Clinical trial NCT03635112
Conditions: Crohn's Disease
Keywords: TD-1473 Janus kinase inhibitor JAK inhibitor Inflammatory Bowel Disease IBD Crohn's Disease Intestinal restriction
Sponsor: Theravance Biopharma
Start date: 2018-11-19; Completion date: 2021-12-30
Enrollment: 167 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 study to evaluate the efficacy, safety and tolerability of TD-1473 in subjects with moderately-to-severely active Crohn's Disease with up to 48 weeks of treatment.

Detailed description:
A Phase 2 multi-center, randomized, double blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of 12 weeks of induction therapy with TD˗1473 in subjects with moderately-to-severely active Crohn's Disease. This study includes 3 phases: Screening, Induction, and Active Treatment Extension (ATE). The Induction phase of the study is a randomized, double blind, placebo controlled, parallel group study evaluating 2 oral dose levels of TD-1473 compared to placebo for 12 weeks in subjects with moderately to-severely active CD. Subjects who complete Induction will continue to receive TD-1473 in the ATE, for up to 48 additional weeks.

Arms: arm 1: 1 oral Dose A daily of TD-1473 for 12 weeks in subjects with moderately to-severely active CD.

Subjects who complete Induction will continue to receive TD-1473 at Dose A in the Active Treatment Arm for up to 48 additional weeks. arm 2: 1 oral Dose B daily of TD-1473 for 12 weeks in subjects with moderately to-severely active CD.

Subjects who complete Induction will continue to receive TD-1473 at Dose B in the Active Treatment Arm for up to 48 additional weeks. arm 3: 1 oral dose daily of placebo for 12 weeks in subjects with moderately to-severely active CD.

Subjects who complete Induction will receive TD-1473 at Dose A in the Active Treatment Arm for up to 48 additional weeks.
Interventions: intervention 1: Placebo intervention 2: TD-1473
Intervention descriptions: intervention 1: Placebo will be taken daily by mouth (orally) for up to 12 weeks in the morning before eating. intervention 2: TD-1473, at Dose A or Dose B depending upon arm, will be taken daily by mouth (orally) for up to 12 weeks in the morning before eating. An additional 48 weeks either at Dose A or Dose B, depending on arm, may be administered if subjects finish the 12 week induction period.

Protocol documents:
Prot_000.pdf: 
Protocol Number: 0173 
 
Official Title: A Phase 2 Multi-Center, Randomized, Double-Blind, Placebo˗Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of Induction Therapy with 2 Doses of TD-1473 in Subjects with 
Moderately-to-Severely Active Crohn’s Disease 
 
NCT Number: NCT03635112 
 
Document Date:  09 June 2020 


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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2 Multi-Center, Randomized, Double-Blind, 
Placebo˗Controlled, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Induction Therapy with 2 Doses of TD-1473 in 
Subjects with Moderately-to-Severely Active Crohn’s Disease 
Study Short Title: 
DIONE - Efficacy and Safety of TD-1473 in Crohn’s Disease 
Sponsor Study No.: 
0173 
Date: 
09 June 2020, 
 
 
 
 
 
 
Test Product: 
TD-1473 
US IND: 
139354 
EudraCT No.: 
2018-001272-37 
Sponsor: 
Theravance Biopharma Ireland Limited 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
Clinical Study Director: 
 
 
Theravance Biopharma US, Inc. 
 
 
 
 
 
 
CRO 24 Hour Study 
Support Center: 
Telephone: 
 
 
 
Facsimile: 
 
 
This study will be conducted according to the principles of 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, Inc. (Unpublished Work). All rights reserved. 


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Confidential – Property of Theravance Biopharma, Inc. 
 
PROTOCOL SYNOPSIS 
Study Number and Title:  Study 0173: A Phase 2 Multi-Center, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Induction 
Therapy with 2 Doses of TD˗1473 in Subjects with Moderately-to-Severely Active Crohn’s 
Disease 
Study Short Title:  DIONE - Efficacy and Safety of TD-1473 in Crohn’s Disease 
Estimated Number of Study Centers and Countries or Regions: 
 
 
Background and Rationale:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS (CONTINUED) 
 
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Objectives:   
The primary objectives of the study are as follows: 
• To assess the effect of TD-1473 compared to placebo in improving Crohn’s Disease 
Activity Index (CDAI) score at Week 12 in subjects with moderately-to-severely 
active CD 
• To assess the safety and tolerability of TD-1473 
The secondary objectives of the study are to assess the effects of TD-1473 given for 12 weeks 
compared to placebo as follows: 
• To induce clinical remission  
• To induce clinical response 
• To induce endoscopic response 
• To improve the Simplified Endoscopy Score for Crohn’s Disease (SES-CD) 
Study Design: This study includes 3 phases: Screening, Induction, and Active Treatment 
Extension (ATE). Screening is up to 5 weeks long. The Induction phase of the study is a 
multi-center, randomized, double-blind, placebo-controlled, parallel-group study evaluating 
2 dose levels of TD-1473 (80 mg or 200 mg; approximately 60 subjects per dose level) 


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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
compared to placebo (approximately 40 subjects) for 12 weeks in subjects with 
moderately-to-severely active CD. Subjects who complete the Induction phase will continue to 
receive TD-1473 in ATE, either at 80 mg or 200 mg, for up to 48 additional weeks.  
Screening: 
To determine eligibility, subjects will undergo assessments during the Screening period 
(up to 35 days prior to Day 1 dosing) as outlined in the Schedule of Study Procedures 
(Table 1). Disease activity will be assessed by the clinical scores, based on symptoms reported 
on a daily diary, which will be captured electronically (or on a paper diary if electronic diary is 
not available) beginning the day after Screening Stage 1.  
Subjects who meet all inclusion (with the exception of the endoscopic subscore criterion) and 
no exclusion criteria, as described in Section 4.1 and Section 4.2, respectively, will undergo 
ileocolonoscopy with biopsies to complete Screening Stage 2. The aim of this endoscopic 
exam is to assess the SES-CD score by central reading and to obtain biopsies.  
Induction: 
If the subject meets all eligibility criteria, the subject may be randomized into one of the 
following 3 treatment groups in a 3:3:2 ratio: TD-1473 80 mg, TD-1473 200 mg, or placebo.  
The randomization will be stratified by prior biologics failure (as defined in Appendix 4) and 
CDAI score category (≤ 300, > 300) at the Screening Stage 2 visit. Approximately 40-60% of 
subjects randomized will have failed prior treatment with biologics. There will be a cap for 
enrollment of subjects once one of the biologics stratum reaches 60% (failure, not failure). 
Subjects will be treated for 12 weeks and assessed for the various endpoints, including those 
that incorporate findings from an ileocolonoscopy and biopsies at the Week 12 visit. 
Corticosteroids will start to be tapered at Week 8 with the tapering regimen described in 
Section 6.4.30.  
Subjects will undergo clinic study visits every 4 weeks in accordance with Table 1. During 
this time, subjects will continue to fill out a daily diary. 
Active Treatment Extension: 
All subjects who complete Induction at the Week 12 visit will continue into ATE, where 
subjects will be treated with either 80 mg or 200 mg of TD-1473 for 48 weeks. Dose during 
ATE depends on treatment assignment during Induction (Figure 1 and Table 2): those who 
were dosed with TD-1473 during Induction will stay on the same dose; those who were dosed 
with placebo during Induction will be dosed with TD-1473 at 80 mg.  
During ATE, subjects will undergo clinic study visits every 4-12 weeks in accordance with 
Table 1. Subjects will continue to complete a daily diary. 
Corticosteroids will continue to be tapered during ATE with the tapering regimen 
recommended in Section 6.4.30. Subjects who have not shown clinical improvement 
(as assessed by the investigator) 16 weeks after initiation of ATE (i.e., ATE Week 16) will be 
discontinued from the study following completion of an End of Study (EOS) visit.  


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PROTOCOL SYNOPSIS (CONTINUED) 
 
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End of Study (EOS) Visit: 
An EOS visit will be required for all subjects 4 weeks following their last dose of study drug. 
Subjects who complete an Early Study Drug Discontinuation visit during Induction or ATE 
will also be required to return for an EOS visit. Subjects will continue to complete a daily 
diary through the last day of the study participation. 
Duration of Study Participation:  Individual subject participation may require up to 
69 weeks: including up to 5 weeks for Screening, 12 weeks of treatment (TD-1473 or placebo) 
in Induction, 48 weeks of TD-1473 treatment during ATE, and 4 weeks of follow-up. 
Number of Subjects per Group:  Approximately 160 subjects (approximately 60 in each of 
the two TD-1473 dose groups and approximately 40 in the placebo group).  
Study Population: 
Subjects with moderately-to-severely active CD [as defined by a CDAI score of 220-450 and 
SES-CD score of ≥ 6 (≥ 4 if isolated ileal disease) with ulceration (corresponding to a score 
of ≥1) in at least 1 of the 5 ileocolonic segments on the Presence of Ulcers subscore of the 
SES-CD] who are corticosteroid-dependent or have demonstrated inadequate response, or 
intolerance to conventional therapy (aminosalicylates, corticosteroids and immunomodulators 
such as azathioprine, 6-mercaptopurine, or methotrexate) or biologics (e.g., anti-TNF therapy, 
anti-IL-12/23, anti-integrin). A subset of subjects (up to approximately 10%) will have an 
SES-CD score between 3 and 5 points, inclusive.  
Inclusion Criteria: 
100. 
Subject is willing and able to provide written, signed informed consent at Screening 
Part 1 prior to start of any study-related procedures 
101. 
Subject is a male or female at least 18 years of age at the time of Screening 
102. 
Subject has a diagnosis of CD with involvement of at least the ileum or any portion 
of the colon at a minimum, diagnosed by radiology, endoscopy, and/or histology at 
least 3 months prior to Screening. The report of a previous diagnostic exam 
(endoscopy, radiology, and/or pathology) must be reviewed by the investigator and 
included in the source documents.  
103. 
Subjects must have up-to-date colorectal cancer screening as per locally adopted 
guidelines (e.g., if subject has had ≥ 8 years of disease involving >30% of the 
colon, surveillance biopsies or chromoendoscopy should be performed if either is 
indicated as per locally adopted guidelines but has not been performed within the 
12 months prior to Screening). If indicated, the surveillance biopsies (if ≥ 10) and 
chromoendoscopy need to be performed during Screening Stage 2 ileocolonoscopy 
after recording of a full ileocolonoscopy has been completed to avoid dye or 
biopsy-related bleeding artifact on the recorded images. 


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104. 
Subject has CDAI score ≥ 220 and ≤ 450  
105. 
Subject has a SES-CD score of ≥ 3 with ulceration (corresponding to a score of ≥1) 
in at least 1 of the 5 ileocolonic segments on the Ulcerated Surface subscore of the 
SES-CD, as assessed by central reading, during Screening 
a. Up to approximately 10% of the study population will have SES-CD score of 
between 3 and 5, inclusive, with the presence of ulceration in any 1 of the 5 
ileocolonic segments, all other subjects (approximately 90% of the study 
population) will require an SES-CD score of ≥ 6 (≥ 4 if isolated ileal disease) 
with ulceration (corresponding to a score of ≥1) in at least 1 of the 5 ileocolonic 
segments on the Ulcerated Surface subscore of the SES-CD 
106. 
Subject is corticosteroid-dependent or had intolerance or inadequate response to 
any of the following: aminosalicylates, corticosteroids, immunomodulators 
(azathioprine, 6-mercaptopurine, or methotrexate), or biologics (anti-TNF anti-IL-
12/IL-23 therapy, or anti-integrin) [Refer to Appendix 10] 
NOTE: For subjects in Portugal, subject must have had intolerance or inadequate 
response to biologics 
107. 
If subject is currently receiving an oral corticosteroid, subject is eligible if:  
a. the subject has been on corticosteroid for a minimum of 4 weeks prior to Day 1 
AND 
b. the dose is equivalent to or less than prednisone 25 mg/day or budesonide 
9 mg/day or beclomethasone at 5 mg/day AND 
c. the dose is stable for at least 2 weeks prior to Screening Stage 2 AND  
d. the subject is willing to continue on the same dose as warranted until Week 8 
108. 
If subject is currently receiving oral aminosalicylate (including, but not limited to 
sulfasalazine or mesalamine), the subject is eligible provided the subject has been 
on a stable dose for ≥ 4 weeks prior to Day 1 and is willing to stay on the same 
dose as warranted until Week 12 
109. 
If subject is on antibiotics or probiotics for CD, subject must have been on the same 
dose for at least 2 weeks before Screening Stage 2 with stable symptoms and is 
willing to remain on the same dose as warranted until Week 12 
110. 
If subject has recently discontinued oral corticosteroids, these must have been 
stopped at least 2 weeks before endoscopy during Screening Stage 2 visit 
111. 
During the Study and for 7 days after receiving the last dose of the Study drug, 
females of childbearing potential or males capable of fathering children must agree 
to use highly effective birth control measures (failure rate <1% when used 
consistently and correctly) or agree to abstain from sexual intercourse. Females of 
childbearing potential must test negative for pregnancy at Screening and at Day 1 
(Refer to Section 4.3). 


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112. 
All male subjects must agree to refrain from semen donation during the study and 
for 7 days after the last dose of study drug 
113. 
Subject has completed the daily diary at least 5 out of 7 days prior to Screening 
Stage 2  
114. 
Subject is able to communicate effectively with the investigator, and willing and 
able to comply with the study procedures, requirements and restrictions, and 
directions of the clinic staff 
Exclusion Criteria: 
Exclusion Criteria Pertinent to GI:  
300. 
Subject with current symptoms or signs suggestive of intestinal perforation, 
intra-abdominal or pelvic abscess, symptomatic internal fistulae, abdominal wall 
fistulae, or symptomatic stricture 
301. 
Subject with a diagnosis of indeterminate colitis, ulcerative colitis, microscopic 
colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, 
or suspected ulcerative colitis 
302. 
Subject with a confirmed or suspected diagnosis or history of primary sclerosing 
cholangitis (PSC) 
303. 
Subject is likely to require bowel surgery or any other type of major surgery 
(e.g., requiring general anesthesia) during the study duration 
304. 
Subject has had extensive colonic resection (i.e., more than half of colon), subtotal 
or total colectomy, intestinal resection within 6 months of Screening, > 2 small 
bowel resections or carries a diagnosis of short bowel syndrome or currently has an 
ostomy 
305. 
Subject has a history of unresected colonic mucosal dysplasia or history of resected 
high-grade colonic dysplasia within 3 years prior to Screening. Subjects will not be 
excluded from the study because of a pathology finding of indefinite dysplasia with 
reactive atypia or because of adenomas that have been completely resected 
306. 
Subject has required enteral feeding via feeding tube or parenteral alimentation 
within 21 days prior to Day 1 
Exclusion Criteria Pertinent to Medications:  
400. 
Medications of exclusion (
 
) below must be discontinued within the timeframe specified 
(if applicable)  
• azathioprine, 6-mercaptopurine, or methotrexate taken within the 14 days prior 
to Day 1 


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• anti-TNFs (e.g., adalimumab, infliximab, golimumab, etanercept, certolizumab, 
or biosimilars) taken within the 60 days or 5 half-lives, whichever is longer, 
prior to Day 1 
• intravenous corticosteroids within the 14 days prior to Day 1 
• rectal mesalamine or corticosteroid (i.e., enemas or suppositories) taken within 
the 14 days prior to Day 1 
• prior exposure to vedolizumab, ustekinumab, mycophenolic acid, tacrolimus, 
sirolimus, or cyclosporine taken within 60 days or 5 half-lives, whichever is 
longer, prior to Day 1 
• any prior exposure to natalizumab, rituximab, efalizumab, fingolimod, 
cyclophosphamide, or thalidomide 
• NSAIDs taken on a regular (more than 3 times per week, on average) basis 
(regular use of aspirin ≤ 325 mg per day for cardiovascular protection is 
allowed). 
• anakinra or any other immune-modifying biologic agent taken within 90 days 
prior to Day 1 
• A JAK inhibitor (e.g., tofacitinib) within 60 days prior to Day 1 
Note: For anti-TNFs, vedolizumab, and ustekinumab, there is no requirement for a 
washout period if there is documented finding of undetectable drug level by a 
validated assay (e.g., through commercially available testing). 
401. 
Prior exposure or potential exposure to a JAK inhibitor that was stopped due to 
intolerance or lack of efficacy. This does not include subjects with prior exposure 
to another JAK inhibitor that was stopped for any other reason (e.g., loss/lack of 
insurance coverage or end of study)  
402. 
Subject has participated in another clinical trial of an investigational drug 
(or medical device) within 30 days prior to Screening or 5x the half-life of the 
investigational drug, whichever is longer, or is currently participating in another 
trial of an investigational drug (or medical device) 
403. 
Subject had inadequate response (i.e., either primary or secondary non-response) to 
≥ 3 biologic agents of 3 different mechanisms of action (i.e., anti-TNF, anti-
integrin, and anti-IL12/23) 
404. 
Subject is currently taking or has taken within 14 days prior to Day 1 any 
concomitant medication, herbal supplement, or dietary substance (e.g., grapefruit) 
known to be a strong inhibitor or inducer of P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), or CYP3A4 or is a substrate of P-gp or BCRP and has a 
narrow therapeutic index (
 For 


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clarity, corticosteroids at doses not excluded elsewhere in the protocol are not 
considered potent inducers of CYP3A4, P-gp, or BCRP 
405. 
Subject is taking non-CD concomitant prescription medications that have started or 
have had a dose adjustment within 4 weeks prior to Day 1 (with the exception of 
corticosteroids as discussed in inclusion criterion #107, antibiotics for recent 
infections, sedating agents for ileocolonoscopy, hormonal contraceptives, hormone 
replacement therapy, vitamin D, insulin therapy, and replacement thyroid hormone 
- see Section 6.4.29) 
406. 
Subject is taking non-CD over-the-counter medications or dietary supplements that 
have started or have had a dose adjustment within 2 weeks prior to Day 1 (with the 
exception of up to 3 times per week use of non-steroid anti-inflammatory drugs or 
acetaminophen used on an as needed basis, aspirin up to 325 mg per day for 
cardiovascular prophylaxis, and over-the-counter doses of vitamin D - see 
Section 6.4.29) 
Exclusion Criteria Pertinent to Infections: 
500. 
Subject is positive for:  
a. hepatitis B virus (HBV) surface antigen  
b. hepatitis B virus core antibody (unless subject has positive hepatitis B surface 
antibody and undetectable serum hepatitis B DNA) 
c. hepatitis C virus (HCV) antibody unless: a) there is evidence of undetectable 
viral load measured twice six months apart after completion of treatment 
regimen and b) viral load during Screening is undetectable 
d. hepatitis E Immunoglobulin M (IgM) antibody 
e. human immunodeficiency virus (HIV) antibody 
501. 
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, 
or any investigational live vaccine) within 4 weeks prior to Screening and/or is 
unwilling or unable to avoid live viral vaccines during the study and for 8 weeks 
following completion of the study; 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 
502. 
The subject has or may have untreated active or latent TB as evidenced by any of 
the following: 
a. Two indeterminate or two positive QuantiFERON®-TB Gold result within 
90 days prior to screening or during the Screening Period, without having 
completed an adequate treatment for latent or active TB before Screening OR 
b. Chest X-ray or equivalent chest imaging within 90 days prior to Screening in 
which active or latent pulmonary TB cannot be excluded. 
Refer to Section 6.4.15 for rationale and required documentation for repeat 
testing. 


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A subject who has a history of latent or active tuberculosis (TB) may be 
eligible for the study if criteria outlined in Section 6.4.15 are met.  
503. 
Subject has: 
a. an active, clinically significant bacterial, parasitic, fungal, mycobacterial 
(including atypical infection), or viral infection, except for local skin or nail 
bed infection, within 30 days prior to Day 1 
b. any infection requiring hospitalization or intravenous antibiotics within 30 days 
prior to Screening 
c. any infection requiring oral antimicrobial treatment within 2 weeks prior to 
Screening 
d. a history of more than one episode of herpes zoster or one or more episodes of 
disseminated or complicated herpes zoster (complicated: multi-dermatomal, 
ophthalmic, or CNS involvement or post-herpetic neuralgia) or disseminated 
herpes simplex 
504. 
Subject has had a chest X-Ray or equivalent chest imaging performed within the 
90 days prior to Screening or at Screening that shows an abnormality suggestive of 
a malignancy or current active infection, including TB, chronic lung disease or a 
potentially active fungal, viral, or bacterial infection    
505. 
Subject has C. difficile or other gastrointestinal infections (e.g., Salmonella, 
Shigella, Yersinia, Campylobacter, E. coli O157, etc.) on stool testing or 
cytomegalovirus [CMV] colitis suspected on endoscopic appearance during 
Screening. Subject may be treated, re-tested, and re-screened. 
506. 
Subject has had a bone marrow transplant 
507. 
Within 4 weeks of Screening or during Screening, subject has: 
a. Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection (coronavirus disease 2019 [COVID-19]) (test positive), OR 
b. 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 
c. 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 
Coexisting Medical Conditions or Past Medical History Exclusion Criteria: 
600. 
Subject is a female who is pregnant, lactating, breastfeeding or planning to become 
pregnant during the study or within 7 days after the last dose of study drug 
601. 
Subject is a male who is planning to father a child or donate semen during the study 
or within 7 days after the last dose of study drug 


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602. 
Subject has clinically significant abnormalities in the results of laboratory 
evaluations at Screening visit as determined by the investigator or Sponsor, 
including but not limited to:   
• AST, ALT, or alkaline phosphatase ≥ 2x the upper limit of normal (ULN),  
• total bilirubin > 2x ULN (unless diagnosed with Gilbert’s syndrome, in which 
case, total bilirubin > 4x ULN),  
• creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min 
(Appendix 1),  
• 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. 
603. 
Subject has a clinically significant abnormal ECG at Screening, including 
QTcF > 450 msec for males and > 470 msec for females  
604. 
Subject has 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 CD), genitourinary, psychiatric, oncologic or 
neurological disease or other medical disorder that would compromise subject 
safety or confound study safety assessments as determined by the investigator at 
Screening and Day 1. 
 
 In addition, subjects with 
a prior history of thrombotic events, including deep vein thromboses (DVT), and 
those with known inherited conditions that predispose to hypercoagulability should 
be excluded. 
605. 
Subject has known hypersensitivity to excipients or contents of the study drug  
606. 
Subject has a history of alcohol or drug abuse within 1 year of Screening, per the 
judgment of the investigator 
607. 
Subject with a current or history of malignancy within 5 years prior to Screening, 
except for completely resected basal cell carcinoma or squamous cell carcinoma in 
situ of the skin, or cervical carcinoma in situ that has been adequately treated and 
without recurrence for ≥ 5 years. Subjects with a history of cervical dysplasia 
within 3 years prior to screening or who currently have unresected cervical 
dysplasia should be excluded. 
608. 
Subject who, for any reason, is deemed by the investigator or Sponsor to be 
inappropriate for this study; or has any condition which would confound or 


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interfere with the evaluation of the safety, tolerability, or PK of the investigational 
drug; or is unable or unwilling to comply with the study protocol 
609. 
Subject with known moderate to severe hepatic impairment (e.g., known 
Child-Pugh Class B or C) 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment: 
Induction: 
• TD-1473 80 mg QD: given orally for up to 12 weeks in the morning before eating. 
Subject must refrain from eating or drinking anything other than water and non-study 
medications for at least 30 minutes after dosing. 
• TD-1473 200 mg QD: given orally for up to 12 weeks in the morning before eating. 
Subject must refrain from eating or drinking anything other than water and non-study 
medications for at least 30 minutes after dosing. 
Active Treatment Extension: 
• TD-1473 80 mg QD: given orally for up to 48 weeks in the morning before eating. 
Subject must refrain from eating or drinking anything other than water and non-study 
medications for at least 30 minutes after dosing 
• TD-1473 200 mg QD: given orally for up to 48 weeks in the morning before eating. 
Subject must refrain from eating or drinking anything other than water and non-study 
medications for at least 30 minutes after dosing. 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment:   
Induction: 
• Placebo QD: given orally for up to 12 weeks in the morning before eating. Subject 
must refrain from eating or drinking anything other than water and non-study 
medications for at least 30 minutes after dosing. 


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Study Evaluations 
Safety Assessments: 
Subject safety will be assessed throughout the study using standard safety measures, including 
vital signs, 12-lead ECGs, blood and urine laboratory tests, physical examinations, 
concomitant medication usage, and adverse event (AE) monitoring. 
Efficacy Assessments: 
• CDAI score 
• SES-CD 
• 
 
• 
 
• Stool Frequency and Abdominal Pain (SFAP) 
• 
  
• 
 
• 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 


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Statistical Methods: 
Efficacy endpoints will be evaluated using the following hypothesis testing schema: Each 
TD-1473 dose will be compared with placebo. The null hypothesis for the treatment 
comparison will be that there is no difference between a given dose of TD-1473 and placebo. 
The alternative hypothesis will be that there is a difference.  
Sample Size: 
Assuming that the less effective TD-1473 dose results in a 45-point improvement in 
placebo-adjusted CDAI score change at Week 12, the more effective dose results in a 60-point 
improvement, the residual SD is 100 points, and a sample size of 160 subjects with 60 subjects 
in each of the active dose groups and 40 subjects in the placebo group, 100,000 simulations 
performed using SAS/IML software yielded the following power estimates for 2-sided testing 
with the familywise Type I error rate controlled at 5% using the Hochberg -step-up procedure: 
• 82% power to show at least one of the two doses effective 
• 58% power to show both doses effective 
The target effect size of 60 points was selected as predictive of a clinically significant increase 
in clinical response rate. Of note, the study is not powered for the secondary endpoints. 
Study Efficacy Endpoints: 
The primary endpoint is: 
• CDAI score change from baseline at Week 12 
The secondary endpoints are: 
• CDAI clinical response (defined as reduction from baseline of ≥ 100 points or 
CDAI < 150) at Week 12 
• CDAI clinical remission (defined as CDAI < 150) at Week 12 
• SES-CD change from baseline at Week 12 
• Endoscopic response (SES-CD reduction of ≥ 50% from baseline or endoscopic 
remission) at Week 12 
• SFAP clinical remission defined as abdominal pain score ≤ 1 (on a scale of 0-3), 
stool frequency ≤ 2.8, and both not worse than baseline at Week 12 
Study Safety Endpoints: 
• Changes from baseline in vital signs, ECGs, and clinical laboratory results 
• Incidence and severity of AEs 
 


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PROTOCOL SYNOPSIS (CONTINUED) 
 
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Analysis: 
The primary analysis set for efficacy analyses will be a modified Intent-to-Treat (mITT) 
set: all randomized subjects who received study drug and had at least one postbaseline CDAI 
score. Efficacy data will be summarized by randomized treatment. The primary analysis set for 
general and safety analyses will be the Safety set: all randomized subjects who received study 
drug. Safety data will be summarized by treatment received. 
Continuous endpoints including score change will be analyzed by fitting analysis of 
covariance (ANCOVA) models which include terms for treatment, stratification factors, and 
baseline score as covariate. Mixed effects model repeated measures analyses will be used to 
analyze efficacy endpoints assessed at multiple postbaseline time points. Confidence intervals 
for means and mean differences with nominal confidence level 95% will be calculated by 
methods which will be specified in the Statistical Analysis Plan (SAP). 
Binary efficacy endpoint rates will be compared using stratified Cochran-Mantel-Haenszel 
tests, stratifying by randomization stratum. Subjects with missing binary outcome will be 
counted as treatment failures. Confidence intervals for rates and rate differences with nominal 
confidence level 95% will be calculated by methods which will be specified in the SAP. 
Logistic regression models may be fitted for selected endpoints to evaluate dose-response 
curves. 
A Hochberg step-up procedure will be used for hypothesis testing of the primary efficacy 
endpoint and the family-wise Type I error rate will be controlled at 5%. All comparisons will 
be 2-sided. 
Safety data will be listed by subject and summarized by received treatment, showing subject 
counts for event data and means, medians, etc. for measurements. 
Listings and summaries will be provided for demographics (age, sex, ethnicity, and race), 
baseline characteristics including baseline disease characteristics (e.g., extent of disease, 
duration of disease, complications) and treatment history, adverse events, laboratory tests, vital 
signs, and ECG data. Concomitant medications will be listed and summarized by received 
treatment. 
 


