A Multicenter, Randomized, Double Blind, Placebo Controlled Clinical Study to Assess the Efficacy and Safety of Tildrakizumab in the Treatment of Moderate to Severe Plaque Psoriasis of the Scalp
Phase: PHASE3
Conditions: Scalp Psoriasis
Sponsor: Sun Pharmaceutical Industries Limited

Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled clinical study 
to assess the efficacy and safety of Tildrakizumab in the treatment of moderate to severe 
plaque psoriasis of the scalp 
 
Document: Clinical Study Protocol 
 
NCT number: NCT03897088 
 
Date: 17-Mar-2020 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
1 
 
TITLE PAGE 
Protocol Title:  
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Clinical Study to Assess the Efficacy and Safety of Tildrakizumab in 
the Treatment of Moderate to Severe Plaque Psoriasis of the Scalp 
Protocol Number:  
 
TILD-18-20 
  
 
  
 
Product:  
 
 
Tildrakizumab 
Short Title:  
Efficacy and Safety Profile of Tildrakizumab in Subjects with 
Moderate to Severe Plaque Psoriasis of the Scalp. 
Study Phase:   
 
3b 
Sponsor Name:  
 
Sun Pharma Global FZE 
Legal Registered Address:  
Office # 43, Block Y,  
SAIF Zone 
Sharjah, 122304 
United Arab Emirates 
Regulatory Agency Identifying Number: IND number 101,389 
  
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
3 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
4 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
5 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
6 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
7 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
9 
 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .........................................................................................................3 
LIST OF APPENDICES .............................................................................................................11 
LIST OF TABLES .......................................................................................................................12 
LIST OF FIGURES .....................................................................................................................12 
1.0 
PROTOCOL SUMMARY ..............................................................................................13 
1.1 
Synopsis .................................................................................................................13 
 
 
 
 
2.0 
INTRODUCTION............................................................................................................25 
2.1 
Background ............................................................................................................25 
2.2 
Study Rationale ......................................................................................................25 
2.3 
Benefit/Risk Assessment .......................................................................................26 
3.0 
OBJECTIVES AND ENDPOINTS ................................................................................27 
4.0 
STUDY DESIGN ..............................................................................................................30 
4.1 
Overall Design .......................................................................................................30 
4.2 
Scientific Rationale for Study Design....................................................................31 
4.3 
Justification for Dose .............................................................................................31 
4.4 
End of Study Definition .........................................................................................32 
5.0 
STUDY POPULATION ..................................................................................................33 
5.1 
Inclusion Criteria ...................................................................................................33 
5.2 
Exclusion Criteria ..................................................................................................34 
5.3 
Lifestyle Considerations ........................................................................................35 
5.4 
Screen Failures .......................................................................................................36 
6.0 
STUDY TREATMENT ...................................................................................................37 
 
 
6.2 
Preparation/Handling/Storage/Accountability .......................................................38 
6.3 
Measures to Minimize Bias: Randomization and Blinding ...................................38 
6.4 
Study Treatment Compliance ................................................................................39 
6.5 
Concomitant Therapy.............................................................................................39 
6.5.1 
Rescue Medicine ...................................................................................40 
 
 
6.6 
Dose Modification .................................................................................................40 
6.7 
Treatment after the End of the Study .....................................................................40 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
10 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ......................................................................41 
7.1 
Discontinuation of Study Treatment ......................................................................41 
7.1.1 
Temporary Discontinuation ..................................................................41 
7.2 
Subject Discontinuation/Withdrawal from the Study ............................................42 
7.3 
Lost to Follow-up ...................................................................................................42 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................44 
8.1 
Efficacy Assessments.............................................................................................44 
8.1.1 
Assessments for Scalp: ..........................................................................45 
8.1.2 
Assessments for Whole Body: ..............................................................45 
8.1.3 
Dermatology Life Quality Index ...........................................................46 
8.2 
Safety Assessments ................................................................................................46 
8.2.1 
Physical Examinations ..........................................................................47 
8.2.2 
Vital Signs .............................................................................................47 
8.2.3 
Assessment of Suicidal Ideation and Behavior .....................................47 
8.2.4 
Electrocardiograms ...............................................................................48 
8.2.5 
Tuberculosis Testing .............................................................................48 
8.2.6 
Chest X-ray ...........................................................................................48 
8.2.7 
Clinical Safety Laboratory Assessments ...............................................48 
8.3 
Adverse Events ......................................................................................................49 
8.3.1 
Time Period and Frequency for Collecting AE and SAE 
Information ............................................................................................49 
8.3.2 
Method of Detecting AEs and SAEs .....................................................50 
8.3.3 
Follow-up of AEs and SAEs .................................................................50 
8.3.4 
Regulatory Reporting Requirements for SAEs .....................................50 
8.3.5 
Pregnancy ..............................................................................................51 
8.3.6 
Adverse Events of Special Interest .......................................................52 
8.3.7 
Events of Clinical Interest .....................................................................52 
8.4 
Treatment of Overdose ..........................................................................................52 
8.5 
Pharmacokinetics ...................................................................................................53 
8.6 
Pharmacodynamics ................................................................................................53 
8.7 
Genetics..................................................................................................................53 
8.8 
Biomarkers .............................................................................................................53 
8.9 
Health Economics or Medical Resource Utilization and Health Economics ........53 
9.0 
STATISTICAL CONSIDERATIONS ...........................................................................54 
9.1 
Statistical Hypotheses ............................................................................................54 
9.2 
Sample Size Determination....................................................................................54 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
11 
9.3 
Populations for Analyses .......................................................................................55 
9.4 
Statistical Analyses ................................................................................................56 
9.4.1 
Efficacy Analyses..................................................................................57 
9.4.2 
Safety Analyses .....................................................................................59 
9.4.3 
Other Analyses ......................................................................................61 
 
 
9.5 
Interim Analyses ....................................................................................................61 
9.6 
Monitoring Committee...........................................................................................61 
 
 
 
 
 
LIST OF APPENDICES 
 
Appendix 2: ................. Regulatory, Ethical and study oversight considerations ............................66 
 
Appendix 4: ................. Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .......................................................77 
Appendix 5: ................. Anaphylaxis ...............................................................................................83 
Appendix 6: ................. Excluded Medications/Therapy .................................................................84 
Appendix 7: ................. Contraceptive guidance and collection of pregnancy ................................85 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 19: ............... Columbia-Suicide Severity Rating Scale .................................................100 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
12 
 
 
LIST OF TABLES 
Table 1 ......................... Study Objectives and Endpoints ................................................................27 
Table 2 ......................... Study Treatment Details ............................................................................37 
Table 3 ......................... Analysis Sets ..............................................................................................56 
Table 4 ......................... Efficacy Analyses ......................................................................................57 
Table 5 ......................... Study Administrative Structure..................................................................68 
Table 6 ......................... Protocol-required Safety Laboratory Assessments ....................................74 
Table 7 ......................... Excluded Medications ................................................................................84 
 
