Conditions: Ulcerative Colitis (UC)
Keywords: TD-1473 Janus kinase inhibitor JAK inhibitor Inflammatory Bowel Disease IBD Ulcerative colitis UC Intestinal restriction Gut-selective
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
A 3-Year Multi-Center, Long-Term Safety (LTS) Study to Evaluate the Safety and Tolerability of TD-1473 in Subjects with Ulcerative Colitis who have participated in the Maintenance Study of Protocol 0157

Detailed description:
This is a multi-center, long-term safety study to evaluate the safety and tolerability of TD-1473 for up to 156 weeks (3 years) + 4 week follow-up in subjects with moderate to severe UC exiting the preceding Maintenance Study of Protocol 0157 (NCT03758443).

Arms:
arm 1: Oral daily dose of TD-1473 for up to 156 weeks arm 2: Oral daily dose of TD-1473 for up to 156 weeks arm 3: Oral daily dose of TD-1473 for up to 156 weeks

Interventions: intervention 1: TD-1473 Dose A intervention 2: TD-1473 Dose B intervention 3: TD-1473 Dose C
Intervention descriptions: intervention 1: See Arm description intervention 2: See Arm description intervention 3: See Arm description

Protocol document:
Prot_000.pdf: 
Protocol Number:  0164 
 
Official Title:  A 3-Year, Multi-Center, Long-Term Safety (LTS) Study to Evaluate the Safety and 
Tolerability of TD-1473 in Subjects with Ulcerative Colitis (UC) 
 
NCT Number: NCT03920254 
 
Document Date:  15 Feb 2021 










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4. Must be able and willing to adhere to the study visit schedule and comply with other 
study requirements.  
Exclusion Criteria: 
Subjects meeting any of the following criteria may not be enrolled in the study:  
Gastrointestinal: 
1. Has current symptoms or signs suggestive of fulminant colitis, toxic megacolon, 
intestinal perforation 
2. Has a high risk of requiring surgery for UC during the study 
3. Has been diagnosed during Protocol 0157 with Crohn’s disease, microscopic colitis, 
ischemic colitis, radiation colitis, diverticular disease associated with colitis, 
indeterminate colitis, or the subject has a current or past diagnosis of a fistula or 
abdominal abscess 
4. Has dysplasia that was not completely resected or high-grade dysplasia detected 
during Protocol 0157; however, subjects with adenomas with low grade dysplasia that 
have been completely resected are eligible 
Concomitant or previous medications /treatments: 
5. Taking any medications/treatments listed in Appendix 4 currently or previously 
during Protocol 0157 Maintenance.  
Coexisting medical conditions or past medical history:   
6. Deemed by the investigator to be inappropriate for this study; or has any condition 
which would confound or interfere with the evaluation of the safety or tolerability of 
the study drug [e.g., developed unstable or uncontrolled and clinically significant 
allergic (except for untreated, asymptomatic, seasonal allergies), hematological, 
endocrine/metabolic, coagulation, immunologic, pulmonary, cardiovascular, hepatic 
(except hepatic steatohepatitis), GI (except UC), genitourinary, psychiatric, oncologic 
thrombotic (e.g., deep vein thrombosis or pulmonary embolism), or neurological 
disease or other medical disorder before, during, or after Protocol 0157]; or is unable 
or unwilling to comply with the study protocol.  
7. Has developed hypersensitivity to excipients or contents of the study drug  
8. Participating in or interested in participating in another investigational study (except 
Protocol 0157)  
9. Has clinically significant abnormalities in the results of laboratory evaluations at the 
most recent laboratory evaluation prior to LTS Day 1 visit as determined by the 
investigator, including:   
• 
AST, ALT, or alkaline phosphatase ≥ 2x the upper limit of normal (ULN) 
• 
Total bilirubin > 2x ULN (unless diagnosis of Gilbert’s syndrome) 


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• 
Creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min 
(Appendix 2) 
• 
Total white blood cell count (WBC) < 3 x 109/L 
• 
Absolute neutrophil count < 1.5 x 109/L 
• 
Absolute lymphocyte count < 0.8 x 109/L 
• 
Hemoglobin < 8 g/dL, or  
• 
Platelet count < 100 x 109/L 
10. Subject has had a live viral vaccine (e.g., MMR, varicella zoster, herpes zoster, oral 
polio virus, FluMist®, attenuated typhoid fever vaccine, attenuated rotavirus vaccine, 
yellow fever vaccine, or any investigational live vaccine) within 4 weeks prior to 
Day 1 and/or is unwilling or unable to avoid live viral vaccines during the Study and 
for 8 weeks following the last dose of study drug. Subject must be willing to avoid 
contact with any household member who has been vaccinated with a live attenuated 
vaccine within 2 weeks after vaccination. 
11. Are pregnant, lactating, breastfeeding or planning to become pregnant during the 
Study or within 7 days after the last dose of Study Drug 
12. Within 4 weeks of Day 1, has [1] confirmed severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]) (test 
positive), OR [2] suspected SARS-CoV-2 infection (clinical features without 
documented test results) unless has a negative test for SARS-CoV-2 two weeks after 
resolution of symptoms and remains asymptomatic until Day 1, OR [3] close contact 
with a person with known or suspected SARS-CoV-2 infection unless has a negative 
test for SARS-CoV-2 two weeks after contact and remains asymptomatic until Day 1.  
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:  
TD-1473 20 mg, 80 mg or 200 mg: given orally, once daily for up to 156 weeks (3 years) in 
the morning. 
Study Evaluations 
Safety Assessments: 
Subject safety will be assessed throughout the study using standard measures, including vital 
signs, ECG, blood and urine safety laboratory tests, physical examinations, concomitant 
medication usage, and adverse event (AE) monitoring with emphasis on adverse events of 
special interest, such as suspected or confirmed intestinal perforation, complicated herpes 
zoster, malignancies, serious infection (e.g., that requires hospitalization or intravenous 
antibiotics), opportunistic infection, thromboembolic disease (e.g., deep vein thrombosis, 
pulmonary embolism), cardiovascular events or clinical laboratory abnormalities of concern. 
 
 










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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS.................................................................................................................2 
LIST OF ABBREVIATIONS ........................................................................................................17 
DEFINITION OF TERMS ............................................................................................................19 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background and Rationale ..........................................................................................22 
1.2. 
Nonclinical Profile ......................................................................................................23 
1.3. 
Pharmacology .............................................................................................................23 
1.3.1. 
Toxicology ..................................................................................................................23 
1.3.2. 
Pharmacokinetics ........................................................................................................24 
1.4. 
Clinical Experience .....................................................................................................25 
1.5. 
Risks and Benefits ......................................................................................................26 
2. 
OBJECTIVES .............................................................................................................28 
3. 
STUDY DESIGN .......................................................................................................29 
3.1. 
Overview .....................................................................................................................29 
3.2. 
Rationale for Study Design .........................................................................................29 
3.3. 
Selection of Dose Ranges and Duration of Treatment ...............................................29 
3.3.1. 
Safety Endpoints .........................................................................................................31 
3.3.2. 
Minimization of Bias ..................................................................................................31 
3.3.3. 
Blinding ......................................................................................................................31 
3.3.4. 
Treatment Assignment ................................................................................................32 
3.3.5. 
End of Trial Definition ...............................................................................................32 
4. 
STUDY POPULATION .............................................................................................33 
4.1. 
Inclusion Criteria ........................................................................................................33 
4.2. 
Exclusion Criteria .......................................................................................................33 
4.3. 
Women of Childbearing Potential (WOCBP) and Acceptable Birth Controls ...........35 
5. 
STUDY DRUGS ........................................................................................................36 
5.1. 
Description of Study Drug ..........................................................................................36 
5.1.1. 
TD-1473 ......................................................................................................................36 
5.2. 
Dosage and Administration ........................................................................................36 
5.3. 
Treatment Compliance ................................................................................................36 
5.4. 
Missed Dose(s) ...........................................................................................................37 


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5.5. 
Drug Accountability and Reconciliation ....................................................................37 
6. 
STUDY PROCEDURES ............................................................................................38 
6.1. 
Schedule of Study Procedures ....................................................................................38 
6.2. 
Total Blood Volume ...................................................................................................38 
6.3. 
Procedures by Visit .....................................................................................................38 
6.3.1. 
Day 1 ...........................................................................................................................38 
6.3.2. 
Week 4 and Week 12 ..................................................................................................38 
6.3.3. 
Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 ................................................38 
6.3.4. 
Weeks 52, 104, and 156 (1 year, 2 year and 3 year) ...................................................38 
6.3.5. 
Early Study Drug Discontinuation ..............................................................................39 
6.3.6. 
End of Study (EOS) ....................................................................................................39 
6.4. 
Description of Study Assessments ..............................................................................39 
6.4.1. 
Demographic and Baseline Assessments ....................................................................39 
6.4.1.1. 
Informed Consent, Demographics, and Inclusion/Exclusion Criteria ........................39 
6.4.1.2. 
Medication History .....................................................................................................39 
6.4.1.3. 
Medical History ..........................................................................................................39 
6.4.1.4. 
Body Weight ...............................................................................................................39 
6.4.1.5. 
Smoking Status ...........................................................................................................40 
6.4.1.6. 
Vital Signs ..................................................................................................................40 
6.4.1.7. 
12-Lead Electrocardiograms .......................................................................................40 
6.4.1.8. 
Physical Examination .................................................................................................41 
6.4.1.9. 
Concomitant Medications / Treatments ......................................................................41 
6.4.1.10. 
Adverse Events (AEs) .................................................................................................41 
6.4.1.11. 
Pregnancy Test (females of child-bearing potential only) ..........................................41 
6.4.1.12. 
Follicle-Stimulating Hormone (FSH) .........................................................................41 
6.4.1.13. 
Chemistry and Hematology ........................................................................................42 
6.4.1.14. 
Overnight Fasting Lipid Panel ....................................................................................42 
 
 
 
 
 
 
 
 
 
 


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6.4.3. 
Safety Assessments .....................................................................................................45 
6.4.3.1. 
Adverse Events ...........................................................................................................45 
6.4.3.2. 
Medical History ..........................................................................................................45 
6.4.3.3. 
12-Lead Electrocardiograms .......................................................................................45 
6.4.3.4. 
Physical Examination .................................................................................................45 
6.4.3.5. 
Vital Signs ..................................................................................................................45 
6.4.3.6. 
Laboratory Tests .........................................................................................................45 
6.5. 
Concomitant Medications ...........................................................................................46 
6.5.1. 
Prohibited Medications / Treatments ..........................................................................46 
6.5.2. 
Permitted Medications ................................................................................................46 
6.5.3. 
Restrictions on Alcohol Consumption and Illicit Drug Use .......................................46 
6.6. 
Discontinuation ...........................................................................................................47 
6.6.1. 
Subject Discontinuation ..............................................................................................47 
6.6.2. 
Subject Replacement ..................................................................................................48 
6.6.3. 
Study Discontinuation ................................................................................................48 
6.7. 
Pregnancy ...................................................................................................................48 
7. 
ADVERSE EVENTS ..................................................................................................49 
7.1. 
Definitions ..................................................................................................................49 
7.1.1. 
Adverse Events (AE) ..................................................................................................49 
7.1.2. 
Serious Adverse Event (SAE) ....................................................................................50 
7.1.3. 
Additional Considerations for Serious Adverse Events .............................................50 
7.1.4. 
Adverse Events of Special Interest (AESI) ................................................................51 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ................................................................52 
7.3. 
Assessment of Adverse Events ...................................................................................53 
7.3.1. 
Severity .......................................................................................................................53 
7.3.2. 
Causal Relationship to Study Drug .............................................................................53 
7.3.3. 
Clinical Events Committee (CEC) ..............................................................................54 
7.4. 
AE Reporting and Recording ......................................................................................54 
7.4.1. 
AE Reporting ..............................................................................................................54 
7.4.2. 
AE, SAE and AESI Recording ...................................................................................54 


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7.4.3. 
SAE and AESI Reporting Timeline ............................................................................55 
7.5. 
Adverse Event Follow-up ...........................................................................................56 
8. 
STATISTICAL CONSIDERATIONS .......................................................................57 
8.1. 
General Considerations ...............................................................................................57 
8.2. 
Sample Size ................................................................................................................57 
8.3. 
Analysis Sets ...............................................................................................................57 
8.3.1. 
Analysis Sets ...............................................................................................................57 
8.3.2. 
Examination of Subgroups .........................................................................................57 
8.3.3. 
Major Protocol Analysis Deviations ...........................................................................58 
8.4. 
General Analyses ........................................................................................................58 
8.4.1. 
Demographics and Baseline Characteristics ...............................................................58 
8.4.2. 
Disposition ..................................................................................................................58 
8.4.3. 
Compliance and Exposure ..........................................................................................59 
8.5. 
Efficacy Analyses .......................................................................................................59 
8.5.1. 
Efficacy Endpoints ......................................................................................................59 
8.5.2. 
Efficacy Summaries ....................................................................................................60 
8.6. 
Safety Analyses ..........................................................................................................61 
8.6.1. 
Adverse Event Data ....................................................................................................61 
8.6.1.1. 
Adverse Events of Special Interest .............................................................................62 
8.6.2. 
Concomitant Medications ...........................................................................................62 
8.6.3. 
Laboratory Data ..........................................................................................................62 
8.6.4. 
Vital Signs Data ..........................................................................................................63 
8.6.5. 
ECG Data ....................................................................................................................63 
8.7. 
Missing Data Handling ...............................................................................................64 
8.8. 
Independent Data Monitoring Committee (IDMC) ....................................................64 
9. 
STUDY ADMINISTRATION ...................................................................................65 
9.1. 
Principal Investigator Responsibilities .......................................................................65 
9.2. 
Institutional Review Board/Independent Ethics Committee ......................................66 
9.3. 
Informed Consent .......................................................................................................66 
9.4. 
Data Recording and Quality Assurance ......................................................................66 
9.5. 
Document Retention ...................................................................................................67 
9.6. 
Confidentiality ............................................................................................................67 




