Clinical trial NCT02980692
Conditions: Active Psoriatic Arthritis
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2017-04-19; Completion date: 2019-09-24
Enrollment: 391 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, multiple-dose, phase 2b study to demonstrate the safety and efficacy of SUNPG1623

Detailed description:

Arms: arm 1: low range dose arm 2: mid range dose arm 3: mid range dose arm 4: mid range dose to high dose arm 5: mid range dose to high dose
Interventions: intervention 1: SUNPG1623 I intervention 2: SUNPG1623 II intervention 3: SUNPG1623 III intervention 4: SUNPG1623 IV intervention 5: PLACEBO
Intervention descriptions: intervention 1: injection intervention 2: injection intervention 3: injection intervention 4: injection intervention 5: injection

Protocol documents:
Prot_002.pdf: 
 
 
 
 
Study title: 
 A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Phase 2b 
Study to Demonstrate the Safety and Efficacy of Tildrakizumab in Subjects with Active 
Psoriatic Arthritis 
Document:  
Clinical Study Protocol 
Version number: 
v4.0 Final 
Date:  
16 Mar 2018 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
Protocol CLR_16_23 
(Final) 
Page 1 of 98 
1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Phase 2b Study to 
Demonstrate the Safety and Efficacy of Tildrakizumab in Subjects with Active Psoriatic 
Arthritis 
Protocol No.:  CLR_16_23 
EUDRACT No.:  2016-003937-62 
Test Product: 
Tildrakizumab 
Indication: 
Treatment 
of 
Adult 
Subjects 
with 
Active 
Psoriatic Arthritis 
Sponsor: 
Sun Pharma Global FZE 
Office at #43, Block Y SAIF Zone 
Sharjah, 122304 
United Arab Emirates 
Development Phase: 
Phase 2b 
Sponsor Signatory: 
Patrick Burnett, M.D., Ph.D. 
2 Independence Way 
Princeton 
NJ 08540 
Sponsor Medical Expert: 
Patrick Burnett, M.D., Ph.D. 
2 Independence Way 
Princeton 
NJ 08540 
Date of the Protocol: 
16 Mar 2018 
Version of the Protocol: 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator, or consultant for review by you, your staff, and applicable Independent Ethics 
Committee and/or Institutional Review Board.  It is understood that the information will not be 
disclosed to others without written authorization from Sun Pharma Global FZE except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. 


Sun Pharma Global FZE 
Tildrakizumab 
2 
SIGNATURE PAGES 
CONFIDENTIAL 
16 Mar 2018 
 
SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, 
Phase 2b Study to Demonstrate the Safety and Efficacy of Tildrakizumab in Subjects with 
Active Psoriatic Arthritis 
PROTOCOL NUMBER: CLR 16 23 
Sun Pharma Global FZE 
Protocol CLR 16 23 
 
(Final) 
Page 2 of98 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
Page 3 of 98 
 
3 
GENERAL INFORMATION 
A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Phase 2b Study to 
Demonstrate the Safety and Efficacy of Tildrakizumab in Subjects with Active Psoriatic 
Arthritis 
Protocol No.: 
CLR_16_23 
Date of the Protocol: 
 
Date and Number of Amendment(s): 
 
 
 
 
 
 
 
Sponsor: 
Sun Pharma Global FZE 
 
Office at #43, Block Y SAIF Zone 
 
Sharjah, 122304 
 
United Arab Emirates 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Signatory: 
Patrick Burnett, M.D., Ph.D. 
 
2 Independence Way 
 
Princeton 
 
NJ 08540 
 
Tel No.: +1 (609) 480 2902 
 
  
 
 
 
 
 
 
 
 
 
 
Sponsor Medical Expert: 
Patrick Burnett, M.D., Ph.D. 
 
2 Independence Way 
 
Princeton 
 
NJ 08540 
 
Tel No.: +1 (609) 480 2902 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
Page 4 of 98 
 
4 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Phase 2b Study to Demonstrate the Safety and 
Efficacy of Tildrakizumab in Subjects with Active Psoriatic Arthritis 
Study Centers: 
The study will be multinational and performed in approximately 100 study centers. 
Publication(s): 
None. 
Planned Study Period: 
Apr 2017 to Sep 2019 
Development Phase: 
Phase 2b 
Objectives: 
Primary Efficacy Objective: 
Parts 1 and 2 
• 
To evaluate the optimal dose regimen of tildrakizumab in subjects with psoriatic arthritis (PsA) as measured by 
the proportion of subjects achieving a 
 from Baseline in American College of Rheumatology 
response criteria [ACR
]) at 
 
 
Primary Safety Objective: 
Parts 1 and 2 
• 
To assess the safety/tolerability and immunogenicity of multiple-dose administration of tildrakizumab in 
subjects with PsA. 
 
Secondary Objectives: 
Parts 1 and 2 
• 
To evaluate the effect of tildrakizumab on ACR
 at 
; and ACR
, ACR
, the components of ACR,  
Disease Activity Score (DAS)28(joints)-C-reactive protein (DAS28-CRP), minimal disease activity (MDA), 
dactylitis and enthesitis, and the Health Assessment Questionnaire Disability Index (HAQ-DI) at 
 
 
• 
To characterize the pharmacokinetics (PK) of tildrakizumab in subjects with PsA. 
 
Exploratory Objectives: 
Parts 1 and 2 
• 
To develop a mechanistic-based exposure-response (i.e. indirect) PK/pharmacodynamics (PD) model to explore 
the relationship of tildrakizumab exposure and ACR response. 
• 
To evaluate the effect of tildrakizumab on Psoriasis Area and Severity Index (PASI) 75/90/100 response rates at 
measured time points for subjects with moderate disease 
 
 
• 
To assess the effect of tildrakizumab on the 36-item Short Form (SF-36) health survey at measured time points. 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
Page 5 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
• 
To evaluate the effect of tildrakizumab on the PsA Impact of Disease (PsAID) questionnaire at measured time 
points. 
• 
To assess the effect of tildrakizumab on ACR
, ACR
, ACR
, the components of ACR, DAS28-CRP, 
MDA, Leeds Dactylitis Index (LDI), and Leeds Enthesitis Index (LEI) at other measured time points. 
 
Part 3 
• 
Assess the effect of the investigational medicinal product (IMP) discontinuation on ACR
, ACR
, ACR
, 
the components of ACR, LDI, LEI, PASI, and HAQ-DI 
• 
Evaluate immunogenicity following IMP discontinuation 
• 
Determine population PK parameters following IMP discontinuation 
Methodology: 
This is a randomized, double-blind, placebo-controlled, multiple-dose, Phase 2b study.  The study will be 
multinational and performed in approximately
 study centers.  At least 
 
 
 
 
 
 
 
 
 
  
 
  On completion of 
 subjects may enter the 
 
 providing they meet the inclusion/exclusion criteria for the
 and the Investigator deems they 
would benefit from continued treatment with tildrakizumab.  In circumstances where the LTE study site activation 
has not occurred at the time the subject reaches the end of Part 2, they may enter from Part 3 if the required 
eligibility conditions are met. 
Randomization will be stratified by prior anti-tumor-necrosis factor (TNF) use 
and Baseline body weight 
  Subjects with prior anti-TNF use will be 
 of the total number of 
subjects. 
Subjects who fail to show minimal response to treatment 
 
 may have their background medications adjusted according to the 
maximum permitted daily dose 
 and continue in the study.  Any subject requiring 
these adjustments will be counted as a non-responder for the primary analysis.  Criteria for other endpoints are 
included in the statistical analysis plan (SAP). 
Subjects who show clinical response to treatment 
 
 
  Subjects receiving tildrakizumab 
 
during Part 1 who fail to show clinical response to treatment at 
 will be 
discontinued from the study drug and will enter Part 3 to receive treatment according to the Investigators’ discretion.  
Subjects receiving 
 who fail to show clinical response to treatment at 
 will enter 
  Subjects in Part 2 who are 
not deriving sufficient clinical benefit in the opinion of the Investigator at any time after 
 should be 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
Page 6 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
discontinued from study drug and enter Part 3 so that they may receive additional treatment as determined by the 
Investigator. 
Subjects discontinued from IMP at any time (apart from withdrawal of informed consent) will be required to 
complete the 
 assessment a 
 and e
 
  Subjects who withdraw from the study during Part 3 will undergo the 
 
assessments 
. 
The primary endpoint is the ACR
 response rate at 
  Secondary efficacy endpoints will include ACR
, 
ACR
 response rates, and the components of ACR response; proportion of subjects who require adjustment of 
background therapy; proportion of subjects who achieve a DAS28-CRP
 proportion of subjects who achieve 
MDA criteria; LDI and LEI change from Baseline; and HAQ-DI change from Baseline.  The PK and 
immunogenicity of tildrakizumab will also be evaluated. 
All sites will have an independent assessor to conduct the tender and swollen joint count, LDI, LEI and PASI 
assessments.  The independent assessor would not be involved in the care of subjects and would not discuss disease 
activity or the treatment with subjects or the Principal Investigator (PI)/designee responsible for performing other 
efficacy and safety evaluations. 
Following the last subject’s
 
. 
A Data Safety Monitoring Board (DSMB) will be established for periodic review of safety data for this study, and a 
Clinical Adjudication Committee will be established to evaluate cardiovascular events. 
The EoS is defined as the last visit of the 
) of the last global subject. 
This study will be conducted in compliance with the protocol and with the International Council for Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical 
Practice (GCP). 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
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Protocol CLR_16_23 
 
(Final) 
 
Page 7 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
 
 
 
Number of Subjects: 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
Page 8 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
Diagnosis and Main Criteria for Inclusion: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
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Protocol CLR_16_23 
 
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Page 9 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
Page 10 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 Version 4.0 
(Final) 
 
Page 11 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
Test Product, Dose and Mode of Administration: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference Therapy, Dose and Duration of Administration: 
 
 
 
 
 
 
Concomitant Medications, Supportive Care, and Study Restrictions: 
Concomitant medications limited throughout the study 
 
• 
Analgesics: Acetaminophen may be used by the subject PRN except within 
 before a scheduled study 
efficacy evaluation. 
Concomitant medications will be limited during Part 1 of the study 
 as follows: 
• 
NSAIDs or low-potency opioids: For subjects receiving NSAIDs or low-potency opioids (including PRN use): 
the subject must be on a stable dose for 
 prior to initiation of IMP and be expected to maintain a stable 
dose for the 
 of the study, unless change in dosage is required due to toxicity.  Stable dose 
(including PRN use) is defined as subjects taking an NSAID or low-potency opioids on 
 per 
. 
• 
Corticosteroids: Subjects taking oral corticosteroids (not to exceed the equivalent of 
 
 must remain on a stable dose.  Subjects who were using topical corticosteroids when they enrolled under 
 
• 
Disease-modifying anti-rheumatic drugs (DMARDs): Subjects taking either MTX 
) 
or leflunomide 
must remain on a stable dose, unless a decrease in dose is required 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
Page 12 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
because of toxicity or intolerance.  Oral MTX cannot be changed to parenteral dosing during the period of 
observation.  Subjects may not use a combination of MTX and leflunomide. 
Tapering of any of these concomitant medications during the study is allowed only if there is toxicity (accompanied 
by recording of an adverse event [AE] on the electronic Case Report Form); otherwise the dosage must remain the 
same throughout Part 1 of the study.  Adjustment of these concomitant medications is permitted throughout Part 2 
 as needed per Investigator discretion and therapeutic needs of the subject, or if the subject does not 
show minimal response to treatment 
 
 
For subjects receiving non-drug therapy (including but not limited to physical therapy, massage, diet, exercise, 
emollients, and joint taping), this must be stable for the 
 prior to IMP initiation through to the end of 
Part 1. 
Duration of Treatment: 
. 
Variables: 
Efficacy:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
− 
A 
 
 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_23 Version 4.0 
(Final) 
 
Page 13 of 98 
 
Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
Pharmacodynamics:   
Incidence of anti-drug antibodies (ADA) and correlations with safety and efficacy endpoints will be investigated 
(
 
Safety:  The following data will be collected for assessment of safety: 
• 
AEs 
• 
Laboratory assessments 
• 
Suicidal ideation and behavior (C-SSRS) 
• 
Vital signs 
• 
Electrocardiogram 
• 
Physical examination 
• 
ADA to tildrakizumab, including titer and neutralizing antibodies 
Statistical Methods: 
Sample Size: 
 
 
 
  Results are 
based on simulations incorporating the use of the 
 the composite hypothesis that the 
response rate for all 
 is not significantly different from placebo versus the alternative 


Sun Pharma Global FZE 
CONFIDENTIAL 
16 Mar 2018 
Tildrakizumab 
 
 
 
Protocol CLR_16_23 
 
(Final) 
 
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Name of Sponsor/Company: 
Sun Pharma Global FZE 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Tildrakizumab 
Name of Active Ingredient: 
Tildrakizumab 
hypothesis that
 has a response rate significantly greater than that of 
placebo.  This is the primary hypothesis test for this study.  
Statistical Analysis: 
The primary efficacy analysis population will be the Full Analysis Set (FAS) defined as all randomized subjects who 
have received at 
 of IMP.  The primary analysis will be based on the Cochran-Mantel-Haenszel test, 
incorporating prior anti-TNF use and Baseline weight as stratification factors, to compare response rates for the 
primary endpoint 
 between placebo and each of the respective active dose arms.  In addition, 
the 
)
 
  In order to control for 
, the 
 
.  Should assumptions per the 
 not be satisfied, pairwise comparisons will be based on 
 
  In this case, 
 
  Early withdrawals with incomplete data will be classified as 
for the 
primary endpoint (ACR
).  Subjects who fail to show minimal response to treatment
 
 
 
  Any subject requiring these adjustments will be counted as a non-responder for the primary analysis. 
All secondary efficacy endpoints will be analyzed using the FAS.  
 
