Clinical trial NCT01999868
Conditions: Psoriasis
Keywords: psoriasis vulgaris ustekinumab abatacept
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2014-03-19; Completion date: 2018-03-01
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if the use of ustekinumab, followed by abatacept, will prevent relapse in people with moderate to severe plaque psoriasis.

Detailed description:
Psoriasis is a chronic immune disease of the skin and joints that affects about 2% of the population. The most common form of psoriasis is plaque psoriasis, also called psoriasis vulgaris. A variety of drugs, including biologics, are available for treatment of moderate to severe psoriasis. When biologic agents are stopped, psoriasis can return (relapse) and often requires the biologic to be restarted and continued. No treatment program has been identified to prevent relapse of psoriasis.

The study design has a lead-in period of weight-based ustekinumab treatment, with all participants receiving either 45 mg ustekinumab (\<= 100 kg) or 90 mg ustekinumab (\> 100 kg) administered subcutaneously at weeks 0 and 4. At week 12, participants will be assessed for a Psoriasis Area and Severity Index (PASI) 75 response to ustekinumab. Participants who do not achieve a PASI 75 score will be discontinued from the investigation and permitted to seek standard therapy.

Arms: arm 1: Participants received 2 subcutaneous injections of open-label ustekinumab (UST) (45 mg for participants weighing \<=100 kg at study entry or 90 mg for those weighing \>100 kg at study entry), at Weeks 0 and 4 during the lead-in phase and were then randomized to receive blinded (masked) treatment of abatacept (ABA) (125 mg) subcutaneous injections weekly from Week 12 to 39, in addition to ustekinumab placebo subcutaneous injections at Weeks 16 and 28. arm 2: Participants received 2 subcutaneous injections of open-label ustekinumab (UST) (45 mg for participants weighing \<=100 kg at study entry or 90 mg for those weighing \>100 kg at study entry), at Weeks 0 and 4 during the lead-in phase and were then randomized to receive blinded (masked) treatment of ustekinumab (45 mg if \<=100 kg or 90 mg if \>100 kg at study entry) subcutaneous injections at Weeks 16 and 28, in addition to abatacept (ABA) placebo subcutaneous injections weekly from Week 12 to 39.
Interventions: intervention 1: Ustekinumab intervention 2: Abatacept intervention 3: UST Placebo intervention 4: ABA Placebo
Intervention descriptions: intervention 1: Ustekinumab interferes with the actions of proteins, interleukin 12 (IL12) and interleukin 23 (IL23), which reduces inflammation (swelling) in the skin. Stelara™ is the trade name for ustekinumab and is approved by the U.S. Food and Drug Administration (FDA) to treat psoriasis.

Dose:

Participants who weigh \<= 100 kg at study entry will receive 45 mg of ustekinumab.

Participants who weigh \> 100 kg at study entry will receive 90 mg of ustekinumab. intervention 2: Abatacept (one form of the protein called CTLA4-Ig) interacts with the immune system, reducing the activity of T-cells and may prevent relapse. Orencia™ is the trade name for abatacept, and it is approved by the FDA to treat rheumatoid arthritis in adults.

Dose:

125 mg sub-cutaneous injection intervention 3: The abatacept treatment group will also receive subcutaneous placebo for ustekinumab (sterile normal saline) at week 16 and week 28, corresponding to the ustekinumab dosing regimen. intervention 4: The ustekinumab treatment group will also receive weekly subcutaneous injections of placebo for abatacept from week 12 to week 39, corresponding to the abatacept dosing regimen.

Protocol documents:
Prot_SAP_000.pdf: 




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Protocol Approval 
 
 
 
 
Trial ID:  ITN059AI 
Protocol Version:  4.0 
Dated:   February 26, 2015 
IND # 117,633 
Protocol Chair:  James Krueger, MD, PhD 
 
Title:  Efficacy of Ustekinumab (Anti-IL-12/23) followed by Abatacept (CTLA4-Ig) for the 
Treatment of Psoriasis Vulgaris 
I confirm that I have read the above protocol in the latest version. I understand it, and I will 
work according to the principles of good clinical practice (GCP) as described in the US 
Code of Federal Regulations (CFR)—45 CFR part 46 and 21 CFR parts 50, 56, and 312, 
and in the International Conference on Harmonization (ICH) document Guidance for 
Industry: E6 Good Clinical Practice: Consolidated Guidance dated April 1996. Further, I 
will conduct the study in keeping with local legal and regulatory requirements. 
 
As the principal investigator, I agree to carry out the study by the criteria written in the 
protocol and understand that no changes can be made to this protocol without written 
permission of the NIAID. 
 
In signing, I also agree to the following: 
i) To use and handle the study drugs only in accordance with the Protocol and for no 
other purpose; 
ii) To not transfer the study drugs to any parties other than the NIH designated drug 
distributor; 
iii) To not chemically modify, replicate, make derivatives of, or reverse engineer the 
study drugs. 
 
 
 
 
__________________________________________                                        
Principal Investigator                        (Print)                     
 
 
__________________________________________         _________________ 
Principal Investigator                        (Sign)                      Date 
 


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Synopsis 
Title 
Efficacy of Ustekinumab (Anti-IL-12/23) followed by Abatacept 
(CTLA4-Ig) for the Treatment of Psoriasis Vulgaris 
Sponsor 
NIAID 
Conducted by 
Immune Tolerance Network 
Protocol Chair  
James G. Krueger, MD, PhD 
Study Treatment 
Sequential treatment with open label ustekinumab, followed by either 
continued ustekinumab and abatacept placebo, or abatacept and 
ustekinumab placebo. 
 
Study Design 
This trial will be conducted as a prospective, randomized, double-blind, 
multicenter, active comparator study in a maximum of 140 participants 
with psoriasis vulgaris to assess the efficacy of abatacept in perpetuating 
the known treatment benefit of ustekinumab following ustekinumab 
withdrawal. Efficacy of abatacept to induce prolonged disease remission 
following cessation of study medication will also be assessed.  
 
The study design has a lead-in period of weight-based ustekinumab 
treatment, with all participants receiving either 45 mg ustekinumab (< 
100 kg) or 90 mg ustekinumab (> 100 kg) administered subcutaneously 
at weeks 0 and 4. At week 12, participants will be assessed for a PASI 75 
response to ustekinumab. Participants who do not achieve a PASI 75 
score will be discontinued from the investigation and permitted to seek 
standard therapy.   
 
The week 12 PASI 75 ustekinumab responders will be randomized 1:1 to 
receive either abatacept plus ustekinumab placebo or continued 
ustekinumab plus abatacept placebo. The trial design requires a sample 
size of 80 randomized participants. Published results indicate that 67.9% 
of participants who receive ustekinumab are expected to achieve a PASI 
75 or greater response by week 12. Therefore, 120 participants are 
expected to be required in order to randomize the 80 required 
participants. The week 12 PASI 75 response rate will be monitored 
during the study. If it falls below the expected rate, a maximum of 20 
additional participants will be enrolled to ensure that 80 participants are 
randomized at week 12. The initial enrollment will be set at 120 
participants, with a maximum enrollment, if necessary, of 140 
participants.  
 
The abatacept treatment group will receive weekly subcutaneous 
injections of 125 mg abatacept from week 12 to week 39. The abatacept 
treatment group will also receive subcutaneous ustekinumab placebo at 
week 16 and week 28, corresponding to the ustekinumab dosing regimen. 
 


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The continued ustekinumab treatment group will receive subcutaneous 
injections of 45 mg ustekinumab (< 100 kg) or 90 mg ustekinumab (> 
100 kg) at week 16 and week 28. The ustekinumab treatment group will 
also receive weekly subcutaneous injections of abatacept placebo from 
week 12 to week 39, corresponding to the abatacept dosing regimen.  
 
Study medication will be discontinued following the week 39 abatacept 
or abatacept placebo injection, and participants will be observed for 
disease relapse from week 40 through week 88. Following relapse, 
participants will be discontinued from observation, and will be permitted 
to seek standard therapy.  There will be a follow-up safety visit 12 weeks 
after discontinuation. 
 
In addition to clinical observation, 6 millimeter punch skin biopsies will 
be obtained from lesional skin at weeks 0, 12, 24, 40, 88, and at the time 
of psoriasis relapse, and from non-lesional skin at weeks 0, 40, 88, and at 
the time of psoriasis relapse. 
 
Study Conduct 
The study will be conducted at multiple sites in the United States and 
Canada. The study participation duration will be up to 100 weeks, which 
includes a treatment phase of 39 weeks, an observation phase of up to 49 
weeks, and a follow-up visit 12 weeks after the observation phase is 
complete. 
 
Primary Objective 
The primary objective of the study is to determine whether co-
stimulatory blockade with abatacept (CTLA4Ig) will induce tolerance 
and prevent relapses after medication has been discontinued in psoriasis 
vulgaris when administered following a decrease in the inflammatory 
response induced with ustekinumab (anti-IL-12/23). 
 
Primary Endpoint 
The primary endpoint is the proportion of participants who experience a 
psoriasis relapse at any time between week 12 and week 88. Psoriasis 
relapse is defined as loss of  > 50% of the initial PASI improvement 
measured at week 12. The primary endpoint will be assessed in all 
randomized participants. 
 
Secondary 
Endpoints 
Efficacy: 
 
1. The proportion of randomized participants who experience a 
psoriasis disease relapse prior to week 40. 
2. The proportion of participants who experience a psoriasis disease 
relapse between week 28 and week 88. 
3. The proportion of participants who experience a psoriasis disease 
relapse between week 40 and week 88. 
4. Mean length of time after week 12 to psoriasis relapse.  
5. Physician’s Global Assessment (PGA) of cleared or minimal at 
week 40 and week 88. 


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6. Dermatology Life Quality Index (DLQI) at week 40 and week 88. 
 
Safety: 
 
1. Frequency and severity of all AEs and SAEs. 
 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for this 
study: 
1. Males or females aged 18-65 years with a diagnosis of plaque 
psoriasis for at least 6 months.  
2. Baseline PASI score > 12. 
3. > 10% body surface area psoriasis involvement. 
4. Willingness to forgo other available psoriasis therapies, live 
vaccines, and pregnancy during the trial. 
5. Ability and willingness to provide informed consent and comply 
with study requirements. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible for 
this study: 
 
1. Non-plaque forms of psoriasis. 
2. Grade 2 or 3 moderate to severe psoriatic arthritis not adequately 
managed with non-steroidal anti-inflammatory drugs (NSAIDs).  
3. Myocardial infarction, unstable angina, cerebrovascular accident, or 
other significant cardiovascular event within the previous one year. 
4. Chronic obstructive pulmonary disease. 
5. Comorbid condition that requires regular systemic corticosteroid 
treatment. 
6. History of malignancy, except treated basal cell skin carcinoma. 
7. Treated basal cell skin carcinoma within the previous 5 years. 
8. Severe, progressive, or uncontrolled renal, hepatic, hematological, 
gastrointestinal, pulmonary, cardiac, or neurological disease, or any 
other medical condition that, in the investigator’s opinion, places 
the participant at risk by participating in this study. 
9. History of recent or ongoing uncontrolled bacterial, viral, fungal, or 
other opportunistic infections. 
10. Evidence of infection with Hepatitis B Virus (HBV), Hepatitis C 
Virus (HCV), or Human Immunodeficiency Virus (HIV).  
11. Positive QuantiFERON-TB Gold test. PPD tuberculin test may be 
substituted for QuantiFERON-TB Gold test.  
12. Severe reaction or anaphylaxis to any human monoclonal antibody. 
13. Any previous treatment with agents targeting IL-12 or IL-23, 
including ustekinumab. 
14. Any previous treatment with abatacept. 
15. Treatment with biologic agents within previous 3 months prior to 
visit 0, including adalimumab, etanercept, and infliximab. 
16. Treatment with immunosuppressive medications, including 
methotrexate, cyclosporine, oral retinoids, prednisone, or 


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phototherapy within previous 4 weeks prior to visit 0. 
17. Topical psoriasis treatment within previous 2 weeks prior to visit 0, 
including topical corticosteroids, vitamin D analogues, retinoids, 
calcineurin inhibitors, salicylic acid, and coal tar. 
18. Investigational study medication within previous 6 months prior to 
visit 0. 
19. Liver function test (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], or alkaline phosphatase) results that are > 
2x the upper limit of normal (ULN). 
20. Serum creatinine > 2x the ULN. 
21. Any of the following hematologic abnormalities, confirmed by 
repeat test at least 1 week apart:  
a. White blood count <3,000/ L or >14,000/L;  
b. Lymphocyte count <1,000/L; 
c. Neutrophil count <1,500/ L;  
d. Platelet count <150,000 /L; or  
e. Hemoglobin <10 g/dL. 
22. Females who are pregnant, lactating, planning on pregnancy during 
the study period, or unwilling to use a medically acceptable method 
of birth control. 
23. Receipt of a live vaccine (e.g., varicella, measles, mumps, rubella, 
cold-attenuated intranasal influenza vaccine, and smallpox) in the 
previous 6 weeks prior to visit 0. 
24. BCG vaccines in the previous one year. 
 
