Clinical trial NCT02980705
Conditions: Active Ankylosing Spondylitis or Non-Radiographic Axial Spondyloarthritis
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2017-11-06; Completion date: 2019-09-03
Enrollment: 180 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-Blind, placebo-controlled Phase 2a study to evaluate the efficacy and safety of SUNPG1622.

Detailed description:

Arms: arm 1: SUNPG1622 I dose arm 2: Placebo dose
Interventions: intervention 1: SUNPG1622 I dose intervention 2: Placebo dose
Intervention descriptions: intervention 1: Injection intervention 2: Injection

Protocol documents:
SAP_002.pdf: 
16.1.9        Documentation of statistical methods 
The following documents are included: 
Analysis of proportions 
The Cochran-Mantel-Haenszel (CMH) test, incorporating prior anti-tumor necrosis factor use 
as a stratification factor, was used to compare response rates of response–type variables 
between 
 tildrakizumab and placebo. In addition, the Mantel-Haenszel common risk 
(the response rate) difference between 
 tildrakizumab and placebo and the 
confidence interval (CI) were estimated. Should assumption per the Mantel-Fleiss criterion 
not be satisfied, the comparison was to be based on a Fisher’s exact test after collapsing across 
levels of the stratification factor. In this case, the response rate difference and CI was based 
on a normal approximation without considering stratification. 
The primary efficacy variable is ASAS20 at 
 ASAS20 was analyzed with CMH test 
as described above. Early withdrawals and any subjects with ASAS20 undeterminable at 
 were classified as non-responders. Subjects who failed to show minimal response to 
treatment (defined as 
 improvement from Baseline in total back pain or inflammation) 
at 
 may have had their background medications adjusted according to the maximum 
permitted daily dose described in the protocol and continued in the study. Any subject 
requiring these adjustments was counted as a non-responder for the primary analysis. 
The sample SAS codes are: 
The secondary and exploratory response-type endpoints (ASAS
, ASAS
, ASAS
 etc.) 
were analyzed similarly. 
Mixed model repeated measures analysis of continuous endpoints 
A mixed model repeated measure (MMRM) analysis was performed. The SAS procedure 
PROC MIXED was used. The preferred model included the fixed categorical effects of 
treatment, visit, treatment-by-visit interaction, and prior TNF use (yes/no), as well as the 
continuous fixed covariate of baseline value. An unstructured matrix for the within-subject 
error variance-covariance was used. The denominator (degrees of freedom) was calculated 
according to the Kenward-Roger method. 
In case of non-convergence with the unstructured matrix, other within-subject error 
variance-covariance matrices, such as compound symmetry (CS), was considered. 
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Sun Pharma Global FZE
CSR CLR_16_22 (Tildrakizumab)


The model provided least-squares mean estimates, standard errors, 
CIs and 
p-values for mean change at all time points between treatments (tildrakizumab vs. placebo). 
Continuous endpoints (change from baseline in PtGA of disease activity, Total Back Pain, 
Nocturnal Pain, Inflammation, BASFI, BASMI, BASDAI, ASQoL, ASDAS-CRP, 
ASDAS-ESR, MASES, SF-36, FACIT-fatigue, TJC46, SJC44, hsCRP, SPARCC MRI Index 
of Disease Activity Score of the SI Joints, SPARCC MRI Index of Disease Activity Score of 
the Spine, and Modified Berlin ASspiMRI) up to 
 analyzed based on a MMRM 
analysis that includes the fixed effects of treatment, visit, treatment by visit interaction, prior 
anti-TNF use (yes/no), and Baseline value. Due to placebo group switching to 
tildrakizumab at 
, the comparison between active drug and placebo was not performed 
for the endpoints collected after 
.  
Below is an example of the SAS code for the MMRM: 
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Sun Pharma Global FZE
CSR CLR_16_22 (Tildrakizumab)


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
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Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Phase 2a 
Study to Evaluate the Efficacy and Safety of Tildrakizumab in 
Subjects with Active Ankylosing Spondylitis or 
Non-Radiographic Axial Spondyloarthritis 
Protocol Number: 
CLR_16_22 
Protocol Version, Date 
Document Version, Date: 
Prepared by: 
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. 
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V3.0 Final, 19 Mar 2018 
Final v2.0, 01 Oct 2019


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
 
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SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved at Sun Pharma Advanced Research Company Ltd 
by: 
Rocco Ballerini 
08 Oct 2019 20:21:022+0000 
REASON: I approve this document 
4527a681-b6fb-4e53-bc97-98fb389dd032 
Rocco Ballerini, Associate Vice President- Biostatistics and Data 
Management 
Date 
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REVISION HISTORY 
Statistical Analysis Plan (SAP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ....................................................................................................................... 2 
REVISION HISTORY .................................................................................................................... 3 
TABLE OF CONTENTS................................................................................................................. 4 
LIST OF ABBREVIATIONS .......................................................................................................... 6 
1 INTRODUCTION ..................................................................................................................... 9 
2 STUDY OBJECTIVES ............................................................................................................ 10 
2.1 Primary objectives .......................................................................................................... 10 
2.2 Secondary objectives ...................................................................................................... 10 
2.3 Exploratory objectives .................................................................................................... 10 
3 STUDY DESIGN .................................................................................................................... 12 
3.1 General study design ....................................................................................................... 12 
3.2 Randomization and blinding ........................................................................................... 13 
3.3 Study treatments and assessments ................................................................................... 14 
4 STUDY ENDPOINTS ............................................................................................................. 23 
4.1 Primary efficacy endpoint ............................................................................................... 23 
4.2 Secondary efficacy endpoints (up to Week 52) .............................................................. 23 
4.3 Exploratory endpoints ..................................................................................................... 24 
4.4 Safety endpoints .............................................................................................................. 26 
5 SAMPLE SIZE AND POWER ................................................................................................ 27 
6 ANALYSIS POPULATIONS ................................................................................................. 28 
6.1 Full Analysis Set (FAS) .................................................................................................. 28 
6.2 Per Protocol Analysis Set (PPAS) .................................................................................. 28 
6.3 Safety Analysis Set ......................................................................................................... 28 
6.4 PK Analysis Set .............................................................................................................. 28 
6.5 ADA Evaluable Set ......................................................................................................... 28 
6.6 Protocol deviations/violations and exclusions from analysis sets ................................... 28 
7 Statistical Considerations and analysis .................................................................................... 30 
7.1 Derived Variables ........................................................................................................... 30 
7.2 Handling of missing data and outliers ............................................................................. 30 
7.2.1 Missing data analysis methods ........................................................................... 30 
7.2.2 Handling of missing or incomplete dates............................................................ 30 
8 STATISTICAL METHODS .................................................................................................... 32 
8.1 General Statistical Conventions ...................................................................................... 32 
8.2 Protocol deviations ......................................................................................................... 33 
8.3 Subject disposition .......................................................................................................... 33 
8.4 Demographics and baseline characteristics ..................................................................... 33 
8.4.1 Demographics ..................................................................................................... 33 
8.4.2 Baseline characteristics ....................................................................................... 34 
8.4.3 Medical history ................................................................................................... 34 
8.4.4 Prior and concomitant medications ..................................................................... 34 
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8.5 Extent of exposure .......................................................................................................... 34 
8.5.1 Treatment Duration ............................................................................................. 34 
8.5.2 Treatment Compliance ........................................................................................ 34 
8.6 Efficacy analyses ............................................................................................................ 35 
8.6.1 Analysis methods ................................................................................................ 35 
8.6.1.1 Multiplicity ......................................................................................................... 36 
8.6.2 Analysis of primary efficacy endpoint ................................................................ 36 
8.6.3 Analysis of secondary endpoints ........................................................................ 37 
8.6.4 Analysis of exploratory endpoints ...................................................................... 37 
8.7 Safety analyses ................................................................................................................ 38 
8.7.1 Adverse events .................................................................................................... 38 
8.7.2 Clinical laboratory evaluations ........................................................................... 40 
8.7.3 Vital signs ........................................................................................................... 40 
8.7.4 Physical examinations ......................................................................................... 40 
8.7.5 Electrocardiograms ............................................................................................. 40 
8.7.6 Assessment of Suicidal Ideation and Behavior ................................................... 41 
8.8 Other analysis ................................................................................................................. 41 
8.8.1 Analysis of Pharmacokinetic Endpoints ............................................................. 41 
8.8.2 ADA to Tildrakizumab ....................................................................................... 41 
8.8.3 Correlation of ADA with Pharmacokinetics ....................................................... 43 
8.8.4 ADA to Efficacy Endpoints ................................................................................ 43 
8.9 Interim analysis ............................................................................................................... 43 
9 REPORTING CONVENTION ................................................................................................ 44 
10 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ............................... 45 
11 REFERENCES ........................................................................................................................ 46 
12 APPENDICES ......................................................................................................................... 47 
12.1 Endpoint definition and Derivation Details .................................................................... 47 
12.1.1 36-item Short Form ............................................................................................. 47 
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LIST OF ABBREVIATIONS 
The following abbreviations will be used within this SAP. 
Abbreviation or 
  special term  
Explanation 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AS 
Ankylosing Spondylitis 
ASAS 
Assessment of SpondyloArthritis International Society 
ASDAS 
Ankylosing Spondylitis Disease Activity Score 
ASQoL 
Ankylosing Spondylitis Quality of Life 
ASspiMRI 
Ankylosing Spondylitis Spine Magnetic Resonance Imaging Activity Score 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
BMI 
Body Mass Index 
CI 
Confidence Interval 
cm 
Centimeter 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DBL 
Database Lock 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
FACIT 
Functional Assessment of Chronic Illness Therapy 
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FAS 
Full Analysis Set 
ESR 
Erythrocyte Sedimentation Rate 
hsCRP 
high sensitivity C-reactive protein 
IA 
Interim Analysis 
IMP 
Investigational Medicinal Product 
IVRS 
Interactive Voice Response System 
kg 
Kilogram 
MACE 
Major Adverse Cardiac Events 
MASES 
Maastricht Ankylosing Spondylitis Enthesitis Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measurements 
MRI 
Magnetic Resonance Imaging 
n 
Number of non-missing observations 
nr-axSpA 
non-radiographic axial Spondyloarthritis 
PGA 
Physician Global Assessment 
PK 
Pharmacokinetics 
PPAS 
Per Protocol Analysis Set 
PT 
Preferred Term 
PtGA 
Patient Global Assessment 
Q1 
Lower Quartile 
Q3 
Upper Quartile 
q4wk 
Every 4 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 
SJC44 
swollen joint count of 44 joints 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPARCC 
SpondyloArthritis Research Consortium of Canada 
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T1/2 
Half-life 
TEAE 
Treatment Emergent Adverse Event 
TJC46 
tender joint count of 46 joints 
TLFs 
Tables, Listings and Figures 
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_22 “A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study to Evaluate the 
Efficacy and Safety of Tildrakizumab in Subjects with Active Ankylosing Spondylitis or Non-
Radiographic Axial Spondyloarthritis” which was originally issued on 
 and 
amended on 
 and 
. 
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_22 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_22. 
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2 
STUDY OBJECTIVES 
 
2.1 
Primary objectives 
Part 1 
 
• 
To evaluate the efficacy of tildrakizumab in subjects with ankylosing spondylitis (AS) or 
non-radiographic axial spondyloarthritis (nr-axSpA), as measured by the proportion of 
subjects achieving Assessment of SpondyloArthritis international Society (ASAS) 
 
response criteria at 
 
Parts 1 and 2 
• 
To assess the safety/tolerability and immunogenicity of tildrakizumab in subjects with AS 
or nr-axSpA. 
2.2 
Secondary objectives 
Parts 1 and 2 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the 
proportion of subjects achieving ASAS20 response criteria at 
, and ASAS40 response 
criteria at 
, and proportion of subjects who require adjustment of background 
therapy. 
• 
To characterize the pharmacokinetics (PK) of tildrakizumab in subjects with AS or nr-axSpA. 
2.3 
Exploratory objectives 
Parts 1 and 2 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or Nr-axSpA, as measured by the 
proportion of subjects who achieve ASAS20 or ASAS40 at other measured time points. 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the 
proportion of subjects who achieve ASAS70 or ASAS5/6. 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the 
change from Baseline in ASAS components, Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing 
Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Quality of Life questionnaire 
(ASQoL), Visual Analog Scale (VAS) (total back pain and nocturnal pain score), Ankylosing 
Spondylitis Disease Activity Score (ASDAS) C-reactive protein (CRP), ASDAS erythrocyte 
sedimentation rate (ESR), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), short 
form  36  (SF-36),  Functional  Assessment  of  Chronic  Illness  Therapy  (FACIT)-fatigue, 
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high-sensitivity CRP (hs)CRP, SpondyloArthritis Research Consortium of Canada (SPARCC) 
magnetic resonance imaging (MRI) Index of Disease Activity of the Sacroiliac (SI) Joints, 
SPARCC MRI Index of Disease Activity of the Spine, and Modified Berlin Ankylosing 
Spondylitis Spine Magnetic Resonance Imaging Activity Score (ASspiMRI), swollen joint 
count of 44 joints (SJC44), and tender joint count of 46 joints (TJC46) at measured time points. 
• 
To evaluate the tildrakizumab exposure/response relationship.  
Part 3 
• 
To assess the effect of investigational medicinal product (IMP) discontinuation on ASAS20, 
ASAS40, ASAS70, ASAS5/6, ASAS components, BASDAI, BASMI, BASFI, VAS (total 
back pain and nocturnal pain score), MASES, SF-36, FACIT-fatigue, TJC46, and SJC44 at 
measured time points. 
• 
To evaluate immunogenicity following IMP discontinuation. 
• 
To characterize the PK of tildrakizumab in subjects with AS or nr-axSpA following IMP 
discontinuation. 
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3 
STUDY DESIGN 
 
3.1 
General study design 
This is a randomized, multinational, double-blind, placebo-controlled, Phase 2a study. The study 
will consist of a Screening Period 
 Part 1, a double-blind, placebo-controlled period 
 Part 2, a 
 follow-up period 
 and Part 3, a 
 During the wash-out period, subjects will no longer 
receive tildrakizumab and will be treated according to the Investigators’ discretion. 
At least 
 subjects with active AS (Stage 1 of study) and 90 subjects with active nr-axSpA (Stage 
2 of study) who satisfy the inclusion criteria and do not meet the exclusion criteria will be enrolled 
in this study. Approximately 
subjects will be randomized into the Double-Blind treatment 
period. 
The Study Flow Chart is presented in Figure 1. 
Figure 1: Study Flow Chart 
 
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Statistical Analysis Plan (SAP) 
 
Abbreviations:    AS = ankylosing spondylitis; mg = milligram; 
nr-axSpA = non-radiographic axial spondyloarthritis; Wk = week 
 
Subjects who fail to show minimal response to treatment (defined as 
 from 
Baseline in pain [assessed by total back pain VAS 
] or inflammation [assessed using the 
last  stiffness assessments in the BASDAI]) at 
 in both stages of the study may have their 
background medications adjusted according to the maximum permitted daily dose and continue in 
the study. 
Tildrakizumab subjects in both stages who achieve ASAS20 at 
will receive treatment 
with 
 tildrakizumab 
 until 
 Subjects receiving tildrakizumab during Part 1 
who do not achieve ASAS20 at 
 will discontinue IMP treatment and enter the 
 
washout period. Subjects randomized to receive placebo during Part 1 of both stages of the study 
who complete the 
 visit will continue to Part 2 and receive tildrakizumab 200 mg q4 
weeks until 
 even if they do not achieve ASAS20. Subjects discontinued from IMP at any 
time (apart from withdrawal of informed consent) will be required to complete the EoT 
 
assessment a minimum of 
 after the last dose of IMP and enter the 
 washout 
period. Subjects who withdraw from the study during Part 3 will undergo the 
 (End of 
Study [EoS]) assessments at least 4 weeks after their last visit. 
On completion of Part 2, subjects may enter the long-term extension (LTE) study, 
, 
providing they meet the inclusion/exclusion criteria for the LTE study 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 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 (i.e., between the 
Screening visit and 
), 
 will be activated in the interactive voice 
recognition system (IVRS), and assigned randomly on a 
basis to the following treatment groups 
for cohorts of 
, respectively: 
• 
A: 
 tildrakizumab, 
 
• 
B: Placebo, administered by 
 
 
Randomization will be performed by the 
. Subjects will be stratified by prior anti-tumor- 
necrosis factor (anti-TNF) use (yes/no). Subjects with prior anti-TNF use will be capped 
 
of the total number of subjects. 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
 
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 (Stage 1) subjects will begin upon study approval; recruitment for 
 
(Stage 2) subjects will begin only upon written notification by the Sponsor to the Competent 
Authorities and Investigators. 
3.2.2 Blinding 
This is a double-blind study. None of the study team, the subject, and the Sponsor (or 
representative) will be aware of the administered study drug to each subject until the completion of 
their double-blind treatment (
 visit) 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 ICON Site Monitor, the medical monitor, and the 
Project Manager 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 2 treatments assigned per the schedule outlined in the study flow chart. Study drug will 
be supplied as pre-filled syringes and a subject at a visit is expected to receive two syringes packed 
in a kit. Below are the details: 
•
 
: subjects will receive tildrakizumab 
 (
 of
) at 
.
•
Placebo arm, 
 will be administered at 
 and
Subjects will then receive tildrakizumab 
 at
. 
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 
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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 
 below. 
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DocUUID : a147708b-918b-4f21-b068-b4cff5ac95cc 
Table 2: Schedule of Assessments (Part 1 and 2) 
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Table 2: Schedule of Assessments (Part 3) 
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Statistical Analysis Plan (SAP) 
4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the proportion of subjects who achieve ASAS20 at 
 
ASAS20 response is defined as an improvement of 
 
 
 
 
 
 
The components of the ASAS
 assessments that will be used in this study are: 
− PtGA of disease activity (VAS in mm) 
− Total Back Pain (VAS in mm) 
− BASFI (VAS in mm) 
− Inflammation [average score of questions 5 and 6 of BASDAI] (VAS in mm) 
For the details on BASFI derivation, see 
 for the related endpoint. For inflammation, if 
either 
 of BASDAI is missing, non-missing score will be used. If both 
 
 are missing, then Inflammation is set to missing. 
For any component which is not on a scale of 
, they will be converted to 0 to 100 before 
calculating ASAS. 
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 ASAS endpoint is a response or non- 
response, then ASAS endpoint is not missing, else if the available non-missing components are not 
sufficient to determine the response status of ASAS 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 equal to 0, 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 ASAS endpoints. 
4.2 
Secondary efficacy endpoints (up to 
) 
The secondary efficacy endpoints of this study are: 
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Parts 1 and 2 
•
The proportion of subjects who achieve ASAS20 at 
•
The proportion of subjects who achieve ASAS40 at 
 
