vessel wall 
inflammation. Macrophages also recruit additional inflammatory cytokines and play a role in atherosclerotic 
plaque destabilization61. We, therefore, propose this open-label clinical trial to investigate the effects of 
apremilast, an oral PDE4 inhibitor, on aortic vascular inflammation, as measured by FDG-PET/CT imaging 
and cardiometabolic biomarkers in patients with moderate to severe psoriasis. In addition, metabolic 
syndrome and obesity are highly prevalent in psoriasis and it is therefore of special interest that in the phase 
III clinical trials for apremilast, 20.2% of patients had weight loss, not associated with gastrointestinal side 
effects62. Because of this, the above CT imaging will also be used to measure changes in abdominal fat 
composition in patients taking apremilast. 
1.2 
Name and Description of the Investigational Product: Apremilast  
Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-
ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. Its 
empirical formula is C22H24N2O7S and the molecular weight is 460.5 g/mol. Each tablet contains 
apremilast as the active ingredient and the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, magnesium. Apremilast is an oral small-molecule 
inhibitor of PDE4 specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in 
increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic 
action in psoriatic arthritis patients and psoriasis patients is not well defined. 
1.3 
Non-clinical Data 
Long-term studies were conducted in mice and rats with apremilast to evaluate its carcinogenic potential. 
No evidence of apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the 
Maximum Recommended Human Dose (MRHD) on an AUC basis (1000 mg/kg/day) or in rats at oral 
doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in 
females, respectively). 
 
Apremilast tested negative in the Ames assay, in vitro chromosome aberration assay of human peripheral 
blood lymphocytes, and the in vivo mouse micronucleus assay.  
 
In a fertility study of male mice, apremilast at oral doses up to approximately 3-times the MRHD based on 
AUC (up to 50 mg/kg/day) produced no effects on male fertility. In a fertility study of female mice, 
apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥1.8-times the MRHD 
(≥20 mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which resulted in a longer 
interval until mating. Mice that became pregnant at doses of 20 mg/kg/day and greater also had 
increased incidences of early post-implantation losses. There was no effect of apremilast approximately 
1.3-times the MRHD (10 mg/kg/day).  
1.4 
Clinical Data to Date 
1.4.1 
Human Pharmacokinetics 
Absorption: Apremilast, when taken orally, is absorbed with an absolute bioavailability of ~73%, with 
peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~2.5 hours. Co-administration 
with food does not alter the extent of absorption of apremilast.  
 
Distribution: Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume 
of distribution is 87 L.  
 
Metabolism: Following oral administration in humans, apremilast is a major circulating component (45%) 
followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is 
extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. 
Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent 
glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily 
mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.  
 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 10
Elimination: The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal 
elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, 
about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 
7% of the radioactive dose recovered as apremilast in urine and feces, respectively. 
1.4.2 
Clinical Studies in Adults 
Two multicenter, randomized, double-blind, placebo-controlled trials (Studies PSOR-1 and PSOR-2) 
enrolled a total of 1257 subjects 18 years of age and older with moderate to severe plaque psoriasis 
[body surface area (BSA) involvement of ≥10%, Physician Global Assessment (PGA) of ≥3 (moderate or 
severe disease), Psoriasis Area and Severity Index (PASI) score ≥12, candidates for phototherapy or 
systemic therapy]. Subjects were allowed to use low-potency topical corticosteroids on the face, axilla 
and groin. Subjects with scalp psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp 
preparations on scalp lesions.  
 
Study PSOR-1 enrolled 844 subjects and Study PSOR-2 enrolled 413 subjects. In both studies, subjects 
were randomized 2:1 to apremilast 30 mg BID or placebo for 16 weeks. Both studies assessed the 
proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved a 
PGA score of clear (0) or almost clear (1) at Week 16. Across both studies, subjects ranged in age from 
18 to 83 years, with an overall median age of 46 years. The mean baseline BSA involvement was 25.19% 
(median 21.0%), the mean baseline PASI score was 19.07 (median 16.80), and the proportion of subjects 
with PGA score of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. 
Approximately 30% of all subjects had received prior phototherapy and 54% had received prior 
conventional systemic and/or biologic therapy for the treatment of psoriasis with 37% receiving prior 
conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of 
subjects had not received prior phototherapy, conventional systemic nor biologic therapy. A total of 18% 
of subjects had a history of psoriatic arthritis.  
 
The proportion of subjects who achieved PASI-75 responses, and PGA score of clear (0) or almost clear 
(1), are presented in Table 1.  The median time to loss of PASI-75 response among the subjects re-
randomized to placebo at Week 32 during the Randomized Treatment Withdrawal Phase was 5.1 weeks 
 
Table 1: Clinical Response at Week 16 in Studies PSOR-1 and PSOR-2 
 
Study PSOR-1 
Study PSOR-2 
 
Placebo 
apremilast 
30mg BID 
Placebo 
apremilast 
30mg BID 
 
N = 282 
N = 562 
N = 137 
N = 274 
PASI-75, n (%) 
15 (5.3) 
186 (33.1) 
8 (5.8) 
79 (28.8) 
PGA of Clear of Almost Clear, n 
(%) 
11 (3.9) 
122 (21.7) 
6 (4.4) 
56 (20.4) 
1.4.3 
Clinical Studies in Children  
The safety and effectiveness of apremilast in pediatric patients less than 18 years of age have not been 
established. 
1.5 
Dose Rationale  
Apremilast is given with an initial dosage titration for the first five days (see Table 2) and then 30mg twice 
daily therefore after. This is the FDA-approved dose regimen for treatment of moderate to severe plaque 
psoriasis. 
 
Table 2: Apremilast Dosage Titration Schedule 
Day 1 
Day 2 
Day 3 
Day4 
Day 5 
Day 6 & 
thereafter 
AM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
10mg 
10mg 
10mg 
10mg 
20mg 
20mg 
20mg 
20mg 
30mg 
30mg 
30mg 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 11
1.6 
Potential Risk  
  
 
The following side effects may be associated with the use of apremilast: 
 
Very common: diarrhea, nausea (stomach upset),  
 
Common: upper abdominal (stomach) pain, vomiting indigestion, frequent bowel movements, 
heartburn, fatigue, bronchitis (infection of the tubes to the lungs), redness/swelling/pain in the 
sinuses, inflammation or infections of the nose and throat, upper respiratory tract infection, 
decreased appetite, back pain, headache (including tension and migraine), difficulty sleeping, 
depression, cough,   
 
Uncommon: allergic reaction,  weight loss, rash 
 
Pregnancy Risks: Apremilast is pregnancy category C. Category C means that animal studies have 
revealed adverse fetal effects but that no controlled studies in women have been done, or that no studies 
in women or animals are available. 
2 
Study Objectives 
2.1 
Primary Objectives 
To assess the effects of apremilast, in patients with moderate to severe psoriasis on: 
 
Vascular inflammation as measured by FDG-PET/CT  
Cardiometabolic biomarkers: lipid particle size, HDL function (cholesterol efflux), TNF-Alpha, IL-6, C 
reactive protein, leptin, adiponectin, insulin levels and glucose to yield HOMA-IR, apolipoprotein B, 
ferritin, interleukin-2 receptor A, , fetuin-A, GlycA,ICAM-1, Serum amyloid A,  VCAM-1,  IFN-g,IL-1b, ,IL-
17A,IL-8, MCP-1, IL-9, IL-10, beta hydroxybutyrate, acetoacetic acid, Acetone, Ketone bodies, TRLTG, 
TRLC, TRLP, VL_TRLP, L_TRLP, M_TRLP, S_TRLP, VS_TRLP, Valine, Leucine, Isoleucine, 
BCAA, Alanine, ApoA1,Citrate and Diabetes Risk Index. 
  