 
 
   
Exploratory endpoints up to 
 will be analyzed based on methods described for secondary endpoints using 
the FAS.  
 the effect of IMP discontinuation on ACR
, ACR
, ACR
, the components of 
ACR, LDI, LEI, PASI, and HAQ-DI will be evaluated using summary statistics. 
Safety endpoints will be analyzed descriptively based on the Safety Analysis Set, defined as all subjects who 
received 
. Subjects will be summarized based on the actual treatment they received.  
A DSMB will be established for periodic review of safety data for this study. 
Following the 
, an
 will be conducted on all available data to 
evaluate the primary efficacy outcome. 
Date of the Protocol:  16 Mar 2018 


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Protocol CLR_16_23 
 
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5 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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(Final) 
 
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5.1 
List of Tables 
 
 
 
 
 
5.2 
List of Figures 
 
 
 
 
 
 


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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
%CV 
coefficient of variation 
ACR
 
American College of Rheumatology (the proportion of subjects 
achieving a 
 reduction from 
 in response criteria) 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Class 
AUC 
area under the curve 
BSA 
body surface area 
β-hCG 
beta human chorionic gonadotropin 
CAC 
Clinical Adjudication Committee 
CASPAR 
Classification of Psoriatic Arthritis 
CI 
confidence interval 
CO2 
carbon dioxide 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DAS(28-CRP) 
Disease Activity Score(28 [joints]-C-reactive protein) 
DIP 
distal interphalangeal 
DMARD 
disease-modifying anti-rheumatic drug 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EC50 
effective concentration at 50% of Emax 
ECI 
events of clinical interest 
EDC 
electronic data capture 
ED50 
median effective dose (for population) 
Emax 
maximum drug effect 
EoS 
End of Study 
EoT 
End of Treatment 
ESR 
erythrocyte sedimentation rate 
EUDRACT 
European Union Drug Regulatory Agency Clinical Trial 


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FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HLA 
human leucocyte antigen 
HAQ 
Health Assessment Questionnaire 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
hsCRP 
high sensitivity C-reactive protein 
IA 
interim analysis 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
ICH 
International Council for Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IL 
interleukin 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS 
interactive voice response system 
kg 
kilogram 
LDI 
Leeds Dactylitis Index 
LEI 
Leeds Enthesitis Index 
LTBI 
latent tuberculosis infection 
LTE 
long-term extension 
MACE 
Major Adverse Cardiovascular Events 
MCP 
metacarpophalangeal 
MDA 
minimal disease activity 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
MMRM 
mixed model repeated measure 
MTX 
methotrexate 
NOAEL 
no-observed-adverse-effect-level 
NSAIDs 
non-steroidal anti-inflammatory drugs 
PA 
posterior-anterior 
PASE 
Psoriatic Arthritis Screening and Evaluation 


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PASI 
Psoriasis Area and Severity Index  
PD 
pharmacodynamic 
PFS 
pre-filled syringe 
PGA 
Physician Global Assessment 
PI 
Principal Investigator 
PIP 
proximal interphalangeal 
PK 
pharmacokinetic 
pM 
picomolar 
PPAS 
Per Protocol Analysis Set 
PQC 
product quality complaint 
PRN 
as needed (pro re nata) 
PsA 
psoriatic arthritis 
PsAID 
PsA Impact of Disease 
PsO 
psoriasis 
PT 
prothrombin time 
PtGA 
Patient Global Assessment 
q 
every 
QA 
quality assurance 
QTcB 
QTc corrected according to Bazetts’ formula 
QTcF 
QTc corrected according to the Fridericia formula 
RA 
rheumatoid arthritis 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
standard deviation 
SF-36 
36-item Short Form 
SIB 
suicidal ideation and behavior 
SOP 
Standard Operating Procedure 
T1/2 
half-life  
TB 
tuberculosis 
TEAE 
Treatment-emergent adverse event 
Tmax 
time of maximal concentration 
TNF 
tumor necrosis factor 
TU 
tuberculin units 
ULN 
upper limit of normal 


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VAS 
Visual Analog Scale 
WBC 
white blood cells 
WHO 
World Health Organization 


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7 
INTRODUCTION 
7.1 
Background 
Psoriasis (PsO) is a chronic inflammatory skin disorder affecting approximately 
 of 
people worldwide.1  Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis 
associated with PsO.  The precise prevalence is unknown, but estimates vary from 0.3% to 1% of 
the population; among patients with PsO the observed prevalence of inflammatory arthritis varies 
from 
  The clinical features typically present as an oligoarticular and mild disease.  
However, with time PsA becomes polyarticular, and it is a severe disease in at least 
of 
patients.2  Symptoms include tenderness, pain and stiffness in and around the joints, dactylitis, 
spondylitis, pain and swelling in the heels, nail disfiguration (discoloration, splitting, or pitting), 
and generalized fatigue
  Patients with PsA who present with polyarticular disease are at risk 
for disease progression.  In addition to progression of clinical and radiological damage, health 
related quality of life is reduced among patients with PsA  
PsA is classified with the spondyloarthropathies because of the presence of spondylitis in up to 
, the occurrence of extra-articular features common to the spondyloarthropathies 
(mucous membrane lesions, iritis, urethritis, diarrhea, aortic root dilatation), and association with 
human leucocyte antigen [HLA]-B27.  PsA may be distinguished from the other 
spondyloarthropathies by the presence of peripheral arthritis, asymmetrical distribution of the 
spinal involvement (both sacroiliac joints and syndesmophytes), lower level of pain, and 
limitation of movement.  Several clinical features help distinguish PsA from rheumatoid arthritis 
(RA).  Although RA is more common in women, PsA occurs just as frequently in both sexes.  
The specific clinical features of PsA include the involvement of distal joints.  Joint distribution 
tends to occur in a ray pattern so that all the joints of a single digit are more likely to get affected 
than the same joints on both sides (which is typical of RA).  The deformities that result from PsA 
lead to shortening of digits because of severe joint or bone lysis, with the most severe form being 
the telescoping of digits.2 
Current treatment choices for PsA include non-steroidal anti-inflammatory drugs (NSAIDs), 
corticosteroids, topical treatments (for skin), light therapy (for skin), physiotherapy, and 
disease-modifying anti-rheumatic drug (DMARDs).3,5  
 
 
 
 
ethotrexate (MTX) is approved by the U.S. Food 
and Drug Administration (FDA) for the skin condition PsO, but it is frequently used off-label for 
PsA.  Methotrexate has been reported as providing symptomatic relief to some patients with 
multiple joint involvement and PsO but there is little scientific evidence to support the use as a 
disease-modifying agent for PsA.5 


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From animal studies and human disease association studies, there is significant evidence that 
IL-23 is a key pro-inflammatory cytokine in PsO and some other inflammatory diseases.  Strong 
support for the relevance of the IL-23 pathway in PsO and some other inflammatory diseases has 
come from recent genome-wide association studies identifying a certain single nucleotide 
polymorphism in the gene coding for IL-23R to be less frequent in patients with PsO and some 
other inflammatory diseases.1 
 
 
 
 
7.2 
Rationale 
Tildrakizumab is being developed for chronic plaque PsO, and Phase 3 studies have recently 
been unblinded, with subjects continuing in the long-term open-label extension.  In the Phase 2b 
study 
for PsO, all 
 
 were demonstrated to 
be safe and more efficacious than placebo 
 
  These data are considered relevant to the PsA development 
program considering PsO and PsA are highly related conditions with a shared pathophysiology, 
and the 2 conditions commonly present in the same patient.  
 
 
 Arthritis 
Screening and Evaluation (PASE), and Health Assessment Questionnaire (HAQ).  
 
 
 
 
 
 
 
  
 
  
 
 
 
Further information relating to efficacy and safety data from clinical trials of tildrakizumab is 
available in the Investigator’s Brochure.1 
7.2.1 
Rationale for Dose 
 
 


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The dosing regimens in this study cover approximately a 
 from a suboptimal dose 
 
 to the anticipated maximally effective dose
) based 
on pharmacokinetic (PK) and pharmacodynamic (PD) modeling. 
Data from Phase 1 studies and the Phase 2b study in PsO patients were incorporated into a 
population PK model.  The Phase 1 study 
) had PK data available from 
 with 
  
  
 
 
 
The PK model that describes tildrakizumab after SC administration is 1-compartmental, with 
first-order absorption and elimination.  Significant covariates were an effect of weight on 
clearance and volume of distribution and an age effect on clearance. Using the individual 
Bayesian estimates, the simulated mean plasma concentrations of tildrakizumab at the proposed 
doses were determined.  From these simulated profiles, a dose-dependent relationship with 
tildrakizumab exposure is anticipated.  Therefore, the 
 separation between each of 
the doses is anticipated to result in appropriate separation of the observed exposures. 
A PK-PD model was subsequently developed, incorporating an indirect-effect maximum drug 
effect (Emax) model.  Sequential PK-PD analysis of the clinical response data from 
 
 yielded estimates of the PD parameters including the effective concentration at 
  Utilizing the individual subject PK parameters yielded the predicted
 
  The 
longitudinal model of PASI reduction utilized an exposure-related suppression of plaque 
formation in an indirect-effect model, together with a placebo-effect on plaque degradation that 
represented the healing process.  
 
  The simulations incorporated PK variability, within- and 
between-subject variability in PASI response, and model uncertainty.  Per arm, the percentage of 
PASI75 responders was tabulated.  
 
 
 


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. 
Based on the predicted ED50, the proposed doses are selected to cover the relevant range 
spanning from a low dose (
 
Considering the significant overlap in effective doses for PsO and PsA observed with 
tildrakizumab and related monoclonal antibodies (e.g., ustekinumab, secukinumab, etanercept, 
and adalimumab), these dose-response curves may be predictive of the clinical response in PsA 
subjects.  
 
 
 
 
.  Together, these doses cover a 
roughly 
 and are anticipated to define the critical areas of the dose-response curve, 
thereby enabling selection of a dose with the optimal benefit:risk profile to be carried into 
Phase 3 studies in subjects with PsA. 


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7.2.2 
Rationale for Study 
The IL-23/IL-17 axis has been studied in PsA and both cytokines are implicated in PsA disease 
activity.  In view of the efficacy of ustekinumab 
 in PsA 
 
 
 
 
  Furthermore, by not blocking 
IL-12, it is anticipated that tildrakizumab may potentially avoid adverse effects on cell-mediated 
immunity where IL-12 has an important role. 
This will be the first study conducted with tildrakizumab exclusively in subjects with PsA.  As 
tildrakizumab is in development (Phase 3 ongoing) for the related PsO indication, substantial PK 
and PD data exist that can inform dose selection in PsA, as described.  Under these 
circumstances, the next step for development is to confirm efficacy in the PsA population and 
understand the relationship between dose and clinical response.  Therefore, this Phase 2b study 
will 
.  The tildrakizumab arms and a placebo arm will be 
analyzed at 
 for the primary endpoint (the proportion of subjects achieving a 
 
reduction from Baseline in American College of Rheumatology response criteria 
). 


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8 
STUDY OBJECTIVES 
8.1 
Primary Efficacy Objective 
 
 
 
 
 
 
8.2 
Primary Safety Objective 
 
 
 
 
8.3 
Secondary Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This is a randomized, double-blind, placebo-controlled, multiple-dose, Phase 2b study 
  
The study will be multinational and performed in approximately 
.  
 
 
 
 
 
 
 
 All subjects will 
 
 
 
 
  During the 
wash-out period, subjects will no longer receive tildrakizumab and will be treated according to 
the Investigators’ discretion.  
 
 
 
 
 
 
 
 
 
Subjects who fail to show minimal response to treatment 
 
 
 
  Any subject requiring these adjustments will be counted as a 
non-responder for the primary analysis.  Criteria for other endpoints are included in the statistical 
analysis plan (SAP). 
 
 
  
 
 


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discontinued from the study drug and will enter Part 3 to receive treatment according to the 
Investigators’ discretion.  
 
 
 
should be 
discontinued from study drug as described in 
 and enter 
 so that they may 
receive additional treatment as determined by the Investigator. 
Subjects discontinued from IMP at any time (apart from withdrawal of informed consent) will 
complete the
 
.  Subjects who withdraw from the study during Part 3 will 
undergo the 
 
The primary endpoint is the ACR
 response rate 
.  Secondary efficacy endpoints 
will include ACR
, ACR
 response rates, and the components of ACR response; proportion of 
subjects who require adjustment of background therapy; proportion of subjects who achieve a 
DAS28-CRP
 proportion of subjects who achieve MDA criteria; LDI and LEI change from 
Baseline; and HAQ-DI change from Baseline.  The PK and immunogenicity of tildrakizumab 
will also be evaluated. 
All sites will have an independent assessor to conduct the assessments detailed in 
  
The independent assessor would not be involved in the care of subjects and would not discuss 
disease activity or the treatment with subjects or the Principal Investigator (PI)/designee 
responsible for performing other efficacy and safety evaluations. 
Following the last subject’s 
 visit (or early termination prior to 
), an interim 
analysis (IA) will be conducted on all available data to evaluate the primary efficacy outcome 
(
 
A Data Safety Monitoring Board (DSMB) will be established for periodic review of safety data 
for this study, and a 
 will be established to evaluate 
cardiovascular events 
 
The EoS is defined as the last visit of the 20-week wash-out period (EoS visit) of the last global 
subject. 
This study will be conducted in compliance with the protocol and with the International Council 
for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) guidelines on Good Clinical Practice (GCP). 


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9.1.2 
Schedule of Assessments 
 
 


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9.1.2.1 
Blood Samples for Determination of Anti-Drug Antibodies  
A sample of blood to obtain sufficient serum for ADA determination will be collected prior to 
IMP administration at the specified time points in 
  The sample will be 
collected into the appropriate tubes (see the laboratory manual for sample volumes, acquisition, 
shipping and labeling instructions).  Sample collection times are to be recorded on the electronic 
Case Report Form (eCRF). 
Sample collection time deviations will be determined by the Sponsor using the actual collection 
times provided and do not need to be recorded in the eCRF.  However, any other deviation (e.g., 
missed sample, broken sample, inappropriate sample handling, etc.) must be recorded on the 
comments page of the eCRF. 
9.1.2.2 
Blood Samples for Determination of Serum Concentrations of Tildrakizumab 
(PK) 
A sample of blood to obtain sufficient serum for PK assessment will be collected prior to IMP 
administration at the specified time points indicated in 
  The sample 
will be collected into the appropriate tubes (see the laboratory manual for sample volumes, 
acquisition, shipping, and labeling instructions).  Actual sample collection times are to be 
recorded on the eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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alysis), 
aterials supplied by 
9.1.3.5 
Unscheduled Visits 
An unscheduled visit is defined as any visit to the Investigator site where the subject is seen by 
study personnel outside of the protocol-specified time points, due to safety reasons or when a 


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repeated measurement is required 
 
 
All unscheduled visits and assessments performed during the visits will be recorded in the 
subject’s eCRF.  During any unscheduled visits the Investigator will record any AEs and 
concomitant medications as well as performing any assessments or collecting samples deemed 
necessary at the discretion of the Investigator. 
9.2 
Discussion of Study Design 
This is a randomized, double-blind, placebo-controlled, multiple-dose, Phase 2b study to 
evaluate the efficacy of 4 dose groups of tildrakizumab administered by SC injection in subjects 
with active PsA.  The study has been developed based on design features used in the completed 
 as well as 
 
  The primary efficacy endpoint is based on the proportion of subjects achieving ACR
 
response criteria at 
 which has been well established for the evaluation of clinical 
outcome.  Secondary efficacy endpoints are based on evaluation of other measures of ACR 
(ACR
 and ACR
), the proportion of subjects requiring adjustment of background 
medication, DAS28-CRP, MDA, dactylitis and enthesitis, and HAQ-DI, which are all accepted 
measures for the evaluation of clinical outcome. 
The study has been designed with 4 distinct phases (Screening, double-blind treatment period, 
double-blind follow-up, and a wash-out period).  This enables scientific evaluation of efficacy at 
 longer term evaluation of efficacy and safety through 
 and ensures subject 
safety via a monitored wash-out period for subjects who do not enter the LTE study.  All safety 
measures are consistent with evaluations used in clinical studies and previous studies with 
tildrakizumab. 
9.2.1 
Risk/Benefit and Ethical Assessment 
Given that efficacy benefits were reported for subjects with concurrent PsA in the completed 
Phase 2b study in 
 there is an expectation that subjects treated with 
tildrakizumab will improve PsA disease activity and measures of quality of life (HAQ) at 
  However, the study design allows early identification of subjects who have not 
received a minimum level of improvement at 
 to enable the Investigator to remove IMP 
and initiate other treatment at their discretion. 
The study has also been designed to minimize potential risks to subjects; all subjects will 
undergo Screening procedures aimed at reducing the likelihood and impact of any such risks.  In 
addition, regular safety monitoring during the treatment period for all subjects will ensure that 
any unanticipated effects of study participation are identified promptly and managed 
appropriately.  In view of the long half-life (T1/2) of tildrakizumab at doses previously studied, 
subjects who do not enter the LTE study will continue to be monitored throughout a 
 
following the EoT visit, during which no active IMP will be administered. 


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In addition, an independent DSMB will review selected data across the study.  The DSMB in 
conjunction with the Sponsor is empowered to make recommendations regarding continuation, 
termination or modification of the study, as appropriate. 
Overall, based on data from non-clinical and clinical studies of tildrakizumab to date and the risk 
minimization strategies discussed above, the risk:benefit profile of the current study is 
considered acceptable. 
9.3 
Selection of Study Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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6. Subject had myocardial infarction, unstable angina pectoris, or ischemic stroke within the 
past 6 months prior to the first IMP dose. 