•
The proportion of subjects who require adjustment of background therapy
4.3 
Exploratory endpoints 
The exploratory endpoints of this study are: 
Parts 1 and 2: 
•
The proportion of subjects who achieve ASAS20 or ASAS40 at other measured time points
•
The proportion of subjects who achieve ASAS70 at measured time points
ASAS70 will be derived similarly as for ASAS40 by using 
 and 
. i.e.
ASAS70 response is defined as an improvement of 
 absolute improvement of 
units from Baseline in a VAS for at 
 domains: PtGA; Total Back Pain; BASFI; and
Inflammation. No worsening of
 VAS on a 
 scale in the remaining
 domain.
•
The proportion of subjects who achieve a ASAS5/6 response at measured time points
ASAS5/6 response is defined as a 
s (physical function
[BASFI], Total Back Pain, PtGA of disease activity, Inflammation [mean of 
of the BASDAI], spinal mobility [BASMI], and acute phase reactants [CRP]).
•
Change from Baseline in ASAS components at measured time points
•
Change from Baseline in BASDAI at measured time points
BASDAI is derived by computing the mean score of the 
)
and then adding that value to the sum of the score for the 
 and then 
It may be written as:
 
In the case of any single missing question, the BASDAI will be calculated using the remaining 
 
 
. 
Specifically, 
if 
 
 
 
 
is 
missing, 
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If more 
. 
BASDAI score ranges from 
. 
•
Change from Baseline in BASMI at measured time points
BASMI is a combined index to assess spinal mobility. BASMI score is collected on the CRF
page and ranges 
•
Change from Baseline in BASFI at measured time points
BASFI is derived by computing the mean of the score for the 10 questions. BASFI can be
calculated with up to 3 missing items by adjusting the denominator for the number of non- 
missing items.  If more than 3 items are missing, BASFI should be set to missing.
•
Change from Baseline in ASQoL at measured time points
ASQoL total score is calculated by summing the 
 and ranges
. Cases with more
than three missing items (ie more than 
) cannot be allocated a total score. For cases with
between one and three missing items, the total score is calculated as follows: 
 for the items affirmed and 
 
•
Change from Baseline in VAS (total back pain and nocturnal pain score) at measured time
points
•
Change from Baseline in ASDAS-CRP and ASDAS-ESR at measured time points
Note: Back Pain is from BASDAI 
); Duration of Morning Stiffness
is from BASDAI 
 Peripheral Pain/Swelling is from BASDAI
); Patient Global is from PtGA of disease activity 
);
CRP - the natural logarithm of CRP in mg/L; ESR- the square root of ESR in mm/h.
•
Change from Baseline in MASES at measured time points
MASES score is recorded in the CRF and ranges
.
•
Change from Baseline in SF-36 at measured time points 
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•
Change from Baseline in FACIT-fatigue at measured time points
FACIT-fatigue is a 
 item questionnaire with each item score ranges from 
 FACIT- 
fatigue total score (
) is calculated by summing the 
 items with 
 being
reversed 
) prior to summing.
In case of some answers are missing, the total score is prorated from the score of the answered
items as long as more than 50% of the items are answered. ie, FACIT-fatigue = 13*mean(non- 
missing of Q1 to Q13).
•
Change from Baseline in TJC46 and SJC44 at measured time points
•
Change from Baseline in hsCRP serum levels at measured time points
•
Change From Baseline in SPARCC MRI Index of Disease Activity Score of the SI Joints at
measured time points
•
Change From Baseline in SPARCC MRI Index of Disease Activity Score of the Spine at
measured time points
•
Change From Baseline in Modified Berlin ASspiMRI at measured time points
Part 3: 
ASAS20, ASAS40, ASAS70, ASAS5/6, ASAS components, BASDAI, BASMI, BASFI, SF-36, 
VAS (total back pain and nocturnal pain score), MASES, FACIT-fatigue, TJC46, and SJC44 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 
In each subject cohort (AS and nr-axSpA), approximately 45 subjects will be randomized per arm 
in a 1:1 ratio to tildrakizumab 200 mg or placebo and will be stratified by anti-TNF use (yes/no). 
This sample size achieves 80% power (accounting for futility assessment) to detect a treatment 
effect in ASAS20 at 
(placebo ASAS20 = 
; tildrakizumab ASAS20 = 
). 
The test statistic used is the 
 Cochran-Mantel-Haenszel (CMH) test at the 
 significance 
level.  A 
drop-out rate has been assumed. 
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6 
ANALYSIS POPULATIONS 
6.1 
Full Analysis Set (FAS) 
The  FAS  will  include  all  randomized  subjects  who  have  received  at  least  1 dose  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 variables. The deviations may 
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 deviation 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 received at least 1 dose 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 least 1 
ADA data point after the date of first IMP administration. Assay results from the placebo portion of 
the trial will not be included in the immunogenicity assessment, although subjects who are 
randomized to placebo in Part 1 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 deviations 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  
lead  statistician  ahead  of  the 
Classification Meeting, based on data recorded on the eCRF. 
• 
Protocol Deviation Logs, provided by 
 Medical/Clinical. 
Further, deviations from the protocol will be classified as major/minor or key/non-key depending 
on documentation 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 
deviations 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 with BASDAI 
 at Screening or Response to the BASDAI 
question ‘How would you describe the overall level of AS neck, back or hip pain you have 
had?’ of 
 on the VAS 
 at Screening 
• 
Non-compliance with study treatment 
) 
• 
Disallowed concomitant medications 
• 
Treatment error - at least one dose of randomized treatment and one dose of incorrect 
treatment were administered to a subject. 
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Statistical Analysis Plan (SAP) 
 
 
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. 
 
Variables 
Formula 
Body mass index (BMI; kg/m2) 
weight (kg)/[height (m)]2 
Study day at any visit 
(visit date – date of first IMP administration) + 1 for visit 
dates on or after first IMP dosing date; (visit date – date of 
first IMP administration) for visit dates before first IMP 
dosing date 
Change from baseline 
 
Percent change from baseline 
 
 
7.2 
Handling of missing data and outliers 
7.2.1 Missing data analysis methods 
In the primary analysis, ASAS20 response rate at 
, missing values will be handled by 
setting the ASAS20 value to nonresponsive. This approach will be used for all “response-type” 
endpoints (ASAS40, ASAS70, and ASAS5/6) at all time points. 
For a composite “response-type” endpoint (such as ASAS
), if values in any of the components 
at a time point are missing, the component variables that are not missing will be used to determine 
the response status. If one cannot determine the response status in the presence of missing 
components, then the composite response-type endpoint status is considered “non-response” for 
that time point. 
For the BASDAI, BASMI, BASFI, MASES, SF-36, and FACIT 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 in 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. 
7.2.2 Handling of missing or incomplete dates 
Imputation rules for missing or partial AE start date are defined below: 
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If the start date has month and year but day is missing, the first day of the month will be imputed 
• 
If this date is earlier than the first dose date, then the first dose date will be used instead. 
• 
If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead. 
If the start date has year, but day and month are missing, the 1st of January will be imputed 
• 
If this date is earlier than the first dose date, then the first dose date will be used instead. 
• 
If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead. 
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: 
• 
If the stop date has month and year but day is missing, the last day of the month will be 
imputed 
• 
If the stop date has year, but day and month are missing,  the 31th  of December will be 
imputed 
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: 
• 
If only Day is missing, use the first day of the month. 
• 
If Day and Month are both missing, use the first day of the year. 
Missing or partial medication stop date: 
 
If only Day is missing, use the last day of the month. 
 
If Day and Month are both missing, use the last day of the year. 
 
If Day, Month and year are all missing, assign ‘continuing’ status to 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
 
Summaries for AS or nr-axSpA will be presented separately. Summary statistics will also be 
presented by treatment group. 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 2 additional decimal points for SD will be 
used. 
For categorical variables, summaries will include counts of subjects and percentages. Percentages 
will be rounded to one decimal place. 
Two-sided 95% confidence intervals (CI) will be provided when relevant. 
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 displayed 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 cohort, 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 Part 1 only: 
• 
 Tildrakizumab 
• 
Placebo 
The treatment groups will be displayed in the format below for tables including Parts 2 and/or 3 
and all listings: 
• 
 Tildrakizumab 
• 
Placebo → 
Tildrakizumab 
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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 from ICON Medical. 
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 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized overall and by treatment group: 
• 
Completed treatment at Parts 1 and 2 
• 
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 
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, race, ethnicity, height and weight will be listed as part of demographic 
listing. 
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8.4.2 Baseline characteristics 
Tender joint counts 
 swollen joint counts 
 PGA of disease activity, PtGA of disease 
activity, total back pain, and nocturnal pain, MASES, ASQoL, SF-36, BASDAI, BASMI, BASFI, 
FACIT, SPARCC MRI Index of Disease Activity Score of the SI Joints and Spine, Modified Berlin 
ASspiMRI, ASDAS-CRP, ASDAS-ESR, hsCRP, ESR at baseline will be summarized. Rheumatoid 
factor and HLA B-27 at screening 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 the following: 
Prior medications and concomitant medications will be summarized descriptively using frequency 
tables by ATC class and preferred name 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. 
 
8.5 
Extent of exposure 
8.5.1 Treatment Duration 
Duration of study drug exposure (in  days)  will  be  calculated  as:  last  dose  date – first  dose 
date + 1 day, 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 
 
 and summarized by treatment group. 
8.5.2 Treatment Compliance 
Study drug compliance  will  be  calculated  as:  
 total  number  of  doses  administered /total 
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number of doses planned to be administered during the study drug exposure period. In case only 
one syringe among the two is administered at a visit, the number of doses will be counted as 
If 
both syringes are administered at a visit, the number of doses will be counted as 1. The total 
number of doses planned will count Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 if a 
subject completes Part 1 and Part 2. If a subject discontinues treatment early, the total number of 
doses will be counted from Week 0 until the last dose before discontinuation. 
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 
” 
and 
” using frequency tables. 
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 as a stratification 
factor, will be used to compare response rates of response–type variables between the 200 mg 
tildrakizumab and placebo within AS and nr-axSpA separately. In addition, the Mantel-Haenszel 
common risk (the response rate) difference between 200 mg tildrakizumab and placebo and the 
95% confidence interval (CI) will be estimated. Should assumptions per the Mantel-Fleiss criterion 
not be satisfied, the comparison will be based on a Fisher’s exact test after collapsing across levels 
of the stratification factor. In this case, the response rate difference and CI will be based on a 
normal approximation without considering stratification. 
Mixed model repeated measures analysis of continuous endpoints 
A mixed model repeated measure (MMRM) 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, and prior TNF use (yes/no), as well as the continuous fixed 
covariate 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 Kenward- 
Roger method. 
In case of non-convergence with the unstructured matrix, other within-subject error variance- 
covariance matrices, such compound symmetry (CS), will be considered. 
The model will provide least-squares mean estimates, standard errors, two-sided 95% confidence 
intervals and p-values (where applicable) for mean change at all time points between treatments 
(tildrakizumab vs. placebo). 
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8.6.1.1 Multiplicity 
Not applicable. 
8.6.2 Analysis of primary efficacy endpoint 
The primary efficacy variable is ASAS20 at 
 ASAS20 will be analysed with CMH test as 
described in 
 for AS and nr-axSpA cohorts separately. Early withdrawals and any 
subjects with ASAS20 undeterminable at 
 will be classified as non-responders. Subjects 
who fail to show minimal response to treatment (defined as 
 improvement from Baseline in 
total back pain or inflammation) at 
 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 sample SAS codes are: 
 
 
To assess the robustness of the primary efficacy analysis, sensitivity analysis will be repeated with 
the PPAS. 
Subgroup analysis will be performed for each of the following subgroup variables: 
 
• 
Prior anti-TNF use (Yes/No) 
• 
Baseline weight (≤ 90 kg, > 90 kg) 
• 
Age (< 65,  ≥ 65) 
• 
Gender 
• 
Methotrexate use (Yes/No) 
The sample SAS codes for anti_TNF subgroup analysis are: 
 
 
 
 
 
 
Estimates of the difference between the treatment groups, along with the 
(but no p-value 
needed), will be presented for each defined category of each subgroup variable. 
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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 factors 
of interest. 
8.6.3 Analysis of secondary endpoints 
All secondary analyses will be performed using the FAS, unless otherwise stated. Proportions in 
ASAS40 at Weeks 24 will be analyzed based on the CMH method described for ASAS20 in 
primary analysis. Due to the placebo group switching to 200 mg tildrakizumab at 
, the 
comparison between active drug and placebo will not be performed for the secondary endpoints 
collected after 
. ASAS20 and ASAS40 up to 
 will be summarized with 
descriptive statistics. 
Analysis on ASAS40 at 
 will also be performed for the PPAS. 
8.6.4 Analysis of exploratory endpoints 
The response-type endpoints (ASAS20/40 at other measurement time points, ASAS70, ASAS5/6 
up to 
 and proportion of subjects who require adjustment of background therapy at Week 
16 will besummarized with descriptive statistics. Continuous endpoints (change from baseline in 
PtGA of disease activity, Total Back Pain, Nocturnal Pain, Inflammation, BASFI, BASMI, 
BASDAI, ASQoL, ASDAS-CRP, ASDAS-ESR, MASES, SF-36, FACIT-fatigue, TJC46, SJC44, 
hsCRP, SPARCC MRI Index of Disease Activity Score of the SI Joints, SPARCC MRI Index of 
Disease Activity Score of the Spine, and Modified Berlin ASspiMRI) up to 
 will be 
analyzed based on a MMRM analysis that includes the fixed effects of treatment, visit, treatment 
by visit interaction, prior anti-TNF use (yes/no), and Baseline value. Due to placebo group 
switching to 200 mg Tildrakizumab at 
, the comparison between active drug and placebo 
will not be performed for the exploratory endpoints collected after 
. Continuous endpoints 
after 
 be summarized descriptively. 
Below is an example of the SAS code for the MMRM 
 
 
 
 
 
 
 
 
For 
, the proportions of subjects who achieve ASAS20, ASAS40, ASAS70, and 
ASAS5/6, at each measured time point during 
 will be summarized by treatment 
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group; change from Baseline in PtGA of disease activity, Total Back Pain, Nocturnal Pain, 
Inflammation, BASFI, BASMI, BASDAI, MASES, SF-36, FACIT-fatigue, TJC46, and SJC44 
during Weeks 53 to 72 will be summarized descriptively by treatment group. In addition, there will 
be sub-groups of patients in Part 3 who either did or did not receive any new therapy for AS and 
these will be analyzed separately for ASAS20, ASAS40, and ASAS70. 
All the exploratory analyses will be based on the FAS. 
 
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. 
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 Part 1 is defined with the event start date on/after the first dose but before 
 dosing date of IMP or on/before the last dose date of IMP if the subject discontinues 
before 
 A TEAE in Part 2 is defined with the event start date on/after 
 dosing 
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date but on/before the last dose date of IMP. A TEAE in Part 3 is defined with the event start date 
after the last dose date of IMP. 
In addition, all TEAEs will be summarized by study part (Parts 1, 2, 3), 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. 
Adverse Events of Special Interest (AESIs) 
The events of severe infections, malignancies (including non-melanoma and melanoma  skin 
cancer, excluding carcinoma in situ of the cervix), confirmed Major Adverse Cardiac Events 
(MACE), and drug-related hypersensitivity reactions will be identified a priori as AESIs for 
summarizing in this study. Severe infections are defined as any infection meeting the regulatory 
definition of a SAE, or any infection requiring IV antibiotics whether or not reported as a serious 
event, as per the regulatory definition. Major Adverse Cardiac Events include non-fatal stroke, non- 
fatal myocardial infarction, and cardiovascular death. All MACE events will be evaluated and 
adjudicated by a Clinical Adjudication Committee. The AESIs will be summarized by study part, 
SOC, PT and treatment group. 
Events of Clinical Interest (ECIs) 
An ECI is a non-serious AE or occurrence that is designated to be of special interest and must be 
reported to the Sponsor as though it were an SAE. The ECIs will be summarized by study part, 
SOC, PT and treatment group. 
The following events are considered ECIs for this study: 
1. An overdose of the Sponsor's product, as defined as any dose greater than the intended 
protocol dose. An overdose that is not associated with clinical symptoms or abnormal 
laboratory results is to be reported as a non-serious ECI, using the terminology "accidental or 
intentional overdose without adverse effect.” 
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2. An elevated AST or ALT laboratory value that is
 the ULN and an elevated total bilirubin 
laboratory value that is
 ULN and, at the same time, an alkaline phosphatase laboratory 
value that is
 ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing, is to be reported as a non-serious ECI. 
3. Infections  that  require  IV  antibiotics  but  do  not  meet  the  definition  of  an  SAE  will  be 
designated a closely monitored AE for this study. 
4. Depression and suicidal ideation and behavior events. 
In addition, a listing containing individual subject adverse event data for TEAEs leading to 
discontinuation from study, Serious TEAEs, TEAEs leading to death, AESIs, and ECIs 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 e.g., less than (<) a 
certain value, or greater than (>) a certain value, 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 table from baseline to post-baseline in lab parameters for each treatment 
group during Part 1 will be displayed by visit. 
Values outside the normal range will be categorized as H (above the normal range) or L (below the 
normal range) based on the laboratory’s reference range and these will be flagged in the listings of 
individual subject data. 
8.7.3 Vital signs 
Vital sign observed values and changes from Baseline 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 “Normal” and “Abnormal” 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 number and percentage of 
subjects with “Normal”, “Abnormal, not clinically significant”, and “Abnormal, clinically 
significant”. In addition, shift table from baseline to post-baseline in overall ECG interpretation 
during Part 1 will be displayed by visit and treatment group. 
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ECG parameter (e.g., QTcF) observed values and changes from Baseline 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:  Set to 1 if any ideation is present and 0 otherwise. 
• 
Presence of Suicidal Behavior:  Set to 1 if any type of suicidal behavior is present and 0 
otherwise. 
• 
Suicidal ideation score: Defined as the maximum suicidal ideation category (1-5) on the 
C-SSRS present at the assessment. A score of 0 is assigned if no ideation is present. 
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-case 
shift tables will be the cross tabulation of the Baseline result score with the worst-case result score 
during the treatment period. 
 