             
 
 
   
2.2 
Secondary Objectives 
To assess the effects of apremilast, in patients with moderate to severe psoriasis on: 
 
Body composition, as measured by FDG-PET/CT 
 
Psoriasis activity and severity 
 
Pruritus, as measured by a VAS 
 
Patient reported quality of life (DLQI) 
 
Safety  
 
3 
Investigational Plan   
3.1 
General Design 
This study is a phase IV, open-label 52-week clinical trial to investigate the efficacy of apremilast in 
reducing vascular inflammation and cardiometabolic risk biomarkers in patients with moderate to severe 
psoriasis. The subject inclusion and exclusion criteria are shown in Sections 4.1 and 4.2. This will be a 
multicenter trial with a goal enrollment of 70 patients.  Subjects will receive apremilast for a total of 52 
weeks at the FDA approved dose for moderate-severe psoriasis. 
 
All study procedures, including screening, will occur only after obtaining signed informed consent. During 
the screening period, baseline, weeks 4, 8, 12, 16, 28, 40 and 52 subjects will be evaluated by 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 12
investigators or designated research personnel. Psoriasis severity will be assessed using the Psoriasis 
Area and Severity Index (PASI) and the Physician Global Assessment (PGA), both widely accepted 
measurement tools for psoriasis63.  The Dermatology Life Quality Index (DLQI) will also be measured to 
collect information regarding patient-oriented outcomes64, 65. 
 
FDG-PET/CT will be conducted at baseline, week 16 and week 52. Subjects will undergo a FDG-PET/CT 
scan using the standard protocol as described below.  Subjects will be required to fast for 8 hours prior to 
the scan. At the imaging center, finger-stick serum glucose levels will be checked to ensure a glucose 
level <150 mg/dL prior to FDG administration. If the glucose level exceeds 150 mg/dL, consultation with 
the principal investigator prior to the imaging will be required to determine if the subject is eligible to 
continue in the study. Neck to iliac crests PET/CT image acquisition will begin about 120 minutes (± 10 
minutes) after IV administration of 15 mCi of [18F]-FDG or other appropriate weight-based dose per 
imaging site’s standard dosing protocol. Axial, sagittal, and coronal PET reconstructions will be 
interpreted with and without attenuation correction, using non-contrast CT images for anatomical 
correlation. Within approximately 24 hours after the completion of the FDG-PET/CT scan, the local 
nuclear medicine personnel will issue a clinical report determining if the subject has any clinically 
significant findings which could preclude the subject’s continued participation in the study.  
 
The arterial uptake of FDG will be measured by the maximum standardized uptake value (SUV) divided 
by the venous SUV mean, a previously reported method for quantifying vascular inflammation65. This will 
yield a maximum target to background ratio (TBRmax) which is considered the standard reporting variable 
in FDG-PET/CT vascular studies66. The PET/CT images obtained from each site’s local imaging center 
will be de-identified and sent to the University of Pennsylvania Imaging Lab where trained nuclear 
medicine personnel will undertake a qualitative review of the PET/CT images. During this review, two-
dimensional (2D) circular regions of interests (ROIs) will be manually placed on the PET images around 
the external aortic contour, around the hepatic margin, and around articular spaces on all transverse 
slices passing through these structures using low-dose CT images for anatomic guidance. The images 
will then be sent to the central core National Institutes of Health (NIH) Imaging Lab for measuring the 
SUVs. The NIH central PET/CT readers will be blinded to time point of scan via Digital Imaging and 
Communication in Medicine (DICOM) file editing applied by the University of Pennsylvania. 
 
In addition to the mean SUV of the whole aorta, mean SUVs will be calculated for five segments of the 
aorta: ascending aorta, aortic arch, descending thoracic aorta, suprarenal abdominal aorta, and infrarenal 
abdominal aorta. These segments are defined to consider separately various regions of aortic disease 
that are associated with different clinical phenotypes (e.g., aortic arch disease with stroke, abdominal 
aortic disease with abdominal aortic aneurysm) 48,49,66,67,68. 
 
Adipose tissue volumes will be assessed at L2–L3 using automated software, as has been previously 
reported69. The algorithm will consist of body masking, noise reduction, adipose tissue labeling, visceral 
adipose tissue (VAT) and subcutaneous adipose tissue (SAT) separation, and quantitation. The adipose 
tissue volume inside the internal contour contributes to the VAT and the adipose tissue volume between 
the external contour and internal contour contributes to SAT.  
 
Laboratory tests will be conducted at screening, baseline and weeks 4, 8, 12, 16 and 52. This includes 
labs for screening safety and cardiometabolic biomarkers. Blood will be collected as described in 
Appendix E. In summary, a total volume of 30 mL (34.5 mL for Penn participants at Week 0 and Week 16 
only)  will be drawn per patient. Tubes will be labeled with an ID that does not contain identifiable 
personal information. The date and time of sample collection will be also indicated on a lab transfer sheet. 
Tubes will be sent directly to a lab at the NIH where the samples will be processed and stored.  
 
The blood will be used for making aliquots of plasma and serum for storage at -80° C after centrifugation 
of samples for 20 minutes at 2,400 RPM.  Any remaining plasma and/or serum will be destroyed at the 
completion of the study, except as required for quality assurance.  All samples are run in duplicate and 
normalized to a control pooled sample run simultaneously.  
 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 13
The expected duration of this open-label trial for each participant is 52 weeks, in addition, to an initial 
screening visit and screening period of up to 30 days. 
3.1.1 
Screening Phase 
Before subjects may be screened for enrollment into this study, full IRB approval of the protocol and 
consent will be obtained. Subjects will be provided with the approved informed consent form and 
complete the informed consent process according to FDA regulations and Good Clinical Practice 
guidelines prior to any study related procedures.  Upon signing consent, subjects will be screened to 
determine their eligibility for the study (see sections 4.1 and 4.2).   
 
Subjects who meet the inclusion and exclusion criteria will undergo a screening assessment within 30 
days of study enrollment. This includes a complete medical history and physical exam; vital signs and 
weight; routine blood work (CBC, CMP), HIV, hepatitis B surface antigen, hepatitis C antibodies, and 
urine pregnancy test. Details of the screening procedures can be found in Section 6.2. If a subject reports 
current use of a psoriasis therapy at time of screening assessment, the study physician will determine, 
based on psoriasis severity and overall medical history, whether the subject can undergo a washout 
period.  The subject will then be informed of what to expect during a washout period and will be asked to 
decide whether they would like to continue with the study.  If the subject decides to continue, he/she will 
be monitored for AEs during the washout period and routine blood work will be repeated for subjects who 
complete a washout period of greater than 30 days.  Subjects who complete all screening visit 
procedures and meet the inclusion and exclusion criteria will undergo baseline FDG-PET/CT and 
cardiometabolic assessments. If screening assessment exceeds 30 days, the study PI should be 
consulted for guidance on determining whether all screening procedures should be repeated or findings 
are considered clinically stable and subject can continue with baseline visit procedures.   
 