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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
adverse event 
ALT 
alanine aminotransferase 
 
 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
BP 
blood pressure 
CFA 
Clinical Flare Assessment  
CFR 
(United States) Code of Federal Regulations 
CRF 
case report form 
 
 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOS 
End-of-Study 
 
 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HDPE 
high-density polyethylene 
HR 
heart rate 
IB 
Investigator's Brochure 
IBD 
Inflammatory Bowel Disease 
 
  
IC50 
quantity of a particular drug/substance needed to inhibit a given biological 
process by half 
ICF 
informed consent form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 


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Abbreviation 
Description 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
JAK 
Janus kinase 
LTS 
Long Term Safety Study 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
NK 
natural killer 
OTC 
Over-the-Counter 
PI 
principal investigator 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic(s) 
 
  
PPI 
proton pump inhibitor 
PT 
Preferred Term 
QD 
Once daily 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
REB 
Research Ethics Board 
RTSM 
randomization and trial supply management 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
SAS® software for statistical analysis 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
standard operating procedure 
STAT 
signal transducer and activator of transcription 
TEAE 
Treatment-Emergent Adverse Event  
TB 
Tuberculosis 
TBPH 
Theravance Biopharma 
 
 
TNF 
tumor necrosis factor 
UC 
ulcerative colitis 
USP 
United States Pharmacopeia  
WOCBP 
Women of Childbearing Potential 
 
  
 


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The potential risks described in this section will be carefully assessed during the Study. 
Assessments include scheduled physical exams, and frequent monitoring of complete blood cell 
counts with differential, kidney and liver function, creatinine phosphokinase, and fasting 
cholesterol panel. 
The clinical and laboratory observations planned for this clinical trial are sufficient to monitor 
for the key observations noted in the nonclinical evaluation of TD-1473 at doses relevant to this 
study, as well as many of the effects noted with use of tofacitinib.  
The current protocol requires pregnancy prevention measures for a duration of the study from 
Day 1 visit to 7 days after the last dose of Study drug for both male and female subjects.  The 
7 day-duration for pregnancy prevention measures after the last dose is to ensure that TD-1473 is 
eliminated from the systemic circulation (i.e., ~ 5 half-lives) before conception to avoid potential 
exposure to a developing embryo/fetus.  This is based upon the following 4 considerations: 
1) TD-1473 is not genotoxic, 2) in the definitive embryo-fetal developmental toxicity studies 
there was no evidence of direct embryo-fetal toxicity or teratogenicity up to 1000 mg/kg/day and 
60 mg/kg/day in rats and rabbits, respectively, 3) systemic exposures in study subjects 7 days 
after the last dose are estimated to be >150-fold below the exposures in rats or rabbits at doses 
without significant findings (1000 mg/kg/day and 60 mg/kg/day in rats and rabbits, respectively), 
and 4) TD-1473 was not measurable in fetal blood in animals treated with TD-1473.   
Pregnancy prevention measures in men are typically recommended when there are concerns 
about genotoxicity.  If a compound is genotoxic, there is a need to require effective contraceptive 
use for male subjects during exposure and for five terminal half-lives plus 74 days (one human 
spermatogenesis cycle).9  For small molecules with genotoxic potential, taking into account a 
spermatogenesis cycle is essential given the potential for DNA damage or impairment of 
chromosome replication which may be passed on to progeny at conception when damage occurs 
to genetic material of germ cells.  However, TD-1473 has been shown to be non-genotoxic in a 
standard battery of genotoxicity assays; thus, ensuring a spermatogenesis cycle has elapsed is not 
required.  Therefore, since accounting for a spermatogenesis cycle is not necessary and for 
simplicity matching the timeframe required for females, the Sponsor has incorporated a 
requirement for pregnancy prevention procedures and avoidance of semen donation to be 
followed by all males for 7 days after the last dose of Study drug. 
 










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A subject’s treatment assignment will be unblinded only when knowledge of the treatment is 
essential for the further clinical management of the subject on this study or may potentially 
impact the safety of subjects currently enrolled or subjects in subsequent enrollment.  
Unblinding at the study site for any other reason will be considered a protocol deviation. In case 
of an emergency, the investigator has the sole responsibility for determining if unblinding of a 
subject’s treatment assignment is warranted and unblinding can be done through the RTSM 
system. Subject safety must always be the first consideration in making such a determination. 
Any investigator unblinding will be documented within the appropriate CRF and will be 
captured in the RTSM system. 
Sponsor Drug Safety personnel may independently unblind cases for expedited reporting of 
suspected unexpected serious adverse reactions (SUSARs).  
3.3.4. 
Treatment Assignment 
Once the subject has been determined to be eligible to receive study treatment, the PI or their 
delegate will use the RTSM system to determine the subject’s treatment assignment and dispense 
Study drug. 
Subject IDs will be carried over from the Protocol 0157 Induction/Maintenance Studies. Subject 
ID will be of format “164 - Site Number - Subject Number. The Site number and subject number 
will remain the same as Protocol 0157 Induction/ Maintenance Studies but Subject ID 
encompasses all these 3 elements. 
Further details regarding the treatment assignment procedure will be provided in the RTSM 
system manual. 
3.3.5. 
End of Trial Definition 
The end of the study is defined as the date of the global, last subject study visit (including the 
4 week follow up visit) in the LTS study. 




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4. Has dysplasia that was not completely resected or high-grade dysplasia detected during 
Protocol 0157; however, subjects with adenomas with low grade dysplasia that have been 
completely resected are eligible 
Concomitant or previous medications / treatments: 
5. Taking any medications / treatments listed in Appendix 4 currently or previously during 
Protocol 0157 Maintenance 
Coexisting medical conditions or past medical history: 
6. Deemed by the investigator to be inappropriate for this study; or has any condition which 
would confound or interfere with the evaluation of the safety or tolerability of the study 
drug [e.g., developed unstable or uncontrolled and clinically significant  allergic (except 
for untreated, asymptomatic, seasonal allergies), hematological, endocrine/metabolic, 
coagulation, immunologic, pulmonary, cardiovascular, hepatic (except hepatic 
steatohepatitis), GI (except UC), genitourinary, psychiatric, oncologic thrombotic 
(e.g., deep vein thromboses (DVT) or pulmonary embolism or neurological disease or 
other medical disorder before during or after Protocol 0157]; or is unable or unwilling to 
comply with the study protocol.  
7. Develops hypersensitivity to excipients or contents of the study drug as noted in 
Protocol 0157. 
8. Participating in or interested in participating in another investigational study (exception 
Protocol 0157) 
9. Has clinically significant abnormalities in the results of laboratory evaluations at the most 
recent laboratory evaluation prior to LTS Day 1 visit as determined by the investigator, 
including:   
• AST, ALT, or alkaline phosphatase ≥ 2x the upper limit of normal (ULN) 
• Total bilirubin > 2x ULN (unless diagnosis of Gilbert’s syndrome) 
• Creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min 
(Refer to Appendix 2) 
• Total white blood cell count (WBC) < 3 x 109/L 
• Absolute neutrophil count < 1.5 x 109/L 
• Absolute lymphocyte count < 0.8 x 109/L 
• Hemoglobin < 8 g/dL  
• Platelet count < 100 x 109/L. 
10. Subject has had a live viral vaccine (e.g., MMR, varicella zoster, herpes zoster, oral polio 
virus, FluMist®, attenuated typhoid fever vaccine, attenuated rotavirus vaccine, yellow 
fever vaccine, or any investigational live vaccine) within 4 weeks prior to Day 1 and/or is 
unwilling or unable to avoid live viral vaccines during the Study and for 8 weeks 
following the last dose of study drug. Subject must be willing to avoid contact with any 


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household member who has been vaccinated with a live attenuated vaccine within 
2 weeks after vaccination. 
11. Are pregnant, lactating, breastfeeding or planning to become pregnant during the Study 
or within 7 days after the last dose of Study Drug 
12. Within 4 weeks of Day 1, has [1] confirmed severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]) (test 
positive), OR [2] suspected SARS-CoV-2 infection (clinical features without documented 
test results) unless has a negative test for SARS-CoV-2 two weeks after resolution of 
symptoms and remains asymptomatic until Day 1, OR [3] close contact with a person 
with known or suspected SARS-CoV-2 infection unless has a negative test for 
SARS-CoV-2 two weeks after contact and remains asymptomatic until Day 1. 
 
4.3. Women of Childbearing Potential (WOCBP) and Acceptable Birth 
Controls 
Women of childbearing potential must have documentation of a negative pregnancy test at Day 1 
and prior to dosing. All female subjects of childbearing potential must agree to abstain from 
sexual intercourse or to use a highly effective method of birth control during the study and for at 
least 7 days after completion of Study drug dosing.  
Females are considered not of childbearing potential if they have had a total hysterectomy and/or 
bilateral tubal ligation or hysteroscopic sterilization (documentation for surgeries must be 
provided before randomization) or are in a postmenopausal state (i.e., females who have had 
cessation of prior occurring menses for ≥24 months without alternative causes or females with 
premature ovarian failure). 
Follicle-stimulating hormone (FSH) will be tested at Day 1 in post-menopausal females only to 
confirm post-menopausal state. 
Highly effective birth control methods are defined as methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly.  Such methods include: combined 
(estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral/intravaginal/transdermal); progestogen-only hormonal contraception associated 
with inhibition of ovulation (oral/injectable/implantable); intrauterine device; intrauterine 
hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual 
abstinence (if this is in line with the preferred and usual lifestyle).  Vasectomised partner is a 
highly effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomised partner has received medical assessment of 
the surgical success.  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 treatments. More restrictive methods of birth control may be required as per local country 
requirements, and this will be defined in the IRB/IEC approved subject informed consent form.   
 




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5.4. 
Missed Dose(s) 
The Study drug will be taken orally and must be swallowed whole with liquid and not chewed, 
divided, dissolved, or crushed. If the subject dose is missed in the morning, it can still be taken 
up to 12 hours after the subject’s nominal dosing time.  If the subject does not take the Study 
drug within 12 hours after the usual time each day, the dose of Study drug should be skipped for 
that day and the subject should be instructed to take the Study drug on the following day.. 
5.5. 
Drug Accountability and Reconciliation 
The investigator or designee is responsible for maintaining accountability records for all Study 
drug(s) received from the Sponsor, in accordance with applicable government regulations and 
Study procedures. The accountability record for Study drug (TD-1473) will be maintained in a 
secure location, accessible only to authorized staff members. The accountability record will 
include entries for receipt, distribution or dispensing, and destruction of the material(s). 
Subjects will be instructed to return all used and unused Study drug at each study visit. 
Unused and expired Study drugs will be disposed of in accordance with written instructions from 
the Sponsor. Drug accountability is maintained in the Randomization and Trial supply 
management system (RTSM), managed by RTSM supplier.  




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6.3.5. 
Early Study Drug Discontinuation  
Subjects who prematurely discontinue the Study drug prior to 3 years completion due to AEs, 
loss of response, lack of efficacy or any other reason besides withdrawal of consent during the 
LTS Study will be asked to return for an Early Study Drug Discontinuation visit. This visit will 
be conducted within 5 days after the last dose of Study drug.  
Subjects should be instructed to fast from food and non-clear liquids on the evening prior to the 
visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
Subjects will also return for the End of Study visit for collection of safety data and assessment of 
disease activity.  
The Schedule of Study Procedures is summarized in Table 1. 
6.3.6. 
End of Study (EOS) 
An EOS visit will be required for all subjects 4 weeks following their last dose of Study drug. 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
EOS visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection.  
The Schedule of Study Procedures is summarized in Table 1. 
6.4. 
Description of Study Assessments 
6.4.1. 
Demographic and Baseline Assessments 
6.4.1.1. 
Informed Consent, Demographics, and Inclusion/Exclusion Criteria 
Written informed consent must be obtained, signed, and dated after the nature of the Study has 
been explained to the subject and before any Study procedure is performed. 
Demographic data may be collected from the Protocol 0157, if applicable. 
Inclusion and exclusion criteria will be assessed at Day 1 prior to entry into the LTS Study. 
Subjects will only be eligible for enrollment into the Study if they meet all of the inclusion and 
none of the exclusion criteria. 
6.4.1.2. 
Medication History 
On Day 1 of the LTS Study, all concomitant medications will be reviewed with the subject, if 
applicable. Protocol 0157 medications ongoing at the time of Day 1 of the Protocol 0164 LTS 
Study may be collected from the Protocol 0157, if applicable.  
Please refer to Inclusion/ Exclusion Criteria and Appendix 4 for Prohibited Medications.  
6.4.1.3. 
Medical History 
Medical history and adverse events may be collected from the Protocol 0157, if applicable. 
6.4.1.4. 
Body Weight 
Weight measurement (in kg and without shoes) will be obtained according to the Schedule of 
Study Procedures (Table 1). 