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. 
PK parameters of AUC, Cmax, Cmin, Tmax, 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 
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Protocol Number: CLR_16_22 
 
Page 42 of 55 
 
 
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 ADA assay at concentrations above the drug 
tolerance level (DTL) of 
.  Therefore, samples with a negative test result in the ADA assay 
can only be described as negative in the case of a tildrakizumab concentration below 6 μg/mL.  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 overall immunogenicity incidence is defined as the proportion of treatment-emergent 
positive subjects to the number of evaluable subjects. The proportion of non-treatment emergent 
positive subjects is similarly reported.  For ADA positive subjects (based on the confirmatory 
assay), the immune response is further characterized for antibody titer and neutralizing capacity. 
When titer is measured to be
 for the purposes of deriving 
ADA subject status. 
Table 3 Immunogenicity Subject Status Definitions 
Subject Status 
Definition 
Negative 
All pre-treatment and post-dose samples were negative in the ADA assay and the 
drug concentration in the last post-dose sample was below the respective DTL 
 
for the ADA assay. 
Inconclusive 
All pre-treatment and post-dose samples were negative in the ADA assay AND the 
drug concentration in the last post-dose sample was equal or above the respective 
DTL for the ADA assay. 
Treatment-emergent 
Positive 
Pre-treatment sample was negative and at least 1 post-dose sample was positive in 
the ADA assay (treatment-induced positive). 
Pre-treatment and post-dose samples were both positive in the ADA assay and the 
titer increased post-dose by ≥2-fold (treatment boosted positive). 
Non-treatment- 
emergent Positive 
Pre-treatment sample was positive and post-dose samples were negative in the 
ADA assay. 
Pre-treatment and post-dose samples were positive in the ADA assay with a 
< 2-fold increase in titer post-dose 
ADA = anti-drug antibodies; DTL = drug tolerance level. 
The anti-tildrakizumab immunogenicity status of evaluable subjects, along with titer and 
neutralizing antibody, will be summarized by dose level in Part 1. Only data from Part 1 is used 
and placebo samples in Part 1 are excluded. The anti-tildrakizumab immunogenicity status of 
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Protocol Number: CLR_16_22 
 
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evaluable subjects will be further summarized by treatment group and by dose level for Parts 1 and 
2 combined. 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 Part 1 and Part 2 will be displayed for subjects in groups of 
tildrakizumab 200 mg and placebo → 200 mg Tildrakizumab, respectively. 
8.8.4 
ADA to Efficacy Endpoints 
The impact of ADA on the responder type of efficacy endpoints (ASAS20 and ASAS40) will be 
summarized by dose level for Part 1. Only data from Part 1 is used and placebo samples in Part 1 
are excluded. 
 
8.9    Interim analysis 
An interim analysis (IA) will be performed for futility assessment after data at Week 16 from 30 
randomized subjects become available. Futility assessment will be based on a futility threshold of 
12% (difference between response rates on active arm and placebo) at Week 16. The purpose of the 
analysis is potentially to stop for futility. If the difference between response rates of ASAS20 for 
tildrakizumab 200mg and placebo is less than the threshold of 12%, the study may be stopped for 
futility. The conditional power of rejecting the null ASAS20 hypothesis will be calculated with 
ADDPLAN software. 
Following the last subject’s Week 24 visit, an IA will be conducted on all available data up to 
Week 24 to evaluate the primary efficacy outcome. The primary endpoint ASAS20 and selected 
other endpoints will be included in the IA. 
Details of the IA methodology and operational processes will be described in a separate document. 
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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, 
 
 
The output alignment will be centered on the page and the 
titles and footnotes will be center aligned. 
• 
The ICH1,2 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 (24 hour clock). 
• 
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 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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Protocol Number: CLR_16_22 
 
Page 45 of 55 
 
 
 
10 
CHANGES TO PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
The sponsor decided not to do PK and ADA analysis due to the study termination. 
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Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
 
Page 46 of 55 
 
 
 
11 
REFERENCES 
1. 
ICH  Topic  E3:  Structure and  Content  of  Clinical  Study  Reports  (CPMP/ICH/137/95- 
adopted December 1995). 
2. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted 
March 1998). 
3. 
Ware JE. User’s Manual for the SF-36v2 Health Survey; 2007. 
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Statistical Analysis Plan (SAP) 
 
 
12 
APPENDICES 
 
12.1 Endpoint definition and Derivation Details 
12.1.1 
 
The 
 is a multi-purpose, 36-item 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).   This score is based on the responses to the 10 items that 
compose Question 3 and reflects the degree to which various physical activities have been 
limited in the previous week by the subject’s health. 
 
b. Role-Physical (RP).   This score is based on the responses to the four items that compose 
Question 4 and reflects the relative amount of time that the subject has had problems with 
work or other regular daily activities as a result of their physical health during the previous 
week. 
 
c. Bodily Pain (BP). This score is based on the responses to Questions 7 and 8 and reflects 
bodily pain and its effects on normal work during the previous week. 
 
d. General Health (GH). This score is based on responses to Question 1 and the four items in 
Question 11 and reflects the subject’s perception of their general health during the previous 
week. 
 
e. Vitality (VT). This score is based on responses to Question 9 items a, e and g, and reflects 
the subject’s physical energy level relative to time during the previous week. 
 
f. Social Functioning (SF).  This score is based on responses to Questions 6 and reflects how 
physical health or emotional problems have interfered with social activities during the 
previous week. 
 
g. Role-Emotional (RE). This score is based on responses to the three items in Question   
5 and reflects the amount of time during the previous week that emotional problems have 
interfered with work or regular daily activities. 
 
h. Mental Health (MH). This score is based on responses to Question 9 items b, c, d, f, and h 
and reflects various mental/emotional states relative to time during the previous week. 
 
The summary component scores are: 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
 
 
 
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a. Physical Component Summary (PCS). 
 
b. Mental Component Summary (MCS). 
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Protocol Number: CLR_16_22 
 
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Data Derivation Details to Obtain Scale Scores for SF-36 
 
VARIABLE 
DERIVATION 
SF-36 PF scale score 
 
 
 
When calculating the raw score, if  or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator.   Substitute the mean for any 
missing scores. 
Otherwise, if 
 of the items are non-missing then PF 
scale score is missing. 
The response scale for each activity ranges from
 
A higher PF scale score indicates better physical functioning. 
SF-36 RP scale score 
 
 
 
When calculating the raw score, if  or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator.   Substitute the mean for any 
missing scores. 
Otherwise, if less than 
 the items are non-missing then RP 
scale score is missing. 
The response scale for each item ranges from
 
  A higher RP 
scale score indicates better role-physical functioning. 
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Statistical Analysis Plan (SAP) 
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Protocol Number: CLR_16_22 
 
Page 50 of 55 
 
 
 
VARIABLE 
DERIVATION 
SF-36 BP scale score 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
If 1 or more questions were answered, calculate BP scale 
score as defined above. If neither question was answered then 
BP scale score is missing. 
The scale for
 
. 
The scale for 
 
 
 
A higher BP scale score indicates lack of bodily pain. 
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Statistical Analysis Plan (SAP) 
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Protocol Number: CLR_16_22 
 
Page 51 of 55 
 
 
 
VARIABLE 
DERIVATION 
SF-36 GH scale score 
 
 
 
 
Reverse direction of Item 1 as follows: 
 
 
 
 
Reverse direction of item 
 by subtracting score from 6. 
When calculating the raw score, if  or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if 
 of the items are non-missing then GH 
scale score is missing. 
Responses for
 
 
Responses for the items in
 
 
 and reflect the subject’s perception of their relative 
health and expectations of their future health status. 
A higher GH scale score indicates better general health perceptions. 
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Statistical Analysis Plan (SAP) 
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Protocol Number: CLR_16_22 
 
Page 52 of 55 
 
 
 
VARIABLE 
DERIVATION 
SF-36 VT scale score 
 
 
 
Reverse direction of Items 
 by subtracting score from . 
When calculating the raw score, if  or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if 
 of the items are non-missing then VT 
scale score is missing. 
The scale for these items ranges from
 
 
SF-36 SF scale score 
 
 
 
Reverse direction of 
 
When calculating the raw score, if  of the items is missing then substitute 
the missing score with the score on the non- missing item. If both items 
are missing then SF scale score is missing. 
Responses to 
 an assessment of the extent to which 
health/emotional problems interfered with social activities,
  
 
 
 
 
 
A higher SF scale score indicates better social functioning. 
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Statistical Analysis Plan (SAP) 
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Protocol Number: CLR_16_22 
 
Page 53 of 55 
 
 
 
VARIABLE 
DERIVATION 
SF-36 RE scale score 
 
 
 
When calculating the raw score, if  or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if 
2 of the items are non-missing then RE 
scale score is missing. 
Responses to the items in
 
 
 
SF-36 MH scale score 
 
 
 
 
Reverse direction of scores for 9D and 9H, by subtracting score from 6. 
If 3 or more of the items are non-missing then replace any missing values 
as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if
 of the items are non-missing then 
MH scale score is missing. 
The scale for these items ranges from
 
 
 
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Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
 
Page 54 of 55 
 
 
VARIABLE 
DERIVATION 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
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Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: CLR_16_22 
 
Page 55 of 55 
 
 
VARIABLE 
DERIVATION 
SF-
 MCS score 
 
 
 
 
 
 
. 
 
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Controlling for patf=1
      
  
  
         
       
  
       
      
      
      
           
  
  
           
  
           
  
       
      
      
      
           
  
  
           
  
           
  
                          
            
    
   
                           
 
                                             
                
                  
        
     
     
           
     
     
     
     
     
           
     
     
     
     
     
           
     
     
     
     
     
      
     
    
     
                      
                        
                           
 
                                             
                
                  
        
     
     
           
     
     
     
     
     
           
     
     
     
     
     
           
     
     
     
     
     
     
     
    
     
                      
                        
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t14_2_2_1_2_cmh2024_002.lst
       
 
                              
               
       
    
    
      
    
        
      
      
    
        
                      
  
 
    
    
       
      
            
              
    
            
           
    
            
              
    
    
                        
 
                   
                  
       
                  
        
        
       
                            
                  
        
       
    
        
        
       
                            
                  
        
       
    
        
        
       
                            
                  
        
       
     
              
                           
              
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t14_2_2_5_2_ptga24_002.lst
                                                
 
 
               
          
               
             
                         
         
        
   
        
   
      
     
   
    
      
      
                                      
     
    
     
     
    
    
                                     
     
   
     
     
     
    
                                     
     
    
     
     
     
    
                                     
     
   
     
     
    
    
                                     
     
    
     
     
    
    
                                     
     
   
     
     
    
    
                                     
     
    
     
     
    
    
                                     
     
   
     
     
    
    
                                     
     
    
     
     
    
    
                                      
     
    
     
     
    
    
                                      
     
   
     
     
     
     
                                     
     
    
     
     
     
    
                                      
     
   
     
     
     
    
                                     
     
    
     
     
     
    
                                     
     
     
     
     
     
    
                                     
     
    
     
     
    
    
                                     
     
   
     
     
    
    
                                     
     
    
     
     
    
    
                                     
     
   
     
     
    
    
                                     
     
    
     
     
    
    
                                     
     
   
     
     
    
    
                                     
     
   
     
     
    
     
                                      
     
   
     
     
     
    
                                      
     
    
     
     
    
     
                                     
     
   
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Prot_000.pdf: 
Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 1 of 95 
 
1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study to Evaluate the Efficacy 
and Safety of Tildrakizumab in Subjects with Active Ankylosing Spondylitis or 
Non-Radiographic Axial Spondyloarthritis 
 
 
Protocol No.:  CLR_16_22 
EUDRACT No.:  2016-003936-19 
Test Product: 
Tildrakizumab 
Indication: 
Ankylosing 
Spondylitis 
or 
Non-Radiographic 
 
Axial Spondyloarthritis 
Sponsor: 
Sun Pharma Global FZE 
 
Office at #43, Block Y SAIF Zone 
 
Sharjah, 122304 
 
United Arab Emirates 
Development Phase: 
Phase 2a 
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: 
14 June 2017 
Version of the Protocol: 
v2.0 Final 
 
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 Phanna Global FZE 
Tildrakizumab 
2 
SIGNATURE PAGES 
CONFIDENTIAL 
14June2017 
 
SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study 
to Evaluate the Efficacy and Safety of Tildrakizumab in Subjects with Active Ankylosing 
Spondylitis or Non-Radiographic Axial Spondyloarthritis 
PROTOCOL NUMBER: CLR 16 22 
Sun Pharma Global FZE 
Patrick Burnett, M.D, Ph.D. 
Protocol CLR 16 22 Version 2.0 
(Final) 
Date (day/month/year) 
Page 2 of95 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 3 of 95 
 
3 
GENERAL INFORMATION 
A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study to Evaluate the Efficacy 
and Safety of Tildrakizumab in Subjects with Active Ankylosing Spondylitis or 
Non-Radiographic Axial Spondyloarthritis 
 
Protocol No.: 
CLR_16_22 
Date of the Protocol: 
14 June 2017 
Date and Number of Amendment(s): 
14 June 2017, Amendment 1 
Sponsor: 
Sun Pharma Global FZE 
 
Office at #43, Block Y SAIF Zone 
 
Sharjah, 122304 
 
United Arab Emirates 
Clinical Research Organization: 
 
 
 
 
 
 
 
 
 
Sponsor Signatory: 
Patrick Burnett, M.D., Ph.D. 
 
2 Independence Way 
 
Princeton 
 
NJ 08540, United States 
 
Tel No.:  +1 (609) 480 2902 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Medical Expert: 
Patrick Burnett, M.D., Ph.D. 
(including medical cover outside ICON hours) 
2 Independence Way 
 
Suite 2100, Princeton 
 
NJ 08540, United States  
 
Tel No.:  +1 (609) 480 2902 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 4 of 95 
 
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 Phase 2a Study to Evaluate the Efficacy and Safety of 
Tildrakizumab in Subjects with Active Ankylosing Spondylitis or Non-Radiographic Axial Spondyloarthritis 
 
Study Centers: 
The study will be multinational and performed in approximately
 study centers. 
Publication(s): 
None. 
Planned Study Period: 
 
Development Phase: 
Phase 2a 
Objectives: 
Primary Efficacy Objective: 
Part 1 
• 
To evaluate the efficacy of tildrakizumab in subjects with ankylosing spondylitis (AS) or non-radiographic axial 
spondyloarthritis (nr-axSpA), as measured by the proportion of subjects achieving Assessment of 
SpondyloArthritis international Society (ASAS)
 response criteria at 
 
Primary Safety Objective: 
Parts 1 and 2 
• 
To assess the safety/tolerability and immunogenicity of tildrakizumab in subjects with AS or nr-axSpA. 
Secondary Objectives: 
Parts 1 and 2 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the proportion of 
subjects achieving ASAS20 response criteria at Week 52, ASAS40 response criteria at Weeks 24 and 52, and 
proportion of subjects who require adjustment of background therapy. 
• 
To characterize the pharmacokinetics (PK) of tildrakizumab in subjects with AS or nr-axSpA. 
Exploratory Objectives 
Parts 1 and 2 
The exploratory objectives for Parts 1 and 2 of the study are: 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the proportion of 
subjects who achieve ASAS20 or ASAS40 at other measured time points. 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the proportion of 
subjects who achieve ASAS70 or ASAS5/6. 
• 
To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the change from 
Baseline in ASAS components, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath 
Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI), 
Ankylosing Spondylitis Quality of Life questionnaire (ASQoL), Visual Analog Scale (VAS) (total back pain 
and nocturnal pain score), Ankylosing Spondylitis Disease Activity Score (ASDAS) C-reactive protein (CRP), 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 5 of 95 
 
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 
ASDAS erythrocyte sedimentation rate (ESR), Maastrict Ankylosing Spondylitis Enthesitis Score (MASES), 
short form 36 (SF-36), Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, high-sensitivity 
CRP (hs)CRP, SpondyloArthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging 
(MRI) Index of Disease Activity of the sacroiliac (SI) Joints, SPARCC MRI Index of Disease Activity of the 
Spine, and Modified Berlin Ankylosing Spondylitis Spine Magnetic Resonance Imaging Activity Score 
(ASspiMRI), swollen joint count of 44 joints (SJC44), and tender joint count of 46 joints (TJC46) at measured 
time points. 
• 
To evaluate the tildrakizumab exposure/response relationship. 
Part 3 
The exploratory objectives for Part 3 of the study are: 
• 
To assess the effect of investigational medicinal product (IMP) discontinuation on ASAS20, ASAS50, 
ASAS70, ASAS5/6, ASAS components, BASDAI, BASMI, BASFI, SF-36, VAS (total back pain and nocturnal 
pain score), MASES, FACIT-fatigue, TJC46, and SJC44 at measured time points. 
• 
To evaluate immunogenicity following IMP discontinuation. 
• 
To characterize the PK of tildrakizumab in subjects with AS or nr-axSpA following IMP discontinuation. 
Endpoints: 
All endpoints will be analyzed separately for AS and nr-axSpA, unless otherwise stated. 
Primary Endpoint: 
• 
The proportion of subjects who achieve ASAS20 at 
 
ASAS20 response is defined as an improvement of 
 and absolute improvement of 
 from 
Baseline in a VAS 
; Patient's 
Global Assessment (PtGA) of disease activity; Total Back Pain VAS; BASFI VAS; and Inflammation VAS (the 
mean of the 
morning stiffness-related BASDAI VAS scores 
 of the 
BASDAI]).  No worsening of 
 VAS on a 
 in the remaining 
 domain. 
Secondary Endpoints 
): 
• 
The proportion of subjects who achieve ASAS20 at 
 