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Table 1: 
Schedule of Study Procedures 
Procedures 
Screening 
Period 
Treatment Period 
Early 
Study 
Drug 
Discontin-
uation A 
End of 
Study B 
(4 weeks 
post last 
study drug 
dose) 
Induction 
(Day 1 to Week 12) 
Active Treatment Extension 
(ATE Day 1 to ATE Week 48) 
Study Day/Week 
Day -35 to -1 
Day 
1 
W4 
W8 
W10 
W12 C 
ATE 
Day 1 D 
ATE 
W4 
ATE 
W8 
ATE 
W16 E 
ATE 
W24 
ATE 
W36 
ATE 
W48 
 
 
Stage 
1 
Stage 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hour Post-
dose/Window 
 
 
- 3 to + 5 
days 
0 to + 7 
days 
0 to + 
3 days  
1 – 7 days 
after W12  
- 3 to + 5 days 
0 to + 5 
days 
- 3 to + 5 
days 
General Procedures and Safety Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/ 
Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication/Medical 
History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco Use Status 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
F 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray G 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X H 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
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Table 1: 
Schedule of Study Procedures 
Procedures 
Screening 
Period 
Treatment Period 
Early 
Study 
Drug 
Discontin-
uation A 
End of 
Study B 
(4 weeks 
post last 
study drug 
dose) 
Induction 
(Day 1 to Week 12) 
Active Treatment Extension 
(ATE Day 1 to ATE Week 48) 
Study Day/Week 
Day -35 to -1 
Day 
1 
W4 
W8 
W10 
W12 C 
ATE 
Day 1 D 
ATE 
W4 
ATE 
W8 
ATE 
W16 E 
ATE 
W24 
ATE 
W36 
ATE 
W48 
 
 
Stage 
1 
Stage 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hour Post-
dose/Window 
 
 
- 3 to + 5 
days 
0 to + 7 
days 
0 to + 
3 days  
1 – 7 days 
after W12  
- 3 to + 5 days 
0 to + 5 
days 
- 3 to + 5 
days 
Study Drug 
Dispensing 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug Dosing I 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense Electronic 
Diary J 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corticosteroid Dosing 
Taper (if applicable) K 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
Telephone Call L 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
-------------------------------------------------------------------------------------------X--------------------------------------------------------------------------------------------- 
Adverse Event 
Assessment M 
-------------------------------------------------------------------------------------------X----------------------------------------------------------------------------------------------- 
Laboratory Assessments 
Pregnancy Test 
(females of 
childbearing potential 
only) N 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH O 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
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Table 1: 
Schedule of Study Procedures 
Procedures 
Screening 
Period 
Treatment Period 
Early 
Study 
Drug 
Discontin-
uation A 
End of 
Study B 
(4 weeks 
post last 
study drug 
dose) 
Induction 
(Day 1 to Week 12) 
Active Treatment Extension 
(ATE Day 1 to ATE Week 48) 
Study Day/Week 
Day -35 to -1 
Day 
1 
W4 
W8 
W10 
W12 C 
ATE 
Day 1 D 
ATE 
W4 
ATE 
W8 
ATE 
W16 E 
ATE 
W24 
ATE 
W36 
ATE 
W48 
 
 
Stage 
1 
Stage 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hour Post-
dose/Window 
 
 
- 3 to + 5 
days 
0 to + 7 
days 
0 to + 
3 days  
1 – 7 days 
after W12  
- 3 to + 5 days 
0 to + 5 
days 
- 3 to + 5 
days 
Chemistry, 
Hematology 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Overnight Fasting 
Lipid Panel 
 
X P  
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Viral hepatitis and 
HIV Serology Panel 
X Q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Test 
(QuantiFeron) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ileocolonoscopy and 
Biopsies 
 
X R 
 
 
 
 
X C 
 
 
 
 
 
 
 
 
 
Fecal Sample for 
Infectious Studies S 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
  


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
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Table 1: 
Schedule of Study Procedures 
Procedures 
Screening 
Period 
Treatment Period 
Early 
Study 
Drug 
Discontin-
uation A 
End of 
Study B 
(4 weeks 
post last 
study drug 
dose) 
Induction 
(Day 1 to Week 12) 
Active Treatment Extension 
(ATE Day 1 to ATE Week 48) 
Study Day/Week 
Day -35 to -1 
Day 
1 
W4 
W8 
W10 
W12 C 
ATE 
Day 1 D 
ATE 
W4 
ATE 
W8 
ATE 
W16 E 
ATE 
W24 
ATE 
W36 
ATE 
W48 
 
 
Stage 
1 
Stage 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hour Post-
dose/Window 
 
 
- 3 to + 5 
days 
0 to + 7 
days 
0 to + 
3 days  
1 – 7 days 
after W12  
- 3 to + 5 days 
0 to + 5 
days 
- 3 to + 5 
days 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Blood Sample 
(Optional – only 
collected for subjects 
who provide genetic 
testing consent) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessments 
CDAI Score 
 
X V 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
SES-CD Score 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Fistula Drainage 
Status (yes/no to 
active drainage), if 
fistula is present 
X 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
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Table 1: 
Schedule of Study Procedures 
Procedures 
Screening 
Period 
Treatment Period 
Early 
Study 
Drug 
Discontin-
uation A 
End of 
Study B 
(4 weeks 
post last 
study drug 
dose) 
Induction 
(Day 1 to Week 12) 
Active Treatment Extension 
(ATE Day 1 to ATE Week 48) 
Study Day/Week 
Day -35 to -1 
Day 
1 
W4 
W8 
W10 
W12 C 
ATE 
Day 1 D 
ATE 
W4 
ATE 
W8 
ATE 
W16 E 
ATE 
W24 
ATE 
W36 
ATE 
W48 
 
 
Stage 
1 
Stage 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hour Post-
dose/Window 
 
 
- 3 to + 5 
days 
0 to + 7 
days 
0 to + 
3 days  
1 – 7 days 
after W12  
- 3 to + 5 days 
0 to + 5 
days 
- 3 to + 5 
days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Diary 
Completion and 
Compliance Review J 
X 
X 
X W 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X A 
Abbreviations: ECG, electrocardiogram; FSH, follicle stimulating hormone; 
; 
; 
; 
; CDAI, Crohn’s Disease Activity Index; SES-CD, Simplified Endoscopy Score; 
 EOS, End-of Study, ATE, Active Treatment Extension 
A. 
This visit is for subjects who prematurely discontinue the study drug. This visit will be conducted within 5 days of the last dose of study drug, if possible. 
Subject will also return for the EOS visit for collection of safety data and assessment of disease activity. Subjects who discontinue study drug early due to AE 
are permitted to optionally complete their daily diary through to the EOS visit. Subjects who have not shown clinical improvement at ATE Week 16 should 
complete an Early Study Drug Discontinuation visit and be discontinued from study drug. 
B. 
An EOS visit will be required for all subjects 4 weeks following their last dose of study drug, whether they completed the full duration of study drug treatment. 
C. 
The Week 12 ileocolonoscopy and biopsies should be performed on the same day as the Week 12 visit, preferably in the early morning, to permit morning 
dosing with study drug. However, if not feasible to perform both the ileocolonoscopy and the clinic visit on the same day, the ileocolonoscopy could be 
performed within 3 days after the Week 12 clinic visit. If the study activities of this Week 12 visit are to be completed over two different visits, the study drug 
should be continued until the later of the two visits. The Week 12 endoscopy must be performed at least 1 day prior to ATE Day 1. 
D. 
ATE Day 1 should occur between 1 and 7 days after the Week 12 clinic visit. No new study drug will be dispensed between the Week 12 clinic visit and ATE 
Day 1. ATE Day 1 must be performed at least 1 day after the Week 12 endoscopy has been conducted.  
E. 
Subjects who have not shown clinical improvement, as deemed by the subject and investigator, 16 weeks after initiation of the ATE (i.e., ATE Week 16), should 
be discontinued from the study. 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
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F. 
Physical exams (PEs) should be performed as per local standard practice (Section 6.4.9).  
G. 
Subjects who have had a documented chest X-ray or equivalent chest imaging or TB testing within 90 days prior to Screening do not require a repeat X-ray 
(or equivalent) or TB testing, respectively, unless subject is deemed by the investigator to be at high risk of recent pulmonary infection. If a chest X-ray is 
indicated, it may be performed anytime during Screening. Subjects with a history of latent TB should not have a TB test but must not live in a region with high 
prevalence of multidrug-resistant TB and have completed a well-accepted treatment regimen (e.g., a ≥ 9-month course of INH or equivalent therapy) within 
5 years (3 years in countries where TB is endemic) prior to Screening, the documentation for which must be included in the source document and reviewed by 
the PI. Subjects who had treated active TB must still have a TB test. Subjects who has a history of latent or active tuberculosis (TB) may be eligible for the 
study if criteria outlined in Section 6.4.15 are met. 
H. 
Subject will be randomized on Day 1 after all pre-dose procedures (ECG, vital signs, and all labs 
) have been completed and 
subject is confirmed to be eligible for the study.  
I. 
Study drug administration will be in clinic on Day 1, Week 4, Week 8, Week 12, ATE Day 1, ATE Week 4, ATE Week 8, ATE Week 16, ATE Week 24, ATE 
Week 36, and ATE Week 48 on an empty stomach from the night before after all pre-dose assessments 
 
 and procedures have been completed. Subject will take the study drug at home for 
the rest of the study. The last dose of Induction study drug will be taken at the Week 12 clinic visit. No new study drug will be dispensed between the Week 12 
clinic visit and ATE Day 1. 
J. 
Subjects will be provided with an electronic diary (or paper diary if electronic diary is not available) at the Screening Stage 1 visit and instructed on daily diary 
completion, including symptom monitoring and study drug dosing details. Diaries of symptoms will be collected daily from the Screening Stage 1 visit through 
the EOS visit. Study drug dosing details will be entered from Day 1 (Induction) through ATE Week 48 (or the last dose of study drug, if the subject prematurely 
withdraws from study drug). Diary completion will be monitored for completeness at each return study visit after the electronic diary is dispensed (i.e., 
Screening Stage 2 through the EOS visit). Subjects will be counseled on missed study drug doses and missed diary entries. 
K. 
Corticosteroid taper, for those that are on corticosteroid at Screening Stage 1, should be initiated at the Week 8 visit. This taper will continue through ATE, as 
outlined in Section 6.4.30. 
L. 
Site personnel to call subjects approximately 2 weeks prior to Week 12 visit for reminder of compliance of diary completion. The site will also review 
compliance on corticosteroid taper (as applicable), review upcoming schedule for Week 12 and the reminders in preparation for the visit. 
M. 
AE assessments are to include collection and reporting of AEs, SAEs, and AEs of Special Interest (AESIs). Please refer to protocol Section 7 for further details. 
N. 
Urine beta human chorionic gonadotropin (b-hCG) testing will be performed before dosing when dosing in-clinic and anytime during all other visits for females 
of childbearing potential to confirm absence of pregnancy. If urine b-hCG test is positive, confirm with serum b-hCG test.  
O. 
Required for postmenopausal females. 
P. 
Any Screening Stage 2 lab testing can be obtained from Day -35* to Day -1 during Screening. Overnight fasting lipid panel may be obtained on Day -35 if 
subjects are fasting as per institutions standard of care procedure, which must be clearly documented in the source documents. *NOTE: Subjects must not be 
requested to come in fasting for study specific assessments prior to signing the informed consent. Results of these labs will not need to be reviewed before 
Screening Stage 2 or Day 1. 
Q. 
Subjects with positive hepatitis B core antibody will undergo testing for hepatitis B DNA and hepatitis B surface antibody during Screening. Subjects with 
known hepatitis C will also undergo testing for hepatitis C RNA viral load (Refer to Section 6.4.14 for details on Serology testing). During re-screening, if there 
is already a negative result from prior screening, the hepatitis B, C, or E or HIV serologies do not need to be repeated. 


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R. 
Ileocolonoscopy and biopsies will be performed after subject’s eligibility is confirmed (upon review of CDAI score prior to the start of bowel preparation and 
no exclusionary criteria are met). Ileocolonoscopy does not need to be repeated for a rescreening if the ileocolonoscopy is within 28 days of Day 1 of the 
re-screen and if the SES-CD score is qualifying. 
S. 
Stool infectious studies to include: C. difficile, other bacteria (including Shigella, Salmonella, Yersinia, Enterohemorrhagic or Enteropathogenic or 
Enterohemorrhagic E. coli O157, and Campylobacter), and ova and parasite.  
T. 
 
 
 
  
U. 
 
 
 
 
 
 
 
  
V. 
Obtained prior to ileocolonoscopy (to assess eligibility criteria at Screening). Any time after Screening Stage 1 and once a minimum of 5 entries have been 
confirmed, the clinician assessments can be completed. Should be performed prior to the start of bowel preparation for the Screening Stage 2 endoscopy. 
The Screening Stage 1 weight and hematocrit result will be used to calculate this CDAI score. 
W. Subject must have completed their electronic diary (or paper diary if electronic diary is not available) at least 5 out of 7 days prior to Screening Stage 2. 
Note: See Appendix 13 for general guidance on study conduct during the COVID-19 pandemic. Variations from planned assessments will still constitute protocol 
deviations.


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................29 
1. 
INTRODUCTION ......................................................................................................32 
1.1. 
Background and Rationale ..........................................................................................32 
1.2. 
Nonclinical Profile ......................................................................................................33 
1.2.1. 
Pharmacology .............................................................................................................33 
1.2.2. 
Toxicology ..................................................................................................................33 
 
 
1.3. 
Clinical Experience .....................................................................................................35 
1.4. 
Risks and Benefits ......................................................................................................36 
2. 
OBJECTIVES .............................................................................................................38 
3. 
STUDY DESIGN .......................................................................................................39 
3.1. 
Overview .....................................................................................................................39 
3.2. 
Rationale for Study Design .........................................................................................41 
3.3. 
Selection of Dose and Duration of Treatment ............................................................41 
3.4. 
Study Endpoints ..........................................................................................................42 
3.5. 
Minimization of Bias ..................................................................................................44 
3.5.1. 
Blinding ......................................................................................................................44 
3.5.2. 
Treatment Assignment ................................................................................................44 
4. 
STUDY POPULATION .............................................................................................46 
4.1. 
Inclusion Criteria ........................................................................................................46 
4.2. 
Exclusion Criteria .......................................................................................................47 
4.3. 
Females of Childbearing Potential and Acceptable Birth Control .............................52 
5. 
STUDY DRUGS ........................................................................................................53 
5.1. 
Description of Study Drugs ........................................................................................53 
5.1.1. 
TD-1473 ......................................................................................................................53 
5.1.2. 
Placebo ........................................................................................................................53 
5.2. 
Dosage and Administration ........................................................................................53 
 
 
5.4. 
Drug Accountability and Reconciliation ....................................................................54 
6. 
STUDY PROCEDURES ............................................................................................55 


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6.1. 
Schedule of Study Procedures ....................................................................................56 
 
 
6.3. 
Procedures by Visit .....................................................................................................56 
6.3.1. 
Screening ....................................................................................................................56 
6.3.1.1. 
Screening Stage 1 .......................................................................................................56 
6.3.1.2. 
Screening Stage 2 .......................................................................................................58 
6.3.2. 
Day 1 (Induction) ........................................................................................................58 
6.3.3. 
Week 4 (Induction) .....................................................................................................60 
6.3.4. 
Week 8 (Induction) .....................................................................................................61 
6.3.5. 
Week 10 Telephone Call (Induction) .........................................................................62 
6.3.6. 
Week 12 (Induction) ...................................................................................................63 
6.3.7. 
ATE Day 1 ..................................................................................................................64 
6.3.8. 
ATE Week 4 ...............................................................................................................65 
6.3.9. 
ATE Week 8 ...............................................................................................................66 
6.3.10. 
ATE Week 16 .............................................................................................................67 
6.3.11. 
ATE Week 24 .............................................................................................................68 
6.3.12. 
ATE Week 36 .............................................................................................................70 
6.3.13. 
ATE Week 48 .............................................................................................................71 
6.3.14. 
End of Study ...............................................................................................................72 
6.3.15. 
Early Study Drug Discontinuation..............................................................................73 
6.4. 
Description of Study Assessments ..............................................................................74 
6.4.1. 
Informed Consent, Demographics, and Inclusion/Exclusion Criteria ........................74 
6.4.2. 
Medication History .....................................................................................................74 
6.4.3. 
Medical History ..........................................................................................................75 
6.4.4. 
Tobacco Use Status .....................................................................................................75 
6.4.5. 
Height Measurements .................................................................................................75 
6.4.6. 
Body Weight ...............................................................................................................75 
6.4.7. 
Vital Signs ..................................................................................................................75 
6.4.8. 
12-Lead Electrocardiograms .......................................................................................76 
6.4.9. 
Physical Examination .................................................................................................76 
6.4.10. 
Pregnancy Test (females of childbearing potential only) ...........................................77 
6.4.11. 
Follicle-Stimulating Hormone (FSH) .........................................................................77 


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6.4.12. 
Chemistry, Hematology, and Urinalysis .....................................................................77 
6.4.13. 
Overnight Fasting Lipid Panel ....................................................................................77 
6.4.14. 
Viral Hepatitis and HIV Serology Panel ....................................................................78 
6.4.15. 
Tuberculosis (TB) Test ...............................................................................................78 
6.4.16. 
Chest X-ray .................................................................................................................79 
 
 
6.4.18. 
Ileocolonoscopy and Biopsies ....................................................................................79 
6.4.19. 
Fecal Sampling ...........................................................................................................80 
 
 
6.4.21. 
Infections ....................................................................................................................81 
6.4.22. 
Pharmacokinetic Sampling .........................................................................................81 
6.4.23. 
Optional Genetic Testing ............................................................................................82 
6.4.24. 
Subject Daily Diary ....................................................................................................82 
6.4.25. 
Disease Activity Assessments ....................................................................................82 
6.4.25.1. 
SES-CD.......................................................................................................................82 
6.4.25.2. 
CDAI ...........................................................................................................................82 
 
 
6.4.25.4. 
Fistula Drainage Assessment ......................................................................................83 
 
 
 
 
 
 
6.4.27. 
Adverse Events (AEs) .................................................................................................84 
6.4.28. 
Concomitant Medications ...........................................................................................84 
 
 
6.4.30. 
Permitted Medications ................................................................................................85 
6.4.31. 
Restrictions on Alcohol Consumption and Illicit Drug Use .......................................86 
6.5. 
Discontinuation ...........................................................................................................86 
6.5.1. 
Subject Discontinuation ..............................................................................................86 
6.5.2. 
Subject Replacement ..................................................................................................87 
6.5.3. 
Study Discontinuation ................................................................................................87 
6.6. 
Pregnancy ...................................................................................................................88 
7. 
ADVERSE EVENTS..................................................................................................89 


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7.1. 
Definitions ..................................................................................................................89 
7.1.1. 
Adverse Events (AE) ..................................................................................................89 
7.1.2. 
Serious Adverse Event ................................................................................................90 
7.1.3. 
Additional Considerations for Serious Adverse Events .............................................90 
7.1.4. 
Adverse Events of Special Interest (AESIs) ...............................................................91 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ................................................................91 
7.3. 
Assessment of Adverse Events ...................................................................................92 
7.3.1. 
Severity .......................................................................................................................93 
7.3.2. 
Causal Relationship to Study Medication ...................................................................93 
7.3.3. 
Clinical Events Committee (CEC) ..............................................................................94 
7.4. 
AE Reporting and Recording ......................................................................................94 
7.4.1. 
AE Reporting ..............................................................................................................94 
7.4.2. 
AE, SAE and AESI Recording ...................................................................................94 
7.4.3. 
SAE and AESI Reporting Timeline ............................................................................95 
7.5. 
Adverse Event Follow-up ...........................................................................................96 
8. 
STATISTICAL CONSIDERATIONS .......................................................................97 
8.1. 
General Considerations ...............................................................................................97 
8.2. 
Sample Size and Power ..............................................................................................98 
8.3. 
Analysis Sets ...............................................................................................................98 
8.3.1. 
Examination of Subgroups .........................................................................................98 
8.3.2. 
Major Analysis Protocol Deviations ...........................................................................99 
8.4. 
General Analyses ........................................................................................................99 
8.4.1. 
Demographics and Other Baseline Characteristics .....................................................99 
8.5. 
Efficacy Analyses .......................................................................................................99 
8.5.1. 
Efficacy Endpoints ......................................................................................................99 
8.5.2. 
Primary Efficacy Evaluations ...................................................................................100 
8.5.3. 
Secondary and Exploratory Efficacy Evaluations ....................................................100 
8.5.4. 
Multiplicity Adjustment............................................................................................100 
8.6. 
Pharmacokinetic Analyses ........................................................................................101 
8.7. 
Pharmacodynamic Analyses .....................................................................................101 
8.8. 
Safety Analyses ........................................................................................................101 


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8.8.2. 
Adverse Events .........................................................................................................101 
8.8.3. 
Concomitant Medications .........................................................................................102 
8.8.4. 
Laboratory Data ........................................................................................................102 
8.8.5. 
Vital Signs Data ........................................................................................................103 
8.8.6. 
ECG Data ..................................................................................................................103 
8.9. 
Handling of Missing Data .........................................................................................104 
8.10. 
Independent Data Monitoring Committee ................................................................104 
9. 
STUDY ADMINISTRATION .................................................................................106 
9.1. 
Principal Investigator Responsibilities .....................................................................106 
9.2. 
Institutional Review Board/Independent Ethics Committee ....................................107 
9.3. 
Informed Consent .....................................................................................................107 
9.4. 
Data Recording and Quality Assurance ....................................................................107 
9.5. 
Document Retention .................................................................................................108 
9.6. 
Confidentiality ..........................................................................................................108 
9.7. 
Access to Data and Documents ................................................................................109 
9.8. 
Quality Control: Study Monitoring and Auditing ....................................................109 
9.9. 
Publication ................................................................................................................110 
10. 
REFERENCES .........................................................................................................111 
APPENDIX 1. COCKCROFT-GAULT CALCULATION ......................................................112 
APPENDIX 2. PROTOCOL SIGNATURE FORM .................................................................113 
APPENDIX 3. MEDICATIONS TO USE WITH CLINICAL DISCRETION ........................114 
APPENDIX 4. DEFINITION OF PRIOR BIOLOGICS FAILURE: PRIMARY AND 
SECONDARY NON˗RESPONSE OR INTOLERANCE TO 
PREVIOUS BIOLOGICS .................................................................................115 
APPENDIX 5. SES-CD .............................................................................................................117 
APPENDIX 6. EXAMPLE OF THE CDAI ..............................................................................118 
APPENDIX 7. EXAMPLE OF THE SUBJECT DAILY DIARY ............................................119 
 
 
APPENDIX 10. DEFINITION OF CD MEDICATION INTOLERANCE OR 
INADEQUATE RESPONSE AND OF CORTICOSTEROID 
DEPENDENCE ................................................................................................124 


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APPENDIX 12. GUIDELINE ALGORITHM FOR MONITORING, ASSESSMENT, 
AND EVALUATION OF ABNORMAL LIVER TESTS IN 
PARTICIPANTS WITH NO UNDERLYING LIVER DISEASE ...................127 
APPENDIX 13. SPONSOR GUIDANCE ON STUDY CONDUCT DURING THE 
CORONAVIRUS DISEASE 2019 (COVID-19) PANDEMIC ........................132 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................16 
Table 2: 
Induction and Active Treatment Dose Assignment ....................................................40 
Table 3: 
Thresholds for Vital Signs ........................................................................................103 
Table 4: 
ECG Interval Ranges ................................................................................................103 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................41 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Anti-IL-12/23 
interleukin 12/23 inhibitor 
Anti-TNF 
tumor necrosis factor inhibitor 
AST 
aspartate aminotransferase 
ATE 
active treatment extension 
BCG 
Bacille Calmette Guerin 
BCRP 
breast cancer resistance protein 
b-HCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
BP 
blood pressure 
CD 
Crohn’s disease 
CDAI 
Crohn’s disease activity index 
CDAI Clinical Remission 
defined as CDAI < 150 
CDAI Clinical Response 
defined as CDAI reduction from baseline of ≥ 100 or CDAI < 150 
CEC 
Clinical Events Committee 
CFR 
(United States) Code of Federal Regulations 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
 
 
CSR 
clinical study report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DNA 
deoxyribonucleic acid 
DVT 
deep vein thrombosis 
ECG 
Electrocardiogram 
eCOA 
electronic clinical outcome assessments 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay  
Endoscopic Remission 
defined as SES-CD2 
Endoscopic Response 
defined as SES-CD reduction of ≥ 50% from baseline or endoscopic remission 
EOS 
End-of-Study 
 
 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle stimulating hormone 


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Abbreviation 
Description 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
H2 antagonists 
Histamine H2 receptor antagonists 
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 
IgM 
immunoglobulin M 
INH 
Isoniazid 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
JAK 
Janus kinase 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
mITT 
modified intent to treat 
mRNA 
messenger ribonucleic acid 
Modified SFAP Clinical 
remission  
defined as abdominal pain score ≤ 1, very soft/liquid stool frequency ≤ 1.5, and 
both not worse than baseline 
Modified SFAP-e Remission 
defined as abdominal pain score ≤ 1, stool frequency ≤ 1.5, neither abdominal 
pain score or stool frequency worse than baseline, and SES-CD ≤ 2 
NK 
natural killer 
 
 
PA 
posterior anterior 
Pack years 
number of packs per day times number of years smoked 
PD 
Pharmacodynamics(s) 
PI 
principal investigator 
P-gp 
p-glycoprotein 


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Abbreviation 
Description 
PIC 
powder in capsule 
PK 
pharmacokinetic(s) 
PP 
Per-protocol 
PPI 
proton-pump inhibitor 
PRO 
Patient-reported outcome 
 
  
PT 
preferred term 
QD 
Once daily 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
REB 
Research Ethics Board 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcriptase polymerase chain reaction 
RTSM 
randomization and trial supply management 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SES-CD 
simplified endoscopy score for Crohn’s disease 
SFAP 
Stool Frequency and Abdominal Pain 
SFAP Clinical Remission 
defined as abdominal pain score ≤ 1, stool frequency ≤ 2.8, and both not worse 
than baseline)  
SFAP-e Remission 
defined as abdominal pain score ≤ 1, stool frequency ≤ 2.8, neither abdominal 
pain score or stool frequency worse than baseline, and SES-CD ≤ 2 
SOC 
system organ class 
SOP 
standard operating procedure 
STAT 
signal transducer and activator of transcription 
TB 
Tuberculosis 
TBPH 
Theravance Biopharma, Inc. 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia  


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1. 
INTRODUCTION 
1.1. 
Background and Rationale 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2. 
Nonclinical Profile 
A review of the nonclinical profile of TD-1473 can be found in the current version of the 
TD-1473 Investigator’s Brochure (IB). The following is a brief summary of the pertinent 
findings. 
1.2.1. 
Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2. 
Toxicology 
 
 
 
 
 
 
 
 
 
 


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1.2.3. 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 


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1.3. 
Clinical Experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4. 
Risks and Benefits 
TD-1473 is potentially effective for the treatment of inflammatory intestinal disorders. 
Tofacitinib, a systemic pan-JAK inhibitor, has demonstrated statistically significantly higher 
rates of induction of remission and higher rates of remission and response at Week 52 during 
maintenance therapy compared to placebo for UC.5,6  Systemic JAK inhibitors filgotinib and 
upadacitinib have demonstrated efficacy in phase 2 trials in Crohn’s disease.7,8  However, given 
limited data from the Phase 1b study in a small number of subjects with moderately-to-severely 
active UC treated with TD-1473 for 4 weeks, efficacy with TD-1473 in UC has not been 
established. TD-1473 has not been studied in subjects with CD.  
Some subjects receiving repeated doses of tofacitinib, a systemic JAK inhibitor, have exhibited 
alterations in cholesterol (LDL, HDL, and total cholesterol), liver function tests, serum 
creatinine, decreased red blood cell and white blood cell (particularly neutrophils and 
lymphocytes) counts, and infection (particularly herpes zoster and tuberculosis), cancer 
(including non-melanoma skin cancer), intestinal perforation, headache, diarrhea, rhinorrhea, 
nasopharyngitis, and sore throat. However, given the relatively low systemic exposure of 
TD-1473, these risks are anticipated to be lower in the current study compared to systemic 
JAK inhibitors.  
In healthy volunteers, doses from 10 mg to 1000 mg as a single dose or 10 mg to 300 mg as a 
daily dose for 14 days were evaluated. TD-1473 was observed to be generally well tolerated up 
to 300 mg for 14 days without alterations to vital signs, electrocardiogram parameters, or 
laboratory evaluations relative to placebo. In the Phase 1 study in healthy volunteers, all 
treatment-emergent adverse events in subjects dosed with TD-1473 (most commonly noted were 
headaches at 100 mg and 300 mg with similar or lower prevalence as placebo) were mild in 
severity and short in duration. In the Phase 1b study in UC subjects, TD-1473 was generally well 
tolerated with only two adverse event (urticaria at 80 mg and papular rash at 20 mg) deemed by 
the Principal Investigator (PI) to be possibly related to Study drug; the adverse events were 
considered mild in severity in both cases and resolved within a few day after the last dose of 
study drug. No adverse event led to drug interruption or discontinuation. Similar to the healthy 
volunteer study, there were no adverse alterations in vital signs, electrocardiogram parameters, or 
laboratory evaluations relative to placebo. 
The current protocol requires pregnancy prevention measures for a duration of 7 days after the 
last dose of study medication for both male and female subjects. The 7 day duration for 
pregnancy prevention measures 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. For these reasons, 7 days 
after the last dose of study drug was chosen such that an adequate safety margin is established 
before implantation.  


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Pregnancy prevention measures in males 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).10  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. 
The potential risks described in this section will be carefully assessed during the study. 
Assessments include adverse event collection and monitoring (including AEs of Special 
Interest), scheduled physical exams, and frequent monitoring of complete blood cell counts with 
differential, kidney and liver function, 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. 


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2. 
OBJECTIVES 
The primary objectives of the study are as follows: 
• To assess the effect of TD-1473 compared to placebo in improving Crohn’s Disease 
Activity Index (CDAI) score at Week 12 in subjects with moderately-to-severely 
active CD 
• To assess the safety and tolerability of TD-1473 
The secondary objectives of the study are to assess the effects of TD-1473 given for 12 weeks 
compared to placebo as follows: 
• To induce clinical remission 
• To induce clinical response 
• To induce endoscopic response 
• To improve the Simplified Endoscopy Score for Crohn’s Disease (SES-CD) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Overview 
This study includes 3 phases: Screening, Induction, and Active Treatment Extension (ATE). 
Screening is up to 5 weeks long. The Induction phase of the study is a multi-center, randomized, 
double-blind, placebo-controlled, parallel-group study evaluating 2 dose levels of TD-1473 
(80 mg or 200 mg; approximately 60 subjects per dose level) compared to placebo 
(approximately 40 subjects) for 12 weeks in subjects with moderately-to-severely active CD. 
Subjects who complete the Induction phase will continue to receive TD-1473 in ATE, either at 
80 mg or 200 mg, for up to 48 additional weeks.  
Screening: 
To determine eligibility, subjects will undergo assessments during the Screening period 
(up to 35 days prior to Day 1 dosing) for CD signs and symptoms, electrocardiogram (ECG), 
tuberculosis (TB) test, chest X-ray, and laboratory testing, including infectious stool studies. 
Refer to Schedule of Study Procedures (Table 1) for a schedule of the Screening requirements. 
Disease activity will be assessed by the clinical scores, based on symptoms reported on a daily 
diary, which will be captured electronically (or on a paper diary if electronic diary is not 
available) beginning the day after Screening Stage 1.  
Subjects who meet all inclusion (with the exception of the endoscopy subscore criterion) and no 
exclusion criteria, as described in Section 4.1 and Section 4.2, respectively, will undergo 
ileocolonoscopy with biopsies to complete Screening Stage 2. The aim of this endoscopic exam 
is to assess the SES-CD score by central reading and to obtain biopsies.  
Induction 
If the subject meets all eligibility criteria, the subject may be randomized into one of the 
following 3 treatment groups in a 3:3:2 ratio: TD-1473 80 mg, TD-1473 200 mg, or placebo.  
The randomization will be stratified by prior biologics failure (as defined in Appendix 4) and 
CDAI score category (≤ 300, > 300) at the Screening Stage 2 visit. Approximately 40-60% of 
subjects randomized will have failed prior treatment with biologics. There will be a cap for 
enrollment of subjects once one of the biologics stratum reaches 60%. There will also be a cap at 
10% for enrollment of subjects with an SES-CD score at screening in the range of 3 to 5. 
Subjects will be treated for 12 weeks and assessed for the various endpoints, including those that 
incorporate findings from an ileocolonoscopy and biopsies at the Week 12 visit. Corticosteroids 
will start to be tapered at Week 8 with the tapering regimen described in Section 6.4.30. 
Subjects will undergo clinic study visits every 4 weeks in accordance with Table 1. During this 
time, subjects will continue to fill out a daily diary. 
ATE: 
All subjects who complete Induction at the Week 12 visit will continue into ATE, where subjects 
will be treated with either 80 mg or 200 mg of TD-1473 for 48 weeks. Dose during ATE depends 
on treatment assignment during Induction (Figure 1 and Table 2); those who were dosed with 
TD-1473 during Induction stay on the same dose; those who were dosed with placebo during 
Induction will be dosed with TD-1473 at 80 mg.  


