A PHASE IV, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE EFFECTS OF USTEKINUMAB ON VASCULAR INFLAMMATION IN PSORIASIS
Phase: PHASE4
Conditions: Psoriasis, Cardiovascular Disease
Sponsor: University of Pennsylvania

 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
A PHASE IV, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CROSSOVER STUDY OF THE EFFECTS OF 
USTEKINUMAB ON VASCULAR INFLAMMATION IN 
PSORIASIS 
 
 
 
 
 
Regulatory Sponsor: 
 
 
 
 
 
 
 
 
Principal Investigator: 
 
 
 
Joel M. Gelfand MD, MSCE  
University of Pennsylvania Department of Dermatology 
 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd, South Tower #730 
Philadelphia, PA 19104 
Phone: 215-614-0635 
Fax: 215-615-3127 
 
 
Joel.Gelfand@uphs.upenn.edu 
 
Joel M. Gelfand MD, MSCE  
University of Pennsylvania Department of Dermatology 
 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd, South Tower #730 
Philadelphia, PA 19104 
Phone: 215-614-0635 
Fax: 215-615-3127 
 
 
 
Joel.Gelfand@uphs.upenn.edu 
 
 
Co-Investigator: 
 
 
 
 
 
 
 
 
 
Funding Source: 
Junko Takeshita MD, PhD 
University of Pennsylvania Department of Dermatology 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd, South Tower #728 
Philadelphia, PA 19104 
Phone: 215-349-5551 
Fax: 215-615-3127 
 
 
 
Junko.Takeshita@uphs.upenn.edu 
 
 
Janssen Scientific Affairs, L.L.C. 
800 Ridgeview Dr   
Horsham, PA 19044 
(610) 651-6000 
 

Vascular Inflammation in Psoriasis - Ustekinumab 
 
Page ii 
Version: 6 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
 
Study Product: 
 
Ustekinumab (Stelara) 
Protocol Number: 
820124 
Study Reference Number:  
CNTO1275PSO4039 
IND Number: 
N/A 
 
 
Initial version: 03/28/2014 
Amended:   
10/30/2014 
Amended: 
08/17/2015 
Amended: 
07/13/2016 
Amended: 
01/20/2017 
Amended: 
 02/25/2019

Vascular Inflammation in Psoriasis - Ustekinumab 
 
page 1 
Version 1 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
Study Summary 
 
Title 
A Phase IV, Randomized, Double-Blind, Placebo-Controlled Study of the 
Effects of Ustekinumab on Vascular Inflammation in Psoriasis 
Short Title 
Vascular Inflammation in Psoriasis – Ustekinumab (VIP-U) 
Protocol Number 
To be assigned.   
Phase 
Phase 4 
Methodology 
Two-arm, randomized, double-blind, placebo-controlled trial 
Study Duration 
64-100 weeks. 
Study Center(s) 
University of Pennsylvania  
Objectives 
The primary objectives of this study are to determine the effect of anti-IL-12/23 
therapy vs. placebo on vascular inflammation and cardiometabolic biomarkers 
in patients with psoriasis. Vascular inflammation will be assessed with multi-
volumetric product, tissue-to-background ratio and total atherosclerotic burden 
using FDG-PET/CT. 
Number of Subjects 
42 
Diagnosis and Main 
Inclusion 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, Dose, 
Route, Regimen 
Ustekinumab (Stelara) subcutaneous injection 45mg (subject weight <100kg) 
or 90mg (subject weight >100kg) at day 0 and week 4 followed by every 12 
week dosing thereafter. 
Duration 
of 
administration 
52 - 64 weeks 
Reference therapy 
Placebo subcutaneous injection at weeks 0 and 4. 
Statistical 
Methodology 
Descriptive statistics, Wilcoxon rank-sum tests, Multivariable linear regression, 
Exploratory analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 