• 
The proportion of subjects who achieve ASAS40 at 
 
ASAS40 response is defined as an improvement of 
 and absolute improvement of 
 from 
Baseline in a VAS for 
 of the 
domains: PtGA; Total Back Pain; BASFI; and Inflammation.  No worsening 
of 
 and 
 VAS on a 
 in the remaining 
domain. 
• 
The proportion of subjects who require adjustment of background therapy 
• 
PK parameters: area under the concentration-time curve (AUC), maximum concentration (Cmax), minimum 
concentration (Cmin), time of maximal concentration (Tmax) and half-life (T1/2).  PK parameters will be analyzed 
separately for each subject population and pooled. 
Exploratory Endpoints 
): 
• 
The proportion of subjects who achieve ASAS
or ASAS
 at other measured time points 
• 
The proportion of subjects who achieve ASAS
 at measured time points 
ASAS70 response is defined as an improvement of 
 and absolute improvement of 
 from 
Baseline in a VAS for 
 of the 
; PtGA; Total Back Pain; BASFI; and Inflammation.  No worsening 
of
 and 
 VAS on a
 in the remaining 
 domain. 
• 
The proportion of subjects who achieve a ASAS5  response at measured time points 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 6 of 95 
 
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 
ASAS5  response is defined as a 
 improvement in 
 (physical function [BASFI], Total 
Back Pain, PtGA of disease activity, Inflammation [mean of Questions 5 and 6 of the BASDAI], spinal mobility 
[BASMI], and acute phase reactants [CRP]). 
• 
Change from Baseline in ASAS components at measured time points 
• 
Change from Baseline in BASDAI, BASMI, BASFI, and ASQoL at measured time points 
• 
Change from Baseline in VAS (total back pain and nocturnal pain score) at measured time points 
• 
Change from Baseline in ASDAS-CRP and ASDAS-ESR at measured time points 
• 
Change from Baseline in MASES at measured time points 
• 
Change from Baseline in SF-36 at measured time points 
• 
Change from Baseline in FACIT-fatigue at measured time points 
• 
Change from Baseline in TJC46 and SJC44 at measured time points 
• 
Change from Baseline in hsCRP serum levels at measured time points 
• 
Change From Baseline in SPARCC MRI Index of Disease Activity Score of the SI Joints at measured time 
points 
• 
Change From Baseline in SPARCC MRI Index of Disease Activity Score of the Spine at measured time points 
• 
Change From Baseline in Modified Berlin ASspiMRI at measured time points 
• 
Population PK of tildrakizumab 
• 
Tildrakizumab exposure/response relationship. 
Exploratory Endpoint 
 
• 
ASAS20, ASAS50, ASAS70, ASAS5/6, ASAS components, BASDAI, BASMI, BASFI, SF-36, VAS (total 
back pain and nocturnal pain score), MASES, FACIT-fatigue, TJC46, and SJC44 at measured time points 
• 
Incidence of anti-drug antibodies (ADA) at measured time points 
• 
Population PK parameters 
Safety Endpoints: 
• 
Adverse events (AEs) 
• 
Laboratory assessments 
• 
Suicidal ideation and behavior (Columbia-Suicide Severity Rating Scale [C-SSRS]) 
• 
Vital signs, electrocardiogram (ECG), physical examination 
• 
ADA to tildrakizumab, including titer and neutralizing antibodies, at measured time points 
Anti-Drug Antibodies Endpoints 
• 
Incidence of ADA and correlations with PK, safety and efficacy endpoints will be investigated across Part 1 to 
Part 3. 
Methodology: 
This is a randomized, double-blind, placebo-controlled, Phase 2a study.  At least 
subjects with active AS (Stage 1 
of the study) and 
 subjects with active nr-axSpA (Stage 2 of the study) will be randomly assigned in a blinded 
fashion in a 
 ratio to receive either
 tildrakizumab or placebo by 
 every
 
weeks (
  Starting at 
 all subjects will receive 
 tildrakizumab administered 
  Recruitment for Stage 1 
) will begin 
upon study approval; recruitment for Stage 2 (
) will begin only upon written notification by 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 7 of 95 
 
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 
the Sponsor to the Competent Authorities and Investigators. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 8 of 95 
 
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 
Subjects randomized to receive tildrakizumab during Part 1 of both stages of the study who achieve ASAS20 at 
 will receive treatment with 
 tildrakizumab 
 until 
.  Subjects receiving 
tildrakizumab during Part 1 who do not achieve ASAS20 at 
 will 
e IMP treatment and enter the 
.  Subjects randomized to receive placebo during Part 1 who complete the Week 24 visit 
will continue to Part 2 and receive tildrakizumab 
 
even if they do not achieve 
ASAS20. 
Subjects discontinued from IMP at any time (apart from withdrawal of informed consent) will be required to 
complete the End of Treatment (EoT) 
 assessment a minimum of
 after the last dose of IMP and 
enter the 
.  Subjects who withdraw from the study during Part 3 will 
 the 
 
(End of Study [EoS]) assessments at 
 their last visit. 
The primary endpoint for efficacy will be ASAS20 at 
  Secondary endpoints will include ASAS20 at 
Week 52; ASAS40 
 and proportion of subjects who require adjustment of background therapy.  
The PK and immunogenicity of tildrakizumab will also be evaluated. 
All sites will have an independent assessor to conduct tender and swollen joint counts, BASMI, and MASES 
assessments.  The independent assessor will not be involved in the care of subjects and will not discuss disease 
activity or the treatment with subjects or the Principal Investigator (PI)/designee responsible for performing other 
efficacy and safety evaluations. 
An interim analysis (IA) will be performed for futility assessment after data from 
 randomized subjects become 
available at 
 
Following the last subject’s 
, an IA will be conducted on all available data to evaluate the primary 
efficacy outcome. 
An independent Data Safety Monitoring Board (DSMB) will be established for periodic review of safety data, and a 
Clinical Adjudication Committee (CAC) will be established to evaluate cardiovascular events for this study. 
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). 
Number of Subjects: 
The sample size is approximately 
 subjects 
 
 
Diagnosis and Main Criteria for Inclusion and Exclusion: 
Inclusion criteria: 
Subjects may be included in the study if they meet all of the following criteria: 
1. Subject has provided informed consent. 
2. Subject is ≥ 18 years of age at time of Screening. 
3. Definite AS based on the modified New York criteria (1984) with symptom duration of at least 3 months at 
Screening as defined by modified New York criteria (1984), or for nr-axSpA, a documented diagnosis of adult 
onset axial spondyloarthritis as defined by the specific ASAS criteria with at least 3 months symptom duration 
before Screening. 
4. Subjects with nr-axSpA must have active inflammation (MRI) on Screening and no radiographic sacroiliitis that 
fulfils the 1984 modified New York criteria. 
5. Active disease at Screening, defined as: 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 9 of 95 
 
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 
− 
 and  
− 
 
 
6. 
 
 
 
 
 
 
 
 
 
 
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 electronic case report form [eCRF]); otherwise the dosage must 
remain the same throughout Part 1 of the study.  Adjustment of concomitant medication 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 (defined as 
improvement from Baseline in pain 
[assessed by Total Back Pain VAS
] and inflammation [assessed using the last  stiffness assessments 
in the BASDAI]) at 
 
8. For subjects receiving NSAIDs (
): the subject must be on a stable dose for ≥ 4 weeks prior to 
initiation of IMP and be expected to maintain a stable dose for the first 24 weeks of the study, unless change in 
dosage is required due to toxicity.  Stable dose (
) is defined as subjects taking an NSAID on 
average 4 days per week over the 4-week period prior to Screening. 
9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 10 of 95 
 
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 
Exclusion Criteria: 
Other medical conditions 
1. Radiographic evidence of total ankylosis of the spine (defined by syndesmophytes present on the lateral views 
of spinal radiographs including intervertebral levels from T6 through S1; films will be read centrally). 
2. Subjects with more than 16 fused cervical, thoracic and lumbar ankylosed discovertebral units (DVUs), 
anteriorly, posteriorly or both, that are radiographically diagnostically compatible with AS. 
3. Subjects with evidence of bilateral SI joint fusion and 12 fused DVUs (per exclusion criterion 2 above). 
4. Subjects with known diagnosis of fibromyalgia or complex regional pain syndromes. 
5. Active uveitis or symptomatic inflammatory bowel disease requiring therapy at Screening. 
6. Subject has a planned surgical intervention between Baseline and the Week 24 evaluation for a pre-treatment 
condition. 
7. Subject has an active infection or history of infections as follows: 
− 
any active infection for which systemic anti-infectives were used within 28 days prior to first IMP dose, 
with the last dose having been received within 7 days of Screening, 
− 
any serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks 
prior to the first investigational product dose, with the last dose having been received within 7 days of 
Screening, 
− 
recurrent or chronic infections, e.g., chronic pyelonephritis, chronic osteomyelitis, bronchiectasis, or other 
active infection that, in the opinion of the Investigator, might cause this study to be detrimental to the 
subject. 
8. Major chronic inflammatory or connective tissue disease other than AS (e.g., psoriatic arthritis [PsA], 
rheumatoid arthritis, systemic lupus erythematosus, Lyme disease, and gout). 
9. Subject has any concurrent medical condition or uncontrolled, clinically significant systemic disease (e.g., renal 
failure, heart failure, hypertension, liver disease, diabetes, or anemia) that, in the opinion of the Investigator, 
could cause this study to be detrimental to the subject. 
10. Subject has known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus. 
11. 
 
. 
12. Subject has any active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or 
melanoma. 
13. Subject has history of malignancy within 5 years EXCEPT treated and considered cured cutaneous basal or 
squamous cell carcinoma, in situ cervical carcinoma, OR in situ breast ductal carcinoma. 
14. Subjects with a history of alcohol or drug abuse in the previous 2 years. 
15. 
 
 
Laboratory abnormalities 
16. Subject has laboratory abnormalities at Screening, including any of the following: 
− 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
 the upper limit of normal 
(ULN), 
− 
creatinine
 ULN, 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 11 of 95 
 
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 
− 
serum direct bilirubin 
, 
− 
white blood cell (WBC) count 
, 
− 
 test for rheumatoid factor, 
− 
any other laboratory abnormality that, in the opinion of the Investigator, will prevent the subject from 
completing the study or will interfere with the interpretation of the study results. 
Washouts and non-permitted drugs 
17. Disease modifying anti-rheumatic drugs (DMARDs) other than NSAIDs, MTX or
 must be 
discontinued 4 weeks prior to randomization, except for 
, which has to be discontinued for 
 
prior to randomization (
 
18. Subject has used any of the following within
: 
− 
high potency opioid analgesics (e.g., methadone, hydromorphone, or morphine), 
− 
topical and parenteral corticosteroids including intramuscular or intraarticular administration, 
− 
live vaccines, 
− 
has a need for use of a live vaccine within 10 weeks of final dose of IMP. 
19. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
General 
20. Subject has known sensitivity to any of the products or any excipients to be administered during dosing. 
21. Female subjects of childbearing potential must agree to abstain from heterosexual activity (as part of an existing 
lifestyle choice) or practice a dual method of contraception, for example, a combination of the following: (1) 
oral contraceptive, depo progesterone, or intrauterine device; and (2) a barrier method (condom or diaphragm). 
Male subjects with female partners of childbearing potential who are not using birth control as described above 
must use a barrier method of contraception (eg, condom) if not surgically sterile (ie, vasectomy). Contraceptive 
methods must be practiced upon entering the study and through 16 weeks after the last dose of study treatment. 
If a subject discontinues prematurely, the contraceptive method must be practiced for 16 weeks following final 
administration of study drug.  A follicle-stimulating hormone test should be performed to confirm menopause 
for those women with no menses for less than 1 year. 
22. Female is pregnant or breast-feeding, or planning to become pregnant or initiate breast-feeding while enrolled in 
the study or up to 16 weeks after the last dose of IMP. 
23. Subject will not be available for protocol-required study visits, to the best of the subject’s and Investigator’s 
knowledge. 
24. 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 12 of 95 
 
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 
 
 
 
26. Subject has any kind of disorder that, in the opinion of the Investigator, may compromise the ability of the 
subject to give written informed consent and/or comply with all required study procedures. 
27. Donation or loss of
 of blood within 8 weeks before dosing. 
28. Subjects who have been placed in an institution on official or judicial orders. 
29. Subjects who are related to or dependent on the Investigator, Sponsor, or study site such that a conflict of 
interest may arise. 
Test Product, Dose and Mode of Administration: 
Each pre-filled syringe (PFS) of IMP contains 
 of tildrakizumab and 
 of solution. 
Placebo will be presented in identical containers with the same excipients (with no active drug) and stored/packaged 
the same as tildrakizumab. 
Subjects will receive either 
 of tildrakizumab as 
 of 
 tildrakizumab, or 
 
of placebo 
 until 
  Starting at 
, all subjects 
will receive 
 tildrakizumab administered 
. 
Concomitant Medications, Supportive Care, and Study Restrictions: 
The following restrictions will apply to all subjects during the study. 
Concomitant medications limited throughout the study 
 
• 
Analgesics: Acetaminophen may be used by the subject 
 except within 
 before a scheduled study 
efficacy evaluation. 
Concomitant medications will be limited during Part 1 of the study 
) as follows: 
• 
NSAIDs: For subjects receiving NSAIDs 
): the subject must be on a stable dose 
for 
 prior to 
 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 
 is defined as 
subjects taking an NSAID on average 
 for the 
 period prior to Screening. 
• 
Corticosteroids: Subjects taking oral corticosteroids (not to exceed the equivalent of 10 mg of prednisone per 
day) must remain on a stable dose. 
• 
DMARDs: Subjects taking either MTX (not to exceed 25 mg/week) or sulfasalazine (up to 3 g a day) must 
remain on a stable dose, unless a decrease in dose is required because of toxicity or intolerance.  Other 
DMARDs are not allowed and oral MTX cannot be changed to parenteral dosing during the period of 
observation.  Subjects may not take MTX and sulfasalazine in combination. 
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 Part 2 
 as needed per 
Investigator discretion and therapeutic needs of the subject, or if the subject does not show minimal response to 
treatment (defined as 
t from Baseline in pain [assessed by Total Back Pain 
] and 
inflammation [assessed using the last 
 assessments in the BASDAI]) at 
 
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 4-week period prior to IMP initiation through to the end of 
Part 1. 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 13 of 95 
 
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 
Statistical Methods: 
Sample Size Calculation 
In each subject cohort (AS and nr-axSpA), approximately 
 subjects will be randomized per arm in a 
ratio to 
tildrakizumab 
 or  placebo, stratified by anti-TNF use (yes/no).  This sample size achieves 
 power 
(accounting for futility assessment) to detect a treatment effect in ASAS20 at 
 of 
 (placebo 
ASAS20 = 
; tildrakizumab ASAS20=
).  The test statistic used is the 
Cochran-Mantel-Haenszel 
(CMH) test at the
 significance level.  A 
 drop-out rate has been assumed. 
An interim analysis will be performed for futility assessment after data at Week 16 from 30 randomized subjects 
become available.  Futility assessment will be based on a futility threshold of 12% (difference between response 
rates on active arm and placebo) at Week 16. 
Statistical Analysis:  
The primary efficacy analysis population will be the Full Analysis Set (FAS) defined as all randomized subjects who 
have received at least 
 of IMP.  The primary analysis will be based on the CMH test, incorporating anti-TNF 
use as a stratification factor, to compare the response rates for the primary endpoint ASAS20 
 between 
placebo and the active dose group within AS and nr-axSpA separately.  In addition, the Mantel-Haenszel common 
risk (the response rate) difference between placebo and the active dose arm and corresponding confidence interval 
(CI) will be estimated.  Should CMH assumptions per the Mantel-Fleiss criterion not be satisfied, the treatment 
comparison will be based on a Chi-square tests following collapsing of the strata.  Early withdrawals or any other 
subjects with incomplete data at
 will be classified as non-responders for the primary endpoint ASAS20.  
Subjects who fail to show minimal response to treatment (defined as 
 from Baseline in pain 
[assessed by Total Back Pain 
] and inflammation [assessed using the last 
 assessments in the 
BASDAI]) at Week 16 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. 
Binary secondary and exploratory efficacy endpoints (e.g. other proportions) will be evaluated similarly. 
Continuous efficacy endpoints measured at several post-Baseline time points will be analyzed based on a mixed 
model repeated measure (MMRM) analysis that will include fixed effects for treatment, visit, treatment by visit 
interaction, prior anti-TNF use and subject specific Baseline values.  Continuous endpoints measured once 
post-Baseline will be evaluated based on an Analysis of Covariance (ANCOVA) with terms for treatment, prior anti-
TNF use, and subject specific Baseline values. 
Efficacy analyses will be based on randomized treatment assignments. 
Safety endpoints will be analyzed descriptively based on the Safety Analysis Set, defined as all subjects who 
received at least
 dose of IMP. 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 last subject’s 
, an IA will be conducted on all available data to evaluate the primary 
efficacy outcome.   
Date of the Protocol:  14 June 2017 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 14 of 95 
 
5 
TABLE OF CONTENTS 
1 
TITLE PAGE ................................................................................................................. 1 
2 
SIGNATURE PAGES ................................................................................................... 2 
3 
GENERAL INFORMATION ........................................................................................ 3 
4 
STUDY SYNOPSIS ...................................................................................................... 4 
5 
TABLE OF CONTENTS ............................................................................................ 14 
5.1 
List of Tables .................................................................................................. 19 
5.2 
List of Figures................................................................................................. 19 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................ 20 
7 
INTRODUCTION ....................................................................................................... 24 
7.1 
Background..................................................................................................... 24 
7.2 
Rationale for Dose Selection .......................................................................... 24 
7.3 
Rationale and Study Purpose .......................................................................... 25 
8 
STUDY OBJECTIVES ............................................................................................... 26 
8.1 
Primary Efficacy Objective ............................................................................ 26 
8.2 
Primary Safety Objective ............................................................................... 26 
8.3 
Secondary Objectives ..................................................................................... 26 
8.4 
Exploratory Objectives ................................................................................... 26 
9 
INVESTIGATIONAL PLAN ...................................................................................... 28 
9.1 
Overall Study Design and Plan....................................................................... 28 
9.1.1 
Description ................................................................................................. 28 
9.1.2 
Schedule of Assessments ........................................................................... 30 
9.1.2.1 
Blood Samples for Determination of Anti-Drug Antibodies 
(ADA) ......................................................................................... 35 
9.1.2.2 
Blood Samples for Determination of Serum Concentrations of 
Tildrakizumab (PK) .................................................................... 35 
9.1.3 
Study Assessments ..................................................................................... 35 
9.1.3.1 
Screening Period (Day -28 to Day 0) and Baseline Assessments36 
9.1.3.2 
Double-Blind Treatment Period (Part 1, Day 1 to Week 24) ..... 39 
9.1.3.3 
Treatment Follow-Up Period (Part 2, Week 28 to Week 52 [End 
of Treatment])............................................................................. 40 
9.1.3.4 
Washout Period (Part 3, Week 56 to Week 72 [EoS]) ............... 41 
9.1.3.5 
Unscheduled Visits ..................................................................... 42 
9.2 
Discussion of Study Design............................................................................ 42 
9.2.1 
Risk/Benefit and Ethical Assessment ........................................................ 42 
9.3 
Selection of Study Population ........................................................................ 43 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 15 of 95 
 