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6.4.1.5. 
Smoking Status 
Subject’s current use of tobacco, number of years used, and annual pack years used will be 
obtained according to the Schedule of Study Procedures (Table 1). 
6.4.1.6. 
Vital Signs 
Heart rate (HR), systolic and diastolic blood pressure (BP), respiratory rate, and body 
temperature will be recorded according to the Schedule of Study Procedures (Table 1). 
Blood pressure and heart rate will be measured after the subject has been resting for at least 
5 minutes in the seated or supine position.  Subject position, measurement device, and arm 
(left vs. right) should be kept consistent throughout the Study.  Blood pressure will be measured 
using a manual or automatic blood pressure device.  Heart rate will be recorded by palpation of 
the radial pulse over at least a 30-second period or by the automated blood pressure device. 
Body temperature will be measured and reported in degrees Celsius.  The method used to collect 
temperature needs to be consistent throughout the subject’s participation. 
Any vital sign outside the normal range may be repeated at the discretion of the investigator.  
The vital sign measurements (BP and HR) should be performed after the subject has rested 
sufficiently as determined by the appropriate site staff.  Collection of additional vital sign 
measurements for routine safety monitoring at additional time points or Study days may be 
performed at the discretion of the investigator, or upon request by the Sponsor.  
6.4.1.7. 
12-Lead Electrocardiograms 
Interpretable ECG recordings (e.g., without artifacts) will be obtained according to the Schedule 
of Study Procedures (Table 1). Twelve-lead safety ECGs will be collected in singlet at each 
scheduled time point. 
ECGs must be performed after the subject has been resting in a supine position for at least 
10 minutes.  
For monitoring purposes, the investigator must review, provide interpretation for ECG 
recordings other than sinus rhythm on the ECG tracing, sign, and date all safety ECG tracings. 
Paper copies of ECG tracings will be kept as part of the subject's Study file at the site. 
If at a particular post dose time point, the QTcF is > 500 msec and/or 60 msec longer than the 
value at Day 1 or the mean QRS interval is > 130 msec, a decision on Study drug discontinuation 
should be made by the investigator with input from the Study Medical Monitor, if feasible. The 
investigator should also consider evaluating the subject for potential concurrent risk factors 
(e.g., electrolyte abnormalities, concomitant medications known to prolong the QT interval, 
severe bradycardia). 
Results from a plasma TD-1473 exposure QTc analysis of data obtained from the SAD and 
MAD Study in healthy subjects and preclinical data were used in considering frequency and 
replicate ECGs required for this Study. 


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6.4.1.8. 
Physical Examination 
The physical examination will be performed by a physician, nurse practitioner, physician’s 
assistant, or equivalent, according to local practice standards, at each scheduled time point as 
specified in the Schedule of Study Procedures (Table 1). 
Completion of additional physical examinations for routine safety monitoring at additional time 
points or Study days may be performed at the discretion of the investigator, or upon request by 
the Sponsor.  A physical exam of the organ system associated with any reported AE, even if 
resolved, should be performed at subsequent Study visits. 
6.4.1.9. 
Concomitant Medications / Treatments 
All concomitant medications (i.e., prescription and over-the-counter medications, herbals, 
vitamins, and supplements) will be reviewed throughout the Study as described in the Schedule 
of Study Procedures (Table 1).  Details such as name of medication, date started and stopped, 
route of administration, indication, and dose will be recorded.  Medical therapy may be altered 
during the study however administration of a prohibited medication/ treatments listed in 
Appendix 4 should result in the subject being discontinued from the Study.   
Refer to Section 6.5 for further details.  
6.4.1.10. Adverse Events (AEs) 
Adverse events, including serious adverse events (SAEs) and adverse events of special interest 
(AESI) will be reviewed and recorded following the time the subject signed the Informed 
Consent Form through the follow-up visit. AEs may be observed by the site Study personnel or 
spontaneously reported by the subject or reported in response to standard questions from site 
Study personnel. Subjects will be reminded to call the site to report AEs that occur between 
visits. Refer to Section 6 for definition, assessment, and reporting of AEs. 
6.4.1.11. Pregnancy Test (females of child-bearing potential only) 
Urine b-hCG testing will be performed during specified visits, as listed in the Schedule of Study 
Procedures (Table 1), before study drug dosing, on females of childbearing potential to confirm 
the absence of pregnancy.  If the urine b-hCG test is positive, a serum b-hCG test must be 
performed.  The pregnancy test must be confirmed negative for a subject to be eligible for this 
Study unless the PI deems the test is falsely positive.   
Detailed instructions and collection kits for sample collection, handling, and shipping will be 
provided by the central laboratory. 
6.4.1.12. Follicle-Stimulating Hormone (FSH) 
Follicle-stimulating hormone (FSH) will be tested at Day 1 in any female that may have become 
or is suspected to be post-menopausal since enrolment in Protocol 0157. The FSH test is to 
confirm post-menopausal state. FSH will be performed as specified in Schedule of Study 
Procedures in Table 1.  












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6.6. 
Discontinuation 
6.6.1. 
Subject Discontinuation 
Any subject may withdraw his/her consent to participate in the Study at any time without 
prejudice. The investigator must withdraw from the study any subject who requests to be 
withdrawn. A subject’s participation in the study may be discontinued at any time at the 
discretion of the investigator and in accordance with his or her clinical judgment. Subjects must 
also be discontinued on study drug for any AESI (except non-melanoma skin cancer, mono-
dermatomal herpes zoster, and certain laboratory abnormalities that are deemed by the 
investigator to not place subjects at immediate safety risk) or if the subject becomes pregnant.  
When possible, the tests and evaluations listed for the Early Study Drug Discontinuation visit 
should be carried out. If a subject withdraws before completing the Study, the reason for 
withdrawal is to be documented on the CRF. 
The Sponsor will be notified of all subject withdrawals. 
Reasons for which the investigator or the Sponsor may withdraw a subject or a subject may 
choose to terminate participation before completion include, but are not limited to, the following: 
• Adverse event 
• Subject choice/Withdrawal of consent 
• Major violation of the protocol 
• Termination of the Study by the Sponsor 
• Initiation of medication / treatments that are prohibited as listed in Appendix 4 
• Investigator’s assessment of lack of clinical benefit 
• Pregnancy 
• Colectomy 
• Lost-to follow-up 
Subjects who discontinue Study drug early because of an adverse reaction should be encouraged 
to continue their participation in the follow-up safety assessments. If a subject fails to return for 
scheduled visits, a documented effort must be made to determine the reason. 
Subjects with laboratory abnormalities as outlined in Section 7.2 (i.e., two sequential occurrences 
of renal, leukocyte, leukocyte subset, or hepatic panel abnormalities or hepatic panel 
abnormalities with clinical sign or symptom of acute liver failure) should discontinue the study 
drug.  Any non-laboratory-related AE considered an AESI defined in Section 7.1.4, except for 
non-melanoma skin cancer and mono-dermatomal herpes zoster, should also lead to study drug 
discontinuation.  
Four weeks following the last dose of study drug, subjects will return for an End of Study (EOS) 
visit to assess safety, laboratory evaluation and symptoms as described in the Schedule of Study 
Procedures.   


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6.6.2. 
Subject Replacement 
There will be no subject replacement in the LTS Study.  
6.6.3. 
Study Discontinuation 
The Sponsor reserves the right to discontinue the study at any time for any reason. 
Periodic reviews of accumulating data by the IDMC may lead to the committee’s 
recommendation of pausing dosing or terminating the Study.  In the event of premature Study 
termination, best efforts to guarantee appropriate safety follow-up of subjects who have already 
been enrolled will be made and IRB/IEC/REBs and the Regulatory Authorities will be informed. 
6.7. 
Pregnancy 
If a female subject or the partner of a male subject becomes pregnant during the Study or within 
7 days of the subject’s last dose of Study drug, the Sponsor clinical Study director (or designee) 
must be notified immediately. If the female subject is still on Study drug treatment, the Study 
drug must be discontinued immediately. Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required. 
All pregnancies whether by the subject participating in the Study or the female partner of the 
male subject in the Study should be reported within 24 hours of awareness using the Pregnancy 
Notification Form.  
 


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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
The definitions below are based on International Conference on Harmonization (ICH) guideline 
E2A, “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting”. 
7.1.1. 
Adverse Events (AE) 
An AE on Protocol 0164 (LTS) is any AE that occurs after the first dose of study drug. An AE 
prior to the first dose of study drug on Protocol 0164 (LTS) will be documented in the 0157 
Study and if continuing at the time of consent to Protocol 0164 (LTS), the AE will be 
documented in the Protocol 0164 (LTS) database as an ongoing event.  
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a 
pharmaceutical product that does not necessarily have to have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the medicinal product.  
• AEs may be new events 
• Preexisting events that increase in frequency, severity or change in nature or 
seriousness during or as a consequence of participation in clinical studies. 
• Pre- or post-treatment complications that occur as a result of a protocol-mandated 
procedure 
 
• AEs may be clinically significant changes from baseline in physical examination, 
laboratory tests, or other diagnostic investigation (e.g., laboratory results, x-ray 
findings). 
• AEs may result from an overdose of the Study drug.  
Whenever possible, the diagnosis (rather than a series of terms related to a diagnosis) should be 
recorded as the AE term. 
An AE does not include the following: 
• Medical or surgical procedures (such as surgery,
, tooth extraction, or 
transfusion); the condition that leads to the procedure is an adverse event 
• Preexisting diseases or conditions present or detected before signing an informed 
consent form that do not worsen 
• Situations where an untoward medical occurrence has not occurred (such as 
hospitalization for elective surgery or social and/or convenience admissions) 
• Overdose of either Study drug or concomitant medication without any signs or 
symptoms, unless the subject is hospitalized for observation 


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Any medical condition or clinically significant laboratory abnormality with an onset date prior to 
the time the subject signed the informed consent form is considered to be preexisting and should 
be documented in the medical history CRF. 
Pregnancy is not an AE; however, if a female subject becomes pregnant during the conduct of 
the Study, the sponsor, will be notified according to the procedures for SAE reporting as outlined 
in Section 7.4.3.  Follow-up information regarding the outcome of the pregnancy and any fetal or 
neonatal sequelae will be obtained and documented. 
7.1.2. 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as any untoward medical occurrence occurring at any 
dose that results in any of the following outcomes: 
• Death 
• Life-threatening situation.  “Life-threatening” refers to a situation in which the patient 
was at risk of death at the time of the event; it does not refer to an event which might 
have caused death if it were more severe. 
• Inpatient hospitalization or prolongation of existing hospitalization 
Note:  “Inpatient hospitalization” means the subject has been formally admitted to a 
hospital for medical reasons, for any length of time. This may or may not be 
overnight. It does not include presentation and care within an emergency department. 
A scheduled hospitalization for a pre-existing condition that has not worsened during 
participation in the Study does not meet this criterion. Pre-planned hospitalizations 
for an elective medical/surgical procedure, scheduled treatments, or routine check-ups 
do not meet this criterion. Complications that occur during hospitalizations are AEs. 
If a complication prolongs hospitalization, it is an SAE. 
• Congenital anomaly/birth defect in the offspring of a subject who received Study drug 
• Disability. A persistent or significant incapacity or substantial disruption to the ability 
to conduct normal life functions. 
• Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such events are as follows: 
− Intensive treatment in an emergency room or at home for allergic bronchospasm 
− Blood dyscrasias or convulsions that do not result in hospitalization 
− Development of drug dependency or drug abuse 
7.1.3. 
Additional Considerations for Serious Adverse Events 
• Death is an outcome of an adverse event and not an adverse event in itself. Deaths of 
unknown cause for which the investigator cannot identify a cause of death will be 
captured as death of unknown cause or death not otherwise specified. 


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• All deaths, regardless of cause, must be reported for subjects if the death occurs while 
the subject is participating in the Study. 
• “Occurring at any dose” does not imply that the subject is receiving Study drug at the 
time of the event; dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE, but may have contributed to the event. 
7.1.4. 
Adverse Events of Special Interest (AESI) 
At each Study visit, the Investigator (or designee) will specifically query for any adverse events 
of special interest (AESI).  The following events are considered AESIs for this Study: 
• Suspected or confirmed intestinal perforation 
• Complicated herpes zoster (multi-dermatomal, disseminated, or with ophthalmic or 
CNS involvement) 
• Malignancy excluding non-melanoma skin cancer 
• Non-melanoma skin cancer 
• Serious infection (e.g., that requires hospitalization or intravenous antimicrobials) 
• Opportunistic infections 
• Thromboembolic disease (e.g., deep vein thrombosis (DVT), pulmonary embolism) 
• Clinical laboratory abnormalities of concern (Refer to Section 7.2) 
• Major cardiovascular event (e.g., myocardial infarction or cerebrovascular accident) 
All AESIs, except for non-melanoma skin cancers and mono-dermatomal herpes zoster, must be 
reported to TBPH Clinical Safety and Pharmacovigilance within 24 hours of the time the 
Investigator or his/her designee becomes aware of an AESI (Refer to Section 7.1.4).  Except for 
non-melanoma skin cancer that has been fully resected, mono-dermatomal herpes zoster, and 
certain laboratory abnormalities that are deemed by the investigator to not place subjects at 
immediate safety risk, all of these AESIs should lead to discontinuation of the study drug. For 
each of these AESI, an additional targeted questionnaire needs to be completed to assess for risk 
factors. For thromboembolic events in particular, the subject should undergo evaluation for 
hypercoagulable state (e.g., with clinically relevant investigations, such as referral to a specialist 
and/or blood testing for a predisposition to a hypercoagulable state) and repeat imaging to assess 
resolution of the finding.  
Besides these AESI, for other AEs, study drug may be interrupted and resumed as deemed 
medically appropriate by the investigator (e.g., during an infection that requires oral 
antimicrobial treatment). 
 