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Table 2: 
Induction and Active Treatment Dose Assignment 
Induction Dose 
(3:3:2 randomization) 
Active Treatment Extension (ATE) Dose 
80 mg 
80 mg 
200 mg 
200 mg 
Placebo 
80 mg 
During ATE, subjects will undergo clinic study visits every 4-12 weeks in accordance with 
Table 1. Subjects will continue to complete a daily diary. 
Corticosteroids will continue to be tapered during ATE with the tapering regimen recommended 
in Section 6.4.30. Subjects who have not shown clinical improvement (as assessed by the 
investigator) 16 weeks after initiation of ATE (i.e., ATE Week 16) should be discontinued from 
the study following completion of an End of Study (EOS) visit.  
End of Study (EOS) Visit: 
An EOS visit will be required for all subjects 4 weeks following their last dose of study drug. 
Subjects who complete an Early Study Drug Discontinuation visit during Induction or ATE will 
also be required to return for an EOS visit. Subjects will continue to complete a daily diary 
through the last day of the study participation. 
Early Study Drug Discontinuation: 
Subjects who prematurely discontinue the study drug due to adverse events (AEs), lack of 
response, or any other reason besides withdrawal of consent during Induction or ATE 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, if possible. Subjects will also return for the EOS visit for 
collection of safety data and assessment of disease activity 4 weeks after the Early Study Drug 
Discontinuation visit.  
During ATE, subjects should be assessed for clinical benefit. If there is no clinical benefit, as 
deemed by the investigator, the subject should stop study drug treatment and be withdrawn from 
the study. 


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Figure 1: 
Study Design Schematic 
 
 
3.2. 
Rationale for Study Design 
 
 
 
 
 
 
 
 
 
 
 
3.3. 
Selection of Dose and Duration of Treatment 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4. 
Study Endpoints 
The primary endpoint is: 
• CDAI score change from baseline at Week 12 
The secondary endpoints are: 
• CDAI clinical response (defined as reduction from baseline of ≥ 100 points or CDAI 
< 150) at Week 12 
• CDAI clinical remission (defined as CDAI < 150) at Week 12 
• SES-CD change from baseline at Week 12 
• Endoscopic response (SES-CD reduction of ≥ 50% from baseline or endoscopic 
remission) at Week 12 
• Stool Frequency and Abdominal Pain (SFAP) clinical remission defined as abdominal 
pain score ≤ 1 (on a scale of 0-3), stool frequency ≤ 2.8, and both not worse than baseline 
at Week 12 
 
 


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The safety endpoints are: 
• Changes from baseline in vital signs, ECGs, and clinical laboratory results 
• Incidence and severity of AEs 
The exploratory endpoints include: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5. 
Minimization of Bias 
This is a double-blind, placebo-controlled, randomized study. Treatments will be assigned 
centrally using a randomization and trial supply management (RTSM) system. 
All persons involved in this study (i.e., physicians, nurses, participants, and site monitors) will 
remain blinded at all times, except in the event of a medical emergency as outlined in 
Section 3.5.1. The principal investigator may be unblinded to a subject’s treatment to determine 
whether stopping criteria have been met, as outlined in Section 6.5.3. 
3.5.1. 
Blinding 
TD-1473 and placebo tablets will be of the same shape, size, and color to ensure that the blind is 
maintained. Also, subjects who are randomized to receive placebo will receive the equivalent 
number of tablets as those randomized to receive TD-1473.  
A subject’s treatment assignment will only be unblinded 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 
participant’s treatment assignment is warranted. Participant 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). With these exceptions, Sponsor 
personnel involved in the conduct of the study, data cleaning, or data analysis will remain 
blinded to subject treatment assignments until the database has been locked for final analysis.  
 
 
 
 
 
 
3.5.2. 
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 randomize the subject and dispense study drug. The 
randomization will be stratified, and the randomization schedule for each of the 4 strata defined 
by the stratification variables (i.e., prior biologics failure [Yes, No] crossed with CDAI category 
at Screening Stage 2 [≤ 300, >300]) will be a reproducible (through use of a pre-specified 
random number seed) sequence of randomly permuted treatment assignment blocks, generated or 


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reviewed by a Theravance Biopharma statistician not involved in the conduct of the study. 
Schedule requirements such as block sizes and the method of generating pseudorandom numbers 
will be specified in a randomization specifications document. Except for cases of emergency 
unblinding as described above, investigational site staff will remain blinded to treatment 
assignments until all subjects have either completed the ATE or been withdrawn from the study. 
An induction analysis will be conducted after all subjects have either completed the induction 
period or been withdrawn from the study to inform the design of additional studies. However, no 
summary results or individual subject data will be disclosed to investigational site staff until the 
entire study including the ATE has been concluded and the database has been locked. 
The RTSM system will implement modifiable enrollment caps designed to ensure that the prior 
biologic failure stratification variable category will be represented by at least a specified fraction 
of subjects enrolled (e.g., at least 40% will and at least 40% will not have had prior biologics 
failure). There will also be an enrollment cap implemented to include a maximum of 
approximately 10% of the total sample size in the study with an SES-CD score in the range 3 to 
5 at screening. The system will be designed to send notifications that an enrollment cap is being 
approached and enrollment will be closed to subjects in the overrepresented category when 
confirmation is received from the Sponsor. 
For ATE dose assignment (noted in Table 2), the PI or their delegate will use the RTSM system 
to report whether the subject experienced clinical benefit at the Week 12 visit, as deemed by the 
investigator, and dispense study drug.  
Further details regarding the randomization procedure and ATE dose assignment will be outlined 
in the RTSM system manual. 


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4. 
STUDY POPULATION 
Subjects with moderately-to-severely active CD [as defined by a CDAI score of 220-450 and 
SES-CD score of ≥ 6 (≥ 4 if isolated ileal disease) with ulceration (corresponding to a score of 1) 
in at least 1 of the 5 ileocolonic segments on the Presence of Ulcers subscore of the SES-CD] 
who are corticosteroid-dependent or have demonstrated inadequate response or intolerance to 
conventional therapy (aminosalicylates, corticosteroids and immunomodulators such as 
azathioprine, 6-mercaptopurine, or methotrexate) or biologics (e.g., anti-TNF therapy, 
anti-IL-12/23, anti-integrin).  A subset of subjects (up to approximately 10%) will have an 
SES-CD score between 3 and 5 points, inclusive. 
4.1. 
Inclusion Criteria 
100. 
Subject is willing and able to provide written, signed informed consent at Screening 
Part 1 prior to start of any study-related procedures 
101. 
Subject is a male or female at least 18 years of age at the time of Screening 
102. 
Subject has a diagnosis of CD with involvement of at least the ileum or any portion of 
the colon at a minimum, diagnosed by radiology, endoscopy, and/or histology at least 
3 months prior to Screening. The report of a previous diagnostic exam (endoscopy, 
radiology, and/or pathology) must be reviewed by the investigator and included in the 
source documents.  
103. 
Subjects must have up-to-date colorectal cancer screening as per locally adopted 
guidelines (e.g., if subject has had ≥ 8 years of disease involving >30% of the colon, 
surveillance biopsies or chromoendoscopy should be performed if either is indicated as 
per locally adopted guidelines but has not been performed within the 12 months prior 
to Screening). If indicated, the surveillance biopsies (if ≥ 10) and chromoendoscopy 
need to be performed during Screening Stage 2 ileocolonoscopy after recording of a 
full ileocolonoscopy has been completed to avoid dye or biopsy-related bleeding 
artifact on the recorded images. 
104. 
Subject has CDAI score ≥ 220 and ≤ 450  
105. 
Subject has a SES-CD score of ≥ 3 with ulceration (corresponding to a score of ≥1) in 
at least 1 of the 5 ileocolonic segments on the Ulcerated Surface subscore of the 
SES-CD, as assessed by central reading, during Screening 
a. Up to approximately 10% of the study population will have SES-CD score of 
between 3 and 5, inclusive, with the presence of ulceration in any 1 of the 5 
ileocolonic segments, all other subjects (approximately 90% of the study 
population) will require an SES-CD score of ≥ 6 (≥ 4 if isolated ileal disease) with 
ulceration (corresponding to a score of ≥ 1) in at least 1 of the 5 ileocolonic 
segments on the Ulcerated Surface subscore of the SES-CD 
106. 
Subject is corticosteroid-dependent or had intolerance or inadequate response to any of 
the following: aminosalicylates, corticosteroids, immunomodulators (azathioprine, 
6-mercaptopurine, or methotrexate), or biologics (anti-TNF anti-IL-12/IL-23 therapy, 
or anti-integrin) [Refer to Appendix 10] 


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NOTE: For subjects in Portugal, subject must have had intolerance or inadequate 
response to biologics 
107. 
If subject is currently receiving an oral corticosteroid, subject is eligible if:  
a. the subject has been on corticosteroid for a minimum of 4 weeks prior to Day 1 
AND 
b. the dose is equivalent to or less than prednisone 25 mg/day or budesonide 
9 mg/day or beclomethasone at 5 mg/day AND 
c. the dose is stable for at least 2 weeks prior to Screening Stage 2 AND  
d. the subject is willing to continue on the same dose as warranted until Week 8 
108. 
If subject is currently receiving oral aminosalicylate (including, but not limited to 
sulfasalazine or mesalamine), the subject is eligible provided the subject has been on a 
stable dose for ≥ 4 weeks prior to Day 1 and is willing to stay on the same dose as 
warranted until Week 12 
109. 
If subject is on antibiotics or probiotics for CD, subject must have been on the same 
dose for at least 2 weeks before Screening Stage 2 with stable symptoms and is willing 
to remain on the same dose as warranted until Week 12 
110. 
If subject has recently discontinued oral corticosteroids, these must have been stopped 
at least 2 weeks before endoscopy during Screening Stage 2 visit 
111. 
During the Study and for 7 days after receiving the last dose of the Study drug, 
females of childbearing potential or males capable of fathering children must agree to 
use highly effective birth control measures (failure rate <1% when used consistently 
and correctly) or agree to abstain from sexual intercourse. Females of childbearing 
potential must test negative for pregnancy at Screening and at Day 1 (Refer to 
Section 4.3). 
112. 
All male subjects must agree to refrain from semen donation during the study and for 
7 days after the last dose of study drug 
113. 
Subject has completed the daily diary at least 5 out of 7 days prior to Screening 
Stage 2  
114. 
Subject is able to communicate effectively with the investigator, and willing and able 
to comply with the study procedures, requirements and restrictions, and directions of 
the clinic staff 
 
4.2. 
Exclusion Criteria 
Exclusion Criteria Pertinent to GI:  
300. 
Subject with current symptoms or signs suggestive of intestinal perforation, 
intra-abdominal or pelvic abscess, symptomatic internal fistulae, abdominal wall 
fistulae, or symptomatic stricture 
301. 
Subject with a diagnosis of indeterminate colitis, ulcerative colitis, microscopic colitis, 
ischemic colitis, radiation colitis, diverticular disease associated with colitis, or 
suspected ulcerative colitis 


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302. 
Subject with a confirmed or suspected diagnosis or history of primary sclerosing 
cholangitis (PSC) 
303. 
Subject is likely to require bowel surgery or any other type of major surgery 
(e.g., requiring general anesthesia) during the study duration 
304. 
Subject has had extensive colonic resection (i.e., more than half of colon), subtotal or 
total colectomy, intestinal resection within 6 months of Screening, > 2 small bowel 
resections or carries a diagnosis of short bowel syndrome or currently has an ostomy 
305. 
Subject has a history of unresected colonic mucosal dysplasia or history of resected 
high-grade colonic dysplasia within 3 years prior to Screening. Subjects will not be 
excluded from the study because of a pathology finding of indefinite dysplasia with 
reactive atypia or because of adenomas that have been completely resected 
306. 
Subject has required enteral feeding via feeding tube or parenteral alimentation within 
21 days prior to Day 1 
Exclusion Criteria Pertinent to Medications:  
400. 
Medications of exclusion 
 
 below must be discontinued within the timeframe specified 
(if applicable)  
• azathioprine, 6-mercaptopurine, or methotrexate taken within the 14 days prior to 
Day 1 
• anti-TNFs (e.g., adalimumab, infliximab, golimumab, etanercept, certolizumab, or 
biosimilars) taken within the 60 days or 5 half-lives, whichever is longer, prior to 
Day 1 
• intravenous corticosteroids within the 14 days prior to Day 1 
• rectal mesalamine or corticosteroid (i.e., enemas or suppositories) taken within the 
14 days prior to Day 1 
• prior exposure to vedolizumab, ustekinumab, mycophenolic acid, tacrolimus, 
sirolimus, or cyclosporine taken within 60 days prior to Day 1 
• any prior exposure to natalizumab, rituximab, efalizumab, fingolimod, 
cyclophosphamide, or thalidomide 
• NSAIDs taken on a regular (more than 3 times per week, on average) basis 
(regular use of aspirin ≤ 325 mg per day for cardiovascular protection is allowed). 
• anakinra or any other immune-modifying biologic agent taken within 90 days prior 
to Day 1 
• A JAK inhibitor (e.g., tofacitinib) within 60 days prior to Day 1 
Note: For anti-TNFs, vedolizumab, and ustekinumab, there is no requirement for a 
washout period if there is documented finding of undetectable drug level by a validated 
assay (e.g., through commercially available testing). 


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401. 
Prior exposure or potential exposure to a JAK inhibitor that was stopped due to 
intolerance or lack of efficacy. This does not include subjects with prior exposure to 
another JAK inhibitor that was stopped for any other reason (e.g., loss/lack of 
insurance coverage or end of study)  
402. 
Subject has participated in another clinical trial of an investigational drug (or medical 
device) within 30 days prior to Screening or 5x the half-life of the investigational drug, 
whichever is longer, or is currently participating in another trial of an investigational 
drug (or medical device) 
403. 
Subject has had inadequate response (i.e., either primary or secondary non-response) 
to ≥ 3 biologic agents of 3 different mechanisms of action (i.e., anti-TNF, anti-integrin, 
and anti-IL12/23) 
404. 
Subject is currently taking or has taken within 14 days prior to Day 1 any concomitant 
medication, herbal supplement, or dietary substance (e.g., grapefruit) known to be a 
strong inhibitor or inducer of P-glycoprotein (P-gp), breast cancer resistance protein 
(BCRP), or CYP3A4 or is a substrate of P-gp or BCRP and has a narrow therapeutic 
index 
). For clarity, corticosteroids 
at doses not excluded elsewhere in the protocol are not considered potent inducers of 
CYP3A4, P-gp, or BCRP 
405. 
Subject is taking non-CD concomitant prescription medications that have started or 
have had a dose adjustment within 4 weeks prior to Day 1 (with the exception of 
corticosteroids as discussed in inclusion criterion #107, antibiotics for recent 
infections, sedating agents for ileocolonoscopy, hormonal contraceptives, hormone 
replacement therapy, vitamin D, insulin therapy, and replacement thyroid hormone - 
see Section 6.4.29) 
406. 
Subject is taking non-CD over-the-counter medications or dietary supplements that 
have started or have had a dose adjustment within 2 weeks prior to Day 1 (with the 
exception of up to 3 times per week use of non-steroid anti-inflammatory drugs or 
acetaminophen used on an as needed basis, aspirin up to 325 mg per day for 
cardiovascular prophylaxis, and over-the-counter doses of vitamin D - see 
Section 6.4.29) 
Exclusion Criteria Pertinent to Infections: 
500. 
Subject is positive for:  
a. hepatitis B virus (HBV) surface antigen  
b. hepatitis B virus core antibody (unless subject has positive hepatitis B surface 
antibody and undetectable serum hepatitis B DNA) 
c. hepatitis C virus (HCV) antibody unless: a) there is evidence of undetectable viral 
load measured twice six months apart after completion of treatment regimen and 
b) viral load during Screening is undetectable 
d. hepatitis E Immunoglobumin M (IgM) antibody 
e. human immunodeficiency virus (HIV) antibody 
501. 
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, or 


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any investigational live vaccine) within 4 weeks prior to Screening and/or is unwilling 
or unable to avoid live viral vaccines during the study and for 8 weeks following 
completion of the study; 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 
502. 
The subject has or may have untreated active or latent TB as evidenced by any of the 
following: 
a. Two indeterminate or one positive QuantiFERON®-TB Gold result within 
90 days prior to screening or during the Screening Period, without having 
completed an adequate treatment for latent or active TB before Screening OR 
b. Chest X-ray or equivalent chest imaging within 90 days prior to Screening in 
which active or latent pulmonary TB cannot be excluded. 
Refer to Section 6.4.15 for rationale and required documentation for repeat 
testing. 
A subject who has a history of latent or active tuberculosis (TB) may be eligible 
for the study if criteria outlined in Section 6.4.15 are met. 
503. 
Subject has: 
a. an active, clinically significant bacterial, parasitic, fungal, mycobacterial 
(including atypical infection), or viral infection, except for local skin or nail bed 
infection, within 30 days prior to Day 1 
b. any infection requiring hospitalization or intravenous antibiotics within 30 days 
prior to Screening 
c. any infection requiring oral antimicrobial treatment within 2 weeks prior to 
Screening 
d. a history of more than one episode of herpes zoster or one or more episodes of 
disseminated or complicated herpes zoster (complicated: multi-dermatomal, 
ophthalmic, or CNS involvement or post-herpetic neuralgia) or disseminated 
herpes simplex 
504. 
Subject has had a chest X-Ray or equivalent chest imaging performed within the 
90 days prior to Screening or at Screening that shows an abnormality suggestive of a 
malignancy or current active infection, including TB, chronic lung disease or a 
potentially active fungal, viral, or bacterial infection.    
505. 
Subject has C. difficile or other gastrointestinal infections (e.g., Salmonella, Shigella, 
Yersinia, Campylobacter, E. coli O157, etc.) on stool testing or cytomegalovirus 
[CMV] colitis suspected on endoscopic appearance during Screening. Subject may be 
treated, re-tested, and re-screened. 
506. 
Subject has had a bone marrow transplant. 
507. 
Within 4 weeks of Screening or during Screening, subject has: 
a. Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection (coronavirus disease 2019 [COVID-19]) (test positive), OR 


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b. 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 
c. 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 
Coexisting Medical Conditions or Past Medical History Exclusion Criteria: 
600. 
Subject is a female who is pregnant, lactating, breastfeeding or planning to become 
pregnant during the study or within 7 days after the last dose of study drug. 
601. 
Subject is a male who is planning to father a child or donate semen during the study or 
within 7 days after the last dose of study drug. 
602. 
Subject has clinically significant abnormalities in the results of laboratory evaluations 
at Screening visit as determined by the investigator or Sponsor, including but not 
limited to:   
• AST, ALT, or alkaline phosphatase ≥ 2x the upper limit of normal (ULN),  
• total bilirubin > 2x ULN (unless diagnosed with Gilbert’s syndrome, in which 
case, total bilirubin > 4x ULN),  
• creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min 
(Appendix 1),  
• 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. 
603. 
Subject has a clinically significant abnormal ECG at Screening, including QTcF 
> 450 msec for males and > 470 msec for females.  
604. 
Subject has 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 CD), genitourinary, psychiatric, oncologic or neurological 
disease or other medical disorder that would compromise subject safety or confound 
study safety assessments as determined by the investigator at Screening and Day 1. 
 
 In addition, subjects with a prior history of 
thrombotic events, including deep vein thromboses (DVT), and those with known 
inherited conditions that predispose to hypercoagulability should be excluded. 
605. 
Subject has known hypersensitivity to excipients or contents of the study drug  


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606. 
Subject has a history of alcohol or drug abuse within 1 year of Screening, per the 
judgment of the investigator 
607. 
Subject with a current or history of malignancy within 5 years prior to Screening, 
except for completely resected basal cell carcinoma or squamous cell carcinoma in situ 
of the skin, or cervical carcinoma in situ that has been adequately treated and without 
recurrence for ≥ 5 years. Subjects with a history of cervical dysplasia within 3 years 
prior to screening or who currently have unresected cervical dysplasia should be 
excluded. 
608. 
Subject who, for any reason, is deemed by the investigator or Sponsor to be 
inappropriate for this study; or has any condition which would confound or interfere 
with the evaluation of the safety, tolerability, or PK of the investigational drug; or is 
unable or unwilling to comply with the study protocol 
609. 
Subject with known moderate to severe hepatic impairment (e.g., known Child-Pugh 
Class B or C) 
4.3. 
Females of Childbearing Potential and Acceptable Birth Control 
Females of childbearing potential must have documentation of a negative pregnancy test at 
screening 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 to be 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 screening in postmenopausal females only 
to confirm postmenopausal state. 
A highly effective method of birth control is defined as one that results in a low failure rate 
(i.e., <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; vasectomized partner; sexual 
abstinence. Vasectomized partner is a highly effective birth control method provided that partner 
is the sole sexual partner of the women of childbearing potential trial participant and that the 
vasectomized 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. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 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. 
STUDY DRUGS 
All study drug supplied by the Sponsor must be stored in a secure location accessible only to 
designated study personnel. 
5.1. 
Description of Study Drugs 
5.1.1. 
TD-1473 
 
 
 
 
  
 
 
5.1.2. 
Placebo 
 
 
  
5.2. 
Dosage and Administration 
During Induction, subjects will take TD-1473 tablets or placebo once daily for up to 12 weeks. 
During ATE, subjects will take TD-1473 tablets once daily for up to 48 weeks. For Induction and 
ATE, subjects will be instructed to take two tablets once daily at approximately the same time 
each morning before eating and to refrain from eating or drinking anything other than water and 
non-study medications for at least 30 minutes after dosing.  
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, as long as the subject has fasted for at 
least 4 hours before. After 12 hours post-nominal dosing time, 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 before the first meal of the day. 
 
 
 
 
 
 
  
 
 
 


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5.4. 
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 medication (TD-1473 and placebo) will be 
maintained in a secure location, accessible only to authorized staff members. Details of receipt, 
distribution or dispensing, and destruction of the material(s) will be recorded in the study 
medication accountability record according to the clinical site’s standard operating procedures. 
Subjects will be instructed to return all used and unused study medication at each study visit. 
Unused and expired study drugs will be disposed of in accordance with written instructions from 
the Sponsor. Copies of the study medication accountability records will be provided to the 
Sponsor at completion of the study and will be made available for review by the site monitor 
during the course of the study. 


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6. 
STUDY PROCEDURES 
Study procedures will be performed only after written informed consent is obtained. The 
Screening visits (i.e., Stage 1 and Stage 2) will be performed within 35 days before dosing. 
One repeat Screening Stage 1 visit is allowed for each subject per the investigator’s discretion. 
No more than one repeat Screening Stage 1 visit or repeat visit-specific procedure/assessment is 
allowed for each subject, unless prior written approval has been provided by the Sponsor. If the 
subject does not begin Induction treatment within this 35-day window, Screening evaluation 
procedures (i.e., Stage 1 and Stage 2) must be repeated. Subjects may be considered for 
re-screening of both Screening Stage 1 and Screening Stage 2 procedures, depending on the 
reason for the initial screening failure, per consultation with and approval from the Sponsor.  
During the study, every effort should be made to perform study procedures as listed in the 
Schedule of Study Procedures (Table 1). Assessments will be made and biological samples will 
be taken in the following recommended order at those study visits at which they coincide: fecal 
sample collection, adverse event assessment, ECG, vital signs, 
 
 clinical laboratory safety samples, 
 and ileocolonoscopy with biopsies 
(although ileocolonoscopy should be done within 3 days prior to the Week 12 clinic visit). Study 
drug administration will be in-clinic on Day 1, Week 4, Week 8, Week 12, ATE Week 16, ATE 
Week 24, ATE Week 36, and ATE Week 48 after all pre-dose assessments 
 
 
 and procedures 
have been completed.  
Throughout the study, the acceptable window for scheduled assessments is as follows: 
• - 3 to + 5 days from the nominal visit date for Week 4, Week 8, ATE Week 4, ATE 
Week 8, ATE Week 16, ATE Week 24, ATE Week 36, ATE Week 48 and the EOS 
visits  
• -1 to +3 days from the nominal Week 12 clinic visit for the Week 12 ileocolonoscopy 
with biopsies. The Week 12 ileocolonoscopy and biopsies should be performed on the 
same day as the Week 12 visit, preferably in the early morning, to permit morning 
dosing with study drug. However, if not feasible to perform both the ileocolonoscopy 
and the clinic visit on the same day, the ileocolonoscopy could be performed within 
3 days after the Week 12 clinic visit. However, the Week 12 endoscopy must be 
performed at least 1 day prior to ATE Day 1. 
• + 3 days from the nominal visit date for the Week 12 clinic visit 
• 1-7 days after the Week 12 clinic visit for ATE Day 1. The Week 12 endoscopy must 
be conducted at least 1 day prior to ATE Day 1. 
• Within 5 days following last dose of study drug for Early IP Discontinuation visit 
(during Induction or ATE) 
 
 
 
 
• Screening CDAI score is to be obtained prior to starting the bowel preparation for 
ileocolonoscopy (to assess eligibility criteria).  


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6.1. 
Schedule of Study Procedures 
The schedule of study procedures is summarized in Table 1. 
Additional safety tests, such as vital signs (blood pressure [BP], heart rate, respiratory rate, and 
body temperature), physical exams, ECGs, and laboratory safety tests, may be obtained during 
the course of the study on the basis of newly available data to ensure appropriate safety 
monitoring. 
6.2. 
Total Blood Volume 
The total estimated volume of blood to be drawn from each subject for safety laboratory 
assessments, serology panel, lipid panel, serum pregnancy test (if applicable), FSH 
(if applicable), 
, QuantiFERON®-TB Gold test, 
 
 
, and genetic testing (if applicable) is 
 For subjects who 
consent to the optional genetic testing, 
 Additional 
samples may be drawn for safety laboratory testing as considered necessary by the investigator.  
6.3. 
Procedures by Visit 
6.3.1. 
Screening  
6.3.1.1. 
Screening Stage 1 
Screening Stage 1 visit assessments will be performed between 35 and 1 days prior to Day 1. 
Initial eligibility assessments will be reviewed and confirmed by the investigator prior to each 
subject continuing on to the endoscopy with biopsy assessments at Screening Stage 2. 
The following procedures will be performed at Screening Stage 1: 
• Written informed consent (signed and dated) after the nature of the study has been 
explained and before any study procedure is performed 
• Review of inclusion and exclusion criteria 
• Medication and medical history 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 


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− Body Temperature 
• 12-lead ECG 
• Physical examination (including fistula exam to determine drainage status if the 
subject has a fistula) to be conducted according to local practice 
• Height and weight 
• Chest X-ray (unless one has been performed within 3 months of Screening, 
documented to be negative, and reviewed by investigator. Subjects who have had a 
chest X-ray within 3 months prior to Screening will not require a repeat X-ray unless 
subject is deemed to be at high risk of recent pulmonary infection) 
• Blood collection 
− Hematology 
− Serum chemistry 
− FSH (postmenopausal females) 
− Viral hepatitis and human immunodeficiency virus [HIV] serology panel (Refer to 
Section 6.4.14 for additional details)  
− QuantiFERON®-TB Gold [unless an exam has been done with negative findings 
within 90 days prior to Screening or subject has a history of latent TB that has 
been adequately treated within the prior 5 years (Refer to Section 6.4.15 for 
additional details)] - If the QuantiFERON®-TB Gold result is indeterminate, a 
repeat QuantiFERON®-TB Gold will be performed.  
− Labs required for Screening Stage 2 can be collected during this visit if the 
subject happens to be fasting during this visit. Subjects should not be instructed to 
come in fasting. 
• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Fecal collection 
− Fecal infectious studies [C. difficile, other bacteria (including Shigella, 
Salmonella, Yersinia, E. coli O157, and Campylobacter), and ova and parasite] 
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Electronic diary dispensation (or paper diary if electronic diary is not available) and 
review of daily diary completion instructions, including symptom monitoring  


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6.3.1.2. 
Screening Stage 2 
Subjects meeting initial eligibility criteria following completion of the Screening Stage 1 
evaluations will return to the clinic for Screening Stage 2 assessments.  
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
visit (which could be Screening Stage 2 visit) to ensure a minimum 8-hour fast prior to the fasted 
blood sample collection for lipid level measurement. 
The following procedures will be performed at Screening Stage 2: 
• Review of inclusion and exclusion criteria 
• Blood collection (if not collected at Screening Stage 1) 
− Overnight fasting lipid panel 
 
 
 
 
• Disease Assessments 
− CDAI Score (must be obtained prior to Screening Stage 2 ileocolonoscopy to 
assess eligibility criteria; must be performed prior to starting the bowel 
preparation for the endoscopy; CDAI score ≥ 220 and ≤ 450 is required for 
continued eligibility) 
− Abdominal Pain and Total Stool Frequency Scores 
− SES-CD Score (to be provided by central reading) 
• Ileocolonoscopy and Biopsies (Refer to Section 6.4.18);  
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Review of diary completion, compliance, and symptom monitoring; counsel subject, 
as needed.  
6.3.2. 
Day 1 (Induction) 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
Day 1 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
Subjects meeting all eligibility criteria following completion of the Screening Stage 1 and 
Screening Stage 2 evaluations will return to the clinic for enrollment assessments on Day 1.  
Prior to dosing on Day 1, the results of the clinical and laboratory evaluations (as described 
in Table 1) must be reviewed by the investigator to confirm the continued eligibility of each 
subject to participate in the study. 
 