LIST OF FIGURES 
Figure 1: ....................... Study Schema.............................................................................................21 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
15 
Objectives 
Endpoints 
• 
To assess the efficacy of tildrakizumab in 
subjects with moderate to severe plaque 
psoriasis of the scalp, as measured by the 
proportion of subjects who achieve at least 
90% improvement from Baseline in the 
Psoriasis Scalp Severity Index (PSSI) 
response at Week 16 compared with placebo. 
• 
To assess the efficacy of tildrakizumab in 
subjects with moderate to severe scalp 
psoriasis, as measured by the proportion of 
subjects who achieve IGA (Scalp only) of 
“clear” and “almost clear” with at least 
2-point reduction from Baseline at Week 16. 
• 
To assess the efficacy of tildrakizumab in 
subjects with moderate to severe scalp 
psoriasis, as measured by the proportion of 
subjects who achieve Investigator Global 
Assessment (IGA) mod 2011 (scalp) score of 
“clear” and “almost clear” with at least 
2-point reduction from Baseline at Week 12. 
• 
To assess the efficacy of tildrakizumab in 
subjects with moderate to severe plaque 
psoriasis of the scalp, as measured by the 
proportion of subjects who achieve at least 
90% improvement from Baseline in the 
Psoriasis Scalp Severity Index (PSSI) 
response at Week 12 compared with placebo. 
To assess the efficacy of tildrakizumab in the 
treatment of moderate to severe plaque 
psoriasis of the scalp compared with placebo 
as measured by scalp surface area 
involvement at Week 16. 
• 
The proportion of subjects with at 
least 90% improvement from 
Baseline in the PSSI at Week 16. 
(Key secondary endpoint). 
• 
The proportion of subjects with IGA 
(scalp only) score of “clear” and 
“almost clear” with at least 2-point 
reduction from Baseline at Week 16. 
(Key secondary endpoint). 
• 
The proportion of subjects with IGA 
mod 2011 (scalp) score of “clear” and 
“almost clear” with at least 2-point 
reduction from Baseline at Week 12 
(key secondary endpoint) 
• 
The proportion of subjects with at 
least 90% improvement from 
Baseline in the PSSI at Week 12. 
(Key secondary endpoint). 
• 
Mean percentage change in PSSI 
score from Baseline to Week 16. 
• 
The proportion of subjects achieving 
PSSI 75 at Week 16. 
• 
The proportion of subjects achieving 
PSSI 100 at Week 16. 
• 
Mean percentage change in scalp 
surface area involvement from 
Baseline to Week 16. 
• 
To assess the effect of Tildrakizumab on IGA 
mod 2011 (scalp) and PSSI at other measured 
time points through week 52. 
• 
To assess the effect of tildrakizumab on, IGA 
(scalp only), Scalp Itch NRS, PASI, PGA-S 
(whole body), IGA mod 2011 (whole body) at 
week 12 and other measured time points 
through Week 52.  
• 
Change from baseline in IGA mod 2011 
(scalp) and PSSI at other measured time 
points through Week 52. 
• 
Change from Baseline in IGA (scalp only), 
Scalp Itch NRS, PASI, PGA-S (whole body), 
and IGA mod 2011 (whole body) at week 12 
and other measured time points through Week 
52. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
 
After a Screening Period of 28 days, all eligible subjects will be randomly allocated 
 
 
 on Day 1 to receive either tildrakizumab 100 mg or placebo by subcutaneous (SC) injection 
 
 
 
 subjects initially randomized to placebo will be switched over to receive tildrakizumab 100 mg 
 and subjects initially randomized to tildrakizumab 100 mg will continue to 
receive tildrakizumab 
In order to maintain the blind, subjects in both treatment 
arms will receive matching placebo injections at specified time points as described in the Schedule of 
Activities (SoA). 
After Week 52 (or early termination of study treatment prior to Week 52), the study treatment should be 
stopped, and the subjects will enter the 
Observational Safety Follow-up Period following the last 
dose of study treatment. During the follow-up period, subjects should continue on study-approved 
concomitant medications only, however may be placed on other appropriate therapies for safety concerns 
or significant worsening of psoriasis based on the judgment of the Investigator. The subjects will not receive 
study treatment during the follow-up period. 
The subject’s disease activity (response to study treatment) will be evaluated using the IGA Mod 2011 
(scalp), PSSI, PASI, IGA (scalp only), PGA-S (whole body), IGA Mod 2011 (whole body), Scalp Itch 
Numeric Rating Scale (NRS), BSA, and Dermatology Life Quality Index (DLQI) scores.  
Safety assessments including adverse event (AE)/serious adverse event (SAE) monitoring, vital signs, 
physical examinations, electrocardiogram, and laboratory measurements will be performed during the 
study.  
 
 
Number of Investigators and Study Centers: 
Up to 
 Investigators and study centers (in United States and Australia) are expected to participate in this 
study. 
Number of Subjects: 
The study will randomize approximately 107 subjects per treatment arm (Total N=214) 
 
randomization to either tildrakizumab 100 mg arm or placebo arm.  
Treatment Groups 
 
 
 
The study consists of a Screening Period 
 treatment period (
double-blind 
placebo-controlled treatment period followed by 
 double-blind active treatment period), and  
 Observational Safety Follow-up Period. 
Part 1: Double-blind placebo-controlled, where subjects will receive either tildrakizumab 
 (Arm A) 
or placebo (Arm B) 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
18 
Part 2: At Week 16, subjects initially randomized to placebo will be switched over to receive tildrakizumab 
100 mg 
 Subjects initially randomized to tildrakizumab 100 mg will continue 
to receive active drug 
 In order to maintain the blind, subjects in both treatment 
arms will receive matching placebo injections at specified time points as described in the SoA.  
Part 3: After Week 52 (or early termination of study treatment prior to Week 52), subjects will enter the 
Observational Safety Follow-up Period where tildrakizumab treatment will be stopped. 
Statistical methods: 
The primary efficacy endpoint for this study is the proportion of subjects with IGA mod 2011(scalp) score 
of “clear” and “almost clear” with at least 2-point reduction from baseline at Week 16. The key secondary 
efficacy endpoints are the proportion of subjects with at least 90% improvement in the PSSI (PSSI90) from 
baseline at Week 16, the proportion of subjects with IGA (scalp only) score of “clear” and “almost clear” 
with at least 2-point reduction from baseline at Week 16, the proportion of subjects with IGA mod 
2011(scalp) score of “clear” and “almost clear” with at least 2-point reduction from baseline at Week 12 
and the proportion of subjects with at least 90% improvement in the PSSI (PSSI90) from baseline at 
Week 12. For each endpoint, the tildrakizumab 100 mg dose will be compared with placebo Both the 
primary and key secondary efficacy endpoints will be analyzed with Cochran-Mantel-Haenszel test 
 