Administration of the initial dose of study treatment (apremilast) must occur 7 days or less from date of 
FDG-PET/CT scan. If initial dose cannot occur within 7 days of FDG-PET/CT scan, the study PI should 
be consulted for guidance on course of treatment.     
3.1.2 
Study Intervention Phase  
All patients will receive apremilast at the FDA-approved dose for plaque psoriasis for a total of 52 weeks.  
At weeks 4, 8, 12, 16, 28, 40 and 52, subjects will be evaluated by investigators or designated research 
personnel. Psoriasis severity will be assessed using the Psoriasis Area and Severity Index (PASI) and the 
Physician Global Assessment (PGA).  Laboratory tests will also be conducted at baseline and weeks 4, 8, 
12, 16, and 52 for screening safety labs and/or cardiometabolic biomarker assessment.  FDG-PET/CT will 
be conducted at baseline, week 16 and week 52. 
3.2 
Study Endpoints  
3.2.1 
Primary Study Endpoints 
The primary endpoints to be measured in this study include: 
 
Change in total vascular inflammation of the whole aorta as assessed on FDG-PET/CT between 
baseline and week 16 
 
Change in cardiometabolic biomarkers (lipid particle size, HDL function (cholesterol efflux), TNF-
Alpha, IL-6, high sensitivity C reactive protein, leptin, adiponectin, insulin levels and glucose to 
yield HOMA-IR, apolipoprotein B, ferritin, interleukin-2 receptor A, interleukin-18, and fetuin-A) 
between baseline and week 16 
3.2.2 
Secondary Study Endpoints 
The secondary endpoints to be measured in this study include: 
 
Change in total vascular inflammation of the five aortic segments as assessed on FDG-PET/CT 
between baseline and week 16, and between baseline and week 52  
 
Change in cardiometabolic biomarkers at week 4, 8, 12, 16 and 52 compared to baseline and 
earlier time points  


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 14
 
Change in total vascular inflammation of the aorta as assessed on FDG-PET/CT between week 
52 and earlier time points (baseline and week 16) 
 
Changes in body composition as measured on FDG-PET/CT between week 52 and earlier time 
points (baseline and week 16) 
 
Changes in physician reported outcomes (PASI, PGA) 
 
Changes in the patient reported outcomes (DLQI, pruritus VAS) 
 
Safety endpoints 
3.2.3 
Primary Safety Endpoints 
The safety endpoints will be assessed by subject interview (and physical exam, if indicated) as well as 
blood laboratory examination. Subjects will be monitored for any adverse event that occur during the 
study including serious adverse events (e.g., serious infection and malignancy). Non-serious adverse 
events, as defined in Section 8.1, will also be noted. A complete review of systems will also be assessed 
and physical exam performed at baseline and week 16.  The following routine laboratory tests will be 
monitored as safety parameters and will be drawn during screening and at weeks16 and 52.    
 
Hematology:  complete blood count (CBC) with differential 
 
Complete metabolic profile: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total and direct bilirubin, total protein, albumin  
4 
Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
1) Males and females 18 years of age and older. 
2) Clinical diagnosis of psoriasis for at least 6 months as determined by subject interview of his/her 
medical history and confirmation of diagnosis through physical examination by Investigator. 
3) Stable plaque psoriasis for at least 2 months before screening and at baseline (Week 0) as 
determined by subject interview of his/her medical history. 
4) Moderate to severe psoriasis defined by ≥ 10 percent Body Surface Area (BSA) involvement at the 
baseline (Week 0) visit. 
5) PASI score of ≥ 12 at the Baseline (Week 0) visit. 
6) Subject is a candidate for systemic therapy and has active psoriasis despite prior treatment with 
topical agents. 
7) Women are eligible to participate in the study if they meet one of the following criteria: 
a) Females of childbearing potential (FCBP) must have a negative pregnancy test at screening and 
baseline. Women of childbearing potential must undergo periodic pregnancy testing during the 
study and agree to use at least one of the following methods of contraception throughout the 
study duration and for at least 28 days after taking the last dose of investigational product: 
i) 
Oral contraceptives 
ii) Transdermal contraceptives 
iii) Injectable or implantable methods 
iv) Intrauterine devices 
v) Vaginal ring 
vi) Vasectomized partner 
vii) Barrier methods Male or female condom  PLUS one additional barrier method: (a) diaphragm 
with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with 
spermicide.);  
b) Women who are postmenopausal (for at least one year), sterile, or hysterectomized; 
c) Women who have undergone tubal ligation will be required to undergo periodic pregnancy testing 
during the duration of the study  
d) Sexual abstinence, defined as total abstinence from sexual intercourse, is considered an 
adequate form of contraception.  (Agreement to comply with sexual abstinence must be recorded 
in the source document). 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 15
e) Subjects using oral or parenteral forms of contraceptives must have been using these methods 
for at least 90 days prior to baseline visit. 
 