Vascular Inflammation in Psoriasis - Ustekinumab 
 
Page 2 
Version: 6 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
1 Statistical Plan 
1.1 Sample Size Determination 
Sample size calculations were based on the primary outcome of changes in standard uptake value (SUV) 
of the tracer measured by FDG-PET/CT. Based on prior work and published literature, we wish to be able 
to detect a difference in SUV between ustekinumab- and placebo-treated groups of 0.1 (which is similar 
to the change in SUV observed over one decade of aging).49 Prior work also indicates that the standard 
deviation (SD) of the change in SUV is approximately 0.11. Using a two-sided test with significance level 
of α=0.05, 19 patients per arm will provide 80% power to detect the clinically significant change of 0.1 
SUV between groups stratified by weight.  To accommodate potential dropout of up to 10%, we intend to 
accrue 21 subjects per arm.  
 
Assuming an effective sample size of 21 subjects per arm, we have 80% power to detect clinically 
relevant differences in biomarker changes between groups of approximately 0.88 SD, well below the 
general threshold for significance of one SD. Table 1 below shows the detectable difference for several 
markers for which we have data on the variability of the change over time.  
 
1.2 Statistical Methods 
Stata 12.0 (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 for Placebo-Controlled 12 Week Period. 
The primary analysis will consist of pairwise comparisons of the two arms using the Wilcoxon rank-sum 
test.  This is a non-parametric test that does not require normally distributed outcomes and is appropriate 
for smaller sample sizes.  The change in outcome (SUV, biomarkers) will be calculated for each subject 
and compared between the two groups.  In addition, we will conduct modeling of predictors for change, 
including indicators of treatment group but also adjusting for clinical and demographic covariates. The 
association between change in SUV over 12 weeks and psoriasis will be analyzed using multivariable 
linear regression with SUV as the dependent variable, and covariates in the model being age, sex, major 
cardiovascular disease risk factors (serum glucose, systolic and diastolic blood pressure, tobacco use, 
family history, serum LDL, HDL and total cholesterol, body mass index (BMI), and psoriasis activity).  
Because the primary outcome is a change score, the analysis will be restricted to subjects who complete 
the trial. Secondary analyses will include multiple imputation to address possible sensitivity to missing 
data. 
 
Primary Analysis for 52 Week Active Treatment Period. 
The primary analysis will consist of comparisons of vascular inflammation and biomarker levels between 
week 52 of the ustekinumab treatment period and baseline (for those subjects initially randomized to 
active treatment) or week 64 of the ustekinumab treatment period and week 12 (for those subjects initially 
randomized to placebo).  Appropriate regression analyses will also be performed using the changes in 
outcome for each subject (SUV, biomarkers) as dependent variables.  In addition, we will conduct 
modeling of predictors for change, including indicators of treatment group (i.e., crossover from placebo or 
continuation) but also adjusting for clinical and demographic covariates. The association between change 
in SUV over the active treatment period and psoriasis will be analyzed using multivariable linear 
regression with SUV as the dependent variable, and covariates in the model being age, sex, major CVD 
risk factors (serum glucose, systolic and diastolic blood pressure, tobacco, family history, serum LDL, 
HDL and total cholesterol, BMI and psoriasis activity).  We will also conduct exploratory analyses to 
Table 1.  Detectable differences for various cardiometabolic biomarkers 
Marker 
HDL 
HOMA 
CRP 
TNF-α 
IL-6 
Detectable difference 
3.56 mg/dL 
0.18 AU 
0.13 g/dL 
0.36 pg/mL 
1.78 pg/mL 

Vascular Inflammation in Psoriasis - Ustekinumab 
 
Page 3 
Version: 6 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
determine whether change in SUV over time is predicted by psoriasis activity, CV biomarkers individually, 
or within subtypes (inflammatory, metabolic and lipoprotein). This modeling will be limited and exploratory 
due to the sample size, but will inform hypothesis generation and future studies. 
 
Additional analyses will include longitudinal models of vascular inflammation 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.