using the Intent-to-treat (ITT) population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Secondary efficacy and exploratory endpoints that are dichotomous will be analyzed 
in the same manner as the primary efficacy endpoint using the ITT population. Continuous secondary 
efficacy and exploratory endpoints will be analyzed using an MMRM procedure 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
20 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
28 
Objectives 
Endpoints 
• 
To assess the efficacy of tildrakizumab in subjects 
with moderate to severe scalp psoriasis, as 
measured by the proportion of subjects who 
achieve IGA (scalp only) score of “clear” and 
“almost clear” with at least 2-point reduction from 
Baseline at Week 16. 
• 
To assess the efficacy of tildrakizumab in subjects 
with moderate to severe scalp psoriasis, as 
measured by the proportion of subjects who 
achieve Investigator Global Assessment (IGA) 
mod 2011 (scalp) score of “clear” and “almost 
clear” with at least 2-point reduction from Baseline 
at Week 12. 
• 
To assess the efficacy of tildrakizumab in subjects 
with moderate to severe plaque psoriasis of the 
scalp, as measured by the proportion of subjects 
who achieve at least 90% improvement from 
Baseline in the Psoriasis Scalp Severity Index 
(PSSI) response at Week 12 compared with 
placebo.To assess the efficacy of tildrakizumab in 
the treatment of moderate to severe plaque 
psoriasis of the scalp compared with placebo as 
measured by scalp surface area involvement at 
Week 16. 
• 
The proportion of subjects with IGA mod 2011 
(scalp) score of “clear” and “almost clear” with at 
least 2-point reduction from Baseline at Week 12 
(key secondary endpoint) 
• 
The proportion of subjects with at least 90% 
improvement from Baseline in the PSSI at 
Week 12. (Key secondary endpoint). 
• 
Mean percentage change in PSSI score from 
Baseline to Week 16. 
• 
The proportion of subjects achieving PSSI 75 at 
Week 16. 
• 
The proportion of subjects achieving PSSI 100 at 
Week 16. 
• 
Mean percentage change in scalp surface area 
involvement from Baseline to Week 16. 
• 
To assess the effect of Tildrakizumab on IGA mod 
2011 (scalp) and PSSI at other measured time 
points through week 52. 
• 
To assess the effect of tildrakizumab on IGA 
(scalp only), Scalp Itch NRS, PASI, PGA-S (whole 
body), and IGA mod 2011 (whole body), at week 
12 and other measured time points through Week 
52. 
• 
Change from baseline in IGA mod 2011 (scalp) 
and PSSI at other measured time points through 
Week 52. 
• 
Change from Baseline in IGA (scalp only), Scalp 
Itch NRS, PASI, PGA-S (whole body) and IGA 
mod 2011 (whole body), at week 12 and other 
measured time points through Week 52. 
• 
To assess the time to response. 
• 
Time to 75% reduction in PSSI during the 
16-week placebo-controlled treatment period. 
• 
Time to IGA mod 2011 (scalp) response during 
the 16-week placebo-controlled treatment period. 
• 
To assess the efficacy of tildrakizumab in the 
improvement of scalp itch as measured by the 
proportion of subjects achieving a 4-point 
reduction in Scalp Itch Numeric Rating Scale 
(NRS) score from Baseline at Week 16 compared 
with placebo. 
• 
Proportion of subjects achieving a 4-point 
reduction in Scalp Itch NRS score from Baseline 
to Week 16. 
• 
To assess the efficacy of tildrakizumab in the 
treatment of moderate to severe psoriasis 
• 
The proportion of subjects achieving PASI 75, 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
30 
4.0 
STUDY DESIGN 
4.1 
Overall Design 
This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy 
and safety of tildrakizumab in the treatment of moderate to severe psoriasis of the scalp. The study 
will be conducted in up to 35 study centers across the United States and Australi
 
 
 
 
Approximately 214 subjects (approximately 107 per arm) with moderate to severe psoriasis of the 
scalp will be enrolled in the study. Eligible subjects will be randomized to 1 of the 2 arms 
 
 Arm A: Tildrakizumab 100 mg, SC (n=107) and Arm B: Placebo, SC (n=107). 
 
 
 
 
 
The study will comprise of 3 parts: 
PART 1: Double-blind Placebo-controlled (Day 1 to Week 16) 
After a Screening Period of up to 28 days and on Day 1, all eligible subjects will be randomized 
 to receive either tildrakizumab 100 mg or placebo 
 
 Subjects should receive the first dose of study treatment within 24 hours of 
randomization.
 
 
PART 2: Double-blind Active Treatment Extension (Week 16 to Week 52) 
subjects initially randomized to placebo will be switched over to receive 
tildrakizumab 
while subjects initially randomized to 
tildrakizumab 100 mg will continue to receive tildrakizumab 
 In order 
to maintain the blind, subjects in both treatment arms will receive matching placebo injections at 
specified time points as described in the Schedule of Activities (SoA) 
 
PART 3: Observational Safety Follow-up (Week 52 to Week 72) 
After Week 52 (or early termination of study treatment prior to Week 52), the study treatment 
should be stopped and all subjects, including those who terminated early from Part 1 and 2 will 
enter the 
Observational Safety Follow-up Period to monitor safety and tolerability 
 
 following last dose of study treatment. During the follow-up period, subjects should 
continue on study-approved concomitant medications only, however may be placed on appropriate 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
33 
5.0 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Subjects should be 18 years or older at the time of signing the informed consent during the 
Screening visit. 
2. Subjects with a clinical diagnosis of chronic plaque psoriasis of at least 6 months (as determined 
by-subject interview and confirmation of diagnosis through physical examination by 
Investigator). 
3. Subjects must have moderate to severe plaque psoriasis of the scalp at Screening and at 
Baseline, defined by: 
• 
Scalp Investigator Global Assessment (IGA mod 2011 (scalp) of ≥3 
• 
Psoriasis Scalp Severity Index (PSSI) score of ≥12 
• 
≥30% or scalp surface area affected. 
4.  Subject must have moderate to severe plaque psoriasis at Screening and Baseline defined by  
• IGA mod 2011 (whole body) of at least moderate severity (score of ≥3 on a 5-pointer 
scale) 
• PASI score of ≥12 
• Body Surface Area (BSA) involvement of >10%  
5. Subjects must be considered candidates for systemic therapy, meaning scalp psoriasis 
inadequately controlled by topical treatments (corticosteroids), and/or phototherapy, and/or 
previous systemic therapy. 
6. Subjects has a negative evaluation for tuberculosis (TB) within 4 weeks before initiating study 
treatment, defined as a negative QuantiFERON® test. Subjects with a positive or 2 successive 
indeterminate. QuantiFERON® tests are allowed if they have all of the following: 
• No history of active TB or symptoms of TB. 
• A posterior-anterior chest radiogram (with associated report available at study center) 
performed within 3 months of Screening with no evidence of active TB (or of any other 
pulmonary infectious diseases). 
• If prior latent TB infection (LTBI), must have history of adequate prophylaxis (per local 
standard of care). 
• If presence of LTBI is established, then treatment according to local country guidelines 
must have been followed for 4 weeks prior to inclusion in the study. 
A maximum of 2 QuantiFERON® tests are allowed. A re-test is only permitted if the first is 
indeterminate; the result of the second test will then be used. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
34 
7. Subjects are unlikely to conceive, as indicated by at least one “Yes” answer to the following 
questions: 
• 
Subject is a male. 
• 
Subject is a female and agrees to abstain from heterosexual activity OR use a highly 
effective method of contraception as per Appendix 7.  
• 
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). 
• 
Subject is a surgically sterilized female or is documented to be postmenopausal.  
For contraceptive guidance see Appendix 7 
8. For women of childbearing potential, a negative serum pregnancy test at Screening and a 
negative urine pregnancy test within 24 hours prior to Day 1 and on subsequent visits at which 
study treatment doses are scheduled. 
9. Subjects must have results of a physical examination within normal limits or clinically 
acceptable limits to the Investigator prior to Day 1. The Investigator is encouraged to consult 
with the Medical Monitor (or appropriate designee) if there are questions regarding the 
significance of any out-of-range values. 
10. Subjects must be capable of giving signed informed consent as described in Appendix 2, which 
includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 
5.2 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
1. Subjects who have laboratory abnormalities at Screening including any of the following: 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 × the upper 
limit of normal (ULN) 
• 
Creatinine ≥2 × the ULN 
• 
Serum direct bilirubin ≥1.5 mg/dL 
• 
White blood cell count <3.0×103/μL 
• 
Any other laboratory abnormality, which, in the opinion of the Investigator, will prevent 
the subject from completing the study or will interfere with the interpretation of the 
study results. 
2. Subjects who have predominantly non-plaque forms of psoriasis specifically erythrodermic 
psoriasis, predominantly pustular psoriasis, medication-induced or medication-exacerbated 
psoriasis, or new-onset guttate psoriasis. 
3. Women of childbearing potential who are pregnant, intend to become pregnant (within 
6 months of completing the study), or are lactating. 
4. Subjects with any infection or history of recurrent infection requiring treatment with systemic 
antibiotics within 2 weeks prior to Screening, or severe infection (eg, pneumonia, cellulitis, 
bone or joint infections) requiring hospitalization or treatment with intravenous (IV) antibiotics 
within 6 weeks prior to Screening. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
35 
5. Subjects with any previous use of tildrakizumab or other IL-23/Th-17 pathway inhibitors, 
including p40, p19 and IL-17 antagonists for psoriasis. 
• 
Prior use of TNF-alpha inhibitors with a wash-out period of 12 weeks would be allowed. 
However, the number of subjects with prior use of TNF-alpha inhibitors would be 
capped at 40% and the analysis will be stratified based on prior use of these biologics. 
6. Subjects with a positive human immunodeficiency virus test result, hepatitis B surface antigen, 
or hepatitis C virus test result. 
7. Subjects with a prior malignancy or concurrent malignancy (excluding successfully treated 
basal cell carcinoma, squamous cell carcinoma of the skin in situ, squamous cell carcinoma of 
skin with no evidence of recurrence within 5 years or carcinoma in situ of the cervix that has 
been adequately treated). 
8. Subjects who have received live viral or bacterial vaccination within 4-weeks prior to Baseline 
or who intend to receive live viral or bacterial vaccination during the study. 
9. Subjects who are currently participating in another interventional clinical study or has 
participated in an interventional clinical study within 5-half-lives (of the drug) to wash-out prior 
to randomization (Subjects participating in observational studies or non-interventional registry 
studies may be included in the study). 
10. Subjects or a family member is among the personnel of the study center or Sponsor/designee 
staff directly involved with this study. 
11. Subjects who have any concomitant medical condition which in the opinion of the Investigator 
could affect the study outcome or present an unacceptable risk. 
12. Subjects who were hospitalized due to an acute cardiovascular event (such as myocardial 
infarction, cerebrovascular accident, 
cardiovascular illness [eg, angina pectoris], or 
cardiovascular surgery [such as coronary artery bypass grafting (CABG)]) within 6 months 
before Screening. 
13. Subjects who, in the opinion of the Investigator, will not be a reliable participant in the study 
and those who can confound the results of the study. 
14. Subjects who have a history of alcohol or drug abuse in the previous year. 
15. 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 “yes” within the last 12 months to 
Questions 4 or 5 in the suicidal ideation section, or any positive response in the behavioral 
section of the C-SSRS.  
16. Subjects with any other clinically significant laboratory abnormality, which, in the opinion of 
the Investigator, will prevent the subject from completing the study or will interfere with the 
interpretation of the study results. 
5.3 
Lifestyle Considerations 
Excessive exposure to sunlight should be avoided during the study. Subjects should avoid use of 
tanning booths or other ultraviolet light sources for the duration of the study. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
36 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. The minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened at the discretion of the Investigator for up to 2 additional times, with a minimum of 
2 weeks between each rescreening. When a subject is rescreened, all Screening procedures will be 
repeated.   
Note:  If the original ICF was signed within 30 days of the rescreening visit, a new ICF does not 
need to be completed. 
Rescreened subjects should not be assigned the same subject number as for the initial Screening. 
Any subject who is started on prophylactic treatment for latent TB during the Screening Period 
may be randomized 4 weeks after initiation of treatment without need for rescreening. 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
 