 
 


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Table of Contents 
BACKGROUND AND RATIONALE......................................................................................... 
16 
1.1 
BACKGROUND 
............................................................................................................. 16 
1.2 
SCIENTIFIC RATIONALE 
.............................................................................................. 
16 
1.2.1 Immunological Basis of Psoriasis 
.............................................................................................. 16
 
1.2.2 Rationale for Combining Ustekinumab and Abatacept for Treatment of Psoriasis 
................... 16 
1.2.3 Assessment of Mechanistic Correlates of Clinical Benefit in Skin 
........................................... 17 
1.3 
PRECLINICAL AND CLINICAL EXPERIENCE 
.............................................................. 18 
1.3.1 Preclinical Studies
 .....................................................................................................................
 18 
1.3.2 Clinical Studies
 ..........................................................................................................................
 19 
1.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR HUMAN 
PARTICIPANTS 
............................................................................................................ 22 
1.4.1 Risks
 ..........................................................................................................................................
 22 
1.4.2 Benefits
 ......................................................................................................................................
 24 
2. OBJECTIVES 
.................................................................................................................... 25 
2.1 
PRIMARY OBJECTIVE 
.................................................................................................. 25 
2.2 
SECONDARY OBJECTIVES .......................................................................................... 25 
2.3 
EXPLORATORY OBJECTIVES 
...................................................................................... 25 
3. STUDY DESIGN................................................................................................................ 
25 
3.1 
DESCRIPTION 
............................................................................................................... 25 
3.2 
STUDY DURATION 
....................................................................................................... 28 
3.3 
STUDY ENDPOINTS 
...................................................................................................... 
28 
3.3.1 Primary Endpoint ......................................................................................................................
 28 
3.3.2 Secondary Endpoints 
.................................................................................................................
 28 
3.3.3 Definitions
 .................................................................................................................................
 28 
3.3.4 Study Population .......................................................................................................................
 29 
3.4 
RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND REGIMEN ................ 29 
3.5 
PREMATURE TERMINATION OR SUSPENSION OF THE TRIAL 
................................. 29 
3.5.1 Ongoing Review
 ........................................................................................................................
 29 
3.5.2 Stopping Rules Guidance 
..........................................................................................................
 30 
4. ELIGIBILITY ................................................................................................................... 30 
4.1 
INCLUSION CRITERIA 
.................................................................................................. 
30 
4.2 
EXCLUSION CRITERIA 
................................................................................................. 
30 


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4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY 
..................... 31 
5. STUDY MEDICATIONS 
................................................................................................... 32 
5.1 
INVESTIGATIONAL MEDICATION:  USTEKINUMAB 
................................................. 32 
5.1.1 Formulation and Packaging 
.......................................................................................................
 32 
5.1.2 Placebo Preparations .................................................................................................................
 32 
5.1.3 Dosage and Administration 
.......................................................................................................
 32 
5.1.4 Recommended Storage Conditions ........................................................................................... 33 
5.1.5 Toxicity Management for Ustekinumab 
.................................................................................... 33 
5.2 
INVESTIGATIONAL MEDICATION:  ABATACEPT 
...................................................... 33 
5.2.1 Formulation and Packaging 
.......................................................................................................
 33 
5.2.2 Abatacept Placebo
 .....................................................................................................................
 34 
5.2.3 Dosage and Administration 
.......................................................................................................
 34 
5.2.4 Recommended Storage Conditions ........................................................................................... 34 
5.2.5 Toxicity Management for Abatacept
 .........................................................................................
 34 
5.3 
DISCONTINUATION OF STUDY TREATMENT AND STUDY OBSERVATION 
............ 34 
5.4 
CONCOMITANT MEDICATIONS 
.................................................................................. 35 
5.4.1 Allowed Medications 
.................................................................................................................
 35 
5.4.2 Prohibited Medications
 ..............................................................................................................
 35 
5.4.3 Contraception ............................................................................................................................
 36 
5.5 
DRUG ACCOUNTABILITY............................................................................................ 
36 
5.6 
ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION .................................. 36 
6. STUDY PROCEDURES .................................................................................................... 36 
6.1 
VISIT WINDOWS 
........................................................................................................... 36 
6.1.1 Scheduled Visits 
........................................................................................................................
 36 
6.1.2 Unscheduled Visits 
....................................................................................................................
 37 
6.1.3 Windows for Ustekinumab Injection 
......................................................................................... 37 
6.1.4 Windows for Abatacept Injection 
.............................................................................................. 37 
6.1.5 Documentation of Psoriasis Relapse ......................................................................................... 37 
6.1.6 Follow-up Visit
 ..........................................................................................................................
 37 
6.2 
ENROLLMENT, RANDOMIZATION, BLINDING, AND UNBLINDING 
......................... 37 
6.2.1 Enrollment
 .................................................................................................................................
 37 
6.2.2 Randomization
 ...........................................................................................................................
 37 
6.2.3 Blinding
 .....................................................................................................................................
 38 
6.2.4 Unblinding
 .................................................................................................................................
 38 


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6.3 
GENERAL ASSESSMENTS 
............................................................................................ 38 
6.4 
CLINICAL LABORATORY ASSESSMENTS 
.................................................................. 39 
6.5 
DISEASE-SPECIFIC ASSESSMENTS 
............................................................................. 39 
6.6 
MECHANISTIC ASSESSMENTS 
.................................................................................... 40 
7. MECHANISTIC ASSAYS ................................................................................................. 40 
7.1 
RATIONALE FOR IMMUNE STUDIES 
.......................................................................... 40 
7.2 
PLANNED MECHANISTIC ASSAYS ............................................................................. 41 
7.2.1 Histological Assessments
 ..........................................................................................................
 41 
7.2.2 Gene Expression in Peripheral Blood and Skin Biopsies
 ..........................................................
 41 
7.2.3 Multi-Parameter Flow Cytometry (MFC) ................................................................................. 42 
7.2.4 Serum Cytokine Assays 
.............................................................................................................
 42 
7.2.5 T-cell Repertoire Analysis 
.........................................................................................................
 42 
7.3 
OVERVIEW OF DATA ANALYSIS 
................................................................................ 43 
7.3.1 Individual Based Longitudinal Profiling
 ...................................................................................
 43 
7.3.2 Exploratory Analysis
 .................................................................................................................
 43 
7.4 
FUTURE / UNPLANNED STUDIES 
................................................................................ 43 
7.5 
SPECIMEN LOGISTICS ................................................................................................. 44 
7.6 
SPECIMEN TRACKING PROCEDURES 
......................................................................... 44 
7.7 
SPECIMEN STORAGE 
................................................................................................... 44 
8. ADVERSE EVENTS 
.......................................................................................................... 45 
8.1 
OVERVIEW ................................................................................................................... 45 
8.2 
PSORIASIS-SPECIFIC SAFETY DEFINITIONS 
.............................................................. 45 
8.2.1 Worsening of Psoriasis
 ..............................................................................................................
 45 
8.2.2 Psoriatic Arthritis ...........................................................................................................
...........
 45 
8.3 
NON-DISEASE SPECIFIC SAFETY DEFINITIONS ........................................................ 46 
8.3.1 Adverse Event ...........................................................................................................................
 46 
8.3.2 Suspected Adverse Reaction and Adverse Reaction ................................................................. 46 
8.3.3 Serious Adverse Event ..............................................................................................................
 46 
8.3.4 ‘Expected’ versus ‘Unexpected’ Suspected Adverse Reaction
 .................................................
 47 
8.4 
COLLECTING AND RECORDING ADVERSE EVENTS 
................................................. 48 
8.4.1 Methods of Collection
 ...............................................................................................................
 48 
8.4.2 Collection Period for Adverse Events and Serious Adverse Events 
.......................................... 48 
8.4.3 Methods of Recording 
..........................................................................................................
.....
 48 
8.5 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS 
.............................................. 48 


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8.5.1 Grading
 ......................................................................................................................................
 48 
8.5.2 Attribution
 .................................................................................................................................
 49 
8.6 
REPORTING SERIOUS ADVERSE EVENTS 
.................................................................. 49 
8.6.1 Reporting SAEs to the IND Sponsor 
......................................................................................... 49 
8.6.2 Reporting SAEs to Health Authorities ...................................................................................... 50 
8.6.3 Reporting SAEs to the DSMB 
................................................................................................... 
51 
8.6.4 Reporting Pregnancy
 .................................................................................................................
 51 
9. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
.................................... 51 
9.1 
ANALYSIS SAMPLES 
.................................................................................................... 
51 
9.2 
ANALYSIS OF ENDPOINTS 
.......................................................................................... 52 
9.2.1 Drop-Outs
 ..................................................................................................................................
 52 
9.2.2 Primary Endpoint ......................................................................................................................
 52 
9.2.3 Secondary Endpoints 
.................................................................................................................
 52 
9.2.4 Safety Analysis
 ..........................................................................................................................
 54 
9.2.5 Follow-up Visit Analysis
 ...........................................................................................................
 55 
9.2.6 Medical History
 .........................................................................................................................
 55 
9.2.7 Use of Medications 
....................................................................................................................
 55 
9.3 
SAMPLE SIZE 
................................................................................................................ 55 
9.4 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN 
.................... 55 
10. ACCESS TO SOURCE DATA/DOCUMENTS .................................................................. 56 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
..................................................... 56 
12. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
................................................................................................................... 57 
12.1 STATEMENT OF COMPLIANCE 
................................................................................... 57 
12.2 INFORMED CONSENT 
.................................................................................................. 57 
12.3 PRIVACY AND CONFIDENTIALITY............................................................................. 
57 
13. PUBLICATION POLICY 
.................................................................................................. 57 
14. REFERENCES 
.................................................................................................................. 58 
APPENDIX 1. SCHEDULE OF EVENTS 
.................................................................................. 63 
 
 


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List of Tables 
Table 1 Attribution of Adverse Events………………………………………………………..49 
Table 2 Primary/Secondary Endpoints and Analysis Samples………………………………..54 
 
 
 
 
List of Figures 
Figure 1 Loss of PASI Response after Ustekinumab Withdrawal……………………………20 
Figure 2 Trial Design………………………………………………………………………….27 
 
 
 
 
 
 


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Abbreviations  
ACR  
American College of Rheumatology 
ADL  
Activities of Daily Living 
AE
 Adverse
 
Event
 
ALT
 Alanine
 
Aminotransferase
 
ANCOVA  
Analysis of Covariance Model 
AR
 Adverse
 
Reaction
 
 
AST
 Aspartate
 
Aminotransferase
 
BCG
 Bacillus
 
Calmette-Guérin
 
BSA  
Body Surface Area 
CFR  
Code of Federal Regulations 
CRF  
Case Report Form 
COPD  
Chronic Obstructive Pulmonary Disease 
CTLA4  
Cytotoxic T-Lymphocyte Antigen 4 
DAIT  
Division of Allergy, Immunology, and Transplantation 
DC
 Dendritic
 
Cells
 
DLQI  
Dermatology Life Quality Index 
DMARD  
Disease-Modifying Antirheumatic Drug 
DSMB  
Data and Safety Monitoring Board 
EAE  
Experimental Autoimmune Encephalomyelitis 
EDC  
Electronic Data Capture 
ELISA  
Enzyme-linked immunosorbent assay 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
HCG  
Human Chorionic Gonadotropin 
HBV  
Hepatitis B Virus 
HCV  
Hepatitis C Virus 


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HIV
 Human
 
Immunodeficiency
 
Virus
 
ICH  
International Conference on Harmonization 
IDO
 Indoleamine-pyrrole
 
2,3-dioxygenase
  
IgG
 Immunoglobulin
 
G
 
IL
 Interleukin
 
IND
 Investigational
 
New
 
Drug
 
IRB
 Institutional
 
Review
 
Board
 
ITN  
Immune Tolerance Network 
ITT  
Intent to Treat 
MACE  
Major Adverse Cardiovascular Events 
MedDRA  
Medical Dictionary for Regulatory Activities 
NCI-CTCAE  National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCT  
National Clinical Trial 
NIAID  
National Institute of Allergy and Infectious Diseases 
OCT  
Optimal Cutting Temperature 
PASE  
Psoriatic Arthritis Screening and Evaluation 
PASI  
Psoriasis Area and Severity Index 
PBMC  
Peripheral Blood Mononuclear Cell 
PCR  
Polymerase Chain Reaction 
PGA
 Physician’s
 
Global
 
Assessment
 
PP
 Per
 
Protocol
 
PPD  
Purified Protein Derivative 
PUVA  
Psoralen Ultra-Violet A 
RA
 Rheumatoid
 
Arthritis
 
RPLS
 Reversible
 
Posterior
 
Leukoencephalopathy Syndrome 
RPR  
Rapid Plasma Reagin 
SAE  
Serious Adverse Event 


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SAP  
Statistical Analysis Plan 
SAR  
Suspected Adverse Reaction 
SAS  
Statistical Analysis System 
SDCC  
Statistical and Data Coordinating Center 
STS  
Specimen Tracking System 
SUSAR  
Serious Unexpected Suspected Adverse Reaction 
TCR  
T cell receptor 
Th
 T
 
helper
 
TNF  
Tumor Necrosis Factor 
ULN  
Upper Limit of Normal 
WHO  
World Health Organization 


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BACKGROUND AND RATIONALE 
1.1  BACKGROUND 
Psoriasis is a chronic multisystem inflammatory disease predominantly involving the 
skin and joints, and affecting approximately 2% of the population. Plaque psoriasis is 
the most common form of psoriasis, affecting 80-90% of psoriasis patients [1]. Most 
of these patients (approximately 80%) have mild to moderate disease, which is 
generally treated with a variety of safe and effective topical agents.  
A number of systemic therapies are available for moderate-severe psoriasis, defined as 
involvement of greater than 5-10% body surface area and/or significant interference 
with activities of daily life due to the regions affected (face, genitals, hands, and feet). 
These include phototherapy, methotrexate, cyclosporine, and acitretin. Though 
efficacious, each is associated with risks and contraindications, especially in the 
setting of comorbidities common among psoriasis patients. A number of US Food and 
Drug Administration (FDA) approved biologics are also available for first line therapy 
in moderate-severe psoriasis [1, 2]. These include the anti-tumor necrosis factor 
(TNF) agents infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). 
In addition, ustekinumab (Stelara) is a monoclonal antibody which targets the 
inflammatory cytokines IL-12 and IL-23. Withdrawal of the biologic agents is 
associated with relapse of psoriasis, so ongoing administration is required. No 
treatment regimen has been identified which induces tolerance or remission.  
1.2  SCIENTIFIC RATIONALE 
1.2.1  Immunological Basis of Psoriasis 
Psoriasis vulgaris is a T-cell mediated, inflammatory disease associated with skin 
lesions that contain activated Th1, Th17, and Th22 T-cell subsets. Human skin is an 
organ that contains a specialized immune system composed of differentiated, skin-
homing memory T-cells and several types of dendritic antigen presenting cells. 
Overall, about 98% of memory T-cells differentiated for skin homing reside in the 
skin in adults, but in a resting state, suggesting they are largely tolerant to common 
cutaneous and environmental antigens. In psoriasis, there is expansion of cutaneous T-
cells, and activation of both dendritic cells (DC) and T-cells, such that cytokines 
produced by activated T-cells and associated inflammatory pathways are increased. 
Because the skin is an accessible organ for biopsy, many biomarkers for T-cell 
activation and disease-related genes have been developed; ex vivo assays of T-cell 
and DC function are also possible for skin-resident cells. 
1.2.2  Rationale for Combining Ustekinumab and Abatacept for Treatment of 
Psoriasis  
One approved therapeutic approach for psoriasis vulgaris involves continuous use of 
the anti-cytokine antibody ustekinumab, which blocks IL-12 and IL-23 by binding to 
the common p40 subunit of these cytokines. The clinical response to ustekinumab has 
been well-documented in the PHOENIX 1, PHOENIX 2, and ACCEPT studies [3-5]. 
When ustekinumab was compared to placebo in moderate-to-severe psoriasis, most 
participants in PHOENIX 1 dramatically improved by week 12 [3]. However, when 