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7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events 
Abnormal laboratory findings (such as clinical chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as electrocardiograms [ECGs], X-rays, or vital signs) that are 
associated with signs and/or symptoms or are considered clinically significant in the judgment of 
the investigator must be recorded as AEs or SAEs if they meet the definition of an adverse event 
(or serious adverse event), as described in Section 7.1.1 (Adverse Event) and Section 7.1.2 
(Serious Adverse Event).  
Clinical laboratory abnormalities of concern may include, but are not limited to, the following 
where the investigator must recheck within 2-7 days, except for AST or ALT > 3x ULN where 
these need to be rechecked within 48-72 hours, as deemed appropriate by the investigator: 
• clinically significant reduction in neutrophils or leukocytes or lymphocytes that may 
place subjects at higher risk for infection such as: 
− moderate or severe neutropenia (e.g., absolute neutrophil count of < 1.0 x 109/L)  
− moderate or severe leukopenia (e.g., white blood cell count of < 2.0 x 109/L)  
− moderate or severe lymphocytopenia (e.g., absolute lymphocyte count of 
< 0.5 x 109/L)  
• abnormal hepatic panel (AST or ALT > 3x ULN) 
• an excessive decrease in creatinine clearance [e.g., a reduction by ≥ 50% from baseline 
(baseline for this purpose is defined as creatinine clearance calculated for Day 1, 
predose activities)] 
Depending on the subject’s baseline and individual scenario, the investigator should report as an 
AESI and stop study drug treatment if any of the below is seen: 
• moderate or severe neutropenia (e.g., absolute neutrophil count of < 1.0 x 109/L) on 
two sequential laboratory reports 
• moderate or severe leukopenia (e.g., white blood cell count of < 2.0 x 109/L) on two 
sequential laboratory reports 
• moderate or severe lymphocytopenia (e.g., absolute lymphocyte count of 
< 0.5 x 109/L) on two sequential laboratory reports 
• a reduction by ≥ 50% from baseline in creatinine clearance on two sequential 
laboratory reports 
• ALT or AST >8x ULN on a single laboratory report. Note:  See Appendix 6 for an 
algorithm of evaluating and managing subjects with ALT or AST > 3x ULN. 
• Abnormal AST or ALT > 3x ULN on two sequential laboratory visits with bilirubin 
> 2x ULN on at least one of the two laboratory reports, or international normalized 
ratio (INR) > 1.5 on at least one of the two reports (INR will be checked locally) 
• AST or ALT > 5x ULN on two sequential laboratory reports, least 2 weeks apart 


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• AST or ALT > 3x ULN associated with signs or symptoms suggestive of acute liver 
injury. 
If there are any AE questions, the investigator is encouraged to contact the Sponsor to discuss.  
Merely repeating an abnormal test does not constitute an adverse event. Any abnormal test result 
that is determined to be an error does not require reporting as an adverse event. 
7.3. 
Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded in the case report form, including the 
dates of onset and resolution, severity, relationship to Study drug, outcome, and action taken 
with Study drug. 
7.3.1. 
Severity 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea).  This is not the same as “serious,” which is based 
on patient/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning.  The severity of AEs will be assessed according to the following 
definitions:   
• Mild:  the AE is noticeable to the patient and/or the Investigator, but does not 
interfere with routine activity. 
• Moderate:  the AE interferes with routine activity, but responds to symptomatic 
therapy or rest. 
• Severe:  the AE significantly limits the patient’s ability to perform routine activities 
despite symptomatic therapy. 
7.3.2. 
Causal Relationship to Study Drug 
The Investigator’s assessment of causality is based on clinical judgment regarding the reasonable 
possibility that the Study drug caused the event and may include consideration of some or all of 
the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, 
co-morbid conditions, other drugs, and environmental factors. 
• The temporal association between drug exposure and onset of the AE.  
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or toxicity of the Study drug. 
• Whether the AE resolved or improved with decreasing the dose or stopping the Study 
drug (“dechallenge”) or recurred or worsened upon re-exposure to the Study drug 
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The causal relationship between the Study drug and the AE will be described using one of the 
following categories: 
• Not Related:  Evidence exists that the adverse event has an etiology other than the 
Study drug (such as a preexisting condition, underlying disease, intercurrent illness, 
or concomitant medication). 
• Related: A temporal relationship exists between the event onset and administration 
of the Study drug. It cannot be readily explained by the subject’s clinical state or 
concomitant therapies and appears with some degree of certainty to be related based 
on the known therapeutic and pharmacologic actions of the drug. In case of cessation 
or reduction of the dose, the event abates or resolves and reappears upon rechallenge. 
It should be emphasized that ineffective treatment should not be considered as 
causally related in the context of adverse event reporting. 
7.3.3. 
Clinical Events Committee (CEC) 
A clinical events committee(s) (CEC) has been established with external experts and will 
adjudicate thromboembolic and major cardiovascular events. If deemed necessary, the same or a 
different CEC may also be requested to adjudicate other AEs of interest (e.g., for opportunistic 
infections, herpes zoster, malignancy). To allow for unbiased assessment, the CEC will remain 
blinded to treatment assignment. A CEC charter will be drafted with descriptions of membership, 
the scope of the CEC members’ responsibilities, adjudication processes, and definitions used to 
review and assess specific AEs. 
7.4. 
AE Reporting and Recording 
7.4.1. 
AE Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials is 
crucial for the protection of subjects and is mandated by regulatory agencies.  Sponsor has 
established standard operating procedures in compliance with regulatory requirements 
worldwide to ensure appropriate reporting of safety information.  All clinical trials sponsored by 
TBPH will be conducted in accordance with these procedures.  
7.4.2. 
AE, SAE and AESI Recording 
All AEs, regardless of seriousness, severity, or causal relationship to Study drug, will be 
recorded from signing informed consent through the last Study visit (or last subject contact in the 
case of a follow-up telephone call).  AEs will be recorded on the AE page of the CRF.  SAEs, 
regardless of relationship to Study drug will be recorded from signing informed consent through 
the last Study visit (or last subject contact in the case of a follow-up telephone call).  
Additionally, investigators may report SAEs assessed as related to Study drug through 30 days 
following the last Study visit (or last subject contact in the case of a follow-up telephone call). 
All SAEs will be recorded on both the SAE Report Form and the AE page of the CRF and 
should include the following:   


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Description of event:   
• Signs and symptoms due to a common etiology should be reported as a single 
diagnosis; for example, cough, runny nose, sneezing, sore throat, and head congestion 
would be reported as “upper respiratory infection”.   
• A diagnosis or description must be as specific and as complete as possible (e.g., 
“lower extremity edema” instead of “edema”).  
• Hospitalization or surgical procedures should not be used as adverse event terms 
(e.g., if a subject was hospitalized for cholecystectomy due to cholecystitis, the 
adverse event term should be recorded as cholecystitis, and not as the procedure, 
cholecystectomy).   
• “Death” should not be used as an adverse event term unless the cause of death is 
unknown.  For events with a fatal outcome, the cause of death should be the adverse 
event term (e.g., if a subject died of an acute myocardial infarction, the adverse event 
term should be recorded as “Myocardial Infarction” and the event outcome as fatal).   
Relationship to Study drug:  
The Investigator will make an assessment of the causal relationship of the Study drug to the AE 
using the guidelines in Section 7.3.2.  
Severity:  
The severity of the AE will be assessed using the guidelines in Section 7.3.1. 
Outcome:   
The outcome of AEs will be recorded.   
Therapeutic measures:   
Measures taken for the treatment or management of the AEs will be recorded. 
7.4.3. 
SAE and AESI Reporting Timeline 
SAEs and AESIs will be reported to Clinical Safety and Pharmacovigilance within 24 hours of 
the time the Investigator or his/her designee becomes aware that a SAE or AESI has occurred, 
whether or not the event is considered to be related to Study drug.  If the initial SAE is reported 
by telephone, a written report signed by the Investigator must be submitted within 24 hours.   
The SAE/AESI Report Form must be completed in accordance with the SAE/AESI Report Form 
Completion Guidelines.  If all information on the SAE/AESI Report Form is not available at the 
time of the initial report, follow-up SAE/AESI reports will be completed and submitted.   
 
 




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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will be 
performed using 
 
Continuous data will be summarized using an 8-point descriptive summary (n, mean, standard 
deviation, median, interquartile range [25% quartile, 75% quartile]), minimum, and maximum) 
or a 7-point descriptive summary (n, mean, SD, coefficient of variation [CV], median, minimum, 
and maximum) unless otherwise specified. 
Categorical data will be summarized using counts and percentages. Percentages will be shown to 
1 decimal place and percentages for zero counts will be omitted. 
The Statistical Analysis Plan (SAP) and the table, figure, and listing shells will be finalized prior 
to database lock. Any changes to protocol-specified analyses will be described in the SAP. 
8.2. 
Sample Size 
The sample size will depend on the number of subjects who are eligible and elect to enter from 
the Maintenance Study of Protocol 0157. It is anticipated that approximately 500 subjects will 
receive TD-1473 for up to 156 weeks (3 years). 
8.3. 
Analysis Sets 
8.3.1. 
Analysis Sets 
The Safety analysis set, comprising all subjects receiving at least one LTS dose of TD-1473, will 
be the analysis set for all summaries except some enrollment summaries. 
8.3.2. 
Examination of Subgroups 
Subgroups to be defined in detail in the SAP for safety analysis purposes will include the 
following: 
• Males, females 
• Subgroups defined by age category, e.g., under 40 years of age, 40 to 64, 65 and over 
• Subgroups defined by geographic region, e.g., North America, Europe, other 
• Subgroups defined by steroid use 
Subgroups may also be defined in the SAP for efficacy endpoint summaries. 


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8.3.3. 
Major Protocol Analysis Deviations 
The following protocol deviations are considered major and as having (unless rare) a substantial 
effect on the interpretation of efficacy or safety results: 
 
 
 
 
 
 
Additional criteria may be specified in the SAP. Listings of all protocol deviations and of major 
analysis protocol deviations, as defined above and in the SAP, will be provided. 
8.4. 
General Analyses 
8.4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics including age, sex, race, ethnicity, creatinine 
clearance, weight, body mass index (BMI), UC characteristics, current UC medications by 
category, and other medical history will be summarized. 
8.4.2. 
Disposition 
An enrollment summary will be provided showing the following counts by previous study 
treatment and clinical status at enrollment: 
• Number of subjects eligible to enroll 
• Number who elected to enroll 
• Number who received at least one LTS dose 
Enrollment will also be summarized for subjects in the Safety analysis set by region and country, 
and by site, ordering sites by descending number of subjects dosed. 
For subjects in the Safety analysis set, a disposition summary will present the following counts: 
• Number of subjects who completed the Week 4 visit 
• Number who completed the Week 12 visit 
• Number who completed the Week 52 (1-yr) visit 
• Number who completed the Week 104 (2-yr) visit 
• Number who completed the Week 156 visit 
• Number who discontinued from the study prior to the Week 156 visit, overall and by 
reason for discontinuation 
Subjects who discontinue study drug prior to the Week 156 visit will complete an End of Study 
visit 4 weeks after their last dose of study drug. 








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8.6.1.1. 
Adverse Events of Special Interest 
A summary will be provided showing, overall and by arm, numbers of subjects who experienced 
events in each of the following categories: 
• Suspected or confirmed intestinal perforation 
• Complicated herpes zoster (multi-dermatomal, disseminated, or with ophthalmic or 
CNS involvement) 
• Malignancy excluding non-melanoma skin cancer 
• Non-melanoma skin cancer 
• Serious infection (e.g., that requires hospitalization or intravenous antibiotics) 
• Opportunistic infections 
• Thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism) 
• Clinical laboratory abnormalities of concern (Refer to Section 7.2) 
• Major cardiovascular event (e.g., myocardial infarction or cerebrovascular accident) 
For events in each category for which at least one event was reported, a time-to-event plot will 
be provided. Time 0 will be the time of the first TD-1473 dose, rather than the time of the first 
LTS TD-1473 dose. 
8.6.2. 
Concomitant Medications 
Medication names will be mapped according to the World Health Organization Drug Dictionary. 
The following summaries will be provided, by drug class and preferred name, overall and by 
arm: 
• UC medications ongoing at LTS study entry 
• Medications with indications other than UC ongoing at LTS study entry 
• Medications started or restarted during the LTS study, including those with indication 
for UC 
8.6.3. 
Laboratory Data 
Safety laboratory values and C-reactive protein values, changes from baseline, values relative to 
normal ranges, and clinical laboratory abnormalities of concern will be summarized by visit, 
overall and by arm. C-reactive protein,
total cholesterol, LDL, HDL, and 
triglycerides levels will be log-transformed for summarization. 
Reference ranges provided by the laboratory for each test will be used to evaluate the clinical 
significance of laboratory test results. Values falling outside the relevant reference range will be 
flagged, as appropriate, in the data listings. Clinical laboratory abnormalities of concern will be 
listed in a separate listing. A listing of pregnancy test results will be provided. 


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8.6.4. 
Vital Signs Data 
For each scheduled visit, vital signs summaries will include summary statistics for observed 
values and changes from baseline. Values above or below the following thresholds will be 
flagged. 
Table 3: 
Vital Signs Thresholds 
Heart Rate (bpm) 
Systolic Blood Pressure 
(mm Hg) 
Diastolic Blood Pressure 
(mm Hg) 
< 40 
< 85 
< 45 
> 110 
> 160 
> 100 
 
8.6.5. 
ECG Data 
HR, QT, QTcF, PR, and QRS values at each time point and changes from baseline at each time 
point after the first dose will be summarized, and counts and percentages will be shown for the 
following categories in Table 4. 
Table 4: 
Thresholds for ECG 
Heart 
Rate 
(bpm) 
Heart Rate Change 
from Baseline (bpm) 
PR 
 Interval 
(msec) 
PR Percent Change 
From Baseline (%) 
QRS 
Interval 
(msec) 
QTcF 
(msec) 
QTcF change from 
Baseline (msec) 
> 120 
≥ 20 
≥ 200 
≥ 15 
≥ 120 
Males: 
≤ 30 
> 130 
≥ 30 
≥ 220 
≥ 25 
 
≤ 430 
> 30, ≤ 60 
 
 
Optional: 
 
 
≥ 430 
> 60 
 
 
≥ 240 
 
 
≥ 450 
 
 
 
≥ 260 
 
 
≥ 470 
 
 
 
≥ 280 
 
 
≥ 480 
 
 
 
≥ 300 
 
 
≥ 500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
≤ 450 
 
 
 
 
 
 
≥ 450 
 
 
 
 
 
 
≥ 470 
 
 
 
 
 
 
≥ 480 
 
 
 
 
 
 
≥ 500 
 
 
A listing of subjects with extreme values or changes, as specified in the SAP (e.g., values of 
QTcF > 500 msec, QTcF increases from baseline > 60 msec) will be provided. 