37 
6.0 
STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a subject according to the study protocol. 
The study treatment in this study is tildrakizumab and placebo. 
 
The study arms will receive study 
treatment during the course of the study as follows: 
Arm A: 
o
Tildrakizumab 100 mg SC injections 
o
Placebo injections 
Arm B: 
o
Placebo injections 
o
Tildrakizumab 100 mg SC injections
 
 
 
 
 
Study Treatment Name: 
Tildrakizumab 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
Unit Dose Strength/Dosage 
Level: 
100 mg 
- 
Route of Administration 
Subcutaneous (SC) 
SC 
 
 
 
 
 
  
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
 
38 
 
 
 
 
 
 
  
 
6.2 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study treatment received and any discrepancies are reported
and resolved before use of the study treatment.
2. Only subjects enrolled in the study may receive study treatment and only authorized study
center staff may supply or administer the study treatment. All study treatments must be stored
in a secure, environmentally controlled, and monitored (manual or automated) area in
accordance with the labeled storage conditions with access limited to the Investigator and
authorized study center staff.
3.
Study treatment experiencing temperature excursions outside this temperature should
be quarantined and can only be released for subject use after consultation with the Sponsor.
4. The Investigator, institution, or the head of the medical institution (where applicable) is
responsible for study treatment accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
5. Further guidance and information for the final disposition of unused study treatment will be
provided by the study center monitor.
The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study treatment using the Drug Accountability 
Form.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
All subjects will be centrally assigned 
 to receive either tildrakizumab 100 mg or 
placebo using an Interactive Web Response System (IWRS). Before the study is initiated, the log 
in information and directions for the IWRS will be provided to each study center. 
This is a double-blind study with limited access to the randomization code. Tildrakizumab and 
placebo will be identical in physical appearance.
 
 
 
 
Study treatment will be dispensed at the study visits summarized in the SoA 
 
 
Returned study treatment should not be re-dispensed to the subjects. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
39 
 In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a subject’s treatment 
assignment is warranted. Subject safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, the Investigator should 
make every effort to contact the Sponsor prior to unblinding a subject’s treatment assignment 
unless this could delay emergency treatment of the subject. If a subject’s treatment assignment is 
unblinded, the Sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and electronic case 
report form (eCRF), as applicable. 
A designated member of the Sponsor’s safety team will be unblinded for any Suspected 
Unexpected Serious Adverse Reactions, for regulatory reporting purposes. Unblinding is for 
regulatory reporting purpose only 
 
 
6.4 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. Any departures 
from the intended regimen must be recorded in the eCRFs. 
 
Study treatment accountability and subject compliance will be documented throughout the 
treatment periods 
 using study-specific study treatment dispensing record forms. 
If a subject does not receive the scheduled dose, every effort should be made to administer the 
dose as soon as possible. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the 
study must be recorded on the eCRF along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
In addition, all prior medications used to treat the disease conditions and any other medications 
taken within 6 months prior to enrollment must be recorded in the eCRF.  
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
40 
 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor if required. 
6.5.1 
Rescue Medicine 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6 
Dose Modification 
No dose modification is allowed in this study. Study treatment can be interrupted temporarily or 
permanently if deemed necessary as per the Investigator’s discretion. 
6.7 
Treatment after the End of the Study 
The Sponsor will not provide any study treatment to the subjects during the Observational Safety 
Follow-up Period. Patient care should not differ from what is normally expected for subjects with 
psoriasis.  
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
41 
7.0 
DISCONTINUATION 
OF 
STUDY 
TREATMENT 
AND 
SUBJECT 
DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Treatment  
Subjects may voluntarily discontinue study treatment for any reason at any time and enter the 
wash-out period, or completely withdraw from the study
 Subjects who 
consent to enter the wash-out period will undergo the Week 52 (EoT) assessment a minimum of 
4-weeks after administration of the last dose of study treatment.  
At any time during Part 1 or Part 2 of the study, the Investigator should discontinue study treatment 
of a given subject if, on balance, he/she believes that continuation would be detrimental to the 
subject’s well-being.  
The study treatment must be discontinued under the following circumstances and the further steps 
need to be discussed with the Medical Monitor: 
• An SAE, drug reaction or complication, or an unacceptable AE, whether attributed to study 
treatment or not, that precludes continuation of treatment with study treatment. This 
includes the development of allergic reactions or the development of other potentially 
serious drug reactions to medication required by the protocol 
• Diagnosis of malignancy (except basal or squamous cell carcinoma of skin) during study 
(at discretion of the subject and Investigator) 
• Subjects who develop suicidal behavior 
• Evidence of pregnancy 
• Withdrawal of informed consent 
• Lost to follow-up 
• Significant non-compliance of the subject with study procedures 
• Decision of the Sponsor to terminate the subject, study center, or the study. 
 