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ustekinumab was discontinued at week 40, the improvement in psoriasis scores began 
to decline by 44 weeks and the majority of participants relapsed by 64 weeks. Thus, 
while ustekinumab is highly effective in suppressing disease activity, discontinuation 
leads to predictable disease relapse, indicating that tolerance has not been achieved. 
One approach to inducing longer-lasting T-cell tolerance is co-stimulatory blockade. 
Co-stimulatory blockade is based on the observation that T-cell activation requires 
two signals: 1) antigen-specific engagement of the T-cell receptor and 2) co-
stimulatory B7/CD28 engagement [6-8]. Antigen-specific engagement of the T-cell 
receptor leads to T-cell tolerance when the co-stimulatory second signal is blocked. In 
theory, it might be possible to tolerize disease-mediating T-cells in psoriasis by a 
sequential approach that 1) decreases overall numbers and the activation state of T-
cells and DCs in the skin by IL-12/23 blockade, thus lowering many co-stimulatory 
pathways that are up-regulated in active disease, and 2) exposes residual T-cells and 
DCs to B7 co-stimulatory blockade during the period where T-cells would be 
reactivated by endogenous antigen-presenting DCs.  
The proposed drugs to test this tolerogenic strategy are 1) ustekinumab (anti-IL12/23), 
a monoclonal antibody approved by the FDA and Health Canada for psoriasis, and 2) 
abatacept (CTLA4-Ig), a co-stimulatory blocking fusion protein approved by the FDA 
and Health Canada for rheumatoid arthritis (RA) and juvenile rheumatoid arthritis. 
Abatacept is a fusion protein consisting of the extracellular domain of the CTLA4 
ligand for B7 coupled to a modified Fc portion of human Immunoglobulin G (IgG). 
Although abatacept is not approved for the treatment of psoriasis by either the FDA or 
Health Canada, a treatment effect in psoriasis participants was demonstrated during 
early development of the drug [9]. In addition, psoriatic arthritis participants who 
received abatacept in a randomized controlled phase 2 trial showed improvement in 
the cutaneous manifestations of psoriasis [10]. In the current proposal, abatacept 
would be administered to participants only after activated DCs and T-cells have been 
suppressed by treatment with ustekinumab, increasing the chances for abatacept to 
induce tolerance in cutaneous T-cells that drive psoriasis. 
1.2.3  Assessment of Mechanistic Correlates of Clinical Benefit in Skin 
Psoriasis vulgaris is a chronic inflammatory skin disease characterized by increased 
epidermal thickening and T-cell infiltration. Treatment with abatacept has been 
associated with reduced cellular activation of T-cells, keratinocytes, DC, and vascular 
endothelium in the skin [11].  
 
Mechanistic effects of ustekinumab on T-cells, DC, and skin pathology has also been 
measured, as a sub-study, in the ACCEPT trial that compared randomized treatment 
with ustekinumab vs. etanercept in moderate-to-severe psoriasis participants [5, 12-
14]. Treatment of psoriasis vulgaris participants with ustekinumab for 12 weeks 
reduced T-cell and DC infiltration, and also reversed pathological epidermal 
hyperplasia so that treated psoriasis plaques resumed the appearance of non-lesional 
skin. Quantification of associated T-cells and DCs showed that both sets of cells are 
significantly reduced by ustekinumab treatment and that overall numbers are similar 
to levels measured in non-lesional skin at baseline. Cytokine production by DCs and 
T-cells was also reduced by ustekinumab treatment as determined by quantitative 


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polymerase chain reaction (PCR) measures for mRNAs encoding IL-23, IL-17, IL-22 
and interferon-gamma. Overall effects on gene transcription were measured, and more 
than 2900 disease-defining transcripts were reversed by ustekinumab. Finally, 
ustekinumab treatment led to a small reduction in circulating Th17 T-cells after 12 
weeks of treatment, but similar effects were not produced by etanercept treatment [12-
14]. 
 
In the proposed study, skin biopsies will be evaluated for cellular and molecular 
correlates of tolerance using immunohistochemistry for T-cell and DC markers, as 
well as mRNA microarrays and quantitative PCR to assess gene expression of 
cytokines and other immune regulatory molecules, according to a well-described 
approach [15, 16]. A successful outcome of tolerance induction at the tissue level in 
the proposed study would be defined as reduced production of IL-12/23 and T helper 
subset cytokines (gamma-interferon, IL-22, and IL-17A/F), along with a reduction of 
T-cells and DC. Other correlates of tolerance may be observed in skin biopsies, such 
as an increase of T-regs (assessed by Foxp3 phenotype), an increase of IDO+ 
regulatory DC, or increases in regulatory molecules such as IL-10, CTLA4, and PD-1. 
Thus, the trial presents the opportunity to define a molecular signature of tolerance 
which corresponds to a clinical response to sequential treatment with inflammatory 
cytokine blockade (ustekinumab) followed by co-stimulatory blockade (abatacept). 
1.3  PRECLINICAL AND CLINICAL EXPERIENCE  
1.3.1  Preclinical Studies 
1.3.1.1  Preclinical studies with ustekinumab 
Preclinical studies with administration of recombinant IL-12 demonstrated 
exacerbation of disease in a murine model of psoriasis [17], and in experimental 
autoimmune encephalomyelitis (EAE) [18], and monoclonal antibodies to the p40 
subunit of IL-12 diminished or prevented disease in preclinical models of colitis, 
collagen-induced arthritis, and EAE [18-20]. These early studies suggested a role for 
IL-12 in the pathogenesis of psoriasis and other autoimmune diseases. It was 
subsequently discovered that IL-12 and IL-23 share the p40 subunit and that IL-23 is 
implicated in disease pathologies that were previously attributed to IL-12 [21-24]. 
An extensive preclinical toxicology program was undertaken in cynomolgus 
macaques during the development of ustekinumab [25]. Ustekinumab was shown to 
be pharmacologically active in this species, and potential immunomodulatory effects 
were explored. Due to specific concerns about exacerbation of Th2 mediated disease, 
ustekinumab was tested and shown not to exacerbate asthmatic responses in 
macaques. Also, the effect of ustekinumab on the cardiovascular system was 
examined and found not to be deleterious. In summary, ustekinumab was well 
tolerated in macaques over a broad therapeutic dosing window. 
1.3.1.2  Preclinical studies with abatacept 
CTLA4Ig has been tested in a variety of animal models. In early studies, investigators 
demonstrated that the effect of CTLA4Ig on the immune response to antigen is both 
dose and timing dependent. When administered within 2 days after antigen priming, 


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CTLA4Ig induces both deletion and non-responsiveness of antigen-specific CD4+ T-
cells [26]. The blockade of B7-CD28 interaction during the secondary exposure of 
CD4+ T-cells to antigen appears to have a more profound effect on Th1 cells than on 
Th2 cells at low doses of antigen, but has no effect at high doses of antigen [27]. 
CD8+ T-cells are more resistant to co-stimulatory blockade than are CD4+ cells [28, 
29]. B cells are highly sensitive to co-stimulatory blockade with CTLA4Ig. Both 
primary and secondary B-cell responses can be abrogated by high doses of CTLA4Ig 
[30, 31]. 
1.3.2  Clinical Studies 
1.3.2.1  Clinical studies with ustekinumab 
1.3.2.1.1  
Clinical studies with ustekinumab in psoriasis 
The safety and efficacy of ustekinumab in moderate-to-severe psoriasis vulgaris was 
demonstrated in two large randomized controlled trials [3, 4]. In the PHOENIX 1 trial, 
ustekinumab was compared to placebo in moderate-to-severe psoriasis, given at weeks 
0, 4, and then every 12 weeks [3]. Greater than 60% of treated participants in 
PHOENIX 1 achieved the primary endpoint of a Psoriasis Area and Severity Index 
(PASI) 75 score by week 12. The PASI 75 score represents a 75% improvement in 
PASI  [32, 33]. The treatment effect of ustekinumab was apparent by week 2, and 
maximum efficacy was achieved by week 24.  
In the PHOENIX 1 study, ustekinumab was administered at weeks 0, 4, 16, and 28. 
Then at week 40, participants were randomized to continued ustekinumab or to 
ustekinumab withdrawal. In the withdrawal participants, the improvement in PASI 
scores began to decline by 44 weeks, with the decline accelerating after week 52 [3]. 
Figure 1 shows the cumulative percent of participants in the ustekinumab withdrawal 
group who experienced a psoriasis relapse in that they lost  > 50% of the initial week 
12 PASI improvement [3]. In contrast, participants maintained on ustekinumab largely 
remained stable through week 76. Durable long term efficacy was maintained in the 
PHOENIX 1 trial for 3 years in participants who continued ustekinumab [34]. 




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similar in the ustekinumab and  placebo groups. In a related report, ustekinumab was 
shown to also improve physical disability and health-related quality of life measures 
in participants with psoriatic arthritis [39]. 
1.3.2.1.3  
Clinical studies with ustekinumab in Crohn’s disease 
Ustekinumab has been tested for efficacy and safety in moderate-to-severe Crohn’s 
disease [40, 41]. In an early blinded placebo-controlled study of 104 participants, 
there was evidence of improved clinical response in participants who had previously 
been non-responders to the anti-TNF inhibitor infliximab [40]. 
 
A follow-up study was conducted in 526 moderate-to-severe refractory Crohn’s 
disease participants whose disease was resistant to anti-TNF treatment [41]. 
Significantly, more participants met the primary endpoint and demonstrated a clinical 
response at week 6 to induction therapy with ustekinumab administered at week 0  
(39.7% for 6 mg/kg ustekinumab versus 23.5% for placebo). Participants with a 
response were re-randomized at week 8 to maintenance therapy with 90 mg 
ustekinumab or placebo administered at weeks 8 and 16. As for the PHOENIX 1 trial 
in psoriasis, maintenance therapy with ustekinumab was required for a sustained 
clinical response. Adverse events were generally similar in the ustekinumab and 
placebo groups.    
1.3.2.2  Clinical studies with abatacept  
1.3.2.2.1  
Clinical studies with abatacept in psoriasis and psoriatic arthritis 
The safety and efficacy of abatacept was first shown in a phase 1 clinical trial in 
psoriasis. This trial was an open-label, dose escalation study in 41 participants with > 
10% body surface area involved, and used a dose range of 0.5 to 50 mg/kg [9]. Four 
doses were given over a 4 week period. Clinical responses were observed at doses of 4 
to 8 mg/kg and above. Overall, 63% of study participants who received doses of at 
least 4 mg/kg achieved a 50% or greater improvement in clinical disease activity, 
compared with 4% of untreated participants. Abatacept was well-tolerated in this 
study. 
Several mechanistic analyses accompanied this first abatacept trial. Clinical 
improvement was associated with reduced cellular activation of T-cells, keratinocytes, 
DC, and vascular endothelium in the skin, supporting the role of co-stimulation in 
maintaining the pathology of psoriasis [11]. Flow cytometry for B- and T-cell markers 
revealed no major alterations in peripheral blood lymphocytes, and serum Ig levels 
were unaffected. 
More recently, a randomized controlled phase 2 trial of abatacept in 170 participants 
with psoriatic arthritis was conducted in which the cutaneous manifestations of 
psoriasis were assessed [10]. Participants received one of three abatacept dosing 
regimens or placebo at days 1, 15, and 29, followed by every 28 days thereafter. 
Compared to placebo, a significantly higher proportion of participants reached the 
ACR20 endpoint in the higher dose groups for abatacept, and the study met its 
primary endpoint. Cutaneous manifestations of psoriasis were assessed as secondary 


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endpoints, and improvement in the PASI scores were observed in all abatacept 
treatment groups. Safety profiles were equivalent in all treatment arms of the study.  
1.3.2.2.2  
Clinical studies with abatacept in rheumatoid arthritis 
In 2005, abatacept was approved by the FDA for the treatment of adults with 
moderately to severely active rheumatoid arthritis who have had an inadequate 
response to one or more disease-modifying antirheumatic drugs (DMARDs). It was 
approved for use as monotherapy or in combination with DMARDs other than TNF 
antagonists. This approval came after a series of studies that consistently showed 
clinical benefit at doses of approximately 10 mg/kg every 4 weeks [42-45]. 
A phase 3 trial examined the response in participants with RA who had an inadequate 
response to methotrexate [44]. This study involved 652 participants who were 
randomized in a 2:1 ratio to receive abatacept 10 mg/kg or abatacept placebo every 4 
weeks for 12 months. The ACR20, ACR50, and ACR70 response rates all showed 
statistically significant improvement for abatacept over placebo at the p<0.001 level.  
Abatacept was also studied in RA participants who had an inadequate response to 
tumor necrosis factor (TNF) inhibition [45, 46]. In this study, 393 participants were 
randomized in a 2:1 ratio to receive abatacept 10 mg/kg or abatacept placebo 
superimposed on background methotrexate therapy. After six months of treatment, the 
ACR20 response rate was 50% in the experimental group and 20% in the control 
group (p<0.001); the ACR50 response in treated participants was 20% vs. 4% 
(p<0.001); and the ACR70 response in treated participants was 10% vs. 1.5% 
(p<0.003). The responses observed at six months were maintained over five years in a 
long term extension study [46]. Adverse events were comparable in both groups.  
1.3.2.2.3  
Clinical studies with abatacept in other disorders 
Abatacept is FDA-approved for the treatment of juvenile idiopathic arthritis in 
children based on an initial 190 person randomized placebo-controlled trial [47]. A 
durable clinical response and long term safety were demonstrated in a follow-up long 
term extension study [48]. Abatacept also slows deterioration in beta cell function in 
Type 1 Diabetes during the initial six months of treatment, although the effect was not 
found to be durable over 2 years of treatment [49]. Abatacept was well tolerated but 
not efficacious in moderate-to-severe Crohn’s disease and ulcerative colitis [50].  
Abatacept is currently being tested by the Immune Tolerance Network (ITN) for 
efficacy and safety in lupus nephritis and multiple sclerosis (MS) (ITN034AI, 
NCT#00774852 and ITN035AI, NCT#01116427). A trial in MS of a drug similar to 
abatacept was discontinued early and efficacy results were inconclusive [51]. 
1.4  SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS 
FOR HUMAN PARTICIPANTS 
1.4.1  Risks 
1.4.1.1  Risks associated with ustekinumab 
Ustekinumab is approved by the FDA and Health Canada for treatment of moderate-
to-severe plaque psoriasis [52]. Serious infections and malignancies have been 


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reported with ustekinumab, but are not common. In patients with a genetic deficiency 
of IL-12/IL-23 there is a particular vulnerability to disseminated infections from 
mycobacteria and salmonella. Ustekinumab is an inhibitor of the cytokines IL-12 and 
IL-23 and poses a theoretical risk for vulnerability to these infections. A heightened 
awareness and early diagnostic evaluations for these infections is indicated. 
Anaphylaxis and anaphylactoid reactions have also been reported, but are not 
sufficiently common to support routine use of premedication with ustekinumab. Live 
vaccines should not be administered with ustekinumab, and Bacillus Calmette-Guérin 
(BCG) vaccines should not be administered during treatment with ustekinumab, or 
one year following discontinuation. One case of reversible posterior 
leukoencephalopathy syndrome (RPLS) was observed during the clinical development 
program. According to the package insert, the most common adverse events (AE) 
include nasopharyngitis, upper respiratory infection, headache, and fatigue [52].  
 