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9. 
STUDY ADMINISTRATION 
This Study will be conducted in compliance with all applicable regulations. 
9.1. 
Principal Investigator Responsibilities 
Before beginning the Study, the principal investigator (PI) at each site must provide to the 
Sponsor or its designee a fully executed and signed Form FDA 01572 and, if applicable, a 
financial disclosure form. For applicable studies, financial disclosure forms must also be 
completed for all sub-investigators who will be directly involved in the treatment or evaluation 
of research subjects in this Study. (A sub-investigator is defined in ICH E6 as any individual 
member of the clinical Study team designated and supervised by the investigator at a Study site 
to perform critical Study-related procedures and/or to make important Study-related decisions 
[e.g., associates, residents, research fellows].) 
The PI will ensure the following: 
• He or she will conduct the Study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
• He or she will personally conduct or supervise the Study. 
• He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent and institutional review board 
(IRB) review and approval are met in accordance with 21 CFR, ICH guidelines, and 
all other applicable local regulations. 
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR, ICH guidelines, and all other applicable 
local regulations. He or she has read and understands the information in the TD-1473 
Investigator’s Brochure, including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the Study are informed 
about their obligations in meeting the above commitments. 
• He or she will ensure that adequate and accurate records are maintained and to make 
those records available for inspection in accordance with in 21 CFR, ICH guidelines, 
and all other applicable local regulations. 
• He or she will ensure that the IRB/IEC complies with the requirements of 
21 CFR Part 56, ICH guidelines and other applicable regulations, and conducts initial 
and ongoing reviews and approvals of the Study. He or she will also ensure that any 
change in research activity and all problems involving risks to human subjects or 
others are reported to the IRB/IEC. Additionally, he or she will not make any changes 
in the research without IRB/IEC approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. 


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• He or she agrees to comply with all other requirements regarding the obligations of 
clinical investigators and all other pertinent requirements in 21 CFR, ICH guidelines, 
and all other applicable local regulations. 
9.2. 
Institutional Review Board/Independent Ethics Committee 
Before beginning Study-specific research, the investigator will obtain written confirmation that 
the IRB, IEC, or Research Ethics Board (REB) is properly constituted and compliant with ICH 
and GCP requirements, applicable laws, and local regulations. A copy of the confirmation from 
the IRB/IEC/REB will be provided to the Sponsor or its designee. The protocol, informed 
consent form (ICF), IB, and any other appropriate written information provided to the subjects 
that the IRB/IEC/REB may require to fulfill its responsibilities will be submitted to the 
IRB/IEC/REB in advance of the Study. The Sponsor or its designee must approve the ICF and all 
subject recruitment materials before they are submitted to the IRB/IEC/REB. The Study will not 
proceed until appropriate documents from the IRB/IEC/REB confirming unconditional approval 
of the protocol and the ICF are obtained by the investigator and copies are received by the 
Sponsor or its designee. If possible, the approval document should refer to the Study by Study 
protocol title and the Sponsor Study number, identify the documents reviewed, and include the 
date of the review and approval. The written approval of the IRB/IEC/REB will be retained as 
part of the Study file. The Study may proceed before approval of consent forms and other Study 
documents translated to a language other than the native language of the clinical site, provided 
that written IRB/IEC/REB approval of the translated documents is obtained before they are used. 
Any amendments to the protocol should be reviewed promptly. 
The investigator must provide the appropriate periodic reports on the progress of the Study to the 
IRB/IEC/REB and the Sponsor in accordance with local IRB/IEC/REB requirements and 
applicable governmental regulations, whichever is strictest. 
9.3. 
Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (GCP Guideline, Section 4.8), 
21 CFR §50, and other applicable local regulations, will be obtained for each subject before 
enrollment of the subject into the Study. The investigator will prepare the ICF or revise the 
template ICF and provide the documents to the Sponsor (or designee) for approval before 
submission to the IRB/IEC/REB. The Sponsor and the IRB/IEC/REB must approve the 
documents before they are implemented. 
The investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the subject’s record file. 
9.4. 
Data Recording and Quality Assurance 
As used in this protocol, the term case report form (CRF) should be understood to refer to either 
a paper form or an electronic data record or both, depending on the data collection method used. 
Electronic data capture (EDC) technology will be used for this Study. All clinical information 
requested in this protocol will be recorded on the electronic case report forms approved by the 
Sponsor, or via other data collection methods, e.g., electronic laboratory data transfer. Study site 
personnel will enter (in English) Study data into the CRFs for each screened subject. Training on 


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the systems used by site personnel (e.g., EDC) or subjects (e.g., eDiary) will be completed and 
documented before access to the system is given. 
In the event of a CRF data change (e.g., correction of an error or addition of new information), 
corrections will be made to the CRF. Corrections to the CRFs, including the reason for change, 
will be automatically documented through the EDC system’s audit trail. 
The investigator is responsible for reviewing all CRFs, verifying them for accuracy, and 
approving them via an electronic signature. The investigator is designated as the signatory 
coordinating investigator. 
An electronic copy of the CRF casebooks, in-clinic assessments, and eDiary data will be sent to 
the site for retention with other Study documents after full completion of the Study, i.e., after 
database lock. 
The investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The investigator is also responsible for ensuring the availability of any 
original source documentation related to the Study (including any films, tracings, computer 
discs, tapes, and worksheets). In most cases the source is the subject’s medical record. Data 
collected on the CRFs must match the source documents. 
In some cases, the CRF may also serve as the source document. In these cases, a document 
should be available at the investigator’s site and clearly identify those data that will be recorded 
in the CRF and for which the CRF will stand as the source document. 
9.5. 
Document Retention 
Until otherwise notified by the Sponsor, an investigative site must retain in a controlled manner 
all Study documents required by the Sponsor and by the applicable regulations. The investigative 
site must take measures to prevent accidental or premature destruction of essential documents, 
that is, documents that individually and collectively permit evaluation of the conduct of a Study 
and the quality of the data produced, including paper copies of Study records (e.g., subject 
charts) and any original source documents that are electronic, as required by applicable 
regulations. 
The investigator must consult the Sponsor representative before disposal of any Study records 
and must notify the Sponsor of any change in the location or disposition of the Study files. If an 
investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping 
the Study documents, custody must be transferred to a person who will accept the responsibility. 
The Sponsor must be notified in writing of the name and address of the new custodian and must 
approve this transfer of responsibility. 
9.6. 
Confidentiality 
The investigator or designee must explain to each subject, before enrollment into the Study, that, 
for evaluation of Study results, the subject’s confidential medical information obtained during 
the Study may be shared with the Study sponsor, the Study sponsor’s affiliated companies, the 
Study sponsor’s designated service providers, regulatory agencies, and the institutional review 
board (IRB) or independent ethics committee (IEC). The investigator (or designee) is responsible 
for obtaining written permission to use confidential medical information in accordance with 


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country-specific regulations (such as the Health Insurance Portability and Accountability Act in 
the United States) from each subject. If permission to use confidential medical information is 
withdrawn, the investigator is responsible for documenting that no further data from the subject 
will be collected. 
Subject medical information obtained during this Study is confidential, and disclosure to 
unauthorized third parties is prohibited. The pertinent sections of data protection laws will be 
complied with in full. Study records containing subject information will only be identified by the 
subject identification number, subject initials, date of birth, and Study number, and not by the 
subject’s full name, except the subject consent form, which is archived at the Study center only. 
The subject’s name will not be used in any public report of the Study. 
During the course of the Study, a confidential subject identification list will be maintained by the 
investigator and archived at the investigative site. 
Before and during the conduct of the Study, no Study-related details may be disclosed, i.e., 
placed on the internet, published, or otherwise publicized, or provided to a third party without 
prior written permission from the Sponsor. The policy for publication of data after completion of 
the Study is described in Section 9.9 (Publication). 
9.7. 
Access to Data and Documents 
Upon receipt of the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. 
Study data recorded on the CRFs must be verifiable to the source data. All original recordings, 
laboratory reports, and subject records generated by this Study must be available to the Sponsor, 
representatives of the Sponsor, the IRB/IEC/REB, and applicable regulatory authorities, and they 
may be used for submission to regulatory authorities. In addition, all source data should be 
attributable (signed and dated), consistent with local medical practice. The investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to their 
medical records, and subjects will be informed of this and will confirm their agreement when 
giving informed consent. 
9.8. 
Quality Control: Study Monitoring and Auditing 
Qualified individuals designated by the Sponsor will monitor all aspects of the Study according 
to GCP and standard operating procedures (SOPs) for compliance with applicable government 
regulations. The investigator agrees to allow these monitors direct access to the clinical data and 
supplies, dispensing, and storage areas and, if requested, agrees to assist the monitors. The 
investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by the Sponsor or its designees. 
Members of the Sponsor’s GCP Quality Assurance Department or designees may conduct an 
audit of a clinical site at any time during or after completion of the Study. The investigator will 
be informed if an audit is to take place and advised as to the scope of the audit. Inspections and 
audits are typically carried out during the clinical and reporting phases of this Study to ensure 
that the Study is conducted, and data are generated, documented, and reported in compliance 
with the protocol, GCP, written SOPs and applicable laws, rules, and regulations. 


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Representatives of the FDA or other Regulatory Agencies, including IRB/IEC representatives 
may also conduct an audit of the Study. If informed of such an inspection, the investigator should 
notify the Sponsor immediately. The investigator will ensure that the auditors have access to the 
clinical supplies, Study site facilities, laboratory and all data (including original source 
documentation) and all Study files are available, if requested. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
investigator, institution, institution staff, or representatives of the Sponsor will lead to prompt 
action by the Sponsor to secure compliance. Continued noncompliance may result in termination 
of the investigator’s involvement in the Study. The IRB/IEC/REB and relevant regulatory 
authority will be informed. 
9.9. 
Publication 
The Sponsor recognizes the importance of communicating medical Study data and therefore 
encourages their publication in reputable scientific journals and presentation at seminars or 
conferences. The Sponsor will retain the ownership of the data collected in this Study. The 
investigator will provide any proposed manuscript or abstract to the Sponsor before submission 
for publication or presentation of any results or data obtained in this Study. 
Additional details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this Study will be described in the Clinical Study 
Agreement between the Sponsor and the investigator. 


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10. 
REFERENCES 
1. Crohn’s and Colitis Foundation of America, About the Epidemiology of IBD. 
http://www.ccfa.org/resources/epidemiology.html, Accessed on 19 October 2015 
2. Johnston RD, Logan RF, What is the peak age for onset of IBD? Inflamm Bowel Dis, 
2008. 14 Suppl 2: p. S4-5. 
3. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, Panaccione R, 
Ghosh S, Wu JCY, Chan FKL, Sung JJY, Kaplan GG.  Worldwide incidence and 
prevalence of inflammatory bowel disease in the 21st century: a systematic review of 
population-based studies.  Lancet. 2018 Dec 23;390(10114):2769-2778. doi: 
10.1016/S0140-6736(17)32448-0. Epub16 Oct. 2017 
4. Dyson JK and Rutter MD, Colorectal cancer in inflammatory bowel disease: what is the 
real magnitude of the risk? World J Gastroenterol, 2012. 18(29): p. 3839-48. 
5. Gunnarsson, C, et al., The employee absenteeism costs of inflammatory bowel disease: 
evidence from US National Survey Data. J Occup Environ Med, 2013. 55(4): p. 393-401. 
6. Kappelman MD, et al., Direct health care costs of Crohn's disease and ulcerative colitis in 
US children and adults. Gastroenterology, 2008. 135(6): p. 1907-13. 
7. Navarro F, SB Hanauer, Treatment of inflammatory bowel disease: safety and tolerability 
issues. Am J Gastroenterol, 2003. 98(12 Suppl): p. S18-23. 
8. Sandborn WJ, et al., Tofacitinib as Induction and Maintenance Therapy for Ulcerative 
Colitis. N Engl J Med, 2017. 376(18): p. 1723-1736. 
9. Banholzer ML, et al., Clinical trial considerations on male contraception and collection of 
pregnancy information from female partners. J Transl Med, 2012. 10: p. 129. 
10. Jairath V, et al., Development of interim patient-reported outcome measures for the 
assessment of ulcerative colitis disease activity in clinical trials. Aliment Pharmacol Ther, 
2015. 42(10): p. 1200-10. 
11. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, 
Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, 
Colombel JF.  Infliximab for induction and maintenance therapy for ulcerative colitis.  
N Engl J Med. 2005 Dec 8;353(23):2462-76. 
 
 


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APPENDIX 1. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:  
0164 
Protocol Title: 
A 3-Year, Multi-Center, Long-Term Safety (LTS) Study to Evaluate the 
Safety and Tolerability of TD-1473 in Subjects with Ulcerative Colitis 
(UC) 
Version: 
Amendment 2 
Version Date: 
15 February 2021 
 
 
I have read the protocol described above and agree to conduct this Study in accordance with 
procedures described therein.  I also agree to conduct the Study in compliance with all 
applicable regulations. 
 