9.3.1 
Inclusion Criteria ....................................................................................... 43 
9.3.2 
Exclusion Criteria ...................................................................................... 45 
9.3.3 
Strategies for Subject Recruitment and Retention ..................................... 48 
9.3.4 
Withdrawal of Subjects .............................................................................. 48 
9.3.5 
Investigational Medicinal Product Discontinuation ................................... 49 
9.3.6 
Continued Study Participation ................................................................... 50 
9.3.7 
Lost to Follow-up ...................................................................................... 50 
9.3.8 
Discontinuation of Study Sites .................................................................. 51 
9.3.9 
Discontinuation of Study ........................................................................... 51 
10 
TREATMENT OF SUBJECTS ................................................................................... 52 
10.1 
Identity of Study Treatment(s) ....................................................................... 52 
10.1.1 
Administration of Study Treatment(s) ....................................................... 52 
10.2 
Study Treatment Packaging and Labeling ...................................................... 52 
10.2.1 
Packaging ................................................................................................... 52 
10.2.2 
Labeling ..................................................................................................... 52 
10.2.3 
Storage ....................................................................................................... 52 
10.2.4 
Blinding and Randomization of Study Treatment(s) ................................. 52 
10.3 
Procedure for Breaking the Randomization Code .......................................... 53 
10.4 
Subject Compliance ........................................................................................ 54 
10.5 
Study Treatment Accountability ..................................................................... 54 
10.6 
Concomitant Therapy ..................................................................................... 54 
11 
ASSESSMENT OF EFFICACY ................................................................................. 56 
11.1 
Efficacy Assessments ..................................................................................... 56 
11.1.1 
ASAS Improvement Criteria ..................................................................... 56 
11.1.2 
Joint Counts ............................................................................................... 56 
11.1.2.1 Tender Joint Counts (TJC46) ..................................................... 56 
11.1.2.2 Swollen Joint Counts (SJC44) .................................................... 57 
11.1.3 
Physician Global Assessment (PGA) of Disease Activity ......................... 57 
11.1.4 
Patient Global Assessment (PtGA) of Disease Activity ............................ 57 
11.1.5 
Total Back Pain (Spine Pain) and Nocturnal Pain ..................................... 57 
11.1.6 
Bath Ankylosing Spondylitis Functional Index (BASFI) .......................... 57 
11.1.7 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ............. 57 
11.2 
Exploratory Assessments................................................................................ 58 
11.2.1 
Bath Ankylosing Spondylitis Metrology Index (BASMI) ......................... 58 
11.2.2 
Ankylosing Spondylitis Quality of Life (ASQoL) ..................................... 58 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 16 of 95 
 
11.2.3 
36-item Short Form (SF-36) ...................................................................... 58 
11.2.4 
Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP and 
ASDAS-ESR .............................................................................................. 58 
11.2.5 
Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue 
Questionnaire ............................................................................................. 58 
11.2.6 
Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) ................ 59 
11.2.7 
Magnetic Image Resonance (MRI) ............................................................ 59 
11.2.7.1 SpondyloArthritis Research Consortium of Canada (SPARCC) 
MRI Indices ................................................................................ 59 
11.2.7.2 Modified 
Berlin 
Ankylosing 
Spondylitis 
Spine 
MRI 
(ASspiMRI) ................................................................................ 59 
12 
ASSESSMENT OF SAFETY...................................................................................... 60 
12.1 
Adverse Events ............................................................................................... 60 
12.1.1 
Definitions ................................................................................................. 60 
12.1.1.1 Adverse Event/Reaction ............................................................. 60 
12.1.1.2 Serious Adverse Event ............................................................... 60 
12.1.1.3 Adverse Events of Special Interest (AESIs) ............................... 61 
12.1.1.4 Events of Clinical Interest (ECI) ................................................ 62 
12.1.1.5 Treatment-Emergent Adverse Event .......................................... 62 
12.1.1.6 Overdose ..................................................................................... 62 
12.1.1.7 Product Quality Complaint ......................................................... 62 
12.1.1.8 Planned Hospitalization .............................................................. 63 
12.1.1.9 Incident ....................................................................................... 63 
12.1.2 
Recording of Adverse Events .................................................................... 63 
12.1.3 
Causal Assessment ..................................................................................... 64 
12.1.4 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms ................. 66 
12.1.5 
Anaphylaxis ............................................................................................... 66 
12.1.6 
Pregnancy .................................................................................................. 67 
12.1.7 
Reporting of Serious Adverse Events, Adverse Events of Special Interest, 
and Events of Clinical Interest ................................................................... 68 
12.1.7.1 Safety Reporting to Sponsor ....................................................... 69 
12.1.7.2 Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards and Investigators ...... 69 
12.2 
Safety Endpoints ............................................................................................. 70 
12.3 
Laboratory Assessments ................................................................................. 70 
12.3.1 
Clinical Laboratory Tests........................................................................... 71 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 17 of 95 
 
12.3.2 
Pregnancy Testing ..................................................................................... 71 
12.4 
Assessment of Suicidal Ideation and Behavior .............................................. 72 
12.5 
Electrocardiogram Assessments ..................................................................... 72 
12.6 
Physical Examination ..................................................................................... 73 
12.7 
Vital Signs ...................................................................................................... 73 
12.8 
Tuberculosis Testing ...................................................................................... 73 
12.8.1 
QuantiFERON Test ................................................................................... 74 
12.9 
Chest Radiograph ........................................................................................... 74 
12.10 
Radiograph of Spine and Sacroiliac Joints ..................................................... 74 
12.10.1 Historical Radiograph ................................................................................ 74 
12.10.2 New Radiograph ........................................................................................ 75 
12.11 
Magnetic Resonance Imaging (MRI) ............................................................. 75 
12.12 
Anti-Drug Antibodies ..................................................................................... 75 
12.13 
24/7 Medical Emergency Coverage ............................................................... 75 
13 
STATISTICAL EVALUATION ................................................................................. 76 
13.1 
Sample Size and Power .................................................................................. 76 
13.2 
Randomization ................................................................................................ 76 
13.3 
Analysis Sets .................................................................................................. 76 
13.3.1 
Full Analysis Set (FAS) ............................................................................. 77 
13.3.2 
Per-Protocol Analysis Set (PPAS) ............................................................. 77 
13.3.3 
Safety Analysis Set .................................................................................... 77 
13.3.4 
Pharmacokinetic Analysis Set ................................................................... 77 
13.4 
Endpoints ........................................................................................................ 77 
13.4.1 
Study Subject Data .................................................................................... 77 
13.4.2 
Primary Efficacy Endpoint ........................................................................ 77 
13.4.3 
Secondary Efficacy Endpoints ................................................................... 78 
13.4.4 
Exploratory Efficacy Endpoints ................................................................. 78 
13.4.5 
Pharmacokinetics ....................................................................................... 79 
13.4.6 
Safety Endpoints ........................................................................................ 79 
13.4.7 
Anti-Drug Antibodies Endpoints ............................................................... 79 
13.5 
Description of Statistical Analyses ................................................................. 79 
13.5.1 
General Considerations .............................................................................. 79 
13.5.2 
General Statistical Methods ....................................................................... 80 
13.5.3 
Analysis of Primary Endpoint.................................................................... 80 
13.5.4 
Analysis of Secondary Endpoints .............................................................. 81 
13.5.5 
Analysis of Exploratory Efficacy Endpoints ............................................. 81 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 18 of 95 
 
13.5.6 
Safety Analyses ......................................................................................... 81 
13.5.7 
Analysis of PK Endpoints .......................................................................... 83 
13.5.8 
Analysis of Anti-Drug Antibodies ............................................................. 83 
13.5.9 
Interim Analysis ......................................................................................... 83 
13.5.10 Data Safety Monitoring Board ................................................................... 84 
13.5.11 Clinical Adjudication Committee .............................................................. 84 
14 
DIRECT ACCESS TO SOURCE DATA/NOTES ..................................................... 85 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 86 
15.1 
Conduct of the Study ...................................................................................... 86 
15.2 
Study Monitoring............................................................................................ 86 
16 
ETHICS ....................................................................................................................... 87 
16.1 
Independent Ethics Committee/Institutional Review Board .......................... 87 
16.2 
Written Informed Consent .............................................................................. 87 
16.3 
Data Monitoring Committee........................................................................... 87 
17 
DATA HANDLING AND RECORD KEEPING ....................................................... 89 
17.1 
Case Report Forms/Source Data Handling..................................................... 89 
17.2 
Retention of Essential Documents .................................................................. 89 
18 
FINANCING AND INSURANCE .............................................................................. 90 
19 
PUBLICATION POLICY ........................................................................................... 91 
20 
CONFLICT OF INTEREST POLICY ........................................................................ 92 
21 
SIGNATURE OF INVESTIGATOR .......................................................................... 93 
22 
REFERENCE LIST ..................................................................................................... 94 
23 
APPENDIX 1 .............................................................................................................. 95 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 19 of 95 
 
5.1 
List of Tables 
Table 9–1 
Schedule of Assessments (Parts 1 and 2) ........................................................... 31 
Table 9–2 
Schedule of Assessments (Part 3) ...................................................................... 34 
 
5.2 
List of Figures 
Figure 1 
Study Design - Randomization Groups .............................................................. 30 
 
 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 20 of 95 
 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AP 
Anterior-posterior 
ASAS 
Assessment of SpondyloArthritis international Society 
ASDAS 
Ankylosing Spondylitis Disease Activity Score 
AS 
Ankylosing Spondylitis 
ASQoL 
Ankylosing Spondylitis Quality of Life questionnaire 
ASspiMRI 
Ankylosing Spondylitis spine Magnetic Resonance Imaging 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
BME 
Bone marrow edema 
β-hCG 
Beta human chorionic gonadotrophin 
CAC 
Clinical Adjudication Committee 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
Cmin 
Minimum concentration 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMARD 
Disease modifying anti-rheumatic drug 
DSMB 
Data Safety Monitoring Board 
DVU 
Discovertebral unit 
ECG 
Electrocardiogram 
ECI 
Event of clinical interest 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EoS 
End of study 
EoT 
End of treatment 


Sun Pharma Global FZE 
CONFIDENTIAL 
14 June 2017 
Tildrakizumab 
 
IND No: 128,807 
 
Protocol CLR_16_22 Version 2.0 
(Final) 
 
Page 21 of 95 
 
ESR 
Erythrocyte sedimentation rate 
EU 
European Union 
EUDRACT 
European Union Drug Regulatory Agency Clinical Trial 
FACIT 
Functional assessment of chronic illness therapy 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HLA 
Human leukocyte antigen 
hsCRP 
High-sensitivity C-reactive protein 
IA 
Interim analysis 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
Interactive voice recognition system 
LATAM 
Latin America 
MACE 
Major adverse cardiovascular events 
MASES 
Maastricht ankylosing spondylitis enthesitis score 
MMRM 
Mixed model repeated measure 
MRI 
Magnetic resonance imaging 
MTX 
Methotrexate 
N 
Number 
NOAEL 
No observed adverse effect level 
nr-axSpA 
Non-radiographic axial spondyloarthritis 
NSAID 
Non-steroidal anti-inflammatory drug 
PA 
Posterior-anterior 
PASI 
Psoriatic Area Severity Index 
PD 
Pharmacodynamic 


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PGA 
Physician’s Global Assessment 
PFS 
Pre-filled syringe 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PPAS 
Per-Protocol Analysis Set 
PRN 
As needed 
PQC 
Product quality complaint 
PsA 
Psoriatic arthritis 
PsO 
Plaque psoriasis 
PtGA 
Patient’s Global Assessment 
q 
Every 
QoL 
Quality of life 
QTcB 
QT corrected according to Bazett’s formula 
QTcF 
QT corrected according to Fridericia’s formula 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
s.c. 
Subcutaneous 
SD 
Standard deviation 
SF-36 
Short form 36 
SI 
Sacroiliac 
SIB 
Suicidal ideation and behavior 
SJC44 
Swollen joint count of 44 joints 
SOP 
Standard operating procedure 
SpA 
Spondyloarthritis 
SPARCC 
SpondyloArthritis Research Consortium of Canada 
T1/2 
Half-life 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TJC46 
Tender joint count of 46 joints 
Tmax 
Time of maximal concentration 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
UK 
United Kingdom 


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US 
United States 
VAS 
Visual analog scale 
WBC 
White blood cell 
 


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7 
INTRODUCTION 
7.1 
Background 
Tildrakizumab (anti-interleukin [IL]-23 humanized monoclonal antibody), also known as 
SCH 900222 or MK-3222, is a high-affinity (297 pM) humanized immunoglobulin G1 (IgG1)/κ 
antibody.  Tildrakizumab specifically binds to the p19 protein of the IL-23 heterodimer but does 
not bind human IL-12 (IL-12p40 and p35 heterodimer) or human p40.1 
The IL-23/IL-17 axis has been studied in ankylosing spondylitis (AS), and both cytokines are 
implicated in AS disease activity.  In view of the efficacy of the anti-IL-17 secukinumab in AS 
and the data emerging on the efficacy of anti-IL-12/23 monoclonal antibodies in AS, it is 
expected that tildrakizumab will also demonstrate efficacy in this population via its targeting the 
IL-23 component of this axis, which is upstream of IL-17.  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.  
Tildrakizumab is being developed for chronic plaque psoriasis (PsO), and Phase 3 studies have 
recently been unblinded, with subjects continuing in the long-term open-label extension.  The 
Phase 3 doses in PsO were 
 
thereafter.  In the Phase 2b study (Protocol P05495) for PsO, all  dose levels 
 
administered at 
 thereafter) were 
demonstrated to be safe and more efficacious than placebo (primary endpoint of Psoriasis Area 
and Severity Index [PASI]75 at 
).  A subset of subjects in the tildrakizumab PsO Phase 
2b study also had psoriatic arthritis (PsA) and received additional assessments to evaluate 
efficacy related to PsA.  These data suggest that for tildrakizumab, clinically effective doses for 
PsO are also potentially effective in PsA, a spondyloarthropathy that is related to AS.  
Further information relating to efficacy and safety data from clinical trials of tildrakizumab is 
available in the Investigator’s Brochure (IB)  
The proposed Phase 2 study in subjects with AS and non-radiographic axial spondyloarthritis 
(nr-axSpA), a related indication that includes patients who do not meet the diagnostic criteria for 
AS, will be the first clinical study of tildrakizumab in these subject populations. 
7.2 
Rationale for Dose Selection 
The proposed tildrakizumab dose is 
 then every 
 
hereafter.  Tildrakizumab 
represents a dose that should provide robust 
suppression of the IL-23 pathway in order to safely test the hypothesis that IL-23 signaling is 
important for disease activity in AS and nr-axSpA. 
The dose of 
 has not been used previously in clinical studies; however, the 
predicted (area under the curve [AUC]0-4wks) exposure for subjects is lower than that tested in 
Phase 1 studies (using a different dosing frequency) and offers a 
 based 


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upon the relevant non-clinical toxicology studies.  The estimated safety margin was derived from 
the systemic exposure at the no observed adverse effect-level (NOAEL) dose 
 
 in the 9-month repeat-dose primate toxicology study, and the human exposures 
obtained from the Phase 1 studies.  At the NOAEL dose, the tildrakizumab exposure (AUC0-14d) 
was 
.  The human exposure at steady-state for the Phase 2/3 dosing paradigm 
(once q12 weeks) was estimated by the observed exposure of AUC0-∞ 
 
 following a 
single dose of 
 in Phase 1 clinical 
studies (P05776 and P06303), respectively.  For the Phase 2/3 studies in PsO, the NOAEL AUC 
was multiplied by the number of doses 
 the monkeys received during the 
 dosing 
interval used in the PsO Phase 2/3 studies.  Hence the most conservative exposure multiple for 
the Phase 2/3 PsO studies of 
  For the dosing 
paradigm of 
s, the monkeys were dosed 2 times for each human dose, hence the 
exposure multiple is
. 
For reference, the AUC0-∞ values observed in Phase 1 studies P05661 and P06303 at exposures 
higher than those associated with 
 were 
 (
 
 
Tildrakizumab 
 administered 
 is the highest dose tested in the PsO dose-range 
finding study 
 
 and the PsO Phase 3 studies.  To date, tildrakizumab has been 
well tolerated at doses up to 
 and no dose-related toxicities have been observed. As 
discussed, tildrakizumab 
 is anticipated to exhibit a similar safety profile. 
Moreover, administration of tildrakizumab 
, as opposed to 
, is expected to 
result in higher serum trough levels, just before the next dose, yielding more consistent 
suppression of IL-23 throughout the entire dosing interval, which may prove to be important for 
the effective treatment of AS. 
7.3 
Rationale and Study Purpose 
This will be the first study conducted with tildrakizumab in subjects with AS and nr-axSpA.  As 
tildrakizumab is in development (Phase 3 completed, long-term safety studies ongoing) for the 
PsO indication, substantial pharmacokinetic (PK) and pharmacodynamics data exist that can 
inform dose selection in AS, as described.  Under these circumstances, the next step for 
development is to evaluate efficacy and safety in the AS population.  The purpose of this study is 
to determine if tildrakizumab, by suppressing the IL-23 pathway, can reduce disease activity in 
subjects with AS or nr-axSpA, as determined by the Assessment of SpondyloArthritis 
international Society (ASAS) criteria defined as 
 in 3 of 4 assessment 
domains (ASAS20) responder rate, compared to placebo.  The study will also provide safety and 
tolerability information for tildrakizumab in these patient populations. 
 