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. 
 
 
 
9.3.3 
Strategies for Subject Recruitment and Retention 
All recruitment material will be approved by an Independent Ethics Committee (IEC) or 
Institutional Review Board (IRB) prior to implementation. 
Regular study monitoring will enable identification of any potential issues related to subject 
retention. 
9.3.4 
Withdrawal of Subjects 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs when a subject does not want to participate in the study anymore 
and does not want to attend any further visits or assessments, have further study-related contact, 
or allow analysis of already obtained biologic material. 
If a subject withdraws consent, the Investigator must make every effort to determine the primary 
reason for this decision and record this information on the treatment disposition eCRF page.  If 
the subject decides to completely withdraw from the study (refuses any further study 
participation or contact), all study participation for that subject will cease and data to be collected 
at subsequent visits will be considered missing.  The IMP must be discontinued and no further 
assessments conducted.  Further attempts to contact the subject are not allowed unless safety 
findings require communication or follow-up. 
However, for safety reasons, 
 assessments should be conducted for subjects 
withdrawing during Part 1 or 2, if the withdrawn subject is willing to undergo the assessments.  
For subjects withdrawing during Part 3 and willing to undergo final assessments, the 
 should be conducted at 
 after their last visit. 
The appropriate personnel from the site and
 will assess whether IMP should be 
discontinued for any subject whose treatment code has been broken inadvertently for any reason. 
The Investigator must also contact the interactive response technology to register the subject’s 
discontinuation from IMP. 


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9.3.5 
Investigational Medicinal Product Discontinuation 
Subjects may voluntarily discontinue IMP for any reason at any time and enter the 20-week 
wash-out period, or completely withdraw from the study 
).  Subjects who 
consent to enter the wash-out period will undergo the 
 
  
At any time during Part 1 or Part 2 of the study, the Investigator should discontinue IMP of a 
given subject if, on balance, he/she believes that continuation would be detrimental to the 
subject’s well-being.  
 
 
 
IMP must be discontinued under the following circumstances and the further steps need to be 
discussed with the medical monitor: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Note: the derivation of clinical response 
 will be made within the IVRS system using information provided by the site.  The 
IVRS system will determine the subject’s eligibility to continue based on treatment received 
during Part 1 of the study. 
 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing may be temporarily suspended in the event of: 
1. Clinically important laboratory abnormalities 
2. Subjects who develop suicidal ideation 


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3. Other intercurrent illnesses or major surgery 
4. Use of prohibited treatment 
5. Any other protocol deviation that results in a significant risk to the subject’s safety 
6. Sponsor decision 
After a laboratory abnormality leading to suspension of dosing normalizes sufficiently, study 
treatment may resume at the discretion of the PI in consultation with the medical monitor.  
Similarly, study treatment may resume after the medication leading to suspension of dosing is 
discontinued.  A decision to discontinue IMP and/or to reinstitute study treatment should be 
discussed with the medical monitor.  The Investigator may suspend study treatment at any time, 
even without consultation with the medical monitor if the urgency of the situation requires 
immediate action and if this is determined to be in the subject’s best interest.  However, the 
medical monitor should be contacted as soon as possible in any case of IMP discontinuation.  
Resumption of study treatment after temporary discontinuation should always be discussed with 
the medical monitor. 
9.3.6 
Continued Study Participation 
The Investigator must determine the primary reason for the subject’s premature discontinuation 
of IMP and record this information on the treatment disposition eCRF page.  The Investigator 
and study staff must discuss with the subject, the subject’s continued participation in the study 
and request subjects to continue attending study visits to 
 according to the study visit 
schedule. 
9.3.7 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject.  Lost to follow-up is 
defined by the inability to reach the subject after a minimum of 3 documented phone calls, faxes 
or emails (not performed on the same day), as well as a lack of response by the subject to 
1 registered mail letter.  All attempts should be documented in the subject’s medical records.  If 
it is determined that the subject has died, the site will use permissible local methods to obtain the 
date and cause of death and as much other information as can be obtained, including 
post-mortem reports. 
Data to be collected at subsequent visits will be considered missing. 
9.3.8 
Discontinuation of Study Sites 
Study site participation may be discontinued if Sun Pharma Global FZE or designee, the 
Investigator or IRB/IEC of the study site judges it necessary for medical or safety reasons 
consistent with applicable laws, regulations and GCP. 


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9.3.9 
Discontinuation of Study 
The study will be discontinued if Sun Pharma Global FZE or designee, including through DSMB 
recommendation, judges it necessary for medical, safety, or business reasons consistent with 
applicable laws, regulation and GCP. 


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10 
TREATMENT OF SUBJECTS 
10.1 
Identity of Study Treatment(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a subject misses a visit and/or a scheduled dose of IMP, the site must reschedule a visit to 
ensure the dose of IMP is taken as soon as possible within the visit window.  If
 
to reschedule or the visit window was missed and the subject still is not able to take the dose, the 
Sponsor should be contacted to determine if the subject should be discontinued from the study. 
 
 
 
10.2 
Study Treatment Packaging and Labeling 
10.2.1 
Packaging 
P
 
 
Placebo will be presented in identical containers with the same excipients (with no active drug) 
and stored/packaged the same as tildrakizumab during the blinded portion of the study. 


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10.2.2 
Labeling 
Medication labels will comply with the legal requirements of each country and be printed in the 
local language. They will supply no information about the subjects. 
10.2.3 
Storage 
All drug supplies for this study must be stored under
 conditions 
 
according to labeled storage conditions.  Until dispensed for administration to subjects, the IMP 
will be stored in a securely locked area, accessible to authorized personnel only 
10.2.4 
Blinding and Randomization of Study Treatment(s) 
This study will be performed as a randomized, double-blind study including 2 stratification 
factors 
.  Subjects will be randomized according to a list produced by 
 
Prior to production, the randomization specification will be reviewed and agreed 
by the study team (Sponsor 
  As 
 is considered 
potentially unblinding information, it will be known to the Study Biostatistician only. 
An IVRS will be responsible for the allocation of randomization numbers to individual subjects.  
Randomization will take place at 
 after confirmation that the subject continues 
to meet the inclusion/exclusion criteria 
  
 
 
 
 
 
  
 
 
A copy of the randomization code with true treatment allocations will be held by 
 
during the study.  Another randomization list (containing kit number and 
treatment) will be provided to clinical supplies.  The randomization codes associated with each 
subject will be disclosed to PK analysts who will keep PK results confidential until database 
lock. 
Should a situation arise where unblinding is required, the Investigator at that site may perform 
immediate unblinding via the IVRS without the need for communication with the Sponsor.  This 
can only occur in emergency situations (
 
Blinding of study medication and dose regimens will be maintained by using a double-dummy 
double-blind design, where all subjects receive medication (active or placebo) at all scheduled 
dosing visits.  If a subject does not receive the scheduled dose, every effort should be made to 
administer the dose as soon as possible (
 


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To ensure validity of assessments, the following assessments will be performed by an 
independent assessor: 
• Joint count 
• PASI 
• LDI/LEI 
The PGA of disease activity will be assessed by the treating physician (using the full 68/66 
tender/swollen joint count assessment
] performed by the independent assessor).  
All other assessments will be administered by the study co-ordinator or PI/designee 
 
  For the DAS28-CRP score 
 the subset of 28 joints (from the full 
counts) will be transcribed to the appropriate page of the eCRF by site staff, and the score will be 
calculated during data reporting using the eCRF data and the central CRP laboratory result. 
At the time of the IA, a specified team of personnel will be unblinded to allow reporting of the 
primary objective at 
 
10.3 
Procedure for Breaking the Randomization Code 
Subjects, Investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until all subjects complete 
their double-blind treatment 
 and wash-out period. 
Following last subject completion of the 
 visit (or earlier withdrawal from study 
treatment), an IA using unblinded data will be performed for the placebo-controlled double-blind 
treatment period 
 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
subject safely and efficaciously.  Most often, IMP discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition.  Emergency code breaks are performed using the IVRS.  When the Investigator 
contacts the system to break a treatment code for a subject, he/she must provide the requested 
subject identifying information and confirm the necessity to break the treatment code for the 
subject.  The Investigator will then receive details of the IMP for the specified subject and a fax 
or email confirming this information.  The system will automatically inform the 
 
the medical monitor, and the 
r that the code has been broken, but 
no treatment assignment will be communicated. 
It is the Investigator’s responsibility to ensure that there is a procedure in place to allow access to 
the IVRS in case of emergency.  The Investigator will inform the subject how to contact his/her 
backup in cases of emergency when he/she is unavailable.  The Investigator will provide the 
protocol number, IMP name if available, subject number, and instructions for contacting the 
local entity which has responsibility for emergency code breaks to the subject in case an 


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emergency treatment code break is required at a time when the Investigator and backup are 
unavailable. 
10.4 
Subject Compliance 
The dosage, timing and mode of administration of study medication may not be changed.  Any 
departures from the intended regimen must be recorded in the eCRF.  
Study medication accountability and subject compliance will be documented throughout the 
treatment periods (Part 1 and Part 2) using study-specific study medication dispensing record 
forms.  If a subject does not receive the scheduled dose, every effort should be made to 
administer the dose as soon as possible 
 
Deviations from the intended regimen could occur due to: (1) receiving unscheduled IMP 
injections, (2) missing an injection, and (3) receiving the incorrect IMP dose. 
10.5 
Study Treatment Accountability 
Records shall be maintained of the delivery of study treatment to the study centers, the inventory 
at the study centers, the use of each subject and the return to the Sponsor. 
These records shall include dates, quantities, batch numbers, expiry dates and the unique code 
numbers assigned to the study medication and to the study subjects. 
The Investigator shall be responsible for ensuring that the records adequately document that the 
subjects were provided the doses specified in the protocol and that all study medication received 
from the Sponsor is reconciled.  All study medication must be returned to the Sponsor at the end 
of the study. 
10.6 
Concomitant Therapy 
Concomitant Medications, Supportive Care, and Study Restrictions: 
The following restrictions will apply to all subjects during the study.  Subjects should abide by 
inclusion and exclusion restrictions. 
Concomitant medications limited throughout the study 
 
• Analgesics: Acetaminophen may be used by the subject PRN
 before a 
scheduled study efficacy evaluation. 
Concomitant medications will be limited during Part 1 of the study 
 as 
follows: 
• 
 
 
 
 


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subjects taking an NSAID or low-potency opioids on average 
 
. 
• Corticosteroids: Subjects taking oral corticosteroids (not to exceed the equivalent of 
 
must remain on a stable dose.  Subjects who were using topical 
corticosteroids when they enrolled under
 may continue using them in line 
with the inclusion and exclusion criteria in 
 
• DMARDs: Subjects taking either MTX 
 
 dose, unless a decrease in dose is required 
because of toxicity or intolerance.  Oral MTX cannot be changed to parenteral dosing during 
the period of observation.  Subjects may not use a combination of MTX and leflunomide. 
Tapering of any of these concomitant medications during the study is allowed only if there is 
toxicity (accompanied by recording of an AE on the eCRF); otherwise the dosage must remain 
the same throughout Part 1 of the study.  Adjustment of these concomitant medications is 
permitted throughout 
 per Investigator discretion and therapeutic needs of 
the subject, or if the subject does not show minimal response to treatment 
 
 
 
For subjects receiving non-drug therapy (including but not limited to physical therapy, massage, 
diet, exercise, emollients. and joint taping), this must be stable for the 
 prior to 
IMP initiation through to the end of Part 1. 


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11 
ASSESSMENT OF EFFICACY 
The following efficacy assessments will be undertaken, as outlined in the Schedule of 
Assessments 
 
11.1 
Efficacy Assessments 
11.1.1 
Joint Counts 
Five clinical patterns have been described among patients with PsA: distal interphalangeal (DIP), 
asymmetrical oligoarticular, symmetric polyarticular, spondylitis, and arthritis mutilans.  
Peripheral joints are assessed for tenderness and swelling.  There is no validated measure to 
assess peripheral joints in PsA; the measure used is the ACR joint count initially developed for 
the assessment of patients with RA.  The ACR joint count ranges from 
 for 
tenderness, and 
 
he ACR joint count of 
 
count includes the majority of joints affected in PsA, and it can be readily performed in a clinic 
visit.  It includes the temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, 
wrist (including the carpometacarpal and intercarpal joints as 1 unit), metacarpophalangeal 
(MCP), proximal interphalangeal (PIP), DIP, hip, knee, talotibial, midtarsal (including subtalar), 
metatarsophalangeal, and interphalangeal joints of the toes (proximal and distal joints of each toe 
is counted as 1 unit). 
11.1.2 
American College of Rheumatology 
 Response Criteria 
The ACR
 response measures the percentage of subjects with at least a 
 improvement from Baseline in both tender joints 
 and swollen joints 
 along 
with associated percentage improvements in 
 
 
 
  A sensitivity analysis will be performed by 
evaluating ACR
 response calculated using ESR. 
11.1.2.1 
Physician Global Assessment of Disease Activity 
The treating physician will evaluate the status of the subject’s PsA by means of a 
S.  The 
subject will be assessed according to how their current arthritis is.  The VAS will be anchored 
with verbal descriptors of 
 
11.1.2.2 
Patient Global Assessment of Disease Activity 
The subject will assess their current global status of PsA by means of a VAS 
 
), anchored 
with verbal descriptors of 
 


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11.1.2.3 
Patient Pain Assessment 
The subject will assess their level of present pain 
 
using a VAS.  The subject will be asked to rate their pain at that time 
on the scale that is anchored with verbal descriptors of 
”. 
11.1.2.4 
Patient Self-assessed Disability 
The subject will assess their general disability over the past week using the HAQ-DI 
questionnaire (
 
11.1.3 
Health Assessment Questionnaire – Disability Index 
The HAQ-DI is designed to assess patients’ usual abilities using their usual equipment. Patients 
usually find the HAQ-DI self-explanatory, and clarifications are seldom required.  There are 
 assessed by the HAQ-DI: 
 
  For each of these 
categories, patients report the amount of difficulty they have in performing 2 or 3 specific 
activities.  The time frame for the disability questions is the 
 and each question can 
be scored as 
 
  The use of aids and devices for these activities is also recorded.  Use of any 
device or aid will result in a 
for that category.  The score for the disability 
index
.  If more than 
, 
, 
.  If 
 of the categories are missing, the sum of the categories is 
divided by the number of answered categories.  A 
. 
11.1.4 
Disease Activity Score 28-item C-Reactive Protein 
The DAS28-CRP is a measure of disease activity as assessed across 
 including the 
shoulder, elbow, wrist, MCP (1 through 5), PIP (1 through 5), and knee, with all 14 joints 
assessed for each side of the body.  It is a 
 of the 
 
 
11.1.5 
Leeds Dactylitis Index and Leeds Enthesitis Index 
The Leeds dactylometer is a validated tool for assessing dactylitis.  The dactylometer is used to 
measure the circumference of the base of the affected digit and is compared to the contralateral 
digit.  The LDI is a measure of this comparison along with a tenderness score 
 
for joints deemed to have 
dactylitis 
 
 The LEI examines tenderness at 6 sites: 
2
 
  For each entheseal site, assessment is made of 
the adjacent joint in terms of tenderness and soft-tissue swelling, with a 
 if present.  
The LEI score range is
 


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11.2 
Exploratory Assessments 
The following exploratory assessments will be undertaken, as outlined in the Schedule of 
Assessments (
 
11.2.1 
Psoriasis Area and Severity Index 
A subject’s PASI is a measure of overall PsO severity and coverage.  It is a commonly used 
measure in clinical studies for PsO treatments.  PASI consists of 2 major steps:  
 
  
 