 
 
Investigator’s Name (print) 
 
 
 
Investigator’s Signature 
 
Date 
 


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APPENDIX 2. COCKCROFT-GAULT CREATININE CLEARANCE 
CALCULATION 
Creatinine clearance (mL/min) will be estimated using the Cockcroft-Gault equation as follows:  
 
Estimated creatinine clearance = 
(140-Age) × Ideal Body Weight (kg) , if male 
72 × Serum Creatinine (mg/dL) 
Ideal body weight = 
50 kg + 2.3 kg for each 
2.54 cm over 152.4 cm 
, if male 
Estimated creatinine clearance = 
(140-Age) × Ideal Body Weight (kg) × 0.85, if female 
72 x Serum Creatinine (mg/dL) 
Ideal body weight = 
45.5 kg + 2.3 kg for each 
2.54 cm over 152.4 cm 
, if female 
 


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APPENDIX 6. GUIDELINE ALGORITHM FOR MONITORING, 
ASSESSMENT, AND EVALUATION OF ABNORMAL 
LIVER TESTS IN PARTICIPANTS WITH NO 
UNDERLYING LIVER DISEASE 
 
Abbreviations: AESI, adverse event of special interest; ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, 
international normalized ratio; IP, investigational product; LFT, liver function test; Tbili, total bilirubin; ULN, upper limit of 
normal


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Item 1 should be performed where “b” appears above; however, the complete work-up 
below (Items 1-5) should be performed in every situation where “c” appears above. Items 
6-7 are optional, to be considered on case-by-case basis. All tests should be reported with 
appropriate source documentation. The study medical monitor should be notified when 
the abnormalities are detected and provided with an update of the results of the 
diagnostic work-up. 
The following definition of patterns of Drug Induced Liver Injury (DILI) is used when directing 
the work-up for potential DILI based on elevations of common laboratory tests (LT): 
Histopathology 
LT 
Ratio 
(ALT/ULN)/(Alk Phos/ULN) 
Hepatocellular 
ALT ≥ 3 × ULN 
≥ 5 
Cholestatic 
ALT ≥ 3 × ULN 
≤ 2 
Mixed 
ALT ≥ 3 × ULN and AP ≥ 2 × ULN 
> 2 to < 5 
1. Obtain detailed history of present illness (abnormal LTs) including (if not already obtained at 
baseline) height, weight, body mass index (BMI). Assess for abdominal pain, nausea, 
vomiting, scleral icterus, jaundice, dark urine, pruritus, rash, fever, and lymphadenopathy. 
Assess for history of prior abnormal liver tests, liver disease including viral hepatitis, obesity, 
metabolic syndrome, congestive heart failure (CHF), occupational exposure to hepatotoxins, 
diabetes mellitus (DM), gallstone disease or family history of gallstone or liver disease. 
Specifically record history of alcohol use, other medications including acetaminophen, 
non-steroidal anti-inflammatory drugs (NSAID), over the counter (OTC) herbal supplements, 
vitamins, nutritional supplements, traditional Chinese medicines, and street drugs; and 
document whether or not there has been any recent change in any other prescription drugs 
and start-stop dates. Obtain travel history to endemic areas for hepatitis A, hepatitis E. Ask 
for history of any prior blood transfusions and when they were performed. Perform physical 
exam, obtain vital signs and BMI, and document presence or absence of scleral icterus, 
palpable liver including size, degree of firmness or tenderness, palpable spleen including 
size, ascites, and stigmata of chronic liver disease (spider angiomata, gynecomastia, palmar 
erythema, testicular atrophy). Allow free text in case report form for other relevant history 
and physical information. 
2. Mandatory liver ultrasound with consideration of further imaging (e.g., computerized 
tomography [CT], magnetic resonance imaging [MRI], magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography 
(ERCP), Doppler studies of hepatic vessels, etc., if indicated based on ultrasound findings or 
clinical situation). 
3. If total bilirubin (Tbili) is > 2 x ULN, request fractionation to document the fraction that is 
direct bilirubin and to rule out indirect hyperbilirubinemia indicative of Gilbert’s syndrome, 
hemolysis or other causes of indirect hyperbilirubinemia. Complete blood count (CBC) with 
white blood count (WBC) and eosinophil count platelet count, international normalized ratio 
(INR), and total protein and albumin (compute globulin fraction) should also be documented. 
If INR is abnormal, prothrombin time (PT), partial thromboplastin time (PTT) should be 


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obtained and these values should be followed until normal, along with documentation of 
whether parenteral vitamin K was given along with the effect of such treatment on INR. 
4. If initial LTs and ultrasound do not suggest Gilbert’s syndrome, biliary tract disease or 
obstruction, viral hepatitis serology should be obtained including anti-hepatitis A virus 
immunoglobin M (anti-HAV IgM), anti-HAV total, hepatitis B surface antigen (HBsAg), 
anti-HBs, anti-HB core total, anti-HB core IgM, anti-hepatitis C virus (anti-HCV), 
anti-hepatitis E virus IgM (anti-HEV IgM) (even if has not traveled to an endemic area for 
hepatitis E), Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) screen. 
− 
If patient is immunosuppressed, test for HCV RNA and HEV RNA. 
− 
If HBsAg or anti-HB core IgM or anti-HB core IgG positive, also get HBV DNA to 
detect active HepB, especially in patients who are immunosuppressed. 
− 
If all other hepatitis B serologic tests are negative and anti-HBc total is the only positive 
test, HBV DNA should be obtained to detect reactivation of hepatitis B. 
5. Assuming that the history, physical, and initial imaging and laboratory has not revealed a 
cause of elevated LTs, screen for other causes of liver disease including: Total protein and 
albumin (estimate globulin fraction and obtain quantitative immunoglobulins if elevated), 
antinuclear antibody (ANA), anti-liver kidney microsomal antibody type 1 (anti-LKM1), 
anti-liver-kidney microsomal antibodies (anti-LKM antibodies), anti-smooth muscle 
antibodies (ASMA), erythrocyte sedimentation rate (ESR), and 
 
If the pattern of laboratory abnormalities is not hepatocellular, but cholestatic or a mixed 
pattern (see definitions in table above), then gamma-glutamyl transferase (GGT), 
anti-mitochondrial antibody (AMA) and anti-neutrophil cytoplasmic antibody (pANCA) 
should also be tested. If there is an indication by history or elevated baseline LTs that there 
may be an underlying chronic liver disease possibly exacerbated by exposure to the study 
intervention in the clinical trial or making the participant more susceptible to DILI, test 
iron/Total iron binding capacity (TIBC) and ferritin (hemochromatosis), and alpha-1-
antitrypsin level. If patient is < 50 years of age, ceruloplasmin should also be tested to 
screen for Wilson’s disease. If patient is sick enough to be hospitalized and is under age 50, 
a slit lamp examination to detect Kayser-Fleischer rings and a 24-hour urine collection for 
copper should be measured. Consider serum ethanol and/or acetaminophen level and urine 
drug screen as clinically appropriate. 
6. A liver biopsy should be considered if autoimmune hepatitis remains a competing etiology 
and if immunosuppressive therapy is contemplated. 
A liver biopsy may be considered: 
− 
if there is unrelenting rise in liver biochemistries or signs of worsening liver function 
despite stopping the suspected offending agent. 
− 
if peak ALT level has not fallen by > 50% at 30-60 days after onset in cases of 
hepatocellular DILI, or if peak Alk P has not fallen by > 50% at 180 days in cases of 
cholestatic DILI despite stopping the suspected offending agent. 
− 
in cases of DILI where continued use or re-exposure to the implicated agent is expected. 


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Confidential – Property of Theravance Biopharma, Inc. 
 
− 
if liver biochemistry abnormalities persist beyond 180 days to evaluate for the presence 
of chronic liver diseases and chronic DILI. 
7. If pertinent, copies of hospital discharge summary, radiology, pathology and autopsy reports 
should be obtained. 
Abbreviations 
Abbreviation Definition 
AlkP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
anti-mitochondrial antibody 
ANA 
antinuclear antibody 
Anti-LKM1 
anti-liver kidney microsomal antibody type 1 
ASMA 
anti-smooth muscle antibodies 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CBC  
complete blood count 
CHF 
congestive heart failure 
CMV 
cytomegalovirus  
 
 
CT 
computerized tomography 
DM 
diabetes mellitus 
DNA 
deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
ERCP 
endoscopic retrograde cholangiopancreatography 
ESR 
erythrocyte sedimentation rate 
EOI 
end of intervention 
GGT 
gamma-glutamyltransferase 
HAV  
hepatitis A virus  
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HepB 
hepatitis B virus 
HEV 
hepatitis E virus 
IgM 
immunoglobin M 
INR 
international normalized ratio 
LT/LFT 
liver tests/liver function tests 
MRI 
magnetic resonance imaging 
MRCP 
magnetic resonance cholangiopancreatography 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over the counter 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RNA 
ribonucleic acid 
Tbili 
total bilirubin 
TIBC 
total iron binding capacity 
ULN 
upper limit of normal 
WBC 
white blood count 




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COVID-19-Related Exclusion 
The field of COVID-19-related testing (for presence of, and immunity to, the SARS-CoV-2 
virus) is rapidly evolving. Additional testing may be performed as part of Day 1 and/or during 
the study if deemed necessary by the investigator and in accordance with current regulations or 
guidance from authorities and standards of care.  
Documentation 
Document what relevant contingency measures are implemented, how restrictions related to 
COVID-19 led to changes to the study conduct, and how the study participant was impacted. 
Related documentation, either in source or systems (e.g., eCRF), should be labelled with the 
prefix “CV19.” Protocol deviations related to the pandemic should also be labeled as such with 
the “CV19” prefix.  
Activities that require the appropriate documentation include, but are not limited to, the 
following: 
•
Missed, delayed, or modified visits and/or assessments;
•
Study drug dosing modification, dosing interruptions, and discontinuation and
withdrawal from the study;
•
Other temporary measures such as those listed in this appendix;
•
If a participant is excluded from the study due to recent COVID-19-related elements,
the reason for screen failure should be documented in the CRF.

SAP_001.pdf: 
Protocol Number:  0164 
 
Official Title:  A 3-Year, Multi-Center, Long-Term Safety (LTS) Study to Evaluate the Safety and 
Tolerability of TD-1473 in Subjects with Ulcerative Colitis (UC) 
 
NCT Number: NCT03920254 
 
Document Date:  11 Nov 2021 


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STATISTICAL ANALYSIS PLAN 
 
Protocol Title:  
A 3-Year, Multi-Center, Long-Term Safety (LTS) Study 
to Evaluate the Safety and Tolerability of TD-1473 in 
Subjects with Ulcerative Colitis (UC) 
Protocol Number:  
0164 
Compound Number: 
TD-1473 
Short Title 
TD-1473 LTS UC Study 
 
 
Sponsor Name:  
Theravance Biopharma Ireland Limited 
Legal Registered Address: 
Theravance Biopharma Ireland Limited 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
 
EudraCT No. 
2018-002135-19 
 
   
 
This study will be conducted in compliance with Good Clinical Practice. 
 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be copied 
or provided to any other party without the express written consent of Theravance Biopharma, Inc 
 
© Theravance Biopharma (Unpublished Work). All rights reserved. 




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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
SAP VERSION HISTORY..............................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
1.1. 
Objectives and Endpoints .............................................................................................8 
1.1.1. 
Primary Objective .........................................................................................................8 
1.1.2. 
Secondary Objective .....................................................................................................8 
1.1.3. 
Exploratory Objectives .................................................................................................8 
1.2. 
Study Design .................................................................................................................8 
1.3. 
Treatment Assignment and Blinding ..........................................................................10 
1.4. 
Schedule of Assessments ............................................................................................12 
1.5. 
Sample Size Determination ........................................................................................15 
2. 
ANALYSIS SETS ......................................................................................................16 
3. 
STATISTICAL ANALYSES .....................................................................................17 
3.1. 
General Considerations ...............................................................................................17 
3.1.1. 
Baseline Definition .....................................................................................................17 
3.1.2. 
Study Day ...................................................................................................................17 
3.1.3. 
Visit Windows ............................................................................................................17 
3.1.4. 
Multiple Assessments .................................................................................................17 
3.1.5. 
Actual Treatment ........................................................................................................18 
3.2. 
Study Subjects ............................................................................................................18 
3.2.1. 
Enrollment ..................................................................................................................18 
3.2.2. 
Subject Disposition and Completion Status ...............................................................18 
3.2.3. 
Demographic and Baseline Characteristics ................................................................18 
3.2.4. 
Protocol Deviations ....................................................................................................19 
3.2.5. 
Medical History ..........................................................................................................19 
3.2.6. 
Prior/Concomitant Medications ..................................................................................19 
3.3. 
Primary Analyses ........................................................................................................19 
3.4. 
Safety Analyses ..........................................................................................................19 
3.4.1. 
Extent of Exposure .....................................................................................................19 
3.4.1.1. 
Treatment Compliance ................................................................................................20 


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3.4.2. 
Adverse Events ...........................................................................................................20 
3.4.2.1. 
Adverse Events of Special Interest .............................................................................21 
3.4.3. 
Additional Safety Assessments...................................................................................21 
3.4.3.1. 
Clinical Laboratory Parameters ..................................................................................21 
3.4.3.2. 
Vital Signs ..................................................................................................................22 
3.4.3.3. 
Electrocardiogram .......................................................................................................22 
3.5. 
Other Analyses ............................................................................................................23 
3.5.1. 
Other Variables and/or Parameters .............................................................................23 
3.5.2. 
Subgroup Analyses .....................................................................................................23 
3.6. 
Interim Analyses .........................................................................................................23 
3.6.1. 
Data Monitoring Committee .......................................................................................24 
4. 
REFERENCES ...........................................................................................................25 
5. 
SUPPORTING DOCUMENTATION ........................................................................26 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses .................................................26 
5.2. 
Appendix 2: Data Conventions and Transformations ................................................26 
5.2.1. 
Derived and Transformed Data ..................................................................................26 
5.2.1.1. 
Study Day ...................................................................................................................26 
5.2.1.2. 
Change from Baseline .................................................................................................26 
5.2.1.3. 
BMI .............................................................................................................................26 
5.2.2. 
Missing Data Imputation ............................................................................................26 
5.2.2.1. 
Missing/Incomplete AE/Start Date .............................................................................26 
5.2.2.2. 
Missing/Incomplete AE/Medication End Date/Time .................................................27 
5.2.2.3. 
Missing/Incomplete Start for Medication ...................................................................27 
5.2.2.4. 
Laboratory Data ..........................................................................................................27 
5.2.2.5. 
AE Severity .................................................................................................................28 
 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................6 
Table 2: 
SAP Version History Summary ....................................................................................7 
Table 3: 
Dosing Regimen in the LTS Study .............................................................................10 
Table 4: 
Schedule of Study Procedures ....................................................................................13 
Table 5: 
Criteria for Marked Abnormalities in Vital Signs ......................................................22 
Table 6: 
ECG Interval Categories .............................................................................................23 
 