8).Subject is judged to be in good general health as determined by the Principal Investigator based upon 
the results of medical history, laboratory profile and physical examination performed at screening. 
4.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Prior treatment with apremilast is permissible under the following conditions: 
a. Prior exposure did not result in a clinical outcome such as side effect or lack of efficacy 
that would contraindicate future treatment with apremilast 
b. For patients who have only taken the apremilast two week starter pack (defined as 13-
tablet blister titration pack containing: (4) 10-mg, (4) 20-mg, and (5) 30-mg tablets with an 
additional (14) 30-mg tablets), apremilast must be discontinued at least 30 days prior to 
baseline (week 0) 
c. For patients with apremilast exposure greater than one two week starter pack, apremilast 
must be discontinued at least 90 days prior to baseline (week 0).  
2. Diagnosis of erythrodermic psoriasis, generalized or localized pustular psoriasis, medication-
induced or medication-exacerbated psoriasis, or new onset guttate psoriasis. 
3. Diagnosis of other active skin diseases or skin infections (bacterial, fungal, or viral) that may 
interfere with evaluation of psoriasis. 
4. Cannot avoid topical prescription medications for psoriasis for at least 14 days prior to the 
baseline visit (week 0) and during the study, with the exception of hydrocortisone 2.5% for the 
face and intertriginous areas. 
5. Cannot avoid UVB phototherapy or Excimer laser for at least 14 days prior to the Baseline (Week 
0) visit and during the study. 
6. Cannot avoid psoralen-UVA phototherapy for at least 30 days prior to the Baseline (Week 0) visit 
and during the study. 
7. Use of systemic therapies for the treatment of psoriasis, or systemic therapies known to improve 
psoriasis, during the study: 
a. Systemic therapies must be discontinued at least 30 days prior to the Baseline (Week 0) 
visit except for biologics and apremilast exposure greater than one two week starter 
pack. 
b. All biologics, except IL-12/IL-23 antagonists, must be discontinued for at least 90 days 
prior to Baseline (Week 0). 
c. Any IL-12/IL-23 antagonist (e.g., ustekinumab, briakinumab) must be discontinued for at 
least 180 days prior to Baseline (Week 0).  
d. Investigational agents must be discontinued at least 30 days or 5 half-lives (whichever is 
longer) prior to the Baseline (Week 0) visit. 
8. Subject is ≥ 300lbs (136.1 kg) at Baseline (Week 0).  
9. Subject is taking or requires oral or injectable corticosteroids during the study. Inhaled 
corticosteroids for stable medical conditions are allowed.   
10. Subject is taking a medication that interferes with metabolism of apremilast, including but not 
limited to rifampin, phenobarbital, carbamazepine, phenytoin 
11. Poorly controlled medical condition, such as unstable ischemic heart disease, cerebrovascular 
accident or myocardial infarction within the prior 6 months, psychiatric disease requiring frequent 
hospitalization, and any other condition, which, in the opinion of the Investigator, would put the 
subject at risk by participation in the study. 
12. Prior history of suicide attempt at any time in the subject’s life time prior to screening or 
randomization, or major psychiatric illness requiring hospitalization within the last 3 years. 
13. Uncontrolled hypertension, with measured systolic blood pressure >180 mmHg or diastolic blood 
pressure >95 mmHg 
14. Subject has infection or risk factors for severe infections, for example 
a. Positive serology or known history of HIV, hepatitis B or C, or other severe, recurrent, or 
persistent infections; 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 16
b. Excessive immunosuppression or other factors associated with it, including human 
immunodeficiency virus infection; 
c. Active tuberculosis (TB) disease; 
d. Any other significant infection requiring hospitalization or intravenous (IV) antibiotics in 
the 30 days prior to baseline; 
e. Infection requiring treatment with oral or parenteral (other than IV) antibiotics within 14 
days prior to baseline; 
f. 
Subject has received vaccination with a live viral agent within 30 days prior to screening 
or will require a live vaccination during study participation including up to 30 days after 
the last dose of study drug. 
15. Subject has history of hematological or solid malignancy other than successfully treated basal cell 
carcinoma, non-metastatic cutaneous squamous cell carcinoma or cervical intraepithelial 
neoplasia or carcinoma in situ of cervix with no evidence of recurrence within the previous 5 
years. 
16. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the 
study. 
17. Screening clinical laboratory analyses showing any of the following abnormal results: 
a. White blood cell (WBC) count <3.0 x 109/L. (Subject can be included if WBC count is <3.0 
x 109/L and absolute neutrophil count (ANC) is >1000 cells / mm3.) 
b. WBC count > 15 x 109/L; 
c. Hemoglobin (Hgb) < 9.0 x 109/L; 
d. Platelet count < 100 x 109/L; 
e. Serum creatinine >1.5 mg/dL ;  
f. 
Serum aspartate transaminase or alanine transaminase >2.0 upper limits of normal  
18. Recent history of substance abuse, within 365 days of Baseline (Week 0) visit that could preclude 
compliance with the protocol. 
19. Alcohol use of more than 14 drinks per week within 14 days of the baseline visit  
20. If subject is on cholesterol-lowering medication (e.g. statin), dose and form of medication must be 
stable for 90 days prior to week 0 and remain stable throughout the duration of the study. 
4.3 
Subject Recruitment  
This study is a multicenter clinical trial with subjects recruited from clinical practices within the 
Dermatology Clinical Effectiveness Research Network (DCERN). At the primary site, the Principal 
Investigator has extensive experience in clinical research in psoriasis, and the University of Pennsylvania 
is a referral center for patients with psoriasis.  All recruitment materials will be submitted to the 
Institutional Review Board (IRB) of the University of Pennsylvania and receive written approval prior to 
their use.  
 
 
Before subjects may be screened for enrollment into this study, full IRB approval of the protocol and 
consent will be obtained. Subjects will be provided with the approved informed consent form and 
complete the informed consent process according to FDA regulations and Good Clinical Practice 
guidelines prior to any study related procedures.  Upon signing consent, subjects will be screened to 
determine their eligibility for the study (see sections 4.1 and 4.2). 
 
Subjects who meet the inclusion and exclusion criteria will undergo a screening assessment within 30 
 days of study enrollment. Details of the screening procedures can be found in Section 6.2. Subjects who 
complete all screening visit procedures, and meet the inclusion and exclusion criteria, will undergo 
baseline FDG-PET/CT and cardiometabolic biomarker assessments. 
4.4 
Duration of Study Participation 
The duration of study participation will be 52 weeks. 
4.5 
Total Number of Subjects and Sites  
Recruitment will end when 70 subjects are enrolled. It is expected that 70 subjects will be enrolled in 
order to produce about 35 evaluable subjects, assuming a dropout rate at week 52 of 50%.  


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 17
4.6 
Vulnerable Populations  
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study. 
5 
Study Drug  
5.1 
Description 
Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-
ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. Its 
empirical formula is C22H24N2O7S and the molecular weight is 460.5.  Tablets are supplied in 10-, 20-, 
and 30-mg strengths for oral administration. Each tablet contains apremilast as the active ingredient and 
the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red, 
iron oxide yellow (20 and 30 mg only) and iron oxide black (30 mg only). 
5.2 
Intervention Regimen 
See section 1.3 
5.3 
Receipt  
Apremilast is an FDA-approved drug manufactured by Amgen Corporation.  It will be provided by Amgen 
Corporation, and delivered to the attention of Kenneth Rockwell, PharmD to the following address: 
 
 
University of Pennsylvania Investigational Drug Service (Penn IDS) 
 
Ground Floor Maloney Building 
 
3600 Spruce Street 
 
Philadelphia, PA 19104 
 
(215) 349-8817 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt 
log filled out and signed by the person accepting the shipment. It is important that the designated study 
staff counts and verifies that the shipment contains all the items noted in the shipment inventory. Any 
damaged or unusable study drug in a given shipment will be documented in the study files. The 
investigator must notify Amgen Corporation, of any damaged or unusable study treatments that were 
supplied to the investigator’s site.  
5.4 
Storage 
Apremilast should be stored between 15 - 30 Celsius. 
5.5 
Preparation and Packaging 
For details regarding the preparation and packaging, see Appendix A 
5.6 
Administration and Accountability   
Study product will be labeled, dispensed, and stored by IDS.  After the baseline FDG-PET/CT scan has 
been reviewed, patients will receive a 28-day supply of the study medication (apremilast) and instructed 
to take oral tablets daily according to the initial titration schedule.  At subsequent visits, they will receive 
pill bottles with a 30 day supply (60 pills) and will continue twice daily dosing. (see section 1.3).  
Packages of study product will be shipped from IDS to study sites outside of the University of 
Pennsylvania (Penn).  The process for study drug dispensing and return at these sub-sites will conducted 
using a similar approach as Penn.   
 