.  
The PASI combines the assessment of the severity of lesions and the area affected into a single 
score 
  Every effort will 
be made to ensure that the Investigator or designee who performed the PASI Screening /Baseline 
evaluation will also perform the PASI for the subject at all subsequent visits.  All PASI 
evaluation will be performed prior to study medication administration.  The PASI evaluation will 
only be conducted for subjects with 
 disease 
 
11.2.2 
36-item Short Form 
The SF-36 v2 is a multi-purpose survey that measures 8 domains of health: physical functioning, 
role limitations due to physical health, bodily pain, general health perceptions, vitality, social 
functioning, role limitations due to emotional problems, and mental health.  It yields scale scores 
for each of these 8 domains and 2 summary measures of physical and mental health: the Physical 
Component Summary and the Mental Component Summary.  The SF-36 v2 acute format will be 
used in this study, which asks the respondent to answer the questions as they pertain to the way 
he or she felt or acted during the past week.  
11.2.3 
Psoriatic Arthritis Impact of Disease 
The PsAID questionnaire is a self-reported tool that assesses the impact of PsA on people’s lives.  
The questionnaire assesses 9 items: pain, fatigue, skin problems, work and/or leisure activities, 
functional capacity, discomfort, sleep disturbance, coping, and anxiety, fear and uncertainty 
 


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12 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in 
 and 
 
12.1 
Adverse Events 
12.1.1 
Definitions 
The definitions for AEs and SAEs are given below.  It is of the utmost importance that all staff 
involved in the study are familiar with the content of this section. The PI is responsible for 
ensuring this. 
12.1.1.1 
Adverse Event/Reaction 
An AE is defined as “any untoward medical occurrence in a subject, or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of a medicinal (investigation) product, 
whether or not related to the medicinal (investigational) product”. 
Any relevant observations made at the Screening and Baseline visit (including Screening 
laboratory test results, and until the first dose of IMP) are to be recorded on the AE eCRF, but 
will not be considered treatment-emergent AEs (TEAEs) and will be reported separately from 
TEAEs.  Any relevant observations following the first dose of IMP will be recorded as an AE in 
the subject’s AE eCRF; this includes physical examination findings, clinically relevant abnormal 
vital signs, clinically relevant laboratory abnormalities, and clinically relevant ECG findings.  An 
AE relating to a pre‑existing condition will only be recorded if there is a worsening of the 
pre-existing condition during study conduct with regard to nature, severity or frequency. 
An adverse drug reaction is an “untoward and unintended response to an IMP related to any dose 
administered”. 
All AEs judged by either the reporting Investigator or the Sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse drug reactions.  The expression of 
“reasonable causal relationship” means to convey in general that there are facts or arguments 
which suggest a causal relationship. 
12.1.1.2 
Serious Adverse Event 
An SAE is defined as, but is not limited to, an event that: 
1. Results in death 
Death is not an AE in itself, but an outcome.  The cause of the death is the AE which resulted 
in death. 
2. Is life-threatening 


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Life-threatening means that the subject was at immediate risk of death at the time of the 
SAE; it does not refer to an SAE that hypothetically might have caused death if it had been 
more severe. 
3. Requires in-patient hospitalization or prolongs existing hospitalization 
Hospitalization is defined as at least 1 overnight formal admission into hospital, usually in 
order to perform additional tests, provide treatment which it is not possible to provide at 
home and/or due to an unstable medical condition which requires specific monitoring of the 
subject.  Pre-planned hospitalizations (known already prior to signing the ICF) will not be 
considered an SAE, unless any of the above criteria are fulfilled over the course of the 
hospitalization due to unplanned complications. “Social” hospitalization whereby it is 
administratively impossible to release the subject home is not necessarily an SAE. 
Complications that occur during hospitalizations are AEs unless they would qualify as an 
SAE for any of the above criteria.  If the complication delays subject release from hospital 
then the AE becomes an SAE.  Hospitalizations which are not performed due to an AE are 
not regarded as SAEs. 
4. Results in persistent or significant disability/incapacity 
The term significant disability refers to any condition that impairs physical/physiological 
well-being to the extent that the subject is unable to function normally.  Physical disability 
may include, but is not limited to, permanent disability of locomotion or motility, but also 
systemic permanent dysfunction including heart failure, liver insufficiency or pulmonary 
fibrosis. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Important medical events that my not result in death, be life-threatening or require 
hospitalization may be considered as an SAE when, based on appropriate medical judgment, 
they may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent 
 listed in this definition. 
12.1.1.3 
 
 
 
 
 
 
 
 


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12.1.1.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.1.1.5 
Treatment-Emergent Adverse Event 
TEAEs are defined as any AE occurring or worsening on or after the first dose of IMP. 
12.1.1.6 
Overdose 
A drug overdose is defined as the accidental or intentional use of a drug or medicine or an 
administration error in an amount that is higher than is normally used.  Every overdose must be 
reported to 
 within 
, 
irrespective of whether the overdose was associated with an AE/SAE. 
Overdose in this study is specifically defined as any dose greater than the intended protocol dose 
  In case of overdose, it is recommended that the subject be monitored for any 
signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be 
instituted immediately. 
12.1.1.7 
Product Quality Complaint 
A product quality complaint (PQC) is related to a potential quality issue during manufacturing, 
release testing, stability monitoring, dose preparation, storage or distribution of the product or 
delivery system.  In addition, it includes any reports in which a suspicion of 
counterfeit/tampering exists.  It is important to note that not all PQCs involve a subject.  A PQC 
should be reported within 24 hours. 


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12.1.1.8 
Planned Hospitalization 
A hospitalization planned by the subject prior to signing the ICF is considered a therapeutic 
intervention and not the result of a new SAE and should be recorded as medical history.  If the 
planned hospitalization or procedure is executed as planned, the record in the subject’s medical 
history is considered complete.  However, if the event/condition worsens during the study, it 
must be reported as an AE. 
12.1.1.9 
Incident 
A device-related incident is any product complaint that led to or might have led to death or 
serious deterioration of health/serious injury/serious illness for the user of the product or any 
other person. Note that "device" refers to the PFS for this study.  The incident should be reported 
within 24 hours. 
12.1.2 
Recording of Adverse Events 
Any relevant observations made before the end of the Screening and Baseline visit (prior to first 
dose of IMP) are to be recorded on the AE eCRF, but will not be considered TEAEs and will be 
reported separately from TEAEs.  Any relevant observations made after the first dose of IMP 
will be recorded as an AE in the subject’s AE eCRF (
 
In view of the long T1/2 of tildrakizumab at doses previously studied, subjects will continue to be 
monitored throughout the 
 following the EoT visit.  For the purposes of 
this study, any detrimental change in the subject’s condition, after the first dose of IMP and up to 
completion of the EoS visit, should be considered an AE.  For those subjects who may withdraw 
during the wash-out period, at least 2 attempts should be made to collect AEs. 
The following variables will be recorded for each AE: verbatim/AE description and date for AE 
start and stop, severity, seriousness, causality rating, whether or not the AE caused the subject to 
discontinue, and the outcome.  A new AE must be recorded if the severity of the AE changes. 
All AEs/SAEs have to be reported to the Sponsor, whether or not considered causally related to 
the IMP or to the study procedure(s). 
All ongoing AEs/SAEs should be followed up until resolution or stabilization or the last visit if 
in the Investigator's opinion, the AE is unlikely to resolve due to the subject's underlying disease. 
At any time after the subject has taken the first dose of IMP, if an Investigator learns of an SAE 
that can be reasonably related to IMP, he/she should promptly notify the Sponsor. 
The Investigator will assess the intensity of AEs based on the following definitions: 
• Mild 
 
• Moderate
• Severe 
 


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It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in 
. 
An AE of severe intensity need not necessarily be considered serious.  For example, nausea that 
persists for several hours may be considered severe nausea, but not an SAE.  On the other hand, 
a stroke that results in only a limited degree of disability may be considered a mild stroke but 
would be an SAE. 
For an AE to be a suspected drug-related event, there should be at least a reasonable possibility 
of a causal relationship between the IMP and the AE. 
12.1.3 
Causal Assessment 
The relationship of AEs to study drug will be assessed by the Investigator 
 
 and will be a clinical decision based on all available information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 


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The Investigator should consider the following, before reaching a decision on causality 
assessment: 
•
Time relationship between IMP intake and event’s onset
•
De-challenge
•
Re-challenge
•
Medical history
•
Study treatment
•
Mechanism of action of IMP
•
Class effect
•
Concomitant treatments in use
•
Withdrawal of study treatment
•
Lack of efficacy/worsening of existing condition
•
Erroneous treatment with study medication or concomitant medication
•
Protocol-related process.


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Action taken with IMP due to the AE: 
 
 
 
 
 
 
. 
 
Other action taken: 
 
 
 
 
 
. 
 
Each single AE must be rated by choosing 1 of the following outcomes: 
 
 
 
 
 
 
 
 
 
 
 
 
12.1.4 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms 
Laboratory/vital signs/ECG abnormalities should be reported as AEs/SAEs if it is clinically 
significant and any of the following criteria is met: 
• Result is associated with signs/symptoms 
• Requires additional diagnostic testing and/or intervention 
• Leads to discontinuation or interruption of the IMP 
Any test result determined to be an error or simple repetition of a laboratory test is not required 
to be reported as an AE. 


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12.1.5 
Anaphylaxis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.1.6 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is suspicion that the IMP may have 
interfered with the effectiveness of a contraceptive medication.  If a pregnancy is reported for a 
subject, no further IMP will be administered to this subject and the outcome of all pregnancies 
(spontaneous miscarriage, elective termination, normal birth or congenital abnormality) must be 
followed up and documented.  Follow-up should be performed up to delivery and examination of 
the new-born, after which a follow-up report should be sent with any new information regarding 
the pregnancy and the outcome of the birth. 
All congenital abnormalities/birth defects should be classified as SAEs.  Spontaneous 
miscarriages should also be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as SAEs, but should be reported as a follow-up report for 
the pregnancy.  All outcomes of pregnancy must be reported to the Sponsor on a Pregnancy 
Outcomes Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 


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Pregnancies must be reported to 
 using the 
reporting details provided in 
. 
12.1.7 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 should be sent to: 
Central Receipt mail box:
 
If the report is sent via email then the completed and signed SAE or Pregnancy Report Form 
must be attached to the email.  A notification email of the event describing it in the email text is 
not sufficient. 
Alternatively, the following fax number can be used for completed SAE reporting forms. 
 
 
 
If the 
 be reported via the email (primary option) or by fax 
(secondary option), the following telephone numbers may be used to record the event: 


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There may be situations when an SAE 
 has occurred and the Investigator has 
minimal information to include in the initial SAE report.  However, it is very important that the 
Investigator always makes an assessment of causality for every event prior to transmission of the 
SAE Report Form.  Minimum criteria are identifiable subject (number), a suspect product 
(i.e., IMP or concomitant medication), an identifiable reporting source (Investigator/study site 
identification), and an event or outcome that can be identified as serious.  The Investigator may 
change his/her opinion of causality in the light of follow-up information, amending the SAE 
report form accordingly.  The causality assessment is the criteria used when determining 
regulatory reporting requirements for SAEs. 
12.1.7.1 
Safety Reporting to Sponsor 
 will forward the SAE and Pregnancy report to the 
following Sponsor’s safety representatives
 (whichever 
is earlier) of becoming aware of it. 
 
Dr. Harshit Mehta, Safety Physician 
17/B Mahal Industrial Estate  
Mahakali Caves Road, Andheri (E), Mumbai-93  
 
 
Dr. Victoria Bodea, EUQPPV 
124 Fabricii Str., Cluj-Napoca 
Romania 400632 
 
 
 
12.1.7.2 
Safety 
Reporting 
to 
Health 
Authorities, 
Independent 
Ethics 
Committees/Institutional Review Boards and Investigators 
 will notify the Sponsor of any SAE and will perform follow-up activities with the 
concerned site.  The Sponsor will bear responsibility of expedited and periodic reporting to the 
Health Authorities according to national requirements. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) to the IEC/IRB that approved the study.  Investigators 
should provide written documentation of IEC/IRB notification for each report to the 
 
 
In accordance with ICH GCP, 
 will inform the 
Investigators of findings that could adversely affect the safety of patients, impact the conduct of 
the study, or alter the IEC’s/IRB’s approval/favorable opinion to continue the study, as assessed 


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by the Sponsor.  In particular and in line with respective regulations, 
 
will inform the Investigators of SAEs.  The Investigator should place copies 
of Safety Reports in the Investigator Site File.  National regulations with regard to Safety Report 
notifications to Investigators will be taken into account. 
When specifically required by regulations and guidelines, the 
 
will provide appropriate Safety Reports directly to the concerned lead IEC/IRB 
and will maintain records of these notifications.  When direct reporting is not clearly defined by 
national or site-specific regulations, the Investigator will be responsible for promptly notifying 
the concerned IEC/IRB of any Safety Reports provided by the 
 
and of filing copies of all related correspondence in the Investigator Site File. 
12.2 
Safety Endpoints 
All safety endpoints are listed in 
. 
12.3 
Laboratory Assessments 
Laboratory measurements for blood chemistry, hematology and urinalysis will be performed 
according to 
 and 
  Specific details not mentioned in this section (including 
shipping requirements) are included in the laboratory manual. 
For visits where lipid panel laboratory parameters will be assessed 
 
blood samples are to be collected 
r 
ECG and vital sign measurements. 
12.3.1 
Clinical Laboratory Tests 
Unless otherwise indicated, all chemistry and hematology parameters will be analyzed using a 
central laboratory.  The following parameters will be collected: 
 


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12.3.2 
Pregnancy Testing 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening visit.  A urine pregnancy test with sensitivity of at
, will be performed 
according to the Schedule of Assessments 
  If at any point during the study there is a 
case of a positive urine beta human chorionic gonadotropin (β-hCG) test, the subject will have 
IMP stopped and will be withdrawn from the study.  To confirm menopause in female subjects 
with no menses for 
 a FSH test should be performed at the Screening visit to 
confirm they are not of childbearing potential. 


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Pregnancy tests will also be performed whenever 
 during the 
treatment period (or when potential pregnancy is otherwise suspected), to confirm the subject has 
not become pregnant during the study.  Pregnancy tests may also be repeated as per request of 
IRB/IECs or if required by local regulations. 
12.4 
Assessment of Suicidal Ideation and Behavior 
Subjects will be assessed for suicidal ideation and behavior at Screening using the Baseline 
(Lifetime) C-SSRS, and each subsequent visit using the C-SSRS Since Last Visit version.  There 
are 5 questions relating to levels of suicidal ideation which prompt questioning about suicidal 
behavior or intensity of ideation, depending on response.  Subjects acknowledging active 
thoughts of self-harm but lacking an articulated plan for doing so are classified at the 
intermediate risk level; those presenting a defined self-harm plan or lacking needed impulse 
control are judged to be at the high risk level.  Subjects who have high risk of suicidality at the 
Screening assessment based on Investigator’s judgment or, if appropriate, as indicated by a 
response of 
 in the suicidal ideation section, or 
any positive response in the behavioral section of the C-SSRS, should not be enrolled in the 
study.  Those who develop suicidal ideation during the study rated as high risk according to the 
above classification must be temporarily discontinued from receiving IMP and referred promptly 
for psychiatric evaluation.  Subjects rated as displaying the intermediate level of suicidal ideation 
should receive psychological support and be assessed on an individual basis.  All individuals 
assessed as exhibiting suicidal behavior, except preparatory acts, must discontinue IMP 
permanently.  The presence of non-suicidal self-injurious behavior should be assessed on an 
individual basis. 
12.5 
Electrocardiogram Assessments 
Computerized 12-lead ECG recordings will be obtained at scheduled study visits after the subject 
has rested for at least 5 minutes in the supine position.  ECG data will be submitted to a central 
laboratory for measurement.  The Investigator will document the occurrence of any clinically 
significant 12-lead ECG abnormalities within the eCRF (AE module) based on correlation 
between the central reading report and clinical findings.  Repeat measurements will be performed 
if needed. 