An acceptable short term safety profile for ustekinumab was established in the 
PHOENIX 1, PHOENIX 2, and ACCEPT  trials, in which adverse events (AE) and 
serious adverse events (SAE) were generally similar in the ustekinumab and placebo 
groups [3-5]. Longer term 3 year safety analyses have recently been reported for 
ustekinumab in psoriasis from pooled trial results, and showed that the safety profile 
of ustekinumab is generally maintained over time  [53, 54]. Non-melanoma skin 
cancers have been reported with ustekinumab in psoriasis [53, 55], but rates were 
comparable to those reported in psoriasis with other biologics [56, 57] and were 
higher in participants who had been previously treated with PUVA (Psoralen Ultra-
Violet A) light therapy. Serious cardiovascular AEs have been reported with 
ustekinumab [3-5], although a recent integrated safety analysis and a meta-analysis 
failed to demonstrate an increased risk of major adverse cardiovascular events 
(MACE) with ustekinumab compared to placebo [58, 59]. In contrast, an increased 
risk of MACE has been observed with briakinumab, another anti-IL-12,23 
monoclonal antibody [60]. Therefore, participants with recent major cardiovascular 
events will be excluded from this study.  
1.4.1.2  Risks associated with abatacept 
Abatacept has been studied extensively in participants with RA, and is approved by 
the FDA and Health Canada for treatment of moderately to severely active RA in 
combination with DMARDs, but should not be given with TNF antagonists. It is also 
approved for severe juvenile idiopathic arthritis. The principal potential risk of 
treatment with abatacept is the suppression of T-cell-mediated immune responses that 
may increase the incidence of serious infections and malignancy, and both have been 
reported but are uncommon. Abatacept has been administered in clinical trials without 
premedication, but, despite this, the infusion tolerability is good. Anaphylaxis and 
anaphylactoid reactions have been reported. According to the package insert, common 
adverse events include headache, upper respiratory infection, nasopharyngitis, and 
nausea. Live vaccines should not be administered concurrently with abatacept, or 
within 3 months of discontinuation [61].  
 
Abatacept is generally well tolerated with a good safety profile [62]. An integrated 
safety analysis of abatacept in combination with DMARDs included data from 2944 


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participants enrolled in five core abatacept trials, for 4764 patient-years of exposure 
[63]. Overall, rates of AE, SAE, and malignancies were similar in those receiving 
abatacept vs. placebo. The frequency of serious infections was low in both groups.  
The ASSURE trial specifically examined the safety of abatacept in combination with 
biologic and nonbiologic DMARDs [64]. Participants were not excluded if they had 
stable comorbid conditions, such as asthma, chronic obstructive pulmonary disease 
(COPD), diabetes mellitus, and congestive heart failure. Again, rates of AEs and 
SAEs were similar in those receiving abatacept vs. placebo. Those receiving abatacept 
experienced more serious infections, all of which were bacterial in origin, than those 
receiving placebo (2.9% vs. 1.9%). There was evidence in this trial that participants 
with COPD may have an  increased risk of AEs and SAEs involving the respiratory 
system, including infection, when treated with the combination of abatacept and 
DMARDs compared with receiving placebo and DMARDs. For this reason, 
participants with COPD have been excluded from this trial.  
1.4.1.3  Risks of combination therapy with ustekinumab and abatacept 
In this trial, ustekinumab and abatacept will be administered sequentially rather than 
combined at the same time. Ustekinumab will be administered at week 0 and week 4, 
with responding participants randomized to begin receiving abatacept at week 12, or 
to continue ustekinumab. Although the two study medications will not be 
administered in combination, there is potential for a limited period of systemically 
combined ustekinumab and abatacept, since the half-life of ustekinumab ranges from 
14.9 to 45.6 days [52].  
When two immunomodulatory biologics are administered in combination, there is a 
potential for synergy and increased risk of AEs and SAEs related to the 
immunosuppressive properties of the medications. In particular, there is a potentially 
greater risk of infection and malignancy. When abatacept was administered in 
combination with TNF antagonists over a one year time period in the ASSURE trial 
[64], AEs, SAEs, and infections were more frequent than with placebo in combination 
with the biologics. 
However, the ARRIVE trial showed that participants with RA could be safely 
switched from TNF antagonists to abatacept without a washout period [46, 65]. 
Similarly, participants in the ACCEPT trial were safely switched from the TNF agent 
etanercept to ustekinumab without a washout period [5]. The results support the safety 
of sequential therapy with ustekinumab or abatacept following TNF antagonists, and 
suggest that systemic combination of these two biologics for a limited time period is 
not likely to present substantial risk to the participants. 
1.4.2  Benefits 
All participants in the study will benefit from receiving two doses of ustekinumab, an 
approved and  highly efficacious treatment for psoriasis vulgaris (see section 3.1). 
Approximately 70% are expected to achieve a 75% or greater improvement in their 
psoriasis scores [3]. Of those participants who respond to ustekinumab, half will 
benefit from receiving two additional doses. The other half will receive abatacept, 
which has been shown in preliminary studies to be effective in psoriasis. Moreover, 


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participants in the abatacept group may experience a long-lasting disease remission, 
since abatacept has the potential to induce immunological tolerance. 
2.  
OBJECTIVES 
2.1  PRIMARY OBJECTIVE 
The primary objective of the study is to determine whether co-stimulatory blockade 
with abatacept (CTLA4Ig) will induce tolerance and prevent relapses after medication 
has been discontinued in psoriasis vulgaris when administered following a decrease in 
the inflammatory response induced with ustekinumab (anti-IL-12/23). 
2.2  SECONDARY OBJECTIVES 
 Determine whether abatacept is as effective as ustekinumab in maintaining a 
clinical response induced by ustekinumab. 
 Determine whether psoriasis relapses occur later following administration of 
abatacept compared to ustekinumab. 
 Assess the effect of sequential treatment with ustekinumab followed by abatacept 
on general well-being and quality of life. 
 Assess the frequency and severity of AEs and SAEs which occur during 
sequential treatment with ustekinumab followed by abatacept. 
2.3  EXPLORATORY OBJECTIVES 
 Assess the effect of sequential treatment with ustekinumab and abatacept on T-
cell and dendritic cell subsets in the target organ (skin) and in peripheral blood. 
 Assess the effect of sequential treatment with ustekinumab and abatacept on gene 
expression of cytokines and other immune regulatory molecules in the target 
organ (skin) and in peripheral blood.  
3.  
STUDY DESIGN 
3.1  DESCRIPTION 
This trial will be conducted as a prospective, randomized, double-blind, multicenter, 
active comparator study in a maximum of 140 participants with psoriasis vulgaris to 
assess the efficacy of abatacept in perpetuating the known treatment benefit of 
ustekinumab following ustekinumab withdrawal. Efficacy of abatacept to induce 
prolonged disease remission following cessation of study medication will also be 
assessed.  
 
The study design is depicted in Figure 2, and has a lead-in period of ustekinumab 
treatment, with all participants receiving either 45 mg ustekinumab (< 100 kg) or 90 
mg ustekinumab (> 100 kg) administered subcutaneously at weeks 0 and 4. At week 
12, participants will be assessed for a PASI 75 response to ustekinumab (see section 
3.3.3.1). Participants who do not achieve a PASI 75 score will be discontinued from 
the investigation and permitted to seek standard therapy.   


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The week 12 PASI 75 ustekinumab responders will be randomized 1:1 to receive 
either abatacept plus ustekinumab placebo or continued ustekinumab plus abatacept 
placebo. The trial design requires a sample size of 80 randomized participants (see 
section 9.3). Published results indicate that 67.9% of participants who receive 
ustekinumab are expected to achieve a PASI 75 or greater response by week 12 [3]. 
Therefore, 120 participants are expected to be required in order to randomize the 80 
required participants. The week 12 PASI 75 response rate will be monitored during 
the study. If it falls below the expected rate, a maximum of 20 additional participants 
will be enrolled to ensure that 80 participants are randomized at week 12. The initial 
enrollment will be set at 120 participants, with a maximum enrollment, if necessary, 
of 140 participants.  
The abatacept treatment group will receive weekly subcutaneous injections of 125 mg 
abatacept from week 12 to week 39. The abatacept treatment group will also receive 
subcutaneous ustekinumab placebo at week 16 and week 28, corresponding to the 
ustekinumab dosing regimen.  
The continued ustekinumab treatment group will receive subcutaneous injections of 
45 mg ustekinumab (< 100 kg) or 90 mg ustekinumab (> 100 kg) at week 16 and 
week 28. The ustekinumab treatment group will also receive weekly subcutaneous 
injections of abatacept placebo from week 12 to week 39, corresponding to the 
abatacept dosing regimen.  
Study medication will be discontinued following the week 39 abatacept or abatacept 
placebo injection, and participants will be observed for disease relapse from week 40 
through week 88 (see section 3.3.3.2). Following relapse, participants will be 
discontinued from observation, and will be permitted to seek standard therapy.  There 
will be a follow-up safety visit 12 weeks after discontinuation. 
In addition to clinical observation, 6 millimeter punch skin biopsies will be obtained 
from lesional skin at weeks 0, 12, 24, 40, 88, and at the time of psoriasis relapse, and 
from non-lesional skin at weeks 0, 40, 88, and at the time of psoriasis relapse.   
 




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3.2  STUDY DURATION 
Total study duration will be 204 weeks: 
 Enrollment phase will be 104 weeks.  
 Study participation phase will be up to 100 weeks, which includes a treatment 
phase of 39 weeks, an observation phase of up to 49 weeks, and a follow-up visit 
12 weeks after the observation phase is complete.  
3.3  STUDY ENDPOINTS 
3.3.1  Primary Endpoint 
The primary endpoint is the proportion of participants who experience a psoriasis 
relapse at any time between week 12 and week 88. Psoriasis relapse is defined as loss 
of  > 50% of the initial PASI improvement measured at week 12 (see Section 3.3.3.2). 
The primary endpoint will be assessed in all randomized participants. 
3.3.2  Secondary Endpoints 
Efficacy: 
1. The proportion of randomized participants who experience a psoriasis disease 
relapse prior to week 40 (see Section 3.3.3.2). 
2. The proportion of randomized participants who experience a psoriasis disease 
relapse between week 28 and week 88 (see Section 3.3.3.2). 
3. The proportion of participants who experience a psoriasis disease relapse between 
week 40 and week 88 (see Section 3.3.3.2). 
4. Mean length of time after week 12 to psoriasis relapse.  
5. Physician’s Global Assessment (PGA) [3] of cleared or minimal at week 40 and 
week 88. 
6. Dermatology Life Quality Index (DLQI) [66, 67] at week 40 and week 88. 
Safety: 
1. Frequency and severity of all AEs and SAEs. 
 
3.3.3  Definitions 
3.3.3.1  Psoriasis response 
A psoriasis response measured at week 12 is defined as greater than or equal to a 75% 
improvement in the PASI, according to the following formula: 
Response PASI  0.25 (Baseline PASI) 
3.3.3.2  Psoriasis relapse 
A psoriasis relapse is defined as loss of  > 50% of the initial PASI improvement 
measured at week 12, according to the following formula: 
Relapse PASI = Week 12 PASI + [(Baseline PASI –Week 12 PASI)/2]  


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3.3.4  Study Population 
Male and female participants age 18-65 with moderate-to-severe plaque psoriasis will 
be recruited at multiple sites in the United States and Canada. Participants will be 
enrolled without regard to gender or race. 
3.4  RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND 
REGIMEN 
Our trial design is built on the framework of the successful phase 3 PHOENIX 1 and 
PHOENIX 2 trials for ustekinumab in psoriasis [3, 4]. The proposed study is a 
prospective randomized controlled trial for individuals with moderate-to-severe 
psoriasis vulgaris. Open label ustekinumab will be administered subcutaneously 
according to the standard dosing regimen used in the PHOENIX 1 and PHOENIX 2 
trials and described in the ustekinumab prescribing information [52].   
 
Abatacept is approved for treatment of RA and juvenile idiopathic arthritis, and has an 
excellent safety record. Although abatacept is not approved by either the FDA or 
Health Canada for the treatment of psoriasis, a treatment effect in psoriasis 
participants was demonstrated during early development of the drug [9]. In addition, 
psoriatic arthritis participants who received abatacept in a randomized controlled 
phase 2 trial showed improvement in the cutaneous manifestations of psoriasis [10]. 
Abatacept will be administered according to the current prescribing information for 
adult rheumatoid arthritis with weekly doses of subcutaneous abatacept which are not 
adjusted for weight [61]. Subcutaneous abatacept has been shown to be effective 
without an intravenous loading dose [68, 69].  
 