Penn IDS will perform ongoing product reconciliation for all study sites by tracking and verifying shipment 
dates, dispensing dates and amounts, administration dates and amounts, local product inventory, and 
return or destruction of unused product.    
 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 18
5.7 
Subject Compliance Monitoring 
During monthly study visits, patients will be asked to bring the empty blister packs or pill bottles, with any 
remaining medication.  The number of pills remaining will be noted and the patient will be provided with 
an additional 30-day supply. 
5.8 
Return or Destruction of Investigational Product 
Unused study drugs will be destroyed with signed documentation of drug administration sent to the IDS. 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, drug 
destroyed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed, 
and dated. Any discrepancies noted will be investigated, resolved, and documented prior to destruction of 
unused study drug.  
6 
Study Procedures 
The study procedures for each visit are summarized in the Appendix C.  
6.1 
Screening (Day -30 to Day -1) 
 
Sign informed consent 
 
Review of inclusion and exclusion criteria 
 
Record demographic information (i.e., sex, date of birth, race/ethnicity, etc.) 
 
Record height and weight 
 
Record vital signs, including temperature, pulse, respiratory rate and blood pressure 
 
Medical and surgical history including date of onset of psoriasis and documentation of history of 
psoriatic arthritis, including specialty of diagnosing physician 
 
Social history, including alcohol, tobacco, and other recreational drug use 
 
Review of systems 
 
Physical exam 
 
% BSA assessment 
 
PASI and PGA score 
 
Laboratory evaluation for safety (within 30 days of baseline visit) 
o 
Hematology: CBC with differential  
o 
Complete Metabolic Profile: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total and direct bilirubin, total protein, albumin 
o 
HIV, hepatitis b surface antigen, hepatitis C antibody 
o 
Urine pregnancy test for women of childbearing potential (includes women who have had 
a tubal ligation) 
 
Review and document medications or therapies and any discontinued medications or therapies in 
the last 90 days 
 
Review and document all prior and current psoriasis medications or therapies, including duration 
of therapy, and if applicable, when and why therapy was discontinued 
6.2 
Study Intervention Phase 
6.2.1 
Visit 1 / Baseline Visit (Day 0)  
 
Review of inclusion and exclusion criteria 
 
Review and update of medical history for any interim events between screening and baseline 
 
Review and update of any changes in medications/therapies between screening and baseline 
 
Monitor concomitant psoriasis therapy 
 
Monitor alcohol and tobacco use 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam,  
 
% BSA assessment 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 19
 
PASI and PGA score 
 
DLQI 
 
Pruritus VAS 
 
Urine pregnancy test for women of childbearing potential (includes women who have had a tubal 
ligation) 
 
FDG-PET/CT scan prior to treatment initiation 
 
Collection of blood samples for  cardiometabolic biomarkers prior to treatment initiation  
 
Review of clinical findings on FDG-PET/CT 
 
Review and evaluation of any adverse events or serious adverse events 
 
Dispense a 28-day supply of apremilast within 7 days of FDG-PET/CT, if no medical 
contraindications are identified on PET/CT 
6.2.2 
Visit 2 / Week 4 Visit (Day 28 +/- 7 days) 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant psoriasis therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam, if indicated by patient report of adverse events 
 
% BSA assessment 
 
PASI and PGA score 
 
Collection of blood for cardiometabolic biomarkers 
 
Collect remaining pills and dispense a 30-day supply of apremilast  
6.2.3 
Visit 3 / Week 8 Visit (Day 56 +/- 7 days) 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant psoriasis therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam if indicated by patient report of adverse events 
 
% BSA assessment 
 
PASI and PGA score 
 
Collection of blood samples for  cardiometabolic biomarkers 
 
Collect remaining pills and dispense a 30-day supply of apremilast  
 
6.2.4 
Visit 4 / Week 12 Visit (Day 84 +/- 7 days) 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant psoriasis therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam if indicated by patient report of adverse events 
 
% BSA assessment 
 
PASI and PGA score 
 
Collection of blood samples for cardiometabolic biomarkers 
 
Collect remaining pills and dispense a 30-day supply of apremilast 
6.2.5 
Visit 5 / Week 16 Visit (Day 112 +/- 7 days) 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant psoriasis therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam  
 
% BSA assessment 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 20
 
PASI and PGA score 
 
DLQI 
 
Pruritus VAS 
 
Laboratory evaluation for safety 
o 
Hematology: CBC with differential  
o 
Complete Metabolic Profile: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total and direct bilirubin, total protein, albumin 
o 
Urine pregnancy test for women of childbearing potential (includes women who have had 
a tubal ligation) 
 
Collection of blood samples for cardiometabolic biomarkers 
 
FDG-PET/CT scan 
 
Collect remaining pills and dispense a 30-day supply of apremilast  
6.2.6 
Visit 6 / Week 28 Visit (Day 196 +/- 7 days) 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant psoriasis therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam if indicated by patient report of adverse events 
 
% BSA assessment 
 
PASI and PGA score 
 
Collect remaining pills and dispense a 30-day supply of apremilast 
6.2.7 
Visit 7 / Week 40 Visit (Day 280 +/- 7 days) 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant psoriasis therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam if indicated by patient report of adverse events 
 
% BSA assessment 
 
PASI and PGA score 
 
Collect remaining pills and dispense a 30-day supply of apremilast 
6.2.8 
Visit 8 / Week 52/EOS Visit (Day 364 +/- 7 days) 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant psoriasis therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam  
 
% BSA assessment 
 
PASI and PGA score 
 
DLQI 
 
Pruritus VAS 
 
Laboratory evaluation for safety 
o 
Hematology: CBC with differential  
o 
Complete Metabolic Profile: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total and direct bilirubin, total protein, albumin 
o 
Urine pregnancy test for women of childbearing potential (includes women who have had 
a tubal ligation) 
 
Collection of  blood for cardiometabolic biomarkers 
 
FDG-PET/CT scan 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 21
 
Collect remaining pills  
6.3 
Unscheduled Visits 
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor concomitant therapy 
 
Review of systems, if indicated 
 
Vital signs, weight 
 
Physical exam, if indicated 
 
Laboratory evaluation, if indicated by patient symptoms and deemed appropriate by investigator 
6.4 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care. They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to intervention or 
study procedures or visit schedules, or AEs. The Investigator may also withdraw subjects who violate the 
study plan, or to protect the subject for reasons of safety or for administrative reasons.  It will be 
documented whether or not each subject completes the clinical study. Subjects who withdraw early will 
have one final visit to collect the remaining study drug, follow up regarding adverse events and undergo 
clinical, laboratory and imaging assessment as described below in section 6.5. 
6.5 
Early Termination Visits   
 
Review and evaluation of any adverse events or serious adverse events 
 
Monitor psoriasis concomitant therapy 
 
Review of systems 
 
Vital signs, weight 
 
Physical exam 
 
% BSA assessment 
 
PASI and PGA score 
 
DLQI 
 
Pruritus VAS 
 
Laboratory evaluation for safety, at the discretion of the investigator 
o 
Hematology: CBC with differential  
o 
Complete Metabolic Profile: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total and direct bilirubin, total protein, albumin 
o 
Urine pregnancy test for women of childbearing potential (includes women who have had 
a tubal ligation) 
 
FDG-PET/CT scan, if previous FDG-PET/CT scan (baseline and/or Week 16) was performed 
more than 28 days ago, or at the discretion of the investigator 
 