 


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The following procedures will be performed on the Day 1 visit: 
• Review of inclusion and exclusion criteria 
• Review of diary completion and compliance 
• Medication and medical history 
• Tobacco use status 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination (including fistula exam to determine drainage status if the 
subject has a fistula) is to be conducted according to local practice  
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
− Genetic blood sample (Optional – only collected for subjects who provide genetic 
testing consent. Refer to Section 6.4.23) 
 
 
 
 
  
 
  
 
 
 
 
• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, the subject does not meet eligibility criteria and cannot proceed with the 
Day 1 visit. A serum b-hCG would need to be performed and confirmed by 
central laboratory testing in order to proceed with randomization.  


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• Fecal collection (may be collected within 72 hours before Day 1 through the end of 
day on Day 1; however, it is preferable that the stool sample be collected during the 
first bowel movement in the morning) 
− 
 
• Disease Assessments 
− CDAI Components  
− Abdominal Pain and Total Stool Frequency Scores 
− 
 
− 
 
• Randomization via RTSM (after all pre-dose procedures have been completed and 
subject is confirmed to be eligible for the study) 
• Subject dosing in clinic (in the morning before eating) 
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Study drug dispensation and review of subject instructions for dosing  
• Re-review diary completion instructions, including symptom monitoring and study 
drug dosing details.  
6.3.3. 
Week 4 (Induction) 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
Week 4 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The following procedures will be performed on the Week 4 visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• Physical examination is to be conducted according to local practice  
• Fistula drainage assessment (if applicable) to determine the number of fistula and 
confirm draining is occurring. 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 


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− 
 
 
 
 
 
  
 
  
 
 
• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Disease Assessments 
− CDAI Components  
− Abdominal Pain and Total Stool Frequency Scores 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating) 
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Study drug dispensation and re-review of subject instructions for dosing  
• Review diary completion and compliance; counsel subject as needed  
6.3.4. 
Week 8 (Induction) 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
Week 8 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The following procedures will be performed on the Week 8 visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• Physical examination is to be conducted according to local practice 
• Fistula drainage assessment (if applicable) to determine the number of fistula and 
confirm draining is occurring. 
• Weight 
• Blood collection 


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− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
 
 
 
 
  
 
  
 
 
• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Disease Assessments 
− CDAI Components 
− Abdominal Pain and Total Stool Frequency Scores 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating) 
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Study drug dispensation and re-review of subject instructions for dosing  
• Review diary completion and compliance; counsel subject as needed  
• Initiate corticosteroid taper by 2.5 mg per week (Section 6.4.30), for subjects who 
entered the study on corticosteroids 
6.3.5. 
Week 10 Telephone Call (Induction) 
Subjects should be called approximately 14 days to 7 days prior to the Week 12 visit. 
The following procedures will be performed at the Week 10 visit: 
• Review concomitant medications 
• Continue corticosteroid taper by 2.5 mg per week (Section 6.4.30), for subjects who 
entered the study on corticosteroids (as applicable) 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 


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• Review diary completion and compliance; counsel subject as needed and remind of 
the importance of completion prior to Week 12 
• Review schedule of upcoming Week 12 visit. Remind the subject not eat anything 
prior to the next visit or take study drug on the morning of their next visit. Review 
bowel preparation activities. 
6.3.6. 
Week 12 (Induction) 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
Week 12 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The Week 12 ileocolonoscopy and biopsies should be performed on the same day as the 
Week 12 visit, preferably in the early morning, to permit morning dosing with study drug. 
However, if not feasible to perform both the ileocolonoscopy and the clinic visit on the same 
day, the ileocolonoscopy could be performed anytime within 3 days after the Week 12 clinic 
visit. If the study activities of this Week 12 visit are to be completed over two different visits, the 
study drug should be continued until the later of the two visits. 
The following procedures will be performed at the Week 12 visit: 
• Tobacco use status 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination is to be conducted according to local practice 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
 
 
 
 
  
 
  
 
 
 
 


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• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Fecal collection [may be collected within 3 full days (approximately 72 hours) prior 
to the visit but must precede the start of a bowel preparation if it is to be collected 
during the same day as the bowel preparation; however, it is preferable that the stool 
sample be collected during the first bowel movement in the morning] 
− 
 
• Ileocolonoscopy and Biopsies (Refer to Section 6.4.18) 
• Disease Assessments 
− CDAI Components  
− Abdominal Pain and Total Stool Frequency Scores 
− SES-CD Score 
− 
 
− 
 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating; last dose of Induction study 
drug)  
• Review concomitant medications 
• Continue corticosteroid taper by 2.5 mg per week (Section 6.4.30), for subjects who 
entered the study on corticosteroids (as applicable) 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Review diary completion and compliance; counsel subject as needed  
6.3.7. 
ATE Day 1  
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
ATE Day1 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
ATE Day 1 may be performed 1 to 7 days following the Week 12 (Induction) visit. However, it 
must be conducted at least 1 day following the Week 12 ileocolonscopy and biopsies. 
The following procedures will be performed at the ATE Day 1 visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 


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− Body Temperature 
• Blood collection 
 
 
 
 
  
 
  
 
 
 
 
• Urine collection 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Assignment of ATE dose (Refer to Table 2 and Section 3.3) 
• Subject dosing in clinic (in the morning before eating) 
• Review concomitant medications 
• Continue corticosteroid taper by 2.5 mg per week (Section 6.4.30), for subjects who 
entered the study on corticosteroids (as applicable) 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Study drug dispensation and re-review of subject instructions for dosing  
• Review diary completion and compliance; counsel subject as needed  
6.3.8. 
ATE Week 4  
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
ATE Week 4 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection.  
The following procedures will be performed at the ATE Week 4 visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• Physical examination is to be conducted according to local practice 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 


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− Overnight fasting lipid panel 
− 
 
 
 
 
 
  
 
  
• Urine collections 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Disease Assessments 
− CDAI Components 
− Abdominal Pain and Total Stool Frequency Scores 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating) 
• Review concomitant medications 
• Continue corticosteroid taper by 2.5 mg per week (Section 6.4.30), for subjects who 
entered the study on corticosteroids (as applicable) 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Study drug dispensation and re-review of subject instructions for dosing  
• Review diary completion and compliance; counsel subject as needed  
6.3.9. 
ATE Week 8 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
ATE Week 8 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The following procedures will be performed at the ATE Week 8 visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination is to be conducted according to local practice 
• Weight 


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• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
 
 
 
 
  
 
  
• Urine collections 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Disease Assessments 
− Abdominal Pain and Total Stool Frequency Scores 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating) 
• Review concomitant medications 
• Confirm corticosteroid taper by 2.5 mg per week (Section 6.4.30) is complete, for 
subjects who entered the study on corticosteroids (as applicable) 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Study drug dispensation and re-review of subject instructions for dosing  
• Review diary completion and compliance; counsel subject as needed  
6.3.10. 
ATE Week 16 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
ATE Week 16 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The following procedures will be performed at the ATE Week 16 visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 


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• Physical examination is to be conducted according to local practice 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
  
• Urine collections 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Disease Assessments 
− CDAI 
− Abdominal Pain and Total Stool Frequency Scores 
− 
 
− 
 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating) 
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Study drug dispensation and re-review of subject instructions for dosing  
• Review diary completion and compliance; counsel subject as needed  
The investigator should consider discontinuation for any subject who has not responded to 
treatment by ATE Week 16. Subjects who have not shown clinical improvement at ATE 
Week 16 should complete an Early Study Drug Discontinuation visit and be discontinued from 
study drug. They will need to return to complete an EOS visit 4 weeks after their last dose.  
6.3.11. 
ATE Week 24 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
ATE Week 24 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The following procedures will be performed at the ATE Week 24 visit: 
• Tobacco use status 
• Vital signs 


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− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination is to be conducted according to local practice 
• Fistula drainage assessment (if applicable) to determine the number of fistula and 
confirm draining is occurring. 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
 
 
 
 
  
 
  
• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Fecal collection [may be collected within 3 full days (approximately 72 hours) prior 
to the visit; however, it is preferable that the stool sample be collected during the first 
bowel movement in the morning] 
− 
 
• Disease Assessments 
− CDAI Components 
− Abdominal Pain and Total Stool Frequency Scores 
− 
 
− 
 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating)  
• Review concomitant medications 


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• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Review diary completion and compliance; counsel subject as needed  
6.3.12. 
ATE Week 36 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
ATE Week 36 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The following procedures will be performed at the ATE Week 36 visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination is to be conducted according to local practice 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Disease Assessments 
− CDAI Components  
− Abdominal Pain and Total Stool Frequency Scores 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating)  
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Review diary completion and compliance; counsel subject as needed  


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6.3.13. 
ATE Week 48 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
ATE Week 48 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The following procedures will be performed at the ATE Week 48 visit: 
• Tobacco use status 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination to be conducted according to local practice 
• Fistula drainage assessment (if applicable) to determine the number of fistula and 
confirm draining is occurring. 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
 
  
• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Fecal collection [may be collected within 3 full days (approximately 72 hours) prior 
to the visit; however, it is preferable that the stool sample be collected during the first 
bowel movement in the morning] 
− 
 
• Disease Assessments 
− CDAI Components 
− Abdominal Pain and Total Stool Frequency Scores 
− 
 


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− 
 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Subject dosing in clinic (in the morning before eating; last dose of ATE study drug)  
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Review diary completion and compliance; counsel subject as needed  
6.3.14. 
End of Study 
An EOS visit will be required for all subjects 4 weeks following their last dose of study drug. 
Subjects who complete an Early Study Drug Discontinuation visit during Induction or ATE will 
also be required to return for an EOS visit. 
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 following procedures will be performed at the EOS visit: 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination is to be conducted according to local practice  
• Fistula drainage assessment (if applicable) to determine the number of fistula and 
confirm draining is occurring. 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 
 
 
• Urine collections 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 


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• Disease Assessments 
− CDAI Components 
− Abdominal Pain and Total Stool Frequency Scores 
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Review diary completion and compliance and collect diary from subject 
6.3.15. 
Early Study Drug Discontinuation 
Subjects who prematurely discontinue the study drug due to adverse events (AEs), lack of 
response, or any other reason besides withdrawal of consent during Induction or ATE 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, if possible. Subjects will also return for the EOS visit for 
collection of safety data and assessment of disease activity.  
During ATE, subjects should be assessed for clinical benefit and if there is no clinical benefit, as 
deemed by the investigator, the subject should stop study drug treatment and be withdrawn from 
the study. 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
Early Study Drug Discontinuation visit to ensure a minimum 8-hour fast prior to the fasted blood 
sample collection. 
The following procedures will be performed at the Early Study Drug Discontinuation visit: 
• Tobacco use status 
• Vital signs 
− Heart rate (HR) and systolic and diastolic blood pressure (BP) 
− Respiratory rate 
− Body Temperature 
• 12-lead ECG 
• Physical examination to be conducted according to local practice 
• Fistula drainage assessment (if applicable) to determine the number of fistula and 
confirm draining is occurring. 
• Weight 
• Blood collection 
− Hematology 
− Serum chemistry 
− Overnight fasting lipid panel 
− 
 


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• Urine collection 
− Urinalysis 
− Pregnancy test for females of childbearing potential – If urine b-hCG test is 
positive, confirmation with serum b-hCG test is required 
• Fecal collection [may be collected within 3 full days (approximately 72 hours) prior 
to the visit; however, it is preferable that the stool sample be collected during the first 
bowel movement in the morning] 
− 
 
• Disease Assessments 
− CDAI Components 
− Abdominal Pain and Total Stool Frequency Scores 
− 
 
− 
 
• Perform drug accountability and review subject’s compliance with study drug dosing 
• Review concomitant medications 
• Adverse event assessment (AEs, SAEs, Adverse Events of Special Interest) 
• Review diary completion and compliance; counsel subject as needed Description of 
Study Assessments 
6.4. 
Description of Study Assessments 
6.4.1. 
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 information to be collected will include: date or year of birth, gender, race, and 
ethnicity. 
Inclusion and exclusion criteria will be assessed at Screening and on Day 1 prior to 
randomization. Subjects will only be eligible for enrollment into the study if they meet all the 
inclusion and none for exclusion criteria. 
6.4.2. 
Medication History 
All medications (i.e., prescription and over-the-counter medications, herbals, vitamins, and 
supplements) used within 60 days of the Screening visit will be recorded. All CD medications 
since diagnosis will be collected, and subjects will be asked at Screening as to whether they ever 
had been or are currently on aminosalicylates, immunomodulators, corticosteroids, biologics, or 
alternative therapies, the names, treatment duration, and the reasons for discontinuation (lack of 
efficacy, loss of efficacy, intolerance, or other).  


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6.4.3. 
Medical History 
A medical history will be taken during Screening and will include evaluation for past and present 
cardiovascular, respiratory, GI, renal, hepatic, neurological, endocrine, lymphatic, hematologic, 
immunologic, dermatologic, psychiatric, genitourinary diseases, surgical history, or any other 
diseases or disorders. An updated medical history will be obtained on Day 1 prior to dosing. 
Medical events or conditions that arise or worsen in severity or frequency following informed 
consent will be recorded as an AE; those after initiation of study drug will be recorded as a 
treatment-emergent AE. 
Regarding the subject’s history of CD, diagnosis date, extent of disease (categorized as ileal, 
colonic, ileocolonic), presence of complications (fistula [including number, location, and 
drainage status], abscess [including location], oral manifestations, arthralgia), documented in the 
appropriate eCRF. The number of stools per day (rounded to the nearest whole digit) when the 
subject was feeling normal (without a flare or before the diagnosis of CD) will be recorded in the 
eCRF. 
6.4.4. 
Tobacco Use Status 
Subject’s current use of tobacco, number of years used, and annual pack years used will be 
obtained at designated study visits according to the Schedule of Study Procedures (Table 1) and 
recorded in the appropriate eCRFs. 
6.4.5. 
Height Measurements 
Height measurement (in cm and without shoes) will be obtained at Screening. 
6.4.6. 
Body Weight  
Weight measurement (in kg and without shoes) will be obtained according to the Schedule of 
Study Procedures (Table 1). 
6.4.7. 
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 calibrated 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.  


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Vital sign measurements should be obtained prior to scheduled blood draws. 
6.4.8. 
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. 
Lead placement should be as consistent as possible for all ECG recordings. ECGs must be 
performed after the subject has been resting in a supine position for at least 10 minutes. All 
ECGs are to be obtained prior to other procedures scheduled at that same time (e.g., vital sign 
measurements, blood draws). Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, phone, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording.  
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 time point during study drug treatment, the QTcF is > 500 msec and/or 60 msec 
longer than the value at Screening or the mean QRS interval is > 130 msec, a repeat ECG should 
be performed for confirmation, and a decision on study drug discontinuation should be made by 
the investigator. 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). 
Of note, it is not necessary to perform more frequent ECG monitoring given an exposure-
response analysis comparing the systemic exposure of TD-1473 with heart rate-corrected 
QT interval (QTcF) was conducted on data collected from performed during the Phase 1 healthy 
volunteer study. At exposures achieved after single doses of up to 1000 mg and steady-state 
exposures following daily doses of up to 300 mg, no concentration-related effect on any cardiac 
intervals was observed. This analysis and preclinical data were used in considering frequency 
and replicate ECGs required for this study. 
6.4.9. 
Physical Examination 
The physical examination will be performed by a physician, nurse practitioner, physician’s 
assistant, or equivalent at each scheduled time point and done according to local practice 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. 


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6.4.10. 
Pregnancy Test (females of childbearing 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. 
6.4.11. 
Follicle-Stimulating Hormone (FSH) 
Follicle-stimulating hormone (FSH) will be tested at Screening in postmenopausal females only 
to confirm postmenopausal state. 
6.4.12. 
Chemistry, Hematology, and Urinalysis 
Laboratory assessments will be performed as specified in Schedule of Study Procedures 
(Table 1). 
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. Repeat laboratory testing of abnormal potentially clinically significant or 
clinically significant results for Screening evaluation of the subject may be repeated at the 
discretion of the investigator. 
Chemistry samples will be analyzed for the following: sodium, potassium, calcium, magnesium, 
chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, alkaline phosphatase, lactate dehydrogenase, ALT, AST, 
gamma-glutamyl transferase, and creatine phosphokinase. 
Hematology samples will be analyzed for the following: hematocrit and hemoglobin; red blood 
cell count; mean corpuscular volume; mean corpuscular hemoglobin; mean corpuscular 
hemoglobin concentration; reticulocyte count; white blood cell count, including differential 
count (percent and absolute) of neutrophils, eosinophils, basophils, monocytes, lymphocytes; and 
platelet count. 
Urinalysis includes determination of specific gravity; presence of blood, glucose, protein, nitrite, 
and leukocytes; and microscopic examination of sediment, if clinically indicated. 
Detailed instructions and collection kits for sample collection, handling, and shipping will be 
provided by the central laboratory. 
6.4.13. 
Overnight Fasting Lipid Panel 
Fasting low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, and total 
cholesterol will be measured at the time points designated in Schedule of Study Procedures 
(Table 1). Subject must fast from food and non-clear fluids for a minimum of 8 hours overnight 
prior to blood collection. 
Detailed instructions and collection kits for sample collection, handling, and shipping will be 
provided by the central laboratory. 


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6.4.14. 
Viral Hepatitis and HIV Serology Panel 
Testing will be performed at Screening for the following: Hepatitis B virus (HBV) surface 
antigen and core antibody (total, which includes IgG and IgM), HCV antibody, hepatitis E 
(IgG and IgM) and Human Immunodeficiency (HIV) antibody. If HBV core antibody is positive 
and the HBV surface antigen is negative, the subject may still be eligible if the HBV DNA is 
undetectable and the HBV surface antibody is present. If HCV antibody is positive, the subject 
may still be eligible for the study if there is documentation of completion of HCV treatment 
followed by two subsequent undetectable viral load test results ≥ 6 months apart before 
Screening and an HCV RNA viral load during Screening is negative. These additional tests 
(hepatitis B DNA, hepatitis B surface antibody, and hepatitis C RNA, if appropriate) may be 
done at Screening Stage 1 or subsequent to it during Screening.  
During rescreening, if there is already negative result from the first screening within 90 days, the 
viral hepatitis B, C, or E or HIV serologies do not need to be repeated. 
Detailed instructions and collection kits for sample collection, handling, and shipping will be 
provided by the central laboratory. 
6.4.15. 
Tuberculosis (TB) Test 
A subject with a history of latent TB or signs of latent TB on chest X-ray or with positive result 
on QuantiFERON®-TB Gold test may be eligible for the Study if the subject:  
1. has completed an adequate course of treatment (e.g., 9-month course of INH or 
equivalent therapy for latent TB) within 5 years (3 years in countries where TB is 
endemic) years prior to Screening, the documentation for which must be included in the 
source document and reviewed by the PI, or currently undergoing an appropriate course 
of treatment (e.g., 9-month course of INH or equivalent therapy for latent TB) and has 
completed at least 3 months of this treatment before Screening with adequate compliance 
(as determined by the investigator), and  
2. has not lived in a region with high prevalence of multidrug-resistant TB.  
3. A subject with a history of latent TB should not undergo TB testing during screening but 
must undergo X-ray if none has been performed within 90 days prior to screening.  
 
A subject with history of active TB may be eligible for the Study if:  
• He or she has completed an adequate course of treatment within 5 years (3 years in 
countries where TB is endemic) prior to Screening (the documentation for which 
must be included in the source document and reviewed by the PI),  
• The QuantiFERON®-TB Gold within 90 days of screening is negative, and  
• The subject has not lived in a region with high prevalence of multidrug-resistant TB  
 
 


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A QuantiFERON®-TB Gold test will be conducted at Screening to assess for signs of latent TB 
unless:  
a. an exam has been done with negative findings within 90 days prior to screening, or  
b. Subject has a history of latent TB that has been adequately treated (e.g., with 
≥ 9 months of INH or equivalent therapy or currently being treated with an 
appropriate course of treatment.  
c. In either case a or b, there must be documentation in the source document, which 
must be reviewed by the investigator.  
 
If the QuantiFERON®-TB Gold result is indeterminate, then repeat QuantiFERON®-TB Gold. 
If results from both tests are indeterminate the subject should be excluded. 
In case of a suspected false-positive QuantiFERON®-TB Gold result (e.g., a negative result by 
the local laboratory and suspicion of sample processing error, both of which must be documented 
in the source document), a second sample may be sent to the central laboratory and the result of 
the second test will be used. 
Detailed instructions and collection kits for QuantiFERON®-TB Gold test, handling, and 
shipping will be provided by the central laboratory.  
6.4.16. 
Chest X-ray 
A chest X-ray will be performed at Screening to assess for signs of latent or active TB or other 
active viral, fungal or bacterial infections unless one has been performed within 90 days prior to 
Screening, documented to be negative, and reviewed by investigator. Posterior anterior (PA) and 
lateral views (lateral view may not be necessary if PA view is deemed adequate) will be 
obtained. Subjects who have had a chest X-ray within 3 months prior to Screening will not 
require a repeat X-ray unless subject is deemed to be at high risk of recent pulmonary infection. 
 
 
 
 
 
 
6.4.18. 
Ileocolonoscopy and Biopsies 
Ileocolonoscopy and biopsies will be performed after subject’s eligibility is confirmed (CDAI 
score within inclusion/exclusion criteria upon review prior to the start of bowel preparation, and 
no exclusionary criteria are met). Subjects who meet locally adapted guidelines for colon cancer 
surveillance should undergo the locally adapted method of surveillance. 
The preparation for any endoscopic procedure is up to the discretion of the investigator. The 
endoscopic score from the Screening procedure performed at Screening Stage 2, assessed by a 
central endoscopy reading team, will be used for eligibility criteria. If possible, it is preferable 
that all endoscopic procedures for each subject are performed by the same endoscopist and the 
same bowel preparation. 


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All procedures can be performed by the investigator or qualified designee using the institution’s 
standard procedure with or without sedation (e.g., conscious sedation, monitored anesthesia, or 
general anesthesia) for endoscopic assessment of disease activity using the SES-CD 
(Appendix 5) and for biopsies. The Week 12 ileocolonoscopy and biopsies should be performed 
on the same day as the Week 12 visit, preferably in the early morning, to permit morning dosing 
with study drug. However, if not feasible to perform both the Week 12 ileocolonoscopy and the 
clinic visit on the same day, the ileocolonoscopy could be performed within 3 days after the 
Week 12 clinic visit. The Week 12 endoscopy must be performed at least 1 day prior to ATE 
Day 1. All procedures will be recorded and the images will be uploaded to the central endoscopy 
reading platform. The SES-CD score will be evaluated by central reading. An endoscopic 
imaging video instruction manual will be provided separately. 
Up to six biopsies per site will be taken at up to three biopsy sites at Screening and Week 12. 
 
During the Week 12 visit, every effort should be made to 
take biopsies in the same areas as done during the Screening ileocolonoscopy regardless of area 
of worst inflammation in the current ileocolonoscopy. Subjects may undergo a total of up to 
three endoscopic procedures during their participation on the study. In subjects who re-screen, 
ileocolonoscopy does not need to be repeated for a rescreening if the ileocolonoscopy is within 
28 days of Day 1 of the re-screen and if the SES-CD score is qualifying.  
Ileal and colonic tissue samples may be preserved and stored in the central laboratory for future 
analysis for up to 20 years or as required by applicable law. A system to ensure optimal 
confidentiality to protect the subjects’ personal information as well as standard processes for 
sample and data collection, storage, analysis, and destruction have been established. Subjects 
who provided tissue samples can withdraw their consent and request disposal of stored samples 
at any time.  
A biopsy manual will be provided with detailed instructions for biopsy site identification, sample 
collection, handling, and shipping. The biopsy sites will be recorded in the eCRF. Biopsy sample 
collection kits will be provided. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4.21. 
Infections 
Infections will be defined as non-treated or treated. Treated infections are infections that require 
anti-microbial therapy. Any infection requiring parenteral anti-microbial treatment resulting in 
hospitalization for treatment or meeting criteria for a SAE is considered to be a serious infection. 
Subjects who experience a serious infection should be discontinued from study drug. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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6.4.23. 
Optional Genetic Testing 
For subjects who provide consent, an additional blood sample will be obtained for possible 
genetic discovery research to identify or validate genetic markers (e.g., pharmacogenomics) that 
may be predictive of the safety, tolerability, efficacy, and/or 
 of TD-1473 
and/or to provide further knowledge of inflammatory bowel disease. This sample should be 
collected at the Day 1 visit if consent for a genetic sample is provided.  
Subjects are not required to consent for optional future genetic research in order to participate in 
this study. If a subject wishes to withdraw consent to the testing of his or her genetic specimen, 
the investigator must inform the Sponsor.  
The optional genetic specimen will be stored for up to 20 years after the end of the study for 
possible future analyses. 
6.4.24. 
Subject Daily Diary 
Subjects will report on a daily basis the time of study drug administration (should be in the 
morning); the use of anti-diarrheal treatments, including opiates if used for anti-diarrheal 
treatment; general well-being; presence of fever; the number of very soft to loose and of normal 
stools; and the severity of the average and of the worst abdominal pain on 4-point (0-3) and 
11-point (0-10) abdominal pain scales, respectively, over the preceding 24-hour period 
(Appendix 7). 
6.4.25. 
Disease Activity Assessments 
The disease activity indices SES-CD and CDAI will be assessed as specified in the Schedule of 
Study Procedures (Table 1). In addition to the patient-reported questions in the CDAI 
questionnaire, subjects will also be asked to rate their worst abdominal pain of the day on a 
 
 and provide the total number of normal stools that occurred within the past 
24 hours. 
6.4.25.1. SES-CD 
The SES-CD incorporates 4 descriptors: the ulcer size, the proportion of surface covered by 
ulcer, the proportion of surface covered by other lesions, and the presence of stenosis. Each 
descriptor is graded from 0-3 and is scored in 5 segments (ileum, right colon, transverse colon, 
left colon, and rectum). The total score is calculated as the sum of all the items in each segment 
and can range from 0 to 56. Please see Appendix 5 for the SES-CD calculation.11  SES-CD data 
will be collected as specified in the Schedule of Study Procedures (Table 1). 
6.4.25.2. CDAI  
The CDAI score is generated using regression coefficients for eight different predictors of 
disease activity: severity of abdominal pain, general well-being, very soft/liquid stool frequency, 
extra-intestinal symptoms, need for antidiarrheal drugs, presence of an abdominal mass, body 
weight and hematocrit. The subject will be provided the Bristol Stool Form Scale as a reference 
for what to consider very soft/liquid stool. See Appendix 6 for the questions that will be asked on 
a daily basis to calculate the CDAI. The subscores of abdominal pain (0-3), general well-being, 
and number of very soft or liquid stools are then summed over the 7 days prior to each visit. 


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CDAI scores should be calculated using the closest previous 7 days not impacted by the 
colonoscopy and/or its preparation. Note that symptoms on the day prior, the day of, and the day 
following a colonoscopy should not be counted as part of the 7 days to avoid effect of the bowel 
preparation or the procedure on symptoms. Additionally, the remaining predictors are also noted 
and weighted to create the total CDAI score. See Appendix 6 for the CDAI calculation.12  
Benchmarks for disease activity as measured by the CDAI are: <150, clinical remission; 150 to 
219, mildly active disease; 220-450, moderately active disease; and >450, very severe disease. 
CDAI data will be collected as specified in the Schedule of Study Procedures (Table 1). Subjects 
will enter the 4 subjective parameters daily from Screening Stage 1 to the last day of study 
participation.  
 
 
 
 
 
 
 
 
  
6.4.25.4. Fistula Drainage Assessment 
Subjects will also undergo fistula exam at Screening, Day 1, and Week 12 as part of the 
complete physical exam. At every visit during Induction, at ATE Week 24, at ATE Week 48 or 
Early Study Drug Discontinuation visit (if applicable), and at the EOS visit, subjects will be 
inquired about any existing fistula. If they have at least one fistula, the subject will confirm 
whether each of the fistula are draining.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4.27. 
Adverse Events (AEs) 
Adverse events, including serious adverse events (SAEs) and adverse events of special interest 
(AESIs) 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 communicate with the site to report AEs that occur 
between visits. Refer to Section 7 for definition, assessment, and reporting of AEs. 
6.4.28. 
Concomitant Medications 
All concomitant non-CD medications (i.e., prescription and over-the-counter medications, 
herbals, vitamins, and supplements) that were used within 60 days of Screening, including name 
of medication, date started and stopped, route of administration, indication, and dose will be 
recorded in the source documentation and on the CRF. Doses of non-CD prescription and 
over-the-counter medications may be altered or new medications may be added during the study 
only if medically indicated and do not confound safety assessment, as deemed by the investigator 
or Medical Monitor; however, such changes should be minimized. Administration of a prohibited 
medication may result in the subject being discontinued from the study. All CD medications the 
subject has ever used should be documented in the eCRF. Medications to be used with clinical 
discretion are listed in Appendix 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4.30. 
Permitted Medications 
Permitted medications include, but are not limited to: 
• Doses of oral aminosalicylate, probiotics, or antibiotics prescribed for CD should be 
stable during the Screening and Induction, after which dose may be adjusted up or 
down during ATE or during the 4 weeks between last dose of study drug and EOS 
visit.  
• Oral corticosteroids for CD are permitted at a stable dose ≤ 25mg/day of prednisone 
or beclomethasone 5 mg/day or equivalent or ≤ 9mg/day budesonide during Day 1 
through Week 12 but need to start to be tapered slowly at Week 8. The required 
tapering regimen is as follows: prednisone (or equivalent) dose should be tapered by 
2.5 mg/day every week until completely off by ATE Week 6. If subject is on 
budesonide, budesonide MMX, or beclamethasone, then the dose should be tapered 
according to clinical practice. Oral, topical, or intranasal corticosteroids for non-CD 
indications are permitted during ATE. 