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The following ECG parameters will be obtained directly from the computerized 12-lead ECG 
recordings: rhythm, ventricular rate, P-R interval (the portion of the ECG between the onset of 
the P wave and the QRS complex), QRS duration and QT/QTcF where, according to the 
, 
 
 
 
 
 
 
 
QTcB (QTc corrected according to Bazetts’ formula) will also be recorded, where: 
 
 
 
 
 
12.6 
Physical Examination 
A standard complete physical examination will be performed at the weeks specified in 
 
and 
  The following parameters and body systems will be examined and any 
abnormalities described: height (Screening only), weight, general appearance, skin (presence of 
rash), head, ears, eyes, nose, throat, lungs (auscultation), heart (auscultation for presence of 
murmurs, gallops, rubs), lower extremity exam, abdomen (palpation and auscultation), 
neurologic (mental status, station, gait, reflexes, motor and sensory function, coordination) and 
lymph nodes.  Any clinically significant changes from Baseline should be recorded as AEs. 
12.7 
Vital Signs 
Body temperature (oral), systolic and diastolic cuff blood pressure 
 
 and pulse rate 
 
will be recorded according to the Schedule of Assessments 
  
Automatic or manual devices may be used, but the same device will be used for any given 
subject throughout the study.  The same method of measuring body temperature will be used 
throughout the study.  The same arm will be used for all measurements.  All devices must hold 
valid calibration at the time of use. 
12.8 
Tuberculosis Testing 
During the Screening Period, it must be determined and documented that a subject does not show 
evidence of active infection with TB.  The subject must have a 
 
, defined as a 
. 
Subjects with a 
 are allowed if they 
have 
 
 
  If there is evidence of prior LTBI, subjects must have 


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history of adequate prophylaxis per local standard of care.  If presence of LTBI is established, 
treatment according to local country guidelines must have been followed for at 
 
prior to inclusion in the study. 
12.8.1 
QuantiFERON®-TB Gold In-Tube Test 
QuantiFERON®-TB Gold In-Tube9 is an in vitro diagnostic test using a peptide cocktail 
simulating 
.  
Detection of interferon by 
 is used to identify in vitro 
responses to these 
. QuantiFERON®-TB 
Gold In-Tube is an indirect test for TB infection (including disease) and is intended for use in 
conjunction with risk assessment, radiography and other medical and diagnostic evaluations. 
Test results will be reported as 
 
.  A maximum 
of 
 are allowed.
 
 
12.9 
Chest Radiograph 
A chest radiograph will be obtained at the 
 in subjects with 
 
unless it has been taken and documented within 
the 
 
  There must be no evidence of 
 for the 
subject to be considered eligible for the study. 
12.10 
Anti-drug Antibodies  
The presence of ADA for tildrakizumab will be assessed at the time points specified in 
 
and 
  Samples will be collected as detailed in 
  Sample testing will be 
conducted as specified in the laboratory manual. 
12.11 
24/7 Medical Emergency Coverage 
In a study-related emergency situation occurring outside of usual business hours, when assigned 
Medical Monitors for a study cannot be reached by a caller, an on-call physician can be reached 
 


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13 
STATISTICAL EVALUATION 
13.1 
Sample Size and Power 
The study will randomize
 
for prior anti-TNF use 
) and Baseline body weight 
 This sample 
size is based on an assumed active treatment effect in ACR
 of up to 
 (ACR
 response 
rate under placebo 
, and 
 in each of the remaining groups); 
a 
, and a 
 dropout rate.  Results are based on simulations 
incorporating the use of the Simes method for testing the composite hypothesis that the response 
rate for all 
active treatment groups is not significantly different from placebo versus the 
alternative hypothesis that at least one of the 
active treatment groups has a response rate 
significantly greater than that of placebo.  This is the primary hypothesis test for this study.  Note 
that
 per group also yields 
 power for testing that an individual treatment group 
response rate exceeds that of the placebo group assuming the true ACR
 rate is 
 for the 
active group and 
 for placebo. 
13.2 
Randomization 
A randomization schedule will be computer-generated before the start of the study.  After all 
Screening procedures are performed and results of Screening tests are available 
 
 eligible subjects will be activated in the IVRS, and assigned 
randomly on a 
 to the following treatment groups: 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization will be performed by the 
.  Subjects will be stratified by prior anti-TNF use 
 and Baseline body weight 
).  
 
 
13.3 
Analysis Sets 
The primary evaluation of the primary efficacy endpoint will be performed using the 
 
  Results for the 
 will be considered 
supportive.  Safety endpoints will be analyzed using the Safety Analysis Set. 
PK data will be analyzed using the PK Analysis Set. 


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13.3.1 
Full Analysis Set 
 
 
13.3.2 
Per Protocol Analysis Set 
 
  The deviations can 
include but are not limited to: 
• Key inclusion/exclusion criteria not satisfied 
• Presence of relevant protocol violations with respect to factors likely to affect the efficacy of 
treatment where the nature of protocol violation will be defined before breaking the blind 
• Rescue medication use 
• Inadequate study medication compliance which will be determined before breaking the blind 
Major protocol violations to be excluded from the 
 will be defined and documented in a 
memo prior to the lock and unblinding of the database. 
13.3.3 
Safety Analysis Set 
The Safety Analysis Set will include all randomized subjects who received at least 1 dose of 
IMP.  Analyses will be based on the actual treatment received. 
The Safety Analysis Set is the same definition as the 
. 
13.3.4 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects in the Safety Analysis Set who have sufficient 
tildrakizumab concentration data to obtain reliable estimates of the key PK parameters. 
13.4 
Endpoints 
13.4.1 
Study Subject Data 
Demographic data and subject characteristics at Baseline will be summarized descriptively. 
Exposure and compliance with IMP will be summarized descriptively. 
Incidence of prior and concomitant medication use will be summarized by World Health 
Organization (WHO) Drug dictionary coded terms - Anatomic Therapeutic Chemical (ATC) 
classification and preferred term. 
13.4.2 
Primary Efficacy Endpoint 
The primary endpoint is: 
Part 1: 
• The proportion of subjects who achieve ACR
 at 
 as defined in
. 


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13.4.3 
Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints are as follows: 
Parts 1 and 2 
• The proportion of subjects who achieve ACR
 at 
 
• The proportion of subjects who achieve ACR
 at 
 
• The proportion of subjects who achieve ACR
 at 
 
• Change from Baseline in the individual components of ACR response at 
 
− Tender joint counts 
 
− Swollen joint counts 
 
− PGA of disease activity (VAS) 
− PtGA of disease activity (VAS) 
− Patient's pain assessment (VAS) 
− Patient's self-assessed disability 
− Acute-phase hsCRP 
− ESR 
• The proportion of subjects who require adjustment of background therapy. 
• Change from Baseline in HAQ-DI 
 
• The proportion of subjects who achieve a DAS28-CRP 
 
• The proportion of subjects who achieve MDA criteria at 
. 
− 
 
 
 
 
• Change from Baseline in LDI and LEI 
 
13.4.4 
Exploratory Efficacy Endpoints  
Exploratory endpoints include: 
Parts 1 and 2: 
• PASI 75/90/100 response rates at measured time points for subjects with moderate disease 
 
• SF-36 at measured time points 
• PsAID questionnaire at measured time points 


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• ACR
 
, the components of ACR, DAS28-CRP, MDA, LDI, and LEI at 
other measured time points 
Part 3: 
• ACR
, 
, the components of ACR, LDI, LEI, PASI, and HAQ-DI at 
measured time points 
13.4.5 
Safety Endpoints 
The following data will be collected for assessment of safety: 
• AEs 
• Laboratory assessments 
• Suicidal ideation and behavior (C-SSRS) 
• Vital signs 
• ECG 
• Physical examination 
• ADA to tildrakizumab, including titer and neutralizing antibodies 
These safety parameters will be assessed using the Safety Population. 
13.4.6 
Pharmacokinetic Endpoints 
Secondary PK endpoints include: 
• AUC 
• Maximum concentration (Cmax) 
• Minimum concentration (Cmin)  
• Time of maximal concentration (Tmax)  
• T1/2 
Exploratory PK endpoints will be based on a mechanistic-based exposure-response (i.e., indirect) 
PK/PD model to explore the relationship of tildrakizumab exposure and PD endpoints. 
These parameters will be assessed using the PK Analysis Set.  
13.4.7 
Anti-Drug Antibodies Endpoints 
Incidence of ADA and correlations with PK, safety and efficacy endpoints will be investigated 
across Part 1 to Part 3. 


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13.5 
Description of Statistical Analyses 
13.5.1 
General Considerations 
The statistical evaluation will be performed by 
 using SAS®, 
. 
13.5.2 
General Statistical Methods 
Summary statistics will be presented by treatment group.  For continuous variables, unless 
otherwise stated, the number of available observations (n), mean, standard deviation (SD), 
median, and range will be provided.  For categorical variables, the number and percentage in 
each category will be displayed. 
Assessments of change from Baseline to post-Baseline will include only those subjects with both 
Baseline and post-Baseline measurements.  The last value of a variable taken before the first 
dose of IMP will be used as the Baseline value.  Unless otherwise specified, missing or dropout 
data will not be imputed for the purpose of data analysis. 
A more detailed description of study analyses will be presented in the Statistical Analysis Plan 
(SAP). 
13.5.3 
Analysis of Primary Endpoint 
The primary analysis will be based on the 
, incorporating prior 
anti-TNF use and Baseline weight as stratification factors, to compare response rates for the 
primary endpoint (ACR
 at 
 between placebo and each of the respective active dose 
arms.  In addition, the 
common risk (the response rate) difference between 
placebo and each of the respective active dose arms and the confidence interval (CI) will be 
estimated.  In order to control for 
, the 
 will be used in the 
determination of dose level success against placebo.  Should assumptions per the 
 
 not be satisfied, pairwise comparisons will be based on 
 following 
.  In this case, the 
 be based on 
 
  Early withdrawals and any other subjects with 
incomplete data at 
 will be classified as 
 for the primary endpoint 
(ACR
).  Subjects who fail to show minimal response to treatment 
 
 may have their 
background medications adjusted according to the maximum permitted daily dose 
 
and continue in the study.  Any subject requiring these adjustments will be 
counted as a non-responder for the primary analysis. 
Analysis of the primary endpoint will be based on the 
.  A sensitivity analysis will be 
performed based on 
. 
Subgroup analysis on prior anti-TNF use 
 and Baseline weight 
 may 
be performed for the primary endpoint.  
. 


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13.5.4 
Analysis of Secondary Endpoint(s) 
All secondary analyses will be performed using the 
.  Binary secondary endpoints up to 
 will be analyzed based on the methods described for ACR
  Continuous endpoints up 
to 
 will be analyzed based on a mixed model repeated measure (MMRM) analysis that 
includes the fixed effects of treatment, visit, treatment by visit interaction, prior TNF use 
(yes/no), Baseline weight (≤ 90 kg, > 90 kg), and Baseline value. 
Key secondary analyses will also be performed for the 
S.  A more detailed description of 
secondary endpoint analysis, including those considered key, will be presented in the SAP. 
13.5.5 
Analysis of Exploratory Endpoints 
Exploratory endpoints up to 
 will be analyzed based on methods described for 
secondary endpoints for the 
. 
For 
 the effect of IMP discontinuation on ACR
, ACR
, ACR
, the 
components of ACR, LDI, LEI, PASI, and HAQ-DI will be evaluated using summary statistics.  
Specifically, the proportions of subjects who achieve ACR
, ACR
, ACR
, and 
PASI75/90/100 at each measured time point during 
 will be summarized 
 
in the components of ACR, LDI, LEI, and 
HAQ-DI during 
 will be summarized descriptively by randomized treatment 
group. 
13.5.6 
Analysis of Pharmacokinetic Endpoints 
Plasma tildrakizumab concentration data will be listed by individual subject and summarized by 
time and tildrakizumab dose group. 
PK parameters of AUC, Cmin, and T1/2 will be summarized with descriptive statistics (n, mean, 
SD, geometric mean, coefficient of variation [%CV], minimum, first, second (i.e., median) and 
third quartiles, and maximum). 
The PK Analysis Set will be used for the analysis. 
Exploratory analysis will be performed as below: 
 
 
  
 
 
Exploratory PK analyses may be described in separate SAPs. 
13.5.7 
Analysis of Anti-Drug Antibodies 
Incidence of ADA will be summarized and explored for correlation with various PK, safety and 
efficacy outcomes. 


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13.5.8 
Safety Analyses 
The analysis of safety parameters will be based on the Safety Analysis Set.  In general, missing 
safety data will not be replaced. 
Adverse Events 
AEs will be coded using the most recent version available of the Medical Dictionary for 
Regulatory Activities (MedDRA).  TEAEs are defined as any AE occurring or worsening on or 
after the first dose of IMP.  
The incidence of TEAEs will be summarized by system organ class and preferred term, as well 
as by study part. If a subject experiences the same preferred term multiple times then the event 
will be counted only once for the greatest severity during the treatment emergence period for the 
part reported.  Separate tables will be presented by severity; TEAEs considered to be related to 
IMP by Investigators will be summarized similarly. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Clinical laboratory parameters 
 
will be summarized at each scheduled visit. 
Values outside the normal range will be 
 
 and these will be flagged in the 
listings of individual subject data. 
Suicidal ideation and behavior 
Suicidal ideation and behavior assessment results will be summarized at each scheduled visit. 


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Vital Signs 
Vital sign 
 will be summarized at each scheduled 
visit. 
ECG 
The overall ECG interpretation will be summarized by presenting the 
ECG parameter 
will be summarized at 
each scheduled visit. 
Physical Examination 
Physical examination results will be summarized with incidence of 
by body system at each scheduled visit. 
ADA to Tildrakizumab 
ADA titer and neutralizing antibodies will be summarized at each scheduled visit. 
13.5.9 
Interim Analysis 
. 
13.5.10 
Data Safety Monitoring Board 
A DSMB will be established for periodic review of safety data for this study. The composition 
and responsibilities of the DSMB will be described in detail within the DSMB Charter for this 
study 
13.5.11 
Clinical Adjudication Committee 
Patients with PsA, especially those patients with severe disease, are at increased risk of 
atherosclerotic cardiovascular events and have high rates of comorbidities associated with 
cardiovascular risk (e.g., hypertension, obesity, diabetes).  As such, a CAC will evaluate an 
extensive set of cardiovascular events and all deaths to determine which of these meet 
pre-specified endpoint criteria.  Cardiovascular events for adjudication will be identified based 
on Investigator reports with specific adverse event terms.  Instructions for obtaining source 
documentation for all events to be adjudicated will be provided to the Investigator sites in a 


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separate document.  All personnel involved in the adjudication process will remain blinded to 
treatment allocation throughout the trial.  Specific details regarding the cardiovascular endpoints 
to be analyzed, including the endpoint definitions and criteria can be found in the Adjudication 
Committee Charter. 


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14 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The Investigator/institution shall provide direct access to source data/documents for study-related 
monitoring, audits, IEC/IRB review and regulatory inspection. 