Abatacept will be administered starting at week 12 in participants who achieve a PASI 
75 or greater response to ustekinumab and are randomized to abatacept. Based on the 
PHOENIX 1 and 2 trials, approximately 70% of participants are expected to achieve a 
response by week 12, with relatively little gain of additional responders after this time 
[3, 4].  
3.5  PREMATURE TERMINATION OR SUSPENSION OF THE TRIAL    
3.5.1  Ongoing Review 
The progress of the study will be monitored by the National Institute of Allergy and 
Infectious Diseases (NIAID) Autoimmune Data and Safety Monitoring Board 
(DSMB), which will review safety data and make recommendations regarding 
continuation, termination, or modification of the study. Based on a 104 week 
enrollment period and an additional study participation period of 100 weeks, the 
DSMB will formally review the safety data approximately 6 months after study 
enrollment begins. Following this initial review, the DSMB will subsequently review 
the safety data at least yearly. The number of subjects who discontinue study 
treatment will also be included in the reports prepared for the DSMB. 
In addition, safety data will be reviewed by the DSMB when an event occurs that is of 
sufficient concern to the NIAID medical monitor, ITN physician or protocol chair to 


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warrant review, or when an event occurs that contributes to a stopping rule listed in 
section 3.5.2. 
3.5.2  Stopping Rules Guidance  
If any of the following events occur, the DSMB chair will be notified and a review of 
safety data will be performed to determine if enrollment in the study should be 
stopped and/or administration of investigational study medication should be halted: 
1. Any death that is at least possibly related to use of the investigational study 
medication.  
2. Two or more of the same Preferred Term grade 3 or greater clinical AEs, or two 
or more of the same cardiovascular System Organ Class grade 3 or greater  AEs, 
involving different participants that are at least possibly related to use of the 
investigational study medication.  
4.  
ELIGIBILITY 
4.1  INCLUSION CRITERIA 
Participants must meet all of the following criteria to be eligible for this study:  
1. Males or females aged 18-65 years with a diagnosis of plaque psoriasis for at least 
6 months.  
2. Baseline PASI score > 12. 
3. > 10% body surface area psoriasis involvement. 
4. Willingness to forgo other available psoriasis therapies, live vaccines, and 
pregnancy during the trial. 
5. Ability and willingness to provide informed consent and comply with study 
requirements. 
4.2  EXCLUSION CRITERIA 
Participants who meet any of the following criteria will not be eligible for this study:  
1. Non-plaque forms of psoriasis. 
2. Grade 2 or 3 moderate to severe psoriatic arthritis not adequately managed with 
non-steroidal anti-inflammatory drugs (NSAIDs). (see section 8.2.2) 
3. Myocardial infarction, unstable angina, cerebrovascular accident, or other 
significant cardiovascular event within the previous one year. 
4. Chronic obstructive pulmonary disease. 
5. Comorbid condition that requires regular systemic corticosteroid treatment. 
6. History of malignancy, except treated basal cell skin carcinoma. 
7. Treated basal cell skin carcinoma within the previous 5 years. 
8. Severe, progressive, or uncontrolled renal, hepatic, hematological, 
gastrointestinal, pulmonary, cardiac, or neurological disease, or any other medical 
condition that, in the investigator’s opinion, places the participant at risk by 
participating in this study. 
9. History of recent or ongoing uncontrolled bacterial, viral, fungal, or other 
opportunistic infections. 


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10. Evidence of infection with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or 
Human Immunodeficiency Virus (HIV).  
11. Positive QuantiFERON-TB Gold test. PPD tuberculin test may be substituted for 
QuantiFERON-TB Gold test.  
12. Severe reaction or anaphylaxis to any human monoclonal antibody. 
13. Any previous treatment with agents targeting IL-12 or IL-23, including 
ustekinumab. 
14. Any previous treatment with abatacept. 
15. Treatment with biologic agents within previous 3 months prior to visit 0, 
including adalimumab, etanercept, and infliximab. 
16. Treatment with immunosuppressive medications, including methotrexate, 
cyclosporine, oral retinoids, prednisone, or phototherapy within previous 4 weeks 
prior to visit 0. 
17. Topical psoriasis treatment within previous 2 weeks prior to visit 0, including 
topical corticosteroids, vitamin D analogues, retinoids, calcineurin inhibitors, 
salicylic acid, and coal tar. 
18. Investigational study medication within previous 6 months prior to visit 0. 
19. Liver function test (aspartate aminotransferase [AST], alanine aminotransferase 
[ALT], or alkaline phosphatase) results that are > 2x the upper limit of normal 
(ULN). 
20. Serum creatinine > 2x the ULN. 
21. Any of the following hematologic abnormalities, confirmed by repeat test at least 
1 week apart:  
a. White blood count <3,000/ L or >14,000/L;  
b. Lymphocyte count <1,000/L; 
c. Neutrophil count <1,500/ L;  
d. Platelet count <150,000 /L; or  
e. Hemoglobin <10 g/dL. 
22. Females who are pregnant, lactating, planning on pregnancy during the study 
period, or unwilling to use a medically acceptable method of birth control. 
23. Receipt of a live vaccine (e.g., varicella, measles, mumps, rubella, cold-attenuated 
intranasal influenza vaccine, and smallpox) in the previous 6 weeks prior to visit 
0.  
24. BCG vaccines in the previous one year.  
4.3  PREMATURE TERMINATION OF A PARTICIPANT FROM THE 
STUDY 
Withdrawal of consent. Participants who withdraw consent for further treatment will 
be asked if they would be willing to complete an end-of-study visit to include the 
assessments in visit 22. 
Investigator decision. The investigator may choose to withdraw a participant from 
the study for any reason.  
Failure to return. Participants who do not return for visits and who do not respond to 
repeated attempts by the site staff to have them return will be considered lost to 
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Participants who prematurely terminate from the study will not be replaced.  
5.  
STUDY MEDICATIONS 
5.1  INVESTIGATIONAL MEDICATION:  USTEKINUMAB 
5.1.1  Formulation and Packaging  
Ustekinumab is supplied as a sterile solution in the following forms: 
 a single-use 2 ml Type 1 glass vial of 45 mg in 0.5 ml. 
 a single-use pre-filled syringe with a 27 gauge fixed passive needle guard 
and a needle cover that is manufactured using a dry natural rubber (a 
derivative of latex) with either 45 mg in 0.5 ml or 90 mg in 1.0 ml. 
Each 45 mg ustekinumab pre-filled syringe or single-use vial also contains: L-
histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 
(0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL. Each 90 mg 
ustekinumab pre-filled syringe also contains: L-histidine and L-histidine 
monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 
mg) to fill to a final volume of 1 mL. Ustekinumab solution is colorless to slightly 
yellow in appearance and has a pH of 5.7-6.3, and does not contain preservatives. 
 
Procurement, packaging and delivery of ustekinumab pre-filled syringes and single-
use vials will be done by a designated drug distributor under contract to NIAID. The 
syringes and single-use vials provided to the pharmacy will have study-specific 
investigational agent labels. 
5.1.2  Placebo Preparations 
Ustekinumab placebo syringes, which consist of sterile normal saline, will be prepared 
by the site pharmacist. 
5.1.3  Dosage and Administration 
Dosage and administration schedule for ustekinumab and ustekinumab placebo is 
described in section 3.1. Ustekinumab will be administered as a subcutaneous 
injection on week 0 and week 4. Ustekinumab or ustekinumab placebo will be 
administered as a subcutaneous injection on week 16 and week 28.  
Participants who weigh  < 100 kg at study entry will receive 45 mg of ustekinumab or 
0.5 ml ustekinumab placebo. Participants who weigh  > 100 kg at study entry will 
receive 90 mg of ustekinumab or 1.0 ml ustekinumab placebo. 
Ustekinumab or ustekinumab placebo should be administered according to the 
instructions provided in the approved package labeling.  
US package insert [52]: 
http://www.stelarainfo.com/hcp/assets/pdf/PrescribingInformation.pdf 
Canada product monograph: http://www.janssen.ca/product/190 


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5.1.4  Recommended Storage Conditions  
Ustekinumab  pre-filled syringes and single-use vials must be refrigerated at 2ºC to 
8ºC (36ºF to 46ºF). Store ustekinumab pre-filled syringes and single-use vials upright. 
Keep the product in the original carton to protect from light until the time of use. Do 
not freeze. Do not shake. Ustekinumab does not contain a preservative; discard any 
unused portion. 
 
When ustekinumab single-use vials are used, ustekinumab syringes will be prepared 
by the site pharmacist on the day of injection.  Ustekinumab placebo syringes will also 
be prepared by the site pharmacist on the day of injection. 
5.1.5  Toxicity Management for Ustekinumab 
Suspend ustekinumab administration if the participant develops an infection or other 
AE that the investigator judges to be significant. The scheduled dose of ustekinumab 
at visit 1 (week 4) may be administered within the specified visit window if the 
infection or AE resolves within this time frame (see section 6.1.1). The scheduled 
dose of ustekinumab at visit 4 (week 16) and visit 7 (week 28)  may be administered 
within 10 days outside of the visit window if the infection or AE resolves within this 
time frame.  
 
Discontinue ustekinumab if any of the following occurs: 
 A grade 3 or greater AE that the protocol chair and/or the medical monitor, in 
consultation with the site investigator, judge to be possibly, probably, or definitely 
related to ustekinumab. 
 One dose of ustekinumab is withheld.  
If ustekinumab is discontinued, the procedures in Section 5.3 should be followed. 
5.2  INVESTIGATIONAL MEDICATION:  ABATACEPT 
5.2.1  Formulation and Packaging  
Abatacept solution for subcutaneous administration is supplied as a sterile, 
preservative-free, clear, colorless to pale yellow solution with a pH of 6.8 to 7.4. Each 
single dose of subcutaneous injection provides 125 mg abatacept, dibasic sodium 
phosphate anhydrous (0.838 mg), monobasic sodium phosphate monohydrate (0.286 
mg), poloxamer 188 (8 mg), sucrose (170 mg), and quantity sufficient to 1 mL with 
water for injection.  
 
Abatacept injection solution for subcutaneous administration is supplied as a single-
dose disposable pre-filled glass syringe with flange extender. The Type I glass syringe 
has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, 1/2-
inch needle) covered with a rigid needle shield. The pre-filled syringe provides 125 
mg of abatacept in 1 mL. The syringes provided to the pharmacy will have study-
specific investigational agent labels. 
 


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Abatacept pre-filled syringes will be provided by Bristol Myers Squibb. Packaging 
and delivery of abatacept pre-filled syringes will be done by a designated drug 
distributor under contract to NIAID. 
5.2.2  Abatacept Placebo 
Abatacept placebo compositionally matches abatacept minus the active ingredient, 
and will be provided by Bristol Myers Squibb, supplied as pre-filled syringes. The 
pre-filled syringes provided to the pharmacy will have study-specific investigational 
agent labels. 
 
Packaging and delivery of abatacept placebo pre-filled syringes will be done by a 
designated drug distributor under contract to NIAID. 
5.2.3  Dosage and Administration 
As described in section 3.1, abatacept or abatacept placebo will be administered 
weekly by subcutaneous injection at weeks 12 through 39 at a dose of 125 mg via 
single use syringe according to the instructions provided in the package insert [61]  
http://packageinserts.bms.com/pi/pi orencia.pdf. 
5.2.4  Recommended Storage Conditions  
Abatacept or abatacept placebo solution supplied in pre-filled syringes should be 
refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on 
the pre-filled syringe. Protect from light by storing in the original package until time 
of use. Do not allow the pre-filled syringe to freeze. 
5.2.5  Toxicity Management for Abatacept 
Suspend abatacept or abatacept placebo administration if the participant develops an 
infection or other AE that the investigator judges to be significant. If the infection or 
AE resolves, abatacept or abatacept placebo may be restarted at the next scheduled 
dose.  
 
Discontinue abatacept or abatacept placebo if any of the following occurs: 
 A grade 3 or greater AE that the protocol chair and/or the medical monitor, in 
consultation with the site investigator, judge to be possibly, probably, or definitely 
related to abatacept. 
 Three sequential doses of abatacept are withheld. 
 More than four total doses of abatacept are withheld.  
If abatacept is discontinued, the procedures in section 5.3 should be followed. 
5.3  DISCONTINUATION OF STUDY TREATMENT AND STUDY 
OBSERVATION  
Study treatment is defined as the dosing and administration of study medication 
according to study specification.  Study observation is defined as study participation 
after week 39 until the time of discontinuation, or through week 88 if discontinuation 


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does not occur earlier.  Study treatment or study observation will be discontinued for 
an individual participant if any of the following criteria are met: 
 The participant meets the criterion for psoriasis relapse (see section 3.3.3.2).  
 Discontinuation criteria for ustekinumab are met prior to week 28, or 
discontinuation criteria for abatacept are met between week 12 and week 39 (see 
section 5.1.5 and 5.2.5). 
 Onset of generalized pustular psoriasis. 
 Onset of erythrodermic psoriasis. 
 Onset of grade 2 or 3 moderate to severe psoriatic arthritis not adequately 
managed with NSAIDs (see section 8.2.2) or with intra-articular corticosteroid 
injection as allowed in section 5.4.1.  
 The investigator determines that it is in the participant’s best interest to 
discontinue treatment. 
 The participant requests that treatment or observation be halted. 
 The participant becomes pregnant. 
Further care will be provided according to the judgment and practice of the principal 
investigator. 
At this time the participant will complete all assessments listed for visit 22 in 
Appendix 1. Randomized participants will be also be asked to return for a follow-up 
visit 12 weeks later, and will complete the assessments listed for visit D. This will 
conclude his or her participation in the study.    
If study treatment or study observation is discontinued, the NIAID medical monitor 
should be notified unless the participant discontinues study treatment or observation 
due to psoriasis relapse, as described in the study design (see section 3.1). 
5.4  CONCOMITANT MEDICATIONS 
5.4.1  Allowed Medications 
Use of the following medications is allowed during study participation: 
 One course of oral or inhaled corticosteroids  not to exceed 2 weeks may be used 
at the investigator’s discretion for the treatment of non-psoriasis conditions. 
 An intra-articular injection of corticosteroids not to exceed one injection every six 
months may be used at the investigator’s discretion for treatment of  joint pain. 
5.4.2  Prohibited Medications 
Use of the following medications is prohibited during study participation: 
 All medications listed in the Exclusion Criteria (section 4.2), except as described 
in section 5.4.1. 