Collection of blood  for cardiometabolic biomarkers, if last labs were drawn more than 28 days 
ago, or at the discretion of the investigator  
7 
Statistical Plan 
7.1 
Primary Endpoint 
 
The primary endpoints to be measured in this study include: 
 
Change in total vascular inflammation of the whole aorta as assessed on FDG-PET/CT between 
baseline and week 16 
 
Change in cardiometabolic biomarkers between baseline and week 16   
7.2 
Secondary Endpoints  
The secondary endpoints to be measured in the study include: 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 22
 
Change in total vascular inflammation of the five aortic segments as assessed on FDG-PET/CT 
between baseline and week 16, and between baseline and week 52  
 
Change in cardiometabolic biomarkers at week 4, 8, 12, 16 and 52 compared to baseline and 
earlier time points  
 
Change in total vascular inflammation of the aorta as assessed on FDG-PET/CT between week 
52 and earlier time points (baseline and week 16) 
 
Changes in body composition as measured on FDG-PET/CT between week 52 and earlier time 
points (baseline and week 16) 
 
Changes in physician reported outcomes (PASI, PGA) 
 
Changes in the patient reported outcomes (DLQI, pruritus VAS) 
 
Safety endpoints 
 
7.3 
Sample Size and Power Determination 
The sample size is based on primary and secondary outcome of changes in tissue-to-background ratio 
(TBR) of the standardized uptake values (SUV) of the tracer measured by FDG-PET/CT.  Using a two 
sided test with alpha=0.05 and prior standard deviation (SD) estimate of the change in TBR (SD=0.263), 
35 patients will provide 90% power to detect a clinically significant change of 0.15 TBR between pre and 
post treatment measurements.  The 35 patients will also provide 90% power to detect clinically relevant 
differences in biomarkers between pre- and post-treatment of approximately 0.57 SD, well below the 
general threshold for significance of one SD.  To accommodate potential dropout of up to 50% at 52 
weeks, we intend to accrue 70 patients.  However, at 16 weeks we assume our dropout rate will only be 
20%.  Assuming 56 patients will have a FDG-PET/CT at 16 weeks, we will have 98.7% power to detect 
the 0.15 change in TBR as discussed above. 
7.4 
Statistical Methods 
Stata 14.0 or a more current version (StataCorp, College Station, TX) will be used for all analyses. All data 
will be summarized using descriptive statistics (mean, SD, range for continuous variables; frequencies for 
categorical variables) and graphical techniques (histograms, scatterplots). Tables will be produced 
describing any missing data patterns due to either withdrawal or other reasons.   
 
Primary Analysis  
The primary analysis will consist of comparisons of total vascular inflammation of the aorta and 
cardiometabolic biomarkers between week 16 and baseline using the endpoints of change as defined in 
Section 3.2.  Statistical significance of the change from baseline to 16 week will be assessed using a one 
sample t-test, and the use of a mixed linear model will also be considered.  Because the primary outcome 
is a change score, the analysis will be restricted to subjects who have completed both the baseline and 
week 16 FDG-PET/CT scans, regardless of their level of adherence to apremilast.   
 
Secondary Analysis 
Secondary analyses will include comparisons in total vascular inflammation of the aorta and its five 
segments, change in cardiometabolic biomarkers and change in body composition between weeks 52, 16 
and at baseline. We will also perform multiple imputation to address possible sensitivity to missing data. 
Additional analyses will also include longitudinal models of psoriasis activity over time, using repeated-
measures approaches to accommodate the correlation within subjects over time. We will explore the use 
of random effects models as well.  The linear trend between changes in TBR and psoriasis will be analyzed 
using multivariable linear regression with TBR as the dependent variable, and covariates in the model being 
age, sex, major cardiovascular disease risk factors. 
7.4.1 
Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive statistics, including 
mean and standard deviation for continuous variables such as age and standard percentages for 
categorical variables such as sex. 


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7.4.2 
Safety Analysis  
Subjects will be monitored for any adverse event that occur during the study treatment period. Laboratory 
evaluation for safety will be completed at baseline, week 16 and week 52.  
7.5 
Subject Population(s) for Analysis 
Primary analyses will be conducted according to the intention-to-treat principle, including all people who 
enrolled in the study and completed an FDG-PET/CT scan at week 16 regardless of their level of 
adherence to apremilast. Additional analyses will be conducted in patients who were at least 90% 
adherent with apremilast dosing. 
8 
Safety and Adverse Events 
8.1 
Definitions  
8.1.1 
Adverse Event 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence occurring at any 
dose 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 below), regardless of etiology. Any medical 
condition that was present prior to study treatment and that remains unchanged or improved should not 
be recorded as an AE. If there is a worsening of that medical condition, this should be considered an AE. 
A diagnosis or syndrome should be recorded on the AE page of the Case Report Form rather than the 
individual signs or symptoms of the diagnosis or syndrome.  All AEs will be recorded by the 
Investigator(s) from the time of signing the informed consent through the end of the designated follow-up 
period. 
 
Abnormal laboratory values defined as adverse events: 
An abnormal laboratory value is considered to be an AE if the laboratory abnormality is characterized by 
any of the following: 
 
Results in discontinuation from the study. 
 
Requires treatment, modification/interruption of study drug dose, or any other therapeutic 
intervention. 
 
Is judged by the Investigator(s) to be of significant clinical importance. 
 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded on the AE page of the CRF. If the abnormality was not a part of a diagnosis 
or syndrome, then the laboratory abnormality should be recorded as the AE. 
8.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is any AE which: 
 
Results in death 
 
Is life-threatening (i.e., in the opinion of the Investigator(s) the subject is at immediate risk of 
death from the AE) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
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 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 24
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 which: were planned before entry into the clinical 
study; are for elective treatment of a condition unrelated to the studied indication or its treatment; occur 
on an emergency outpatient basis and do not result in admission (unless fulfilling other criteria above); 
are part of the normal treatment or monitoring of the studied indication and are not associated with any 
deterioration in condition. 
 
If an AE is considered serious, both the AE pages of the CRF and the SAE Report Form must be 
completed. 
 
For each SAE, the Investigator(s) will provide information on severity, start and stop dates, relationship to 
study drug, action taken regarding study drug, and outcome. 
8.2 
Recording of Adverse Events 
For each subject, AEs and SAEs occurring after informed consent is obtained should be recorded until 
the subject has completed his/her participation in the study. A serious adverse event must be reported if it 
occurs during a subject’s participation in the study and/or within 30 days of receiving the last dose of the 
study drug. 
 
Any serious adverse event that is ongoing when a subject completes his/her participation in the Study 
must be followed until any of the following occurs: 
 
The event resolves or stabilizes; 
 
The event returns to baseline condition or value (if a baseline value is available); 
 
The event can be attributed to agents(s) other than the Study Product, or to factors unrelated to 
Study conduct. 
 
Any subsequent AE felt to be causally related to the use of the study product should be reported. 
8.3 
Relationship of AE to Study  
The Investigator(s) must determine the relationship between the administration of study drug and the 
occurrence of an AE/SAE as not suspected or suspected as defined below: 
 
Not suspected: 
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship unlikely or remote, or 
other medications, therapeutic interventions, or underlying conditions 
provide a sufficient explanation for the observed event 
 
Suspected: 
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions do not 
provide a sufficient explanation for the observed event. 
 