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• The only rescue medication permitted (i.e., that allows subjects to stay in the study 
and continue study drug) is the addition or increase in oral corticosteroid dose up to 
or above the dose at baseline.  
− If a subject requires one increase of the corticosteroid dose up to baseline dose 
(defined as dose at Day 1) during the taper, he/she can continue study as usual.  
− If subject requires during Induction a) use of a higher corticosteroid dose than the 
baseline dose, or b) de novo initiation of corticosteroids of any route of 
administration for CD symptoms, the subject can continue study drug (but may be 
deemed as meeting treatment failure definition).  The subject would need to taper 
the steroid dose within two weeks after initiation using the tapering regimen as 
outlined above.  
− If subject requires during ATE a) use of a higher corticosteroid dose than the 
baseline dose, or b) de novo initiation of corticosteroids of any route of 
administration for CD symptoms after ATE Week 16, the subject should 
discontinue study drug treatment and return for an EOS Visit. For those who 
initiate or increase corticosteroid dose before ATE Week 16, consider tapering the 
steroids within two weeks after initiation using the tapering regimen as outlined 
above. 
• Addition of, cessation of, or dose adjustments for the following are allowed during 
the study: 
− Hormonal therapy for postmenopausal females 
− Oral contraception for females of childbearing potential 
− Aspirin for cardio protection at a maximum dose of 325 mg/day 
• Any medication used on a long-term basis at a stable dose (e.g., oral contraceptive 
pill, multivitamins); doses of non-CD prescription and over-the-counter medications 
may be altered or new medications may be added during the study only if they are 
medically indicated and do not confound safety assessment, as deemed by the 
investigator or Medical Monitor; however, such changes should be minimized during 
Weeks 1-12. 
6.4.31. 
Restrictions on Alcohol Consumption and Illicit Drug Use 
Alcohol or illicit drug abuse, per the judgment of the investigator, within 1 year of Screening 
until the EOS visit is not allowed. 
6.5. 
Discontinuation 
6.5.1. 
Subject Discontinuation 
Any subject may withdraw their 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.  


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When possible, the tests and evaluations listed for the Early Study Drug Discontinuation visit 
and EOS visit should be carried out, as noted in Sections 6.3.12 and 6.3.15. 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 from the study or a 
subject may choose to terminate participation before completion of the study include the 
following: 
• Adverse event  
• Subject choice / Withdrawal of consent 
• Major violation of the protocol 
• Termination of the study by the Sponsor 
• Need for a new prohibited medication for CD or surgery 
• Lost to follow-up 
• Subject demonstrates lack of clinical benefit (e.g., ATE Week 16 visit)  
• Pregnancy 
• Other 
Subjects with laboratory abnormalities must recheck lab values or discontinue study drug as 
outlined in Section 7.2. Any non-laboratory-related AE considered an AESI defined in 
Section 7.1.4, except for non-melanoma skin cancer, should also lead to study drug 
discontinuation. 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. 
6.5.2. 
Subject Replacement 
At the Sponsor’s discretion, subjects who withdraw or are withdrawn before taking study drug 
may be replaced. Should greater than 10% of treated patients withdraw before the primary 
endpoint visit or miss the primary endpoint visit due to events that could not be foreseen during 
study design planning (e.g., COVID-19 pandemic) then treated subjects may be replaced. Safety 
data will be presented for all subjects in the Clinical Study Report (CSR) regardless of whether 
the subject was a replacement. 
6.5.3. 
Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. Periodic 
review of unblinded safety data by an external Independent Data Monitoring Committee (IDMC) 
(Section 8.10) may lead to the board’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 IRBs and the Regulatory 
Authorities will be informed. 


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6.6. 
Pregnancy 
If a female subject becomes pregnant during the study from the time of consent until 7 days after 
the subject’s last dose of study drug, the Sponsor Clinical Study Director (or designee) must be 
notified immediately, and study drug discontinued if subject is still on study drug treatment. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. If the partner of a male subject becomes pregnant during the study from 
the time of consent until 7 days after the subject’s last dose of study drug, the Sponsor’s Clinical 
Study Director (or designee) must be notified immediately. Follow-up information regarding the 
outcome of the pregnancy and any postnatal sequelae in the infant will be required. 
All pregnancies whether of a subject participating in the study or in the female partner of a 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 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 (such as a biopsy). 
• 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 medication.  
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, endoscopy, 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 
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 study from 
the time of consent until 7 days after the subject’s last dose of study drug, Theravance 
Biopharma, Inc. (TBPH) will be notified according to the procedures for SAE reporting as 


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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 
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 preexisting 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. 
Disability. A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• 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. 
• 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. 


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7.1.4. 
Adverse Events of Special Interest (AESIs) 
At each study visit, the Investigator (or designee) will specifically query for any adverse events 
of special interest (AESIs). 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 antibiotics)  
• opportunistic infections 
• thromboembolic disease (e.g., DVT, pulmonary embolism) 
• clinical laboratory abnormalities of concern (Section 7.2) 
• cardiovascular event (e.g., myocardial infarction or cerebrovascular accident) 
All AESIs, except for non-melanoma skin cancers, must be reported to TBPH Clinical Safety 
and Pharmacovigilance within 24 hours of awareness by the Investigator or his/her designee 
(Section 7.4.3). 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 AESIs, 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.  
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 
considered clinically significant in the judgment of the investigator may be recorded as AEs or 
SAEs if they meet the definition of an adverse event (or serious adverse event), as described in 
Sections 7.1.1 (Adverse Event) and 7.1.2 (Serious Adverse Event). 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. 
Clinical laboratory abnormalities of concern may include, but are not limited to, the following 
where the investigator must recheck within 2-7 days, as deemed appropriate by the investigator, 
except for AST or ALT > 3x ULN where these need to be rechecked within 48-72 hours: 
• clinically significant reduction in leukocytes or leukocyte subsets that may place 
subjects at higher risk for infection such as: 
− moderate neutropenia (e.g., absolute neutrophil count of < 1.0 x 109/L)  


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− moderate leukopenia (e.g., white blood cell count of < 2.0 x 109/L)  
− moderate 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, pre-dose)  
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 neutropenia (e.g., absolute neutrophil count of < 1.0 x 109/L) on two 
sequential lab results 
• moderate leukopenia (e.g., white blood cell count of < 2.0 x 109/L) on two sequential 
lab results 
• moderate lymphocytopenia (e.g., absolute lymphocyte count of < 0.5 x 109/L) on two 
sequential lab results 
• a reduction by ≥ 50% from baseline in creatinine clearance on two sequential lab 
results 
• Abnormal AST or ALT > 3x ULN on two sequential lab results with associated 
bilirubin > 2x ULN on at least one of the two lab results or international normalized 
ratio (INR) >1.5 on at least one of the two reports (INR will need to be checked 
locally), 
• ALT or AST > 8x ULN on a single lab result 
• AST or ALT > 5x ULN on two sequential lab results at least 2 weeks apart, or 
• AST or ALT > 3x ULN on a single lab result associated with signs or symptoms 
suggestive of acute liver injury (e.g., the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
Appendix 12 presents an algorithm for evaluating and managing subjects with ALT or 
AST > 3x ULN 
The first occurrence of these laboratory abnormalities may not trigger the definition of an AESI 
and study drug discontinuation until the second sequential abnormality (except for the two 
bolded circumstances above). If there are any questions as to whether a laboratory abnormality 
should be reported as an AE or an AESI, the investigator is encouraged to contact the Medical 
Monitor to discuss.  
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 medication. 


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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 Medication 
The Investigator’s assessment of causality is based on clinical judgment regarding the reasonable 
possibility that the study medication 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 medication. 
• Whether the AE resolved or improved with decreasing the dose or stopping the study 
medication (“dechallenge”) or recurred or worsened upon re-exposure to the study 
medication (“rechallenge”).  
The causal relationship between the study medication 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. 


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7.3.3. 
Clinical Events Committee (CEC) 
A clinical events committee (CEC) has been established with external experts who 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 describe the membership, 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 patients 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 medication, 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 medication 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 medication 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:   
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).   


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− Relationship to study medication: The Investigator will make an assessment of the 
causal relationship of the study medication 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 (except for non-melanoma skin cancer) 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 medication. 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.  
To report an SAE or AESI, complete and fax or email the appropriate Case Report Form to the 
following: 
Theravance Biopharma Clinical Safety and Pharmacovigilance 
 
 
  
 
For medical questions regarding an SAE or an AESI, contact the Sponsor’s medical monitor by 
telephone as follows: 
Medical Monitor Contact Information: 
 
 
 
  
 
 
 
 


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For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, and 
other documents when requested. Additional information may be requested from the investigator 
to ensure the timely completion of accurate safety reports.  
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable to 
the study drug and is unexpected/unlisted based on the current TD-1473 Investigator’s Brochure. 
In this case, all investigators will receive notification of the event. The investigator is responsible 
for notifying the Institutional Review Board or Ethics Committee and documenting the 
notification, as required by local regulatory authorities and in accordance with the local 
institutional policy. 
7.5. 
Adverse Event Follow-up 
A subject experiencing an AE, SAE or AESI will be followed by the investigator or his/her 
trained delegate(s) through the follow-up visit or until the investigator and/or the Sponsor has 
determined that the AE, SAE or AESI has resolved or a stable clinical endpoint is reached, 
whichever is longer. The Sponsor may request follow-up of certain adverse events until 
resolution and documentation of assessments made during this period. 
The investigator must take all therapeutic measures necessary for resolution of an SAE or an 
AESI. Any medications necessary for treatment of the SAE or AESI must be recorded in the 
concomitant medication section of the case report form. 


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
General Considerations 
All data for each subject will be listed as collected. All statistical summaries and analyses will be 
performed using 
 
Continuous data will be summarized using an 8-point summary (n, mean, standard deviation 
[SD], median, interquartile range [25% quartile, 75% quartile], minimum, and maximum) unless 
otherwise specified in the SAP or table shell. Categorical data will be summarized using counts 
and percentages. 
Study Day 1 is defined as the day of the first study drug dose. The preceding day is 
Study Day -1. 
Baseline is the last assessment (scheduled or unscheduled) obtained before start of study drug 
dosing, unless otherwise specified in the SAP (e.g., for fecal sample assessments). Baseline for 
endpoints that have more than one component is calculated from the individual component 
baselines, whether or not they were assessed during the same visit. 
The study will include 2 formal database locks, one after all 160 subjects have either completed 
or withdrawn from the Induction phase, and one after all subjects have completed or withdrawn 
from the ATE phase. Separate SAPs will be prepared for the following unblinded analyses, and 
finalized before the database are locked for analysis: 
Database lock after the Induction Phase is completed: 
• Analyses of induction data, to include specifications for 
 
SAP, when not otherwise specified, refers to this SAP) 
•
 
 
 
Database lock after the ATE phase is completed: 
• Analyses of ATE data 
 
Any changes to the data summaries and analyses outlined in this section will be described in the 
applicable SAP. Any major changes to the definition of the primary endpoint will also be 
included in a protocol amendment. 


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8.2. 
Sample Size and Power 
Assuming that the less effective TD-1473 dose results in a 45-point improvement in 
placebo-adjusted CDAI score change at Week 12, the more effective dose results in a 60 point 
improvement, the residual SD is 100 points, and a sample size of 160 subjects with 60 subjects in 
each of the active dose groups and 40 subjects in the placebo group, 100,000 simulations 
performed using SAS/IML software yielded the following power estimates for 2-sided testing 
with the familywise Type I error rate controlled at 5% using the Hochberg step-up procedure: 
• 82% power to show at least one of the two doses effective 
• 58% power to show both doses effective 
The target effect size of 60 points was selected as predictive of a clinically significant increase in 
clinical response rate. Of note, the study is not powered for the secondary endpoints. 
8.3. 
Analysis Sets 
The modified Intent-to-Treat (mITT) analysis set comprises all randomized subjects who receive 
at least one dose of study drug and have at least one postbaseline CDAI score. The mITT set is 
the primary analysis set for efficacy summaries and analyses. 
The Per-Protocol (PP) analysis set comprises all subjects in the mITT analysis set with no major 
analysis protocol deviations (Section 8.3.2). If the number of mITT subjects excluded from the 
PP analysis set is ≤ 5 per treatment group, PP analyses will not be performed. Otherwise, both 
the mITT and the PP analysis set will be used for selected efficacy summaries and analyses. 
The Safety analysis set comprises all subjects who receive at least one dose of study drug. The 
Safety analysis set will be the analysis set for both general (baseline, exposure, and compliance) 
and safety analyses. 
 
, 
 
 
 
 
 
 
 
Except for the 
 
 Analyses using the 
mITT analysis set will be by randomized treatment. Analyses using the PP analysis set and the 
Safety analysis set will be by actual treatment.  
8.3.1. 
Examination of Subgroups 
Predefined subgroups will include the following: 
• Prior biologics failure (Yes, No) 
• CDAI score at Screening Stage 2 (≤ 300 or > 300) 


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Others will be defined in the applicable SAP. For analysis purposes, prior biologics failure status 
and baseline CDAI score will be determined using the information captured in the clinical 
database rather than the information in the RTSM database.  
For selected efficacy endpoints, results will be provided by subgroup. 
8.3.2. 
Major Analysis Protocol Deviations 
The following protocol deviations are considered major and as affecting analyses of efficacy 
data: 
 
 
 
 
 
 
 
 
 
Additional categories may be specified in the applicable SAP. 
8.4. 
General Analyses 
8.4.1. 
Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics including age, sex, race, ethnicity, 
creatinine clearance, weight, body mass index, CD characteristics, previous and current CD 
medications by category, and other medical history will be summarized. 
8.5. 
Efficacy Analyses 
8.5.1. 
Efficacy Endpoints 
The primary endpoint is: 
• CDAI score change from baseline at Week 12 
The secondary endpoints are: 
• CDAI clinical response (defined as reduction from baseline of ≥ 100 points or CDAI 
< 150) at Week 12 
• CDAI clinical remission (defined as CDAI < 150) at Week 12 
• SES-CD change from baseline at Week 12 
• Endoscopic response (SES-CD reduction of ≥ 50% from baseline or endoscopic 
remission) at Week 12 
• Stool Frequency and Abdominal Pain (SFAP) clinical remission defined as abdominal 
pain score ≤ 1 (on a scale of 0-3), stool frequency ≤ 2.8, and both not worse than 
baseline at Week 12 


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8.5.2. 
Primary Efficacy Evaluations 
The primary analysis of CDAI score change at Week 12 will be performed by fitting a mixed 
effects repeated measures model to values at Weeks 4, 8, and 12, with baseline CDAI score as a 
covariate, using SAS procedure MIXED to fit a model with random subject effects, an 
unstructured covariance matrix, and including terms for prior biologics failure status, visit, and 
baseline CDAI score by visit and treatment by visit interactions. 
The effect of each TD-1473 dose on reduction in CDAI at Week 12 (and also at Week 4 and at 
Week 8) will be estimated. These estimates are unbiased if missing data are missing at random 
(MAR). This assumption will be assessed with a missing data sensitivity analysis if at least one 
TD-1473 dose is shown to reduce Week 12 CDAI more than placebo. 
As a sensitivity analysis, CDAI score change at Week 12 will also be analyzed by fitting the 
equivalent analysis of covariance (ANCOVA) model, using SAS procedure MIXED to fit an 
equal-slopes model with terms for prior biologics failure status, baseline CDAI score, and 
treatment. 
8.5.3. 
Secondary and Exploratory Efficacy Evaluations 
Binary efficacy endpoint rates will be compared using stratified Cochran-Mantel-Haenszel tests, 
stratifying by randomization stratum as determined from information in the clinical database. 
Selected binary endpoints will also be analyzed by fitting logistic regression models. Confidence 
intervals for treatment effects with nominal confidence level 95% will be calculated by methods 
specified in the SAP. 
 and other efficacy endpoints assessed only at baseline and Week 12 will 
be analyzed by fitting an ANCOVA model like the one given for CDAI score change at 
Week 12. The covariate in each model will be the baseline value of the endpoint. 
 
 
 and other efficacy endpoints assessed at baseline and Weeks 4, 8, and 12 will be analyzed 
by fitting a mixed effects repeated measures model like the one given for CDAI score change at 
Week 12. The covariate in each model will be the baseline value of the endpoint. 
 
 
8.5.4. 
Multiplicity Adjustment 
A Hochberg step-up procedure will be used for testing hypotheses associated with the primary 
efficacy endpoint (mean change in CDAI at Week 12): 
Each TD-1473 dose will be compared with placebo. The null hypothesis will be that there is no 
difference between the TD-1473 dose level mean and the placebo mean, and the alternative 
hypothesis will be that they differ. To control the family-wise type 1 error rate at 5%, the 
Hochberg step-up procedure will be used: 
Step 1. If both p-values are ≤ 0.05, reject both no-effect null hypotheses and conclude that both 
TD-1473 doses reduce the CDAI score at Week 12, compared to placebo; otherwise 
Step 2. If the smaller p-value is ≤ 0.025, reject the no-effect null hypothesis for that dose; 
otherwise 


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Step 3. Fail to reject both no-effect null hypotheses and conclude that TD-1473 does not reduce 
the CDAI score compared to placebo. 
 
 
 
 
 
  
 
 
 
 
 
 
8.7. 
Pharmacodynamic Analyses 
Tissue markers of inflammation and whole blood and serum samples will be collected as 
described in the Schedule of Study Procedures tables (Table 1). PD analyses will be detailed as 
appropriate. 
 
 
8.8. 
Safety Analyses 
Safety data will be summarized by treatment received; specifically, induction safety data will be 
summarized by treatment received during induction and ATE safety data by treatment received 
during the ATE. Summaries will be provided by nominal visit and time point or for the entire 
treatment period, as appropriate for the type of data. Quantitative data collected at unscheduled 
times will be listed but will not be included in summaries. Categorical data collected at 
unscheduled times (e.g., ECG finding categories) will not be included in summaries by time 
point but will be included in summaries of findings during the entire treatment period. 
 
 
 
 
 
 
 
8.8.2. 
Adverse Events 
AEs will be coded to the preferred terms of the Medical Dictionary for Regulatory Activities 
(MedDRA®). Summaries will present by system organ class (SOC), preferred term (PT), and 
severity (mild, moderate, severe) the number and percentage of subjects for whom events were 
reported. 


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In general, a treatment-emergent adverse event (TEAE) will be defined as any AE that begins on 
or after the date and time of the first dose of study drug and up to the date of last dose of study 
drug plus the number of days in the follow-up period.  
TEAEs will be summarized separately for the Induction and ATE phases. Assignment of TEAEs 
to different phases of the study (Induction or ATE) will be detailed in the SAPs. 
All AEs will be listed by subject. The number and percentage of subjects who experience TEAEs 
will be summarized. Summaries of TEAEs will include the following types of summaries: 
• All AEs, by SOC and PT and also by PT (by descending overall frequency) 
• All AEs, by SOC, PT, and severity 
• All study drug-related AEs, by SOC and PT 
• All study drug-related AEs, by SOC, PT, and severity 
• All AEs leading to premature discontinuation of study drug, by SOC and PT 
• All AEs leading to temporary interruption of study drug, by SOC and PT 
• All SAEs, by SOC and PT 
• All study drug-related SAEs, by SOC and PT 
A listing will be provided for all subjects who experience an SAE. Listings will also be provided 
for subjects who discontinued study treatment prematurely because of AEs and subjects who 
temporarily interrupted study treatment because of AEs. AEs of Special Interest, as described in 
Section 7.1.4, will be listed and summarized. 
8.8.3. 
Concomitant Medications 
Medication names will be mapped according to the World Health Organization Drug Dictionary. 
The following induction summaries will be provided, by drug class and preferred name: 
• Prior CD medications 
• Prior medications with indications other than CD 
• Concomitant medications including those with indication for CD 
The prior medications summaries will be restricted to medications stopped before first study 
drug dose. The summary of concomitant medications will comprise all medications taken during 
the treatment period, including medications ongoing at entry. 
Concomitant medication use during the ATE will be summarized separately. 
8.8.4. 
Laboratory Data 
Laboratory values, changes from baseline, values relative to normal ranges, and values and 
changes meeting specified criteria, including the numeric criteria given as examples in 
Section 7.2, will be summarized. 
Clinical laboratory test results will be listed by subject. Reference ranges provided by the 
laboratory for each test will be used to evaluate the clinical significance of laboratory test results. 


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Values falling outside the relevant reference range will be flagged, as appropriate, in the data 
listings. Abnormalities in clinical laboratory test results will be listed in a separate listing. 
8.8.5. 
Vital Signs Data 
HR, systolic and diastolic BP, respiratory rate, and body temperature values at each visit and 
time point and changes from baseline at each visit and time point after the first dose will be 
summarized, and counts and percentages will be shown for the categories in Table 3. 
Table 3: 
Thresholds for Vital Signs 
Heart Rate 
(bpm) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
< 40 
> 110 
< 85 
> 160 
< 45 
> 100 
8.8.6. 
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: 
Table 4: 
ECG Interval Ranges 
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 
  
In addition, QTcF (msec) 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). 


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All recorded ECG interval values and ECG assessments will be presented in a by-subject listing. 
A separate listing of subjects with extreme values or changes, as specified in the SAP 
(e.g., values of QTcF > 450 msec if male or > 470 msec if female, QTcF increases from baseline 
> 60 msec) will be provided. 
8.9. 
Handling of Missing Data 
For the primary analysis of score change endpoints (e.g., CDAI score change, SES-CD 
score change), missing values will not be imputed. Sensitivity analyses for the primary endpoint 
will be specified in the SAP, and will be performed if one or both TD-1473 doses are shown to 
reduce Week 12 CDAI more than placebo. 
Subjects with missing data for binary efficacy endpoints will be counted as treatment failures. 
Alternative approaches may be specified in the SAP.  
In addition, subjects who had nonmissing data for a binary efficacy endpoint meeting the 
criterion for success but met one of the following criteria prior to the visit will be counted as 
treatment failures: 
• Received rescue medication, defined as any medication given to treat CD symptoms, 
other than antidiarrheal medication for control of chronic diarrhea, if started 
postbaseline or if the dose was increased postbaseline to a dose higher than at 
baseline (both induction and ATE; ATE baseline is Week 12) 
• Experienced disease worsening, defined as an increase in CDAI score from baseline 
of ≥ 100 points at consecutive visits (ATE only; ATE baseline is Week 12) 
 
 
 
 
 
8.10. 
Independent Data Monitoring Committee 
There will be an external independent data monitoring committee (IDMC) comprising four 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 1572 and, if applicable, a 
financial disclosure form. For applicable studies, financial disclosure forms must also be 
completed for all subinvestigators who will be directly involved in the treatment or evaluation of 
research subjects in this study. (A subinvestigator 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 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. 
• 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. 


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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 diary, electronic laboratory data 
transfer. Study site personnel will enter (in English) study data into the CRFs for each subject 
that is screened. Training on systems used by site personnel (e.g., EDC) or study subjects 
(e.g., electronic diary) will be completed and documented before access to the system is given. 


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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, electronic clinical outcome assessments (eCOA), and 
electronic diary 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 
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. 


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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. 
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. 


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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. Behzadi, Payam, Elham Behzadi, and Reza Ranjbar. "The incidence and prevalence of 
Crohn’s disease in global scale." SOJ Immunol 3.2 (2015): 1-6. 
2. Ng, S.C., et al., Worldwide incidence and prevalence of inflammatory bowel disease in 
the 21st century: a systematic review of population-based studies. Lancet, 2017. 
3. 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. 
4. Kappelman, M.D., 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. 
5. Longobardi, T., P. Jacobs, and C.N. Bernstein, Work losses related to inflammatory 
bowel disease in the United States: results from the National Health Interview Survey. 
Am J Gastroenterol, 2003. 98(5): p. 1064-72. 
6. Sandborn, William J., et al. OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE 
Sustain Investigators. N Engl J Med. 2017 May 4;376(18):1723-1736. 
7. Vermeire et al. Clinical remission in patients with moderate-to-severe Crohn’s disease 
treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, 
randomized, placebo-controlled trial. Lancet 2016. 
8. Sandborn, William J., et al. Safety and Efficacy of ABT-494 (Upadacitinib), an Oral Jak1 
Inhibitor, as Induction Therapy in Patients with Crohn's Disease: Results from 
Celest. Gastroenterology 152.5, 2017. S1308-S1309. 
9. Molnar T., Annaházi A. (2014) Pathogenesis of Ulcerative Colitis and Crohn’s Disease: 
Similarities, Differences and a Lot of Things We Do Not Know Yet. J Clin Cell Immunol 
5: 253. doi:10.4172/2155-9899.1000253 
10. Banholzer, M.L., et al., Clinical trial considerations on male contraception and collection 
of pregnancy information from female partners. J Transl Med, 2012. 10: p. 129. 
11. Koutroumpakis E, Katsanos KH. Implementation of the simple endoscopic activity score 
in Crohn's disease. Saudi J Gastroenterol. 2016;22(3):183‐191. 
12. Best, W.R., Becktel, J.M., Singleton, J.W. and Kern, F., 1976. Development of a Crohn's 
disease activity index. Gastroenterology, 70(3), pp.439-444. 
 
 
 
 


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APPENDIX 1. COCKCROFT-GAULT CALCULATION 
The estimated creatinine clearance (mL/min) will be calculated 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 2. PROTOCOL SIGNATURE FORM 
Protocol Signature Form 
Protocol #: 
0173 
Protocol Title:   
A Phase 2 Multi-Center, Randomized, Double-Blind, 
Placebo˗Controlled, Parallel-Group Study to Evaluate the Efficacy and 
Safety of Induction Therapy with 2 Doses of TD-1473 in Subjects with 
Moderately-to-Severely Active Crohn’s Disease 
Version: 
 
Version Date: 
09 June 2020 
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 


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APPENDIX 3. MEDICATIONS TO USE WITH CLINICAL DISCRETION 
In vitro metabolism data indicate that CYP3A4/5 and CYP2D6 are the primary human CYP 
enzymes involved in the metabolism of TD-1473. Since TD-1473 is expected to have a low 
fraction absorbed, the potential for a CYP-mediated drug-drug interaction (DDI) with 
inhibitors/inducers of the CYP450 enzymes (i.e., the impact of other drugs on TD-1473) is 
considered to be low. However, limited data exist in humans at this time. Due to the potential for 
interaction with TD-1473, strong CYP3A4 inducers and inhibitors should be avoided. 
In vitro CYP450 inhibition and induction metabolism data suggest that TD-1473 has a low 
potential to inhibit or induce CYP450 enzymes. TD-1473 did not induce the expression or 
activity of CYP enzymes (CYP1A2, CYP2B6, CYP3A4) in cultured human hepatocytes and is 
not expected to achieve free plasma concentrations high enough to activate hepatic PXR. 
TD-1473 showed competitive inhibition of CYP3A4 (IC50 = 4.5 μg/mL) and CYP2D6 
(IC50 = 6.0 µg/mL), but the maximum unbound TD-1473 plasma concentrations observed in 
healthy subjects dosed up to 1000 mg were > 500-fold lower than the CYP3A4 IC50. Therefore, 
it is unlikely that TD-1473 would impact the exposure of any concomitantly administered CYP 
substrates.  
In vitro evaluation indicate that TD-1473 is a substrate for both the efflux transporters P-gp and 
BCRP. The potential for a transporter-mediated DDI with inhibitors of P-gp or BCRP 
(i.e., impact to TD-1473 systemic exposure due to a change in fraction absorbed) is considered to 
be moderate.  
TD-1473 is an inhibitor of BCRP (IC50 = 1.2 μg/mL), P-gp (IC50 = 32 μg/mL), and OATP2B1 
(IC50 <4.0 µg/mL). Due to the low systemic exposure observed in the Phase 1 healthy subject 
study and Phase 1b study in subjects with UC (detailed in Section 1.3 and Section 1.4, 
respectively), hepatic inhibition of these transporters is not expected. However, based on fecal 
and intestinal tissue concentrations observed in clinical studies, inhibition of intestinal BCRP and 
OATP2B1 by TD-1473 may occur at doses above 30 mg. For medications with limited 
bioavailability due to BCRP-mediated restriction to the GI tract, caution should be exercised if 
concurrent therapy with TD-1473 is required since TD-1473 may result in a change in systemic 
exposure (e.g., sulfasalazine). All medications that are substrates of P-gp or BCRP with a narrow 
therapeutic index (e.g., digoxin and dabigatran) should be avoided. Although limited clinical 
evidence exists to assess the impact of OATP2B1 inhibition on concomitantly administered 
drugs which are OATP2B1 substrates, the potential for TD-1473 to have a clinically meaningful 
impact is considered to be low.   
Due to the potential for interaction with TD-1473, medications that are strong P-gp or BCRP 
inhibitors should be avoided. A non-exhaustive list of CYP3A4, P-gp, and BCRP inducers and 
inhibitors is provided. A non-exhaustive list of examples is provided. Examples: amiodarone, 
carbamazepine, carvedilol, clarithromycin, curcumin, cyclosporine, daclatasvir, dronedarone, 
eltrombopag, fostamatinib, grapefruit or grapefruit juice, itraconazole, ketoconazole, lapatinib, 
ledipasvir, paritaprevir, phenytoin, posaconazole, propafenone, ombitasvir, quinidine, ranolazine, 
rifampin, ritonavir, sofosbuvir, St. John’s wort, telaprevir, velpatasvir, verapamil, and 
voriconazole. For clarity: 1) any amount of grapefruit in the diet is prohibited; 2) curcumin is 
prohibited as a concentrated supplement, but dietary intake is allowed; 3) corticosteroids at doses 
not excluded elsewhere in the protocol are not considered strong CYP3A4/P-gp/BCRP inducers. 