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 Live vaccines concurrently or within 3 months of study medication 
discontinuation. 
 BCG vaccines concurrently or within one year following study medication 
discontinuation. 
5.4.3  Contraception 
All female participants of childbearing age must use a medically acceptable form of 
contraception during study participation, and must continue its use for 8 weeks after 
receiving their last dose of study medication. 
5.5  DRUG ACCOUNTABILITY 
Under US and Canadian regulations (21CFR 312.62 and C.05.012) an investigator is 
required to maintain adequate records of the disposition of the investigational product, 
including the date and quantity of drug that was received, the participants to whom 
drug was dispensed (participant by participant accounting), and an account of any 
drug accidentally or deliberately destroyed. The investigator will ensure that the 
investigational product supplies are stored as specified in the protocol and pharmacy 
manual in a secured area, with access limited to authorized study personnel as 
described in the clinical study agreement. 
Records for receipt, storage, use, and disposition of the study drug will be maintained 
by the study sites. A drug-dispensing log will be kept current for each participant and 
will contain the identification of each participant, and the date and quantity of drug 
dispensed. All remaining unused investigational product will be returned to the 
sponsor or sponsor’s representative after study termination, or destroyed with the 
permission of the sponsor in accordance with applicable law and study site 
procedures. If investigational product is to be destroyed locally, the investigator will 
provide documentation in accordance with sponsor’s specifications. 
All records regarding disposition of the investigational product will be available for 
inspection by the clinical trial monitor. 
5.6  ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION 
Ustekinumab and ustekinumab placebo will be administered by trained medical staff. 
Compliance, therefore, will be monitored by medical staff and documented on the 
case report form (CRF). Abatacept and abatacept placebo will be self-administered by 
the participant; compliance will be monitored by return of unused syringes to study 
coordinators and documented on the CRF.  
6.  
STUDY PROCEDURES 
6.1  VISIT WINDOWS 
6.1.1  Scheduled Visits 
Appendix 1 presents the schedule of events for this trial. Visit 0 must occur within 28 
days of Visit –1. All other scheduled study visits must occur within the time limits 
specified below: 


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Visits 1 through 22:  ±5 days 
6.1.2  Unscheduled Visits 
Unscheduled visits may be performed to document any symptoms or to document a 
psoriasis relapse during the study. Assessments for an unscheduled visit are listed in 
Appendix 1. Some of the assessments may be omitted at the discretion of the 
investigator if they are not indicated.  
6.1.3  Windows for Ustekinumab Injection 
The schedule for ustekinumab or ustekinumab placebo injection is described in 
Appendix 1. Ustekinumab or ustekinumab placebo injections must occur with the 
scheduled visit windows described in section 6.1.1, except as specified in the special 
circumstances described in section 5.1.5. 
6.1.4  Windows for Abatacept Injection 
The schedule for abatacept or abatacept placebo injection is described in Appendix 1. 
Abatacept or abatacept placebo injections must occur within 72 hours of the scheduled 
injection. 
6.1.5  Documentation of Psoriasis Relapse 
Psoriasis relapse may be documented at a scheduled or an unscheduled visit. Psoriasis 
relapse is a criterion for discontinuation of study treatment and study observation (see 
section 5.3).  All assessments listed at visit 22 should be completed. 
6.1.6  Follow-up Visit 
Randomized participants will be asked to return for a follow-up visit D 12 weeks 
following discontinuation from the study, as described in section 5.3, or 12 weeks 
after completing the study at week 88.  All assessments listed at visit D should be 
completed.  The visit window for visit D is specified below. 
Visit D:  ±7 days 
6.2  ENROLLMENT, RANDOMIZATION, BLINDING, AND UNBLINDING 
6.2.1  Enrollment 
Participants who meet the eligibility criteria will be enrolled at study visit 0. 
6.2.2  Randomization 
Participants who meet the response criteria of PASI 75 (see section 3.3.3.1) will be 
randomly assigned to treatment in either the ustekinumab group or the abatacept 
group. Randomization will be accomplished through a password-protected, web-
based, randomization system (RhoRAND™) maintained by the Statistical and Data 
Coordinating Center (SDCC).  
Random assignment will be stratified according to PASI score 12-20 versus PASI 
score > 20 at visit 0. Stratification based on the PASI score at visit 0 was chosen 


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because the study is evaluating a sequential strategy consisting of a lead-in phase with 
open label ustekinumab, followed by either abatacept or continued ustekinumab. 
6.2.3  Blinding 
Blinding will be maintained for all study participants and trial personnel from the time 
of randomization at week 12 throughout the study, with the exception of the site 
pharmacist. In the event that pre-filled ustekinumab syringes rather than single-use 
vials are supplied for the week 16 and week 28 blinded ustekinumab doses, one 
unblinded trained medical professional at each site who will administer ustekinumab 
or ustekinumab placebo at week 16 and week 28 will also be required.  This unblinded 
individual will not otherwise be involved in any other aspect of the study. The week 
16 and week 28 doses of ustekinumab and ustekinumab placebo will be delivered 
from the pharmacy and administered  in masked fashion in order to preserve blinding 
of participants and all other site personnel. 
6.2.4  Unblinding 
Unblinding before the study is completed will occur only if a participant’s well-being 
is threatened and the investigator believes unblinding is necessary to protect the 
participant.  
Before treatment assignment for an individual participant is unblinded, the 
investigator must confer with the NIAID medical monitor. The investigator will notify 
the protocol chair of the unblinding event, and the medical monitor will notify the 
study management team.  
The emergency unblinding will be recorded and reported to the DSMB. A full account 
of the event will be recorded, including the date and time of the emergency, the reason 
for the decision to unblind, and the names of the medical monitor and others who 
were notified of the emergency. During site visits, the site monitor must verify that the 
medical monitor was notified and that a written account was completed. The reasons 
for unblinding of a participant’s treatment will be included in the final study report. 
Immune Tolerance Network (ITN) and NIAID approval is required for unblinding the 
treatment of an individual participant or subgroups of participants for unplanned 
interim analyses to support DSMB reviews and final analysis.  
An exception to the above rule is that Investigational New Drug (IND) Safety Reports 
will be reported to the FDA, Health Canada, DSMB, and Institutional Review Boards 
(IRB) or ethics review committee in an unblinded fashion as requested by current ICH 
and local guidance. 
6.3  GENERAL ASSESSMENTS 
 Informed consent. Written informed consent will be obtained before any study 
assessments or procedures are performed. 
 Randomization. 
 Demographics: age and ethnicity.  


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 Medical history: to determine if the there are any clinically significant diseases or 
medical procedures other than the disease under study. 
 Psoriasis history to determine time of diagnosis. 
 Comprehensive physical examination. 
 Brief physical examination: a physical examination focused on participant’s 
current complaints and clinical status at the study visit will be conducted.  
 Adverse events: participants will be assessed for AEs. 
 Concomitant medications: all concomitant medications will be recorded. 
 Vital signs: weight, temperature, blood pressure, respiration, and pulse will be 
obtained at all visits.  
6.4  CLINICAL LABORATORY ASSESSMENTS 
 Serum Chemistry (AST, ALT, bilirubin, alkaline phosphatase, random glucose) 
 Hematology (CBC, differential and platelet count) 
 Serum Creatinine  
 Rapid Plasma Reagin (RPR) 
 Serum Human Chorionic Gonadotropin (HCG) 
 QuantiFERON-TB Gold, unless test has been performed within 30 days of visit -1 
and documented test results are available. (PPD tuberculin skin test may be 
substituted for the QuantiFERON-TB Gold.) 
 Urinalysis 
 STAT Urine Human Chorionic Gonadotropin (HCG) 
 HIV, unless test has been performed within 30 days of visit -1 and documented 
test results are available. 
 Hepatitis B (surface antibody, core antibody, and surface antigen), unless test has 
been performed within 30 days of visit -1 and documented test results are 
available. 
 Hepatitis C (RNA or antibody), unless test has been performed within 30 days of 
visit -1 and documented test results are available. 
 Chest x-ray, unless x-ray has been performed within 30 days of visit -1 and 
documented test results are available. 
6.5  DISEASE-SPECIFIC ASSESSMENTS 
 Psoriasis Area and Severity Index (PASI) [32, 33] 
 Physician’s Global Assessment (PGA) [3] 
 Dermatology Life Quality Index (DLQI) [66, 67] 


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http://www.dermatology.org.uk/quality/dlqi/quality-dlqi-questionnaire.html 
 Psoriatic Arthritis Screening and Evaluation (PASE) [70, 71] 
 Skin photography (optional) 
6.6  MECHANISTIC ASSESSMENTS 
 Lesional and non-lesional six millimeter punch skin biopsy. Two four millimeter 
biopsies can be substituted for each six millimeter biopsy. The week 24 lesional 
skin biopsy and the relapse non-lesional biopsy are considered optional. In 
participants who do not experience a psoriasis relapse, the week 88 non-lesional 
biopsy will be considered optional. 
 Plasma/Serum assays 
 PBMC assays  
 RNA assays 
See section 7 for detailed discussion of mechanistic assays. 
7.  
MECHANISTIC ASSAYS 
7.1  RATIONALE FOR IMMUNE STUDIES 
Psoriasis vulgaris is a chronic inflammatory skin disease characterized by increased 
epidermal thickening and T-cell infiltration. Clinical response to ustekinumab in 
psoriasis vulgaris has been associated with the restoration on skin biopsy of near 
normal levels of T-cells and DC, elimination of most activated DC, suppression of T-
cell cytokine levels, and reversal of pathological epidermal hyperplasia so that treated 
psoriasis plaques resumed the appearance of non-lesional skin [5]. Treatment with 
abatacept has also been associated with reduced cellular activation of T-cells, 
keratinocytes, DCs, and vascular endothelium in the skin [11].   
 
In this study, skin and blood samples will be collected with the objective of analyzing 
circulating cytokine levels, cellular infiltration, and genetic signatures of disease and 
tolerance. It is hypothesized that tolerance can be induced by 1) decreasing T-cell and 
DC numbers and activation (ustekinumab) and 2) prevention of T-cell reactivation 
(abatacept). The primary mechanistic objective for the study will be the evaluation of 
cellular and molecular correlates of tolerance in skin. The skin biopsies will be 
evaluated using immunohistochemistry for T-cell and DC markers, as well as mRNA 
microarrays and quantitative PCR to assess gene expression of cytokines and other 
immune regulatory molecules, according to a well-described approach [15, 16].  
 
A successful outcome of tolerance induction at the tissue level in the proposed study 
would be defined as reduced production of IL-12/23 and T helper subset cytokines 
(gamma-interferon, IL-22, and IL-17A/F), along with a reduction of T-cells and DC. 
Other correlates of tolerance may be observed in skin biopsies, such as an increase of 
T-regs (assessed by Foxp3 phenotype), an increase of IDO+ regulatory DC, or 
increases in regulatory molecules such as IL-10, CTLA4, and PD-1. Thus, the trial 


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presents the opportunity to define a molecular signature of tolerance which 
corresponds to a clinical response to sequential treatment with inflammatory cytokine 
blockade (ustekinumab) followed by co-stimulatory blockade (abatacept). 
7.2  PLANNED MECHANISTIC ASSAYS 
Samples will be collected from psoriasis participants at weeks 0, 12, 24, 40, 56, 72, 
88, and at the time of psoriasis relapse. Six millimeter skin biopsies will be collected 
from lesional and non-lesional (unaffected) skin and cut into two halves, one half for 
RNA isolation and one half for immunohistochemical analysis. Alternatively, two 
four millimeter biopsies can be substituted for each six millimeter biopsy. Blood will 
be collected in ABI Tempus™ blood collection tubes for gene expression analysis and 
in heparinized tubes for PBMC isolation and plasma characterization. Samples will be 
shipped for processing, storage, and/or analysis to the Core Laboratories as specified 
in the General Information description of the ITN Tolerance Assay Core Facilities. 
The laboratory at Rockefeller University has extensive experience processing skin 
biopsies for immunohistochemical analysis and gene expression analysis [15, 16, 72, 
73]. 
7.2.1  Histological Assessments  
The laboratory at Rockefeller University has worked out conditions for the evaluation 
of infiltrating T-cell subsets and DC in skin biopsies [72, 74, 75]. Therefore, lesional 
and non-lesional (unaffected) skin biopsies will be submerged in OCT compound 
upon collection and shipped to Rockefeller for processing and analysis. Skin sections 
will be stained with antibodies directed against T-cell, dendritic cell, and cytokines. 
Cellular infiltration will be compared between treatment groups to evaluate the 
efficacy of treatment on reducing T-cell subsets and DC in lesional skin. Lesional skin 
biopsies will additionally be compared to non-lesional skin biopsies from the same 
participant. 
7.2.2  Gene Expression in Peripheral Blood and Skin Biopsies 
Systemic treatment with biologics has previously been shown to modulate gene 
expression in psoriasis vulgaris participants [76]. The accessibility of skin provides 
the opportunity to evaluate the direct effect of treatment on the target organ. Whole 
blood will additionally be collected in ABI Tempus™ blood collection tubes to 
evaluate changes in the periphery due to immunomodulation of the disease or the 
systemic nature of the treatment. Skin biopsies and whole blood will be collected from 
enrolled participants to evaluate genomic changes following treatment with 
ustekinumab or the combination of ustekinumab followed by abatacept. RNA will be 
isolated, and gene expression of selected cytokines and other immune regulatory 
molecules will be further evaluated using quantitative PCR as previously described 
[77]. 
 
Biopsy tissue will be compared pre- and post-treatment to determine the effect of 
treatment on the global gene expression in participants with psoriasis. Since drug 
effects may confound mechanistic observations, care needs to be taken in the 
interpretation of data comparing participants treated with ustekinumab compared to 
ustekinumab followed by abatacept. Therefore, comparisons at baseline will be 


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important to demonstrate that all participants have similar inflammatory signatures 
prior to treatment.  
7.2.3  Multi-Parameter Flow Cytometry (MFC) 
Flow cytometry will be done at ITN laboratories to analyze the peripheral blood 
immune-cell-phenotype and identify specific cells or cellular subsets that correlate 
with tolerance or other clinical phenotype. We hypothesize that the combination of 
ustekinumab followed by abatacept will decrease plasmacytoid dendritic cells and 
Th17 cells, while up-regulating regulatory T-cell populations.  
 
Peripheral blood will be collected and shipped to the ITN core laboratory for flow 
cytometric analysis. Frozen flow cytometry experiments will use banked specimens to 
investigate longitudinal changes in T-cells, monocytes, and dendritic cells. Circulating 
T-cells, DC, monocytes, and other inflammatory cells will be characterized by 
staining cells with antibodies directed against immune markers, such as CD19, CD3, 
CD4, CD8, CD25, CD45RA, CD45RO, CD11b/Mac-1, CD11c, CD16, CCR6, CTLA-
4, IDO, PD-1, CLA, HLA-DR, BDCA1, BDCA2, CD80, CD86, CD28, IL-22, IFN-g, 
IL-17, IL-13, Foxp3, and CD127. Proposed frozen flow antibody panels will be 
finalized and validated by the ITN flow core prior to starting assays. Levels of 
circulating cells will be compared between the baseline and time points following 
treatment. Additional comparisons will be made between treatment groups to evaluate 
effectiveness of ustekinumab or ustekinumab followed by abatacept on circulating 
cells. 
7.2.4  Serum Cytokine Assays 
Participant serum/plasma will be analyzed for circulating levels of cytokines, such as 
IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17, G-CSF, GM-
CSF, IFN-, MCP-1, MIP1, and TNF-, using the Bio-Plex Pro Human Cytokine 17-
plex assay (Bio-Rad) or equivalent. Additionally, circulating levels of additional 
inflammatory mediators, such as MIP-3/CCL20, IL-22, IL-12/23p40, and IL-23p19 
will be evaluated by enzyme-linked immunosorbent assay (ELISA).  
 