8.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
Immediate reporting of serious adverse events: 
Any AE that meets any criterion for a SAE requires the completion of an SAE Report Form in addition to 
being recorded on the AE pages of the CRF.  The Investigator(s) is required to ensure that the data on 
these forms is accurate and consistent.  This applies to all SAEs, regardless of relationship to study drug, 
that occur after informed consent has been obtained, those made known to the Investigator(s) within 30 
days after a subject’s last dose of study drug, and those made known to the investigator(s) at any time 
that are suspected of being related to study drug. 
 


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Investigators who are not Penn faculty or affiliated with a Penn research site are responsible for reporting 
consistent with timeframes and guidance here as well as consistent with their local IRB requirements.   
 
The SAE must be reported immediately (i.e., within 24 hours of the Principal Investigators’ knowledge of 
the event) to Amgen Safety by facsimile (see below for contact information).  A written report, prepared by 
the sub-site Investigator or Penn Principal Investigator(s) using an SAE Report Form or a 3500A 
Medwatch form, is to be faxed to Amgen Safety (see below for contact information).  
 
The SAE report should provide a detailed description of the SAE.  If a subject has died and an autopsy 
has been performed, copies of the autopsy report and death certificate are to be sent to Amgen as soon 
as these become available.  Any follow-up data will be detailed in a subsequent SAE Report Form or 
Medwatch form and sent to Amgen Safety. 
 
The Investigator(s) is responsible for informing the Institutional Review Board/Ethics Committee (IRB/IEC) 
of the SAE and providing them with all relevant initial and follow-up information about the event. The 
Investigator(s) must keep copies of all SAE information, including correspondence with Amgen and the 
IRB/IEC, on file.  All SAEs that have not resolved upon discontinuation of the subject’s participation in the 
study must be followed until either the event resolves completely, stabilizes/resolves with sequelae, or 
returns to baseline (if a baseline value is available). 
 
Pregnancies:  
When a female subject of childbearing potential’s contraceptive measures or ability to become pregnant 
changes at the time of study entry or at any time during the study, the Investigator will educate the subject 
regarding options and correct and consistent use of effective contraceptive methods in order to 
successfully prevent pregnancy. 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject or the female partner of a male subject occurring while the subject is on 
study drug, or within 30 days of the subject’s last dose of study drug, are considered immediately 
reportable events.  Study drug is to be discontinued immediately and the subject instructed to return any 
unused portion of the study drug to the investigator(s).  The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Amgen Safety immediately facsimile (see below for contact 
information) using the Pregnancy Report form provided by Amgen. 
 
The female should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for 
further evaluation and counseling. 
 
The Investigator(s) will follow the female subject until completion of the pregnancy, and must notify 
Amgen Safety of the outcome of the pregnancy as a follow-up on the follow up Pregnancy Reporting 
form. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the 
Investigator(s) should follow the procedures for reporting SAEs (i.e., report the event to Amgen Safety by 
facsimile within 24 hours of the Investigator’s knowledge of the event). In the case of a live “normal” birth, 
Amgen Safety should be advised by facsimile within 24 hours of the Investigator’s knowledge of the 
event. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to causality, as 
SAEs.  In addition, any infant death after 30 days that the Investigator(s) suspects is related to the in 
utero exposure to the study drug should also be reported to Amgen Safety by facsimile within 24 hours of 
the Investigators’ knowledge of the event. 
 
If the female is found not to be pregnant, any determination regarding the subject’s continued 
participation in the study will be determined by the Investigator(s) and the Amgen Medical Monitor. 


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Overdose: 
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 as an AE.  Any sequela of an accidental or intentional overdose of an investigational product 
should be reported as an AE. 
 
If the sequela of an overdose is an SAE, then the sequela must be reported on 
an SAE report form. The overdose resulting in the SAE should be identified as the cause of the event on 
the SAE report form but should not be reported as an SAE itself. 
 
In the event of an 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. 
 
Overdose for this protocol, on a per dose basis, is defined as ingestion of any more than the amount 
prescribed of apremilast tablets in any 24 hour period whether by accident or intentionally.  
 
8.4.1 
Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) should be submitted to Amgen Safety and the 
IRB. The investigator is responsible for ensuring that all SAEs are followed until either resolved or stable.  
8.4.2 
Investigator reporting: notifying Amgen 
 
 Amgen should receive copies of all safety reports submitted to the FDA, or any other regulatory 
agency, IRB or IEC, within 24 hours of such submission. Such notifications should be submitted as 
E2B, MedWatch or CIOMS I reports using the enclosed ISS Safety Fax Transmittal Cover Sheet and 
faxed to 888-814-8653.   
  
Investigator Reporting: Notifying the Penn IRB  
The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related to 
study participation that are unforeseen and indicate that participants or others are at increased risk of 
harm.  The Penn IRB will not acknowledge safety reports or bulk adverse event submissions that do not 
meet the all of the following criteria: 
 
Unexpected (in terms of nature, severity or frequency) given (a)the research procedure 
described in this protocol and the informed consent document and (b) the characteristics of the 
population being studied 
 
Related or possibly related to participation in the research  
 
Suggests that the research places subjects or other at a greater risk of harm (physical, 
psychological, economic or social harm) than was previously known or recognized    
 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn 
IRB via the HS-ERA online system (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation) within 10 working days from the time the Investigator becomes aware of the event.  
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Reporting Deaths:   


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Concerning deaths that occur during the course of a research study, the following describes the more 
rapid reporting requirement of the Penn IRB for specific situations: 
 Report the event within 24 hours when the death is unforeseen (unexpected) and indicates 
participants or others are at increased risk of harm. 
 Report the event within 72 hours, for all other deaths, regardless of whether the death is related to 
study participation. 
 