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8 
STUDY OBJECTIVES 
8.1 
Primary Efficacy Objective 
Part 1 
• To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by 
the proportion of subjects achieving ASAS20 response criteria at Week 24. 
Hypothesis: tildrakizumab is superior to placebo in the treatment of AS and nr-axSpA, as 
measured by the proportion of subjects achieving ASAS20 response at Week 24. 
8.2 
Primary Safety Objective 
Parts 1 and 2 
• To assess the safety/tolerability and immunogenicity of tildrakizumab in subjects with AS or 
nr-axSpA. 
8.3 
Secondary Objectives 
Parts 1 and 2 
Secondary objectives for Part 2 of the study are: 
• To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by 
the proportion of subjects achieving ASAS20 response criteria at Week 52, ASAS40 
response criteria at Weeks 24 and 52, and proportion of subjects who require adjustment of 
background therapy. 
• To characterize the PK of tildrakizumab in subjects with AS or nr-axSpA. 
8.4 
Exploratory Objectives 
Parts 1 and 2 
The exploratory objectives for Parts 1 and 2 of the study are: 
• To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by 
the proportion of subjects who achieve ASAS20 or ASAS40 at other measured time points. 
• To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by 
the proportion of subjects who achieve ASAS70 or ASAS5/6. 
• To evaluate the efficacy of tildrakizumab in subjects with AS of nr-axSpA, as measured by 
the change from Baseline in ASAS components, Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath 
Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Quality of Life 
questionnaire (ASQoL), Visual Analog Scale (VAS) (total back pain and nocturnal pain 
score), Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-reactive protein (CRP), 


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ASDAS-erythrocyte sedimentation rate (ESR), Maastricht Ankylosing Spondylitis Enthesitis 
Score (MASES), short form 36 (SF-36), Functional Assessment of Chronic Illness Therapy 
(FACIT)-fatigue, high-sensitivity CRP (hs)CRP, SpondyloArthritis Research Consortium of 
Canada (SPARCC) Magnetic Resonance Imaging (MRI) Index of Disease Activity of the 
Sacroiliac (SI) Joints, SPARCC MRI Index of Disease Activity of the Spine, and Modified 
Berlin Ankylosing Spondylitis Spine Magnetic Resonance Imaging Activity Score 
(ASspiMRI), swollen joint count of 44 joints (SJC44), and tender joint count of 46 joints 
(TJC46) at measured time points. 
• To evaluate the tildrakizumab exposure/response relationship. 
Part 3 
The exploratory objectives for Part 3 of the study are: 
• To assess the effect of investigational medicinal product (IMP) discontinuation on ASAS20, 
ASAS50, ASAS70, ASAS5/6, ASAS components, BASDAI, BASMI, BASFI, VAS (total 
back pain and nocturnal pain score), MASES, SF-36, FACIT-fatigue, TJC46, and SJC44 at 
measured time points. 
• To evaluate immunogenicity following IMP discontinuation. 
• To characterize the PK of tildrakizumab in subjects with AS or nr-axSpA following IMP 
discontinuation. 
 


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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, Phase 2a study.  The study will be 
multinational and performed in approximately 
study centers.  At least 
subjects with active 
AS (Stage 1 of study) and 
 subjects with active nr-axSpA (Stage 2 of study) will be randomly 
assigned in a blinded fashion in a 
ratio to receive either 
 tildrakizumab or placebo by 
 
  Starting at 
 all subjects will receive 
 tildrakizumab administered 
 until 
  
A flow diagram of the study design is presented in 
.  Recruitment for Stage 1 
(subjects with AS) will begin upon study approval; recruitment for Stage 2 (subjects with 
nr-axSpA) will begin only upon written notification by the Sponsor to the Competent Authorities 
and Investigators. 
Each stage of the study will consist of a Screening period 
, a double-blind, 
placebo-controlled period 
 Part 2, a 
 period 
 and Part 3, a 
).  The Sponsor and some 
 members not directly related to the clinical conduct of the study will be unblinded 
during Part 2.  Investigational sites and subjects will remain blinded to individual study treatment 
assignments until the last subject completes the study (
  During the washout period 
subjects will no longer receive tildrakizumab and will be treated according to the physicians’ 
discretion. 
Randomization will be stratified by prior anti-tumor necrosis factor (TNF) use (yes, no).  
Subjects with prior anti-TNF use will be capped at 
the total number of subjects. 
Subjects who fail to show minimal response to treatment 
 
 and inflammation [assessed using 
the 
]) at 
 in both stages of the study may 
have their background medications adjusted according to the maximum permitted daily dose (see 
inclusion criterion 7) and continue in the study. 
Subjects randomized to receive tildrakizumab during Part 1 of both stages of the study who 
achieve ASAS20 at 
 receive treatment with 
 tildrakizumab 
 until 
  Subjects receiving tildrakizumab during Part 1 
 
will discontinue IMP treatment and enter the 
.  Subjects 
randomized to receive placebo during Part 1 of both stages of the study who complete the 
Week 24 visit will continue to Part 2 and receive tildrakizumab 
 until 
 
even if they do not achieve ASAS20.  Subjects discontinued from IMP at any time (apart from 
withdrawal of informed consent) will be required to complete the End of Treatment (EoT) 
 a minimum of 
 after the last dose of IMP and enter the 
 


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washout period.  Subjects who withdraw from the study during Part 3 will undergo the 
 
(End of Study [EoS]) assessments at 
 after their last visit. 
The primary endpoint for efficacy will be ASAS20 at 
  Secondary endpoints will 
include ASAS20 at 
 ASAS40 at 
; and the proportion of subjects who 
require adjustment of background therapy.  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 will not be involved in the care of subjects and will not discuss disease 
activity or the treatment with subjects or the Principal Investigator (PI)/designee responsible for 
performing other efficacy and safety evaluations. 
An interim analysis (IA) will be performed for futility assessment after data from 
 randomized 
subjects become available at 
 
Following the last subject’s 
, an 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 Clinical Adjudication Committee (CAC) will be established to evaluate 
cardiovascular events 
 
Central review of radiographs used for inclusion/exclusion (except chest X-rays for tuberculosis 
[TB] evaluation, where applicable) will be performed to ensure consistent assessment across 
sites.  Scoring of MRI data collected throughout the study will be conducted by a central reader 
who will be blinded to the time sequence and subject treatment. 
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 Pharmaceuticals for Human Use (ICH) 
guidelines on Good Clinical Practice (GCP). 
 


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Protocol
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.2 
Schedule of Assessments 
The Schedule of Assessments is presented in 
 
and is applicable to both Stage 1 and Stage 2 of the study. 


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Table 9–1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.1.2.1 
Blood Samples for Determination of Anti-Drug Antibodies (ADA) 
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 appropriate tubes (see laboratory manual for sample volumes, acquisition, shipping 
and labeling instructions).  Sample collection times are to be recorded in 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 blood sample to obtain sufficient serum for PK assessment will be collected prior to IMP 
administration at specified time points indicated in 
  The sample will be 
collected into the appropriate tubes (see laboratory manual for sample volumes, acquisition, 
shipping and labeling instructions).  Actual sample collection times are to be recorded on the 
eCRF. 
Samples for both PK and ADA should be collected pre-dose. 
9.1.3 
Study Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 all test results are available, the Sponsor 
should be consulted to confirm if this is acceptable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 window can be extended, with approval by the Sponsor, to allow completion of the 
MRI. 
Further details of radiographs and MRI are provided in the Imaging Manual. 
Laboratory assessments may be repeated once for any laboratory parameter that falls within the 
relevant exclusion criteria provided they are completed within the 4-week period.  The repeat 
laboratory test finding will be used for any decision regarding subject eligibility. 
Clinic personnel must contact the 
Medical Advisor if they wish to 
re-screen a subject.  Such requests will be handled on a case-by-case basis, in discussion with the 
Sponsor’s Regional Clinical Lead or a delegate where necessary, and will only be allowed once 
per subject.  The decision on allowing the re-screening or not will be documented in an email 
sent to the clinic personnel and the relevant members of the Sponsor and 
 
 
team.  A re-screened subject will receive a new subject number and 
will undergo full re-screening; all laboratory tests should be performed again.  However, repeat 
QuantiFERON testing is not required if the result was negative at first Screening; additional 
chest X-rays and MRIs are not required if the previous tests were performed in the last months; 
and additional spine and SI joint X-rays are not required if performed within the last  months.  
There is not a study-specific re-screening form for this study.  Any subject who is started on 
prophylactic treatment for latent TB during the Screening period may be randomized 
weeks 
after initiation of treatment without the need for re-screening.  This process is also included in 
the 
 plan and communicated to the clinic personnel at study 
initiation visits and at the Investigator meeting. 


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Baseline assessments (prior to IMP administration) 
• Record physical examination findings and concomitant medications. 
• Check inclusion/exclusion criteria (e.g., results of tests performed at Screening and 
Baseline). 
• Perform a urine pregnancy test (at the site using materials supplied by the central laboratory). 
• 
 
 
 
 
 
 
 
 
 
− 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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9.1.3.2 
Double-Blind Treatment Period 
 
Following randomization, subjects will receive their 
 dose of IMP 
 
During the 
k double-blind, placebo-controlled period, all subjects will receive 
tildrakizumab 
 or placebo as described in 
 
 
 
 
 
 
 
 
 
 
 
 
: 
− 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Perform safety assessments including: 
 
 
 
 
 
 
 
 
 
 
 will be performed at the site using materials supplied by the 
central laboratory), 


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9.1.3.5 
Unscheduled Visits 
An unscheduled visit is defined as any visit to the Investigator site outside of the 
Protocol-specified time points due to safety reasons or when a repeated measurement is required 
(e.g., obvious measurement errors, confirmation of out-of-range results), where the subject is 
seen by study personnel. 
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, Phase 2a study designed to evaluate the 
efficacy and safety of tildrakizumab in subjects with AS (Stage 1 of the study) or nr-axSpA 
(Stage 2 of the study), a related indication.  The primary efficacy endpoint is based on the 
proportion of subjects achieving ASAS20 at 
 which is well established for the 
evaluation of clinical outcome.  Secondary endpoints are based on the proportion of subjects 
achieving ASAS20 at Week 52, ASAS40 at Weeks 24 and 52, proportion of subjects who 
require adjustment of background medication, and on evaluation of PK parameters. 
The study has been designed with  phases 
 
for both 
 of the study.  
This enables scientific evaluation of efficacy at 
, a longer evaluation of safety and 
efficacy through 
, and ensures subject safety via a monitored 
 period.  
All safety measures are consistent with evaluations used in clinical studies and previous studies 
with tildrakizumab. 
9.2.1 
Risk/Benefit and Ethical Assessment 
As this is the first study in patients with AS and nr-axSpA the benefits of tildrakizumab in these 
patient populations remains uncertain.  Given that efficacy benefits were reported for subjects 
with concurrent PsA in the completed Phase 2b study in PsO (Protocol PO5495), there is an 
expectation that subjects treated with tildrakizumab may experience improvement in AS and 


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nr-axSpA disease activity as these conditions are related to PsA.  However, the study design 
allows early identification of subjects who have not received a minimum level of improvement at 
 to enable the Investigator to adjust background therapy or 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.  
Radiographs used for inclusion/exclusion at Screening will be read centrally to ensure consistent 
assessment across sites.  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 will continue to be monitored throughout a 
 period 
following the 
visit, during which no active IMP will be administered and subjects can 
receive other treatments at the Investigator’s discretion. 
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 
9.3.1 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1. Subject has provided informed written consent 
2. Subject is ≥ 18 years of age at time of Screening. 
3. Definite AS based on the modified New York criteria (1984) with symptom duration of at 
least 3 months at Screening as defined by modified New York criteria (1984), or for 
nr-axSpA, a documented diagnosis of adult onset axial spondyloarthritis as defined by the 
specific ASAS criteria with at least 3 months symptom duration before Screening (see 
Appendix 1 for defined AS and nr-axSpA diagnostic criteria). 
4. Subjects with nr-axSpA must have active inflammation (MRI) on Screening and no 
radiographic sacroiliitis that fulfils the 1984 modified New York criteria. 
5. Active disease at Screening, defined as: 
− BASDAI score of at
 and  


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6. 
 
, 
 
 
 
 
 
 
 
 
 
 
 
 
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 concomitant medication 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 (defined as 
 
improvement from Baseline in pain [assessed by Total Back Pain VAS 
] and 
inflammation [assessed using the last  stiffness assessments in the BASDAI]) at 
 
8. For subjects receiving NSAIDs 
 the subject must be on a 
stable dose for ≥ 4 weeks prior to initiation of investigational product and be expected to 
maintain a stable dose for the first 24 weeks of the study, unless change in dosage is required 
due to toxicity.  Stable dose 
) is defined as subjects taking an NSAID on 
average 4 days per week for the 4-week period prior to Screening. 
9. 
 
 
 
 
 
 
 
 
 


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9.3.2 
Exclusion Criteria 
Subjects should be excluded from the study if they meet any of the following criteria: 
Other medical conditions 
1. Radiographic evidence of total ankylosis of the spine (defined by syndesmophytes present on 
the lateral views of spinal radiographs including intervertebral levels from T6 through S1; 
films will be read centrally).  
2. Subjects with more than 16 fused cervical, thoracic and lumbar ankylosed discovertebral 
units (DVUs), anteriorly, posteriorly or both, that are radiographically diagnostically 
compatible with AS.  
3. Subjects with evidence of bilateral SI joint fusion and 12 fused DVUs (per exclusion 
criterion 2 above).  
4. Subjects with known diagnosis of fibromyalgia or complex regional pain syndromes.  
5. Active uveitis or symptomatic inflammatory bowel disease requiring therapy at Screening.  
6. Subject has a planned surgical intervention between Baseline and the Week 24 evaluation for 
a pre-treatment condition. 
7. Subject has an active infection or history of infections as follows: 
− any active infection for which systemic anti-infectives were used within 28 days prior to 
first IMP dose, with the last dose having been received within 7 days of Screening, 
− any serious infection, defined as requiring hospitalization or IV anti-infectives within 
8 weeks prior to the first investigational product dose, with the last dose having been 
received within 7 days of Screening, 
− recurrent or chronic infections, e.g., chronic pyelonephritis, chronic osteomyelitis, 
bronchiectasis, or other active infection that, in the opinion of the Investigator, might 
cause this study to be detrimental to the subject.  


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8. Major chronic inflammatory or connective tissue disease other than AS (e.g., PsA, 
rheumatoid arthritis, systemic lupus erythematosus, Lyme disease, and gout).  
9. Subject has any concurrent medical condition or uncontrolled, clinically significant systemic 
disease (e.g., renal failure, heart failure, hypertension, liver disease, diabetes, or anemia) that, 
in the opinion of the Investigator, could cause this study to be detrimental to the subject.  
10. Subject has known history of infection with hepatitis B, hepatitis C, or human 
immunodeficiency virus.  
11. 
 
 
12. Subject has any active malignancy, including evidence of cutaneous basal or squamous cell 
carcinoma or melanoma. 
13. Subject has history of malignancy within 5 years EXCEPT treated and considered cured 
cutaneous basal or squamous cell carcinoma, in situ cervical carcinoma, OR in situ breast 
ductal carcinoma. 
14. Subjects with a history of alcohol or drug abuse in the previous 2 years. 
15. 
 
 
 
 
Laboratory abnormalities 
16. Subject has laboratory abnormalities at Screening, including any of the following: 
− aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
 the upper 
limit of normal (ULN), 
− creatinine 
 ULN, 
− serum direct bilirubin 
 
− white blood cell (WBC) count 
 
− positive test result for rheumatoid factor, 
− any other laboratory abnormality that, in the opinion of the Investigator, will prevent the 
subject from completing the study or will interfere with the interpretation of the study 
results. 
Washouts and non-permitted drugs 
17. Disease modifying anti-rheumatic drugs (DMARDs) other than NSAIDs, MTX or 
 must be discontinued 4 weeks prior to randomization, except for 
, 


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which has to be discontinued for 
 prior to randomization 
 
 
18. Subject has used any of the following within 
 
− high potency opioid analgesics (e.g., methadone, hydromorphone, or morphine), 
− topical and parenteral corticosteroids including intramuscular or intraarticular 
administration, live vaccines, 
− has a need for use of a live vaccine within 10 weeks of final dose of IMP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General 
20. Subject has known sensitivity to any of the products or any excipients to be administered 
during dosing. 
21. Female subjects of childbearing potential must agree to abstain from heterosexual activity (as 
part of an existing lifestyle choice) or practice a dual method of contraception, for example, a 
combination of the following: (1) oral contraceptive, depo progesterone, or intrauterine 
device; and (2) a barrier method (condom or diaphragm). Male subjects with female partners 
of childbearing potential who are not using birth control as described above must use a 
barrier method of contraception (eg, condom) if not surgically sterile (ie, vasectomy). 
Contraceptive methods must be practiced upon entering the study and through 16 weeks after 
the last dose of study treatment. If a subject discontinues prematurely, the contraceptive 
method must be practiced for 16 weeks following final administration of study drug.  A FSH 
test should be performed to confirm menopause for those women with no menses for less 
than 1 year. 


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22. Female is pregnant or breast-feeding, or planning to become pregnant or initiate 
breast-feeding while enrolled in the study or up to 16 weeks after the last dose of IMP. 
23. Subject will not be available for protocol-required study visits, to the best of the subject’s and 
Investigator’s knowledge. 
24. 
 
 
 
 
25. 
 
26. Subject has any kind of disorder that, in the opinion of the Investigator, may compromise the 
ability of the subject to give written informed consent and/or comply with all required study 
procedures. 
27. Donation or loss of 
 of blood within 8 weeks before dosing. 
28. Subjects who have been placed in an institution on official or judicial orders. 
29. Subjects who are related to or dependent on the Investigator, Sponsor, or study site such that 
a conflict of interest may arise. 
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.  Investigational treatments 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. 