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APPENDIX 4. DEFINITION OF PRIOR BIOLOGICS FAILURE: 
PRIMARY AND SECONDARY NON˗RESPONSE OR 
INTOLERANCE TO PREVIOUS BIOLOGICS 
Primary non-response:  
Subjects were to have received induction doses of at least one of the following: 
• Infliximab (3 doses of 5 mg/kg or 10 mg/g at Weeks 0, 2, and 6 or earlier) 
• Adalimumab (dose of 160 mg at Week 0 followed by a dose of 80 mg at Week 2 or 
earlier) 
• Certolizumab pegol (3 doses of 400 mg at Weeks 0, 2, and 4 or earlier)  
• Vedolizumab 300 mg administered by intravenous infusion at Weeks 0, 2, and 6 or 
earlier 
• Ustekinumab single intravenous weight-based infusion 260 mg (< 55 kg), 390 mg 
(55-85 kg) or 520 mg (> 85 kg) 
And did not respond to these induction doses as evidenced by at least 1 of the following signs or 
symptoms related to persistently active Crohn’s disease occurring within 2 weeks after receiving 
the last dose: 
• Lack of improvement or worsening in stool frequency. 
• Lack of improvement or worsening in daily abdominal pain. 
• Occurrence, lack of improvement or worsening fever thought to be related to Crohn’s 
disease. 
• Recurring drainage from a previously non-draining fistula or development of a new 
draining fistula. 
• Lack of improvement or worsening in rectal bleeding. 
• Initiation or increase in antidiarrheal medication. 
 
Secondary non-response: 
Initially responded to induction therapy and received at least 2 of the following maintenance 
doses: 
• Infliximab (at a dose of ≥ 5 mg/kg every 8 weeks or more frequently) 
• Adalimumab (at a dose of 40 mg every week or every other week) 
• Certolizumab pegol (at a dose of 400 mg every four weeks or more frequently) 
• Vedolizumab 300 mg administered every 8 weeks or more frequently 
• Ustekinumab subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, 
then every 8-12 weeks thereafter or more frequently. 


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And had at least 1 of the following signs or symptoms related to recurrence of Crohn’s disease 
occurring within two weeks of receiving the last dose: 
• Worsening in stool frequency. 
• Worsening in daily abdominal pain. 
• Occurrence or worsening in fever thought to be related to Crohn’s disease. 
• Recurring drainage from previously non-draining fistula or development of a new 
draining fistula. 
• Worsening rectal bleeding. 
• Initiation or increase in antidiarrheal medication. 
 


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APPENDIX 5. SES-CD 
The SES-CD incorporates 4 descriptors: the ulcer size, the proportion of surface covered by 
ulcer, the proportion of surface covered by other lesions, and the presence of stenosis. Each 
descriptor is graded from 0-3 and is scored in 5 segments (ileum, right colon, transverse colon, 
left colon, and rectum). The total score is calculated as the sum of all the items in each segment 
and can range from 0 to 56.11  
Simple Endoscopic Score (SES-CD) 
Variable 
0 
1 
2 
3 
Size of ulcers (cm) 
None 
Aphthous ulcers 
(diameter 0.1-0.5) 
Large ulcers 
(diameter 0.5-2) 
Very large ulcers 
(diameter >2) 
Ulcerated surface 
None 
< 10% 
10-30% 
> 30% 
Affected surface 
Unaffected 
segment 
< 50% 
50-75% 
> 75% 
Presence of 
narrowings 
None 
Single, can be 
passed 
Multiple, can be 
passed 
Cannot be passed 
 
SES-CD score equals the sum of all variables for the 5 bowel segments. Values are given to each 
variable for every examined bowel segment.11   
 
 
 


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APPENDIX 6. EXAMPLE OF THE CDAI 
Crohn's Disease Activity Index (CDAI)12 
Variable 
Day 
7 Day 
Total 
Weighting 
Factor 
Total 
  
1 
2 
3 
4 
5 
6 
7 
 
x2= 
1. Number of liquid or very soft stools 
 
 
 
 
 
 
 
2. Abdominal pain 
0=none, 1=mild, 2=moderate, 3=severe 
 
 
 
 
 
 
 
 
x5= 
 
3. General well-being 
0=generally well, 1=slightly under par, 2=poor, 
3=very poor, 4=terrible 
 
 
 
 
 
 
 
 
x7= 
4. Extra-intestinal manifestations, Current 
Check all that Apply 
a. Arthritis/arthralgia 
 
 
b. Iritis/uveitis 
 
 
c. Erythema nodosum, pyoderma gangrenosum, 
aphthous stomatitis 
 
 
d. Anal fissure, fistula, or abscess 
 
 
e. Other fistula 
 
 
f. Fever over 37.8C (100F) during past 7 days 
 
 
Total number of checked boxes= 
 
x20= 
 
5. Lomitil, Imodium, Opiates for diarrhea in the 
last 7 days 
No=0, Yes=1 
 
x30= 
 
6. Abdominal mass 
None=0, Questionable=2, Definite=5 
 
x10= 
 
7. Local Haematocrit (%, rounded to whole) 
If Male, 47-______= 
If Female, 42-_____= 
If negative, enter 0 
 
x6= 
8. Body weight calculation 
Percentage deviation from standard weight x1= 
If value is less than -10, enter -10 
CDAI TOTAL= 
 
 
 


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APPENDIX 7. EXAMPLE OF THE SUBJECT DAILY DIARY 
The following questions will be assessed daily in the subject daily diary. The first 6 pertain to the 
CDAI: 
 
Variable 
Day 
1 
2 
3 
4 
5 
6 
7 
1. Number of liquid or very soft stools (collected 
via the Bristol Stool Form Scale) 
 
 
 
 
 
 
 
2. Number of normal stools (collected via the 
Bristol Stool Form Scale) 
 
 
 
 
 
 
 
3. Average abdominal pain 
0=none, 1=mild, 2=moderate, 3=severe 
 
 
 
 
 
 
 
4. Fever (yes/no) 
 
 
 
 
 
 
 
5. Use of Imodium, Lomotil, or opiates for 
diarrhea (yes/no) 
 
 
 
 
 
 
 
6. Well-being  
0=generally well, 1=slightly under par, 2=poor, 
3=very poor, 4=terrible 
 
 
 
 
 
 
 
7. Worst abdominal Pain of the day 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additionally, there will be daily information collected on the timing of dosing. 
 


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APPENDIX 10. DEFINITION OF CD MEDICATION INTOLERANCE OR 
INADEQUATE RESPONSE AND OF CORTICOSTEROID 
DEPENDENCE 
1. Definition of intolerance or inadequate response: 
a. Aminosalicylates: 
• Signs and symptoms suggestive of persistence of active disease despite an 8-week 
regimen at the highest dose either defined by local guidelines or by subject’s 
tolerance 
b. Corticosteroids: 
• Signs and symptoms suggestive of persistence of active disease despite a 4-week 
regimen that included ≥ 2 weeks of ≥ 25 mg/day of prednisone or beclomethasone 
diproprionate (i.e., Clipper) at 5 mg/day or equivalent 
• Intolerance (including, but not limited to hyperglycemia, infection, Cushing’s 
syndrome, anxiety, weight gain, blurry vision, corticosteroid-induced 
hypertension, intolerable insomnia, osteopenia/osteoporosis)  
c. Immunomodulators (azathioprine, 6-mercaptopurine or methotrexate): 
• Signs and symptoms suggestive of persistence of active disease despite a regimen 
≥ 8 weeks of oral azathioprine (≥ 1.5 mg/kg) or 6-mercaptopurine (≥ 0.75 mg/kg) 
• Signs and symptoms suggestive of persistence of active disease despite a history 
of at least one 12-week regimen of methotrexate of 12.5 mg/week 
• Intolerance of at least one immunomodulator (including, but not limited to 
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, 
TPMT genetic mutation, infection)  
d. Biologics (anti-TNF or anti-integrin; Refer to Appendix 4 for further detail):   
• Signs and symptoms suggestive of persistence of active disease despite 
completing an Induction regimen 
• Symptom recurrence during Maintenance dosing following previously 
demonstrating clinical benefit 
• Intolerance (including, but not limited to infusion-related reaction, rash, injection 
site reaction, demyelination, congestive heart failure, infection) 
2. Definition of corticosteroid dependence: 
a. Requiring prednisolone ≥10mg/d (or equivalent) or ≥budesonide 3mg/d for 
≥3 months to control CD, OR 
b. Relapse within 3 months of stopping steroid therapy, OR 
c. Unable to discontinue corticosteroids without flare within 3 months after initiating 
them 
 


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APPENDIX 12. 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 (eg, 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 obtained and these values should be followed until 


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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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− 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. 
 
Abbreviation 
Description 
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 


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Abbreviation 
Description 
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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APPENDIX 13. SPONSOR GUIDANCE ON STUDY CONDUCT DURING 
THE CORONAVIRUS DISEASE 2019 (COVID-19) 
PANDEMIC 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
drug including follow-up, to the extent possible. However, the sponsor recognizes that the 
COVID-19 pandemic may have an impact on the conduct of this clinical study including, but not 
limited to: self-isolation or quarantine by study participants and study-site personnel, travel 
restrictions and limited access to public places (including hospitals), and study site personnel 
being reassigned to critical tasks. Thus, while aligning with recent health authority guidances, the 
sponsor is providing options for managing study participants in the event of a disruption to the 
conduct of the study due to the COVID-19 pandemic. This sponsor guidance does not supersede 
local or government guidelines, requirements, or the clinical judgement of the investigator. 
Protecting the safety, welfare, and rights of study participants must be of utmost priority. If a 
participant’s safety is at risk, study drug should be discontinued at the discretion of the 
investigator, and study follow-up should be conducted. The sponsor will continue to monitor the 
conduct and progress of the clinical study, and any changes will be communicated to the sites 
and to the health authorities according to local guidance. If a participant has confirmed or 
suspected COVID-19, the investigator should contact the Medical Monitor to discuss plans for 
study drug and follow-up and report as an AE. 
Measures Considered 
Protocol-required visits to the clinical site may not be possible during the COVID-19 pandemic. 
Hence, temporary measures may be implemented, if deemed appropriate by the sponsor and 
investigator, to maintain continuity of participant care and study integrity. Certain measures, 
including but not limited to, those listed below, may be necessary and should be taken in 
accordance with applicable laws, regulations, guidelines, and procedures:  
• Virtual or remote (e.g., by phone/telemedicine) and/or off-site (e.g., in-home) 
interactions between site staff (or designees) and participants for study procedures 
such as those related to safety monitoring, efficacy evaluation, and study drug 
administration (including training where pertinent). 
− Conduct interview with participants to collect safety data and include questions 
regarding general health status.  
− Perform key efficacy endpoint assessments (endoscopy, 
 
 
 in-person 
as required, and if feasible. If an in-person visit is not feasible, the minimum 
assessment to be performed remotely include obtaining information for the 
 
• Procurement of study drug by participants (or designee) from the site or shipment of 
study drug directly to participants for at home administration. 
• Laboratory assessments using a suitably accredited local laboratory; for selected 
assessments such as urine pregnancy, home testing may be conducted. 
 
 


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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 screening 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: 0173 
Official Title: A Phase 2 Multi-Center, Randomized, Double-Blind, Placebo˗Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of Induction Therapy with 2 Doses of TD-1473 in Subjects with 
Moderately-to-Severely Active Crohn’s Disease 
NCT Number: NCT03635112 
Document Date:  27 January 2022


 
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STATISTICAL ANALYSIS PLAN 
Protocol Title:  
A Phase 2 Multi-Center, Randomized, Double-Blind, 
Placebo˗Controlled, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Induction Therapy with 2 Doses of TD-1473 in 
Subjects with Moderately-to-Severely Active Crohn’s Disease 
 
Protocol Number:  
0173 
Compound Number: 
TD-1473 
Short Title:  
DIONE – Efficacy and Safety of TD-1473 in Crohn’s Disease 
 
 
Sponsor Name:  
Theravance Biopharma Ireland Limited 
Legal Registered Address: 
Theravance Biopharma Ireland Limited Connaught House 
1 Burlington Road  
Dublin 4  
D04 C5Y6  
Ireland 
 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
IND 
139354 
EudraCT 
2018-001272-37 
 
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. 


SIGNATURE PAGE 
TD-1473 
 
0173 
Author: 
 
 
Date 
 
 
Reviewer: 
 
 
Date 
 
 
Reviewer: 
 
 
 
 
Date 
 
27 January 2022 | 12:2
27 January 2022 | 13:0
27 January 2022 | 12:54


 
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................8 
SAP VERSION HISTORY............................................................................................................10 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Objectives and Endpoints ...........................................................................................12 
1.1.1. 
Primary Objective(s) ...................................................................................................12 
1.1.2. 
Secondary Objective(s) ...............................................................................................12 
 
 
1.2. 
Study Design ...............................................................................................................12 
1.2.1. 
Summary of Study Design ..........................................................................................12 
1.2.2. 
Definition of Study Drugs ..........................................................................................14 
1.3. 
Treatment Assignment and Blinding ..........................................................................15 
1.4. 
Schedule of Assessments ............................................................................................15 
1.5. 
Sample Size Determination ........................................................................................21 
2. 
ANALYSIS SETS ......................................................................................................22 
3. 
STATISTICAL ANALYSES .....................................................................................23 
3.1. 
General Considerations ...............................................................................................23 
3.1.1. 
Baseline Definition .....................................................................................................23 
3.1.2. 
Study Day ...................................................................................................................23 
3.1.3. 
Visit Windows ............................................................................................................23 
3.1.4. 
Multiple Assessments .................................................................................................24 
3.1.5. 
Study Period Definitions.............................................................................................25 
3.1.5.1. 
Induction Period ..........................................................................................................25 
3.1.5.2. 
Active Treatment Extension Period ............................................................................25 
3.1.5.3. 
Overall Study Period ...................................................................................................25 
3.1.6. 
Actual Treatment ........................................................................................................25 
3.2. 
Study Subjects ............................................................................................................25 
3.2.1. 
Subject Disposition and Completion Status ...............................................................26 
3.2.2. 
Demographic and Baseline Characteristics ................................................................26 
3.2.3. 
Protocol Deviations ....................................................................................................28 


3.2.4. 
Medical History ..........................................................................................................29 
3.2.5. 
Prior/Concomitant Medications ..................................................................................29 
3.3. 
Primary Endpoint(s) Analysis .....................................................................................30 
3.3.1. 
Definition of Primary Endpoint(s) ..............................................................................30 
3.3.2. 
CDAI Score ................................................................................................................30 
3.3.3. 
Statistical Hypotheses .................................................................................................30 
3.3.4. 
Primary Efficacy Analyses .........................................................................................31 
3.3.4.1. 
Primary Estimand .......................................................................................................31 
3.3.4.2. 
Analysis Methods .......................................................................................................32 
3.3.4.3. 
Missing Data Handling ...............................................................................................33 
3.3.5. 
Sensitivity Analyses ....................................................................................................33 
3.3.5.1. 
Sensitivity Analyses 1.................................................................................................33 
3.3.5.2. 
Sensitivity Analyses 2.................................................................................................33 
3.3.6. 
Supplementary Analyses ............................................................................................33 
3.3.6.1. 
Supplementary Estimand 1 .........................................................................................33 
3.3.6.2. 
Supplementary Estimand 2 .........................................................................................33 
3.3.6.3. 
Subgroup Analysis ......................................................................................................34 
3.3.6.4. 
CDAI Component Analysis ........................................................................................35 
3.3.6.5. 
Liquid or very soft stool definition analysis ...............................................................35 
3.3.6.6. 
CDAI Completeness and Intercurrent Event Summaries ...........................................35 
3.4. 
Secondary Endpoint(s) Analyses ................................................................................36 
3.4.1. 
Secondary Endpoint(s) ................................................................................................36 
3.4.2. 
Statistical Hypotheses .................................................................................................36 
3.4.3. 
Definition of Secondary Endpoint(s) ..........................................................................36 
3.4.3.1. 
CDAI Clinical Response .............................................................................................36 
3.4.3.2. 
CDAI Clinical Remission ...........................................................................................36 
3.4.3.3. 
Simplified Endoscopy Score for Crohn's Disease (SES-CD) .....................................36 
3.4.3.4. 
Endoscopic Response .................................................................................................37 
3.4.3.5. 
Stool Frequency and Abdominal Pain (SFAP) Clinical Remission ...........................37 
3.4.4. 
Secondary Efficacy Analyses .....................................................................................38 
3.4.4.1. 
Estimands ....................................................................................................................38 
3.4.4.2. 
Analysis Methods .......................................................................................................38 
3.4.4.3. 
Missing Data Handling ...............................................................................................38 


 
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3.4.5. 
Sensitivity Analyses ....................................................................................................39 
3.4.6. 
Supplementary Analyses ............................................................................................39 
3.5. 
Multiplicity Adjustment..............................................................................................39 
 
 
 
 
 
 
3.6.2.1. 
Endoscopic Remission ................................................................................................40 
3.6.2.2. 
Patient-Reported Outcome (PRO) clinical response ..................................................40 
3.6.2.3. 
SFAP-e Remission ......................................................................................................40 
3.6.2.4. 
Modified Stool Frequency and Abdominal Pain (Modified SFAP) Clinical 
Remission ...................................................................................................................40 
3.6.2.5. 
Modified SFAP-e Remission ......................................................................................40 
 
 
 
 
 
 
3.6.4. 
Supplementary Analyses ............................................................................................42 
3.6.4.1. 
Subgroup analysis .......................................................................................................42 
3.7. 
Safety Analyses ..........................................................................................................42 
3.7.1. 
Extent of Exposure .....................................................................................................42 
3.7.1.1. 
Treatment Compliance ................................................................................................42 
3.7.2. 
Adverse Events ...........................................................................................................43 
3.7.2.1. 
Adverse Events of Special Interest .............................................................................44 
3.7.3. 
Additional Safety Assessments...................................................................................45 
3.7.3.1. 
Clinical Laboratory Parameters ..................................................................................45 
3.7.3.2. 
Vital Signs ..................................................................................................................45 
3.7.3.3. 
Electrocardiograms .....................................................................................................46 
3.8. 
Other Analyses ............................................................................................................47 
 
 
 
 
 
 
 
 


 
 
 
 
 
3.9. 
Interim Analyses .........................................................................................................48 
3.9.1. 
Maintenance of blind following interim analysis .......................................................49 
3.9.2. 
Data Monitoring Committee .......................................................................................49 
4. 
REFERENCES ...........................................................................................................50 
5. 
SUPPORTING DOCUMENTATION ........................................................................51 
5.1. 
Changes to Protocol-Planned Analyses ......................................................................51 
5.2. 
CDAI Questionnaire ...................................................................................................51 
5.3. 
Data Conventions and Transformations .....................................................................52 
5.3.1. 
Derived and Transformed Data ..................................................................................52 
5.3.1.1. 
Study Day ...................................................................................................................52 
5.3.1.2. 
Change from Baseline .................................................................................................52 
5.3.1.3. 
BMI .............................................................................................................................52 
5.3.1.4. 
Ideal Body Weight ......................................................................................................52 
5.3.1.5. 
Creatinine Clearance ...................................................................................................53 
5.3.1.6. 
Time Since Crohn’s Disease Diagnosis ......................................................................53 
5.3.1.7. 
Prior Biologic Failure .................................................................................................53 
5.3.1.8. 
Prior Biologic Classes.................................................................................................53 
5.3.1.9. 
Presence of extra-intestinal manifestations ................................................................54 
5.3.2. 
Missing Date Imputation ............................................................................................54 
5.3.2.1. 
Missing/Incomplete AE/Start Date .............................................................................54 
5.3.2.2. 
Missing/Incomplete AE/Medication End Date/Time .................................................54 
5.3.2.3. 
Missing/Incomplete Start for Medication ...................................................................54 
5.3.3. 
Laboratory Data ..........................................................................................................55 
5.3.4. 
AE Severity .................................................................................................................55 
5.4. 
Adverse Event Start and End Date/Time Imputation Rules .......................................55 
 
 
 
 
 
 
 
 
 
 


 
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5.8. 
CTCAE Grading .........................................................................................................64 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................8 
Table 2: 
Induction and Active Treatment Dose Assignment ....................................................14 
Table 3: 
Randomization ............................................................................................................15 
Table 4: 
Schedule of Study Procedures ....................................................................................16 
Table 5: 
Analysis Sets ...............................................................................................................22 
Table 6: 
Baseline Specifications for Specific Variables ........... Error! Bookmark not defined. 
Table 7: 
Visit Analysis Windows .............................................................................................24 
Table 8. 
SES-CD Scoring .........................................................................................................37 
Table 9: 
Criteria for Marked Abnormalities in Vital Signs ......................................................45 
Table 10: ECG Interval Categories .............................................................................................46 
 
LIST OF FIGURES 


LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BMI  
Body Mass Index 
C 
Continuous reporting format 
CD 
Crohn’s Disease 
CDAI 
Crohn’s Disease Activity Index  
CI 
Confidence interval 
CMH 
Cochran Mantel-Haenszel / CMH reporting format 
CRF 
Case Report Form 
  
 
CSR 
Clinical Study Report 
DOB 
Date of Birth 
dy 
Days 
ECG  
Electrocardiogram 
 
 
F 
Frequency reporting format 
G 
Geometric mean reporting format 
GCP 
Good Clinical Practices 
ICF  
Informed consent form 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
LS 
Least Square 
LSM 
Least Square mean 
LSP 
Least Square Proportion 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MF 
Multiple frequency reporting format 
mITT 
Modified Intent-to-Treat 
mo 
Months 
N 
Total Sample Size 
NLSM 
Normal Least Square Mean 
NBLSM 
Negative Binomial Least Square Mean 
  
 
PK 
Pharmacokinetics  
pMS 
Partial Mayo Score 
PP 
Per-Protocol Population 
PRO  
Patient-reported outcome 
  
 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SES-CD 
Simplified Endoscopy Score for Crohn’s Disease 
SOC  
System Organ Class 


 
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Abbreviation 
Term 
TBPH  
Theravance Biopharma, Inc. 
TEAE  
Treatment-emergent adverse event 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell Count 
WHO 
World Health Organization  
yr 
Years 




 
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1. 
INTRODUCTION 
This document describes the plan for the summarization and analysis of clinical data collected in 
Study 0173 for TD-1473.  
 
 
  
 
 
This document describes the plan for analysis. Once the analyses are in progress, it may become 
apparent from the data that the planned analyses should be modified. Any substantial 
modification to the plan will be described in the clinical study report. 
Due to the decision to terminate the study early, the exploratory ATE efficacy analyses will not 
be performed. 


1.1. 
Objectives and Endpoints 
1.1.1. 
Primary Objective(s)  
The primary objectives of the study are as follows: 
 To assess the effect of TD-1473 compared to placebo in improving Crohn’s Disease 
Activity Index (CDAI) score at Week 12 in subjects with moderately-to-severely 
active CD 
 To assess the safety and tolerability of TD-1473 
1.1.2. 
Secondary Objective(s)  
The secondary objectives of the study are to assess the effects of TD-1473 given for 12 weeks 
compared to placebo: 
 To induce clinical remission 
 To induce clinical response 
 To induce endoscopic response 
 To improve the Simplified Endoscopy Score for Crohn’s Disease (SES-CD) 
1.1.3. 
Exploratory Objective(s)  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
1.2. 
Study Design 
1.2.1. 
Summary of Study Design 
This study includes 3 phases: Screening, Induction, and Active Treatment Extension (ATE).  
Screening is up to 5 weeks long.  The Induction phase of the study is a multi-center, randomized, 
double-blind, placebo-controlled, parallel-group study evaluating 2 dose levels of TD-1473 (80 
mg or 200 mg; approximately 60 subjects per dose level) compared to placebo (approximately 40 
subjects) for 12 weeks in subjects with moderately-to-severely active Crohn’s Disease (CD).  


 
 
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Subjects who complete the Induction phase will continue to receive TD-1473 in ATE, either at 
80 mg or 200 mg, for up to 48 additional weeks.   
Figure 1: 
Study Design Schematic 
 
Screening: 
To determine eligibility, subjects will undergo assessments during the Screening period (up to 35 
days prior to Day 1 dosing) as outlined in the Schedule of Study Procedures (Section 1.4).  
Disease activity will be assessed by the clinical scores, based on symptoms reported on a daily 
diary, which will be captured electronically beginning the day after Screening Stage 1.   
Subjects who meet all inclusion (with the exception of the endoscopic subscore criterion) and no 
exclusion criteria, will undergo ileocolonoscopy with biopsies to complete Screening Stage 2.  
The aim of this endoscopic exam is to assess the SES-CD score by central reading and to obtain 
biopsies.   
Induction 
If the subject meets all eligibility criteria, the subject may be randomized into one of the 
following 3 treatment groups in a 3:3:2 ratio: TD-1473 80 mg, TD-1473 200 mg, or placebo.   
The randomization will be stratified by prior biologics failure and CDAI score category (≤ 300, > 
300) at the Screening Stage 2 visit (using laboratory data from Screening Stage 1 for the score 
calculation).  Approximately 40-60% of subjects randomized will have failed prior treatment 
with biologics.  Subjects will be treated for 12 weeks and assessed for the various endpoints, 
including those that incorporate findings from an ileocolonoscopy and biopsies at the Week 12 
visit.  Corticosteroids will start to be tapered at Week 8. Subjects will undergo clinic study visits 
every 4 weeks in accordance with the Schedule of Assessments 
(Section 1.4).  During this time, subjects will continue to fill out a daily diary. 
ATE: 


All subjects who complete Induction at the Week 12 visit will continue into ATE, ATE Day 1 is 
scheduled for between 1 and 7 days after the Induction Week 12 visit where subjects will be 
treated with either 80 mg or 200 mg of TD-1473 for 48 weeks.  Dose during ATE depends on 
treatment assignment during Induction (Figure 1 and  Table 2): those who were dosed with TD-
1473 during Induction will stay on the same dose; those who were dosed with placebo during 
Induction will be dosed with TD-1473 at 80 mg. 
Table 2: 
Induction and Active Treatment Dose Assignment 
Induction Dose 
(3:3:2 randomization) 
Active Treatment Extension (ATE) 
Dose 
80 mg 
80 mg 
200 mg 
200 mg 
Placebo 
80 mg 
 
During ATE, subjects will undergo clinic study visits every 4-12 weeks. Subjects will continue 
to complete a daily diary. 
Subjects who have not shown clinical improvement (as assessed by the investigator) 16 weeks 
after initiation of ATE (i.e., ATE Week 16) will be discontinued from the study following 
completion of an End of Study (EOS) visit.   
End of Study (EOS) Visit: 
An EOS visit will be required for all subjects 4 weeks following their last dose of study drug. 
Subjects who complete an Early Study Drug Discontinuation visit during Induction or ATE will 
also be required to return for an EOS visit. 
1.2.2. 
Definition of Study Drugs 
Study drug comprises the following (placebo and 2 doses of TD-1473): 
 TD-1473 80 mg once daily: Taken orally for up to 60 (including ATE) weeks in the 
morning before eating. Subject must refrain from eating or drinking anything other 
than water and non-study medications for at least 30 minutes after dosing. Subjects 
from placebo arm will take from start of ATE Day 1 to ATE week 48. 
 TD-1473 200 mg once daily: Taken orally for up to 60 (including ATE) weeks in the 
morning before eating. Subject must refrain from eating or drinking anything other 
than water and non-study medications for at least 30 minutes after dosing. 


 
 
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Placebo once daily: Taken orally for up to 12 weeks in the morning before eating. Subject must 
refrain from eating or drinking anything other than water and non-study medications for at least 
30 minutes after dosing. 
1.3. 
Treatment Assignment and Blinding  
Central randomization for treatment allocation will be implemented. A computer-generated 
randomization schedule will be prepared for this study under the supervision of the sponsor. 
The randomization will be stratified by history of biologic treatment failure (Yes, No) crossed 
with baseline CDAI category (≤ 300, > 300). A sequence of randomly permuted blocks will be 
used to centrally assign subjects in each stratum to TD-1473 at 80 mg, TD-1473 at 200 mg, or 
placebo in a 3:3:2 ratio. Enrollment targets are shown in Table 3: 
Table 3: 
Randomization 
Stratum\Treatment Group 
All Treatment 
Groups 
Placebo once 
daily 
TD-1473 80 mg 
once daily 
TD-1473 200 
mg once daily 
All Strata 
160 
40 
60 
60 
Randomization caps will be placed on both prior biologics failure subgroups (no to biologic failure (up to 
60%) and yes to biologic failure (up to 60%)) to ensure that neither subgroup is overrepresented. There 
will also be a cap at 10% for enrollment of subjects with an SES-CD score at screening in the range of 3 
to 5.  
1.4. 
Schedule of Assessments 
The schedule of assessments is presented in Schedule of Assessments 
.


Table 4: 
Schedule of Study Procedures 
Procedures 
Screening 
Period 
Treatment Period 
Early 
Study 
Drug 
Discontin-
uation A 
End of 
Study B 
(4 weeks 
post last 
study drug 
dose) 
Induction 
(Day 1 to Week 12) 
Active Treatment Extension 
(ATE Day 1 to ATE Week 48) 
Study Day/Week 
Day -35 to -1 
Day 
1 
W4 
W8 
 
W10 
W12 C 
ATE 
Day 1 D 
ATE 
W4 
ATE 
W8 
ATE 
W16 E 
ATE 
W24 
ATE 
W36 
ATE 
W48 
 
 
Stage 
1 
Stage 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hour Post-
dose/Window 
 
 
- 3 to + 5 
days 
0 to + 7 
days 
0 to + 
3 days  
1 – 7 days 
after 
W12  
- 3 to + 5 days 
0 to + 5 
days 
- 3 to + 5 
days 
General Procedures and Safety Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/ 
Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication/Medic
al History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco Use 
Status 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination F 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray G 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X H 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Dispensing 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug 
Dosing I 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Dispense 
Electronic Diary J 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corticosteroid 
Dosing Taper 
(if applicable) K 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
Telephone Call L 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
-------------------------------------------------------------------------------------------X--------------------------------------------------------------------------------------------- 
Adverse Event 
Assessment M 
-------------------------------------------------------------------------------------------X----------------------------------------------------------------------------------------------- 
Laboratory Assessments 
Pregnancy Test 
(females of 
childbearing 
potential only) N 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH O 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry, 
Hematology 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Overnight Fasting 
Lipid Panel 
 
X P  
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Viral hepatitis and 
HIV Serology 
Panel 
X Q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Test 
(QuantiFeron) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ileocolonoscopy 
and Biopsies 
 
X R 
 
 
 
 
X C 
 
 
 
 
 
 
 
 
 
Fecal Sample for 
Infectious Studies 
S 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
  
  
  


 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Blood 
Sample (Optional 
– only collected 
for subjects who 
provide genetic 
testing consent) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessments 
CDAI Score 
 
X V 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
SES-CD Score 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Fistula Drainage 
Status (yes/no to 
active drainage), if 
fistula is present 
X 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Diary 
Completion and 
Compliance 
Review J 
X 
X 
X W 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X A 
 
 
Abbreviations: ECG, electrocardiogram; FSH, follicle stimulating hormone; 
 
 
 
; CDAI, Crohn’s Disease Activity Index; SES-CD, Simplified Endoscopy Score; 
 EOS, End-of Study, ATE, Active Treatment Extension 
A. 
This visit is for subjects who prematurely discontinue the study drug. This visit will be conducted within 5 days of the last dose of study drug, if possible.  
Subject will also return for the EOS visit for collection of safety data and assessment of disease activity. Subjects who discontinue study drug early due to 
AE are permitted to optionally complete their daily diary through to the EOS visit. Subjects who have not shown clinical improvement at ATE Week 16 
should complete an Early Study Drug Discontinuation visit and be discontinued from study drug. 