For reportable deaths, the initial submission to the Penn IRB may be made by contacting the IRB Director 
or Associate Director. The SAE report can follow via the HS-ERA online system.   
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious unexpected 
adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic 
necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause Amgen to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
subjects. 
 Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol. 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
 Incarceration of a participant when the research was not previously approved under Subpart C and 
the investigator believes it is in the best interest of the subject to remain on the study. 
 Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
8.5 
Stopping Rules  
Since these study treatments are FDA-approved treatments for psoriasis, standard of care for monitoring 
apremilast treatment will be used to ensure primary safety endpoints outlined in Section 3.2. Subjects will 
be monitored for adverse events and serious adverse events by the Investigators at each study visit. 
Subjects who experience adverse events may be removed from study participation at the discretion of the 
Investigator. 
8.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above.  Medical monitoring will include regular assessments of the number and type of adverse and 
serious adverse events as well as implementation of a Data and Safety Monitoring Plan (Appendix F).     
8.6.1 
Data and Safety Monitoring Plan 
See AppendixF. 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 28
9 
Study Administration, Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
The study will take the following precautionary measures to protect subjects’ privacy and the 
confidentiality of research and/or medical records. Research records are kept in offices that are locked, 
only accessible by study staff.  Computerized records are entered only with subject ID, are kept in 
databases on institutionally secure servers and managed network drives maintained and backed-up on a 
regular basis, protected using firewall technologies, and restricted to individuals authorized to work on the 
study with regular monitoring for unauthorized access and other potential security and operational events.  
External laboratories that will analyze biologic samples from this study will not receive information that 
could identify the subject. These laboratories will only receive a number to identify the samples. It is a 
requirement that subjects involvement in the study be noted in his/her medical records. Medical records 
also include electronic medical records or EMR. If a subject’s primary care physician is different from the 
study doctor for this study, he/she may also be notified. Medical records may also be reviewed and 
copies made by members of either the institutional review board/independent ethics committee 
responsible for this trial site, or a regulatory agency. These individuals will see subjects name, other 
personal information such as date of birth and gender, and medical information, but shall not disclose this 
information to anyone else. At the conclusion of the data collection phase of the study, de-identified data 
sets will be prepared for analyses purposes.  Only the study data manager will retain the ability to re-
identify data, if needed for AE reporting or medical monitoring. 
9.2 
Data Collection and Management  
Designated investigator staff will enter the data required by the protocol into the Electronic Case Report 
Forms (CRF) using fully validated software that conforms to US 21 CFR Part 11 requirements.  
Automatic validation programs check for data discrepancies and, by generating appropriate error 
messages, allow the data to be confirmed or corrected online by the designated investigator site staff. 
The Investigator must certify via electronic approval that the data entered into the CRFs are complete and 
accurate. After database lock, the Investigator will receive copies of the subject data for archiving at the 
investigational site.  
 
The Investigator must maintain source documents for each subject in the study.  Source data is 
all information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical trial. 
 
Electronic study case report form (CRF) is the primary data collection instrument for the study.  If 
data is recorded directly on the CRF (i.e. no prior written or electronic record of data), the CRF is to be 
considered the source data (per ICH GCP Section 6.4.9).  All data requested on the CRF must be 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 29
recorded.  All missing data must be explained.  If any entry error has been made, all correction changes 
must be initialed and dated. For clarification of illegible or uncertain entries, the clarification must be 
initialed and dated. 
 
The Investigator must also keep the original informed consent form signed by the subject (A 
signed copy is given to the subject). 
9.3 
Records Retention  
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the final 
study results are presented in a public forum.  These documents should be retained for a longer period if 
required by an agreement with Amgen.  In such an instance, it is the responsibility of Amgen to inform the 
investigator/institution as to when these documents no longer need to be retained. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Auditing and Inspecting 
The Investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, Amgen, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.). The Investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an Investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to Amgen before 
commencement of this study.  The investigator should keep a list of EC/IRB members and their affiliate 
on file. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  (See 
Appendix B for a copy of the Subject Informed Consent Form.) This consent form will be submitted with 
the protocol for review and approval by the EC/IRB for the study. The formal consent of a subject, using 
the EC/IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
11.1 Risks 
Apremilast is a FDA-approved, first-line treatment for psoriasis with very low risk of serious side effects 
with short-term exposure and minimized by careful adherence to FDA prescribing guidance and strict 
exclusion of subjects with significant contraindications to the medication. Subjects will undergo regular 
medical monitoring for any adverse reactions.  
 
Potential risks from the study assessment procedures are low. Exposure to radiation from this study is not 
significant and is within the acceptable range for research studies involving the administration of 
radiopharmaceuticals and use of CT as outlined by the regulatory agencies. This radiation dose is not 
necessary for medical care and will occur only as a result of subject participation in the study.  At doses 


Vascular Inflammation in Psoriasis - Apremilast (VIP-A)                                                                Page: 30
much higher than the subject will receive in this study, radiation is known to increase the risk of 
developing cancer after many years. At the doses of radiation subjects will receive in this study, it is very 
likely that no effects will be seen. There is a risk of allergic or other adverse type reaction to FDG but this 
is extremely rare. Phlebotomy required for cardiometabolic assessments is potentially associated with 
pain, bruising, bleeding, vasovagal syncope, thrombosis, and, rarely, infection at the venipuncture site.  
11.2 Benefits 
Direct Benefits: Potential benefits for study participation include comprehensive laboratory safety tests 
and FDG-PET/CT assessment at no cost, the results of which will be reviewed with each subject and that 
can be brought to each subject’s medical provider(s) for optimization and management of their CV risk. 
Subjects will receive apremilast, an FDA-approved psoriasis treatment with substantial efficacy and 
established safety profile, at no cost for 52 weeks.  
 
Indirect Benefits: Data derived from this study will provide critical information on the impact of apremilast 
on vascular inflammation cardiometabolic function and body composition. 
11.3 Risk Benefit Assessment 
Overall, we expect that the risks of the research study are outweighed by the potential benefits to the 
participants and others.   
11.4 Informed Consent Process / HIPAA Authorization  
Eligible subjects may only be included in the study after providing written (witnessed, where required by 
law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing so, after such consent 
has been provided by a legally acceptable representative(s) of the subject. In cases where the subject’s 
representative gives consent, the subject should be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she should indicate assent by personally 
signing and dating the written informed consent document or a separate assent form. Informed consent 
must be obtained before conducting any study-specific procedures (i.e., all of the procedures described in 
the protocol). The process of obtaining informed consent should be documented in the subject source 
documents. 
12 Study Finances 
12.1 Funding Source 
The study is financed through a grant from Amgen Corporation.  
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the institution prior to participation in this study.  All University of 
Pennsylvania investigators will follow the University conflict of interest policy. 
12.3 Subject Stipends or Payments 
Subjects will be asked to commute to study sites at 4 week intervals for monitoring visits and to receive 
the study drug. Visits that involve laboratory evaluation without FDG-PET/CT scan are estimated to take 
up to two hours. Visits that involve FED-PET/CT scan are estimated to take up to 6 hours. 
 
For each study visit, including the screening visit, subjects will be reimbursed $30 to offset travel and 
other indirect costs for study participation. For visits including an FDG-PET/CT scan subjects will receive 
$150 per visit.  Additional assistance for travel-related expenses may be available. In the event additional 
assistance is made available, the costs would have to be paid for by the participant up front and would be 
reimbursed by the study as set forth by the study team. When the subject has reached the end of study 


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participation, after the last study visit, the subject will receive a check in the mail with the total amount to 
be reimbursed for all study visits, minus any amount they have already received for their travel and/or 
related costs associated with travel to study visits. If the subject does not complete all study visits the 
amount received will be pro-rated to reflect the number and type of visits completed. Subjects will need to 
complete a W-9 form which is required by the IRS when study participation will result in a subject 
receiving more than $600 in a calendar year. This form will be provided for subjects. 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by Amgen and University of Pennsylvania for the purposes of performing the study, 
will be published or passed on to any third party without the consent of the study principal investigator 
and Amgen.  Any investigator involved with this study is obligated to provide Amgen with complete test 
results and all data derived from the study. 
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15 Attachments 
15.1 Appendix A - Apremilast Prescribing Information 
15.2 Appendix B -  Informed Consent 
15.3 Appendix C - Study Flow Chart 
15.4 Appendix D - Dermatology Life Quality Index (DLQI) 
15.5 Appendix E - Sample Preparation and Handling 
15.6 Appendix F - Data Safety and Management Plan