Serum cytokine levels for individual cytokines and inflammatory mediators will be 
compared between baseline and the time points following treatment. Additionally, 
levels will be evaluated for correlations with circulating T-cell and monocyte 
populations. Additional comparisons will be made between treatment groups to 
evaluate effectiveness of ustekinumab or ustekinumab followed by abatacept on 
circulating levels of inflammatory mediators.  
7.2.5  T-cell Repertoire Analysis 
Psoriasis is a chronic inflammatory skin disease characterized by epidermal 
hypoproliferation and dermal infiltration leading to the formation of raised scaly 
plaques or “lesions.” The dermal infiltrate of psoriatic lesions is predominantly 
characterized by increased numbers of plasmacytoid dendritic cells and T-cells (both 
CD4+ and CD8+ T-cells). Current biological therapies (i.e. adalimumab, etanercept) 
targeting the inflammatory process provide a clinical benefit and disease resolution, 
however, relapse and lesion materialization occurs in the absence of continued therapy 
due, in part, to a remnant disease signature in the skin [77]. The proposed treatment 


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paradigm of ustekinumab followed by abatacept is hypothesized to disrupt this 
interaction by inhibiting the inflammatory response of the pDC and preventing T-cell 
activation by blocking co-stimulation, thereby leading to disease resolution and 
remission. Using T-cell receptor (TCR) repertoire sequencing, we will evaluate 
whether therapeutic treatment and the subsequent immunological disruption 
modulates the antigen specificity of infiltrating and resident T-cells in psoriatic skin. 
In order to characterize the repertoire of autoreactive T-cells and determine whether 
disease relapse involves the same T-cells, TCR sequencing will be performed on skin 
biopsies collected from enrolled patients at baseline, following therapeutic treatment, 
and during disease relapse in those that fail to maintain remission. 
7.3  OVERVIEW OF DATA ANALYSIS 
This study is designed to assess the ability of combination therapy to induce sustained 
disease resolution as evidenced clinically by a decreased PASI score and sustained 
remission. Mechanistic data collected as secondary endpoints will be analyzed as both 
cohort and individual participant-based longitudinal profiling which includes graphic 
plotting and descriptive statistics. Exploratory analysis is also planned to discover 
potential molecular and cellular patterns that might be linked to disease resolution.  
7.3.1  Individual Based Longitudinal Profiling  
Mechanistic samples from participants enrolled in this study will be assayed as 
described in the individual sections above with the aim to identify specific cell 
phenotypes, intracellular responses and /or gene sets (tissue and/or peripheral blood) 
that correlate with successful disease resolution. These data may also be assessed in 
support of evaluating the safety of the treatment regimen. Graphic plots will facilitate 
longitudinal monitoring of relevant cellular populations, immune cell repertoire, and 
gene expression etc., in conjunction with the treatment process, adverse events and 
clinical outcomes. Descriptive statistics will be provided as appropriate. 
7.3.2  Exploratory Analysis 
The study participants may be grouped based on primary clinical outcome (disease 
resolution success and failure). The primary objective of exploratory analysis is to 
discover molecular, cellular, and immunogenetic patterns among the participants at 
clinical milestones during the study that may provide insights into potential 
association with the suppression of the inflammatory process in skin and disease 
resolution. Pattern recognition methods including hierarchical clustering and principal 
component analysis may be used for the analysis. The exploratory analysis will be 
conducted on individual assay datasets (flow cytometry, gene expression, histological 
assessment assays, etc.) as well as integrated multi-assay data. 
7.4  FUTURE / UNPLANNED STUDIES 
Specimens stored during the trial may be used in future assays to reevaluate biological 
responses as research tests are developed over time. Additionally, samples may be 
used for assays/experiments outside the scope of this proposal, such as investigation 
of differences in the T-cell receptor (TCR) repertoire as evaluated by sequencing, 
proteomics or other assays that may emerge and be compelling. Re-evaluations or new 
assays will only be performed on samples of participants who have consented for 


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future research. The ITN sample sharing policy will apply for the provision of 
samples to study or outside investigators (www.immunetolerance.org).  
7.5  SPECIMEN LOGISTICS 
The clinical sites will be trained in collection, processing, shipment, and tracking of 
mechanistic research specimens. The ITN will monitor specimen quality, shipping 
compliance etc. and retrain the clinical site if not producing optimum quality 
mechanistic samples. The Rockefeller University clinical site will process mechanistic 
samples for gene expression and histological analysis according to the ITN standard 
operating procedures and use the ITN Specimen Tracking System (STS) software to 
identify and track all mechanistic specimens. The site is required to have its own 
laboratory equipment for use in standard ITN procedures, such as a centrifuge for 
spinning primary blood tubes, a micropipettor to aliquot specimens and freezer to 
store frozen specimens until they can be shipped. Additional mechanistic samples will 
be shipped to ITN repositories/ core labs, per ITN standard procedures. All shipping 
will conform to country-specific regulations for Diagnostic Specimens. 
7.6  SPECIMEN TRACKING PROCEDURES 
The ITN will track all mechanistic specimens until the final disposition of all material 
is known. Samples will remain in the ITN repository until used for assays or 
destroyed. 
7.7  SPECIMEN STORAGE 
Samples sent to the ITN repository will be stored under specific conditions to 
maintain long-term sample integrity, as well as specimen tracking from receipt to 
shipment to alternate locations. The ITN STS will be used to track date of shipment, 
location shipped to, carrier, items shipped, amount shipped, barcode numbers, 
protocol number, and associated comments about each individual specimen. Storage 
temperature, location, processing, aliquoting, and freeze/thaw events may also be 
recorded. 
 
If the study subject allows storage, the subject’s specimens will be stored indefinitely. 
The subject can change their mind at any time and have their stored specimens 
destroyed by notifying the study physician in writing. In such cases, the site 
coordinator would send all requests for sample destruction to the ITN. The site will 
receive confirmation that the specimen was destroyed as requested. If the subject’s 
samples have already been analyzed, then the data will be used as part of the overall 
analysis. The subject can only request to have samples destroyed if they still exist, i.e. 
have not already been used in an experiment. 
 
Specimens at the ITN core or repository can only be transferred to another destination 
with appropriate authorization per ITN standard procedures. The following items are 
checked prior to authorization for the purpose of accessing/transferring the specimen 
(within study assay as defined by the protocol or future studies): 1) evaluation of 
subject consent for the purpose provided 2) verification of specimen identifiers, and 3) 
quality and quantity of the specimen. 


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8.  
ADVERSE EVENTS 
8.1  OVERVIEW 
The investigator is responsible for the detection and documentation of events meeting 
the criteria and definition of an AE or SAE as described in sections 8.2 and 8.3 in this 
protocol. All AEs and SAEs will be recorded in the source documents and on the 
appropriate electronic CRF(s). All data will be reviewed periodically by the DSMB, 
which may provide recommendations to NIAID about withdrawing any participant 
and/or terminating the study because of safety concerns. 
 
Adverse events that are classified as serious according to the definition of health 
authorities must be reported promptly and appropriately to the NIAID, ITN, principal 
investigators in the trial, IRBs or ethics review committees, and health authorities as 
appropriate. This section defines the types of AEs and outlines the procedures for 
appropriately collecting, grading, recording and reporting them. Information in this 
section complies with 21CFR 312; Division 5 of the Canadian Food and Drug 
Regulations; International Conference on Harmonization (ICH) Guideline E2A: 
Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting; and ICH Guideline E-6: Guidelines for Good Clinical Practice; and 
applies the standards set forth in the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events Version 4.03 (published June 14, 2010). 
(This document is referred to herein as the “NCI-CTCAE manual.”)  
8.2  PSORIASIS-SPECIFIC SAFETY DEFINITIONS 
8.2.1  Worsening of Psoriasis 
Psoriasis severity will be assessed by PASI and recorded on a designated electronic 
CRF. Worsening psoriasis will not be collected as an AE. Psoriasis relapse is defined 
in section 3.3.3.2, and will be a criteria for discontinuation of study medication as 
described in section 5.3. 
8.2.2  Psoriatic Arthritis 
New onset or worsening psoriatic arthritis will be graded according to the following  
functional scale: 
 
Grade 1:  Mild pain with inflammation, erythema, or joint swelling. 
 
Grade 2:  Moderate pain associated with signs of inflammation, erythema, or joint 
swelling; limiting instrumental activities of daily living (ADL). 
 
Grade 3: Severe pain associated with signs of inflammation, erythema, or joint 
swelling; irreversible joint damage; disabling; limiting self-care ADL. 


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8.3  NON-DISEASE SPECIFIC SAFETY DEFINITIONS 
8.3.1  Adverse Event 
An AE is any occurrence or worsening of an undesirable or unintended sign, 
symptom, laboratory finding, or disease that occurs during participation in the trial. 
An AE will be followed until it resolves or until 30 days after a participant terminates 
from the study, whichever comes first. All AEs will be recorded as specified in 
section 8.4.3 whether they are or are not related to disease progression or study 
participation. 
8.3.2  Suspected Adverse Reaction and Adverse Reaction  
Suspected adverse reaction (SAR) means any adverse event for which there is a 
reasonable possibility that the study drug caused the adverse event. For the purposes 
of safety reporting, “reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the adverse reaction. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug (21 CFR 312.32(a) and ICH E2A). 
 
An adverse reaction (AR) means any adverse event caused by a study drug. Adverse 
reactions are a subset of all suspected adverse reaction for which there is reason to 
conclude that the drug caused the event. 
8.3.3  Serious Adverse Event  
An AE or SAR is considered “serious” if, in the view of either the investigator or 
Division of Allergy, Immunology, and Transplantation (DAIT)/NIAID it results in 
any of the following outcomes (21 CFR 312.32(a), Division 5 of the Canadian Food 
and Drug Regulations, and ICH E2A): 
 
 Death:  A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up period must be reported whether 
it is considered treatment related or not. 
 A life-threatening event: An AE or SAR is considered “life-threatening” if, in the 
view of either the investigator or DAIT/NIAID, its occurrence places the subject at 
immediate risk of death. It does not include an AE or SAR that, had it occurred in a 
more severe form, might have caused death.  
 Inpatient hospitalization or prolongation of existing hospitalization. 
 Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 An event that requires intervention to prevent permanent impairment or damage. 
An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based on appropriate 
medical judgment, it may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 Congenital anomaly or birth defect. 


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If an event meets any of the above serious adverse event definitions, regardless of the 
relationship of the event to study drug, the event must be reported to the sponsor as 
described in section 8.6.1. 
8.3.3.1  Events considered study specific SAEs 
 Potential drug induced liver injury (DILI) defined as: 
o ALT or AST elevation > 3 times ULN.  
AND 
o Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase), 
AND 
o No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
 Suspected transmission of an infectious agent (e.g. any organism, virus or infectious 
particle, pathogenic or non-pathogenic) via the study drug. 
 
If an event meets any of the above criteria, regardless of the relationship of the event 
to study drug, the event must be reported to the sponsor as described in section 8.6.1. 
8.3.3.2  Non-serious study specific events tracked as SAEs 
 Any cancer. 
 Overdose. 
If an event meets any of the above criteria, regardless of the relationship of the event 
to study drug, the event must be reported to the sponsor as described in section 8.6.1.  
If such an event does not meet serious criteria as described in Section 8.3.3, it will 
nonetheless be reported on the SAE form as a non-serious event and entered into the 
safety database for tracking purposes. 
8.3.4  ‘Expected’ versus ‘Unexpected’ Suspected Adverse Reaction 
A SAR is considered “expected” when it is listed in the investigator brochure, the 
package insert or the protocol. A SAR is considered “unexpected” when its nature 
(specificity), severity, or rate of occurrence is not consistent with applicable product 
information as described in the safety information provided in the investigator 
brochure, the package insert, the Canada product monograph, or the protocol (21 CFR 
312.32(a), Division 5 of the Canadian Food and Drug Regulations, and ICH E2A). A 
serious unexpected suspected adverse reaction is referred to as a SUSAR. For this 
study, expectedness will be determined by product information provided in the 
package insert for ustekinumab and abatacept [52, 61].  


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8.4  COLLECTING AND RECORDING ADVERSE EVENTS 
8.4.1  Methods of Collection 
Adverse events may be collected as follows: 
 Observing the participant. 
 Questioning the participant in an objective manner. 
 Receiving an unsolicited complaint from the participant. 
An abnormal value or result from a clinical or laboratory evaluation (e.g., a 
radiograph, an ultrasound, or an electrocardiogram) can also indicate an AE if it is a 
Grade 2 or greater AE per CTCAE criteria. The evaluation that produced the value or 
result should be repeated until that value or result returns to normal or can be 
explained and the participant’s safety is not at risk. 
8.4.2  Collection Period for Adverse Events and Serious Adverse Events 
All AEs and SAEs will be collected from visit -1 until 30 days after the participant 
completes the study (visit 22) or prematurely withdraws from the study.  AEs and 
SAEs will also be collected at visit D.  
8.4.3  Methods of Recording 
8.4.3.1  Recording AEs 
Throughout the study, the investigator will record all clinical AEs and all laboratory 
AEs  grade 2 on the appropriate eCRF regardless of their relation to study 
participation. The investigator will treat participants experiencing AEs appropriately 
and observe them at suitable intervals until their symptoms resolve or their status 
stabilizes. 
8.4.3.2  Recording SAEs 
Serious AEs will be recorded on the SAE eCRF and health authorities will be notified 
as outlined in section 8.6.2. 
8.5  GRADING AND ATTRIBUTION OF ADVERSE EVENTS 
8.5.1  Grading  
The study site will grade the severity of AEs experienced by study participants 
according to the criteria set forth in the NCI-CTCAE manual (v 4.03 published June 
14, 2010). This manual provides a common language to describe levels of severity, to 
analyze and interpret data, and to articulate the clinical significance of all AEs. 
 
Adverse events will be graded on a scale from 1 to 5 according to the following 
standards in the NCI-CTCAE manual: 
 
 Grade 1 = mild adverse event. 
 Grade 2 = moderate adverse event. 
 Grade 3 = severe and undesirable adverse event.  






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 An aggregate analysis of specific serious adverse events observed in a 
clinical trial (such as known consequences of the underlying disease or 
condition under investigation or other events that commonly occur in the 
study population independent of drug therapy) that indicates those events 
occur more frequently in the drug  treatment group than in a concurrent or 
historical control group. 
 