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However, for safety reasons, 
 assessments should be conducted for subjects 
withdrawing during 
 if the withdrawn subject is willing to undergo the assessments.  
For subjects withdrawing during 
 and willing to undergo final assessments, the 
 
 assessments should be conducted at least 
 after their 
 
The appropriate personnel from the site and 
will assess whether investigational treatment 
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 (IRT) to register the 
subject’s discontinuation from investigational treatment. 
9.3.5 
Investigational Medicinal Product Discontinuation 
Subjects may voluntarily discontinue IMP for any reason at any time and enter the 
 
, or completely withdraw from the study 
  Subjects who 
consent to enter the washout period will undergo the 
 assessments a minimum of 
 after administration of the 
 of IMP.  
The Investigator should discontinue investigational treatment of a given subject if, on balance, 
he/she believes that continuation would be detrimental to the subject’s well-being. 
Investigational treatment must be discontinued under the following circumstances and the further 
steps need to be discussed with the medical monitor: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing may be temporarily suspended in the event of: 
 
 
 
 
 
 
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 study drug 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 study drug 
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 investigational treatment 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 follow-up study visits 
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. 


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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. 
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) 
10.1.1 
Administration of Study Treatment(s) 
Subjects will receive either 
 of tildrakizumab as 
 of 
 tildrakizumab, 
or 
 of placebo 
 
.  Starting at
 all subjects will receive 
 tildrakizumab administered 
 
until 
. 
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 is still unable 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 
Each pre-filled syringe (PFS) of IMP contains
 of solution.  A PFS of tildrakizumab 
contains 
/mL) of active drug. 
Placebo will be presented in identical containers with the same excipients (with no active drug) 
and stored/packaged the same as tildrakizumab. 
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 refrigerated conditions 
 and 
according to labeled storage conditions.  Until dispensed for administration to subjects, the study 
drug will be stored in a securely locked area, accessible to authorized personnel only. 
10.2.4 
Blinding and Randomization of Study Treatment(s) 
Both Stage 1 and Stage 2 of this study will be performed as a randomized, double-blind study 
stratified by prior anti-TNF use 
  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 
block size is considered potentially unblinding information, it will be known to the Study 
Biostatistician only. 
An 
 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 


Sun Pharma Global FZE 
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  Subjects will be randomized
 either tildrakizumab 
 or placebo, administered by 
. 
A copy of the 
 with true treatment allocations will be held by 
 
 during the study.  Another 
 list (containing 
 and 
) 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 
without the need for communication with the Sponsor.  This 
can only occur in emergency situations 
 
At the time of the IA, a specified team of personnel will be unblinded to allow reporting of the 
primary objective at 
 
The following assessments will be performed by an independent joint assessor:  
 
 
 
 
 
 
The PGA of disease activity will be performed by the treating physician.  All other assessments 
will be administered by the study co-ordinator or PI/designee 
 
10.3 
Procedure for Breaking the Randomization Code 
Following the last subject’s 
 visit 
 an IA 
will be conducted on all available data to evaluate the primary efficacy outcome.  
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
subject safely and efficaciously.  Most often, investigational treatment 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 
.  
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 investigational 
drug treatment for the specified subject and a fax or email confirming this information.  The 
system will automatically inform the 
, the medical monitor, and the
 
Project Manager that the 
 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 
 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 


Sun Pharma Global FZE 
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protocol number, investigational treatment 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 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 (Parts 1 and 2) using study-specific medication administration 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 
The following restrictions will apply to all subjects during the study. 
Concomitant medications limited throughout the study 
 
• Analgesics: Acetaminophen may be used by the subject 
 except within 
 before a 
scheduled study efficacy evaluation. 
Concomitant medications will be limited during Part 1 of the study 
 as 
follows: 
• NSAIDs: For subjects receiving NSAIDs 
 the subject must be on a 
stable dose for
 prior to 
 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 
 is defined as subjects taking an NSAID on average 
 per 
week for the 
 prior to 
g. 


Sun Pharma Global FZE 
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• Corticosteroids: Subjects taking oral corticosteroids 
 
 
• DMARDs: Subjects taking either MTX 
 or
 
 
 must remain on a stable dose, unless a decrease in dose is required because of 
toxicity or intolerance.  Other 
 and oral MTX 
 be changed to 
dosing during the period of observation.  Subjects 
 MTX and 
. 
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 Part 2 (Week 25 to 52) as needed per Investigator discretion and 
therapeutic needs of the subject, or if the subject does not show minimal response to treatment 
(defined as < 10% improvement from Baseline in pain [assessed by Total Back Pain VAS 0 to 
100] and inflammation [assessed using the last 2 stiffness assessments in the BASDAI]) at 
Week 16. 
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 4-week period 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 
ASAS Improvement Criteria 
The ASAS has developed improvement criteria for clinical studies in AS which include the 
ASAS20, ASAS40 and ASAS5/6 assessments
.  These composite scores are derived from 
several of the Patient Reported Outcome measures or Disease Activity Assessments.  ASAS20 
and ASAS40 assess  domains: the PtGA of disease activity, Total Back Pain, Function (BASFI) 
and Inflammation (mean of BASDAI 
). 
ASAS20 response is defined as an improvement of 
 
 domains: PtGA; Total Back Pain; BASFI; 
and Inflammation.  No worsening of 
 on a 
 in the 
remaining 
domain. 
ASAS40 response is defined as an improvement of 
 
 
domains; PtGA of disease activity; Total Back Pain VAS; BASFI VAS; and 
Inflammation VAS 
 
.  No worsening of
 on a 
 in the remaining 
 domain. 
ASAS70 response is defined as an improvement of 
 
 domains; PtGA; Total Back Pain; BASFI; 
and Inflammation.  No worsening of 
 in the 
remaining 
 domain. 
ASAS5/6 improvement is defined as and improvement of 
 domains 
(PtGA, Total Back Pain, Function and Inflammation, CRP, Spinal mobility [lateral spinal 
flexion]). 
11.1.2 
Joint Counts 
11.1.2.1 
Tender Joint Counts (TJC46) 
The number of tender or painful joints from 
 anatomical joints will be assessed for both the 
right and left side of the body by an independent joint assessor.  The presence of a tender or 
painful joint will be scored as and absence as
  The total TJC will be the sum of the scores for 
a range of TJC from 
 
  Joints to be assessed for tenderness include sternoclaviculars, 


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acromioclaviculars, shoulders, elbows, wrists, metacarpophalangeals, interphalangeal of thumb, 
proximal interphalangeal, hips, knees, ankles, and metatarsophalangeals. 
11.1.2.2 
Swollen Joint Counts (SJC44) 
The number of swollen joints from 
 anatomical joints will be assessed for both the right and 
left side of the body by an independent joint assessor.  The presence of a swollen joint was 
scored as  and absence as .  The total SJC will be the 
 of the scores for a range of SJC from 
  The 
joints to be assessed for swelling are the same as those assessed for tenderness, except the hip 
joints are not included. 3 
11.1.3 
Physician Global Assessment (PGA) of Disease Activity 
The treating physician will evaluate the status of the subject’s AS by means of a VAS.  The 
subject will be assessed according to how their AS is at the time.  The VAS will be anchored 
with verbal descriptors of “very good” to “very poor”. 
11.1.4 
Patient Global Assessment (PtGA) of Disease Activity 
The subject will make an overall assessment of their condition 
 
 by means of a VAS.  The VAS 
will be anchored with verbal descriptors of “no pain” to “very severe pain”. 
11.1.5 
Total Back Pain (Spine Pain) and Nocturnal Pain 
The subject will assess total back pain 
 
 and nocturnal back pain 
 
 using 
a VAS (“no pain” to “most severe pain”). 
11.1.6 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
BASFI is a validated index for the assessment of functional limitation in patients with AS.  It 
comprises 
 questions; the first  questions evaluate activities related to functional anatomical 
limitations and the final  questions evaluate ability to cope with everyday life.  A VAS (“easy” 
to “impossible”) is used to score each question. 
11.1.7 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
BASDAI is a simple index demonstrating statistically significant 
 reliability.  The 
index is sensitive to change within a short period of time 
 physiotherapy course, 
 
 improvement.  The VAS ranges from “
 and comprises 
 questions pertaining to the  major symptoms of AS –
 
 
  To give each symptom equal weighting, the mean of the  scores relating to morning 
stiffness is taken. 


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11.2 
Exploratory Assessments 
11.2.1 
Bath Ankylosing Spondylitis Metrology Index (BASMI) 
BASMI is a combined index to assess spinal mobility.  Tragus-to-wall distance, lumbar flexion, 
lumbar side flexion and intermalleolar distance are measured in centimeters.  Cervical rotation is 
measured in degrees using a gravity goniometer.  A scale in 
 
and in 
 is associated with a numerical scale from  
 
11.2.2 
Ankylosing Spondylitis Quality of Life (ASQoL) 
The ASQoL is a validated 
 self-administered questionnaire which has been used 
worldwide in clinical studies.  The scale can measure the quality of life (QoL) associated with a 
wide range of perceived disease severity and activity.  The amount of restriction on daily 
activities, level of pain and fatigue, and impact on the subject’s emotional state is assessed.  Each 
item is scored as “yes” or “no”. 
11.2.3 
36-item Short Form (SF-36) 
The SF-36 v2 is a multipurpose survey that measures 
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.  
11.2.4 
Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP and ASDAS-ESR 
The ASDAS-CRP and ASDAS-ESR endpoint is derived from the BASDAI, CRP and ESR.  It 
comprises Total Back Pain (BASDAI Question 2), PtGA, Peripheral pain/swelling (BASDAI 
Question 3), Duration of morning stiffness (BASDAI Question 6), CRP (in mg/L) or ESR.  
 
 
 
. 
11.2.5 
Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue 
Questionnaire  
FACIT scales are a collection of QoL questionnaires targeted to the management of chronic 
illness.  They are designed for self-administration but can also be administered by an 
appropriately trained interviewer.  The questionnaires are used by major co-operative clinical 
study groups, for international industry-sponsored research, government and military research, 


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and in health practice self-studies.  They have demonstrated equivalence in mode of 
administration, as well as reliability, validity and sensitivity to change.  The FACIT-fatigue 
questionnaire is a 
 standalone subscale (
  
11.2.6 
Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 
MASES was originally a clinical scoring system for enthesitis in AS and is now also used in PsA 
and spondyloarthritis (SpA) in general.  It is recommended by the ASAS for use in randomized 
controlled studies of AS and SpA.  Tenderness on examination is recorded as either present (1) 
or absent (0) for the fifth lumbar spinous process and each of 12 bilateral sites, including the first 
costachondral joints, seventh costochondral joints, anterior superior iliac spines, iliac crests, 
posterior iliac spines, and the proximal insertion of Achilles tendons.  
11.2.7 
Magnetic Image Resonance (MRI) 
MRI allows objective measurement of disease activity in AS by monitoring changes in 
inflammation.  Through the incorporation of
n techniques, MRI enables direct 
visualization of inflammatory lesions within the bone marrow that are often obscured by marrow 
fat.  These lesions are thought to be predictive of future locations of erosion and subsequent 
osteoproliferation, and thus may offer detection and objective monitoring of active disease which 
is not possible with radiography.   
11.2.7.1 
SpondyloArthritis Research Consortium of Canada (SPARCC) MRI Indices 
SPARCC MRI indices are validated scoring methodologies for spine and SI joint inflammation 
in patients with AS.  These indices assess the presence, 3-dimensional extent and signal intensity 
of active inflammatory lesions represented by bone marrow edema (BME) in the spine and SI 
joints of affected patients.  In the spine, the scoring system measures BME in the bone marrow 
of DVUs, each unit representing the region between 
imaginary lines drawn through the middle 
of adjacent vertebrae.  The
 DVU are selected for assessment, a method that has been 
shown to be equally discriminatory as an assessment of all 
DVUs.  The scoring system also 
measures BME in the iliac and sacral bone marrow of the SI joints by assessing lesions in 
consecutive coronal slices through the synovial portion of the joint.  
11.2.7.2 
Modified Berlin Ankylosing Spondylitis Spine MRI (ASspiMRI) 
The volume of BME in each DVU is scored on a scale of 
 
  The score is 
designed to evaluate MRIs of the total spine including 
 DVUs; score range
 
 


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12 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in
. 
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 
 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
 
 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 one that: 
 
 
 
 
 


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12.1.1.3 
Adverse Events of Special Interest (AESIs) 
The events of severe infections, malignancies (including non-melanoma and melanoma skin 
cancer), confirmed Major Adverse Cardiovascular Events (MACE), and drug-related 
hypersensitivity reactions 
 will be identified a priori as AESIs for 
summarizing in this study 
  Major Adverse Cardiovascular Events include 
non-fatal stroke, non-fatal myocardial infarction and cardiovascular death.  All MACE events 
will be evaluated and adjudicated by a CAC 
 


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An AESI must be reported as if it were an SAE (Section 12.1.7). 
12.1.1.4 
Events of Clinical Interest (ECI) 
An ECI is a non-serious AE or occurrence that is designated to be of special interest and must be 
reported to the Sponsor as though it were an SAE 
 
The following events are considered ECIs for this study: 
 
 
 
 
 
 
 
 
 
 
 
12.1.1.5 
Treatment-Emergent Adverse Event 
TEAEs are defined as any AE occurring or worsening on or after the 
 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 
Pharmacovigilance and Safety Services within 24 hours of awareness, using 
the details provided in 
 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 using the details provided in 
 


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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 using the details provided in 
 
12.1.2 
Recording of Adverse Events 
Any relevant observations made before the end of the 
 
 are to be recorded on the AE eCRF, but 
 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 
 period following the 
visit.  For the purposes of 
this study, any detrimental change in the subject’s condition, after 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
, at least 
 should be made to collect AEs from sites. 
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 study drug, he/she should promptly notify the Sponsor. 
The Investigator will assess the intensity of AEs based on the following definitions: 
 
 
 
 
 
 


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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 
.  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 
 
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 (Global Introspection 
assessment), 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: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. 
12.1.5 
Anaphylaxis 
The clinical criteria for diagnosing anaphylaxis are as follows: 


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12.1.6 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is suspicion that the study drug 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 


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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. 
Pregnancies must be reported to 
 Pharmacovigilance and Safety Services using the 
reporting details provided in 
 within 24 hours of awareness. 
12.1.7 
Reporting of Serious Adverse Events, Adverse Events of Special Interest, and 
Events of Clinical Interest 
All SAEs must be reported according to ICH GCP or local regulations, applying the regulation 
with the stricter requirements. 
Investigators and other site personnel must inform appropriate
 Pharmacovigilance and 
Safety Services of any SAE that occurs during the course of the study (from the time of informed 
consent until 30 days after the last EoS visit), whether or not it is considered causally related to 
the IMP or to the study procedure(s), and within 24 hours of when he or she becomes aware of it.  
An SAE with an onset day greater than 30 days from the EoS visit will be recorded only for fatal 
SAEs and those deemed by the Investigator to be drug-related or AESIs/ECIs 
 
  The Investigator should make every effort to obtain follow-up 
information on the outcome until the event is considered resolved, chronic and/or stable. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to 
within 24 hours as described above.  The start date of the SAE is not the start 
date, but the date when the AE becomes serious; analogously, the stop date is the date when any 
seriousness criterion is no longer applicable, not the date when the AE is resolved. 
All SAEs will also be recorded in the eCRF.  The Investigator is responsible for informing the 
Ethics Committee of the SAE as per local requirements. 
Paper SAE forms should be completed at the site and faxed/emailed to the relevant 
 
Pharmacovigilance and Safety Services or emailed to the global email distribution list within 
24 hours of awareness of the event. 
SAE, AESI, and ECI reports 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. 
Telefax: 
 


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Telefax: (US/LATAM): +1 215 616 3096 
 
If the SAE/AESI/ECI cannot be reported via the email (primary option) or by fax (secondary 
option), the following telephone numbers may be used to record the event: 
 
 
 
There may be situations when an SAE (or AESI/ECI) 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 
Pharmacovigilance and Safety Services will forward the SAE and Pregnancy report to the 
following Sponsor’s safety representatives within 1 business day or 3 calendar days (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.  Procedure and timelines for safety 
reporting are provided in the Safety Management Plan as agreed by 
 the Sponsor. 


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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
 
Pharmacovigilance and Safety Services. 
In accordance with ICH GCP, 
 Pharmacovigilance and Safety Services 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 
by the Sponsor.  In particular and in line with respective regulations, 
 Pharmacovigilance 
and Safety Services 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 
 Pharmacovigilance and 
Safety Services 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 
 Pharmacovigilance and 
Safety Services 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 the Schedule of Assessments 
  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 (pre-dose where applicable) after 
, 
following ECG and vital sign measurements. 


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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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
12.3.2 
Pregnancy Testing 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening visit.  Urine pregnancy test with sensitivity of at least 
, will be performed 
according to the Schedule of Assessments 
  If at any point during the 
study there is a case of a positive urine β-hCG test, the subject will have IMP stopped and will be 


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withdrawn from the study.  To confirm menopause in female subjects with no menses for less 
than 
, a FSH test should be performed at the Screening visit to confirm they are not of 
childbearing potential. 
Pregnancy tests will also be performed whenever  menstrual cycle is missed 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 
.  There 
are 
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 
within the last 
 to Questions 
 in the suicidal ideation section, 
or any 
 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 
 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 
d ECG recordings will be obtained at scheduled study visits after the subject 
has rested for at least 
 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 
 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. 
The following ECG parameters will be obtained directly from the computerized 
 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 
Fridericia formula, (QTcF) is the observed QT interval (the time from the beginning of the Q 


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wave to the end of the T wave) divided by the cubed root of the R-R interval (interval from the 
peak of one QRS complex to the peak of the next) in seconds: 
  
 
 
 
 
 
 
QTcB (QTc corrected according to Bazett’s 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, weight, general appearance, skin (presence of rash), HEENT 
(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 (measured after at least 
 in the supine position) and pulse rate (measured after at least 
 in the supine 
position) 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 
 TB.  The subject must have a negative evaluation for TB within 
 before initiating IMP, defined as a negative QuantiFERON test. 
Subjects with a positive or 2 successive indeterminate QuantiFERON tests are allowed if they 
have no history of active TB or symptoms of TB, and a PA chest radiogram performed (and with 
a report available at the site) within 3 months of Screening with no evidence of TB (or of any 
other pulmonary infectious diseases).  If there is evidence of prior latent TB infection, subjects 
must have history of adequate prophylaxis per local standard of care.  If presence of latent TB is 
established, treatment according to local country guidelines must have been followed for at least 
4 weeks prior to inclusion in the study. 