 
 
LIST OF FIGURES 
 


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LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
AESI 
adverse event of special interest 
BMI 
body mass index 
CRF 
case report form 
 
 
CSR 
clinical study report 
DMC 
data monitoring committee 
LOD 
limit of detection 
LTS 
Long-term safety 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
preferred term 
RTSM 
randomization and trial supply management 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TESAE 
treatment emergent serious adverse event 
UC 
ulcerative colitis 
WHODD 
World Health Organization Drug Dictionary 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) outlines the planned summarization and analysis of clinical 
data collected in the long-term safety (LTS) study of Protocol 0164 for TD-1473. Specifications 
for tables, figures, and data listings are contained in a separate document. 
The results of the planned analyses will be presented in a synoptic clinical study report (CSR) 
which will include analyses of study subject data and safety endpoints. Inferential statistical tests 
will not be performed. The protocol-planned efficacy analyses will be excluded as they are not 
necessary for a synoptic CSR. 
The 0164 study was terminated early due to lack of efficacy in the 0157 study, for all subjects 
the date of last dose occurred by 09SEP2021 and the end of study visit by 11OCT2021. 
The analysis of pharmacokinetics data (derivation and summarization of individual PK 
parameters) is outside the scope of this document and is not addressed here. 
This document describes the a priori plan for analysis. Any substantive modification to this 
analysis plan will be identified in the CSR. 
Information in the appendices to the SAP are not considered a formal section of the signed SAP. 
1.1. 
Objectives and Endpoints 
1.1.1. 
Primary Objective 
The primary objective of the study is as follows: 
 To assess the safety and tolerability of TD-1473 administered up to 3 years in subjects 
with moderate to severe ulcerative colitis (UC) after participation in the Maintenance 
Study of Protocol 0157. 
1.1.2. 
Secondary Objective 
Not applicable for the synoptic CSR. 
1.1.3. 
Exploratory Objectives 
Not applicable for the synoptic CSR. 
1.2. 
Study Design 
This LTS Study 0164 will utilize a multi-center, parallel-group design to evaluate the safety of 
long-term TD-1473 treatment in subjects with moderate to severe UC rolling over from Protocol 
0157 for up to 3 years. 
Subjects eligible for the study are those who are rolling over from Protocol 0157 Maintenance 
Study who meet all inclusion and no exclusion criteria, including having achieved clinical 
response during an Induction Study and during the Maintenance Study who: 
a) demonstrate persistent 
 loss of response (no improvement 
for approximately 6 to 8 weeks after meeting loss of response criteria despite more time 
on study drug and potentially concurrent rescue medication) 


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OR 
b) have repeated (two) Clinical Flares after an episode 
 
 
OR 
c) complete the Maintenance Study and confirmation of clinical remission status results are 
available 
 
 
All subjects will receive active drug at three dose levels of 20 mg, 80 mg and 200 mg, and thus, 
this study will not be placebo-controlled, but blinding as to the specific dose of TD-1473 will be 
maintained. The dosing regimen for subjects (Table 3) entering the Long-Term Study from the 
Maintenance Study will be based on: 
1. The subject’s clinical remission status from Protocol 0157 upon entry into the LTS Study 
2. The subject’s study drug assignment during the Protocol 0157 Maintenance Study. 
Subjects entering the LTS Study after completing the Maintenance Study in clinical remission on 
active drug will continue with the same dose of TD-1473. Subjects entering the LTS Study after 
completing the Maintenance Study in clinical remission on placebo will be placed on 20 mg. 
Subjects who enter the LTS Study not in clinical remission on TD-1473 upon completion of the 
Maintenance Study and subjects who exit the Maintenance study prematurely due to persistent 
loss of response or recurrent clinical flare with loss of response (also not in clinical remission) 
will receive an escalated dose in the LTS Study, based on their Maintenance Dose. Subjects on 
20 mg and 80 mg of TD-1473 will be dose-escalated one level up to 80 mg and 200 mg, 
respectively. Subjects on the highest dose (200 mg) will remain on the highest dose. Placebo 
subjects entering the LTS Study not in remission will be dose escalated to 80 mg. 
The dose assigned to subjects entering the LTS is thus partially dependent on the clinical 
remission status upon entry. For subjects completing the Maintenance Study in remission on 
active drug, continuing on the same dosing regimen will potentially allow for maintenance of 
clinical benefit and continued assessments for maintenance of response/remission. For subjects 
on TD-1473 entering LTS with persistent loss of response or recurrent clinical flare after loss of 
response, dose escalation in LTS may allow for the possibility of achieving clinical benefit and 
even recapture of clinical response at a potentially higher dose than that administered during the 
Maintenance Study. For placebo subjects entering LTS not in clinical remission, dose escalation 
to 80 mg would potentially allow for achievement of clinical response or remission. For placebo 
subjects entering LTS in clinical remission, escalation to 20 mg would potentially allow for a 
higher likelihood of maintenance of clinical remission. 
After the global, last subject study visit (including the 4 week follow up visit), an analysis of 
safety data will be performed. 
No interim analyses are planned for this study. 
 


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1.3. 
Treatment Assignment and Blinding 
The dosing regimen and schedule for this study are as follows: 
 TD-1473 20 mg (2 x 10 mg tablets) once daily: Taken orally for up to 3 years in the 
morning. With the exception of clinic visit days, subjects will be instructed to take two 
tablets once daily at approximately the same time each morning. 
 TD-1473 80 mg (2 x 40 mg tablets) once daily: Taken orally for up to 3 years in the 
morning. With the exception of clinic visit days, subjects will be instructed to take two 
tablets once daily at approximately the same time each morning. 
 TD-1473 200 mg (2 x 100 mg tablets) once daily: Taken orally for up to 3 years in the 
morning. With the exception of clinic visit days, subjects will be instructed to take two 
tablets once daily at approximately the same time each morning. 
Maintenance of the Blind 
In order to maintain the blind in subjects whose treatment is known once database lock has 
occurred for the Maintenance Study, a firewall will be maintained ensuring that Sponsor 
employees who are aware of treatment assignments will not have contact with site personnel. 


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In order to maintain the study blind, the study medications will have a label containing the study 
name, Kit ID number, and reference number. The KIT ID number will be automatically entered in 
the case report form (CRF) when the drug is dispensed. The study medications will be identical in 
appearance and packaging. 
The investigator will not be provided with randomization codes. The codes will be maintained 
within the Randomization and Trial Supply Management System (RTSM), which has the 
functionality to allow the investigator to break the blind for an individual subject. The date and 
reason for the unblinding will be documented in the appropriate section of the CRF and in the 
source document. The documentation received from the RTSM indicating the code break will be 
retained with the subject's source documents in a secure manner. Subjects who had their treatment 
assignment unblinded by the investigator will be discontinued from study medications. 
Data that may potentially unblind the treatment assignment (i.e., study medication, plasma 
concentrations and treatment allocation) will be handled by the use of subject aliases at the 
Bioanalytical Lab that conducts initial data analyses to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized when transferring said information to the 
Sponsor.  
 
  
Treatment assignment blinding will be maintained for investigative sites, site monitors, and 
subjects participating in this protocol until the analyses for the study have been completed.  
An independent DMC will regularly review unblinded safety data. The committee and its 
statistical support group will have access to unblinded treatment information. They will not 
divulge any information to the Sponsor that may potentially unblind an individual subject’s 
treatment group. 
 
 


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1.4. 
Schedule of Assessments  






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1.5. 
Sample Size Determination 
The sample size will depend on the number of subjects who are eligible and elect to enter from 
the Maintenance Study of Protocol 0157. Prior to study termination it was anticipated that 
approximately 500 subjects will receive TD-1473 for up to 156 weeks (3 years). 


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2. 
ANALYSIS SETS 
The Safety analysis set, comprising all subjects receiving at least one LTS dose of TD-1473, will 
be the analysis set for all summaries except some enrollment summaries. 
 
 


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3. 
STATISTICAL ANALYSES 
3.1. 
General Considerations  
All individual data will be listed as measured. All statistical summaries and analyses will be 
performed using SAS software (SAS Institute, Cary, North Carolina, USA). 
All data from scheduled and unscheduled visits will be presented in the subject listings. 
However, unless noted otherwise, only data from scheduled/windowed visits will be included in 
the summaries, statistical analysis, and calculation of derived parameters. 
Summary tables and listings (e.g., post text tables and individual subject data listings are 
prepared according to ICH Guideline E3) include a “footer” providing explanatory notes. 
Continuous data will be summarized using an 8-point descriptive summary (n, mean, standard 
deviation, median, interquartile range [25% quartile, 75% quartile]), minimum, and maximum) 
unless otherwise specified. 
Categorical data will be summarized using counts and percentages. Percentages will be shown to 
1 decimal place and percentages for zero counts will be omitted. 
For safety assessments, summary statistics will be reported by treatment. 
3.1.1. 
Baseline Definition 
In general, the baseline value for efficacy variables and for safety variables is the value 
associated with the last available pre first dose visit/time point at which the variable was to be 
collected according to the schedule of study procedures, and must have been collected pre-dose. 
3.1.2. 
Study Day 
If the date of interest occurs on or after the first dose/randomization date, then study day will be 
calculated as (date of interest – date of first dose) + 1.  
If the date of interest occurs prior to the first dose/randomization date, then study day will be 
calculated as (date of interest – date of first dose). 
3.1.3. 
Visit Windows 
The visit indicated on the CRF will be used in summaries of the data.  
3.1.4. 
Multiple Assessments 
In general, if multiple, valid, non-missing observations exist at a visit or collection time point 
then records will be chosen based on the following:  
• The record closest to the nominal time point in question. 
If 2 records are equidistant: 
• The later record of the two visits.  
If 2 records with same date/time 
• Average (generally applies to assessments done in triplicate). 


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There is a special rule for laboratory test results: if there are multiple valid records within the 
visit window for the same visit or time point, the record(s) with the latest collection time will be 
selected rather than the record(s) with collection time closest to the nominal time. The protocol 
states that: 
Additional and repeat laboratory safety testing for the evaluation of abnormal results and/or 
adverse events during the Study may be performed at the discretion of the investigator or upon 
request of the Sponsor. 
Hence, the latest laboratory test result associated with a visit or time point will be selected for 
summarization. All results will be provided in listings. 
3.1.5. 
Actual Treatment 
Data will be summarized by actual treatment group which will be determined by the treatment 
that was dispensed at the Day 1 visit. 
3.2. 
Study Subjects 
3.2.1. 
Enrollment  
Not applicable for the synoptic CSR. 
3.2.2. 
Subject Disposition and Completion Status 
A summary of study disposition will be provided by study treatment on the Safety analysis set 
showing the following: 
 Number of subjects enrolled 
 Number of subjects treated 
 Number of treated subjects who completed the study 
 Number of treated subjects who discontinued early from the study 
 Primary reasons for early study discontinuation, with frequencies 
 Number of treated subjects who completed treatment 
 Number of treated subjects who discontinued treatment early 
 Primary reasons for early treatment discontinuation, with frequencies 
A listing of subject disposition will include Safety analysis set flag [Yes/No], dates of first and 
last dose of study drug, primary reason for subject discontinuation of study treatment, study 
completion status, primary reason for study termination, and date of last contact. 
3.2.3. 
Demographic and Baseline Characteristics 
Demographic data including age, sex, race, ethnicity, weight, height, and body mass index (BMI) 
will be summarized overall and by treatment group. Sex, race, and ethnicity frequency 
distributions will be provided. 


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3.2.4. 
Protocol Deviations 
The number and percentage of subjects reporting important protocol deviations will be 
summarized overall and by treatment group for the Safety analysis set. Important protocol 
deviations are defined in the protocol deviation plan. 
A listing of all important protocol deviations will be provided. 
3.2.5. 
Medical History 
Medical and surgical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), version 24.0 or later. A listing of medical history coded to each system 
organ class and preferred term for each subject will be provided. 
3.2.6. 
Prior/Concomitant Medications 
Prior medications include all medications taken prior to the first dose of study drug, regardless of 
when they were stopped. Concomitant medications include all nonstudy medications that the 
subject was taking prior to the Day 1 visit that were ongoing at the visit, in addition to all 
medications with a start date on or after the first dose date and no later than the last dose 
date + 28 days. Medications with a start date after the last dose date + 28 days will be included in 
a listing of concomitant medications with a flag. 
Recorded prior and concomitant medication names will be mapped according to 
 
 
 
3.3. 
Primary Analyses 
The primary objective is to assess the safety and tolerability of TD-1473 administered up to 3 
years in subjects with moderate to severe UC after participation in the Maintenance Study of 
Protocol 0157. The analyses for this objective are outlined in Section 3.4 Safety Analyses. No 
efficacy endpoints are considered primary endpoints. 
3.4. 
Safety Analyses 
The analysis of safety data includes an overall summary of adverse event preferred terms by 
body/organ system, drug exposure (duration of treatment), dosing information/compliance, 
clinical laboratory results, vital signs and ECGs. Tables summarizing the adverse events reported 
by subjects who died, experienced non-fatal serious adverse events (SAE), or prematurely 
discontinued the study due to adverse event (AEs) will be prepared. Summaries of potentially 
clinically notable laboratory results and vital sign abnormalities are presented. 
Inferential statistical tests will not be performed for adverse event incidence rates. 
For all safety analyses, the safety analysis population will be used. 
3.4.1. 
Extent of Exposure 
Study drug exposure will be summarized using the 8-point descriptive summary presenting 
number of doses and duration of treatment for the study. 