Subjects who withdraw from the study at any part will undergo the Week 52 (EoT) assessments. 
Patient related outcome (PRO) measurement should be obtained immediately after subject 
withdrawal.  Week 52 (EoT) assessments should be conducted a minimum of 4-weeks after 
administration of the last dose of study treatment. 
See the SoA 
 for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.1.1 
Temporary Discontinuation  
Study treatment can be interrupted temporarily in case of:  

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
42 
• Clinically important laboratory abnormalities. 
• Subjects who develop suicidal ideation. 
• Other intercurrent illnesses or major surgery. 
• Use of prohibited treatment. 
• Any other protocol deviation that results in a significant risk to the subject’s safety. 
• Sponsor decision. 
The Medical Monitor should be informed. Re-starting of study treatment at the next scheduled 
administration study visits can be done after discussion with the Medical Monitor. 
7.2 
Subject Discontinuation/Withdrawal from the Study 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs when a subject does not want to participate in the study anymore 
and does not want to attend any further visits or assessments, have further study-related contact, 
or allow analysis of already obtained biologic material. 
If a subject withdraws consent, the Investigator must make every effort to determine the primary 
reason for this decision and record this information on the treatment disposition eCRF page. If the 
subject decides to completely withdraw from the study (refuses any further study participation or 
contact), all study participation for that subject will cease and data to be collected at subsequent 
visits will be considered missing. The study treatment must be discontinued, and no further 
assessments conducted. Further attempts to contact the subject are not allowed unless safety 
findings require communication or follow-up. 
However, for safety reasons, Week 52 (EoT) assessments should be conducted for subjects 
withdrawing during Part 1 or 2, if the withdrawn subject is willing to undergo the assessments. For 
subjects withdrawing during Part 3 and willing to undergo final assessments, the Week 72 (EoS) 
assessments should be conducted at least 4 weeks after their last visit. 
The appropriate personnel from the study center and CRO will assess whether the study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently for 
any reason. 
The Investigator must also contact the IWRS to register the subject’s discontinuation from the 
study treatment. 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study center. 
The following actions must be taken if a subject fails to return to the study center for a required 
study visit: 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
43 
• The study center must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
45 
8.1.1 
Assessments for Scalp:  
8.1.1.1 
Investigator Global Assessment (IGA) mod 2011 rating scale (Scalp) 
The IGA mod 2011 is a 
scale that is static 
 
 
 This scale met the evidence standard 
for pivotal trials, and has supported previous product labeling claims
 
 
 
 
 
 
 
 
8.1.1.2 
Investigator Global Assessment (Scalp only) 
The 
 IGA score is a useful clinician assessment of scalp lesions based on thickness, 
erythema, and scaling that is here retained as a secondary endpoint
 
 
 
 
 
 
 
 
 
 
 
 
8.1.1.5 
Psoriasis Scalp Severity Index (PSSI) 
The PSSI is a modification of the PASI to specifically assess severity of scalp disease. The PSSI 
use a 
 scale to grade the 3 clinical parameters
 in the same 
way as the PASI, but for scalp only.
 
8.1.2 
Assessments for Whole Body:  
8.1.2.1 
Investigator Global Assessment (IGA) mod 2011 rating scale (whole body) 
The IGA mod 2011 is a 
scale
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
46 
This scale met the evidence standard 
for pivotal trials, and has supported previous product labeling claims 
 
 
 
 
 
 
 
8.1.2.2 
Physician Global Assessment of Skin (Whole body) 
The PGA-S is a 
 useful clinician assessment of psoriasis lesions on 
the skin based on degree of erythema, thickness, and scale averaged over the entire body. 
 
 
8.1.2.3 
Psoriasis Area and Severity Index 
Psoriasis Area and Severity Index will be used to determine the treatment response (PASI 75, PASI 
90, and PASI 100) in subjects with scalp psoriasis. 
 
8.1.2.4 
Body Surface Area 
Body Surface Area is a commonly used measure of severity of skin disease. It is defined as the 
percentage of the total BSA affected by psoriasis, it represents the area of affected scalp. 
 
 
 
 
8.1.3 
Dermatology Life Quality Index 
The DLQI questionnaire will be used to assess treatment response on the subject’s quality of life. 
The aim of this questionnaire is to measure how much the skin condition has affected the subject’s 
life during the previous week.  
 
 
The questionnaire is self-explanatory and handed to the subject who is asked to fill it 
in without the need for a detailed explanation 
 
8.2 
Safety Assessments  
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
 
• A central laboratory will be used to perform all laboratory tests except urine pregnancy 
dipstick which will be assessed by the center staff. However, local laboratory tests will be 
allowed in the event that the central laboratory results will not be available immediately 
and the Investigator needs to take an immediate decision for any safety concerns based on 
the laboratory results.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the subject’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study including the subject’s last EoS visit should be repeated until the 
values return to normal or Baseline or until stabilized or are no longer considered clinically 
significant by the Investigator or Medical Monitor. 
If such values do not return to normal/Baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, if possible and the Sponsor notified. 
All protocol-required laboratory assessments,
 must be conducted in 
accordance with the Laboratory Manual 
  
8.3 
Adverse Events 
The safety and tolerability of subjects will be assessed by the incidence of treatment-emergent 
adverse events (TEAEs), laboratory test results, vital signs, ECGs, and physical examination 
findings. 
The definitions of an AE or SAE can be found in Appendix 4. 
The Investigator will document all AEs in the subject’s source document and eCRF. All entries 
should contain an event term, date of onset, date of resolution, severity, action taken, outcome, 
relationship to study treatment, and a seriousness assessment. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
Any relevant observations made before the end of the Screening and Baseline visit (prior to first 
dose of study treatment) are to be recorded on the AE eCRF, but will not be considered TEAEs 
and will be reported separately from TEAEs. Any relevant observations made after the first dose 
of study treatment will be recorded as an AE in the subject’s AE eCRF 
 
 
 