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B. 
An EOS visit will be required for all subjects 4 weeks following their last dose of study drug, whether they completed the full duration of study drug 
treatment. 
C. 
The Week 12 ileocolonoscopy and biopsies should be performed on the same day as the Week 12 visit, preferably in the early morning, to permit morning 
dosing with study drug.  However, if not feasible to perform both the ileocolonoscopy and the clinic visit on the same day, the ileocolonoscopy could be 
performed within 3 days after the Week 12 clinic visit. If the study activities of this Week 12 visit are to be completed over two different visits, the study 
drug should be continued until the later of the two visits.  The Week 12 endoscopy must be performed at least 1 day prior to ATE Day 1. 
D. 
ATE Day 1 should occur between 1 and 7 days after the Week 12 clinic visit. No new study drug will be dispensed between the Week 12 clinic visit and 
ATE Day 1.  ATE Day 1 must be performed at least 1 day after the Week 12 endoscopy has been conducted.   
E. 
Subjects who have not shown clinical improvement, as deemed by the subject and investigator, 16 weeks after initiation of the ATE (i.e., ATE Week 16), 
should be discontinued from the study. 
F. 
Physical exams (PEs) should be performed as per local standard practice.   
G. 
Subjects who have had a documented chest X-ray or equivalent chest imaging or TB testing within 90 days prior to Screening do not require a repeat X-ray 
(or equivalent) or TB testing, respectively, unless subject is deemed by the investigator to be at high risk of recent pulmonary infection.  If a chest X-ray is 
indicated, it may be performed anytime during Screening.  Subjects with a history of latent TB should not have a TB test but must not live in a region with 
high prevalence of multidrug-resistant TB and have completed a well-accepted treatment regimen (e.g., a ≥ 9-month course of INH or equivalent therapy) 
within 5 years (3 years in countries where TB is endemic) prior to Screening, the documentation for which must be included in the source document and 
reviewed by the PI.  Subjects who had treated active TB must still have a TB test. Subjects who has a history of latent or active tuberculosis (TB) may be 
eligible for the study if criteria are met. 
H. 
Subject will be randomized on Day 1 after all pre-dose procedures (ECG, vital signs, and all labs 
) have been completed and 
subject is confirmed to be eligible for the study.  
I. 
Study drug administration will be in clinic on Day 1, Week 4, Week 8, Week 12, ATE Day 1, ATE Week 4, ATE Week 8, ATE Week 16, ATE Week 24, 
ATE Week 36, and ATE Week 48 on an empty stomach from the night before after all pre-dose assessments (with the exception of 
 
, which may be done post-visit on the same day) and procedures have been completed.  Subject will take the study drug at home 
for the rest of the study.  The last dose of Induction study drug will be taken at the Week 12 clinic visit. No new study drug will be dispensed between the 
Week 12 clinic visit and ATE Day 1. 
J. 
Subjects will be provided with an electronic diary (or paper diary if electronic diary is not available) at the Screening Stage 1 visit and instructed on daily 
diary completion, including symptom monitoring and study drug dosing details.  Diaries of symptoms will be collected daily from the Screening Stage 1 
visit through the EOS visit.  Study drug dosing details will be entered from Day 1 (Induction) through ATE Week 48 (or the last dose of study drug, if the 
subject prematurely withdraws from study drug). Diary completion will be monitored for completeness at each return study visit after the electronic diary is 
dispensed (i.e., Screening Stage 2 through the EOS visit).  Subjects will be counseled on missed study drug doses and missed diary entries. 
K. 
Corticosteroid taper, for those that are on corticosteroid at Screening Stage 1, should be initiated at the Week 8 visit.  
L. 
Site personnel to call subjects approximately 2 weeks prior to Week 12 visit for reminder of compliance of diary completion. The site will also review 
compliance on corticosteroid taper (as applicable), review upcoming schedule for Week 12 and the reminders in preparation for the visit. 
M. 
AE assessments are to include collection and reporting of AEs, SAEs, and AEs of Special Interest (AESIs).  
N. 
Urine beta human chorionic gonadotropin (b-hCG) testing will be performed before dosing when dosing in-clinic and anytime during all other visits for 
females of childbearing potential to confirm absence of pregnancy.  If urine b-hCG test is positive, confirm with serum b-hCG test.  
O. 
Required for postmenopausal females. 
P. 
Any Screening Stage 2 lab testing can be obtained from Day -35* to Day -1 during Screening. Overnight fasting lipid panel may be obtained on Day -35 if 
subjects are fasting as per institutions standard of care procedure, which must be clearly documented in the source documents. *NOTE: Subjects must not 


be requested to come in fasting for study specific assessments prior to signing the informed consent. Results of these labs will not need to be reviewed before 
Screening Stage 2 or Day 1. 
Q. 
Subjects with positive hepatitis B core antibody will undergo testing for hepatitis B DNA and hepatitis B surface antibody during Screening.  Subjects with 
known hepatitis C will also undergo testing for hepatitis C RNA viral load (for details on Serology testing).  During re-screening, if there is already a 
negative result from prior screening, the hepatitis B, C, or E or HIV serologies do not need to be repeated. 
R. 
Ileocolonoscopy and biopsies will be performed after subject’s eligibility is confirmed (upon review of CDAI score prior to the start of bowel preparation 
and no exclusionary criteria are met). Ileocolonoscopy does not need to be repeated for a rescreening if the ileocolonoscopy is within 28 days of Day 1 of the 
re-screen and if the SES-CD score is qualifying. 
S. 
Stool infectious studies to include: C. difficile, other bacteria (including Shigella, Salmonella, Yersinia, Enterohemorrhagic or Enteropathogenic or 
Enterohemorrhagic E. coli O157, and Campylobacter), and ova and parasite.   
T. 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
V. 
Obtained prior to ileocolonoscopy (to assess eligibility criteria at Screening).  Any time after Screening Stage 1 and once a minimum of 5 entries have been 
confirmed, the clinician assessments can be completed.  Should be performed prior to the start of bowel preparation for the Screening Stage 2 endoscopy. 
The Screening Stage 1 weight and hematocrit result will be used to calculate this CDAI score. 
W. Subject must have completed their electronic diary (or paper diary if electronic diary is not available) at least 5 out of 7 days prior to Screening Stage 2. 


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1.5. 
Sample Size Determination 
Assuming that the less effective TD-1473 dose results in a 45-point improvement in 
placebo-adjusted CDAI change from baseline at Week 12, the more effective dose results in a 
60-point improvement, and the residual SD is 100 points, 100,000 simulations performed using 
SAS/IML software yielded the following power estimates for 2-sided testing with the family-wise 
type 1 error rate for the primary efficacy endpoint controlled at 5% using the Hochberg step-up 
procedure1: 
 82% power to show at least one of the two doses effective 
 58% power to show both doses effective 
A more detailed rationale, including the basis for estimating the SD of CDAI change as 
100 points, is given in “TD-1473 Study 0173 Sample Size Determination v1.0” 
                                                 
1 The Hochberg step-up procedure is as follows: if both TD-1473 doses vs placebo p-values are < .05, 
reject both no-effect null hypotheses; otherwise, if the smaller p-value is < .025, reject the no-effect null 
hypothesis for that dose. 


2. 
ANALYSIS SETS 
 
Table 5: 
Analysis Sets 
Analysis Set 
Definition 
Treatment 
Assignment 
Screen Failures* 
Subjects who give informed written consent but are 
not randomized are considered screen failures. 
Screen failure subjects and the main reason for 
screen fail will be captured in the EDC. 
N/A 
Randomized* 
The randomized analysis set will include all subjects 
who were randomized into the study. 
Randomized 
treatment 
Safety* 
The Safety analysis set will include all subjects who 
received at least one dose of study drug ( or 
placebo).  
The Safety analysis set is the primary analysis set for 
safety analyses. 
Actual Treatment 
received (see 
Section 3.1.6) 
ITT* 
The Intent-to-Treat (ITT) analysis set comprises all 
randomized subjects who receive at least one dose of 
study drug.  
Randomized 
treatment 
Modified ITT* 
The modified Intent-to-Treat (mITT) analysis set 
comprises all randomized subjects who receive at 
least one dose of study drug and have at least one 
postbaseline CDAI score.  
Only include subjects randomized prior to the 
23Aug2021. 
The mITT set is the primary analysis set for efficacy 
summaries and analyses.  
Randomized 
treatment 
PP* 
The Per-Protocol (PP) analysis set comprises all 
subjects in the mITT analysis set who complete their 
Week 12 visit and have no major analysis protocol 
deviations 
Randomized 
treatment 
Active Draining 
Fistulae* 
The active draining fistulae analysis set comprises 
all subjects in the mITT analysis set with at least one 
draining fistula at baseline. 
Randomiznaed 
treatment 
* Due to confirmed data integrity violations the data for site 36016 (deviation report GCP-XX) 
and site 38915 (deviation report GCP-11) will be excluded from all analysis sets. 


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3. 
STATISTICAL ANALYSES 
3.1. 
General Considerations 
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 variables will be summarized using an 8-point descriptive summary (number of 
subjects [n], mean, standard deviation [SD], median [Q2], interquartile range [25th percentile Q1, 
75th percentile Q3], minimum, and maximum) unless otherwise indicated. Categorical variables 
will be summarized by frequency and percentage of subjects in each category. All summaries 
will be presented by treatment and visit when applicable. 
For binary endpoint comparisons to placebo when the expected number of responders/non-
responders are less than 5 per treatment groups being analyzed a fishers exact test will be 
performed. For safety assessments, summary statistics will be reported by treatment. 
Analyses and tabulations will generally be prepared using SAS, version 9.4 or later. 
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 prior to 
first dose.  
The exceptions are for fecal samples and electronic tablet data that can be submitted within 3 
days of first dose. 
3.1.2. 
Study Day 
If the assessment occurs on or after the first dose date then induction study day will be calculated 
as (date of assessment – date of first dose/randomization) + 1.  
If the date of interest occurs prior to the first dose date then induction study day will be 
calculated as (date of assessment – date of first dose).  
There is no induction study day 0. 
ATE study day will calculated in a similar manner with first dose in ATE period used to 
calculate the day (expected to be ATE Day 1). 
3.1.3. 
Visit Windows 
All assessments will be summarized using analysis windows.  


The terminology of unscheduled will be applied to assessments that are outside an analysis 
window regardless of the nominal label associated with the assessments in the EDC system. 
The following visit windows will be used in the summary of clinical data. 
Table 6: 
Visit Analysis Windows 
Nominal Visit Nominal Day 
Start (days) 
Stop (days) 
Screening 
NA 
-28 
-1 
Baseline 
1 
1 
Induction Day 1 
Week 4 
Induction Day 
28 
Induction Day 21 
Induction Day 35 
Week 8 
Induction Day 
56 
Induction Day 49 
Induction Day 63 
Week 12 
Induction Day 
84 
Induction Day 77 
Earliest of:  
 ATE Day 1 dose date 
 Induction Day 98 (Induction 
Day 112 for SES-CD score) 
ATE Week 4 
ATE Day 28 
ATE Day 21 
ATE Day 35 
ATE Week 8 
ATE Day 56 
ATE Day 49 
ATE Day 63 
ATE Week 16 ATE Day 112 
ATE Day 105 
ATE Day 126 
ATE Week 24 ATE Day 168 
ATE Day 161 
ATE Day 182 
ATE Week 36 ATE Day 252 
ATE Day 245 
ATE Day 266 
ATE Week 48 ATE Day 336 
ATE Day 329 
ATE Day 350 
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). 
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: 


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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. Repeat laboratory testing of abnormal potentially clinically significant or 
clinically significant results for Screening evaluation of the subject may be repeated at the 
discretion of the investigator. 
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. 
Study Period Definitions 
3.1.5.1. 
Induction Period 
For analysis and summaries of the induction period, only data collected for each subject from first dose 
up until the earliest event between the ATE Day 1 dose or date of last dose + 5 days will be presented. 
3.1.5.2. 
Active Treatment Extension Period 
Active Treatment Extension is the period from first dose at ATE Day 1 until date of last dose + 5 
days. 
3.1.5.3. 
Overall Study Period 
For analysis and summaries of the overall study period, only data collected for each subject from 
first dose up until date of last dose + 5 days will be presented. 
3.1.6. 
Actual Treatment 
In the event that a subject is dispensed incorrect treatment the following rules will be used to 
decide actual treatment during the period that the incorrect treatment was dispensed and 
returned: 
Mean Dose 
Actual Treatment 
<=140 mg 
80mg 
>140 mg  
200mg 
Mean dose is calculated over a period as the summation of each tablet taken (where placebo is 
considered 0mg) and divided by total number of days on treatment in the period.   
3.2. 
Study Subjects 
Unless otherwise noted, the ITT analysis set is the main analysis set used in the summarization 
of general (Study Population) analyses. 


3.2.1. 
Subject Disposition and Completion Status 
The number of subjects screened for the study will be provided. A summary of study disposition 
will be provided by study treatment showing the following: 
 Number of subjects randomized 
 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 
The following additional disposition summary will be provided: 
 Number of subjects who completed the Week 12 Visit 
 Number of subjects who discontinued prior to the Week 12 Visit 
 Primary reasons for discontinuation prior to the Week 12 Visit, with frequencies 
A listing of subject disposition will include analysis set flags (ITT, Safety, mITT, PP [Yes/No], 
Active Draining Fistula),  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. 
A listing of subject eligibility (inclusion or exclusion criteria exceptions) and a listing of subjects 
randomized but not treated will be provided. 
3.2.2. 
Demographic and Baseline Characteristics 
Demographics 
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. Age will be further categorized as 18 to 64 vs. ≥ 65 years. 
Tobacco Consumption 
A summary of Tobacco Consumption taken at baseline or screening will be provided 
summarizing: 
Parameter 
Units/Response category 
Tobacco Consumption Status 
Never, Current,  
Former 
Number of Tobacco Units Per Day  
Converted Units 
Number of Years With Tobacco Use  
Years 
Total Number Of Pack Years  
Pack Years 
Type of Tobacco Product Used 
Cigarettes, Cigars, Pipe, Smokeless Tobacco 


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The following conversion process is used to standardize a unit of tobacco consumption: 
1 unit = 1 pack (20 cigarettes) = 5 cigars = 8 pipes = 8 pinches 
Number of years of tobacco use is calculated as follows where current smokers use the Day 1 
Visit date as end date: 
(𝑇𝑜𝑏𝑎𝑐𝑐𝑜 𝑢𝑠𝑒 𝑒𝑛𝑑 𝑑𝑎𝑡𝑒 - 𝑇𝑜𝑏𝑎𝑐𝑐𝑜 𝑢𝑠𝑒 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒 +  1) 
365.25
 
Pack Years is calculated as number of years of tobacco use multiplied by number of tobacco 
units per day (converted units). 
A listing will also be provided.  
Crohn’s Disease Clinical Characteristics 
A summary of Crohn’s Disease Clinical Characteristics taken at baseline or screening will be 
provided. A listing will also be provided. 
Parameter 
Units/Response category 
Time since diagnosis of Crohn’s 
disease 
Years 
Time Since Diagnosis categories 
≤ 5years; 
>5 to <=15 years; 
> 15 years 
Extent of disease  
Ileal, Colonic, Ileocolonic 
Baseline CDAI score 
Points 
Baseline CDAI score categories 
≤300 points, >300 points 
Baseline Abdominal Mass 
None, Questionable, Definite 
Baseline average daily Abdominal 
Pain 
None, Mild, Moderate, Severe 
Baseline average daily liquid or very 
soft Stool Frequency 
Stools 
Baseline average daily total Stool 
Frequency 
Stools 
Baseline SES-CD score 
Points 
Upper GI Crohn’s 
Yes, No 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Prior Crohn’s Disease Therapy Characteristics 
A summary of Prior Crohn’s Disease Therapy Characteristics will be provided. A listing will 
also be provided. 
Parameter 
Units/Response category 
Prior biologic failure 
Yes, No 
Prior biologic experience 
Failed, Naïve, Experienced but no documented failure 


Number of prior biologics failed 
0, 1, 2, ≥3 
Biologic classes failed 
0, 1, 2, 3 
Primary Non-responder to at least 1 Biologic 
Yes, No 
Secondary Non-responder to at least 1 Biologic 
Yes, No 
Intolerant to at least 1 Biologic 
Yes, No 
Oral corticosteroid use at enrollment 
Yes, No 
History of steroid non-response 
Yes, No 
History of steroid dependence 
Yes, No 
History of steroid dependence or non-response 
Yes, No 
Prior immunomodulator use 
Yes, No 
Prior immunomodulator non-response or intolerance 
Yes, No 
Prior aminosalicylate use 
Yes, No 
Aminosalicylate use at baseline 
Yes, No 
Prior aminosalicylate non-response 
Yes, No 
Prior Jak-inhibitor use 
Yes, No 
 
Complications of Crohn’s Disease at Baseline 
A summary of complications at Baseline will be provided. A listing will also be provided. 
A summary of complications of Crohn’s Disease at Baseline will be provided, the number and 
percentage of subjects with each complication collected on the Crohn’s Disease History page 
will be presented. A listing will also be provided. 
Fistula Drainage at Baseline 
A summary of Fistula Drainage at Baseline will be provided. A listing of Fistula drainage over 
time will also be provided. 
Parameter 
Units/Response category 
Fistula 
Yes, No 
Location 
Small Intestine to Small Intestine,  
Small Intestine to Colon,  
Small Intestine to Bladder,  
Small Intestine to Skin On Abdominal Wall,  
Colon to Skin on Abdominal Wall, 
Small Intestine to Vagina,  
Colon to Vagina,  
Colon or Rectum to Skin in Pelvic Area,  
Small Intestine to Skin in Pelvic Area,  
Other  
Active Drainage 
Yes, No 
3.2.3. 
Protocol Deviations 
Unique subjects reporting major protocol deviations that have significant impact on primary 
efficacy analyses (major analysis protocol deviations) will be summarized overall and by 
treatment group for the ITT set. 
 
 
 
 


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A subject listing with all protocol deviations identified prior to database lock will be provided. 
Moreover, a listing of all major analysis protocol deviations will be provided. All subject listings 
will be based on the randomized analysis set. 
A summary and listing of COVID-19 protocol deviations will also be presented, along with a 
listing of COVID-19 impacts. 
3.2.4. 
Medical History 
Medical history data will be coded using the Medical Dictionary for Regulatory Activities, 
version 23.0 or later. The number and percentage of subjects with medical history coded to each 
system organ class and preferred term will be summarized by treatment group for the safety 
analysis set. 
3.2.5. 
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 non-study 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 not be 
included in summaries but will be included in the listing of concomitant medications, with a flag. 
Recorded prior and concomitant medication names from the Prior and Concomitant Medications 
eCRF page will be mapped according to the 
 
 
 
Prior and concomitant medication use will be tabulated separately. The number and percentage 
of subjects who have taken each medication will be provided by study treatment. 
On-going Crohn’s Disease Medications of Interest at Baseline will also be presented. Crohn’s 
Disease Medications of Interest include aminosalicylates, corticosteroids and antibiotics for 
Crohns Disease. Should a subject enter the study on prohibited biologics and immunomodulators 
these medications will also be presented. 


On-treatment rescue medication use will be summarized. Rescue medications are defined as the 
following medications if used to treat CD or AE of worsening CD: 
 Addition of oral corticosteroids, aminosalicylates or antibiotics  
 Increase in oral corticosteroids dose up to or above baseline  
 Prohibited medications  
3.3. 
Primary Endpoint(s) Analysis 
3.3.1. 
Definition of Primary Endpoint(s) 
The primary efficacy endpoint is defined as the change from baseline in CDAI score at Week 12. 
3.3.2. 
CDAI Score 
CDAI score is calculated as sum of a Subscore x Multiplier from Appendix 5.2. The following 
subscores are calculated based on the most recent evaluable 7 days. 
 Number of liquid or very soft stools subscore 
 Average Abdominal pain subscore 
 General well-being subscore 
Evaluable days are defined as any non-missing diary days during the 10 days prior to the study 
visit. The day prior to endoscopy, day of endoscopy and the day following endoscopy will be 
treated as non-evaluable and treated as missing. 
If fewer than 5 evaluable days data are available for any of the above subscores then the subscore 
is set to missing for that timepoint. If only 5 or 6 evaluable days’ data are available for the above 
mentioned subscores then the subscore total is calculated as: 
(Total score over available days/Number of available days)*7 
The weight component of the CDAI will be based on ideal weight (see Section 5.3.1.4). 
The CDAI score should be calculated for a visit only if ≥ 4 subscores are available at a visit, with 
missing subscores imputed by carrying forward the last non-missing subscore. If <4 subscores 
are available at a visit then the CDAI score will be set to missing.  
3.3.3. 
Statistical Hypotheses 
The primary estimate of interest, change from baseline in CDAI score at Week 12, is used to 
evaluate the effectiveness of  therapy relative to the placebo comparator in the mITT population.  
The following hypothesis testing schema will be employed to assess the primary endpoint:  The 
null hypothesis for the treatment comparison will be that there is no difference between the mean 
responses at a given dose level of 1473 (active) and the mean response on the placebo treatment 
in change from baseline CDAI score at Week 12.  The alternative hypothesis will be that there is 
a difference.  Symbolically, this is expressed as follows: 
 
0
placebo
1
placebo
:
:






Active
Active
H
H
  


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In order to control for the comparison of 2 active treatment groups versus placebo for the 
primary endpoint, a multiplicity procedure is planned.   
Only the primary endpoint is covered under multiplicity control and all other endpoints will be 
presented with nominal p-values. 
A step-up Hochberg procedure will be used.  The resulting nominal p-values for the primary 
endpoint will be ordered, largest to smallest.   
If the largest p-value < 0.05, then both treatment groups will be declared as statistically 
significant. 
If the largest p-value is > 0.05, then the smaller p-value will be compared to 0.025. If this p-value 
is < 0.025, then the treatment group with the smaller p-value will be declared as statistically 
significant. 
If no p-values meet the above conditions, the primary endpoint will be considered not 
statistically significant and the primary objective of the study was not met. 
3.3.4. 
Primary Efficacy Analyses   
3.3.4.1. 
Primary Estimand 
The primary estimand uses a treatment policy strategy that considers the efficacy response in 
subjects regardless of use of rescue medication.  
Population:  
Subjects with moderately-to-severely active CD [as defined by a CDAI score of 220-450 and 
SES-CD score of ≥ 6 (≥ 4 if isolated ileal disease) with ulceration (corresponding to a score of 1) 
in at least 1 of the 5 ileocolonic segments on the Presence of Ulcers subscore of the SES-CD] 
who are corticosteroid-dependent or have demonstrated inadequate response or intolerance to 
conventional therapy (aminosalicylates, corticosteroids and immunomodulators such as 
azathioprine, 6-mercaptopurine, or methotrexate) or biologics (e.g., anti-TNF therapy, 
anti-IL-12/23, anti-integrin). A subset of subjects (up to approximately 10%) will have an SES-
CD score between 3 and 5 points, inclusive. 
Variable: 
Change from baseline in CDAI score at Week 12. Subjects with any of the following intercurrent 
events (ICE) prior to Week 12 will have data analyzed as collected following ICE under 
Treatment Policy approach. 
Intercurrent events: 
The following are the intercurrent events considered for this study: 
Treatment Failure ICE: 
1. Prohibited medication for AE of worsening CD (Section 5.7) 
2. Any gastrointestinal resection 
3. Increase in dose of oral corticosteroids for CD above baseline dose 


4. Initiation of oral corticosteroids or aminosalicylates for CD where they were not ongoing 
at baseline 
5. Discontinued study intervention due to AE of worsening CD or lack of clinical benefit 
Other ICE: 
6. Discontinued study intervention due to COVID-19 
7. Discontinued study intervention for reasons other than COVID-19, AE of worsening CD 
or lack of clinical benefit 
8. No attempt to taper steroids from Week 8 
Population-level summary: 
The mean difference in change from baseline CDAI score at Week 12 between each TD-1473 
group and placebo. 
3.3.4.2. 
Analysis Methods 
The primary endpoint of CDAI score change from baseline at Week 12 will be analyzed based 
on the Primary Estimand by fitting a mixed effects repeated measures model using the change 
from baseline values at Weeks 4, 8, and 12 as the dependent variable. The model will include 
baseline CDAI score as a covariate and independent fixed effects for treatment group and prior 
biologics failure status (yes, no). The time effect of visit, the interaction of baseline CDAI score 
with visit and treatment with visit will also be included. Within-subject correlation will be 
modelled using an unstructured covariance structure. The Kenward and Roger method for 
approximating the denominator degrees of freedom will be used. 
Summaries will be on the mITT population and include observed values, change from baseline 
values and least square (LS) means estimates. For testing of the primary endpoint, each TD-1473 
dose versus placebo will be compared by displaying the LS mean difference estimate to placebo 
and associated 95% confidence interval. Nominal p-values will also be reported.   
A CDAI score figure will also be presented with the LS mean change from baseline in CDAI 
score over time to Week 12 displayed.  A placebo-adjusted figure will be also be provided 
displaying the LS mean difference to placebo in CDAI score over time to Week 12. 
A 2-group forest plot will summarize the LS mean difference from placebo in CDAI at Week 12 
with 95% confidence interval. The forest plot will also display the differences from placebo for 
Supplementary Estimand 1 (Section 3.3.6.1) and Supplementary Estimand 2 (Section 3.3.6.2). 
Graphical inspection of the model assumptions on the primary analysis will be performed and 
will include inspection of linearity of regression, equal variances and the independence and 
normality of errors. In the event that the assumptions are not met then p-values will be generated 
from the nonparametric randomization-based analysis of covariance methodology of Koch et al. 
(1998). 


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3.3.4.3. 
Missing Data Handling  
Missing data (including data missing due to COVID-19) will be assumed missing at random 
(MAR) and accounted for through correlation of repeated measures. 
3.3.5. 
Sensitivity Analyses  
3.3.5.1. 
Sensitivity Analyses 1 
To assess the impact of the MAR assumption on missing data a sensitivity analysis be performed 
assuming data is missing completely at random (MCAR) and not imputed. An analysis of 
covariance (ANCOVA) on change from baseline in CDAI score at Week 12 will be performed 
fitting an equal-slopes model with terms for prior biologics failure status, baseline CDAI score, 
and treatment. 
3.3.5.2. 
Sensitivity Analyses 2 
To assess the sensitivity of the treatment effect to the stool frequency component of the CDAI 
score, the primary analysis will be repeated where the CDAI score is calculated without the stool 
frequency component.   
3.3.6. 
Supplementary Analyses 
3.3.6.1. 
Supplementary Estimand 1 
This estimand will follow a composite strategy and has the same components as the Primary 
Estimand except for the handling of the intercurrent events. Here subjects who have any 
intercurrent event under treatment failure (ICE 1-5) will have their change from baseline set equal 
to zero following the ICE. Subjects experiencing intercurrent events (6, 7 and 8) will have their 
data following the intercurrent event set to missing. 
Analysis will follow the same methodology to the primary estimand with missing data after the 
adjustment for intercurrent events assumed to be MAR. 
3.3.6.2. 
Supplementary Estimand 2 
This estimand has the same variable, intercurrent events and population level summary as the 
primary estimand; however, this estimand has a different population and is defined as below. 
Population:  
Subjects who reach the Week 12 visit without any major protocol deviations and who enter the 
study with moderately-to-severely active CD [as defined by a CDAI score of 220-450 and SES-
CD score of ≥ 6 (≥ 4 if isolated ileal disease) with ulceration (corresponding to a score of 1) in at 
least 1 of the 5 ileocolonic segments on the Presence of Ulcers subscore of the SES-CD] who are 
corticosteroid-dependent or have demonstrated inadequate response or intolerance to 
conventional therapy (aminosalicylates, corticosteroids and immunomodulators such as 
azathioprine, 6-mercaptopurine, or methotrexate) or biologics (e.g., anti-TNF therapy, 
anti-IL-12/23, anti-integrin). A subset of subjects (up to approximately 10%) will have an SES-
CD score between 3 and 5 points, inclusive. 