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Duration of treatment will be displayed in days and calculated as: 
𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 −𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒 +  1 
Calculated values will be rounded to 1 significant digit in the analysis datasets. 
3.4.1.1. 
Treatment Compliance 
Study drug compliance will be calculated as: 
 100 ×  0.5 × (𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑 − 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑) 
(𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 − 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 +  1)
 
Study drug compliance over the interval from first to last dose will be summarized as a 
continuous variable and by rounding to the nearest 0.1% and showing counts and percentages for 
the following disjoint categories: ≥ 120%; 110% to 120%; 90% to 110%; 80% to 90%; < 80%. 
Study drug administration information (date/time and study day) will be provided in a data 
listing. Study drug accountability information and study drug exposure and compliance will also 
be provided in data listings. 
Study drug discontinuations and reasons for study drug discontinuation will be listed. 
3.4.2. 
Adverse Events 
Adverse events (AEs) will be coded to the preferred terms (PT) of the Medical Dictionary for 
Regulatory Activities (MedDRA®). Summaries will be presented by system organ class (SOC), 
preferred term, and severity and/or relatedness, the number and percentage of subjects for whom 
events were reported. 
Adverse events (AEs) are recorded from signing of the informed consent form through the final 
follow-up assessment. Adverse events observed prior to first dose are non-treatment emergent. 
Treatment emergent adverse events are defined as follows: 
 TEAEs are AEs with onset on or after the first initiation of study drug up to the date 
of last dose of study drug + 28 days. 
Only treatment-emergent AEs will be summarized in the tables. A listing of all TEAEs by 
subject will be provided.  
An AE will be considered a treatment emergent serious AE (TESAE) if it is a TEAE that 
additionally meets any SAE criteria. 
If more than 1 AE is coded to the same preferred term for the same subject, the subject will be 
counted only once for that preferred term using the most severe and most related occurrence for 
the summarizations by severity and by relationship to study drug. 
Summary tables will also be provided for subjects with: 
 TESAEs by SOC and PT 
 TEAEs leading to discontinuation of study drug by SOC and PT 
 TEAEs leading to temporary interruption of study drug by SOC and PT 


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 TEAEs by severity and by SOC and PT 
 Drug related TEAEs by severity and by SOC and PT 
Listings of all AEs, SAEs, AEs resulting in death, and AEs leading to discontinuation by subject 
will be presented. 
An overall summary of adverse events will also be presented and will include the following 
summary lines: Any AE, Moderate or Severe AEs, AEs Related to Study Drug, Moderate or 
Severe AEs Related to Study Drug, Serious AEs, Serious AEs Related to Study Drug, AEs 
Leading to Premature Study Drug Discontinuation, AEs Leading to Temporary Interruption of 
Study Drug, and Deaths During Study.  
3.4.2.1. 
Adverse Events of Special Interest 
An AE of special interest (AESI) is one of scientific and medical interest specific to 
understanding the investigational product and may require close monitoring and rapid 
communication by the investigator to the sponsor. The following are the AESI’s defined for the 
study: 
 Suspected or Confirmed Intestinal Perforation 
 Complicated Herpes Zoster (multi-dermatomal, disseminated, or with ophthalmic or 
CNS involvement) 
 Malignancy excluding non-melanoma skin cancer 
 Non-melanoma skin cancer 
 Serious Infection (e.g., that requires hospitalization or intravenous antimicrobials) 
 Opportunistic Infections 
 Thromboembolic disease (e.g. deep vein thrombosis, pulmonary embolism) 
 Clinical Laboratory Abnormalities of Concern 
 Major Cardiovascular Event (e.g. myocardial infarction or cerebrovascular accident) 
The incidence of AESI’s will be summarized overall and by AESI category and preferred term. 
3.4.3. 
Additional Safety Assessments 
3.4.3.1. 
Clinical Laboratory Parameters 
Laboratory data, hematology, serum chemistry and urinalysis, will be summarized in terms of 
observed values and changes from baseline.  In addition, changes from baseline relative to 
normal ranges from the central lab (e.g., shifts from normal to abnormal high/low) will be 
summarized. 
The number and percentage of subjects with clinically abnormal lab values will also be 
summarized by timepoint for the following criteria:  
 absolute neutrophil count of < 1.0 x 109/L 


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 white blood cell count of < 2.0 x 109/L  
 absolute lymphocyte count of < 0.5 x 109/L 
A listing of all abnormal lab values will be provided. 
3.4.3.2. 
Vital Signs 
Descriptive statistics for vital signs (heart rate, systolic and diastolic blood pressures, respiratory 
rate, and body temperature) and changes from baseline values at each visit and at the end of 
study will be presented by treatment group. 
The number and percentage of subjects with marked abnormalities as defined in Table 5 will be 
summarized and flagged in a listing of all vital signs values. 
Table 5: 
Criteria for Marked Abnormalities in Vital Signs 
Heart Rate (bpm) 
Systolic Blood Pressure 
(mm Hg) 
Diastolic Blood Pressure 
(mm Hg) 
< 40 
< 85 
< 45 
> 110 
> 160 
> 100 
 
3.4.3.3. 
Electrocardiogram 
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS interval, QT interval, and 
QTcF) and changes from baseline values at each assessment time point to the end of study will 
be presented by treatment group. The QTcF will be calculated using the Fridericia correction. 
All recorded values for the standard 12 lead electrocardiogram parameters will be presented in a 
by-subject listing. 
Categorical Analyses 
The number and percentage of subjects with absolute ECG values and change from baseline in 
the ranges shown in Table 6 will be presented in Electrocardiogram Categorical Summary by 
Visit and Time Point. 
Subjects without a postbaseline measurement for a given treatment period will be excluded from 
the summary statistics (e.g., denominator of the summary statistic) for that time point. 
In addition, in the same summary, QTcF will also be summarized by the following categories, 
Normal (males < 430, females ≤ 450), Borderline (males (> 430, ≤ 450); females (> 450, ≤ 470)) 
and Prolonged (males > 450, females > 470). 
Individual ECG data collected during the study will be presented in a listing. A separate listing 
of subjects with values of QTcF > 500 msec or an increase > 60 msec will be provided, as 
necessary. 


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Table 6: 
ECG Interval Categories 
Heart Rate 
(bpm) 
Heart Rate 
Change 
from 
Baseline 
(bpm) 
PR 
 Interval 
(msec) 
PR 
Percentage 
Change 
from 
Baseline 
(%) 
QRS 
 Interval 
(msec) 
QTcF 
(msec) 
QTcF 
change 
from 
Baseline 
(msec) 
> 120 
≥ 20 
≥ 200 
≥ 15 
≥ 120 
Males: 
≤ 30 
> 130 
≥ 30 
≥ 220 
≥ 25 
 
< 430 
>30, ≤ 60 
 
 
 
 
 
≥ 430 
> 60 
 
 
 
 
 
≥ 450 
 
 
 
 
 
 
≥ 470 
 
 
 
 
 
 
≥ 480 
 
 
 
 
 
 
≥ 500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
< 450 
 
 
 
 
 
 
≥ 450 
 
 
 
 
 
 
≥ 470 
 
 
 
 
 
 
≥ 480 
 
 
 
 
 
 
≥ 500 
 
3.5. 
Other Analyses 
Not applicable for the synoptic CSR. 
3.5.1. 
Other Variables and/or Parameters 
Not applicable for the synoptic CSR. 
3.5.2. 
Subgroup Analyses 
Not applicable for the synoptic CSR. 
3.6. 
Interim Analyses 
No interim analysis is planned for this study but the database lock for the Maintenance Study 
Protocol 0157 will occur prior to the end of the study. 
Blinding 
Bias in safety evaluation will be minimized through partial dose-blinding. The dose will be 
blinded however it will be known to all parties that all subjects are on TD-1473. In the case of 
subjects completing the Maintenance Study, the investigator will have firsthand observation of 
remission status but initially remain blinded to the precedent dose assignment in Maintenance. 


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Thus, the specific dose assignment in LTS for Maintenance completers in remission will not be 
known to investigator, Sponsor, or subject. The dose assignment in LTS for subjects who enter 
without completing the Maintenance Study or who complete the Maintenance Study but are not 
in remission is also partially dose-blinded, as the consent form will include the treatment 
assignment scheme and all subjects will be assigned to an escalated dose from their preceding 
Maintenance TD-1473 dose. Once the database lock and unblinding have occurred in the 
precedent Maintenance Study Protocol 0157, the prior dose assignment may be disclosed. 
3.6.1. 
Data Monitoring Committee 
 
 
 
 
 
 


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4. 
REFERENCES 
SAS Institute Inc. 2017. Base SAS® 9.4 Procedures Guide, Seventh Edition. Cary, NC: SAS 
Institute Inc. 
 
  
 
 


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5. 
SUPPORTING DOCUMENTATION 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses  
The protocol-planned efficacy analyses are not required for the synoptic CSR. 
5.2. 
Appendix 2: Data Conventions and Transformations  
5.2.1. 
Derived and Transformed Data 
5.2.1.1. 
Study Day 
If the date of interest occurs on or after the first dose/randomization date, then study day will be 
calculated as (date of interest – date of first dose/randomization) + 1. 
If the date of interest occurs prior to the first dose/randomization date, then study day will be 
calculated as (date of interest – date of first dose/randomization). 
There is no Study Day 0. 
5.2.1.2. 
Change from Baseline 
Change from baseline is calculated as (postbaseline result – baseline result). 
Percent change from baseline is calculated as (change from baseline/baseline result) × 100 or 
equivalently as 100 × (postbaseline value/baseline value - 1). 
If either the baseline or the postbaseline result is missing, the change from baseline and 
percentage change from baseline values are missing. 
5.2.1.3. 
BMI 
BMI is calculated as: 





2
2
/
.
weight kg
BMI kg m
height m

 
5.2.2. 
Missing Data Imputation  
5.2.2.1. 
Missing/Incomplete AE/Start Date 
Imputation of dates with missing day and/or month is only applied to TEAEs. TEAE start dates 
with missing day or month will be imputed as follows: 
 If day and month are missing but year is available, then the imputed day and month will be 
01 Jan [with a time of 00:00 if applicable] or first study drug dose date if they have the 
same year, whichever is later (because TEAE onset is not expected prior to administration 
of study treatment) 
 If day is missing but the month and year are available, then the imputed day will be the 
first day of the month [with a time of 00:00 if applicable] or the first study drug dose date 
if they have the same month and year, whichever is later. 


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5.2.2.2. 
Missing/Incomplete AE/Medication End Date/Time 
Imputation of dates with missing day and/or month is only applied to TEAEs when AE duration 
is calculated. TEAE end dates with missing day or month will be imputed as following: 
 If day and month are missing but year is available, then the imputed day and month will 
be 31 Dec [with a time of 23:59 if applicable] or the date and time of last study drug dose 
if they have the same year, whichever is earlier 
 If day is missing but the month and year are available, then the imputed day will be the 
last day of the month [with a time of 23:59 if applicable] or the date and time of the last 
study dose if they have the same month and year, whichever is earlier. 
5.2.2.3. 
Missing/Incomplete Start for Medication 
To determine whether medications were used prior to initiation of dosing and whether they were 
used after initiation of dosing, missing or partial dates for medications will be imputed according 
to the following rule: 
Missing medication start date/time: 
 If day and month are missing but year is available, then the imputed day and month 
will be 31 Dec [with a time of 23:59 if applicable] or the study exit date if they have 
the same year, whichever is earlier. 
 If day is missing but the month and year are available, then the imputed day will be 
the first day [or 1 minute after midnight if applicable] of the month or the first dose 
date if they have the same month and year, whichever is later. 
 If day, month and years are completely missing, impute as date and time of first dose 
if 1) end date is not missing and occurs on and after date of first dose, or 2) end date 
is missing but marked as “ongoing”. 
5.2.2.4. 
Laboratory Data 
For non-efficacy laboratory data, a missing baseline value will be replaced with the last available 
assessment, generally the screening assessment. A retest value will be used if the original test 
result is invalid, e.g., specimen hemolyzed. 
Laboratory data that are continuous in nature but are less than the lower limit of 
quantitation/limit of detection (LOD) will be, in general, imputed as follows: 
 A value that is 1 unit less than the LOD will be used for calculation of descriptive 
statistics if the data are reported in the form of “< x” (x is considered as the LOD).  
More specifically, x−1 is used for data summarization if the data are reported in the 
form of “< x”; and x.e where e = d−1, will be used for analysis if the data are reported 
in the form of “< x.d”. 
Laboratory data that are continuous in nature and above the upper limit of quantitation/limit of 
detection (LOD) will be, in general, imputed as follows: 
 A value that is 1 unit more than the LOD will be used for calculation of descriptive 
statistics if the data are reported in the form of “> x” (x is considered as the LOD).  


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More specifically, x+1 is used for data summarization if the data are reported in the 
form of “> x”; and x.e where e = d+1, will be used for analysis if the data are reported 
in the form of “< x.d”. 
5.2.2.5. 
AE Severity 
For graded adverse event summaries, AEs with no grade reported will be graded as severe.