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15 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 
Conduct of the Study 
 Sun Pharma Global FZE shall implement and maintain quality control and quality 
assurance procedures with written Standard Operating Procedures (SOPs) to ensure that the 
study is conducted and data are generated, documented and reported in compliance with the 
protocol, ICH GCP and applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 2013)11, FDA (CFR, Sections 312.50 and 312.56), EU (Annex 1, Directive 
2001/83/EC) and UK regulations (The Medicines for Human Use [Clinical Trials] Regulations 
2004 [no.1031]), and with ICH GCP (CPMP 135/95). 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IEC/IRB, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study.  Any deviations may result in the subject having to be 
withdrawn from the study and render that subject non-evaluable. 
15.2 
Study Monitoring 
The Investigator shall permit the 
 to review study data as frequently as 
deemed necessary to ensure that data are being recorded in an adequate manner and that protocol 
adherence is satisfactory. 
The Investigator will provide access medical records for the monitor in order that entries in the 
eCRF may be verified.  The Investigator, as part of his/her responsibilities, is expected to 
co-operate with 
n ensuring that the study adheres to GCP requirements. 
The Investigator may not recruit subjects into the study until such time that a visit, or with the 
agreement of the Sponsor, attendance at the Investigator meeting, has been made by a 
Sponsor/
 to conduct a detailed review of the protocol and eCRF. 


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16 
ETHICS 
16.1 
Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC/IRB.  The IEC/IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH GCP and local 
requirements as applicable. 
The IEC/IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, subject recruitment 
procedures (e.g., advertisements), written information to be provided to the subjects, 
Investigator's Brochure, available safety information, information about payment and 
compensation available to subjects, the Investigator's curriculum vitae and/or other evidence of 
qualifications and any other documents requested by the IEC/IRB and Regulatory Authority 
(Competent Authority) as applicable. 
16.2 
Written Informed Consent 
The nature and purpose of the study shall be fully explained to each subject (or their legally 
responsible guardian). 
Written informed consent must be obtained from each subject (or guardian) prior to any study 
procedures being performed.  The process of obtaining informed consent must be documented in 
the subject source documents. 
The consent documents to be used for the study shall include all the elements of informed 
consent as outlined in accordance with FDA, ICH GCP and local requirements as applicable and 
be reviewed and approved by the appropriate IEC/IRB prior to use. 
16.2.1 
Data Monitoring Committee 
An independent DSMB will be established to periodically review safety results.  The DSMB will 
have access to unblinded data.  Based on the results of the interim review the DSMB will submit 
its recommendations in written form to the Sponsor who is responsible for responding to the 
recommendations of the DSMB and to take appropriate action.  The Investigators will only be 
informed by the Sponsor in case of stopping the study.  The DSMB may choose to request 
additional evaluations at any time if they feel this is warranted from the standpoint of safety. 
The DSMB will act according to its own written SOP described in a charter and will prepare 
written minutes of its meetings. 
In order not to disseminate unblinded data and to ensure that all staff involved in the conduct and 
final analysis of the study remains blind to the results of the safety review, only the members of 
the DSMB and the unblinded statistician will have access to these data. 


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At each planned safety review, the randomization codes of the subjects to be included in the 
analysis will be unblinded.  Before unblinding, a SAP will be prepared for the safety review and 
approved by the Sponsor.  The results will be sent confidentially to the DSMB by the unblinded 
statistician. 


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17 
DATA HANDLING AND RECORD KEEPING 
17.1 
Case Report Forms/Source Data Handling 
All required study data must be entered in the eCRF created for the study.  This data collection 
tool is a validated electronic data capture (EDC) system that contains a system generated audit 
trail.  Data required according to this protocol are recorded by investigational site personnel via 
data entry into the internet based EDC software system.  The Investigator shall ensure that all 
data from subject visits are promptly entered into the eCRFs in accordance with the specific 
instructions given.  The Investigator must sign each eCRF to verify the integrity of the data 
recorded.  All internal 
 and external investigational site personnel seeking access to the 
eCRF are supported by a Service Desk (if applicable).  At the end of the study all data captured 
electronically will be provided to the Investigator on CD-ROM for archiving at the 
investigational site. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start.  If a central laboratory has been selected to 
conduct any or all tests, it is essential that all samples be analyzed at that laboratory, unless 
otherwise specified (e.g., ESR). 
The Investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports.  All 
information in the eCRF must be traceable to the source documents in the subject’s file. 
17.2 
Retention of Essential Documents 
The Investigator/institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements.  The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents should be retained until 
 
 
 
 
  These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor.  It is the responsibility of the Sponsor to inform the Investigator/institution as 
to when these documents no longer need to be retained. 


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18 
FINANCING AND INSURANCE 
The Sponsor shall carry an insurance policy to cover compensation of subjects’ health injuries 
arising from the study.  If a subject incurs a study-related injury, the subject may be treated (and 
other necessary measures taken) at the study site and/or another medical institution.  If it is 
necessary to compensate for the treatment, the Sponsor will cover the cost.  The Sponsor shall 
not impose on the subject the burden of proving the causal relation between the study and the 
injury. 
If any of the following is confirmed, the Sponsor may refuse or restrict the payment of the 
compensation: 
1. 
A serious GCP or protocol deviation by the Investigator or Sub-Investigator (except 
deviation medically necessary to avoid an immediate hazard to the study subjects) 
2. 
Intentional act or negligence on the part of the Investigator or Sub-Investigator or 
malpractice thereby 
3. 
Injury caused by unlawful act or delinquency of a third party 
4. 
Injury caused by intentional act or negligence of the subject 
If compensation becomes necessary for a study-related injury, the site will promptly notify the 
Sponsor and will co-operate with the Sponsor and its insurer (or their legal representatives) in 
their handling thereof. 
 


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19 
PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data. When the study is complete the Sponsor shall 
arrange the analysis and tabulation of data.  A clinical study report shall then be prepared, which 
may be used for publication, presentation at scientific meetings or submission to regulatory 
authorities.  All proposed publications based on this study must be subject to the Sponsor's 
approval requirements. 
The Sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov.  In addition, upon study completion and 
finalization of the study report, the results of this study will be submitted for publication and/or 
posted in a publicly accessible database of clinical study results. 


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20 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore any actual conflict of interest of persons who have 
a role in the design conduct, analysis, publication, or any aspect of this study will be disclosed 
and managed.  Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the study.  The 
study leadership in conjunction with the Sponsor has established policies and procedures for all 
study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 


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21 
SIGNATURE OF INVESTIGATOR 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 


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22 
REFERENCE LIST 
1. MK-3222 (SCH 900222) Investigators Brochure.  Edition 7.  10 October 2016. 
2. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P.  Psoriatic arthritis: epidemiology, 
clinical features, course, and outcome.  Ann Rheum Dis.  2005;64(Suppl II):ii14–ii17. 
3. Arthritis Research UK Web site.  Available at http://www.arthritisresearchuk.org/arthritis-
information/conditions/psoriatic-arthritis/symptoms.aspx) and 
http://www.arthritisresearchuk.org/arthritis-information/conditions/psoriatic-
arthritis/treatments.aspx.  Accessed August 31, 2016. 
4. National 
Psoriasis 
Foundation. 
 
Available 
at 
https://www.psoriasis.org/psoriatic-
arthritis/diagnosis.  Accessed September 06, 2016. 
5. Arthritis 
Foundation 
Web 
site: 
 
 
Available 
at 
http://www.arthritis.org/about-
arthritis/types/psoriatic-arthritis/treatment.php 
and 
http://www.arthritis.org/about-
arthritis/types/psoriatic-arthritis/articles/methotrexate-and-psoriatic-arthritis.php.  Accessed 
August 31, 2016. 
6. Felson DT, Anderson JA, Boers M, Bombardier C, Furst D, Goldsmith C, et al.  American 
College of Rheumatology Preliminary Definition of Improvement in Rheumatoid Arthritis.  
Arthritis Rheum.  1995;38(6):727-35. 
7. The Leeds Dactylitis Manual and Score Sheet.  Available at http://www.mie-
uk.com/dactylometer/index.html.  Accessed September 06, 2016 
8. Healy PJ, Helliwell PS.  Measuring clinical enthesitis in psoriatic arthritis: Assessment of 
existing measures and development of an instrument specific to psoriatic arthritis.  Arthritis 
Care and Research.  2008;59(5):686-691. 
9. Guidelines for using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection.  Available at 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm.  Accessed 
September 06, 2016. 
10. Coates LC, Fransen J, Helliwell PS.  Defining minimal disease activity in psoriatic arthritis: a 
proposed objective target for treatment.  Ann Rheum Dis.  2010;69:48-53. 
11. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects.  Available at http://www.wma.net/en/20activities/10ethics/10helsinki/DoH-
Oct2013-JAMA.pdf.  Accessed October 07, 2016. 


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23 
APPENDIX 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

SAP_003.pdf: 
 
 
 
Study title: 
 A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Phase 2b 
Study to Demonstrate the Safety and Efficacy of Tildrakizumab in Subjects with Active 
Psoriatic Arthritis 
Document:  
Statistical Analysis Plan (SAP) 
Version number: 
Final v2.0 
Date:  
10 Oct 2019 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23  
Page 1 of 56
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Multiple-
Dose, Phase 2b Study to Demonstrate the Safety and Efficacy 
of Tildrakizumab in Subjects with Active Psoriatic Arthritis 
Protocol Number: 
CLR_16_23 
Protocol Version, Date 
 
  
 
Document Version, Date: 
 
 
 
 
 
 
Prepared by: 
 
 
On behalf of: 
Sun Pharma Global FZE  
 
 
 
 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23  
Page 2 of 56
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The Recipients of the SAP must not disclose the confidential document and any 
related information to other persons. 
 
In addition, they must keep this confidential document in a controlled 
environment which prevents unauthorized access to the document. 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23  
Page 3 of 56
 
SIGNATURE PAGE 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23 
Page 4 of 56
 
REVISION HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocUUID : 006a4d8b-d093-4786-8f63-841db8a57ce7


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23  
 
Page 5 of 56
  
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23  
 
Page 6 of 56
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23  
 
Page 7 of 56
  
LIST OF ABBREVIATIONS 
The following abbreviations will be used within this SAP. 
Abbreviation or 
special term 
Explanation 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CASPAR 
Classification of Psoriatic Arthritis 
CI 
Confidence Interval 
cm 
Centimetre 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DAS 
Disease Activity Score 
DBL 
Database Lock 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
hsCRP 
high sensitivity C-reactive protein 
IA 
Interim Analysis 
IMP 
Investigational Medicinal Product 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_23  
 
Page 8 of 56
  
IVRS 
Interactive Voice Response System 
kg 
Kilogram 
LDI 
Leeds Dactylitis Index 
LEI 
Leeds Enthesitis Index 
MACE 
Major Adverse Cardiac Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDA 
Minimal Disease Activity 
MMRM 
Mixed Model for Repeated Measurements 
n 
Number of non-missing observations 
PASI 
Psoriasis Area and Severity Index 
PGA 
Physician Global Assessment 
PK 
Pharmacokinetics 
PPAS 
Per Protocol Analysis Set 
PsA 
Psoriatic Arthritis 
PsAID 
PsA Impact of Disease 
PT 
Preferred Term 
PtGA 
Patient Global Assessment 
Q1 
Lower Quartile 
Q3 
Upper Quartile 
q4wk 
Every 4 weeks 
q12wk 
Every 12 weeks 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SF-36 
36-item Short Form 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T1/2 
Half-life 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings and Figures 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
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Tmax 
Time of maximal concentration 
TNF 
Tumor-necrosis factor 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 


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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a detailed description of the 
statistical methods, data derivations and data presentations to be employed for study protocol 
CLR_16_23 “A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Phase 2b Study 
to Demonstrate the Safety and Efficacy of Tildrakizumab in Subjects with Active Psoriatic 
Arthritis” which was originally 
 
  
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
This SAP supersedes the statistical considerations identified in Protocol CLR_16_23 and where 
considerations are substantially different, they will be identified as such in this document.  
This SAP has been developed and approved prior to database lock and unblinding of the clinical 
database for Protocol CLR_16_23. 


 
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2 
STUDY OBJECTIVES 
2.1 
Primary objectives 
 
 
 
 
 
 
 
 
 
2.2 
Secondary objectives 
 
 
 
 
 
 
 
 
2.3 
Exploratory objectives 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
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3 
STUDY DESIGN 
3.1 
General study design 
This is a randomized, multinational, double-blind, placebo-controlled, multiple-dose, Phase 2b 
study. The study will consist of a Screening Period 
 a double-blind, placebo-
controlled period 
 a double-blind follow-up period 
 
and 
  During the wash-out period, subjects will 
 receive tildrakizumab and will be treated according to the Investigators’ discretion. 
Adult patients with active PsA who satisfy the inclusion criteria and do not meet the exclusion 
criteria will be enrolled in this study. Approximately 
 will be randomized into the 
Double-Blind treatment period. 
The Study Flow Chart is presented in Figure 1. 
t 
 
 
 
  


 
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Subjects who fail to show minimal response to treatment 
 
 may have their background 
medications adjusted according to the maximum permitted daily dose as described in the protocol 
and continue in the study.  
Subjects who show clinical response to treatment 
 
 
 
 
 
 
Subjects receiving placebo or 
 tildrakizumab during 
 
 
 Subjects in 
 are not deriving sufficient clinical benefit in the opinion of the 
Investigator at any time
, should be discontinued from study drug and 
 so 
that they may receive additional treatment as determined by the Investigator. 
Subjects discontinued from IMP at any time (apart from withdrawal of informed consent) will be 
required to complete the 
 assessment a minimum of 
 
 enter the 
.  Subjects who withdraw from the study during 
 
will undergo the 
 assessments 
. 
On completion of
 subjects may enter the 
 
providing they meet the inclusion/exclusion criteria for the 
and the Investigator deems 
they would benefit from continued treatment with tildrakizumab.  In circumstances where the 
 
study site activation has not occurred at the time the subject reaches the end of 
 they may 
enter from washout period if the required eligibility conditions are met. 
3.2 
Randomization and blinding 
3.2.1 
Randomization 
A randomization schedule will be computer-generated before the start of the study.  After all 
Screening procedures are performed and results of screening tests are available 
 
, eligible subjects will be activated in the interactive voice 
recognition system (IVRS), and 
 to the following treatment 
groups: 
 
 
 
 
 
 
DocUUID : 006a4d8b-d093-4786-8f63-841db8a57ce7


 
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3.2.2 
Blinding 
This is a double-blind study. Investigational sites, subjects, and study team members directly 
involved in study activities will remain blinded to study treatment assignments until the last subject 
completes their double-blind follow-up period and wash-out period. A separate document will 
provide further details related to unblinding of personnel involved in reporting activities for the 
Interim Analysis (IA). 
PK and anti-drug antibodies (ADA) data will be kept confidential only after database lock and 
unblinding at study completion. 
3.2.3 
Unblinding 
In an emergency, in which the Investigator must know a subject’s treatment allocation to ensure the 
subject’s safety, the Investigator will contact IVRS. When the Investigator contacts the system to 
break a treatment code for a subject, he/she must provide the requested subject identifying 
information and confirm the necessity to break the treatment code for the subject.  The Investigator 
will then receive details of the IMP for the specified subject.  The system will automatically inform 
the 
, the medical monitor, and the 
 that the code has been 
broken, but no treatment assignment will be communicated.  
3.3 
Study treatments and assessments 
The maximum study duration from screening to end of the wash-out period is 
 
All subjects eligible for study participation will enter the double blind treatment period and receive 
one of the 5 treatments assigned per the schedule outlined in the study flow chart.  
 
 
 
 
 
 


 
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If a subject misses a visit and/or a scheduled dose of IMP, the site must reschedule a visit to ensure 
the dose of IMP is taken as soon as possible within the visit window.  If after 2 attempts to 
reschedule, the subject still is not able to take the dose, the Sponsor should be contacted to 
determine if the subject should be discontinued from the study. 
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the Schedule of Assessments in 
. 
 