For the purposes of this study, any detrimental change in the subject’s condition, 
after the first dose of study treatment and up to completion of the EoS visit, should be considered 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
50 
an AE. For those subjects who may withdraw during the Observational Safety Follow-up Period 
or wash-out period, at least 2 attempts should be made to collect the AEs. 
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. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the AE section of the eCRF, however will not be considered as TEAEs.  
All SAEs will be recorded and reported to the CRO within 24 hours, as indicated in Appendix 4. 
The Investigator will submit any updated SAE data to the CRO within 24 hours of it being 
available. The Investigator is responsible for informing the Ethics Committee of the SAE as per 
local requirements. All AEs/SAEs have to be reported to the Sponsor, whether or not considered 
causally related to the study treatment or to the study procedures. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must promptly notify the CRO. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in Section 
8.3.6), will be followed until resolution, stabilization, the event is otherwise explained, or the 
subject is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
All SAEs must be reported according to ICH GCP or local regulations, applying the regulation 
with the stricter requirements. The report will contain as much available information concerning 
the SAE to enable the Sponsor’s designated pharmacovigilance personnel/ CRO to file a report, 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
51 
which satisfies regulatory reporting requirements. The SAE report will be notified by Investigator 
within 24-hours of his/her awareness to the Sponsor’s designated pharmacovigilance 
personnel/CRO. These timelines apply to initial reports of SAEs and to all follow-up reports. 
All SAEs will be recorded on the SAE report form in the eCRF and source documents. 
The following minimum information must be included in the SAE form: 
• Name, address and telephone number of the reporting Investigator 
• Study treatment details 
• Subject identification number, initials, sex and date of birth 
• Description of the SAE, measures taken and outcome 
Relevant pages from the eCRF may be provided in parallel (eg, medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (eg, laboratory 
results, hospital report, autopsy report).  
The Investigator must respond to any request for follow-up information (eg, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor’s designated pharmacovigilance personnel/CRO may have on the SAE. This is necessary 
to ensure prompt assessment of the event by the Sponsor’s designated pharmacovigilance 
personnel to allow the Sponsor to meet strict regulatory timelines associated with expedited safety 
reporting obligations. 
8.3.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is suspicion that the study treatment may 
have interfered with the effectiveness of a contraceptive medication. If a pregnancy is reported for 
a subject, no further study treatment 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 newborn, after which a follow-up report should be sent with any new 
information regarding the pregnancy and the outcome of the birth. 
The pregnancy shall be followed every 3 months during pregnancy until its outcome and 1 month 
post-delivery. If there are abnormalities present at delivery, the newborn will be followed for an 
appropriate period, or up to 3 months, to assess the functional and health status of the child. 
All congenital abnormalities/birth defects should be classified as SAEs. Spontaneous miscarriages 
should also be reported and handled as SAEs. Elective abortions without complications should not 
be handled as SAEs but should be reported as a follow-up report for the pregnancy. All outcomes 
of pregnancy must be reported to the Sponsor on a Pregnancy Outcomes Report Form. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
52 
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 Novella Clinical Pharmacovigilance and Safety Services using 
the reporting details provided in Appendix 4 within 24 hours of becoming aware of the pregnancy. 
8.3.6 
Adverse Events of Special Interest 
The events of severe infections, injection site reactions (e.g. pain, edema, erythema), malignancies 
(including non-melanoma and melanoma skin cancer), Major Adverse Cardiovascular Events, and 
study treatment -related hypersensitivity reactions (see Appendix 5) will be identified as adverse 
events of special interest (AESIs) for summarizing in this study. Major Adverse Cardiovascular 
Events include non-fatal stroke, non-fatal myocardial infarction and cardiovascular death. An 
AESI must be reported as if it were an SAE. 
8.3.7 
Events of Clinical Interest 
An Event of Clinical Interest (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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Treatment of 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.
 
 
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 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
53 
or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted 
immediately. 
8.5 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Health Economics or Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
9.3 
 Populations for Analyses 
For purposes of analysis, the analysis sets in Table 3 are defined. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
56 
Table 3 
Analysis Sets 
Analysis Set 
Description 
Intent-to-Treat (ITT) 
All randomized subjects who have received 
 dose of study 
treatment 
 
 
Subjects will be analyzed according to their planned treatment 
assignment. 
Per Protocol Set (PPS) 
All subjects in the ITT population who complete the 
 placebo-
controlled treatment 
 
 
 
 
 
 
Safety Analysis Set (SAS) 
All randomized subjects who receive 
 dose of study 
treatment.  Subjects will be analyzed according to the treatment they 
actually received. Safety endpoints will be analyzed descriptively 
based on the SAS. 
9.4 
Statistical Analyses 
The statistical analysis will be performed using statistical analysis system (SAS®) Version 9.3 or 
higher if available. All details regarding the statistical analysis and the preparation of tables, 
listings and figures will be described in the Statistical Analysis Plan (SAP). The SAP will be 
developed and finalized before database lock after the completion of the 
 
placebo-controlled treatment period. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
The following descriptive statistics will be used as applicable to summarize the study data unless 
otherwise specified: 
• Continuous variables: sample size (n), mean, standard deviation (SD), median, minimum 
(min), and maximum (max). 
• Categorical variables: frequencies and percentages. 
Unless otherwise specified, “Baseline” is defined as the last observed value of the parameter of 
interest prior to the first intake of study treatment (this includes unscheduled visits).
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
60 
tabulated for each treatment arm. Commonly occurring TEAEs,
 
 in either treatment arm, will be summarized using descriptive statistics. 
The safety of tildrakizumab will be evaluated by and reported as the percentage of subjects for 
the following TEAEs: 
• Incidence, seriousness and severity of all AEs, death cases and discontinuations from the 
study. 
• Percentage of subjects with severe infections, defined as any infection meeting the 
regulatory definition of a serious adverse event, or any infection requiring IV antibiotics 
whether or not reported as a serious event as per the regulatory definition. 
• Percentage of subjects with malignancies (excluding carcinoma in situ of the cervix). 
• Percentage of subjects with non-melanoma skin cancer. 
• Percentage of subjects with melanoma skin cancer. 
• Percentage of subjects with MACE 
 
• Percentage of subjects with study treatment-related hypersensitivity reactions (eg, 
anaphylaxis, urticaria, angioedema, etc). 
• Percentage of subjects with injection site reactions (eg, pain, erythema, edema, etc). 
9.4.2.2 
Physical Examinations, 12-Lead ECG, Vital Signs and Clinical Safety 
Laboratory Tests (Hematology, Biochemistry, and Urinalysis) 
Summaries and listings of data for physical examination findings, vital signs, hematology, 
biochemistry, and urinalysis laboratory tests will be presented. Appropriate descriptive statistics 
will be summarized for the observed value at each scheduled assessment and for the 
corresponding change from Baseline. 
For hematology and biochemistry tests, listings of subject data will also flag up any abnormal or 
out-of-range values. Clinically significant changes in the laboratory test parameters will be 
summarized and listed. Hematology and clinical laboratory data will be reported in System 
International units. 
Descriptive statistics will be used to present the safety outcomes including, physical examination 
results, weight, body mass index, 12-Lead ECG, vital signs measurements, and clinical 
laboratory test results. 
Change from Baseline will also be summarized for vital signs measurements and clinical 
laboratory test results. 
All ECG data results (normal/abnormal) will be summarized using frequency and percentages. 
Clinically significant abnormalities will be presented in by-subject listings. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
66 
APPENDIX 2: 
REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
o Applicable International Council for Harmonisation Good Clinical Practice (ICH 
GCP) Guidelines. 
o Applicable laws and regulations. 
• The protocol, protocol amendments, informed consent form (ICF), Investigator Brochure, 
and other relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the Investigator and reviewed and approved by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC and regulatory authority approval, 
when applicable, before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to subjects.  
• The Investigator will be responsible for the following: 
o 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
o 
Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety 
findings as required by IRB/IEC procedures. 
o 
Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
o 
After reading the protocol, each Investigator will sign the protocol signature page and 
send a copy of the signed page to the Sponsor or representative (see Appendix 20). 
o 
The study will not start at any study center at which the Investigator has not signed 
the protocol. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
67 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects in this study. The terms of the insurance will be kept in the study files. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding the 
study.  
• Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the subject was entered in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
• A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 
Data Protection 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
• The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the subject.  
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality Control and Quality Assurance 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
69 
 Quality control will be applied to each stage of data 
handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• Central laboratories for clinical laboratory parameters. 
• Study center Initiation visit. 
• Early study center visits post-enrollment. 
• Routine study center monitoring. 
• Ongoing study center communication and training. 
• Data management quality control checks. 
• Continuous data acquisition and cleaning. 
• Internal review of data. 
• Quality control check of the final clinical study report (CSR). 
In addition, Sponsor 
may conduct periodic audits 
of the study processes, including, but not limited to study center, central laboratories, vendors, 
clinical database, and final CSR. When audits are conducted, access must be authorized for all 
study-related documents including medical history and concomitant medication documentation 
to authorized Sponsor’s representatives and regulatory authorities. 
Monitoring 
Sponsor has engaged the services of a contract research organization,
 to perform all 
monitoring functions within this clinical study. 
monitors will work in accordance with 
SOPs. The monitor will establish and maintain regular contact between the Investigator 
and Sponsor. 
The monitor will evaluate the competence of the study center, informing Sponsor about any 
problems relating to facilities, technical equipment, or medical staff. During the study, the 
monitor will check that written informed consent has been obtained from all subjects correctly 
and that data are recorded correctly and completely. The monitor is also entitled to compare 
entries in the eCRFs with corresponding source data and to inform the Investigator of any errors 
or omissions. The monitor will also assess and control adherence to the protocol and ICH/GCP 
guidelines at the study center. The monitor will arrange for the supply of study treatment, ensure 
proper study treatment dispensing/accountability, and appropriate storage conditions are 
maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each center while subjects are enrolled in 
the study.  