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12.8.1 
QuantiFERON Test 
QuantiFERON-TB Gold In-Tube7 is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10 and TB 7.7 proteins to stimulate cells in heparinized whole blood.  
Detection of interferon-γ by Enzyme-Linked Immunoabsorbent Assay is used to identify in vitro 
responses to these peptide antigens that are associated with TB infection.  QuantiFERON-TB 
Gold In-Tube is an indirect test for Mycobacterium tuberculosis 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 positive, negative, or indeterminate (indeterminate results are 
generated when either of the control tubes does not produce their intended values).  A maximum 
of  QuantiFERON tests are allowed.  A re-test is only permitted if the 
 is indeterminate; the 
result of the 
 will then be used. 
12.9 
Chest Radiograph 
A chest radiograph will be obtained at the Screening visit in subjects with positive or 
 successive indeterminate QuantiFERON tests unless it has been previously taken and 
documented within the
 prior to Screening and is available with the associated report at 
the site.  There must be no evidence of active TB or any other pulmonary infectious diseases for 
the subject to be considered eligible for the study. 
12.10 
Radiograph of Spine and Sacroiliac Joints 
A radiograph of the spine and SI joints is 
 
  Subjects with AS must meet 
 for diagnosis, and 
nr-axSpA subjects must have no
 that fulfils these criteria in order to be eligible for the 
study.  Subjects must not have evidence of 
 as defined in the 
 
.  At Screening, the following radiographs must be acquired: AP, LPO and RPO SI joints; 
AP and lateral lower thoracic spine (T5 to L1); AP and lateral lumbar spine (T12 to S1).  
Radiographs must be submitted to the central reader for evaluation of quality and confirmation 
that the subject meets inclusion and exclusion criteria.  Subjects should not be scheduled for MRI 
or Baseline visit until confirmation is received from the central reader. 
12.10.1 
Historical Radiograph 
Previous radiographs of the spine and SI joints documenting diagnosis of AS or nr-axSpA will 
be acceptable providing they were performed within 
months of the date of Screening.  They 
should be used in lieu of performing Screening radiographs if they can be obtained and sent to 
the central reader for confirmation.  The original films, or a copy must remain at the site and a 
copy should be sent to the central reader.  If results are considered unevaluable by the central 
reader, the X-ray must be repeated. 


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12.10.2 
New Radiograph 
If historical radiographs cannot be obtained,
 
 must be obtained 
at the Screening visit to visualize the spine and SI joints.  This should be done after all Screening 
activities have been completed and if the subject does not fail to meet other study criteria. 
12.11 
Magnetic Resonance Imaging (MRI) 
MRI of the entire spine and SI joints will be performed at the Screening visit (except for subjects 
who have an MRI scan and associated report available within the past  months), at 
 and 
at 
 using standard clinical scanners.  If a subject is unable to complete the MRI 
procedure within the protocol-defined time window due to technical issues at the site (e.g. the 
MRI is not working) or subject difficulties (e.g. the subject is unable to lie flat and cannot 
achieve a quality scan), the Screening window can be 
, with approval by the Sponsor, to 
allow completion of the MRI.  Imaging will use standardized commercially available sequences 
for evaluation of a validated endpoint such as the SPARCC MRI indices and/or ASspiMRI.  
Scoring of the data will be conducted by a central reader who will be blinded to the time 
sequence and subject treatment.  Detailed procedures for obtaining and processing the MRI, 
conducting image Quality Assurance/Quality Control and endpoint analyses will be developed in 
study-specific documents and provided as appropriate to Investigators, MRI technicians and the 
central reader. 
12.12 
Anti-Drug Antibodies 
The presence of ADA will be assessed at the visits indicated in the Schedule of Assessments 
Table 9–1 and Table 9–2.  Samples will be collected as detailed in 
. 
12.13 
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 
24 hours per day, 7 days per week 
 


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13 
STATISTICAL EVALUATION 
13.1 
Sample Size and Power 
In each subject cohort 
, approximately 
 subjects will be randomized per 
arm in a 
 ratio to tildrakizumab 
 or placebo, stratified by anti-TNF use 
).  This 
sample size achieves 
 power (accounting for futility assessment) to detect a treatment effect 
in ASAS20 at 
).  The 
test statistic used is the 
 significance 
level.  A 
drop-out rate has been assumed. 
An IA will be performed for futility assessment after data at 
 from 
 randomized 
subjects become available.  Futility assessment will be based on a futility threshold of 
 
 
13.2 
Randomization 
A randomization schedule will be computer-generated before the
.  After all 
Screening procedures are performed and results of Screening tests are available 
 
, eligible subjects will be activated in 
 and assigned 
randomly on a 
 basis to the following treatment groups: 
• A: 
 tildrakizumab 
• B: Placebo 
by 
  Starting 
at 
, all subjects, except 
 
 will receive 200 mg tildrakizumab administered q4 weeks 
until Week 48.  Subjects receiving tildrakizumab during 
 
 will discontinue IMP treatment and enter the 
 period.  Subjects 
randomized to receive 
will receive 
 tildrakizumab administered 
weeks until 
 even if they do not achieve ASAS20. 
Randomization will be performed by the 
.  Subjects will be stratified by prior anti-TNF use 
(yes/no).  Subjects with prior anti-TNF use will be capped at 
 
. 
13.3 
Analysis Sets 
The primary evaluation of the efficacy endpoint will be performed using the 
 
  Results for the Per-Protocol Analysis Set (PPAS) will be considered 
  
Secondary endpoints will be analyzed for both the 
.  Safety endpoints will be 
analyzed using the 
. 
PK data will be analyzed using the 
. 


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13.3.1 
Full Analysis Set (FAS) 
The FAS will include all randomized subjects who have received 
dose of IMP 
).  Analyses will be based on 
.  The evaluation of 
the efficacy endpoints will be performed based on the
 
13.3.2 
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 variables.  The deviations can 
include but 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 
 dose of 
IMP.  Analyses will be based on the actual treatment received.  Safety endpoints will be analyzed 
based on the 
. 
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 
 to obtain reliable estimates of the key PK parameters. 
13.4 
Endpoints 
13.4.1 
Study Subject Data 
Demographic data and Baseline subject characteristics will be summarized descriptively. 
IMP exposure and compliance will be summarized descriptively. 
Incidence of prior and concomitant medication use will be summarized by World Health 
Organization Drug dictionary coded terms – Anatomic Therapeutic Chemical (ATC) 
classification and preferred term. 
13.4.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects who achieve ASAS20 at Week 24. 


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13.4.3 
Secondary Efficacy Endpoints 
Secondary endpoints include: 
• The proportion of subjects who achieve ASAS20 at Week 52. 
• The proportion of subjects who achieve ASAS40 at Weeks 24 and 52. 
• The proportion of subjects who require adjustment of background therapy. 
13.4.4 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints through Week 52 include: 
• The proportion of subjects who achieve ASAS20 or ASAS40 at other measured time points. 
• The proportion of subjects who achieve ASAS70 at measured time points. 
• The proportion of subjects who achieve a ASAS5/6 response at measured time points. 
• ASAS5/6 response is defined as a 20% improvement in 5 out of 6 domains (physical function 
[BASFI], Total Back Pain, Patient's Global Assessment of Disease Activity, Inflammation 
[mean of Questions 5 and 6 of the BASDAI], spinal mobility [BASMI], and acute phase 
reactants [CRP]). 
• Change from Baseline in ASAS components at measured time points. 
• Change from Baseline in BASDAI, BASMI, BASFI, and ASQoL at measured time points. 
• Change from Baseline in VAS (total back pain and nocturnal pain score) at measured time 
points. 
• Change from Baseline in ASDAS-CRP and ASDAS-ESR at measured time points. 
• Change from Baseline in MASES at measured time points. 
• Change from Baseline in SF-36 at measured time points. 
• Change from Baseline in FACIT-fatigue at measured time points. 
• Change from Baseline in TJC46 and SJC44 at measured time points. 
• Change from Baseline in hsCRP serum levels at measured time points. 
• Change from Baseline in SPARCC MRI Index of Disease Activity Score of the SI Joints at 
measured time points. 
• Change from Baseline in SPARCC MRI Index of Disease Activity Score of the Spine at 
measured time points. 
• Change from Baseline in Modified Berlin ASspiMRI of the Spine at measure time points. 
Exploratory efficacy endpoints Weeks 53 to 72 include: 


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• Endpoints noted as primary and secondary above, relating to the following after IMP 
discontinuation:  ASAS20, ASAS40, ASAS70, ASAS5/6, ASAS components, BASDAI, 
BASMI, BASFI, VAS (total back pain and nocturnal pain score), MASES, SF-36, 
FACIT-fatigue, TJC46, and SJC44. 
• Incidence of ADA to tildrakizumab and their correlation with safety and efficacy. 
13.4.5 
Pharmacokinetics 
Secondary PK endpoints through 
 include: 
• AUC. 
• Maximum concentration (Cmax). 
• Minimum concentration (Cmin). 
• Time of maximal concentration (Tmax). 
• T1/2. 
PK parameters will be analyzed separately for each subject population and pooled.  Exploratory 
PK endpoints through 
 include an exposure-response relationship of tildrakizumab with 
ASAS.  Other exploratory PK endpoints include population PK parameters through 
 and 
following IMP discontinuation (
). 
13.4.6 
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. 
13.4.7 
Anti-Drug Antibodies Endpoints 
• Incidence of ADA and correlations with PK, safety and efficacy endpoints will be 
investigated across 
. 
13.5 
Description of Statistical Analyses 
13.5.1 
General Considerations 
The statistical evaluation will be performed by 
using SAS®, Version 9.4 or later. 


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13.5.2 
General Statistical Methods 
Summaries for AS or nr-axSpA will be presented separately.  Summary statistics will also be 
presented by treatment group.  For 
 variables, unless otherwise stated, the number of 
available observations (n), mean, standard deviation (SD), median, and range will be provided.  
For 
 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 
 of a variable taken before the 
 
 will be used as the Baseline value.  Unless otherwise specified, 
 
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 
 test, incorporating prior anti-TNF use as a 
stratification factor, to compare response rates for the primary endpoint 
 
between placebo and active dose arm within AS and nr-axSpA 
.  In addition, the 
 difference between placebo and the active 
dose arm and corresponding confidence interval (CI) will be estimated.  Should assumptions per 
the 
 criterion not be satisfied, pairwise comparisons will be based on 
 
tests following collapsing of the strata.  In this case, the 
 difference and CI will be 
based on normal approximation without considering stratification.  Early withdrawals or any 
other subjects with incomplete data at 
 will be classified as 
 for the 
primary endpoint
  Subjects who fail to show minimal response to treatment 
 
 and 
inflammation 
 may 
have their background medications adjusted according to the maximum permitted daily dose 
 
and continue in the study.  Any subject requiring 
 will be 
counted as a non-responder for the primary analysis. 
In the analysis of primary endpoint ASAS20 at 
, the overall p-value will be calculated 
using 
 against the critical value corresponding to the stage at which 
the study was stopped. 
Analysis of the primary endpoint will be based on the 
. 
A sensitivity analysis will be performed based on the 
 
Subgroup analyses may be performed for the following: 
• Prior anti-TNF use 
 
• Body weight 
 


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• Age 
 
• Gender. 
• MTX 
 
Reasons for prior anti-TNF failure will be summarized. 
13.5.4 
Analysis of Secondary Endpoints 
 endpoints up to 
 will be analyzed based on the methods described for 
. 
Secondary endpoints will be analyzed for both the FAS and PPAS. 
13.5.5 
Analysis of Exploratory Efficacy Endpoints 
 endpoints up to 
 will be analyzed based on the methods described 
for secondary endpoints above for the 
.  Continuous endpoints up to 
 will be 
analyzed based on a 
 analysis that includes the fixed 
effects of treatment, visit, treatment by visit interaction, prior anti-TNF use (Yes/No), and 
Baseline value. 
 endpoints measured once post-Baseline will be evaluated based on an Analysis of 
Covariance (ANCOVA) with terms for treatment, prior anti-TNF use, and subject specific 
Baseline values. 
For 
, the following will be summarized descriptively based on the 
 
  Changes in Baseline for the components of 
 
 
 will also be summarized descriptively. 
Incidence of ADA, defined as the % of subjects with positive ADA based on the 
 
, will be summarized and explored for correlation with various PK, 
safety and efficacy outcomes. 
13.5.6 
Safety Analyses 
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.  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 


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part reported.  Separate tables will be presented by severity; TEAEs considered to be related to 
IMP by Investigators will be summarized similarly. 
AESIs and ECIs will be summarized descriptively.  AESI-related safety endpoints include: 
• Percent of subjects with severe infections, defined as any infection meeting the regulatory 
definition of a SAE, or any infection requiring IV antibiotics whether or not reported as a 
serious event, as per the regulatory definition. 
• Percent of subjects with malignancies (excluding carcinoma in situ of the cervix). 
• Percent of subjects with non-melanoma skin cancer. 
• Percent of subjects with melanoma skin cancer. 
• Percent of subjects with confirmed MACE. 
• Percent of subjects with drug-related hypersensitivity reactions (e.g. anaphylaxis, urticaria, 
angioedema, etc.). 
All AEs will be presented in full in a comprehensive listing including 
 
 
.  Details of SAEs and AEs leading to withdrawal will be listed separately.  A more 
detailed description regarding presentation of AE data will be provided in the SAP. 
AESIs and ECIs will be summarized descriptively. 
Clinical Laboratory 
Clinical laboratory parameter (e.g., albumin, etc.) observed values and changes from Baseline 
will be summarized at each scheduled visit. 
Values outside the normal range will be categorized as 
 
 based on the laboratory’s reference range 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. 
Vital Signs 
Vital sign observed values and changes from Baseline will be summarized at each scheduled 
visit. 
ECG 
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with “Normal” “Abnormal, not clinically significant” and “Abnormal, clinically 
significant”. 


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ECG parameter (e.g., QTcF) observed values and changes from Baseline 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. 
13.5.7 
Analysis of PK Endpoints 
Plasma tildrakizumab concentration data will be listed by individual subject and summarized by 
time. 
PK parameters of AUC, Cmax, Cmin, Tmax and T1/2 will be summarized with descriptive statistics 
(n, mean, SD, geometric mean, % coefficient of variation, minimum, 1st, 2nd [i.e., median] and 
3rd quartiles and maximum). 
Exploratory analyses will be performed as below: 
• Develop a mechanistic-based exposure-response (i.e. indirect) PK/PD model to explore the 
relationship of tildrakizumab exposure and ASAS response. 
• Determine population PK parameters during and following IMP discontinuation. 
Exploratory PK analyses may be described in separate SAPs. 
 
13.5.8 
Analysis of Anti-Drug Antibodies 
Incidence of ADA will be summarized and explored for correlation with various PK, safety and 
efficacy outcomes. 
13.5.9 
Interim Analysis 
After 
 randomized subjects complete 
, futility assessment will be based on a futility 
threshold of 
  
The purpose of the analysis is potentially to stop for futility.  
 
  If the difference between response rates of 
ASAS20 for the active arm and placebo is 
 the study will be 
stopped for futility. 
Following the last subject’s 
, an 
 will be conducted on all available data to 
evaluate the primary efficacy outcome.  The Sponsor and some 
 members not directly 
related to the clinical conduct of the study will be unblinded during Part 2.  Subjects, Investigator 
staff, persons performing the assessments, and data analysts will remain blind to the identity of 


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the treatment from the time of randomization until the last subject completes the study 
.  A separate document will provide further details related to 
unblinding of personnel involved in reporting activities for the IA.  Sharing of subject-level 
unblinded information for the IA will be confined to a designated unblinded study team. 
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 
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 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 
 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)8, 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 
 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 
in 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 
 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, IB, 
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. 
16.3 
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 
 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 
 
. 


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At each planned safety review, the 
 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 
 
 


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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 at least 
 after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 
 have elapsed since the formal 
discontinuation of clinical development of the IMP.  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: 
• 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) 
• Intentional act or negligence on the part of the Investigator or Sub-Investigator or 
malpractice thereby 
• Injury caused by unlawful act or delinquency of a third party 
• 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 
I agree to conduct the study outlined above in accordance with the terms and conditions of the 
protocol, ICH guidelines on GCP and with applicable regulatory requirements. All information 
pertaining to the study shall be treated in a confidential manner. 
 
 
 
 
 
 
((Type name and job title))   
 
 
 
 
 
Date (day/month/year) 
 


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22 
REFERENCE LIST 
1. MK-3222 (SCH 900222) Investigator’s Brochure, edition 7, 10 October 2016. 
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Study of Subcutaneous SCH 900222 in Subjects with Moderate-to-Severe Chronic Plaque 
Psoriasis (Protocol No. P05495), 16 July 2010. 
3. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al.  The 
Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess 
spondyloarthritis.  Ann Rheum Dis. 2009;68(Suppl.2):ii1-ii44. 
4. Zochling J, Braun J.  Assessment of ankylosing spondylitis.  Clin Exp Rheumatol. 
2005;23(Suppl.39):S133-S141. 
5. Maksymowych WP, Lambert RG, Brown S and Pangan AL.  Defining the Minimally 
Important Change for the SpondyloArthritis Research Consortium of Canada Spine and 
Sacroiliac Joint Magnetic Resonance Imaging Indices for Ankylosing Spondylitis.  
J Rheumatol. 2012;39(8):1666-1674. 
6. Pedersen SJ, Sørensen IJ, Lambert RGW, Hermann K-GA, Garnero P, Johansen JS, et al.  
Radiographic Progression is Associated with Resolution of Systemic Inflammation in 
Patients with Axial Spondyloarthritis Treated with Tumor Necrosis Factor α Inhibitors.  
Arthritis Rheum. 2011;63(12):3789-3800. 
7. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report – 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol 2006;117(2):391-397. 
8. 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 
October 11, 2016. 
9. World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Medical 
Research Involving Human Subjects, 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013. 
Available at: http://www.wma.net/en/20activities/10ethics/10helsinki/DoH-Oct2013-
JAMA.pdf.  Accessed October 07, 2016. 
10. van der Linden S, Valkenburg HA, Cats A.  Evaluation of diagnostic criteria for ankylosing 
spondylitis.  A proposal for modification of the New York criteria.  Arth Rheum.  
1984;27(4):361 368. 


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23 
APPENDIX 1