 
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2626 may 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the proportion of subjects who achieve ACR20 at Week 24.  
The ACR20 is defined as at least a 
 and 
: 1) the Physician 
Global Assessment (PGA) of disease activity (as measured using a VAS), 2) the Patient Global 
Assessment (PtGA) of disease activity (as measured using a VAS), 3) patient pain assessment (as 
measured using a VAS), 4) patient self-assessed disability (as measured using the HAQ-DI), and 
5) acute-phase CRP1.  
The components of the ACR assessments that will be used in this study are: 
− Tender joint counts 
 
− Swollen joint counts 
 
− PGA of disease activity 
 
− PtGA of disease activity 
 
− Patient's pain assessment 
 
− Patient's self-assessed disability (HAQ-DI) 
− Acute-phase hsCRP 
If the value in any of the components at a time point is missing, the component variables that are 
not missing will be used to determine the response status.  As a general principle, if there are 
sufficient non-missing components to determine whether the ACR endpoint is a response or non-
response, then ACR endpoint is not missing, else if the available non-missing components are not 
sufficient to determine the response status of ACR endpoint then it is considered missing.   
If the baseline value of any component is 
, the following algorithm will be used in 
evaluating the percent change from baseline: 
• 
If change from baseline is also 
 then percent change from baseline is set to be 
 
• 
If change from baseline is 
, then percent change from baseline is set to be 
 
These percentages will be used to derive the ACR endpoints.  
In addition, any CRP value below the LLOQ will be reported as
 in database and will be 
 and used in analyses.   
Another version of ACR20 will be derived with ESR replacing hsCRP. 


 
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4.2 
Secondary efficacy endpoints 
 
The secondary efficacy endpoints of this study are: 
Parts 1 and 2 
• 
The proportion of subjects who achieve ACR20 
 
• 
The proportion of subjects who achieve ACR50 
 
ACR50 will be derived similarly as for ACR20 
 
• 
The proportion of subjects who achieve ACR70 
 
ACR70 will be derived similarly as for ACR20 
 
• 
Change from Baseline in the individual components of ACR response at 
 
− Tender joint counts 
 
− Swollen joint counts 
 
− PGA of disease activity (VAS) 
− PtGA of disease activity (VAS) 
− Patient's pain assessment (VAS) 
− Patient's self-assessed disability (HAQ-DI) 
 
− Acute-phase hsCRP 
− ESR 
• 
The proportion of subjects who require adjustment of background therapy 
 
• 
The proportion of subjects who achieve a DAS28-CRP
 
The DAS28-CRP is a composite score derived from examination of the 
 for swelling 
and tenderness, CRP level, and patient global health assessment.  
DAS28-CRP takes into account the following items: 
o TJC28: 
 
o SJC28: 
 
o CRP: 
 
o GH: 
 
 
 


 
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If any of the components is missing, DAS28-CRP will be missing. 
• 
The proportion of subjects who achieve MDA criteria at 
. 
A psoriatic arthritis patient is defined as having a Minimal Disease Activity (MDA) response 
when the patient meets
 of the  following criteria: 1) tender joint count 
; 
2) swollen joint count 
 3) PASI score 
 or BSA
 4) patient Arthritis Pain (VAS) 
; 5) patient’s global arthritis assessment 
 
; 6) HAQ-DI score 
; 7) 
tender entheseal points
 
  
 If there are sufficient non-missing components to determine whether the MDA is a response or 
non-response, then MDA is not missing. If the available non-missing components are not 
sufficient to determine the response status of MDA then it is considered missing.   
• 
Change from Baseline in LDI and LEI at 
 
The Leeds dactylometer is a validated tool for assessing dactylitis.  The dactylometer is used to 
measure the circumference of the base of the affected digit and is compared to the contralateral 
digit.  
 
 The final score for 
each digit is calculated and recorded on the CRF page.
 
   
The LEI examines tenderness at 6 sites: 
 
.  For 
each entheseal site, assessment is made of the adjacent joint in terms of tenderness and soft-
tissue swelling, 
. LEI is the number of sites in which enthesitis is 
present. The LEI score range is
  A missing assessment (ie, no box checked) or not assessed 
(ie, NOT DONE box checked) for any site will result in the LEI score being coded as missing. 
4.3 
Exploratory endpoints 
The exploratory endpoints of this study are: 
Parts 1 and 2: 
• 
 
 
A subject’s PASI is a measure of overall PsO severity and coverage.  PASI consists of 2 major 
steps:  1) calculating the BSA covered with lesions and 2) assessment of the severity of lesions.   
o Body surface area involvement (%BSA): 
 
 


 
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o Lesion severity: The basic characteristics of psoriatic lesions – erythema, 
induration and scaling – provide a means for assessing the severity of lesions.  
 
  
 
 
 
In each area, the sum of the intensity rating scores for erythema, induration and scaling is 
multiplied by the score representing the percentage of this area involved by psoriasis, 
multiplied by a weighting factor 
  The 
sum of the numbers obtained for each of the four body areas is the PASI. 
 
 
 
 
The PASI combines the assessment of the intensity of lesions and the area affected into a single 
score in the 
  The PASI 
evaluation will only be conducted for subjects with moderate disease 
 
 
PASI75/90/100 is defined as at least 75%, 90%, and 100% reduction from baseline in PASI 
total score, respectively. 
• 
SF-36 at measured time points (
 
• 
PsAID questionnaire at measured time points 
The PsAID questionnaire is a self-reported tool that assesses the impact of PsA on people’s 
lives.  The questionnaire assesses 9 items: pain, fatigue, skin problems, work and/or leisure 
activities, functional capacity, discomfort, sleep disturbance, coping, and anxiety, fear and 
uncertainty (
). The PsAID is calculated based on the 9 item ratings. 
  
  
  
 
 


 
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If one of the items has missing value for rating, it will be imputed with the mean values of the 
ratings for the rest 8 items. The PsAID will be calculated with above formula. 
 
  
 
• 
ACR20, ACR50, ACR70, the components of ACR, DAS28-CRP, MDA, LDI, and LEI at other 
measured time points 
Part 3: 
ACR20, ACR50, ACR70, the components of ACR, LDI, LEI, PASI, and HAQ-DI at measured 
time points 
4.4 
Safety endpoints 
The safety endpoints of this study are: 
• 
Adverse events (AEs) 
• 
Laboratory assessments 
• 
Suicidal ideation and behavior (C-SSRS) 
• 
Vital signs 
• 
ECG 
• 
Physical examination 
• 
ADA to tildrakizumab, including titer and neutralizing antibodies 


 
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5 
SAMPLE SIZE AND POWER 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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6 
ANALYSIS POPULATIONS 
6.1 
Full Analysis Set (FAS) 
The FAS will include all randomized subjects who have received at 
 of IMP 
(tildrakizumab or placebo).  Analyses will be based on randomized treatment. 
6.2 
Per Protocol Analysis Set (PPAS) 
The PPAS will include all subjects in the FAS without any major protocol deviations that could 
have influenced the validity of the data for the primary efficacy endpoint.  The deviations can 
include but are not limited to: 
• 
Key inclusion/exclusion criteria not satisfied 
• 
Presence of relevant protocol deviations with respect to factors likely to affect the efficacy of 
treatment where the nature of protocol deviations will be defined before breaking the blind 
• 
Rescue medication use 
• 
Inadequate  study medication compliance which will be determined before breaking the blind 
Major protocol deviations  to be excluded from the PPAS will be finalized and documented in a 
memo prior to the lock and unblinding of the database.  
6.3 
Safety Analysis Set 
The Safety Analysis Set will include all randomized subjects who 
 of IMP.  
Analyses will be based on the actual treatment received. 
6.4 
PK Analysis Set 
The PK Analysis Set will include all subjects in the Safety Analysis Set who have sufficient 
tildrakizumab concentration data to obtain reliable estimates of at least one PK parameters. 
6.5 
ADA Evaluable Set 
The ADA Evaluable Set will include all subjects in the Safety Analysis Set who have at 
 
 Assay results from the placebo portion of 
the trial will not included in the immunogenicity assessment, although subjects who are 
randomized to 
 will be included in the assessment if they are treated with 
tildrakizumab in Part 2.  
6.6 
Protocol deviations/violations and exclusions from analysis sets 
All violations and exclusions of subjects from analysis sets will be identified at the Classification 


 
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Meeting just prior to study unblinding, through clinical review input provided by Sponsor, using 
the following sources of information: 
• 
Supportive subject listings, provided by the 
 
 
 ahead of the 
Classification Meeting, based on data recorded on the eCRF.  
• 
Protocol Deviation Logs, provided by 
. 
Further, deviations from protocol will be classified as major/minor or key/non-key depending on 
what is available in 
 
The protocol deviations that will lead to subject exclusion from the PPAS are listed as below. It is 
possible that unexpected deviations will arise as the study moves forward. Therefore, more 
deviation categories may be added to the list later. Prior to database lock, a classification meeting 
will be conducted to identify subjects to be excluded from PPAS, and the decision will be 
documented in a separate file. 
• 
Subject without a diagnosis of PsA by the Classification of Psoriatic Arthritis (CASPAR) 
criteria with symptoms present for at least 6 months 
• 
 
• 
Non-compliance with study treatment
 
• 
Disallowed concomitant medications 
• 
 
  
 
 


 
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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 
Derived variables 
Details for deriving efficacy variables are discussed in 
 The below set of 
variables are the basic demographic variables and some general variables. 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
7.2 
 Handling of missing data and outliers 
7.2.1 Missing data analysis methods 
In the primary analysis, ACR20 response rate at 
, missing values will be handled by 
setting the ACR20 value to nonresponsive.  This approach will be used for all 
 
endpoints (ACR20, ACR50, ACR70, DAS28-CRP, PASI75/90/100, and MDA) at all time points.  
For a composite 
 endpoint (such as ACR20), if the values for any of the 
components at a time point are missing, the non-missing component variables will be used to 
determine the response status.  If the response status cannot be determined due to missing 
components, then the composite response-type endpoint status is considered 
for 
that time point. 
For the HAQ-DI, LDI, LEI, SF-36 and PsAID instruments, rules suggested by the developers of 
these will be followed in calculating scores when individual question/items may be missing.  
Details on handling missing data are outlined in 
.  
In general, missing values for any of the endpoints will not be imputed when summarizing these 
endpoints using descriptive statistics.  
In addition, missing values for safety endpoints will not be imputed. 


 
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7.2.2 Handling of missing or incomplete dates 
Imputation rules for missing or partial AE start date are defined below: 
If the start date has month and year but day is missing, the first day of the month will be imputed 
 
 
 
 
 
If the start date has year, but day and month are missing, the 1st of January will be imputed 
 
 
 
 
 
If the start date of an event is completely missing, then it is imputed with the first dose date. 
Imputation rules for missing or partial AE stop date are defined below: 
 
 
 
 
  
 
 
 
 
After the imputation, the imputed dates will be compared against the date of death, if available.  If 
the date is later than the date of death, the date of death will be used as the imputed date instead. 
Imputation rules for missing or partial medication start/stop dates are defined below: 
Missing or partial medication start date: 
 
  
 
  
Missing or partial medication stop date: 
 
 
 
 
 
 
 
 


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8 
STATISTICAL METHODS 
8.1 
General Statistical Conventions   
All statistical procedures will be completed using SAS version 9.4 or higher. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05.  
Continuous variables will be summarized using descriptive statistics, including number of subjects 
(n), mean, median, standard deviation (SD), minimum and maximum. One additional decimal point 
for mean and median and 
 for SD will be used. 
For categorical variables, summaries will include counts of subjects and percentages. 
 
  
 
For summary purposes, baseline will be defined as the last available value prior to the date of first 
IMP administration; all summaries will be presented by treatment group, unless otherwise 
specified. 
For reporting purpose, summary tables for efficacy variables and safety variables will be displayed 
by nominal visit as appropriate. Unscheduled assessments will not be included in the summary 
tables, but will be in data listings. 
All subject data, including those derived, will be presented in individual subject data listings. 
Unless otherwise stated, unscheduled visit results will be included in date/time chronological order, 
within patient listings only. All listings will be sorted by treatment group, subject number, 
date/time and visit. The treatment group as well as patient’s sex and age will be stated on each 
listing. Unless otherwise stated, data listings will be based on all randomized subjects. 
The treatment groups will be displayed in the format below in tables including 
: 
 
 
 
 
 
 
 
 
 
 
The treatment groups will be displayed in the format below for tables including 
 
and all listings: 


 
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8.2 
Protocol deviations 
Population membership details will be listed, including reason for exclusion from each population. 
All major protocol deviations identified will be summarized by treatment group and overall. 
A listing will include the inclusion/exclusion criteria violated at Screening and at Baseline Visits as 
well as other protocol deviations identified based on data recorded on the eCRF and/or protocol 
deviation Logs 
 
8.3 
Subject disposition 
The number of subjects in the following categories will be summarized overall and by treatment 
group:  
• 
Randomized 
• 
Full Analysis Set (FAS) 
• 
Per Protocol Analysis Set (PPAS) 
• 
Safety Analysis Set 
• 
PK Analysis Set 
• 
ADA Evaluable Set 
The number and percentage 
) of subjects in each of the following disposition 
categories will be summarized overall and by treatment group: 
• 
Completed treatment at 
 
• 
Prematurely discontinued the treatment and the reasons for discontinuation  
• 
Completed study (i.e., completed the wash-out period) 
• 
Prematurely discontinued the study and the reason for discontinuation  
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation.  
8.4 
Demographics and baseline characteristics 
The demographics and baseline characteristics, medical history, prior and concomitant medications 


 
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will be summarized by treatment group and overall for the FAS. Individual subject listings will be 
provided to support the summary tables. 
8.4.1 Demographics 
Age (years), height (cm), weight (kg) and other continuous demographic variables at Screening 
will be summarized descriptively. Gender, primary race, ethnicity and other categorical variables 
will be summarized using FAS. 
Year of birth, age, gender, primary race, ethnicity, height and weight will be listed as part of 
demographic listing. 
8.4.2 Baseline characteristics 
Rheumatoid factor, body surface area (BSA) affected by psoriasis, tender joint counts, swollen 
joint counts, PGA of disease activity, PtGA of disease activity, patient’s pain assessment, HAQ-DI, 
hsCRP, ESR, DAS28-CRP, LDI, LEI, PASI, SF-36, and PsAID at baseline will be summarized.  
 affected by psoriasis at baseline will be 
summarized as well. 
8.4.3 Medical history 
A summary of medical history will be presented by system organ class (SOC) and preferred term 
(PT) using the most recently available version of the Medical Dictionary for Regulatory Affairs® 
(MedDRA). A listing of medical history will be provided as well. 
Quantiferon testing and chest X-ray results at screening will be summarized using frequency counts 
for FAS. 
8.4.4 Prior and concomitant medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary and categorized as follows: 
Prior medications and concomitant medications will be summarized descriptively using frequency 
tables by ATC class and preferred term by treatment group on the Safety Analysis Set. Prior 
medications are those with a stop date before the first dose of study drug, and concomitant 
medications are those with a stop date on or after the first dose of study drug or ongoing. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
 
Prior biologic and prior anti-TNF medications will be summarized in a separate table.