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
70 
During monitoring visits, all entries in the eCRFs will be compared with the original source 
documents (source data verification). For the following and all other items, this check will be 
100%: 
• Subject identification number. 
• Subject consent obtained. 
• Subject eligibility criteria (inclusion and exclusion criteria). 
• Efficacy variables (not directly entered into PRO). 
• Safety variables. 
• Medical record of AE. 
Quality Management 
A system should be implemented to manage quality throughout all stages of the study process 
with the focus on study activities essential to ensuring human subject protection and the 
reliability of study results. The methods used to assure and control the quality of the clinical 
study should be proportionate to the risks inherent in the trial and the importance of the 
information collected. All aspects of the study should be operationally feasible and should avoid 
unnecessary complexity, procedures, and data collection.  
During protocol development, processes and data that are critical to ensure human subject 
protection and the reliability of trial results should be identified. Risks should be considered at 
both the system level (eg, standard operating procedures, computerized systems, personnel) and 
clinical trial level (eg, trial design, data collection, informed consent process). The approach used 
to reduce risk to an acceptable level should be proportionate to the significance of the risk. 
Predefined quality tolerance limits should be established, taking into consideration the medical 
and statistical characteristics of the variables as well as the statistical design of the trial, to 
identify systematic issues that can impact subject safety or reliability of trial results. Detection of 
deviations from the predefined quality tolerance limits should trigger an evaluation to determine 
if action is needed. 
Quality management activities should be documented and communicated to those who are 
involved in or affected by such activities, to facilitate risk review and continual improvement 
during clinical trial execution. 
Data Management/Coding 
 
 
Electronic data capture will be used for this study, meaning that all eCRF data will be entered in 
electronic forms at the study centers. Data collection will be completed by authorized study 
center staff designated by the Investigator. Appropriate training and security measures will be 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
 
completed with the Investigator and all designated study center staff prior to the study being 
initiated and any data being entered into the system for any study subjects. 
All data must be entered in English. The eCRFs should always reflect the latest observations on 
the subjects participating in the study. Therefore, the eCRFs are to be completed as soon as 
possible during or after the subject’s visit. To avoid inter-observer variability, every effort should 
be made to ensure that the same individual who made the initial Baseline determinations 
completes all efficacy and safety evaluations. The Investigator must verify that all data entries in 
the eCRFs are accurate and correct. If some assessments are not done, or if certain information is 
not available or not applicable or unknown, the Investigator should indicate this in the eCRF. 
The Investigator will be required to electronically sign off on the clinical data when all the data 
is clean prior to database lock. 
The monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. The monitor cannot enter data in the eCRFs. All entries, corrections and 
alterations are to be made by the responsible Investigator or his/her designee. If additional 
corrections are needed, the responsible monitor or Data Manager will raise a query in the EDC 
application. The appropriate study center staff will answer queries sent to the Investigator. This 
will be audit trailed by the EDC application meaning that the name of investigational staff, time, 
and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by 
the Investigator or hospital that relate to the subject’s medical history, that verify the existence of 
the subject, the inclusion and exclusion criteria and all records covering the subject’s 
participation in the study. They include but are not limited to laboratory notes, ECG results, 
memoranda, pharmacy dispensing records, subject files, etc. Source data should be attributable, 
legible, contemporaneous, original, accurate, and complete. Any changes to the source 
documents or cancellations should be signed and initialed with date. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained if necessary 
(eg, via an audit trail). 
The Investigator is responsible for maintaining source documents. These will be made available 
for inspection by the study monitor at each monitoring visit. The Investigator must submit a 
completed eCRF for each subject who is screened and enrolled in the study regardless of 
duration. All supportive documentation submitted with the eCRF, such as laboratory or hospital 
records, should be clearly identified with the study and subject number. Any personal 
information, including subject name, should be removed or rendered illegible to preserve 
individual confidentiality. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
 