2. Any findings from clinical or epidemiological studies, analysis of data pooled 
across multiple studies, published or unpublished scientific papers, or from 
animal or in vitro testing that would result in a safety-related change in the 
protocol, informed consent, investigator brochure, or other aspects of the 
overall conduct of the trial will be reported. 
Expedited safety reports must be reported by DAIT/NIAID to the appropriate health 
authorities within 15 calendar days; fatal or immediately life-threatening, serious, 
unexpected, suspected adverse reactions must be reported within 7 calendar days.  
 
All principal investigators must report SAEs to their respective IRBs or ethics review 
committees as mandated by them. 
 
Final Study Report:  A complete summary of safety information (including both 
Standard and Expedited reports as defined above) is included in the final study report 
to be submitted to both US FDA and Health Canada at the closure of the protocol. 
8.6.3  Reporting SAEs to the DSMB 
The NIAID and ITN will provide the DSMB with data of all SAEs on an ongoing 
basis, including quarterly reports of all SAEs. 
8.6.4  Reporting Pregnancy  
The principal investigator should be informed immediately of any pregnancy and all 
available pregnancy information should be entered into the electronic data capture 
(EDC) system within 24 hours of becoming aware of the event. The investigator 
should counsel the participant and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. Monitoring of the participant should continue 
until the conclusion of the pregnancy. Follow-up information detailing the outcome of 
the pregnancy should be entered into the EDC system as it becomes available. Any 
premature termination of the pregnancy will be reported.  
Pregnancies are tracked as SAEs for tracking purposes only. Any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE or SAE as described in sections 8.4 and 8.6, respectively.  
9.  
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
9.1  ANALYSIS SAMPLES  
Intent to treat (ITT) sample will be defined as all participants who are found to be 
eligible after the initial 12 week lead-in period and undergo random assignment. 


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Per protocol (PP) sample will be defined as treated participants in the ITT sample 
who receive study regimen, as defined below, until 39 weeks: 
 
 Receive 2 injections of ustekinumab during lead-in period. 
 Receive 2 injections of ustekinumab or ustekinumab placebo during the treatment 
period. 
 Receive at least 24 of the 28 abatacept or abatacept placebo injections prescribed. 
 
Safety sample (SS) will be defined as all participants who receive at least one dose of 
study treatment after enrollment into the study. 
9.2  ANALYSIS OF ENDPOINTS 
9.2.1  Drop-Outs 
The analysis of the primary and secondary endpoints will treat subjects who drop out 
of the study prior to week 88 as having experienced a psoriasis relapse at the time of 
study withdrawal. Sensitivity analyses will be performed to assess the effect of the 
drop-out assumptions on the analysis results by repeating the primary endpoint 
analysis but with different assumptions applied to the drop-out subjects. The primary 
endpoint analysis will be repeated, but with drop-out subjects assumed to have not 
experienced a psoriasis relapse at the time of study withdrawal, and with drop-out 
subjects as having a missing psoriasis relapse status. 
9.2.2  Primary Endpoint 
The proportion of participants who experience a psoriasis relapse at any evaluation 
between week 12 and week 88, as defined in section 3.3.1, will be analyzed for the 
ITT and PP samples using a logistic regression model with the participant’s relapse 
status (relapse or no relapse) as the dependent variable and treatment as the 
independent variable. PASI score at Visit 0 (12-20 or >20) will be used as a covariate 
in the logistic regression model due to the inclusion of this variable as a stratification 
factor in the randomization.  The ITT sample analysis will be the primary endpoint.  
 
The duration of disease prior to screening (i.e. time from onset of psoriasis to 
screening visit) will also be used as an additional covariate in the logistic regression 
model. 
9.2.3  Secondary Endpoints 
 The proportion of participants who experience a psoriasis disease relapse at any 
evaluation between week 12 and week 40, as defined in section 3.3.2, will be 
analyzed for the ITT and PP samples using a logistic regression model similar to 
the one used in the primary endpoint analysis. 
 The proportion of participants who experience a psoriasis disease relapse at any 
evaluation between week 28 and week 88, as defined in Section 3.3.2, will be 
analyzed for the ITT and PP samples using a logistic regression model similar to 
the one used in the primary endpoint analysis.  Due to inherent bias, caution will 
be exercised in interpreting the results. 


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 The proportion of participants who experience a psoriasis disease relapse at any 
evaluation between week 40 and week 88, as defined in section 3.3.2, will be 
analyzed for the ITT and PP samples using a logistic regression model similar to 
the one used in the primary endpoint analysis.  Due to inherent bias, caution will 
be exercised in interpreting the results. 
 The length of time until psoriasis relapse, as defined in section 3.3.2, in the 
intervals from week 12 to 40 and from week 12 to 88 will be analyzed for the ITT 
and PP samples using a survival analysis model. The exact time of relapse will not 
be known precisely. It will only be known to have occurred at some point since 
the previous evaluation visit. Thus, the grouped survival model [78, 79] will be 
applied using a logistic regression approach. The same covariates as described 
above will be included. The predicted survival curves for the 2 treatment 
sequences will be derived from this model. 
 The proportions of participants who are classified as cleared or minimal in the 
PGA score at week 40 and at week 88, as defined in section 3.3.2, will be 
analyzed for the ITT and PP samples using a logistic regression model similar to 
the one used in the primary endpoint analysis. The participant’s PGA score (0 or 1 
vs. 2+) will be the dependent variable in the model.  PGA scores assessed at the 
follow-up Visit D will not be included in this endpoint, and will be analyzed 
separately (section 9.2.5). 
 The change in Dermatology Life Quality Index (DLQI) at week 40 and at week 
88, as defined in section 3.3.2, will be analyzed for the ITT and PP samples using 
an analysis of covariance model (ANCOVA) with the change in DLQI score as 
the dependent variable, treatment as the independent variable, and baseline DLQI 
score, screening PASI score and disease duration at screening as covariates. 
Table 2 summarizes the samples and analysis week intervals for which each 
secondary endpoint will be analyzed. 


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Table 2 Primary/Secondary Endpoints and Analysis Samples 
Primary / Secondary Endpoints 
Analysis 
Week 
Interval  
ITT  
PP  
SS 
Proportion Psoriasis Relapse 
12 to 88  
X 
X 
 
 
12 to 40  
X 
X 
 
 
28 to 88  
X 
X 
 
 
40 to 88  
X 
X 
 
Time to Psoriasis Relapse 
12 to 40  
X 
X 
 
 
12 to 88  
X 
X 
 
Physician Global Assessment 
12 to 40  
X 
X 
 
 
12 to 88  
X 
X 
 
Dermatology Life Quality Index 
12 to 40  
X 
X 
 
 
12 to 88  
X 
X 
 
Safety Analysis 
12 to 88  
 
 
X 
 
9.2.4  Safety Analysis 
Descriptive analysis will be performed on the safety sample. AEs collected at the 
follow-up Visit D will not be included in the safety analysis, and will be analyzed 
separately (section 9.2.5). Following standard ITN practice, safety information will 
not be imputed. 
 
Safety will be analyzed in each treatment group through the reporting of AEs, vital 
signs, physical examinations, and changes in routine laboratory values. 
All AEs will be classified by body system and preferred term, according to a 
standardized thesaurus:  Medical Dictionary for Regulatory Activities (MedDRA). 
The severity of AEs will be classified using the NCI-CTCAE toxicity scale. The total 
number of events and the number of participants experiencing AEs will be 
summarized by body system and preferred term for each treatment group and overall.  
 
Adverse events will also be summarized by maximum severity and relationship to the 
study drug for each treatment group and overall. Separate data listings will be 
provided for serious AEs, treatment-related AEs and AEs leading to study 
discontinuation. 
 
Abnormal vital signs, physical examinations results, and laboratory values that are 
deemed clinically significant by the investigators will be graded by the NCI-CTCAE 
toxicity scale and reported as AEs. 
 
For each treatment group and overall, physical examination results will be 
summarized by body system and visit. 


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Descriptive statistics of laboratory values and the change from baseline of laboratory 
values will be presented for each treatment group and overall. Laboratory 
measurements include serum chemistry, urinalysis and hematology. 
9.2.5  Follow-up Visit Analysis 
A separate descriptive analysis will be performed on the data collected at the follow-
up visit D (AEs, PGA scores, and concomitant medications). 
9.2.6  Medical History 
Medical history within the past 12 months—including the existence of current signs 
and symptoms—will be collected for each body system. 
9.2.7  Use of Medications 
All medications taken by or administered to study participants beginning 30 days 
before enrollment and continuing throughout the study will be collected. All 
medications used will be coded according to the World Health Organization (WHO) 
drug dictionary. The number and percentage of participants receiving prior and 
concomitant medications/therapies will be presented overall and by medication class. 
9.3  SAMPLE SIZE  
The required study size is driven by the treatment comparison during the interval from 
Week 12-88. Based on results of  the PHOENIX 1 study [3], 80% of participants 
randomized at week 12 to ustekinumab, and subsequently discontinued from study 
medication at week 40, are expected to relapse by week 88. A rate of 50% relapse is 
expected in participants randomized to abatacept at week 12, for a differential of 30 
percentage points. The type-I error was set to  = .05 (two-sided) and the type-II error 
rate was set to  = 0.20 representing power at 80%. Assuming equal allocation, and 
applying standard techniques for binary outcomes [80], a sample of 39 participants is 
required in each treatment group, for a total of 78 randomized participants. This is 
rounded up to 80 participants. As discussed above in section 9.2.1, drop-outs are 
considered to have relapsed, so there is no need to inflate the sample size to take drop-
outs into consideration. To be eligible for the randomized phase, participants must 
respond to ustekinumab therapy during the lead-in phase. Considering the two 
PHOENIX studies [3, 4], a response rate between 67.9% and 71.1% can be expected 
in this study. Thus, it is anticipated that a total of 80 ÷ 0.679 = 118 participants will be 
enrolled into the study. This is rounded up to 120 participants. To provide some 
protection against incorrect modeling assumptions, the response rate will be 
monitored during the study. If it falls below 67.9%, more participants will be recruited 
to ensure that 80 participants are ultimately randomized at Week 12. This 
notwithstanding, no more than 140 participants will be enrolled into the lead-in phase.    
9.4  REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL 
PLAN 
The principal features of both the study design and the plan for statistical data analysis 
are outlined in this protocol and in the statistical analysis plan (SAP). Any change in 
these features requires either a protocol or an SAP amendment, which is subject to 


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review by the DSMB, the study sponsor(s), and the health authorities. These changes 
will be described in the final study report as appropriate. 
10.  ACCESS TO SOURCE DATA/D
OCUMENTS 
The investigational sites participating in this study will maintain the highest degree of 
confidentiality permitted for the clinical and research information obtained from 
participants in this clinical trial. Medical and research records should be maintained at 
each site in the strictest confidence. However, as a part of the quality assurance and 
legal responsibilities of an investigation, the investigational sites must permit 
authorized representatives of the ITN, sponsor, and health authorities to examine (and 
to copy when required by applicable law) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety and progress. Unless 
required by the laws permitting copying of records, only the coded identity associated 
with documents or other participant data may be copied (and any personally 
identifying information must be obscured). Authorized representatives as noted above 
are bound to maintain the strict confidentiality of medical and research information 
that may be linked to identified individuals. The investigational sites will normally be 
notified in advance of auditing visits. 
11.  QUALITY CONTROL AND QUALITY ASSURANCE 
The principal investigator is required to keep accurate records to ensure that the 
conduct of the study is fully documented. The principal investigator is required to 
ensure that all eCRFs are completed for every participant entered in the trial. 
The sponsor is responsible for regular inspection of the conduct of the trial, for 
verifying adherence to the protocol, and for confirming the completeness, consistency, 
and accuracy of all documented data. 
 
The eCRFs will be completed online via a web-based EDC system that has been 
validated and is compliant with Part 11 Title 21 of the Code of Federal Regulations. 
Some data requirements will be addressed outside the EDC using statistical analysis 
system ( SAS
®) software. Data queries will be issued and resolved within the EDC 
system or SAS
®. 
 
Study staff at the site will enter information into the electronic CRFs, and the data will 
be stored remotely at a central database. Data quality will be ensured through the EDC 
system’s continuous monitoring of data and real-time detection and correction of 
errors. All elements of data entry (i.e. time, date, verbatim text, and the name of the 
person performing the data entry) will be recorded in an electronic audit trail to allow 
all changes in the database to be monitored and maintained in accordance with US and 
Canadian regulations.  
 
Study staff will enter data from a study visit on the relevant eCRFs within 3 days 
following the visit or the time when data become available. 
 
Skin photographs will be transferred to the SDCC using a secure file transfer process 
and stored in a password-protected environment. 


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12.  ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
12.1  STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, current GCP guidelines 
— adopting the principles of the Declaration of Helsinki — and all applicable 
regulatory requirements. 
 
Prior to study initiation, the protocol and the informed consent documents will be 
reviewed and approved by the sponsor and the appropriate health authorities and 
ethics review committee or institutional review board (IRB). Any amendments to the 
protocol or consent materials must also be approved by the Sponsor, the IRB or ethics 
review committee, and submitted to FDA before they are implemented in the US.  
Amendments in Canada must be approved by the relevant ethics committees and 
Health Canada before being implemented. 
12.2  INFORMED CONSENT 
The informed consent form is a means of providing information about the trial to a 
prospective participant and allows for an informed decision about participation in the 
study. All participants must read, sign, and date a consent form before participating in 
the study, taking the study drug, and/or undergoing any study-specific procedures. If a 
participant does not speak and read English, the consent materials must be translated 
into the appropriate language. 
 
The informed consent form must be updated or revised whenever important new 
safety information is available, whenever the protocol is amended, and/or whenever 
any new information becomes available that may affect participation in the trial. 
 
A copy of the informed consent will be given to a prospective participant for review. 
The study investigator, in the presence of a witness, will review the consent and 
answer questions. The participant will be informed that participation is voluntary and 
that he/she may withdraw from the study at any time, for any reason. 
12.3   PRIVACY AND CONFIDENTIALITY 
A participant’s privacy and confidentiality will be respected throughout the study. 
Each participant will be assigned a sequential identification number. This number, 
rather than the participant’s name, will be used to collect, store, and report participant 
information. 
13.  PUBLICATION POLICY 
The ITN policy on publication of study results will apply to this study. Authorized 
participants may find details regarding the policy statement on the ITN internet 
website at http://www.immunetolerance.org.  
 


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