 
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8.5 
Extent of exposure 
8.5.1 Treatment Duration 
Duration of study drug exposure 
 will be calculated as: 
 
 regardless of study drug interruption. 
Study drug exposure will be summarised by treatment group on the Safety Analysis Set using 
descriptive statistics. 
Exposure to randomized study drug will also be categorised in intervals 
.  
8.5.2 Treatment Compliance 
Study drug compliance will be calculated as: 
  
 
. If only one 
syringe among the two is administered at a visit, the number of dose will be counted 
If both 
syringes are administered at a visit, the number of dose will be counted 
 total number of 
doses planned will count 
 
 If a subject discontinues treatment, the total number of doses will be 
counted from 
.  
Study drug compliance will be summarized by treatment group by the number of subjects (n), 
mean, SD, median, min, and max. They will also be summarized in categories 
 
. 
Study drug compliance summaries will be based on the Safety Analysis Set. 
8.6 
Efficacy analyses 
8.6.1 Analysis methods 
 
Analysis of proportions 
The Cochran-Mantel-Haenszel (CMH) test, incorporating prior anti-TNF use 
 and Baseline 
weight 
, will be used to compare response rates of 
response–type variables between each of the respective active dose arms and placebo.  In addition, 
the 
 
 
  Should 
assumptions per the 
 not be satisfied, pairwise comparisons will be based on 
 after collapsing across levels of the stratification factors.  In this case, the 
response rate difference and CI will be based on normal approximation without considering 
stratification. 
 repeated measures analysis of continuous endpoints 


 
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A 
 analysis will be performed. The SAS procedure PROC 
MIXED will be used. The preferred model will include the fixed categorical effects of treatment, 
visit, treatment-by-visit interaction, prior TNF use
 Baseline weight 
 as 
well as the continuous fixed covariates of baseline value. An unstructured matrix for the within-
subject error variance-covariance will be used. The denominator degrees of freedom will be 
calculated according to the 
 
In case of non-convergence with the unstructured matrix, other within-subject error variance-
covariance matrices, such as 
 will be considered. 
The model will provide 
 
 
 
8.6.1.1 Multiplicity 
In order to control for
 the 
 will be used in the determination of 
dose level success against placebo.  There are 
 for the primary endpoint 
ACR20: 
 
. The 
from 
 the four comparisons above are ordered from lowest to highest value. The first p-
value 
 the sequence will be compared with 
 the second lowest will be 
compared with 
 the third lowest will be compared with 
 and the 
highest will be compared with 
 If any p-value is less than the specified value, the 
corresponding test is declared significant. This test procedure will protect 
at 
the 
 level. 
8.6.2 Analysis of primary efficacy endpoint(s) 
The primary efficacy variable is ACR20 at 
 ACR20 will be analysed with 
 as 
described in 
 Early withdrawals and any other subjects with ACR20 undeterminable 
 will be classified as 
. Subjects who fail to show minimal response to 
treatment
 
 may have their background medications adjusted according to the maximum 
permitted daily dose described in the protocol and continue in the study.  Any subject requiring 
these adjustments will be counted as a non-responder for the primary analysis. 
The primary efficacy analysis will be carried out using the subjects from the FAS. To control for 
, the 
 will be used. The pair-wise comparisons for the primary 
endpoints 
 
 
 
 
 


 
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Subgroup analysis will be performed for each of the following subgroup variables: 
• 
Prior anti-TNF use 
 
• 
Baseline weight 
 
 
 
 
  
 
  
 
  
 
 
Estimates of the difference between the treatment groups, along with the 
 CI (
), 
will be presented for each defined category of each subgroup variable.   
If sample size for a category of a subgroup factor is too small, the analysis for that subgroup may 
not be performed. 
The primary purpose of the subgroup analyses is to check for consistency of results across 
stratification factors. 
A sensitivity analysis of ACR20 with ESR replacing CRP will be performed. 
8.6.3 Analysis of secondary endpoints 
All secondary analyses will be performed using the FAS, unless otherwise stated. The response-
type endpoints 
 will be 
analyzed based on the methods described for ACR20 in primary analysis.  Continuous endpoints 
(
 
 
will be analyzed based on an MMRM analysis that includes the fixed effects of treatment, visit, 
treatment by visit interaction, prior anti-TNF use
 Baseline weight 
 and 
Baseline value. Due to 
 
Tildrakizumab and placebo group switching 
 
 
Tildrakizumab 
, the comparisons between active drug and placebo will not be 


 
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performed for the secondary endpoints collected after 
. Response-type and continuous 
endpoints after 
 will be summarized descriptively. In addition, proportion of subjects who 
require adjustment of background therapy at 
 be presented with descriptive statistics. 
 
 
 
   
 
   
 
 
   
 
   
 
   
 
 
. 
8.6.4 Analysis of exploratory endpoints 
The response-type endpoints (PASI 75/90/100) up to 
 will be analyzed based on the CMH 
methods described for ACR20.  Continuous endpoints (
) up 
 will be analyzed based on an MMRM analysis as described for secondary endpoints. 
Response-type and continuous endpoints after 
 will be summarized descriptively. 
In addition, there will be sub-groups of patients in Part 3 who either did or did not receive any new 
therapy for PsA and these will be analyzed separately for ACR20, ACR50, and ACR70. 
All the exploratory analyses will be based on the FAS except PASI, which will be based on the 
subjects in 
 who have baseline 
 
8.7 
Safety analyses 
Safety analyses will be conducted on the Safety Analyses Set (treated subjects) and will be 
performed for all safety variables specified below.  
All safety data will be summarized by treatment group.  
The safety analyses of changes from baseline to a specific time point in safety variables (e.g., 
laboratory parameters, vital signs, and ECG) will only include subjects from the Safety Analysis 
Set who have data available for both the baseline and the time point under consideration unless 
otherwise specified. 
No statistical test will be performed. 
8.7.1 Adverse events 
All AEs will be classified by Primary System Organ Class (SOC) and Preferred Term (PT) 
according to the most recently available version of the MedDRA dictionary. 


 
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In summaries by SOC and PT, adverse events will be sorted within each SOC and PT in 
alphabetical order. In summaries by PT, AEs will be sorted within each PT in alphabetical order. 
Details for imputing missing or partial start dates of adverse events are described in 
. 
TEAEs are defined as any AE occurring or worsening on or after the first dose of IMP. AE 
summary tables will be presented for TEAEs only and will include the following: 
• 
All TEAEs 
• 
Related TEAEs (AE will be defined as related if causality is possibly, probably, or certain)  
• 
TEAEs by maximum severity 
• 
TEAEs leading to discontinuation  
• 
Serious TEAEs 
• 
TEAEs leading to death. 
An overall summary for the categories above will be prepared by study part, treatment group and 
overall. A TEAE in 
 is defined with the event start date on/after the 
 but before 
 date of IMP or on/before the last dose date of IMP if the subject discontinues 
treatment before 
 A TEAE in 
 defined with the event start date on/after 
 
dosing date but on/before the 
 A TEAE in 
 is defined with the event 
start date after the last dose date of IMP. 
In addition, all TEAEs will be summarized by study part 
 SOC, PT and treatment 
group using frequency counts and percentages (i.e., number and percentage of subjects with an 
event). 
Where a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a specific study part, the subject will only be counted once at the preferred terminology 
level in adverse event frequency tables. 
Where a subject has multiple adverse events within the same system organ class in a specific study 
part, the subject will only be counted once at the system organ class level in adverse event 
frequency tables. 
When reporting adverse events by intensity, in addition to providing a summary table based on the 
event selection criteria detailed above, summary table will also be provided based on the most 
intense event - independent of relationship to study treatment. 
 
 
 
 
  
 
 


 
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In addition, a listing containing individual subject adverse event data for TEAEs leading to 
discontinuation from study, Serious TEAEs, TEAEs leading to death, 
 will be 
provided separately. All AEs, including pre- and post-treatment AEs, will be presented in an 
individual subject data listing. 
8.7.2 Clinical laboratory evaluations 
For the purposes of summarization in both the tables and listings, all laboratory values will be 
presented in SI units. If a lab value is reported using a nonnumeric qualifier 
 
, the given numeric value will be used in the 
summary statistics, ignoring the nonnumeric qualifier. 
Clinical laboratory parameters observed values and changes from Baseline will be summarized at 
each scheduled visit. Shift tables from baseline to post-baseline in lab parameters for each 
treatment group during 
 will be displayed by visit. 


 
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Values outside the 
 
 
 
8.7.3 Vital signs 
Vital sign 
 will be summarized at each scheduled visit.  
A listing of vital signs by subject will be produced. 
8.7.4 Physical examinations 
Physical examination results will be summarized with incidence of 
” by 
body system at each scheduled visit. All physical examination data and abnormalities will be listed.  
8.7.5 Electrocardiograms 
The overall ECG interpretation will be summarized by presenting the 
 
 with 
 
 
 
 
 
 
. In addition, shift tables from baseline to post-baseline in overall ECG interpretation 
during 
 will be displayed by visit and treatment group. 
ECG parameter 
 will be summarized at 
each scheduled visit.  
An accompanying listing of subjects will be produced and it will display all ECG findings during 
the study in subjects with abnormal ECGs, as determined by the investigator. 
8.7.6 Assessment of Suicidal Ideation and Behavior 
Subjects will be assessed for suicidal ideation and behavior at the Screening Visit using the 
Baseline (Lifetime) C-SSRS, and each subsequent visit using the C-SSRS Since Last Visit version. 
The C-SSRS consists of 2 major aspects: Suicidal Ideation and Suicidal Behavior. Based on 
outcomes and data analyses suggested by the C-SSRS website, the following endpoints will be 
used to analyze C-SSRS data: 
• 
Presence of Suicidal Ideation:  
 
• 
Presence of Suicidal Behavior:  
 
. 
• 
Suicidal ideation score: 
 
  
The number
 of subjects with presence of suicidal ideation/behavior will be summarized at each 
assessment time. The C-SSRS data will be summarized using worst-case shift tables. Worst-
 
 
  


 
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8.8 
Other analysis 
8.8.1 Analysis of Pharmacokinetic Endpoints 
Plasma tildrakizumab concentration data will be listed by individual subject and summarized by 
time and tildrakizumab dose group. 
PK parameters of AUC, Cmax, Cmin, and T1/2 will be summarized with descriptive statistics (n, mean, 
SD, geometric mean, coefficient of variation [%CV], minimum, first, second (i.e., median) and 
third quartiles, and maximum). 
The PK Analysis Set will be used for the analysis. 
Exploratory PK analyses will be performed by another vendor and described in a separate SAP. 
8.8.2 ADA to Tildrakizumab 
For each subject, tildrakizumab serum concentrations and ADA sample results are matched to 
actual sampling times and treatment.  Subjects are grouped based on the actual treatment received, 
rather than the treatment group at randomization.  Subjects have baseline samples taken prior to 
dosing to assess for any preexisting immune response that may be detected by the ADA assays.  
Subjects are considered positive if at least one pre-treatment or post-dose sample is positive at any 
time.  Positive subjects are subsequently categorized into treatment-emergent positive if the 
positive sample occurs following treatment with tildrakizumab or non-treatment emergent positive 
if the subject has an immune response present at baseline and the response is not boosted following 
treatment. 
The presence of tildrakizumab can interfere with the 
 at concentrations
 the drug 
tolerance level (DTL) of
  Therefore, samples with a negative test result in the 
 
can only be described as 
 in the case of a tildrakizumab concentration below 
.  The 
immunogenicity status of a subject is considered to be negative if all pre-treatment and post-dose 
samples tested negative in the ADA assay and if the concentration of tildrakizumab in the last 
post-dose sample is below the DTL.  Therefore, an integrated evaluation of ADA results and drug 
serum concentrations is required for interpretation of immunogenicity results. 
To summarize, subjects are categorized in one of four immunogenicity categories as described in 
Table 3.  
 
.  The proportion of non-treatment emergent 
positive subjects is similarly reported.  
 
 
 
 
Table 3 Immunogenicity Subject Status Definitions 


 
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The anti-tildrakizumab immunogenicity status of evaluable subjects, along with titer and 
neutralizing antibody, will be summarized by dose level in 
 Only data from 
 is used 
and placebo samples in 
 are excluded. The anti-tildrakizumab immunogenicity status of 
evaluable subjects will be further summarized by treatment group and by dose level for 
 
.  ADA data will be presented in a listing. 
8.8.3 Correlation of ADA with Pharmacokinetics 
Mean plots of tildrakizumab concentration (µg/mL) versus time for ADA positive and ADA 
negative or inconclusive during 
 will be displayed for subjects in groups of 
 
.  
8.8.4 ADA to Efficacy Endpoints 
The impact of ADA on the responder type of efficacy endpoints 
 will be 
summarized by dose level for 
 Only data from 
 is used and placebo samples in 
 
are excluded. 
8.9 
 
 
 
 
 
 
 


 
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9 
REPORTING CONVENTION 
This section details the format and layout of all TFLs and statistical output that will be produced in 
conjunction with the Clinical Study Report. The table of contents and templates for the TFLs will 
be produced in a separate document. 
All data analyses and generation of TLFs will be performed using SAS 9.4® or higher. 
The following reporting conventions will be adopted for the presentation of study data: 
• 
The tables and listings will be provided in a Word document in landscape format, Courier 
New 8 with the following margins: top: 1.50 in, bottom: 1.00 in, left: 1.00 in, right: 1.00 in, 
header: 1.50 in, footer: 0.50 in. The output alignment will be centered on the page and the 
titles and footnotes will be center aligned.  
• 
The ICH3,4 numbering convention will be used for all TLFs.  
• 
The analysis population represented on the tables will be clearly identified in the title of the 
table.  
• 
Dates will appear as DDMMMYY format; times as HH:MM format
  
• 
For the presentation of summary data, results will be aligned on the decimal point and be 
centered within the column. Unless otherwise stated, tables will summarize the results per 
treatment group (Active treatment, Placebo) and overall.  
• 
All listings will be ordered by investigational site, patient number, date/time and visit. The 
treatment group (Active treatment, Placebo) as well as patient’s sex and age will be stated 
on each listing. Line break spacing will be added (for example between different patients, 
visits) to facilitate review of the listings.  
• 
All TLFs will have the SAS program path and name, output filename and date/time of 
production in the footnote, and will include the following hierarchy of titles and footnotes 
(as an example): 
 
 
 
 
  
  
  
 
 
 


 
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10 
CHANGES TO PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
. 
 
 
 
 
 


 
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11 
REFERENCES 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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12 
APPENDICES 
12.1 Endpoint definition and derivation details 
12.1.1 Health Assessment Questionnaire – Disability Index (HAQ-DI) 
There are 8 categories assessed by the HAQ-DI5: 1) dressing and grooming, 2) arising, 3) eating, 4) 
walking, 5) hygiene, 6) reach, 7) grip, and 8) common daily activities.  For each of these 
categories, patients report the amount of difficulty they have in performing 2 or 3 specific 
activities.  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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For each question in the questionnaire, the level of difficulty is 
  
 
  
  
 
   
 
In order to compute score patient must complete 6 of the 8 categories 
 
1.
 
 
 
 
 
 
 
 
 
 
 
 
 of categories answered 
  This yields a single 
disability score. 
 
. 
12.1.2 
36-item Short Form 
The SF-36 v26 is a multi-purpose survey that measures 8 domains of health: physical functioning, 
role limitations due to physical health, bodily pain, general health perceptions, vitality, social 
functioning, role limitations due to emotional problems, and mental health. It yields scale scores for 
each of these 8 domains and 2 summary measures of physical and mental health. All domains and 
summary components are scored such that a higher score indicates a higher functioning or health 
level. 
These 8 domains are as follows: 
a. Physical Functioning (PF).  
 
 
 
b. Role-Physical (RP).  
 
 
 
 


 
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c. Bodily Pain (BP).  
 
 
d. General Health (GH).  
 
 
 
e. Vitality (VT).  
 
 
f. Social Functioning (SF).  
 
 
 
g. Role-Emotional (RE).  
 
 
 
h. Mental Health (MH).  
 
 
The summary component scores are: 
a. Physical Component Summary (PCS). 
b. Mental Component Summary (MCS).  


 
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Data Derivation Details to Obtain Scale Scores for SF-36 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 


 
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. 


 
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. 


 
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