User Roles and Responsibilities:  
Once clinical data of the eCRF have been submitted to the central server, corrections to the data 
fields will be audit trailed, meaning that the reason for change, the name of the person who 
performed the change, together with time and date will be logged. Roles and rights of the study 
center staff responsible for entering the clinical data into the eCRF will be determined in 
advance. 
Electronic CRF records will be automatically appended with the identification of the creator, by 
means of their unique User ID. Specified records will be electronically signed by the Investigator 
to document his/her review of the data and acknowledgement that the data are accurate. This will 
be facilitated by means of the Investigator’s unique User ID and password; date and time stamps 
will be added automatically at time of electronic signature.  
Data Handling and Record Keeping 
The Investigator must maintain essential study documents (protocol and protocol amendments, 
completed eCRFs, signed ICFs, relevant correspondence, and all other supporting 
documentation). The study center should plan on retaining such documents for approximately 
15 years after study completion. The study center should retain such documents until at least 
2 years 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 at least 2 years after the 
formal discontinuation of clinical development of the study treatment. These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the 
hospital, institution, or private practice in which the study is being conducted. Subject 
identification codes (subject names and corresponding study numbers) will be retained for this 
same period of time. These documents may be transferred to another responsible party, 
acceptable to Sponsor, who agrees to abide by the retention policies. Written notification of 
transfer must be submitted to Sponsor. The Investigator must contact Sponsor prior to disposing 
of any study records. 
Direct Access to Source Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record all 
observations and other pertinent data for each subject randomized into the study. 
The Investigator will allow Sponsor, 
 and authorized regulatory authorities to have direct 
access to all documents pertaining to the study, including individual subject medical records, as 
appropriate. Such information must be kept confidential and must have locked facilities that 
allow for this. Subject identification number will be recorded on all documents related to the 
study. 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
73 
Study and Study Center Closure 
The Sponsor designee reserves the right to close the study center or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centers will be closed upon study 
completion. A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the Investigator. 
• Discontinuation of further study treatment development. 
Publication Policy 
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study center will be set forth in the Clinical Trial Agreement. 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
74 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
77 
APPENDIX 4: 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or subject, temporally associated with the use 
of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study treatment. 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
Baseline, considered clinically significant in the medical and scientific judgment of the Investigator 
(ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE 
or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the 
definition of an AE or SAE. 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
78 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
• 
Pregnancy itself is not regarded as an AE unless there is suspicion that the study treatment may have 
interfered with the effectiveness of a contraceptive medication. If a pregnancy is reported for a subject, 
no further study treatment 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 
newborn, after which a follow-up report should be sent with any new information regarding the 
pregnancy and the outcome of the birth. 
• 
All congenital abnormalities/birth defects should be classified as SAEs. Spontaneous miscarriages 
should also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as SAEs but should be reported as a follow-up report for the pregnancy. All outcomes of 
pregnancy must be reported to the Sponsor on a Pregnancy Outcomes Report Form. 
• 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment 
in this study. Consent to report information regarding these pregnancy outcomes should be obtained 
from the female partner. 
• 
The pregnancy shall be followed every 3 months during pregnancy till its outcome and 1 month post-
delivery. If there are abnormalities present at delivery, the newborn will be followed for an appropriate 
period, or up to 3 months, to assess the functional and health status of the child. 
• 
Pregnancies must be reported to 
 using the 
reporting details provided in Section 8.3.4within 24 hours of awareness. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as, but is not limited to, an event that: 
a) Results in death 
Death is not an AE in itself, but an outcome. The cause of the death is the AE which resulted in death. 
b) Is life-threatening 
Life-threatening means that the subject was at immediate risk of death at the time of the SAE; it does not 
refer to an SAE that hypothetically might have caused death if it had been more severe. . 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
79 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as at least 1 overnight formal admission into hospital, usually in order to perform 
additional tests, provide treatment which it is not possible to provide at home and/or due to an unstable 
medical condition which requires specific monitoring of the subject. Pre-planned hospitalizations (known 
already prior to signing the ICF) for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health or if the hospitalization is clearly not associated 
with an AE (eg, social hospitalization) will not be considered an SAE, unless any of the above criteria are 
fulfilled over the course of the hospitalization due to unplanned complications. Any Hospitalization due to 
logistic reason will not be considered as SAE” “Social” hospitalization whereby it is administratively 
impossible to release the subject home is not necessarily an SAE. Complications that occur during 
hospitalizations are AEs unless they would qualify as an SAE for any of the above criteria. If the 
complication delays subject release from hospital, then the AE becomes an SAE. Hospitalizations which 
are not performed due to an AE are not regarded as SAEs. 
d) Results in persistent or significant disability/incapacity 
The term significant disability refers to any condition that impairs physical/physiological well-being to the 
extent that the subject is unable to function normally. Physical disability may include, but is not limited to, 
permanent disability of locomotion or motility, but also systemic permanent dysfunction including heart 
failure, liver insufficiency or pulmonary fibrosis. 
e) Is a congenital anomaly/birth defect 
f) 
Is an important medical event: 
Important medical events that may not result in death, be life-threatening or require hospitalization may be 
considered as an SAE when, based on appropriate medical judgment, they may jeopardize the subject, or 
the subject may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
80 
Recording and Follow-up of AE and/or SAE 
Definition of the Adverse Event Reporting Period 
The AE/ SAE reporting period for safety surveillance begins after subject signs ICF. The safety 
surveillance continues until 20 weeks from last dose of study treatment administration. Any 
AE/-SAE occurred post 20 weeks from last dose of study treatment administration will be 
reported if it is considered related to study treatment by the Investigator. 
Unexpected Adverse Event 
Any adverse event that is not identified in nature, severity, frequency or outcome in Investigator 
Brochure (IB) will be considered as unexpected. Most recent version of IB will serve as 
reference safety information for assessment of expectedness of SAEs. 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. Each event must be 
recorded separately. 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
 
 in lieu of completion of the/AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
 
. In this case, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the medical records before submission to 
. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering 
with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not 
be confused with a SAE. Severe is a category utilized for rating the intensity of an event; and both AEs 
and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
81 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE. The AE must be characterized as certainly/definitely related, unrelated, unlikely to be 
related, possibly related, or probably related. 
o 
“Certainly/definitely related” suggests that a clinical event, including laboratory test 
abnormality, occurring in a plausible time relationship to drug administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (de-challenge) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory re-challenge 
procedure if necessary. 
o 
“Probably related” conveys that there are facts, evidence, and/or arguments to suggest a 
causal relationship, rather than a relationship cannot be ruled out. 
o 
“Possibly related” suggests that the association of the AE with the study treatment is 
unknown; however, the AE is not reasonably supported by other conditions. 
o 
“Unlikely to be related” suggests that only a remote connection exists between the study 
treatment and the AE. Other conditions, including chronic illness, progression or expression 
of the disease state or reaction to concomitant therapy, appear to explain the reported AE. 
o 
“Unrelated” is used if there is not a reasonable possibility that the study treatment caused the 
AE.  
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well 
as the temporal relationship of the event to study treatment administration will be considered and 
investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her 
assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information 
to include in the initial report to 
. However, it 
is very important that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to 
. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send a 
SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Action Taken with respect to study treatment 
Action taken is categorized as “none”, “study treatment discontinued permanently”, “study treatment 
discontinued temporarily and restarted”, or unknown. 
Event Outcome 
Event outcome recorded and categorized as “Fatal”, “Resolved”, “Resolved with sequelae”, “Resolving”, 
“Not Resolved”, or “Unknown”. 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
82 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by 
 
 to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide 
 with a copy of any postmortem findings including 
histopathology.  
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the 
 
 within 24 hours of receipt of the information. 
Follow-up of unresolved AEs and SAEs 
Any AE/ SAE unresolved at end of study visit will be followed until resolution/ stabilization or as per 
medical judgment of the Investigator. 
 
Reporting of SAEs 
SAE Reporting to 
 via Paper Case Report 
Form (CRF) 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this information to 
the 
 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the 
SAE CRF pages within the designated reporting time frames. 
Safety Reporting to Sponsor 
• 
 will forward the SAE and Pregnancy report to 
the Sponsor’s safety representatives within 1 business day or 3 calendar days (whichever is earlier) of 
becoming aware of it. 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
84 
APPENDIX 6: 
EXCLUDED MEDICATIONS/THERAPY 
Excluded medications/therapy is listed below. The concomitant use of an excluded 
medication/therapy with study treatment is not in compliance with the study protocol and must 
be recorded in the eCRF. 
 
 
   
 
 
  
 
 
 
 
  
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
85 
APPENDIX 7: 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY  
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
6. Premenarchal 
7. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
Note: Documentation can come from the study center personnel’s: review of the subject’s 
medical records, medical examination, or medical history interview. 
8. Postmenopausal female: 
a) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Contraception Guidance 
Male subjects 
• Male subjects with female partners of childbearing potential are eligible to participate if they 
agree to 1 of the following during the study and for 6 months after the last dose of study 
treatment:  
o Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
o Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
86 
• In addition, male subjects must refrain from donating sperm for the duration of the study and 
for 6 months after the last dose of study treatment. 
• Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
for the duration of the study and for 6 months after the last dose of the study treatment. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb  
• 
Oral.  
• 
Intravaginal.  
• 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable.  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD). 
• 
Intrauterine hormone-releasing system (IUS). 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.  
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during 
the treatment period and for at least 6 months, after the last dose of study treatment.  

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
88 
Investigator is not obligated to actively seek this information in former subjects, he or she 
may learn of an SAE through spontaneous reporting.  
• Any female subject who becomes pregnant while participating in the study will discontinue 
study treatment or be withdrawn from the study. 
• The pregnancy shall be followed every 3 months during pregnancy till its outcome and one 
month post-delivery. If there are abnormalities present at delivery, the newborn will be 
followed for an appropriate period, or up to 3 months, to assess the functional and health 
status of the child. 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
89 
 
  
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
90 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
91 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
95 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
96 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
97 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
98 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
99 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
100 
APPENDIX 19: 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
1) C-SSRS Screening 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
101 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
103 
2) C-SSRS Baseline  

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
106 
3) C-SSRS Since Last Visit 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
107 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
 
 

CONFIDENTIAL 
Protocol TILD-18-20- 
  
 
109