Analysis:  
An ANCOVA model incorporating the change from baseline in CDAI score at Week 12 as the 
dependent variable in the model will be used to assess this supplementary estimand.  
The model will include independent fixed-effect class terms for treatment group, prior biologic 
failure status (yes, no) and baseline CDAI score as a covariate. 
3.3.6.3. 
Subgroup Analysis 
To characterize the consistency of the treatment effect for the primary and supplementary 
estimands, the primary endpoint analysis will be repeated for each examination group specified 
below.  
The subgroups will be analyzed with the inclusion of a 3-way interaction term 
treatment*visit*subgroup category into the primary analysis model. The exceptions are, (1) 
baseline CDAI category (≤ 300, > 300) where along with the inclusion of the of a 3-way 
interaction term treatment*visit*[baseline CDAI category (≤ 300, > 300)], the baseline 
continuous CDAI score is replaced in the primary analysis model with the baseline CDAI 
category and (2) subgroups listed (2-5) below where prior biologic failure in the model is 
replaced with the subgroup along with the addition of the 3 way interaction term. 
The following subgroups at baseline are pre-defined: 
1. Biologic Failure Status:  [a] Yes, [b] No 
(definition see section 5.3.1.7 )   
2. Biologics experience categories:  [a] Failed, [b] naïve, [c] bio-experienced [but not failed] 
3. Number of prior biologics failed [a] 0 [b] 1 [c] 2 [d] >=3 
4. Number of biologic mechanism of actions failed [a]0 [b] 1 [c] 2 [d] 3 
5. Intolerant to at least one biologic:  [a] Yes, [b] No 
6. Baseline CDAI category: [a] ≤ 300 pts, [b] > 300 pts 
7. Tobacco use Status: [a] no use, [b] prior use, [c] current use 
8. Extent of disease: [a] Ileal, [b] Colonic, [c] Ileocolonic 
9. Age: [a] ≤ 40 years, [b] > 40 years  
10. Duration of disease: [a] ≤ 5 years, [b] > 5 to ≤ 15 years, [c] > 15 years 
11. Age at diagnosis: [a] ≤ median, [b] > median 
12. Baseline Fistula: [a] Yes, [b] No 
 
 
15. Baseline SES-CD score: [a] ≤ median, [b] > median 
16. Presence of extra-intestinal manifestations at baseline: [a] Yes, [b] No 


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17. Corticosteroid-use at baseline: [a] Yes, [b] No 
18. Refractory or intolerant to 6-MP/AZA: (yes, no) 
19. Refractory or dependent to oral or IV corticosteroids: (yes, no) 
20. Refactory, intolerant or dependent to to 6-MP/AZA OR corticosteroids: [a] yes to both, 
[b] No to 6-MP/AZA and yes to steroids, [c] yes to 6-MP/AZA and no to steroids, [d] No 
to both 
21. History of intestinal resection: [a] Yes, [b] No  
22. Geographic Region: [a] North America [b] Eastern Europe [c] Europe (excluding Eastern 
Europe)[d] Other;  
3.3.6.4. 
CDAI Component Analysis 
Descriptive summaries of each individual CDAI component will be presented by treatment group 
and visit over time. Summaries will be presented as follows: 
 Change from baseline by visit in: 
o Average daily liquid or very soft stools over last 7 evaluable days 
o Haematocrit 
o Percent deviation from ideal body weight 
 Shift tables of change from baseline in: 
o Average daily abdominal pain over last 7 evaluable days 
o Average general well-being over last 7 evaluable days 
o Abdominal mass 
 Number and percentage of subjects by visit with: 
 
 
o Requiring anti-diarrheal medication in last 7 days 
3.3.6.5. 
Liquid or very soft stool definition analysis 
The primary endpoint analysis will be repeated with the definition of liquid and very soft 
updated to include Type 5 stools from the Bristol Stool Scale (Perez et al, 2009). 
3.3.6.6. 
CDAI Completeness and Intercurrent Event Summaries 
Summaries of the completeness of CDAI subscores at Week 12 will be performed where the 
number of subjects missing 1, 2, 3, 4 or >=5 subscores will be presented. For subjects with >=5 
subscores missing the summary will be further broken down by those who discontinue prior to 
Week 12 and those who missed the Week 12 visit.  


The number of subjects who experience an intercurrent event prior to Week 12 and those who 
don’t will also be presented for the subset of subjects with at least five CDAI component missing 
at Week 12.  
An analysis of all subjects who experience an intercurrent event will also be performed where 
the number of subjects overall who experience an ICE and the number who experience each 
specific ICE criteria will be presented.  
3.4. 
Secondary Endpoint(s) Analyses 
3.4.1. 
Secondary Endpoint(s) 
The secondary endpoints are: 
 CDAI clinical response (defined as reduction from baseline of ≥ 100 points or CDAI 
< 150) at Week 12 
 CDAI clinical remission (defined as CDAI < 150) at Week 12 
 SES-CD change from baseline at Week 12 
 Endoscopic response (SES-CD reduction of ≥ 50% from baseline or SES-CD ≤ 4, a 
reduction of ≥ 2 from baseline, and no subscore ≥ 2) at Week 12 
 Stool Frequency and Abdominal Pain (SFAP) clinical remission defined as abdominal 
pain score ≤ 1 (on a scale of 0-3), stool frequency ≤ 2.8, and both not worse than baseline 
at Week 12 
3.4.2. 
Statistical Hypotheses 
There is no hypothesis testing of secondary endpoints.  
3.4.3. 
Definition of Secondary Endpoint(s) 
3.4.3.1. 
CDAI Clinical Response 
CDAI score reduction from baseline of ≥ 100 or CDAI score < 150 
3.4.3.2. 
CDAI Clinical Remission 
CDAI score < 150 
3.4.3.3. 
Simplified Endoscopy Score for Crohn's Disease (SES-CD) 
The SES-CD incorporates 4 descriptors: the ulcer size, the proportion of surface covered by 
ulcer, the proportion of surface covered by other lesions, and the presence of stenosis. Each 
descriptor is graded from 0-3 as shown in Table 7 and is scored in 5 segments (ileum, right 
colon, transverse colon, left colon, and rectum). The total score is calculated as the sum of all the 
items in each segment and can range from 0 to 56. The SES-CD score will be performed by a 
central reader. 


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Table 7. 
SES-CD Scoring 
Variable\Score 
0 
1 
2 
3 
Size of ulcers (cm) 
None 
Aphthous ulcers 
(diameter 0.1-0.5) 
Large ulcers 
(diameter 0.5-2) 
Very large ulcers 
(diameter >2) 
Ulcerated surface 
None 
< 10% 
10-30% 
> 30% 
Affected surface 
Unaffected 
segment 
< 50% 
50-75% 
> 75% 
Presence of 
narrowings 
None 
Single, can be 
passed 
Multiple, can be 
passed 
Cannot be passed 
To calculate the SES-CD score at a visit, the sum of the segments that were present at baseline 
will be used. For segments that were present at baseline but missing post-baseline, the baseline 
score for the missing segment(s) will be carried forward.  In the event that a segment is missing 
at baseline but non-missing at post-baseline, the non-missing post-baseline score is not used in 
the calculation of SES-CD. 
3.4.3.4. 
Endoscopic Response 
Endoscopic response is met when a subject meets either of the following two criteria: 
 SES-CD reduction from baseline of ≥ 50% 
 SES-CD ≤ 4, a reduction of ≥ 2 from baseline, and no subscore ≥ 2 
3.4.3.5. 
Stool Frequency and Abdominal Pain (SFAP) Clinical Remission  
To achieve SFAP clinical remission a subject needs to have average daily abdominal pain score 
≤1 (on a scale of 0 to 3), average daily stool frequency ≤ 2.8, and neither worse than baseline. 
A subject’s electronic diary records the total number of different stool types they pass each day 
as defined by the Bristol Stool Form Scale which classifies stools from Type 1 (hard lumps and 
hard to pass) to Type 7 (watery and entirely liquid). A subject’s daily stool total is calculated for 
a given day by summing the total number of Type 1 to Type 7 stools entered by the subject in the 
electronic diary. 
The average daily stool frequency is the mean of daily stool total from the stool diary over the 
most recent 7 evaluable days prior to endpoint visit. A minimum of 5 evaluable days data are 
required to calculate average score. 
Abdominal pain (CDAI) score is derived as the mean of abdominal pain subscore from the CDAI 
questionnaire over the most recent 7 evaluable days prior to endpoint visit.  The abdominal pain 
question scores pain on a scale of 0 (mild) to 3 (severe) and a minimum of 5 days evaluable data 
are required to calculate average score. 


3.4.4. 
Secondary Efficacy Analyses  
3.4.4.1. 
Estimands 
The treatment policy strategy that was used for the primary estimand for the primary endpoint 
analysis will be used for change from baseline in SES-CD Score at Week 12.  
The remaining secondary endpoints of response/remission will be analyzed through a composite 
strategy as follows: 
 Population: Same as primary estimand 
 Variable: Endpoints(Section 3.4.1)  and Definition (3.4.3) 
 Intercurrent Events: For this estimand, meeting the criteria of an ICE (1-5) is 
considered an unfavorable outcome and subjects who meet these criteria prior to 
Week 12 will be considered not to be in response/remission. 
3.4.4.2. 
Analysis Methods  
The proportion of subjects at Week 12 with CDAI clinical response, CDAI clinical remission, 
Endoscopic Response and SFAP clinical remission will be analyzed separately using a stratified 
Cochran-Mantel-Haenszel (CMH) test, stratifying by prior biologic status (yes, no) and CDAI 
baseline score category (≤ 300, >300) as determined from information in the clinical database. 
Summaries of the proportion of subjects in response/remission will be presented by treatment 
group, the adjusted treatment difference in proportions between each TD-1473 and placebo will 
also be presented along with associated 95% CIs calculated based on the Wald method. P-values 
from the CMH Chi-square test for the comparison of each dose of TD-1473 versus placebo will 
also be presented. 
Separate 2-group forest plots for the difference in proportion of each secondary endpoint of 
response/remission versus placebo at Week 12 will display the CMH weighted difference in 
proportions and associated 95% CI. 
Analysis of change from baseline in SES-CD at Week 12 will be performed using an ANCOVA 
model. The model will include independent fixed-effect class terms for treatment group, prior 
biologic failure status (yes, no) and CDAI baseline score category (≤ 300, >300) with baseline 
SES-CD as a covariate. 
Summaries will be on the mITT population and include observed values, change from baseline 
values and least square (LS) means estimates. Each TD-1473 dose versus placebo will be 
compared by displaying the LS mean difference estimate to placebo and associated 95% 
confidence interval. Nominal p-values will also be reported.   
A 3-group forest plot will summarize the LS mean change from baseline in SES-CD at Week 12 
with 95% confidence interval.  
3.4.4.3. 
Missing Data Handling  
For change in SES-CD at Week 12, missing data will be assumed MCAR there will be no 
imputation of missing data. 


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For binary endpoints missing data will be imputed with non-responder imputation with the 
exception of data missing due to COVID-19, in these instances the data will be assumed missing 
completely at random and not analyzed. 
3.4.5. 
Sensitivity Analyses 
No sensitivity analysis will be performed for secondary endpoints. 
3.4.6. 
Supplementary Analyses 
All subgroup analyses outlined in section 3.3.6.3 will be performed on the secondary endpoints. 
Descriptive summaries of change in each SES-CD segment at Week 12 will also be presented. 
3.5. 
Multiplicity Adjustment 
There will be no hypothesis testing of secondary endpoints. Adjustment of multiplicity on the 
primary endpoint is outlined in Section 3.3.3.  
3.6. 
Exploratory Endpoint(s) Analyses 
3.6.1. 
Exploratory Endpoint(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.2. 
Definition of Exploratory Endpoint(s) 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 


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3.6.3. 
Exploratory Efficacy Analyses  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


3.6.4. 
Supplementary Analyses  
3.6.4.1. 
Subgroup analysis 
To characterize the consistency of the treatment effect for endoscopic remission each of the 
subgroups in  Section 3.3.6.3 will be performed. 
3.7. 
Safety Analyses 
The analysis of safety and tolerability data includes an overall summary of tolerability, 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.   
In general, inferential statistical tests are not performed for adverse event incidence rates. 
For all safety analyses, the safety analysis population will be used. 
For summaries on exposure, compliance and adverse events for the study overall (Induction and 
ATE), 
3.7.1. 
 Extent of Exposure 
Study drug exposure will be summarized using the 8-point descriptive summary presenting 
number of doses and duration of treatment separately for the induction phase and complete study 
separately.   
Duration of treatment will be displayed in weeks and calculated for the induction period as: 
(𝑙𝑎𝑠𝑡 𝑖𝑛𝑑𝑢𝑐𝑡𝑖𝑜𝑛 𝑝ℎ𝑎𝑠𝑒 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒 - 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒 +  1) 
7
 
*Last induction phase dose date is considered to be the Week 12 visit dose administration date for those 
that reach the Week 12 visit or equal to date of last study drug return for those who discontinue prior to 
Week 12 visit. 
Duration of treatment for the entire study period will also be displayed in weeks and calculated 
as: 
(𝑙𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑟𝑒𝑡𝑢𝑟𝑛 𝑑𝑎𝑡𝑒 - 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒 +  1) 
7
 
Calculated values will be rounded to 1 significant digit in the analysis datasets and summary 
statistics will be presented to the follow significant digits: 
 Mean, median, Q1, Q3: 1 significant digit  
 Standard deviation: 2 significant digits 
 Minimum, maximum: 1 significant digit 
3.7.1.1. 
Treatment Compliance 
Study drug compliance will be calculated as: 


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 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 in the induction period  and the 
study overall 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. 
3.7.2. 
Adverse Events 
Adverse events (AEs) will be coded to the preferred terms (PT) of the Medical Dictionary for 
Regulatory Activities (MedDRA®). Summaries for induction period and for the complete study 
period will be presented separately and 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. 
All summaries will be presented for both the Induction Period and the overall study period 
separately. 
Treatment emergent adverse events are defined as follows for induction period and overall: 
 Induction period TEAEs are events with a start date/time after the first dose date/time 
in Induction period up to the date/time of ATE Day 1 dose or date of last dose of 
study drug + 28 days, whichever is earlier.  
 TEAEs for the whole study and listings are defined as AEs with onset on or after the 
first initiation of study drug up to the date of last dose study drug + 28 days.  
Only treatment-emergent AEs will be summarized in the tables. Separate by-subject listings of 
all TEAEs and all non-TEAEs 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 Induction period and overall for subjects with: 
 TESAEs by SOC and PT 
 TEAEs leading to discontinuation of study drug by SOC and PT 
 Drug related TEAEs by SOC and PT 
 TEAEs by severity and by SOC and PT 
 TEAEs resulting in death by PT 
Listings of all AEs, SAEs, and AEs leading to premature study drug 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. 
3.7.2.1. 
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 antibiotics) 
 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) 


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The incidence of AESI will be summarized overall and by AESI category and preferred term. 
3.7.3. 
Additional Safety Assessments  
3.7.3.1. 
Clinical Laboratory Parameters 
Laboratory data, hematology, serum chemistry and urinalysis, will be summarized in terms of 
observed values and changes from baseline for Induction period and overall separately.  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.  
Summaries for laboratory parameters of special interest will also be presented, these will include:   
 
Neutrophils  
 
Leukocytes 
 
Lymphocytes  
 
Hemoglobin  
 
Lipids [LDL cholesterol, HDL cholesterol, Cholesterol, and Triglyceride]  
 
Liver Function Test's [ALT, AST, Bilirubin]  
 
Creatinine   
 
Creatinine Kinase 
A summary of maximum National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) toxicity grade (Appendix 5.8) for postbaseline laboratory values through 
Week 12 and ATE Week 48.  
Listings will flag laboratory values that are outside of normal range. 
A listing of all abnormal lab values will be provided. Listings of subjects with any abnormal 
postbaseline laboratory values of CTCAE grade ≥2 will also be provided. 
3.7.3.2. 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures, pulse rate, and 
weight) and changes from baseline values at each visit and at the end of study will be presented 
by treatment group. 
For each nominal time point, vital signs will be summarized in terms of observed values and 
changes from baseline. Marked abnormalities as defined in Table 8 will be flagged in the listing. 
Table 8: 
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 


 
3.7.3.3. 
Electrocardiograms 
Descriptive statistics for ECG parameters (heart rate, RR interval, 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 
corrections. 
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. 
All recorded values by central reader at ECG core lab for the standard 12-lead electrocardiogram 
parameters will be presented in a by-subject listing. 
Categorical Analyses 
The number (percentage) of subjects with absolute ECG values and change from baseline in the 
ranges shown in Table 9 will be presented in Electrocardiogram Categorical Summary by Visit 
and 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. 
Figures 
Cumulative distribution plots will be provided for maximum change in QTcF at Week 8. 
Investigator Assessment of ECG Readings 
The investigators’ assessment of ECGs as normal, abnormal and clinically significant, or 
abnormal but not clinically significant will be summarized for baseline and for each visit. 
Table 9: 
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 
 


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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) 
 
 
 
 
 
> 480 
 
 
 
 
 
 
> 500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
≤ 450 
 
 
 
 
 
 
> 450 
 
 
 
 
 
 
> 470 
 
 
 
 
 
 
> 480 
 
 
 
 
 
 
> 500 
 
 
3.8. 
Other Analyses 
3.8.1. 
Patient Reported Outcomes 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
 
  
 
 
 
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑤𝑖𝑡ℎ 𝑝𝑟𝑜𝑏𝑙𝑒𝑚𝑠 𝑎𝑡 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 
  


 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
3.9. 
Interim Analyses 
The study will have an interim freeze to perform the primary analysis after the last subject 
reaches the Week 12 timepoint or discontinues prior to Week 12. 


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3.9.1. 
Maintenance of blind following interim analysis 
Study team members with access to subject level during the interim analysis that reveals a 
subjects dose (i.e. 80mg or 200mg) during the ATE period cannot participate in study-related 
activities from that point on. Full details on maintenance of the blind and who has access to 
subject level data are detailed in the study unblinding plan. 
3.9.2. 
Data Monitoring Committee 
 
 
 
 


4. 
REFERENCES 
Devine, B.J. (1974). Gentamicin therapy. Drug Intelligence and Clinical Pharmacy 8:650-655. 
 
 
 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. 
Changes to Protocol-Planned Analyses 
5.2. 
CDAI Questionnaire 
Subscore 
Definition 
Multiplier 
Number of liquid or very soft stools 
Number of liquid or very soft stools (7 day total) 
Note: Liquid or very soft stools are entered as 
Type 6 and Type 7 in the patient diary  
x 2  
 
Abdominal pain 
Abdominal pain (7 day total)  
Daily scores calculated as (0=none, 1=mild, 
2=moderate, 3=severe) 
x 5 
General well-being 
General well-being (7 day total) 
Daily scores calculated as (0=generally well, 
1=slightly under par, 2=poor, 3=very poor, 
4=terrible) 
x 7 
Extra-intestinal maifestations 
Arthritis/arthralgia (yes=1, no=0) 
x 20 
Iritis/uveitis (yes=1, no=0) 
x 20 
Erythema nodosum, pyoderma gangrenosum, 
aphthous stomatitis (yes=1, no=0) 
x 20 
Anal fissure, fistula, or abscess (yes=1, no=0) 
x 20 
Other fistula (yes=1, no=0) 
x 20 
Fever over 37.8C (100F) during past 7 days 
(yes=1, no=0) 
x 20 
Any anti-diarrhea 
Any anti-diarrhea medication in the last 7 days 
(yes=1, no=0) 
x 30 
Abdominal mass 
Abdominal mass (None=0, Questionable=2, 
Definite=5)  
 
x 10 
Haematocrit (%) 
If male, (47 – local hematocrit) [note: if negative 
impute with 0] 
If female, (42 – local hematocrit) [note: if 
negative impute with 0] 
 
x 6 


Body Weight 
[(ideal weight – current weight) x 100]/ ideal 
weight 
[note: if < -10 impute with -10] 
x 1 
Final Score 
Add totals: 
 
5.3. 
Data Conventions and Transformations 
5.3.1. 
Derived and Transformed Data 
5.3.1.1. 
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. 
5.3.1.2. 
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. 
5.3.1.3. 
BMI 
BMI is calculated as: 





2
2
/
weight kg
BMI kg m
height m

 
5.3.1.4. 
Ideal Body Weight 
 
Ideal body weight is calculated as follows (Devine 1974): 
 
50 kg + 2.3 kg for each 2.54 cm (1 in) over 152.4 cm (5 ft), if male 
 
45.5 kg + 2.3 kg for each 2.54 cm (1 in) over 152.4 cm (5 ft), if female 
This is a conversion to metric units of the following simple rule: 
 
For women, allow 100 lb for the first 5 feet and 5 lb for each additional inch.  
 
For men, allow 110 lb for the first 5 feet and 5 lb for each additional inch. 


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5.3.1.5. 
Creatinine Clearance 
Creatinine clearance (mL/min) will be estimated using the Cockcroft-Gault equation, as follows: 
Estimated 
creatinine clearance (mL/min) = 
(140-Age) × Ideal Body 
Weight (kg) 
, if male 
72 × Serum Creatinine 
(mg/dL) 
 
(140-Age) × Ideal Body 
Weight (kg) 
× 0.85, if female 
72 × Serum Creatinine 
(mg/dL) 
Creatinine clearance will also be estimated using actual body weight in the Cockcroft-Gault equation 
above. In tables, figures, and listings, estimates using actual body weight (ABW) will be labeled 
“Creatinine Clearance - ABW.” 
5.3.1.6. 
Time Since Crohn’s Disease Diagnosis 
Time since CD diagnosis (years) as of the first dose date is calculated as 
(diagnosis date - first dose date)/365.25. It is left unrounded for calculation of summary statistics 
but rounded to 1 decimal place for display. 
5.3.1.7. 
Prior Biologic Failure  
Subjects who have entered primary or secondary non-response and/or intolerance to a biologic 
treatment on the Prior Crohn’s Disease Medications page are defined as failing prior biologic 
treatment. All other subjects regardless of receiving prior biologic treatment are not considered 
failures. 
5.3.1.8. 
Prior Biologic Classes 
Anti-tumor necrosis factor-alpha therapies: 
 Adalimumab  
 Certolizumab 
 Infliximab  
Anti-integrin therapy: 
 Vedolizumab 
Anti-interleukin-12 and interleukin-23 therapy 
 Ustekinumab  


5.3.1.9. 
Presence of extra-intestinal manifestations  
Subjects who have any extra-intestinal manifestations ongoing at baseline as collected in the 
electronic tablet at site will be categorized as having a presence of extra-intestinal 
manifestations. 
5.3.2. 
Missing Date Imputation 
5.3.2.1. 
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 or the initial treatment 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 or the initial  dosing date if they have the same month and 
year, whichever is later. 
5.3.2.2. 
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 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 last day of the month or the study exit date if they have the same month and year, 
whichever is earlier. 
5.3.2.3. 
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”. 


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5.3.3. 
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, eg, 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”; Note:  
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 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”; 
 
5.3.4. 
AE Severity 
Instructions: 
 AE severity should be provided through data cleaning process as much as possible. If 
AE severity is not available because a subject was lost to follow-up, sample text for 
the data imputation is provided below. 
 
For graded adverse event summaries, AEs with no grade reported will be graded as severe. 
5.4. 
Adverse Event Start and End Date/Time Imputation Rules 
Missing start date and times will be handled as follows: 
 
AE onset date completely missing: 
o If AE is not ongoing and AE onset date missing and AE end date missing, then 
impute AE onset as date/time of first dose. 
o Else if AE is not ongoing and AE onset date missing and AE end date not missing 
and date/time of first dose <= AE end date, then impute AE onset as date/time of first 
dose of study drug. 
o Else if AE is not ongoing and AE onset date missing and AE end date not missing 
and AE end date is BEFORE first dose of study drug, then impute AE onset as AE 
end date YEAR and MONTH with 01 as the day and 00:00 as time. 


o Else if AE IS ongoing and AE onset date missing, then impute AE onset as date/time 
of first study drug dose. 
 
AE onset date has year and month only: 
o If AE onset date has year and month only and they are the year and month of first 
dose of study drug, then impute AE onset as date/time of first dose: 
o Else if AE onset date has year and month only and date/time of first dose is not 
missing, then impute AE onset as AE onset year and month with 01 as the date and 
00:00 as the time. 
 
AE onset date has year only: 
o If AE onset date has year only and it is year of first dose of study drug, then impute 
AE onset as date/time of first dose of study drug. 
o Else if AE onset date has year only and date of first study drug dose is not missing 
and year of AE onset is NOT the year of first dose of study drug, then impute AE 
onset as Jan. 1 of the AE onset year and 00:00 as the time. 
 
AE onset missing (where it was not handled by the above cases): 
o If AE onset date is missing, then impute AE onset as date/time of first study drug 
dose. 
 
AE onset has complete date but missing time: 
o If AE onset date is a date only and is same as date of first study drug dose, then 
impute AE onset as date/time of first study drug dose: 
o Else if AE onset date is a date only and is NOT = date of first study drug dose, then 
impute AE onset as AE onset date with 00:00 as the time: 
Missing end date and times will be handled as follows: 
 
AE end date - completely missing:  
o If AE if not ongoing and both AE onset and AE end dates are missing, then impute 
AE end date as date/time of last study drug dose. 
o Else if AE is not ongoing and AE onset date not missing and AE end date missing 
AND AE onset date <= date/time of last dose, then impute AE end date as date/time 
of last study drug dose. 
o Else if AE is not ongoing and AE onset date is not missing and AE end date is 
missing and date of last dose is not missing and AE onset is AFTER date of last dose, 
then impute AE end date as the last day of the month of AE onset date, with 23:59 as 
time.  
 
 
AE end date = year and month only: 
o If AE is NOT ongoing and AE end date consists of year and month only, then impute 
AE end date as the last day of the month of AE end date month and year, with 23:59 
as time.  
 
AE end date = year only: 


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o If AE is NOT ongoing and AE end date consists of a year only, and year = year of 
AE onset and AE onset date <= date of last study drug dose, then impute AE end date 
as the date of last study drug dose. 
o Else if AE is NOT ongoing and AE end date consists of a year only, and year = year 
of AE onset and AE onset date > date of last study drug dose, then impute AE end 
date as the year and month of AE onset, with the last day of the month as the day, and 
23:59 as the time. 
 
AE end date = complete date but no time: 
If AE is NOT ongoing and AE end date consists of a complete date but no time, then impute AE end date 
= trim(AE end date) || "T23:59". 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 




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5.8. 
CTCAE Grading 
Grading Criteria for Clinical Laboratory Tests [CTCAE Version 5.0] 
Hematology Tests 
 
Criteria 
Test 
Direction 
1 
2 
3 
4 
Hemoglobin (g/L) 
Decrease 
≥100 - <LLN 
≥80 - <100.0 
<80 
 
Leukocytes (WBC) 
(109/L) 
Decrease 
≥3.0 - <LLN 
≥2.0 - <3.0 
≥1.0 - <2.0 
<1.0 
Lymphocytes 
(109/L) 
Decrease 
≥0.8 - <LLN 
≥0.5 - <0.8 
≥0.2 - <0.5 
<0.2 
Neutrophils (109/L) 
Decrease 
≥1.5 - <LLN 
≥1.0 - <1.5 
≥0.5 - <1.0 
<0.5 
Platelets (109/L) 
Decrease 
≥75.0 - <LLN 
≥50.0 - <75.0 
≥25.0 - <50.0 
<25.0 
Chemistry Tests 
 
Criteria 
Test 
Direction 
1 
2 
3 
4 
ALT 
Increase 
>ULN - ≤3.0 
Xuan if baseline 
was normal; 1.5 - 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 xULN - ≤5.0 
xULN if baseline 
was normal; >3.0 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0 xULN - ≤20.0 
xULN if baseline 
was normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 xULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
Albumin (g/L) 
Decrease 
≥30 - <LLN 
≥20 - <30 
<20 
 
Alkaline 
Phosphatase 
Increase 
>ULN - ≤2.5 
xULN if baseline 
was normal; 2.0 - 
2.5 x baseline if 
baseline was 
abnormal 
>2.5 xULN - ≤5.0 
xULN if baseline 
was normal; >2.5 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0 xULN - ≤20.0 
xULN if baseline 
was normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 xULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 


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AST 
Increase 
>ULN - ≤3.0 
xULN if baseline 
was normal; 1.5 - 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 xULN - ≤5.0 
xULN if baseline 
was normal; >3.0 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0 xULN - ≤20.0 
xULN if baseline 
was normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 xULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
Bilirubin 
Increase 
>ULN - ≤1.5 
xULN if baseline 
was normal; > 
1.0 - 1.5 x 
baseline if 
baseline was 
abnormal 
>1.5 xULN - ≤3.0 
xULN if baseline 
was normal; >1.5 - 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 xULN - ≤10.0 
xULN if baseline 
was normal; >3.0 - 
10.0 x baseline if 
baseline was 
abnormal 
>10.0 xULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal 
Calcium (mmol/L) 
Increase 
>ULN - ≤2.9 
>2.9 - ≤3.1 
 
>3.1 - ≤3.4 
>3.4 
Calcium (mmol/L) 
Decrease 
[Albumin ≥40 
g/L or missing 
and calcium ≥2.0 
- <LLN]; or 
[Albumin < 40 
g/L and (calcium 
– 0.8 x (albumin 
– 40)) ≥2.0 - 
<LLN] 
[Albumin ≥40 g/L 
or missing and 
calcium ≥1.75 - 
<2.0]; or 
[Albumin < 40 g/L 
and (calcium – 0.8 
x (albumin – 40)) 
≥1.75 - <2.0] 
[Albumin ≥40 g/L 
or missing and 
calcium ≥1.5 - 
<1.75]; or 
[Albumin < 40 g/L 
and (calcium – 0.8 
x (albumin – 40)) 
≥1.5 - <1.75] 
[Albumin ≥40 
g/L or missing 
and calcium 
<1.5]; or 
[Albumin < 40 
g/L and 
(calcium – 0.8 x 
(albumin – 40)) 
<1.5] 
Creatinine 
Increase 
>ULN - ≤1.5 
xULN 
>1.5 xULN - ≤3.0 
xULN 
>3.0 xULN - ≤6.0 
xULN 
>6.0 xULN 
GGT 
Increase 
>ULN - 2.5 x 
ULN if baseline 
was normal; 2.0 - 
2.5 x baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN 
if baseline was 
normal; >2.5 - 5.0 
x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 20.0 
x baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
Phosphate 
(mmol/L) 
Decrease 
≥0.8 - <LLN 
≥0.6 - <0.8 
≥0.3 - <0.6 
<0.3 
Potassium 
(mmol/L) 
Increase 
>ULN - ≤5.5 
>5.5 - ≤6.0 
>6.0 - ≤7.0 
>7.0 
Potassium 
(mmol/L) 
Decrease 
≥3.0 - <LLN 
 
≥2.5 - <3.0 
<2.5 
Sodium (mmol/L) 
Increase 
>ULN - ≤150 
>150 - ≤155 
 
>155 - ≤160 
>160 
Sodium (mmol/L) 
Decrease 
≥130 - <LLN 
 
 125-129 mmol/L 
symptomatic; 120-
<120 


124 mmol/L 
regardless of 
symptoms